2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart DiseaseA Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines
Author + information
- Rick A. Nishimura, MD, MACC, FAHA, Co-Chair, Writing Committee†,
- Catherine M. Otto, MD, FACC, FAHA, Co-Chair, Writing Committee†,
- Robert O. Bonow, MD, MACC, FAHA, Writing Committee Member†,
- Blase A. Carabello, MD, FACC, Writing Committee Member∗,†,
- John P. Erwin III, MD, FACC, FAHA, Writing Committee Member‡,
- Robert A. Guyton, MD, FACC, Writing Committee Member∗,§,
- Patrick T. O’Gara, MD, FACC, FAHA, Writing Committee Member†,
- Carlos E. Ruiz, MD, PhD, FACC, Writing Committee Member†,
- Nikolaos J. Skubas, MD, FASE, Writing Committee Member¶,
- Paul Sorajja, MD, FACC, FAHA, Writing Committee Member#,
- Thoralf M. Sundt III, MD, Writing Committee Member∗∗∗,†† and
- James D. Thomas, MD, FASE, FACC, FAHA, Writing Committee Member‡‡
- ACC/AHA Practice Guidelines
- anticoagulation therapy
- aortic regurgitation
- aortic stenosis
- bicuspid aortic valve
- cardiac surgery
- heart valves
- infective endocarditis
- mitral stenosis
- mitral regurgitation
- prosthetic valves
- pulmonic regurgitation
- pulmonic stenosis
- transcatheter aortic valve replacement
- tricuspid stenosis
- tricuspid regurgitation
- valvular heart disease
ACC/AHA Task Force Members
Jeffrey L. Anderson, MD, FACC, FAHA, Chair, Jonathan L. Halperin, MD, FACC, FAHA, Chair-Elect, Nancy M. Albert, PhD, CCNS, CCRN, FAHA, Biykem Bozkurt, MD, PhD, FACC, FAHA, Ralph G. Brindis, MD, MPH, MACC, Mark A. Creager, MD, FACC, FAHA§§, Lesley H. Curtis, PhD, FAHA, David DeMets, PhD, Robert A. Guyton, MD, FACC§§, Judith S. Hochman, MD, FACC, FAHA, Richard J. Kovacs, MD, FACC, FAHA, E. Magnus Ohman, MD, FACC, Susan J. Pressler, PhD, RN, FAHA, Frank W. Sellke, MD, FACC, FAHA, Win-Kuang Shen, MD, FACC, FAHA, William G. Stevenson, MD, FACC, FAHA§§, Clyde W. Yancy, MD, FACC, FAHA§§
Table of Contents
Preamble.....e60
1. Introduction.....e62
1.1. Methodology and Evidence Review.....e62
1.2. Organization of the Writing Committee.....e62
1.3. Document Review and Approval.....e62
1.4. Scope of the Guideline.....e62
2. General Principles.....e63
2.1. Evaluation of the Patient With Suspected VHD.....e63
2.2. Definitions of Severity of Valve Disease.....e64
2.3. Diagnosis and Follow-Up.....e64
2.3.1. Diagnostic Testing–Initial Diagnosis: Recommendation.....e64
2.3.2. Diagnostic Testing—Changing Signs or Symptoms: Recommendation.....e65
2.3.3. Diagnostic Testing—Routine Follow-Up: Recommendation.....e65
2.3.4. Diagnostic Testing—Cardiac Catheterization: Recommendation.....e65
2.3.5. Diagnostic Testing—Exercise Testing: Recommendation.....e65
2.4. Basic Principles of Medical Therapy.....e66
2.4.1. Secondary Prevention of Rheumatic Fever: Recommendation.....e66
2.4.2. IE Prophylaxis: Recommendations.....e67
2.5. Evaluation of Surgical and Interventional Risk.....e68
2.6. The Heart Valve Team and Heart Valve Centers of Excellence: Recommendations.....e69
3. Aortic Stenosis.....e71
3.1. Stages of Valvular AS.....e71
3.2. Aortic Stenosis.....e71
3.2.1. Diagnosis and Follow-Up.....e71
3.2.1.1. Diagnostic Testing—Initial Diagnosis: Recommendations.....e71
3.2.1.2. Diagnostic Testing—Changing Signs or Symptoms.....e73
3.2.1.3. Diagnostic Testing—Routine Follow-Up.....e73
3.2.1.4. Diagnostic Testing—Cardiac Catheterization.....e73
3.2.1.5. Diagnostic Testing—Exercise Testing: Recommendations.....e74
3.2.2. Medical Therapy: Recommendations.....e74
3.2.3. Timing of Intervention: Recommendations.....e75
3.2.4. Choice of Intervention: Recommendation.....e79
4. Aortic Regurgitation.....e82
4.1. Acute AR.....e82
4.1.1. Diagnosis.....e83
4.1.2. Intervention.....e83
4.2. Stages of Chronic AR.....e83
4.3. Chronic AR.....e83
4.3.1. Diagnosis and Follow-Up.....e83
4.3.1.1. Diagnostic Testing—Initial Diagnosis: Recommendations.....e83
4.3.1.2. Diagnostic Testing—Changing Signs or Symptoms.....e85
4.3.1.3. Diagnostic Testing—Routine Follow-Up.....e85
4.3.1.4. Diagnostic Testing—Cardiac Catheterization.....e85
4.3.1.5. Diagnostic Testing—Exercise Testing.....e85
4.3.2. Medical Therapy: Recommendations.....e85
4.3.3. Timing of Intervention: Recommendations.....e86
5. Bicuspid Aortic Valve and Aortopathy.....e88
5.1. Bicuspid Aortic Valve.....e88
5.1.1. Diagnosis and Follow-Up.....e88
5.1.1.1. Diagnostic Testing—Initial Diagnosis: Recommendations.....e88
5.1.1.2. Diagnostic Testing—Routine Follow-Up: Recommendation.....e89
5.1.2. Medical Therapy.....e89
5.1.3. Intervention: Recommendations.....e89
6. Mitral Stenosis.....e90
6.1. Stages of MS.....e90
6.2. Rheumatic MS.....e90
6.2.1. Diagnosis and Follow-Up.....e90
6.2.1.1. Diagnostic Testing—Initial Diagnosis: Recommendations.....e90
6.2.1.2. Diagnostic Testing—Changing Signs Or Symptoms.....e91
6.2.1.3. Diagnostic Testing—Routine Follow-Up.....e91
6.2.1.4. Diagnostic Testing—Cardiac Catheterization.....e92
6.2.1.5. Diagnostic Testing—Exercise Testing: Recommendation.....e93
6.2.2. Medical Therapy: Recommendations.....e93
6.2.3. Intervention: Recommendations.....e94
6.3. Nonrheumatic MS.....e96
7. Mitral Regurgitation.....e97
7.1. Acute MR.....e97
7.1.1. Diagnosis and Follow-Up.....e97
7.1.2. Medical Therapy.....e97
7.1.3. Intervention.....e98
7.2. Stages of Chronic MR.....e98
7.3. Chronic Primary MR.....e98
7.3.1. Diagnosis and Follow-Up.....e98
7.3.1.1. Diagnostic Testing—Initial Diagnosis: Recommendations.....e98
7.3.1.2. Diagnostic Testing—Changing Signs or Symptoms.....e101
7.3.1.3. Diagnostic Testing—Routine Follow-Up.....e101
7.3.1.4. Diagnostic Testing—Cardiac Catheterization.....e101
7.3.1.5. Diagnostic Testing—Exercise Testing: Recommendations.....e102
7.3.2. Medical Therapy: Recommendations.....e102
7.3.3. Intervention: Recommendations.....e102
7.4. Chronic Secondary MR.....e106
7.4.1. Diagnosis and Follow-Up: Recommendations.....e106
7.4.2. Medical Therapy: Recommendations.....e106
7.4.3. Intervention: Recommendations.....e107
8. Tricuspid Valve Disease.....e107
8.1. Stages of TR.....e107
8.2. Tricuspid Regurgitation.....e108
8.2.1. Diagnosis and Follow-Up: Recommendations.....e108
8.2.2. Medical Therapy: Recommendations.....e111
8.2.3. Intervention: Recommendations.....e111
8.3. Stages of Tricuspid Stenosis.....e113
8.4. Tricuspid Stenosis.....e113
8.4.1. Diagnosis and Follow-Up: Recommendations.....e113
8.4.2. Medical Therapy.....e113
8.4.3. Intervention: Recommendations.....e113
9. Pulmonic Valve Disease.....e114
9.1. Stages of Pulmonic Regurgitation.....e114
9.2. Stages of Pulmonic Stenosis.....e114
10. Mixed Valve Disease.....e114
10.1. Mixed VHD.....e114
10.1.1. Diagnosis and Follow-Up.....e114
10.1.2. Medical Therapy.....e115
10.1.3. Timing of Intervention.....e115
10.1.4. Choice of Intervention.....e115
11. Prosthetic Valves.....e116
11.1. Evaluation and Selection of Prosthetic Valves.....e116
11.1.1. Diagnosis and Follow-Up: Recommendations.....e116
11.1.2. Intervention: Recommendations.....e117
11.2. Antithrombotic Therapy for Prosthetic Valves.....e119
11.2.1. Diagnosis and Follow-Up.....e119
11.2.2. Medical Therapy: Recommendations.....e120
11.3. Bridging Therapy for Prosthetic Valves.....e122
11.3.1. Diagnosis and Follow-Up.....e122
11.3.2. Medical Therapy: Recommendations.....e122
11.4. Excessive Anticoagulation and Serious Bleeding With Prosthetic Valves: Recommendation.....e123
11.5. Thromboembolic Events With Prosthetic Valves.....e124
11.5.1. Diagnosis and Follow-Up.....e124
11.5.2. Medical Therapy.....e124
11.5.3. Intervention.....e125
11.6. Prosthetic Valve Thrombosis.....e125
11.6.1. Diagnosis and Follow-Up: Recommendations.....e125
11.6.2. Medical Therapy: Recommendations.....e126
11.6.3. Intervention: Recommendations.....e127
11.7. Prosthetic Valve Stenosis.....e127
11.7.1. Diagnosis and Follow-Up.....e127
11.7.2. Medical Therapy.....e128
11.7.3. Intervention: Recommendation.....e128
11.8. Prosthetic Valve Regurgitation.....e128
11.8.1. Diagnosis and Follow-Up.....e128
11.8.2. Medical Therapy.....e128
11.8.3. Intervention: Recommendations.....e128
12. Infective Endocarditis.....e129
12.1. IE: Overview.....e129
12.2. Infective Endocarditis.....e129
12.2.1. Diagnosis and Follow-Up: Recommendations.....e130
12.2.2. Medical Therapy: Recommendations.....e134
12.2.3. Intervention: Recommendations.....e135
13. Pregnancy and VHD.....e139
13.1. Native Valve Stenosis: Recommendations.....e139
13.1.1. Diagnosis and Follow-Up: Recommendation.....e140
13.1.2. Medical Therapy: Recommendations.....e140
13.1.3. Intervention: Recommendations.....e141
13.2. Native Valve Regurgitation.....e143
13.2.1. Diagnosis and Follow-Up: Recommendations.....e143
13.2.2. Medical Therapy: Recommendation.....e144
13.2.3. Intervention: Recommendations.....e144
13.3. Prosthetic Valves in Pregnancy.....e145
13.3.1. Diagnosis and Follow-Up: Recommendations.....e145
13.3.2. Medical Therapy: Recommendations.....e146
14. Surgical Considerations.....e149
14.1. Evaluation of Coronary Anatomy: Recommendations.....e149
14.2. Concomitant Procedures.....e151
14.2.1. Intervention for CAD: Recommendation.....e151
14.2.2. Intervention for AF: Recommendations.....e151
15. Noncardiac Surgery in Patients With VHD.....e152
15.1. Diagnosis and Follow-Up.....e152
15.2. Medical Therapy.....e153
15.3. Intervention: Recommendations.....e153
16. Evidence Gaps and Future Directions.....e154
16.1. Prevention of Valve Diseased Stage A.....e155
16.2. Medical Therapy to Treat or Prevent Disease Progression—Stage B.....e155
16.3. Optimal Timing of Interventiond Stage C.....e155
16.4. Better Options for Interventiond Stage D.....e155
References.....e156
Appendix 1. Author Relationships With Industry and Other Entities (Relevant).....e178
Appendix 2. Reviewer Relationships With Industry and Other Entities (Relevant).....e179
Appendix 3. Abbreviations.....e185
Preamble
The medical profession should play a central role in evaluating evidence related to drugs, devices, and procedures for detection, management, and prevention of disease. When properly applied, expert analysis of available data on the benefits and risks of these therapies and procedures can improve the quality of care, optimize patient outcomes, and favorably affect costs by focusing resources on the most effective strategies. An organized and directed approach to a thorough review of evidence has resulted in the production of clinical practice guidelines that assist clinicians in selecting the best management strategy for an individual patient. Moreover, clinical practice guidelines can provide a foundation for other applications, such as performance measures, appropriate use criteria, and both quality improvement and clinical decision support tools.
The American College of Cardiology (ACC) and the American Heart Association (AHA) have jointly engaged in the production of guidelines in the area of cardiovascular disease since 1980. The ACC/AHA Task Force on Practice Guidelines (Task Force) directs this effort by developing, updating, and revising practice guidelines for cardiovascular diseases and procedures.
Experts in the subject under consideration are selected from both ACC and AHA to examine subject-specific data and write guidelines. Writing committees are specifically charged with performing a literature review; weighing the strength of evidence for or against particular tests, treatments, or procedures; and including estimates of expected health outcomes where such data exist. Patient-specific modifiers, comorbidities, and issues of patient preference that may influence the choice of tests or therapies are considered, as well as frequency of follow-up and cost effectiveness. When available, information from studies on cost is considered; however, a review of data on efficacy and outcomes constitutes the primary basis for preparing recommendations in this guideline.
In analyzing the data and developing recommendations and supporting text, the writing committee uses evidence-based methodologies developed by the Task Force (1). The Class of Recommendation (COR) is an estimate of the size of the treatment effect, with consideration given to risks versus benefits, as well as evidence and/or agreement that a given treatment or procedure is or is not useful/effective or in some situations may cause harm. The Level of Evidence (LOE) is an estimate of the certainty or precision of the treatment effect. The writing committee reviews and ranks evidence supporting each recommendation, with the weight of evidence ranked as LOE A, B, or C, according to specific definitions. The schema for the COR and LOE is summarized in Table 1, which also provides suggested phrases for writing recommendations within each COR. Studies are identified as observational, retrospective, prospective, or randomized, as appropriate. For certain conditions for which inadequate data are available, recommendations are based on expert consensus and clinical experience and are ranked as LOE C. When recommendations at LOE C are supported by historical clinical data, appropriate references (including clinical reviews) are cited if available. For issues with sparse available data, a survey of current practice among the clinician members of the writing committee is the basis for LOE C recommendations and no references are cited.
Applying Classification of Recommendations and Level of Evidence
A new addition to this methodology is separation of the Class III recommendations to delineate whether the recommendation is determined to be of “no benefit” or is associated with “harm” to the patient. In addition, in view of the increasing number of comparative effectiveness studies, comparator verbs and suggested phrases for writing recommendations for the comparative effectiveness of one treatment or strategy versus another are included for COR I and IIa, LOE A or B only.
In view of the advances in medical therapy across the spectrum of cardiovascular diseases, the Task Force has designated the term guideline-directed medical therapy (GDMT) to represent optimal medical therapy as defined by ACC/AHA guideline (primarily Class I)-recommended therapies. This new term, GDMT, is used herein and throughout subsequent guidelines.
Because the ACC/AHA practice guidelines address patient populations (and clinicians) residing in North America, drugs that are not currently available in North America are discussed in the text without a specific COR. For studies performed in large numbers of subjects outside North America, each writing committee reviews the potential impact of different practice patterns and patient populations on the treatment effect and relevance to the ACC/AHA target population to determine whether the findings should inform a specific recommendation.
The ACC/AHA practice guidelines are intended to assist clinicians in clinical decision making by describing a range of generally acceptable approaches to the diagnosis, management, and prevention of specific diseases or conditions. The guidelines attempt to define practices that meet the needs of most patients in most circumstances. The ultimate judgment about care of a particular patient must be made by the clinician and patient in light of all the circumstances presented by that patient. As a result, situations may arise in which deviations from these guidelines may be appropriate. Clinical decision making should involve consideration of the quality and availability of expertise in the area where care is provided. When these guidelines are used as the basis for regulatory or payer decisions, the goal should be improvement in quality of care. The Task Force recognizes that situations arise in which additional data are needed to inform patient care more effectively; these areas are identified within each respective guideline when appropriate.
Prescribed courses of treatment in accordance with these recommendations are effective only if followed. Because lack of patient understanding and adherence may adversely affect outcomes, clinicians should make every effort to engage the patient’s active participation in prescribed medical regimens and lifestyles. In addition, patients should be informed of the risks, benefits, and alternatives to a particular treatment and should be involved in shared decision making whenever feasible, particularly for COR IIa and IIb, for which the benefit-to-risk ratio may be lower.
The Task Force makes every effort to avoid actual, potential, or perceived conflicts of interest that may arise as a result of relationships with industry and other entities (RWI) among the members of the writing committee. All writing committee members and peer reviewers of the guideline are required to disclose all current healthcare-related relationships, including those existing 12 months before initiation of the writing effort.
In December 2009, the ACC and AHA implemented a new RWI policy that requires the writing committee chair plus a minimum of 50% of the writing committee to have no relevant RWI (Appendix 1 includes the ACC/AHA definition of relevance). The Task Force and all writing committee members review their respective RWI disclosures during each conference call and/or meeting of the writing committee, and members provide updates to their RWI as changes occur. All guideline recommendations require a confidential vote by the writing committee and require approval by a consensus of the voting members. Authors’ and peer reviewers’ RWI pertinent to this guideline are disclosed in Appendixes 1 and 2. Members may not draft or vote on any recommendations pertaining to their RWI. Members who recused themselves from voting are indicated in the list of writing committee members with specific section recusals noted in Appendix 1. In addition, to ensure complete transparency, writing committee members’ comprehensive disclosure information—including RWI not pertinent to this document—is available as an online supplement.
Comprehensive disclosure information for the Task Force is also available online at http://www.cardiosource.org/en/ACC/About-ACC/Who-We-Are/Leadership/Guidelines-and-Documents-Task-Forces.aspx. The ACC and AHA exclusively sponsor the work of the writing committee without commercial support. Writing committee members volunteered their time for this activity. Guidelines are official policy of both the ACC and AHA.
In an effort to maintain relevance at the point of care for clinicians, the Task Force continues to oversee an ongoing process improvement initiative. As a result, several changes to these guidelines will be apparent, including limited narrative text, a focus on summary and evidence tables (with references linked to abstracts in PubMed), and more liberal use of summary recommendation tables (with references that support LOE) to serve as a quick reference.
In April 2011, the Institute of Medicine released 2 reports: Finding What Works in Health Care: Standards for Systematic Reviews and Clinical Practice Guidelines We Can Trust (2,3). It is noteworthy that the Institute of Medicine cited ACC/AHA practice guidelines as being compliant with many of the proposed standards. A thorough review of these reports and of our current methodology is under way, with further enhancements anticipated.
The recommendations in this guideline are considered current until they are superseded by a focused update, the full-text guideline is revised, or until a published addendum declares it out of date and no longer official ACC/AHA policy.
Jeffrey L. Anderson, MD, FACC, FAHA
Chair, ACC/AHA Task Force on Practice Guidelines
1 Introduction
1.1 Methodology and Evidence Review
The recommendations listed in this document are, whenever possible, evidence based. An extensive review was conducted on literature published through November 2012, and other selected references through October 2013 were reviewed by the guideline writing committee. Searches were extended to studies, reviews, and other evidence conducted on human subjects and that were published in English from PubMed, EMBASE, Cochrane, Agency for Healthcare Research and Quality Reports, and other selected databases relevant to this guideline. Key search words included but were not limited to the following: valvular heart disease, aortic stenosis, aortic regurgitation, bicuspid aortic valve, mitral stenosis, mitral regurgitation, tricuspid stenosis, tricuspid regurgitation, pulmonic stenosis, pulmonic regurgitation, prosthetic valves, anticoagulation therapy, infective endocarditis, cardiac surgery, and transcatheter aortic valve replacement. Additionally, the committee reviewed documents related to the subject matter previously published by the ACC and AHA. The references selected and published in this document are representative and not all-inclusive.
1.2 Organization of the Writing Committee
The committee was composed of clinicians, who included cardiologists, interventionalists, surgeons, and anesthesiologists. The committee also included representatives from the American Association for Thoracic Surgery, American Society of Echocardiography (ASE), Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Anesthesiologists, and Society of Thoracic Surgeons (STS).
1.3 Document Review and Approval
This document was reviewed by 2 official reviewers each nominated by both the ACC and the AHA, as well as 1 reviewer each from the American Association for Thoracic Surgery, ASE, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Anesthesiologists, and STS and 39 individual content reviewers (which included representatives from the following ACC committees and councils: Adult Congenital and Pediatric Cardiology Section, Association of International Governors, Council on Clinical Practice, Cardiovascular Section Leadership Council, Geriatric Cardiology Section Leadership Council, Heart Failure and Transplant Council, Interventional Council, Lifelong Learning Oversight Committee, Prevention of Cardiovascular Disease Committee, and Surgeon Council). Reviewers’ RWI information was distributed to the writing committee and is published in this document (Appendix 2).
This document was approved for publication by the governing bodies of the ACC and AHA and endorsed by the American Association for Thoracic Surgery, ASE, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Anesthesiologists, and STS.
1.4 Scope of the Guideline
The focus of this guideline is the diagnosis and management of adult patients with valvular heart disease (VHD). A full revision of the original 1998 VHD guideline was made in 2006, and an update was made in 2008 (4). Some recommendations from the earlier VHD guidelines have been updated as warranted by new evidence or a better understanding of earlier evidence, whereas others that were inaccurate, irrelevant, or overlapping were deleted or modified. Throughout, our goal was to provide the clinician with concise, evidence-based, contemporary recommendations and the supporting documentation to encourage their use.
This guideline was created in a different format from prior VHD guidelines to facilitate access to concise, relevant bytes of information at the point of care when clinical knowledge is needed the most. Thus, each COR is followed by a brief paragraph of supporting text and references. Where applicable, sections were divided into subsections of 1) diagnosis and follow-up, 2) medical therapy, and 3) intervention. The purpose of these subsections was to categorize the COR according to the clinical decision-making pathways that caregivers use in the management of patients with VHD. New recommendations for assessment of the severity of valve lesions have been proposed, based on current natural history studies of patients with VHD.
The present document applies to adult patients with VHD. Management of patients with congenital heart disease and infants and children with valve disease are not addressed here. The document recommends a combination of lifestyle modifications and medications that constitute GDMT. Both for GDMT and other recommended drug treatment regimens, the reader is advised to confirm dosages with product insert material and to carefully evaluate for contraindications and drug–drug interactions. Table 2 is a list of associated guidelines that may be of interest to the reader. The table is intended for use as a resource and obviates the need to repeat extant guideline recommendations.
Associated Guidelines and Statements
2 General Principles
2.1 Evaluation of the Patient With Suspected VHD
Patients with VHD may present with a heart murmur, symptoms, or incidental findings of valvular abnormalities on chest imaging or noninvasive testing. Irrespective of the presentation, all patients with known or suspected VHD should undergo an initial meticulous history and physical examination. A careful history is of great importance in the evaluation of patients with VHD, because decisions about treatment are based on the presence or absence of symptoms. Due to the slow, progressive nature of many valve lesions, patients may not recognize symptoms because they may have gradually limited their daily activity levels. A detailed physical examination should be performed to diagnose and assess the severity of valve lesions based on a compilation of all findings made by inspection, palpation, and auscultation. The use of an electrocardiogram (ECG) to confirm heart rhythm and use of a chest x-ray to assess the presence or absence of pulmonary congestion and other lung pathology may be helpful in the initial assessment of patients with known or suspected VHD. A comprehensive transthoracic echocardiogram (TTE) with 2–dimensional (2D) imaging and Doppler interrogation should then be performed to correlate findings with initial impressions based on the initial clinical evaluation. The TTE will also be able to provide additional information, such as the effect of the valve lesion on the cardiac chambers and great vessels, and to assess for other concomitant valve lesions. Other ancillary testing such as transesophageal echocardiography (TEE), computed tomography (CT) or cardiac magnetic resonance (CMR) imaging, stress testing, and diagnostic hemodynamic cardiac catheterization may be required to determine the optimal treatment for a patient with VHD. An evaluation of the possible surgical risk for each individual patient should be performed if intervention is contemplated, as well as other contributing factors such as the presence and extent of comorbidities and frailty. Follow-up of these patients is important and should consist of an annual history and physical examination in most stable patients. An evaluation of the patient may be necessary sooner than annually if there is a change in the patient’s symptoms. In some valve lesions, there may be unpredictable adverse consequences on the left ventricle in the absence of symptoms necessitating more frequent follow-up. The frequency of repeat testing, such as echocardiography, will be dependent on the severity of the valve lesion and its effect on the left or right ventricle, coupled with the known natural history of the valve lesion.
2.2 Definitions of Severity of Valve Disease
Classification of the severity of valve lesions should be based on multiple criteria, including the initial findings on the physical examination, which should then be correlated with data from a comprehensive TTE. Intervention should primarily be performed on patients with severe VHD in addition to other criteria outlined in this document.
This document provides a classification of the progression of VHD with 4 stages (A to D) similar to that proposed by the “2013 ACCF/AHA Guideline for the Management of Heart Failure.” Indication for intervention in patients with VHD is dependent on 1) the presence or absence of symptoms; 2) the severity of VHD; 3) the response of the left and/or right ventricle to the volume or pressure overload caused by VHD; 4) the effect on the pulmonary or systemic circulation; and 5) a change in heart rhythm. The stages take into consideration all of these important factors (Table 3). The criteria for the stages of each individual valve lesion are listed in Section 3 (Table 8), Section 4.2 (Table 11), Section 6.1 (Table 13), Section 7.2 (Tables 15 and 16), and Section 8.1 (Table 19), Section 8.3 (Table 20), Section 9.1 (Table 21), and Section 9.2 (Table 22).
Stages of Progression of VHD
The purpose of valvular intervention is to improve symptoms and/or prolong survival, as well as to minimize the risk of VHD-related complications such as asymptomatic irreversible ventricular dysfunction, pulmonary hypertension, stroke, and atrial fibrillation (AF). Thus, the criteria for “severe” VHD are based on studies describing the natural history of patients with unoperated VHD, as well as observational studies relating the onset of symptoms to measurements of severity. In patients with stenotic lesions, there is an additional category of “very severe” stenosis based on studies of the natural history showing that prognosis becomes poorer as the severity of stenosis increases.
Supporting References: (14).
2.3 Diagnosis and Follow-Up
Diagnostic testing is very important for the diagnosis and treatment of patients with VHD. TTE provides morphological and hemodynamic information for diagnosis and quantitation of VHD, as well as for determining optimal timing for intervention. In selected patients, additional testing such as stress testing, TEE, cardiac catheterization, and CT or CMR imaging might be indicated. However, both the performance and interpretation of these diagnostic tests require meticulous attention to detail as well as expertise in cardiac imaging and evaluation of hemodynamics.
2.3.1 Diagnostic Testing–Initial Diagnosis: Recommendation
Class I1. TTE is recommended in the initial evaluation of patients with known or suspected VHD to confirm the diagnosis, establish etiology, determine severity, assess hemodynamic consequences, determine prognosis, and evaluate for timing of intervention (17–32). (Level of Evidence: B)
TTE is now the standard diagnostic test in the initial evaluation of patients with known or suspected VHD. Echocardiographic imaging can accurately assess the morphology and motion of valves and can usually determine the etiology of the VHD. TTE can also assess for concomitant disease in other valves and associated abnormalities such as aortic dilation. Left ventricular (LV) chamber size and function can be reliably assessed. It is the LV linear dimensions from echocardiography, either from 2D images or 2D-directed M-mode, that have been used in studies to determine timing of valve operation. Until further studies are available using LV volumes, the recommendations in this guideline will refer to LV dimensions. It is also important to understand the variability in measurements of LV dimensions so that decisions on intervention are based on sequential studies rather than a single study, especially in asymptomatic patients. A semiquantitative assessment of right ventricular (RV) size and function is usually made by a visual subjective analysis. Doppler TTE is used for noninvasive determination of valve hemodynamics. In stenotic lesions, measurements of the peak velocity, as well as calculation of valve gradients and valve area, characterize the severity of the lesion. Hemodynamic measurements can be performed at rest and during provocation. The quantitation of the severity of valve regurgitation is based on multiple hemodynamic parameters using color Doppler imaging of jet geometry, continuous wave Doppler recordings of the regurgitant flow, and pulsed wave Doppler measures of transvalvular volume flow rates and flow reversals in the atria and great vessels. The hemodynamic effect of valve lesions on the pulmonary circulation can be determined using tricuspid regurgitation (TR) velocity to provide a noninvasive measurement of RV systolic pressure. TTE quantitation of valve stenosis and valve regurgitation has been validated against catheterization data, in animal models with direct measures of disease severity, and in prospective clinical studies using valve replacement and mortality as the primary endpoint. On the basis of their value in predicting clinical outcomes, these echocardiographic parameters are now used to determine timing of valve intervention in conjunction with symptom status.
Supporting References: (17–32)
2.3.2 Diagnostic Testing—Changing Signs or Symptoms: Recommendation
Class I1. TTE is recommended in patients with known VHD with any change in symptoms or physical examination findings. (Level of Evidence: C)
Patients with VHD should be instructed to always report any change in symptomatic status. Patients with known VHD who have a change in symptoms should undergo a repeat comprehensive TTE study to determine whether the etiology of the symptoms is due to a progression in the valve lesion, deterioration of the ventricular response to the volume or pressure overload, or another etiology. New signs on physical examination also warrant a repeat TTE. The findings on TTE will be important in determining the timing of intervention.
Supporting References: (33–40)
2.3.3 Diagnostic Testing—Routine Follow-Up: Recommendation
Class I1. Periodic monitoring with TTE is recommended in asymptomatic patients with known VHD at intervals depending on valve lesion, severity, ventricular size, and ventricular function. (Level of Evidence: C)
After initial evaluation of an asymptomatic patient with VHD, the clinician may decide to continue close follow-up. The purpose of close follow-up is to prevent the irreversible consequences of severe VHD that primarily affect the status of the ventricles and pulmonary circulation and may also occur in the absence of symptoms. At a minimum, the follow-up should consist of a yearly history and physical examination. Periodic TTE monitoring also provides important prognostic information. The frequency of a repeat 2D and Doppler echocardiogram is based on the type and severity of the valve lesion, the known rate of progression of the specific valve lesion, and the effect of the valve lesion on the affected ventricle (Table 4). This table does not refer to patients with stage D VHD, who will usually undergo intervention, as will other select patient populations with stage C VHD.
Frequency of Echocardiograms in Asymptomatic Patients With VHD and Normal Left Ventricular Function
Supporting References: (22,29,32–35,37–41)
2.3.4 Diagnostic Testing—Cardiac Catheterization: Recommendation
Class I1. Cardiac catheterization for hemodynamic assessment is recommended in symptomatic patients when noninvasive tests are inconclusive or when there is a discrepancy between the findings on noninvasive testing and physical examination regarding severity of the valve lesion. (Level of Evidence: C)
Although TTE (and in some instances TEE) is now able to provide the required anatomic and hemodynamic information in most patients with VHD, there is still a subset of patients in whom hemodynamic catheterization is necessary to ensure that the proper decision about treatment is made. TTE may provide erroneous or inadequate information in some patients. Severity of stenosis may be underestimated when imaging is difficult or when the Doppler beam is not directed parallel to the valvular jet velocities. TTE quantitation of valve regurgitation shows considerable variability in measurement, and severity of disease may be overestimated or underestimated if image or Doppler data quality is suboptimal. If there are inconclusive, noninvasive data, particularly in the symptomatic patient, or if there is a discrepancy between the noninvasive tests and clinical findings, a hemodynamic cardiac catheterization is indicated. The measurements of valve gradients and cardiac output are important for assessing valve stenosis. Contrast angiography is still useful for a semiquantitative assessment of the severity of regurgitation in those instances in which the noninvasive results are discordant with the physical examination. A major advantage of cardiac catheterization is the measurement of intracardiac pressures and pulmonary vascular resistance, which may further aid in decision making about valve intervention. Diagnostic interventions that can be performed in the catheterization laboratory include the use of dobutamine in low-flow states, pulmonary vasodilators in pulmonary hypertension, and exercise hemodynamics in patients with discrepant symptoms. It must be emphasized that there is no longer a “routine” cardiac catheterization. Patients who come to the catheterization laboratory present complex diagnostic challenges because the noninvasive testing in these patients has not provided all pertinent information. Thus, hemodynamic catheterization needs to be done with meticulous attention to detail and performed by persons with knowledge and expertise in assessing patients with VHD.
Supporting References: (42,43)
2.3.5 Diagnostic Testing—Exercise Testing: Recommendation
Class IIa1. Exercise testing is reasonable in selected patients with asymptomatic severe VHD to 1) confirm the absence of symptoms, or 2) assess the hemodynamic response to exercise, or 3) determine prognosis (44–48). (Level of Evidence: B)
In a subset of patients, exercise stress testing will be of additional value in determining optimal therapy. Because of the slow, insidious rate of progression of many valve lesions, patients may deny symptoms as they gradually limit their activity level over years to match the gradual limitation imposed by the valve lesion. In patients with an equivocal history of symptoms, exercise testing helps identify those who are truly symptomatic. There may be patients in whom resting hemodynamics do not correlate with symptoms. In these patients, exercise hemodynamics may be helpful in determining the etiology of the symptoms, specifically in patients with mitral VHD. Exercise stress testing is of prognostic value in patients with asymptomatic severe aortic stenosis (AS) and provides further information about timing of intervention. Exercise testing in patients with severe VHD should always be performed by trained operators with continuous monitoring of the ECG and blood pressure (BP).
Supporting References: (44–48)
2.4 Basic Principles of Medical Therapy
All patients being evaluated for VHD should also undergo GDMT for other risk factors associated with cardiac disease. These include hypertension, diabetes mellitus, and hyperlipidemia. The safety and efficacy of an exercise program for patients with VHD has not been established, but patients will benefit from an exercise prescription in which a regular aerobic exercise program is followed to ensure cardiovascular fitness. Although heavy isometric repetitive training will increase the afterload on the LV, resistive training with small free weights or repetitive isolated muscle training may be used to strengthen individual muscle groups.
Most patients with LV systolic dysfunction and severe VHD should undergo intervention for the valve itself. However, if the decision has been made for medical therapy, these patients should receive the GDMT drug therapy for LV systolic dysfunction, including angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs) and beta-adrenergic blockers. Care must be taken to not abruptly lower BP in patients with stenotic lesions.
Rheumatic fever prophylaxis and infective endocarditis (IE) prophylaxis should be given to appropriate groups of patients as outlined in Sections 2.4.1 and 2.4.2. The maintenance of optimal oral health remains the most important component of an overall healthcare program in preventing IE. Influenza and pneumococcal vaccinations should be given to appropriate patient groups with VHD.
Supporting Reference: (49)
2.4.1 Secondary Prevention of Rheumatic Fever: Recommendation
Rheumatic fever is an important cause of VHD. In the United States, acute rheumatic fever has been uncommon since the 1970s. However, there has been an increase in the number of cases of rheumatic fever since 1987. Understanding of the causative organism, group A Streptococcus, has been enhanced by the development of kits that allow rapid detection of this organism. Prompt recognition and treatment of streptococcal pharyngitis constitute primary prevention of rheumatic fever. For patients with previous episodes of well-documented rheumatic fever or in those with evidence of rheumatic heart disease, long-term antistreptococcal prophylaxis is indicated for secondary prevention.
Supporting Reference: (50)
Class I1. Secondary prevention of rheumatic fever is indicated in patients with rheumatic heart disease, specifically mitral stenosis (MS) (Tables 5 and 6) (50). (Level of Evidence: C)
Secondary Prevention of Rheumatic Fever
Duration of Secondary Prophylaxis for Rheumatic Fever
Recurrent rheumatic fever is associated with a worsening of rheumatic heart disease. However, infection with group A Streptococcus does not have to be symptomatic to trigger a recurrence, and rheumatic fever can recur even when the symptomatic infection is treated. Prevention of recurrent rheumatic fever requires long-term antimicrobial prophylaxis rather than recognition and treatment of acute episodes of group A Streptococcus pharyngitis. The recommended treatment regimens and duration of secondary prophylaxis are shown in Tables 5 and 6. In patients with documented VHD, the duration of rheumatic fever prophylaxis should be at least 10 years or until the patient is 40 years of age (whichever is longer).
2.4.2 IE Prophylaxis: Recommendations
Because of the lack of published evidence on the use of prophylactic antibiotics to prevent IE, the value of antibiotic prophylaxis has been questioned by several national and international medical societies. Antibiotic prophylaxis is now indicated for only a subset of patients who are at high risk for developing IE and at highest risk for an adverse outcome if IE occurs. The maintenance of optimal oral health care remains the most effective intervention to prevent future valve infection.
Supporting References: (51–53)
Class IIa1. Prophylaxis against IE is reasonable for the following patients at highest risk for adverse outcomes from IE before dental procedures that involve manipulation of gingival tissue, manipulation of the periapical region of teeth, or perforation of the oral mucosa (54–56) (Level of Evidence: B):
• Patients with prosthetic cardiac valves;
• Patients with previous IE;
• Cardiac transplant recipients with valve regurgitation due to a structurally abnormal valve; or
• Patients with congenital heart disease with:
○ Unrepaired cyanotic congenital heart disease, including palliative shunts and conduits;
○ Completely repaired congenital heart defect repaired with prosthetic material or device, whether placed by surgery or catheter intervention, during the first 6 months after the procedure; or
○ Repaired congenital heart disease with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device.
The risk of IE is significantly higher in patients with a history of prosthetic valve replacement. Even in those patients at high risk for IE, the evidence for significant reduction in events with prophylaxis is conflicting. This lack of supporting evidence along with the risk of anaphylaxis and increasing bacterial resistance to antimicrobials led to a significant revision in the AHA recommendations for prophylaxis so that only those patients at the highest risk of developing IE (e.g., those with prosthetic valves) should be treated. Furthermore, evidence for prophylaxis has only been found to be reasonable in dental procedures that involve manipulation of gingival tissue, manipulation of the periapical region of teeth, or perforation of the oral mucosa. In the case of other prosthetic material (excluding surgically created palliative systemic-pulmonary shunts or conduits) such as annuloplasty rings, neochords, Amplatzer devices, and MitraClips, there have been only sporadic case reports of infected devices. Given the low infection rate and scarcity of data, there is no definitive evidence that prophylaxis in these patients is warranted in the absence of the patient having other high risks of intracardiac infection.
There are no randomized controlled trials (RCTs) or large observational cohort studies for prophylaxis in patients with a previous episode of IE, but given the cumulative risks of mortality with repeated infection, the potentially disabling complications from repeated infections, and the relatively low risk of prophylaxis, prophylaxis for IE has been recommended in this high-risk group of patients. IE is substantially more common in heart transplant recipients than in the general population. The risk of IE is highest in the first 6 months after transplantation due to endothelium disruption, high-intensity immunosuppressive therapy, frequent central venous catheter access, and endomyocardial biopsies. If there is a structurally abnormal valve, IE prophylaxis should be continued indefinitely, given the high risk of IE in post-transplant patients.
In patients in whom IE prophylaxis is reasonable, give prophylaxis before dental procedures that involve manipulation of gingival tissue or the periapical region of teeth or cause perforation of the oral mucosa. Bacteremia commonly occurs during activities of daily living such as routine brushing of the teeth or chewing. Persons at risk for developing bacterial IE should establish and maintain the best possible oral health to reduce potential sources of bacterial seeding. Optimal oral health is maintained through regular professional dental care and the use of appropriate dental products, such as manual, powered, and ultrasonic toothbrushes; dental floss; and other plaque-removal devices. There is no evidence for IE prophylaxis in gastrointestinal procedures or genitourinary procedures absent known enterococcal infection.
Multiple epidemiological studies show no increase in the rate of IE since adoption of the AHA and European Society of Cardiology guidelines recommending more restrictive use of IE prophylaxis. The NICE (National Institute for Health and Clinical Excellence, United Kingdom) guidelines took an even more radical departure from the previous prophylaxis standards in not recommending antibiotic prophylaxis for dental or nondental procedures (e.g., respiratory, gastrointestinal, and genitourinary). Similarly, subsequent epidemiological studies performed in the wake of the NICE guideline revisions have demonstrated no increase in clinical cases or deaths from IE. For the recommended choice of antibiotic regimen when IE prophylaxis is recommended, see http://www.heart.org/idc/groups/heart-public/@wcm/@hcm/documents/downloadable/ucm_307644.pdf.
Supporting References: (50–59)
Class III: No Benefit1. Prophylaxis against IE is not recommended in patients with VHD who are at risk of IE for nondental procedures (e.g., TEE, esophagogastroduodenoscopy, colonoscopy, or cystoscopy) in the absence of active infection (60). (Level of Evidence: B)
The incidence of IE following most procedures in patients with underlying cardiac disease is low, and there is a lack of controlled data supporting the benefit of antibiotic prophylaxis. Furthermore, the indiscriminate use of antibiotics can be associated with the development of resistant organisms, Clostridium difficile colitis, unnecessary expense, and drug toxicity. The risk of IE as a direct result of a flexible endoscopic procedure is small. Transient bacteremia may occur during or immediately after endoscopy; however, there are few reports of IE attributable to endoscopy. For most gastrointestinal endoscopic procedures, the rate of bacteremia is 2% to 5%, and organisms typically identified are unlikely to cause IE. The rate of bacteremia does not increase with mucosal biopsy, polypectomy, or sphincterotomy. There are no data to indicate that deep biopsy, such as that performed in the rectum or stomach, leads to a higher rate of bacteremia. The rate of transient bacteremia is more commonly seen in routine activities such as brushing teeth and flossing (20% to 68%), using toothpicks (20% to 40%), and simply chewing food (7% to 51%). Some gastrointestinal procedures, such as esophageal dilation (as high as 45%), sclerotherapy (31%), and endoscopic retrograde cholangiopancreatography (6% to 18%) have higher rates of bacteremia than simple endoscopy. However, no studies indicate reduced rates of IE with antibiotic prophylaxis.
Surgery, instrumentation, or diagnostic procedures that involve the genitourinary tract may cause bacteremia. The rate of bacteremia following urinary tract procedures is high in the presence of urinary tract infection. Sterilization of the urinary tract with antimicrobial therapy in patients with bacteriuria should be attempted before elective procedures, including lithotripsy. Results of a preprocedure urine culture will allow the clinician to choose antibiotics appropriate for the recovered organisms.
Supporting References: (61–73)
2.5 Evaluation of Surgical and Interventional Risk
The decision to intervene, as well as the type of intervention for a patient with severe VHD, should be based on an individual risk–benefit analysis. The risk of the procedure and intermediate-term mortality must be weighed against the benefits of the procedure in altering the natural history of the disease and acknowledging the long-term consequences of the intervention. Operative mortality can be estimated from a number of different scoring systems by using a combination of risk factors such as the STS risk estimate or Euroscore (http://www.euroscore.org/). There are limitations to these scores, including that they derive only from surgical patients and that they do not take into consideration procedure-specific impediments, major organ system compromise, comorbidities, or the frailty of the patient. A risk-assessment scheme combining these factors is presented in Table 7. The STS risk estimate is an accepted tool to predict the risk of a surgical operation. In an analysis of aortic valve operations in the STS database from 2002 to 2010, 80% of patients had a predicted risk of mortality (PROM) of <4% and an actual mean mortality rate of 1.4%. Fourteen percent had a PROM of 4% to 8% and an actual mean mortality rate of 5.1%, and 6% of patients had a PROM of >8% and an actual mortality rate of 11.1%. Other factors such as the frailty of the patient, major organ system compromise, and procedure-specific impediments must be taken into consideration. A number of mechanisms to evaluate frailty assess the ability to perform activities of daily living (independence in feeding, bathing, dressing, transferring, toileting, urinary continence, etc.) and measurements of gait speed, grip strength, and muscle mass. Published frailty scores are available, but a limited evaluation may use the following: no frailty (able to perform all activities of daily living and perform a 5–meter walk in <6 seconds), mild degree of frailty (unable to perform 1 activity of daily living or unable to perform a 5–meter walk in <6 seconds), and moderate-to-severe degree of frailty (unable to perform ≥2 activities of daily living). Further research is required to enhance the predictive accuracy of current risk scores, particularly in patients undergoing transcatheter therapy. The overall risks versus benefits should then be discussed with the patient and family using a shared decision-making process.
Risk Assessment Combining STS Risk Estimate, Frailty, Major Organ System Dysfunction, and Procedure-Specific Impediments
In addition to the risk classification in Table 7, it is appropriate to defer any type of intervention in patients who will not benefit in terms of symptoms or improved life span from the procedure. This group of patients in whom surgical or transcatheter intervention for severe VHD is futile are those with 1) a life expectancy of <1 year, even with a successful procedure, and 2) those who have a chance of “survival with benefit” of <25% at 2 years. Survival with benefit means survival with improvement by at least 1 New York Heart Association (NYHA) or Canadian Cardiovascular Society class in heart failure (HF) or angina symptoms, improvement in quality of life, or improvement in life expectancy. Those patients with severe frailty may fall into this category.
Supporting References: (41,74–78)
2.6 The Heart Valve Team and Heart Valve Centers of Excellence: Recommendations
The number of patients presenting with VHD in developed countries is growing, primarily due to the increasing age of the population. In addition, more patients with VHD are referred to cardiovascular specialists due to enhanced awareness of various treatments, as well as improved noninvasive imaging tests. When patients with VHD are referred for intervention in a timely manner, there is an improved outcome in preservation of ventricular function as well as enhanced survival. However, the management of patients with VHD is becoming increasingly complex, due to the use of more sophisticated noninvasive imaging modalities and technological advances in therapies. These advances result in changing thresholds for valve interventions. There remain a number of patients who are referred for intervention too late in the course of their disease or not referred at all, either of which results in poor long-term outcomes. Alternatively, intervention in the asymptomatic patient requires expertise in evaluation and noninvasive imaging assessment. The advent of transcatheter valve therapies has transformed the treatment of elderly high-risk patients with severe VHD but imposes difficult decision making in terms of risk–benefit analysis. Patient care should be customized to the patient’s needs, values, and expectations.
A competent practicing cardiologist should have the ability to diagnose and direct the treatment of most patients with VHD. For instance, otherwise healthy patients with severe VHD who become symptomatic should nearly always be considered for intervention. However, more complex decision-making processes may be required in select patient populations, such as those who have asymptomatic severe VHD, those who are at high risk for intervention, or those who could benefit from specialized therapies such as valve repair or transcatheter valve intervention.
The management of patients with complex severe VHD is best achieved by a Heart Valve Team composed primarily of a cardiologist and surgeon (including a structural valve interventionist if a catheter-based therapy is being considered). In selected cases, there may be a multidisciplinary, collaborative group of caregivers, including cardiologists, structural valve interventionalists, cardiovascular imaging specialists, cardiovascular surgeons, anesthesiologists, and nurses, all of whom have expertise in the management and outcomes of patients with complex VHD. The Heart Valve Team should optimize patient selection for available procedures through a comprehensive understanding of the risk–benefit ratio of different treatment strategies. This is particularly beneficial in patients in whom there are several options for treatment, such as the elderly high-risk patient with severe symptomatic AS being considered for transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (AVR). The patient and family should be sufficiently educated by the Heart Valve Team about all alternatives for treatment so that their expectations can be met as fully as possible using a shared decision-making approach.
The optimal care of the patient with complex heart disease is best performed in centers that can provide all available options for diagnosis and management, including the expertise for complex aortic or mitral valve repair, aortic surgery, and transcatheter therapies. This has led to the development of Heart Valve Centers of Excellence. Heart Valve Centers of Excellence 1) are composed of experienced healthcare providers with expertise from multiple disciplines; 2) offer all available options for diagnosis and management, including complex valve repair, aortic surgery, and transcatheter therapies; 3) participate in regional or national outcome registries; 4) demonstrate adherence to national guidelines; 5) participate in continued evaluation and quality improvement processes to enhance patient outcomes; and 6) publicly report their available mortality and success rates. Decisions about intervention at the Heart Valve Centers of Excellence should be dependent on the centers’ publicly available mortality rates and operative outcomes. It is recognized that some Heart Valve Centers of Excellence may have expertise in select valve problems.
Class I1. Patients with severe VHD should be evaluated by a multidisciplinary Heart Valve Team when intervention is considered. (Level of Evidence: C)
Decisions about selection and timing of interventions for patients with severe VHD are best done through the Heart Valve Team. The Heart Valve Team is composed primarily of a cardiologist and surgeon (including a structural valve interventionist if a catheter-based therapy is being considered). In selected cases, there may be a multidisciplinary, collaborative group of caregivers, including cardiologists, structural valve interventionalists, cardiovascular imaging specialists, cardiovascular surgeons, anesthesiologists, and nurses, many of whom have expertise in the management and outcomes of patients with complex VHD. For patients with infections of the heart, infectious disease specialists should be involved. For pregnant women, high-risk obstetrics should be involved. The Heart Valve Team 1) reviews the patient's medical condition and valve abnormality, 2) determines the possible interventions that are indicated, technically feasible, and reasonable, and 3) discusses the risks and outcomes of these interventions with the patient and family. This approach has been used for patients with complex coronary artery disease (CAD) and is supported by reports that patients with complex CAD referred specifically for percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery in concurrent trial registries using a heart team approach have lower mortality rates than those randomly assigned to PCI or CABG in controlled trials.
Supporting References: (35,79–84)
Class IIa1. Consultation with or referral to a Heart Valve Center of Excellence is reasonable when discussing treatment options for 1) asymptomatic patients with severe VHD, 2) patients who may benefit from valve repair versus valve replacement, or 3) patients with multiple comorbidities for whom valve intervention is considered. (Level of Evidence: C)
With the advent of newer surgical techniques and lower rates of operative mortality, it is reasonable to lower the threshold for valve intervention to prevent the adverse consequences of severe VHD, particularly in the asymptomatic patient with severe VHD. However, the overall benefit of operating on these patients requires that the patient be evaluated by those with expertise in assessment of VHD and that they undergo operation in a center with low operative mortality and excellent patient outcomes. If a “watchful waiting” approach is taken in asymptomatic patients with severe VHD, a Heart Valve Center of Excellence may be beneficial in ensuring proper follow-up.
Surgical outcomes depend on the expertise and experience of the surgeons, especially with highly specialized operations such as complex mitral valve repair and surgical treatment of aortic disease. It is well documented that operative risks and outcomes are better for patients undergoing mitral valve repair versus mitral valve replacement (MVR) in patients with primary mitral regurgitation (MR) and morphology suitable for repair. Although the rate of mitral valve repair has increased, a number of patients with primary MR will still undergo MVR. The rate of successful mitral valve repair in patients with primary MR is dependent on the experience of the surgeon as well as the surgical volume. Optimal outcomes are best achieved in Heart Valve Centers of Excellence dedicated to the management and treatment of patients with VHD and that offer all available treatment options, including complex valve repair, aortic surgery, and transcatheter therapies. At Heart Valve Centers of Excellence, healthcare providers have experience and expertise from multiple disciplines, demonstrate adherence to national guidelines, participate in regional or national outcome registries, and publicly report their available mortality and success rates with a continued quality improvement program in place. Decisions on early operation in the asymptomatic patient can then be made based on the reported data from the specific Heart Valve Center of Excellence, including mortality and morbidity statistics as well as durable repair rates for patients with primary MR. Heart Valve Centers of Excellence have also been shown to increase the proportion of patients managed according to GDMT, decrease unnecessary testing, optimize timing of intervention, and best handle other problems such as operations for complex multivalve disease, multiple reoperations, and complex IE. Heart Valve Centers of Excellence can play an important role in patient and clinician education to help ensure timely referral for evaluation and proper protocol for follow-up.
Supporting References: (35,85–88)
3 Aortic Stenosis
See Table 8 for the stages of valvular AS and Tables 9 and 10 for a summary of recommendations for choice and timing of intervention.
Stages of Valvular AS
Summary of Recommendations for AS: Timing of Intervention
Summary of Recommendations for AS: Choice of Surgical or Transcatheter Intervention
3.1 Stages of Valvular AS
Medical and interventional approaches to the management of patients with valvular AS depend on accurate diagnosis of the cause and stage of the disease process. Table 8 shows the stages of AS ranging from patients at risk of AS (stage A) or with progressive hemodynamic obstruction (stage B) to severe asymptomatic (stage C) and symptomatic AS (stage D). Each of these stages is defined by valve anatomy, valve hemodynamics, the consequences of valve obstruction on the left ventricle and vasculature, as well as by patient symptoms. Hemodynamic severity is best characterized by the transaortic maximum velocity (or mean pressure gradient) when the transaortic volume flow rate is normal. However, some patients with AS have a low transaortic volume flow rate due to either LV systolic dysfunction with a low LV ejection fraction (LVEF) or due to a small hypertrophied left ventricle with a low stroke volume. These categories of severe AS pose a diagnostic and management challenge distinctly different from the challenges faced by the majority of patients with AS, who have a high gradient and velocity when AS is severe. These special subgroups with low-flow AS are designated D2 (with a low LVEF) and D3 (with a normal LVEF).
The definition of severe AS is based on natural history studies of patients with unoperated AS, which show that the prognosis is poor once there is a peak aortic valve velocity of >4 m per second, corresponding to a mean aortic valve gradient >40 mm Hg. In patients with low forward flow, severe AS can be present with lower aortic valve velocities and lower aortic valve gradients. Thus, an aortic valve area should be calculated in these patients. The prognosis of patients with AS is poorer when the aortic valve area is <1.0 cm2. At normal flow rates, an aortic valve area of <0.8 cm2 correlates with a mean aortic valve gradient >40 mm Hg. However, symptomatic patients who have a calcified aortic valve with reduced opening and an aortic valve area between 0.8 cm2 and 1.0 cm2 should be closely evaluated to determine whether they would benefit from valve intervention. Meticulous attention to detail is required when assessing aortic valve hemodynamics, either with Doppler echocardiography or cardiac catheterization, and the inherent variability of the measurements and calculations should always be considered in clinical-decision making.
3.2 Aortic Stenosis
3.2.1 Diagnosis and Follow-Up
The overall approach to the initial diagnosis of VHD is discussed in Section 2.3, and additional considerations specific to patients with AS are addressed here.
3.2.1.1 Diagnostic Testing—Initial Diagnosis: Recommendations
Class I1. TTE is indicated in patients with signs or symptoms of AS or a bicuspid aortic valve for accurate diagnosis of the cause of AS, hemodynamic severity, LV size, and systolic function, and for determining prognosis and timing of valve intervention (24,25,89). (Level of Evidence: B)
Most patients with AS are first diagnosed when cardiac auscultation reveals a systolic murmur or after a review of TTE requested for other indications. Physical examination findings are specific but not sensitive for evaluation of stenosis severity. The classic findings of a loud (grade ≥3/6), late-peaking systolic murmur that radiates to the carotid arteries, a single or paradoxically split second heart sound, and a delayed and diminished carotid upstroke confirm the presence of severe AS. However, carotid upstroke may be normal in elderly patients because of the effects of aging on the vasculature, and the murmur may be soft or may radiate to the apex. The only physical examination finding that is reliable in excluding the possibility of severe AS is a normally split second heart sound.
TTE is indicated when there is an unexplained systolic murmur, a single second heart sound, a history of a bicuspid aortic valve, or symptoms that might be due to AS. Echocardiographic imaging allows reliable identification of the number of valve leaflets along with qualitative assessment of valve motion and leaflet calcification. In nearly all patients, the hemodynamic severity of the stenotic lesion can be defined with Doppler echocardiographic measurements of maximum transvalvular velocity, mean pressure gradient, and continuity equation valve area, as discussed in the European Association of Echocardiography (EAE)/ASE guidelines for evaluation of valve stenosis. Doppler evaluation of severity of AS has been well validated in experimental and human studies compared with direct measurements of intracardiac pressure and cardiac output. In addition, Doppler measures of severity of AS are potent predictors of clinical outcome. However, Doppler may underestimate or overestimate aortic velocity and disease severity in some patients, so clinical evaluation should include symptoms, physical examination findings, and results of other diagnostic testing as well.
TTE is also useful for determining the LV response to pressure overload. Systolic function is evaluated using 2D or 3–dimensional (3D) measurement of LVEF. LV diastolic function can be evaluated using standard Doppler approaches and an estimate of pulmonary systolic pressure derived from the TR jet. In addition, TTE allows diagnosis and evaluation of concurrent valve lesions, with MR being common in patients with AS.
Supporting References: (8,19,24,25,27,89–94)
Class IIa1. Low-dose dobutamine stress testing using echocardiographic or invasive hemodynamic measurements is reasonable in patients with stage D2 AS with all of the following (95–97) (Level of Evidence: B):
a. Calcified aortic valve with reduced systolic opening;
b. LVEF less than 50%;
c. Calculated valve area 1.0 cm2 or less; and
d. Aortic velocity less than 4.0 m per second or mean pressure gradient less than 40 mm Hg.
Patients with severe AS and concurrent LV systolic dysfunction often present with a relatively low transvalvular velocity and pressure gradient (i.e., mean pressure gradient <40 mm Hg) but with a small calculated valve area. In some of these patients, severe AS is present with LV systolic dysfunction due to afterload mismatch. In others, primary myocardial dysfunction is present with only moderate AS and reduced aortic leaflet opening due to a low transaortic volume flow rate. In these patients with low-flow/low-gradient AS and LV systolic dysfunction (LVEF <50%), it may be useful to measure aortic velocity (or mean pressure gradient) and valve area during a baseline state and again during low-dose pharmacological (i.e., dobutamine infusion) stress testing to determine whether AS is severe or only moderate and to evaluate for contractile or flow reserve.
Dobutamine is infused in progressive stages, beginning at 5 mcg/kg per minute and increasing in increments of 5 mcg/kg per minute to a maximum dose of 20 mcg/kg per minute with appropriate clinical and hemodynamic monitoring. Echocardiographic and Doppler data (or hemodynamic data) are recorded at each dose of dobutamine for measurement of aortic velocity, mean pressure gradient, valve area, and LVEF. Patients who do not have true anatomically severe AS will exhibit an increase in valve area with only a modest increase in transaortic velocity or gradient as transaortic stroke volume increases. In contrast, patients with severe AS have a relatively fixed valve area even with an increase in LV contractility and transaortic volume flow rate. The document “Echocardiographic Assessment of Valve Stenosis: EAE/ASE Recommendations for Clinical Practice” defines severe AS on low-dose dobutamine stress testing as a maximum velocity ≥4.0 m per second with a valve area ≤1.0 cm2 at any point during the test protocol. In addition to moderate AS and true severe AS, low-dose dobutamine stress testing helps identify a third group of patients who fail to show an increase in stroke volume ≥20% with dobutamine, referred to as “lack of contractile reserve” or “lack of flow reserve.” This subgroup of patients appears to have a very poor prognosis with either medical or surgical therapy. Low-dose dobutamine stress testing in patients with AS requires center experience in pharmacological stress testing as well as continuous hemodynamic and electrocardiographic monitoring with a cardiologist in attendance.
Supporting References: (8,43,95,96,98–101)
See Online Data Supplement 1 for more information on outcomes in patients with low-flow/low-gradient AS with reduced LVEF.
3.2.1.2 Diagnostic Testing—Changing Signs or Symptoms
In patients with known valvular AS, repeat TTE is appropriate when physical examination reveals a louder systolic murmur or a change in the second heart sound or when symptoms occur that might be due to AS because valve obstruction may have progressed since the last evaluation. Repeat TTE is also appropriate in patients with AS who are exposed to increased hemodynamic demands either electively, such as noncardiac surgery or pregnancy, or acutely, such as with a systemic infection, anemia, or gastrointestinal bleeding. In these clinical settings, knowledge of the severity of valve obstruction and LV function is critical for optimizing loading conditions and maintaining a normal cardiac output.
Supporting References: (24,25,89,102,103)
3.2.1.3 Diagnostic Testing—Routine Follow-Up
Timing of periodic clinical evaluation of patients with severe asymptomatic AS depends on comorbidities and patient-specific factors. TTE for re-evaluation of asymptomatic patients with AS with normal LV systolic function who have no change in signs or symptoms is performed at intervals of 6 months to 1 year when aortic velocity is ≥4.0 m per second (stage C), 1 to 2 years when aortic velocity is between 3.0 m per second and 3.9 m per second (stage B), and 3 to 5 years when aortic velocity is 2.0 m per second to 2.9 m/s (stage B) (Table 4).
Valvular AS is a progressive disease, and an increase in hemodynamic severity is inevitable once even mild AS is present. The rate of progression of the stenotic lesion has been estimated in a variety of invasive and noninvasive studies. When severe AS is present (aortic velocity ≥4.0 m per second), the rate of progression to symptoms is high, with an event-free survival of only 30% to 50% at 2 years. Therefore, patients with asymptomatic severe AS require frequent monitoring for progressive disease because symptom onset may be insidious and not recognized by the patient.
Once even moderate AS is present (aortic velocity between 3.0 m per second and 3.9 m per second), the average rate of progression is an increase in velocity of 0.3 m per second per year, an increase in mean pressure gradient of 7 mm Hg per year, and a decrease in valve area of 0.1 cm2 per year. There is marked individual variability in the rate of hemodynamic change. Progression of AS can be more rapid in older patients and in those with more severe leaflet calcification. Because it is not possible to predict the exact rate of progression in an individual patient, regular clinical and echocardiographic follow-up is mandatory in all patients with asymptomatic mild-to-moderate AS.
In patients with aortic sclerosis, defined as focal areas of valve calcification and leaflet thickening with an aortic velocity <2.5 m per second, progression to severe AS occurs in about 10% of patients within 5 years. Patients with bicuspid aortic valve disease are also at risk for progressive valve stenosis, with AS being the most common reason for intervention in patients with a bicuspid aortic valve (Section 5.1.1).
Supporting References: (28,104–115)
See Online Data Supplement 2 for more information on hemodynamic progression of AS.
3.2.1.4 Diagnostic Testing—Cardiac Catheterization
Diagnostic TTE and Doppler data can be obtained in nearly all patients, but severity of AS may be underestimated if image quality is poor or if a parallel intercept angle is not obtained between the ultrasound beam and aortic jet. CMR imaging shows promise for evaluation of severity of AS but is not widely available. Cardiac CT imaging is useful for quantitation of valve calcification (severe calcification is considered to be present with an aortic valve calcification score >1,000 Agatston units) and in patients undergoing TAVR for measurement of annulus area, leaflet length, and the annular to coronary ostial distance. However, CT imaging is less useful for evaluation of severity of AS. When noninvasive data are nondiagnostic or if there is a discrepancy between clinical and echocardiographic evaluation, cardiac catheterization for determination of severity of AS is recommended. Transaortic pressure gradients should be recorded for measurement of mean transaortic gradient, based on simultaneous LV and aortic pressure measurements. Aortic valve area should be calculated with the Gorlin formula, using a Fick or thermodilution cardiac output measurement. See Section 14.1 for recommendations on coronary angiography in patients with AS.
Supporting References: (42,116)
3.2.1.5 Diagnostic Testing—Exercise Testing: Recommendations
Class IIa1. Exercise testing is reasonable to assess physiological changes with exercise and to confirm the absence of symptoms in asymptomatic patients with a calcified aortic valve and an aortic velocity 4.0 m per second or greater or mean pressure gradient 40 mm Hg or higher (stage C) (25,46,47,117). (Level of Evidence: B)
When performed under the direct supervision of an experienced clinician, with close monitoring of BP and ECG, exercise testing in asymptomatic patients is relatively safe and may provide information that is not evident during the initial clinical evaluation, particularly when the patient’s functional capacity is unclear. Patients with symptoms provoked by exercise testing should be considered symptomatic, even if the clinical history is equivocal. Although it can be challenging to separate normal exercise limitations from abnormal symptoms due to AS, particularly in elderly sedentary patients, exercise-induced angina, excessive dyspnea early in exercise, dizziness, or syncope are consistent with symptoms of AS. In 1 series, exercise testing brought out symptoms in 29% of patients who were considered asymptomatic before testing; in these patients, spontaneous symptoms developed over the next year in 51% of patients, compared with only 11% of patients who had no symptoms on exercise testing.
Exercise testing can also identify a limited exercise capacity, abnormal BP response, or arrhythmia. An abnormal hemodynamic response (e.g., hypotension or failure to increase BP with exercise) in patients with severe AS is considered a poor prognostic finding. In another series, patients with AS who manifested symptoms, an abnormal BP response (<20 mm Hg increase), or ST-segment abnormalities with exercise had a significantly reduced symptom-free survival at 2 years (19% compared with 85%). However, electrocardiographic ST-segment depression is seen in >80% of patients with AS with exercise and is nonspecific for diagnosis of CAD. Ventricular tachycardia was reported in early exercise studies but has not been reported in contemporary series.
Some studies suggest additional value for measuring changes in valve hemodynamics with exercise. In a series of 186 patients with moderate-to-severe AS, stress testing was normal in 73% of patients; however, adverse cardiac events occurred in 67 of these patients at a mean follow-up interval of 20±14 months. Predictors of cardiac events, primarily symptom onset requiring AVR, were age >65 years, diabetes mellitus, LV hypertrophy, a resting mean pressure gradient >35 mm Hg, and an increase of >20 mm Hg in mean pressure gradient with exercise. However, a prospective study of 123 patients with asymptomatic AS did not show additive value for exercise hemodynamics for predicting clinical outcome when baseline measures of hemodynamic severity and functional status were considered. Recording hemodynamics with exercise is challenging, and simpler parameters are adequate in most patients.
Supporting References: (25,28,46,47,117–121)
See Online Data Supplement 3 for more information on exercise testing in patients with AS.
Class III: Harm1. Exercise testing should not be performed in symptomatic patients with AS when the aortic velocity is 4.0 m per second or greater or mean pressure gradient is 40 mm Hg or higher (stage D) (122). (Level of Evidence: B)
As reported in several prospective and retrospective studies, the risk of exercise testing is low in asymptomatic patients with AS. However, even in asymptomatic patients, complications include exertional hypotension in up to 10% of patients, exercise-induced symptoms, and ventricular premature beats. A retrospective study of 347 patients with AS who underwent cardiopulmonary exercise testing showed no deaths or major complications. Most of these patients had no (78%) or equivocal (16%) symptoms at baseline, with only 20 symptomatic patients (6%) with AS in this series (123).
Exercise testing should not be performed in symptomatic patients with AS owing to a high risk of complications, including syncope, ventricular tachycardia, and death. In a prospective survey of 20 medical centers in Sweden that included 50,000 exercise tests done over an 18–month period, the complication rate was 18.4; morbidity rate, 5.2; and mortality rate, 0.4 per 10,000 tests. Although the number of patients with AS was not reported, 12 of the 92 complications occurred in patients with AS: 8 had an exercise decline in BP, 1 had asystole, and 3 had ventricular tachycardia.
Supporting References: (46,47,117–120,122,123)
3.2.2 Medical Therapy: Recommendations
Class I1. Hypertension in patients at risk for developing AS (stage A) and in patients with asymptomatic AS (stages B and C) should be treated according to standard GDMT, started at a low dose, and gradually titrated upward as needed with frequent clinical monitoring (124–126). (Level of Evidence: B)
Hypertension is common in patients with AS, may be a risk factor for AS, and adds to the total pressure overload on the left ventricle in combination with valve obstruction. Concern that antihypertensive medications might result in a fall in cardiac output has not been corroborated in studies of medical therapy, including 2 small RCTs, likely because AS does not result in “fixed” valve obstruction until late in the disease process. In 1,616 patients with asymptomatic AS in the SEAS (Simvastatin Ezetimibe in Aortic Stenosis) study, hypertension (n=1,340) was associated with a 56% higher rate of ischemic cardiovascular events and a 2-fold increased mortality rate (both p<0.01) compared with normotensive patients with AS, although no impact on AVR was seen. Medical therapy for hypertension should follow standard guidelines, starting at a low dose and gradually titrating upward as needed to achieve BP control. There are no studies addressing specific antihypertensive medications in patients with AS, but diuretics should be avoided if the LV chamber is small, because even smaller LV volumes may result in a fall in cardiac output. In theory, ACE inhibitors may be advantageous due to the potential beneficial effects on LV fibrosis in addition to control of hypertension. Beta blockers are an appropriate choice in patients with concurrent CAD.
Supporting References: (124–128)
Class IIb1. Vasodilator therapy may be reasonable if used with invasive hemodynamic monitoring in the acute management of patients with severe decompensated AS (stage D) with NYHA class IV HF symptoms. (Level of Evidence: C)
In patients who present with severe AS and NYHA class IV HF, afterload reduction may be used in an effort to stabilize the patient before urgent AVR. Invasive monitoring of LV filling pressures, cardiac output, and systemic vascular resistance is essential because of the tenuous hemodynamic status of these patients, in whom a sudden decline in systemic vascular resistance might result in an acute decline in cardiac output across the obstructed aortic valve. However, some patients do benefit with an increase in cardiac output as systemic vascular resistance is slowly adjusted downward due to the reduction in total LV afterload. AVR should be performed as soon as feasible in these patients.
Supporting Reference: (129)
Class III: No Benefit1. Statin therapy is not indicated for prevention of hemodynamic progression of AS in patients with mild-to-moderate calcific valve disease (stages B to D) (109,130,131). (Level of Evidence: A)
Despite experimental models and retrospective clinical studies that suggest that lipid-lowering therapy with a statin might prevent disease progression of calcific AS, 3 large well-designed RCTs failed to show a benefit either in terms of changes in hemodynamic severity or in clinical outcomes in patients with mild-to-moderate valve obstruction. Thus, at the time of publication, there are no data to support the use of statins for prevention of progression of AS. However, concurrent CAD is common in patients with AS, and all patients should be screened and treated for hypercholesterolemia using GDMT for primary and secondary prevention of CAD.
Supporting References: (109,130–133)
See Online Data Supplement 4 for more information on clinical trials of lipid-lowering therapy to slow progression of AS (stage B) and prevent cardiovascular outcomes.
3.2.3 Timing of Intervention: Recommendations
See Table 9 for a summary of recommendations from this section and Figure 1 for indications for AVR in patients with AS. These recommendations for timing of intervention for AS apply to both surgical and transcatheter AVR. The integrative approach to assessing risk of surgical or transcatheter AVR is discussed in Section 2.5. The specific type of intervention for AS is discussed in Section 3.2.4.
Class I1. AVR is recommended in symptomatic patients with severe AS (stage D1) with (9,91,134,135) (Level of Evidence: B):
a. Decreased systolic opening of a calcified or congenitally stenotic aortic valve; and
b. An aortic velocity 4.0 m per second or greater or mean pressure gradient 40 mm Hg or higher; and
c. Symptoms of HF, syncope, exertional dyspnea, angina, or presyncope by history or on exercise testing.
Indications for AVR in Patients With AS
Arrows show the decision pathways that result in a recommendation for AVR. Periodic monitoring is indicated for all patients in whom AVR is not yet indicated, including those with asymptomatic AS (stage D or C) and those with low-gradient AS (stage D2 or D3) who do not meet the criteria for intervention.
*AVR should be considered with stage D3 AS only if valve obstruction is the most likely cause of symptoms, stroke volume index is <35 mL/m2, indexed AVA is ≤0.6 cm2/m2, and data are recorded when the patient is normotensive (systolic BP <140 mm Hg).
AS indicates aortic stenosis; AVA; aortic valve area; AVR, aortic valve replacement by either surgical or transcatheter approach; BP, blood pressure; DSE, dobutamine stress echocardiography; ETT, exercise treadmill test; LVEF, left ventricular ejection fraction; ΔPmean, mean pressure gradient; and Vmax, maximum velocity.
Hemodynamic progression eventually leading to symptom onset occurs in nearly all asymptomatic patients with AS. However, survival during the asymptomatic phase is similar to age-matched controls with a low risk of sudden death (<1% per year) when patients are followed prospectively and promptly report symptom onset. The rate of symptom onset is strongly dependent on severity of AS, with an event-free survival rate of about 75% to 80% at 2 years in those with a jet velocity <3.0 m per second compared with only 30% to 50% in those with a jet velocity ≥4.0 m per second. Patients with asymptomatic AS require periodic monitoring for development of symptoms and progressive disease, but routine AVR is not recommended (Section 3.1).
However, once even mild symptoms caused by severe AS are present, outcomes are extremely poor unless outflow obstruction is relieved. Typical initial symptoms are dyspnea on exertion or decreased exercise tolerance. The classical symptoms of syncope, angina, and HF are late manifestations of disease, most often seen in patients in whom early symptom onset was not recognized and intervention was inappropriately delayed. In patients with severe, symptomatic, and calcific AS, the only effective treatment is surgical or transcatheter AVR, resulting in improved survival rates, reduced symptoms, and improved exercise capacity. In the absence of serious comorbid conditions that limit life expectancy or quality of life, AVR is indicated in virtually all symptomatic patients with severe AS and should be performed promptly after onset of symptoms. Age alone is not a contraindication to surgery, with several series showing outcomes similar to age-matched normal subjects in the very elderly.
Severe AS is defined as an aortic velocity ≥4.0 m per second or mean pressure gradient ≥40 mm Hg based on outcomes in a series of patients with AS of known hemodynamic severity. Although transaortic velocity and mean pressure gradient are redundant measures of AS severity—with native valve AS there is a close linear correlation between velocity and mean pressure gradient whether measured by catheterization or Doppler methods—both are included in this guideline so that either Doppler or invasive measurements can be used in decision making. There is substantial overlap in hemodynamic severity between asymptomatic and symptomatic patients, and there is no single parameter that indicates the need for AVR. Instead, it is the combination of symptoms, valve anatomy, and hemodynamics (Table 8) that provides convincing evidence that AVR will be beneficial in an individual patient. Many patients with a high transaortic velocity/pressure gradient will remain asymptomatic for several years and do not require AVR until symptom onset. However, if symptoms are present, a high velocity/gradient confirms valve obstruction as the cause of symptoms. With mixed stenosis and regurgitation, a high velocity/gradient indicates severe mixed aortic valve disease. Calculation of valve area is not necessary when a high velocity/gradient is present and the valve is calcified and immobile; most patients will have a valve area ≤1.0 cm2 or an indexed valve area ≤0.6 cm2/m2, but some will have a larger valve area due to a large body size or coexisting aortic regurgitation (AR). Thus, the primary criterion for the definition of severity of AS is based on aortic velocity or mean pressure gradient. Calculations of valve area may be supportive but are not necessary when a high velocity or gradient is present. In contrast, valve area calculations are essential for patients with AS and a low ejection fraction or stroke volume as defined for stages D2 and D3.
Supporting References: (24,25,29,89,92,94,108,109,134,135,139,140,143–148)
See Online Data Supplements 5, 6, and 7 for more information on clinical outcomes with asymptomatic AS (stages B and C) of known hemodynamic severity, incidence of sudden death in asymptomatic patients with AS (stages B and C), and clinical outcomes with symptomatic AS of known hemodynamic severity, respectively.
Class I2. AVR is recommended for asymptomatic patients with severe AS (stage C2) and an LVEF less than 50% with decreased systolic opening of a calcified aortic valve with an aortic velocity 4.0 m per second or greater or mean pressure gradient 40 mm Hg or higher (136,137). (Level of Evidence: B)
In patients with a low LVEF and severe AS, survival is better in those who undergo AVR than in those treated medically. The depressed LVEF in many patients is caused by excessive afterload (afterload mismatch), and LV function improves after AVR in such patients. If LV dysfunction is not caused by afterload mismatch, survival is still improved, likely because of the reduced afterload with AVR, but improvement in LV function and resolution of symptoms might not be complete after AVR.
Supporting References: (98,136,141,142,149–153)
See Online Data Supplement 1 for more information on outcomes in patients with low-flow/low-gradient AS with reduced LVEF.
Class I3. AVR is indicated for patients with severe AS (stage C or D) when undergoing cardiac surgery for other indications when there is decreased systolic opening of a calcified aortic valve and an aortic velocity 4.0 m per second or greater or mean pressure gradient 40 mm Hg or higher (108,138). (Level of Evidence: B)
Prospective clinical studies demonstrate that disease progression occurs in nearly all patients with severe asymptomatic AS. Symptom onset within 2 to 5 years is likely when aortic velocity is ≥4.0 m per second or mean pressure gradient is ≥40 mm Hg. The additive risk of AVR at the time of other cardiac surgery is less than the risk of reoperation within 5 years.
Supporting References: (108,138,154,155)
Class IIa1. AVR is reasonable for asymptomatic patients with very severe AS (stage C1) with (139,140) (Level of Evidence: B):
a. Decreased systolic opening of a calcified valve;
b. An aortic velocity 5.0 m per second or greater or mean pressure gradient 60 mm Hg or higher; and
c. A low surgical risk.
In patients with very severe AS and an aortic velocity ≥5.0 m per second or mean pressure gradient ≥60 mm Hg, the rate of symptom onset is approximately 50% at 2 years. Several observational studies have shown higher rates of symptom onset and major adverse cardiac events in patients with very severe, compared with severe, AS. In addition, a study comparing early surgery with surgery at symptom onset in 57 propensity score−matched pairs showed a lower all-cause mortality risk with early surgery (hazard ratio [HR]: 0.135; 95% confidence interval [CI]: 0.030 to 0.597; p=0.008). Thus, it is reasonable to consider elective AVR in patients with very severe asymptomatic AS if surgical risk is low rather than waiting for symptom onset. A low surgical risk is defined as an STS PROM score of <4.0 in the absence of other comorbidities or advanced frailty. At Heart Valve Centers of Excellence, this corresponds to an operative mortality of <1.5% (Section 2.5). Patient age, avoidance of patient-prosthesis mismatch, anticoagulation issues, and patient preferences should be taken into account in a decision to proceed with AVR or continue watchful waiting.
Supporting References: (115,139,140,145,156–158)
Class IIa2. AVR is reasonable in apparently asymptomatic patients with severe AS (stage C1) with (25,47) (Level of Evidence: B):
a. A calcified aortic valve;
b. An aortic velocity of 4.0 m per second to 4.9 m per second or mean pressure gradient of 40 mm Hg to 59 mm Hg; and
c. An exercise test demonstrating decreased exercise tolerance or a fall in systolic BP.
Exercise testing may be helpful in clarifying symptom status in patients with severe AS. When symptoms are provoked by exercise testing, the patient is considered symptomatic and meets a Class I recommendation for AVR. In patients without overt symptoms who demonstrate 1) a decrease in systolic BP below baseline or a failure of BP to increase by at least 20 mm Hg or 2) a significant decrease in exercise tolerance compared with age and sex normal standards, symptom onset within 1 to 2 years is high (about 60% to 80%). Thus, it is reasonable to consider elective AVR in these patients when surgical risk is low, taking into account patient preferences and clinical factors such as age and comorbid conditions.
Supporting References: (25,46,47,117,119–121)
See Online Data Supplement 3 for more information on exercise testing.
Class IIa3. AVR is reasonable in symptomatic patients with low-flow/low-gradient severe AS with reduced LVEF (stage D2) with a (43,141,142) (Level of Evidence: B):
a. Calcified aortic valve with reduced systolic opening;
b. Resting valve area 1.0 cm2 or less;
c. Aortic velocity less than 4 m per second or mean pressure gradient less than 40 mm Hg;
d. LVEF less than 50%; and
e. A low-dose dobutamine stress study that shows an aortic velocity 4 m per second or greater or mean pressure gradient 40 mm Hg or higher with a valve area 1.0 cm2 or less at any dobutamine dose.
Mean pressure gradient is a strong predictor of outcome after AVR, with better outcomes with higher gradients. Outcomes are poor with severe low-gradient AS but are still improved with AVR compared with medical therapy in those with a low LVEF, particularly when contractile reserve is present. The document “Echocardiographic Assessment of Valve Stenosis: EAE/ASE Recommendations for Clinical Practice” defines severe AS on dobutamine stress testing as a maximum velocity >4.0 m per second with a valve area ≤1.0 cm2 at any point during the test protocol, with a maximum dobutamine dose of 20 mcg/kg per minute. On the basis of outcome data in several prospective nonrandomized studies, AVR is reasonable in these patients. LVEF typically increases by 10 LVEF units and may return to normal if afterload mismatch was the cause of LV systolic dysfunction. Some patients without contractile reserve may also benefit from AVR, but decisions in these high-risk patients must be individualized because there are no data indicating who will have a better outcome with surgery.
Supporting References: (43,99,137,141,142,150,151)
See Online Data Supplement 1 for more information on outcomes in patients with low-flow/low-gradient AS with reduced LVEF.
Class IIa4. AVR is reasonable in symptomatic patients with low-flow/low-gradient severe AS (stage D3) with an LVEF 50% or greater, a calcified aortic valve with significantly reduced leaflet motion, and a valve area 1.0 cm2 or less only if clinical, hemodynamic, and anatomic data support valve obstruction as the most likely cause of symptoms and data recorded when the patient is normotensive (systolic BP <140 mm Hg) indicate (Level of Evidence: C):
a. An aortic velocity less than 4 m per second or mean pressure gradient less than 40 mm Hg; and
b. A stroke volume index less than 35 mL/m2; and
c. An indexed valve area 0.6 cm2/m2 or less.
Most patients with severe AS present with a high transvalvular gradient and velocity. However, a subset present with severe AS despite a low gradient and velocity due either to concurrent LV systolic dysfunction (LVEF <50%) or a low transaortic stroke volume with preserved LV systolic function. Studies suggest that low-flow/low-gradient severe AS with preserved LVEF occurs in 5% to 25% of patients with severe AS. Some studies suggest that even asymptomatic patients with low-flow/low-gradient severe AS with a normal LVEF have a poor prognosis and might benefit from AVR. Other studies suggest that many of these asymptomatic patients have only moderate AS with outcomes similar to other patients with moderate AS and normal transaortic flow rates. However, both case-control and prospective studies suggest that outcomes are worse in symptomatic patients with low-flow/low-gradient AS with a normal LVEF compared with patients with high-gradient severe AS. Although no RCTs have been done, a post hoc subset analysis of an RCT suggests that survival may be improved with TAVR or AVR versus medical management in the symptomatic patient with low-flow severe AS.
The clinical approach to patients with low-flow AS relies on integration of multiple sources of data. Low-flow/low-gradient severe AS with preserved LVEF should be considered in patients with a severely calcified aortic valve, an aortic velocity <4.0 m per second (mean pressure gradient <40 mm Hg), and a valve area ≤1.0 cm2. However, even with low flow, severe AS is unlikely with a velocity <3.0 m per second or mean pressure gradient <20 mm Hg. Typically, there is a small left ventricle with thick walls, diastolic dysfunction, and a normal LVEF (≥50%). The first diagnostic step is to ensure that data have been recorded and measured correctly. If the patient was hypertensive, repeat evaluation after control of BP should be considered. Next, the valve area should be indexed to body size because an apparent small valve area may be only moderate AS in a small patient; an aortic valve area index ≤0.6 cm2/m2 suggests severe AS. Transaortic stroke volume should be calculated from the LV outflow tract diameter and Doppler velocity time integral; a stroke volume indexed to body surface area <35 mL/m2 is consistent with low flow. If the degree of valve calcification cannot be adequately assessed on TTE, TEE, CT imaging, or fluoroscopy may be considered. The patient should be evaluated for other potential causes of symptoms to ensure that symptoms are most likely due to valve obstruction. The risk of surgery and patient comorbidities should also be taken into account.
Supporting References: (8,146,159–166)
See Online Data Supplement 8 for more information on outcomes in patients with low-flow/low-gradient AS with preserved LVEF.
Class IIa5. AVR is reasonable for patients with moderate AS (stage B) with an aortic velocity between 3.0 m per second and 3.9 m per second or mean pressure gradient between 20 mm Hg and 39 mm Hg who are undergoing cardiac surgery for other indications. (Level of Evidence: C)
Calcific AS is a progressive disease, and once moderate AS is present, the likelihood of symptom onset within 5 years is significant. When the risk of progressive VHD is balanced against the risk of repeat surgery within 5 years, it is reasonable to perform AVR at the time of other cardiac surgery when moderate AS is present (Sections 4.3.3. and 10). This decision must be individualized based on the specific operative risk in each patient, clinical factors such as age and comorbid conditions, valve durability, and patient preferences.
Supporting References: (25,92,138,154,155)
Class IIb1. AVR may be considered for asymptomatic patients with severe AS (stage C1) with an aortic velocity 4.0 m per second or greater or mean pressure gradient 40 mm Hg or higher if the patient is at low surgical risk and serial testing shows an increase in aortic velocity 0.3 m per second or greater per year. (Level of Evidence: C)
Predictors of rapid disease progression include older age, more severe valve calcification, and a faster rate of hemodynamic progression on serial studies. In patients with severe AS and predictors of rapid disease progression, elective AVR may be considered if the surgical risk is low and after consideration of other clinical factors and patient preferences.
Supporting References: (115,167,168)
3.2.4 Choice of Intervention: Recommendations
See Table 10 for a summary of recommendations from this section.
These recommendations for choice of intervention for AS apply to both surgical and transcatheter AVR; indications for AVR are discussed in Section 3.2.3. The integrative approach to assessing risk of surgical or transcatheter AVR is discussed in Section 2.5. The choice of proceeding with surgical versus transcatheter AVR is based on multiple parameters, including the risk of operation, patient frailty, and comorbid conditions. Concomitant severe CAD may also affect the optimal intervention because severe multivessel coronary disease may best be served by AVR and CABG.
Class I1. Surgical AVR is recommended in patients who meet an indication for AVR (Section 3.2.3) with low or intermediate surgical risk (Section 2.5) (74,148). (Level of Evidence: A)
AVR is indicated for survival benefit, improvement in symptoms, and improvement in LV systolic function in patients with severe symptomatic AS (Section 3.2.3.). Given the magnitude of the difference in outcomes between those undergoing AVR and those who refuse AVR in historical series, an RCT of AVR versus medical therapy would not be appropriate in patients with a low to intermediate surgical risk (Section 2.5). Outcomes after surgical AVR are excellent in patients who do not have a high procedural risk. Surgical series demonstrate improved symptoms after AVR, and most patients have an improvement in exercise tolerance as documented in studies with pre- and post-AVR exercise stress testing. The specific choice of prosthetic valve type is discussed in Section 11.1. Surgical AVR should be considered over TAVR in patients who are at higher surgical risk but have severe multivessel coronary disease.
Supporting References: (74,93,173–176)
Class I2. For patients in whom TAVR or high-risk surgical AVR is being considered, a Heart Valve Team consisting of an integrated, multidisciplinary group of healthcare professionals with expertise in VHD, cardiac imaging, interventional cardiology, cardiac anesthesia, and cardiac surgery should collaborate to provide optimal patient care. (Level of Evidence: C)
Decision making is complex in the patient at high surgical risk with severe symptomatic AS. The decision to perform surgical AVR, TAVR, or to forgo intervention requires input from a Heart Valve Team. The primary cardiologist is aware of coexisting conditions that affect risk and long-term survival, the patient’s disease course, and the patient’s preferences and values. Cardiac imaging specialists who are knowledgeable about AS and TAVR provide evaluation of aortic valve anatomy and hemodynamic severity, vascular anatomy, aortic annulus size, and coronary anatomy, including the annular-ostial distance. Interventional cardiologists help determine the likelihood of a successful transcatheter procedure. The cardiac surgeon can provide a realistic estimate of risk with a conventional surgical approach, at times in conjunction with a cardiac anesthesiologist. An expert in VHD, typically a cardiologist or cardiac surgeon with expertise in imaging and/or intervention, provides the continuity and integration needed for the collaborative decision-making process. Nurses and other members of the team coordinate care and help with patient education. The cardiac surgeon and interventional cardiologist are the core of the Heart Valve Team for patients being considered for AVR or TAVR.
Supporting References: (79,177)
Class I3. TAVR is recommended in patients who meet an indication for AVR (Section 3.2.3) who have a prohibitive risk for surgical AVR (Section 2.5) and a predicted post-TAVR survival greater than 12 months (169,170). (Level of Evidence: B)
TAVR has been studied in numerous observational studies and multicenter registries that include large numbers of high-risk patients with severe symptomatic AS. These studies demonstrated the feasibility, excellent hemodynamic results, and favorable outcomes of the procedure. In addition, TAVR was compared with standard therapy in a prospective RCT of patients with severe symptomatic AS who were deemed inoperable. Severe AS was defined as an aortic valve area <0.8 cm2 plus a mean pressure gradient ≥40 mm Hg or a maximum aortic velocity ≥4.0 m per second. All patients had NYHA class II to IV symptoms. Patients were considered to have a prohibitive surgical risk when predicted 30–day surgical morbidity and mortality were ≥50% due to comorbid disease or a serious irreversible condition. Patients were excluded if they had a bicuspid aortic valve, acute myocardial infarction (MI), significant CAD, an LVEF <20%, an aortic annulus diameter <18 mm or >25 mm, severe AR or MR, a transient ischemic attack within 6 months, or severe renal insufficiency. TAVR was performed by either the transfemoral or transapical approach using the SAPIEN heart-valve system (Edwards Lifesciences LLC, Irvine, CA). Standard therapy included percutaneous aortic balloon dilation in 84%.
All-cause death at 2 years was lower with TAVR (43.3%) compared with standard medical therapy (68%), with an HR for TAVR of 0.58 (95% CI: 0.36 to 0.92; p=0.02). There was a reduction in repeat hospitalization with TAVR (55% versus 72.5%; p<0.001). In addition, only 25.2% of survivors were in NYHA class III or IV 1 year after TAVR, compared with 58% of patients receiving standard therapy (p<0.001). However, the rate of major stroke at 30 days was higher with TAVR (5.05% versus 1.0%; p=0.06) and remained higher at 2 years with TAVR compared with standard therapy (13.8% versus 5.5%; p=0.01). Major vascular complications occurred in 16.2% with TAVR versus 1.1% with standard therapy (p<0.001).
Thus, in high-risk patients with severe symptomatic AS who are unable to undergo surgical AVR due to a prohibitive surgical risk and who have an expected survival of >1 year after intervention, TAVR is recommended to improve survival and reduce symptoms. This decision should be made only after discussion with the patient about the expected benefits and possible complications of TAVR and surgical AVR. Patients with severe AS are considered to have a prohibitive surgical risk if they have a predicted risk with surgery of death or major morbidity (all cause) of >50% at 1 year; disease affecting ≥3 major organ systems that is not likely to improve postoperatively; or anatomic factors that preclude or increase the risk of cardiac surgery, such as a heavily calcified (e.g., porcelain) aorta, prior radiation, or an arterial bypass graft adherent to the chest wall.
Supporting References: (169,170,178)
Class IIa1. TAVR is a reasonable alternative to surgical AVR in patients who meet an indication for AVR (Section 3.2.3) and who have high surgical risk for surgical AVR (Section 2.5) (171,172). (Level of Evidence: B)
TAVR has been studied in numerous observational studies and multicenter registries that include large numbers of high-risk patients with severe symptomatic AS. These studies demonstrated the feasibility, excellent hemodynamic results, and favorable outcomes of the procedure. In addition, TAVR was compared with standard therapy in a prospective RCT of patients with severe symptomatic AS who were deemed high risk for surgery. Severe symptomatic calcific AS was defined as aortic valve area <0.8 cm2 plus a mean transaortic gradient ≥40 mm Hg or aortic velocity ≥4.0 m per second with NYHA class II to IV symptoms. Patients were deemed at high surgical risk if risk of death was ≥15% within 30 days after the procedure. An STS score ≥10% was used for guidance, with an actual mean STS score of 11.8%±3.3%. Exclusions included bicuspid aortic valve anatomy, acute MI, significant CAD, an LVEF <20%, an aortic annulus diameter <18 mm or >25 mm, severe AR or MR, transient ischemic attack within 6 months, or severe renal insufficiency. On an intention-to-treat analysis, all-cause death was similar in those randomized to TAVR (n=348) compared with surgical AVR (n=351) at 30 days, 1 year, and 2 years (p=0.001) for noninferiority of TAVR compared with surgical AVR. The composite endpoint of all-cause death or stroke at 2 years was 35% with surgical AVR compared with 33.9% with TAVR (p=0.78). TAVR was performed by the transfemoral approach in 244 patients and the transapical approach in 104 patients. Only limited data on long-term durability of bioprosthetic valves implanted by the transcatheter approach are available.
Given the known long-term outcomes and valve durability with surgical AVR, TAVR currently remains restricted to patients with prohibitive or high surgical risk. High surgical risk is defined as an STS PROM score of 8% to 15%, anatomic factors that increase surgical risk, or significant frailty (Section 14.2).
Supporting References: (171,172,179,180)
See Online Data Supplement 9 for more information on choice of intervention.
Class IIb1. Percutaneous aortic balloon dilation may be considered as a bridge to surgical AVR or TAVR in patients with severe symptomatic AS. (Level of Evidence: C)
Percutaneous aortic balloon dilation has an important role in treating children, adolescents, and young adults with AS, but its role in treating older patients is very limited. The mechanism by which balloon dilation modestly reduces the severity of stenosis in older patients is by fracture of calcific deposits within the valve leaflets and, to a minor degree, stretching of the annulus and separation of the calcified or fused commissures. Immediate hemodynamic results include a moderate reduction in the transvalvular pressure gradient, but the postdilation valve area rarely exceeds 1.0 cm2. Despite the modest change in valve area, an early symptomatic improvement usually occurs. However, serious acute complications, including acute severe AR and restenosis and clinical deterioration, occur within 6 to 12 months in most patients. Therefore, in patients with AS, percutaneous aortic balloon dilation is not a substitute for AVR.
Some clinicians contend that despite the procedural morbidity and mortality and limited long-term results, percutaneous aortic balloon dilation can have a temporary role in the management of some symptomatic patients who are not initially candidates for surgical AVR or TAVR. For example, patients with severe AS and refractory pulmonary edema or cardiogenic shock might benefit from percutaneous aortic balloon dilation as a “bridge” to AVR; an improved hemodynamic state may reduce the risks of TAVR or surgery. In some patients, the effects of percutaneous aortic balloon dilation on symptoms and LV function may be diagnostically helpful as well, but many clinicians recommend proceeding directly to AVR in these cases. The indications for palliative percutaneous aortic balloon dilation in patients in whom AVR cannot be recommended because of serious comorbid conditions are even less well established, with no data to suggest improved longevity; however, some patients do report a decrease in symptoms. Most asymptomatic patients with severe AS who require urgent noncardiac surgery can undergo surgery at a reasonably low risk with anesthetic monitoring and attention to fluid balance. Percutaneous aortic balloon dilation is not recommended for these patients. If preoperative correction of AS is needed, they should be considered for AVR.
Supporting References: (171,172,181–183)
Class III: No Benefit1. TAVR is not recommended in patients in whom existing comorbidities would preclude the expected benefit from correction of AS (169). (Level of Evidence: B)
The survival and symptom reduction benefit of TAVR is only seen in appropriately selected patients. Baseline clinical factors associated with a poor outcome after TAVR include advanced age, frailty, smoking or chronic obstructive pulmonary disease, pulmonary hypertension, liver disease, prior stroke, anemia, and other systemic conditions. The STS estimated surgical risk score provides a useful measure of the extent of patient comorbidities and may help identify which patients will benefit from TAVR. In patients with a prohibitive surgical risk for AVR in the PARTNER (Placement of Aortic Transcatheter Valve) study, the survival benefit of TAVR was seen in those with an STS score <5% (n=40, HR: 0.37; 95% CI: 0.13 to 1.01; p=0.04) and in those with an STS score between 5% and 14.9% (n=227, HR: 0.58; 95% CI: 0.41 to 0.8; p=0.002) but not in those with an STS score ≥15% (n=90, HR: 0.77; 95% CI: 0.46 to 1.28; p=0.31). The relative prevalence of oxygen- dependent lung disease was similar in all 3 groups. However, the other reasons for inoperability were quite different, with a porcelain aorta or prior chest radiation damage being most common in those with an STS score of <5% and frailty being most common in those with an STS score ≥15%. These data emphasize the importance of evaluating the likely benefit of TAVR, as well as the risks, in weighing the risk–benefit ratio of intervention in an individual patient. TAVR is not recommended in patients with 1) a life expectancy of <1 year, even with a successful procedure, and 2) those with a chance of “survival with benefit” of <25% at 2 years.
Supporting References: (115,169,178,184)
4 Aortic Regurgitation
4.1 Acute AR
Acute AR may result from abnormalities of the valve, primarily IE, or abnormalities of the aorta, primarily aortic dissection. Acute AR may also occur from iatrogenic complications, such as following percutaneous aortic balloon dilation or TAVR or following blunt chest trauma. The acute volume overload on the left ventricle usually results in severe pulmonary congestion as well as a low forward cardiac output. Urgent diagnosis and rapid intervention can be lifesaving.
4.1.1 Diagnosis
TTE is indispensable in confirming the presence, severity, and etiology of AR, estimating the degree of pulmonary hypertension, and determining whether there is rapid equilibration of aortic and LV diastolic pressure. Short deceleration time on the mitral flow velocity curve and early closure of the mitral valve on M-mode echocardiography are indicators of markedly elevated LV end-diastolic pressure. A short half-time of <300 milliseconds on the AR velocity curve indicates rapid equilibration of the aortic and LV diastolic pressures. Assessing reversed flow during diastole in the aortic arch in comparison with the forward systolic flow provides a quick semiquantitative estimate of regurgitant fraction.
Acute severe AR caused by aortic dissection is a surgical emergency that requires particularly prompt identification and management. However, the presence of new, even mild, AR, diagnosed by auscultation of a diastolic murmur or findings on echocardiography, may be a sign of acute aortic dissection. The sensitivity and specificity of TTE for diagnosis of aortic dissection are only 60% to 80%, whereas TEE has a sensitivity of 98% to 100% and a specificity of 95% to 100%. CT imaging is also very accurate and may provide the most rapid approach to diagnosis at many centers. CMR imaging is useful with chronic aortic disease but is rarely used in unstable patients with suspected dissection. Angiography should be considered only when the diagnosis cannot be determined by noninvasive imaging and when patients have suspected or known CAD, especially those with previous CABG.
4.1.2 Intervention
In patients with acute severe AR resulting from IE or aortic dissection, surgery should not be delayed, especially if there is hypotension, pulmonary edema, or evidence of low flow (Section 12). Numerous studies have demonstrated improved in-hospital and long-term survival in such patients if they are treated with prompt AVR, as long as there are no complications (such as severe embolic cerebral damage) or comorbid conditions that make the prospect of recovery remote. In a prospectively enrolled multinational cohort of 1,552 patients with definite native valve endocarditis (NVE), evidence of new AR was present in 37% of patients. HF (HR: 2.33; 95% CI: 1.65 to 3.28; p<0.001) and pulmonary edema (HR: 1.51; 95% CI: 1.04 to 2.18; p=0.029) were associated with increased in-hospital mortality. Early surgery was associated with reduced in-hospital mortality (HR: 0.56; 95% CI: 0.38 to 0.82; p=0.003). The effect of early surgery on in-hospital mortality was also assessed by propensity-based matching adjustment for survivor bias and by instrumental variable analysis. Compared with medical therapy, early surgery in the propensity-matched cohort after adjustment for survivor bias was associated with an absolute risk reduction of 5.9% (p<0.001) for in-hospital mortality.
Intra-aortic balloon counterpulsation is contraindicated in patients with acute severe AR. Augmentation of aortic diastolic pressure will worsen the severity of the acute regurgitant volume, thereby aggravating LV filling pressures and compromising forward output.
Beta blockers are often used in treating aortic dissection. However, these agents should be used very cautiously, if at all, for other causes of acute AR because they will block the compensatory tachycardia and could precipitate a marked reduction in BP.
Supporting References: (185–195)
4.2 Stages of Chronic AR
The most common causes of chronic AR in the United States and other developed countries are bicuspid aortic valve and calcific valve disease. In addition, AR frequently arises from primary diseases causing dilation of the ascending aorta or the sinuses of Valsalva. Another cause of AR is rheumatic heart disease (the leading cause in many developing countries). In the majority of patients with AR, the disease course is chronic and slowly progressive with increasing LV volume overload and LV adaptation via chamber dilation and hypertrophy. Management of patients with AR depends on accurate diagnosis of the cause and stage of the disease process. Table 11 shows the stages of AR ranging from patients at risk of AR (stage A) or with progressive mild-to-moderate AR (stage B) to severe asymptomatic (stage C) and symptomatic AR (stage D). Each of these stages is defined by valve anatomy, valve hemodynamics, severity of LV dilation, and LV systolic function, as well as by patient symptoms.
Stages of Chronic AR
4.3 Chronic AR
See Figure 2 for indications for AVR for chronic AR.
Indications for AVR for Chronic AR
AR indicates aortic regurgitation; AVR, aortic valve replacement (valve repair may be appropriate in selected patients); ERO, effective regurgitant orifice; LV, left ventricular; LVEDD, left ventricular end-diastolic dimension; LVEF, left ventricular ejection fraction; LVESD, left ventricular end-systolic dimension; RF, regurgitant fraction; and RVol, regurgitant volume.
4.3.1 Diagnosis and Follow-Up
4.3.1.1 Diagnostic Testing—Initial Diagnosis: Recommendations
Class I1. TTE is indicated in patients with signs or symptoms of AR (stages A to D) for accurate diagnosis of the cause of regurgitation, regurgitant severity, and LV size and systolic function, and for determining clinical outcome and timing of valve intervention (32,196–205). (Level of Evidence: B)
The clinical stages that characterize the severity of chronic AR (Table 11) are defined by symptomatic status, severity of regurgitation, and LV volume and systolic function. TTE is an indispensable imaging test for evaluating patients with chronic AR and guiding appropriate management decisions. It provides diagnostic information about the etiology and mechanism of AR (including valve reparability), severity of regurgitation, morphology of the ascending aorta, and LV response to the increases in preload and afterload. Quantitative measures of regurgitant volume and effective regurgitant orifice area were strong predictors of clinical outcome in a prospective study of 251 asymptomatic patients with isolated AR and normal LV function (stages B and C). This was confirmed in a subsequent study involving 294 patients. Observation of diastolic flow reversal in the aortic arch or more distally can help identify patients with severe AR. Numerous studies involving a total of >1,150 patients have consistently shown that measures of LV systolic function (LVEF or fractional shortening) and LV end-systolic dimension (LVESD) or volume are associated with development of HF symptoms or death in initially asymptomatic patients (stages B and C1). Moreover, in symptomatic patients undergoing AVR (stage D), preoperative LV systolic function and end-systolic dimension or volume are significant determinants of survival and functional results after surgery. Symptomatic patients (stage D) with normal LVEF have significantly better long-term postoperative survival than those with depressed systolic function.
Supporting References: (17,32,196–220)
See Online Data Supplement 10 for more information on the natural history of asymptomatic AR.
Class I2. TTE is indicated in patients with dilated aortic sinuses or ascending aorta or with a bicuspid aortic valve (stages A and B) to evaluate the presence and severity of AR (221). (Level of Evidence: B)
A diastolic regurgitant murmur is not always audible in patients with mild or moderate AR. TTE is more sensitive than auscultation in detecting AR in patients at risk for development of AR. In a series of 100 patients referred for echocardiographic evaluation of a systolic murmur, 28 had AR on echocardiography. Auscultation had high specificity (96%) for detecting AR but low sensitivity (21%), and diagnostic accuracy was only 75%.
Supporting Reference: (221)
Class I3. CMR is indicated in patients with moderate or severe AR (stages B, C, and D) and suboptimal echocardiographic images for the assessment of LV systolic function, systolic and diastolic volumes, and measurement of AR severity (222,223). (Level of Evidence: B)
CMR imaging provides accurate measures of regurgitant volume and regurgitant fraction in patients with AR, as well as assessment of aortic morphology, LV volume, and LV systolic function. In addition to its value in patients with suboptimal echocardiographic data, CMR is useful for evaluating patients in whom there is discordance between clinical assessment and severity of AR by echocardiography. CMR measurement of regurgitant severity is less variable than echocardiographic measurement.
Supporting References: (222–228)
4.3.1.2 Diagnostic Testing—Changing Signs or Symptoms
Symptoms are the most common indication for AVR in patients with AR. In patients with previous documentation of mild or moderate AR, new-onset dyspnea or angina may indicate that AR has progressed in severity. If AR remains mild, further investigation for other etiologies is indicated. In patients with previous documentation of severe AR, onset of symptoms is an indication for surgery and repeat TTE is indicated to determine the status of the aortic valve, aorta, and left ventricle preoperatively.
Supporting References: (31,214,220,229,230)
4.3.1.3 Diagnostic Testing—Routine Follow-Up
Patients with asymptomatic severe AR with normal LV systolic function are at risk for progressive increases in LV end-diastolic and end-systolic volumes and reduction in systolic function. In a series of asymptomatic patients with AR and normal LV systolic function who underwent serial echocardiograms, predictors of death or symptoms in a multivariate analysis were age, initial end-systolic dimension, and rate of change in end-systolic dimension and rest LVEF during serial studies. In asymptomatic patients who do not fulfill the criteria for AVR, serial imaging is indicated to identify those who are progressing toward the threshold for surgery (Table 4).
Supporting Reference: (32)
4.3.1.4 Diagnostic Testing—Cardiac Catheterization
When there is discordance between clinical assessment and noninvasive tests about the severity of AR, additional testing is indicated. Under most circumstances, another noninvasive test such as CMR is used when TTE and clinical findings are discordant. Invasive assessment is indicated when CMR is not available or there are contraindications for CMR, such as implanted devices. In symptomatic patients with equivocal echocardiographic evidence of severity of AR, cardiac catheterization is useful to assess hemodynamics, coronary artery anatomy, and severity of AR.
Supporting References: (222,224–228)
4.3.1.5 Diagnostic Testing—Exercise Testing
Exercise stress testing can be used to assess symptomatic status and functional capacity in patients with AR. Such testing is helpful in confirming patients’ reports that they have no symptoms with daily life activities and in assessing objective exercise capacity and symptom status in those with equivocal symptoms.
4.3.2 Medical Therapy: Recommendations
Class I1. Treatment of hypertension (systolic BP >140 mm Hg) is recommended in patients with chronic AR (stages B and C), preferably with dihydropyridine calcium channel blockers or ACE inhibitors/ARBs (204,209). (Level of Evidence: B)
Vasodilating drugs are effective in reducing systolic BP in patients with chronic AR. Beta blockers may be less effective because the reduction in heart rate is associated with an even higher stroke volume, which contributes to the elevated systolic pressure in patients with chronic severe AR.
Supporting References: (204,209,231–233)
Class IIa1. Medical therapy with ACE inhibitors/ARBs and beta blockers is reasonable in patients with severe AR who have symptoms and/or LV dysfunction (stages C2 and D) when surgery is not performed because of comorbidities (232,234). (Level of Evidence: B)
Vasodilating drugs improve hemodynamic abnormalities in patients with AR and improve forward cardiac output. However, 2 small RCTs yielding discordant results did not conclusively show that these drugs alter the natural history of asymptomatic patients with chronic severe AR and normal LV systolic function. Thus, vasodilator therapy is not recommended routinely in patients with chronic asymptomatic AR and normal LV systolic function.
In symptomatic patients who are candidates for surgery, medical therapy is not a substitute for AVR. However, medical therapy is helpful for alleviating symptoms in patients who are considered at very high risk for surgery because of concomitant comorbid medical conditions. In a cohort study of 2,266 patients with chronic AR, treatment with ACE inhibitors or ARBs was associated with a reduced composite endpoint of AVR, hospitalization for HF, and death from HF (HR: 0.68; 95% CI: 0.54 to 0.87; p<0.01). In that study, 45% had evidence of LV systolic impairment. In another retrospective cohort study of 756 patients with chronic AR, therapy with beta-adrenergic blockers was associated with improved survival (HR: 0.74; 95% CI: 0.58 to 0.93; p<0.01). Also, 33% of patients had associated CAD, 64% had hypertension, 20% had renal insufficiency, 70% had HF, and 25% had AF. Patients treated with beta blockers were more likely to also be taking ACE inhibitors (53% versus 40%; p<0.001) and dihydropyridine calcium channel blockers (22% versus 16%; p=0.03). Importantly, more patients receiving beta blockers in that study underwent AVR (49% versus 29%; p<0.001), but this was accounted for in the multivariate model. When patients were censored at the time of surgery, beta-blocker therapy remained associated with higher survival rates (p<0.05).
Supporting References: (204,209,231,232,234–239)
See Online Data Supplement 11 for more information on vasodilator therapy in AR.
4.3.3 Timing of Intervention: Recommendations
See Table 12 for a summary of recommendations from this section.
Summary of Recommendations for AR Intervention
The vast majority of patients who require surgery for chronic severe AR will require AVR. Valve-sparing replacement of the aortic sinuses and ascending aorta is a possible strategy in patients with AR caused by aortic dilation in whom a trileaflet or bicuspid valve is not thickened, deformed, or calcified. Despite advances in primary aortic valve repair, especially in young patients with bicuspid aortic valves, the experience at a few specialized centers has not yet been replicated at the general community level, and durability of aortic valve repair remains a major concern. Performance of aortic valve repair should be concentrated in those centers with proven expertise in the procedure.
Supporting References: (244–247)
Class I1. AVR is indicated for symptomatic patients with severe AR regardless of LV systolic function (stage D) (31,229,230). (Level of Evidence: B)
Symptoms are an important indication for AVR in patients with chronic severe AR, and the most important aspect of the clinical evaluation is taking a careful, detailed history to elicit symptoms or diminution of exercise capacity. Patients with chronic severe AR who develop symptoms have a high risk of death if AVR is not performed. In a series of 246 patients with severe AR followed without surgery, those who were NYHA class III or IV had a mortality rate of 24.6% per year; even NYHA class II symptoms were associated with increased mortality (6.3% per year). Numerous other studies indicate that survival and functional status after AVR are related to severity of preoperative symptoms assessed either subjectively or objectively with exercise testing, with worse outcomes in patients who undergo surgery after development of moderately severe (NYHA class III) symptoms or impaired exercise capacity. In a series of 289 patients followed after AVR, long-term postoperative survival was significantly higher in patients who were in NYHA class I or II at the time of surgery compared with those in NYHA class III or IV (10–year survival rates 78%±7% versus 45%±4%, respectively; p<0.001). The importance of preoperative symptoms in the study was observed for both patients with normal LV systolic function and those with LV systolic dysfunction. Postoperative survival is significantly higher in symptomatic patients with normal LVEF compared with those with impaired systolic function, but even in symptomatic patients with severely depressed systolic function, surgery is recommended over medical therapy. In a postoperative series of 450 patients undergoing AVR from 1980 to 1995, patients with markedly low LVEF incurred high short- and long-term mortality after AVR. However, postoperative LV function improved significantly, and most patients survived without recurrence of HF. This was confirmed in a series of 724 patients who underwent AVR from 1972 to 1999, in which long-term survival was significantly reduced in the 88 patients with severe LV dysfunction (LVEF <30%) compared with the 636 patients with either less severe LV dysfunction or normal LVEF (81% versus 92% at 1 year, 68% versus 81% at 5 years, 46% versus 62% at 10 years, 26% versus 41% at 15 years, and 12% versus 24% at 20 years, respectively; p=0.04). Among propensity-matched patients operated on in the latter time frame since 1985, these trends were no longer significant (survival at 1, 5, and 10 years after surgery was 92%, 79%, and 51%, respectively for patients with severe LV dysfunction and 96%, 83%, and 55% for the others, respectively; p=0.9).
Supporting References: (31,211–221,229,230,240,241,248,249)
See Online Data Supplement 12 for more information on outcome after surgery for AR.
Class I2. AVR is indicated for asymptomatic patients with chronic severe AR and LV systolic dysfunction (LVEF <50%) at rest (stage C2) if no other cause for systolic dysfunction is identified (211,229,240,241). (Level of Evidence: B)
After AVR, LV systolic function is an important determinant of survival and functional status for chronic severe AR. Optimal outcomes are obtained when surgery is performed before LVEF decreases below 50%. However, among patients with LV systolic dysfunction, LV function will improve in many after surgery, especially those with minimal or no symptoms, mild versus severe LV systolic dysfunction, and a brief duration of LV dysfunction. A series of 37 patients with severe AR who underwent AVR were studied, all of whom had preoperative LV dysfunction but preserved exercise capacity (including 8 asymptomatic patients). In the 10 patients in whom LV dysfunction had developed <14 months preoperatively, there was a greater improvement in LV systolic function and regression of LV dilatation compared with those patients who had a longer duration of LV dysfunction. Patients with preserved exercise capacity had higher survival rates, a shorter duration of LV dysfunction, and a persistent improvement in LV size and systolic function at late postoperative studies at 3 to 7 years. Thus, once LV systolic dysfunction (LVEF <50%) is demonstrated, results are optimized by referring for surgery rather than waiting for onset of symptoms or more severe LV dysfunction.
Supporting References: (17,211–220,229,240–242,249,250)
Class I3. AVR is indicated for patients with severe AR (stage C or D) while undergoing cardiac surgery for other indications. (Level of Evidence: C)
Patients with chronic severe AR should undergo AVR if they are referred for other forms of cardiac surgery, such as CABG, mitral valve surgery, or replacement of the ascending aorta. This will prevent both the hemodynamic consequences of persistent AR during the perioperative period and the possible need for a second cardiac operation in the near future.
Class IIa1. AVR is reasonable for asymptomatic patients with severe AR with normal LV systolic function (LVEF ≥50%) but with severe LV dilation (LVESD >50 mm or indexed LVESD >25 mm/m2) (stage C2) (225,242,243). (Level of Evidence: B)
LVESD in patients with chronic AR reflects both the severity of the LV volume overload and the degree of LV systolic shortening. An elevated end-systolic dimension often reflects LV systolic dysfunction with a depressed LVEF. If LVEF is normal, an increased LVESD indicates a significant degree of LV remodeling and is associated with subsequent development of symptoms and/or LV systolic dysfunction. In a series of 104 initially asymptomatic patients with normal LV systolic function followed for a mean of 8 years, an LVESD >50 mm was associated with a risk of death, symptoms, and/or LV dysfunction of 19% per year. In a second study of 101 similar patients followed for a mean of 5 years, this risk was 7% per year. In a third study of 75 similar patients followed for a mean of 10 years, the risk was 7.6% per year. Among patients undergoing AVR, a smaller LVESD is associated with both better survival and improvement in LV systolic function after surgery. Most studies used unadjusted LV dimension, with more recent data suggesting that indexing for body size may be appropriate, particularly in women or small patients. A study of 246 patients that adjusted end-systolic dimension for body size suggested that an end-systolic dimension ≥25 mm/m2 is associated with a poor outcome in asymptomatic patients. This has been confirmed by a subsequent study of 294 asymptomatic patients in which an end-systolic dimension >24 mm/m2 was an independent predictor of LV systolic dysfunction, symptoms, or death, and an earlier study of 32 patients in which an end-systolic dimension >26 mm/m2 was associated with persistent LV dilation after AVR. Other studies have suggested that end-systolic volume index is a more sensitive predictor of cardiac events than end-systolic dimension in asymptomatic patients, but values of end-systolic volume index identifying high-risk patients have varied between 35 mL/m2 and 45 mL/m2 in 2 studies. Thus, more data are needed to determine threshold values of end-systolic volume index with which to make recommendations for surgery in asymptomatic patients.
Supporting References: (17,31,32,196,197,199,203–205,208,212–216,218,242,243,249,251–254)
See Online Data Supplement 12 for more information on AVR in asymptomatic patients.
Class IIa2. AVR is reasonable in patients with moderate AR (stage B) while undergoing surgery on the ascending aorta, CABG, or mitral valve surgery. (Level of Evidence: C)
Because of the likelihood of progression of AR and the need for future AVR in patients with moderate AR, it is reasonable to replace the aortic valve in patients who have evidence of primary aortic valve leaflet disease or significant aortic dilation if they are referred for other forms of cardiac surgery, such as CABG, mitral valve surgery, or replacement of the ascending aorta.
Class IIb1. AVR may be considered for asymptomatic patients with severe AR and normal LV systolic function at rest (LVEF ≥50%, stage C1) but with progressive severe LV dilatation (LV end-diastolic dimension >65 mm) if surgical risk is low. (Level of Evidence: C)
LV end-diastolic dimension is indicative of the severity of LV volume overload in patients with chronic AR. It is significantly associated with development of symptoms and/or LV systolic dysfunction in asymptomatic patients but less so than LVESD. Similarly, end-diastolic volume index is less predictive than end-systolic volume index in asymptomatic patients. However, especially in young patients with severe AR, progressive increases in end-diastolic dimension are associated with a subsequent need for surgery. In a series of 104 initially asymptomatic patients with normal LV systolic function followed for a mean of 8 years, an LV end-diastolic dimension of ≥70 mm was associated with a risk of death, symptoms, and/or LV dysfunction of 10% per year. In a second study of 101 patients followed for a mean of 5 years, this risk was 6.3% per year; in a third study of 75 patients followed for a mean of 10 years, the risk was 5.8% per year. Marked increases in end-diastolic dimension (≥80 mm) have been associated with sudden death. The writing committee thought that AVR may be considered for the asymptomatic patient with severe AR, normal LV systolic function, and severe LV dilatation (LV end-diastolic dimension >65 mm) if there is a low surgical risk and particularly if there is evidence of progressive LV dilation.
New markers of severity of AR and its resultant LV volume overload are under investigation. These include measures of regurgitant fraction, regurgitant volume, and effective regurgitant orifice area; LV volume assessment with 3D echocardiography; noninvasive measures of LV end-systolic stress and systolic and diastolic strain rates; and biomarkers such as brain natriuretic peptide. Further experience with these new markers pertaining to patient outcomes is necessary before firm recommendations can be proposed.
Supporting References: (32,196,197,203–207)
5 Bicuspid Aortic Valve and Aortopathy
Patients with a bicuspid aortic valve may also have an associated aortopathy consisting of aortic dilation, coarctation, or even aortic dissection.
5.1 Bicuspid Aortic Valve
5.1.1 Diagnosis and Follow-Up
5.1.1.1 Diagnostic Testing—Initial Diagnosis: Recommendations
Class I1. An initial TTE is indicated in patients with a known bicuspid aortic valve to evaluate valve morphology, to measure the severity of AS and AR, and to assess the shape and diameter of the aortic sinuses and ascending aorta for prediction of clinical outcome and to determine timing of intervention (255–260). (Level of Evidence: B)
Most patients with a bicuspid aortic valve will develop AS or AR over their lifetime. Standard echocardiographic approaches for measurement of stenosis and regurgitant severity are key to optimal patient management as detailed in the recommendations for AS and AR (Sections 3 and 4).
Bicuspid aortic valves are frequently associated with aortic dilation either at the level of the sinuses of Valsalva or, more frequently, in the ascending aorta. In some patients, severe aneurysmal aortic dilation may develop. The incidence of aortic dilation is higher in patients with fusion of the right and noncoronary cusps than the more common phenotype of fusion of the right and left coronary cusps. In a series of 191 patients with bicuspid aortic valves undergoing echocardiography, those with fusion of the right or left coronary cusp and the noncoronary cusp had a greater prevalence of aortic dilation than those with the fusion of the right and left coronary cusps (68% versus 40%). This was confirmed in a subsequent report of 167 patients with bicuspid aortic valves studied with CT and echocardiography. Patients with fusion involving the noncoronary cusp are also more likely to have dilation of the ascending aorta, rather than the sinuses, which often extends to the transverse arch.
In nearly all patients with a bicuspid aortic valve, TTE provides good quality images of the aortic sinuses with accurate diameter measurements. Further cephalad segments of the ascending aorta can be imaged in many patients by moving the transducer up 1 or 2 interspaces to view the arch from a suprasternal notch approach. The echocardiographic report should include aortic measurements at the aortic annulus, sinuses, sinotubular junction, and mid-ascending aorta, along with an indicator of the quality and completeness of aortic imaging in each patient with a bicuspid aortic valve. Doppler interrogation of the proximal descending aorta allows evaluation for aortic coarctation, which is associated with the presence of a bicuspid aortic valve.
In 20% to 30% of patients with bicuspid valves, other family members also have bicuspid valve disease and/or an associated aortopathy. A specific genetic cause has not been identified, and the patterns of inheritance are variable, so it is important to take a family history and inform patients that other family members may be affected. Imaging of first-degree relatives is clearly appropriate if the patient has an associated aortopathy or a family history of VHD or aortopathy. Many valve experts also recommend screening all first-degree relatives of patients with bicuspid aortic valve, although we do not yet have data addressing the possible impact of screening on outcomes or the cost-effectiveness of this approach.
Supporting References: (255–261)
Class I2. Aortic magnetic resonance angiography or CT angiography is indicated in patients with a bicuspid aortic valve when morphology of the aortic sinuses, sinotubular junction, or ascending aorta cannot be assessed accurately or fully by echocardiography. (Level of Evidence: C)
TTE can provide accurate assessment of the presence and severity of aortic dilation in most patients. However, in some patients, only the aortic sinuses can be visualized, because the ascending aorta is obscured by intervening lung tissue. When echocardiographic images do not provide adequate images of the ascending aorta to a distance ≥4.0 cm from the valve plane, additional imaging is needed. TEE may be considered but requires sedation and still may miss segments of the mid-ascending aorta. Magnetic resonance angiography or chest CT angiography provide accurate diameter measurements when aligned perpendicular to the long axis of the aorta. Advantages of magnetic resonance angiography and CT angiography compared with TTE include higher spatial (but lower temporal) resolution and the ability to display a 3D reconstruction of the entire length of the aorta. Magnetic resonance angiography and CT angiography aortic diameters typically are 1 mm to 2 mm larger than echocardiographic measurements because of inclusion of the aortic wall in the measurement and because echocardiographic measurements are made at end-diastole, whereas magnetic resonance angiography or CT angiography measurements may represent an average value. Magnetic resonance angiography imaging is preferred over CT angiography imaging, when possible, because of the absence of ionizing radiation exposure in patients who likely will have multiple imaging studies over their lifetime.
Supporting References: (261–263)
5.1.1.2 Diagnostic Testing—Routine Follow-Up: Recommendation
Class I1. Serial evaluation of the size and morphology of the aortic sinuses and ascending aorta by echocardiography, CMR, or CT angiography is recommended in patients with a bicuspid aortic valve and an aortic diameter greater than 4.0 cm, with the examination interval determined by the degree and rate of progression of aortic dilation and by family history. In patients with an aortic diameter greater than 4.5 cm, this evaluation should be performed annually. (Level of Evidence: C)
Patients with bicuspid aortic valves who have documented dilation of the sinuses of Valsalva or ascending aorta should have serial assessment of aortic morphology because the aortopathy may progress with time. In a series of 68 patients with bicuspid aortic valves, the mean rate of diameter progression was 0.5 mm per year at the sinuses of Valsalva (95% CI: 0.3 to 0.7), 0.5 mm per year at the sinotubular junction (95% CI: 0.3 to 0.7), and 0.9 mm per year at the proximal ascending aorta (95% CI: 0.6 to 1.2). Others have reported mean rates of increase of up to 2 mm per year. Aortic imaging at least annually is prudent in patients with a bicuspid aortic valve and significant aortic dilation (>4.5 cm), a rapid rate of change in aortic diameter, and in those with a family history of aortic dissection. In patients with milder dilation that shows no change on sequential studies and a negative family history, a longer interval between imaging studies is appropriate.
Supporting References: (264–266)
5.1.2 Medical Therapy
There are no proven drug therapies that have been shown to reduce the rate of progression of aortic dilation in patients with aortopathy associated with bicuspid aortic valve. In patients with hypertension, control of BP with any effective antihypertensive medication is warranted. Beta blockers and ARBs have conceptual advantages to reduce rate of progression but have not been shown to be beneficial in clinical studies.
5.1.3 Intervention: Recommendations
Class I1. Operative intervention to repair the aortic sinuses or replace the ascending aorta is indicated in patients with a bicuspid aortic valve if the diameter of the aortic sinuses or ascending aorta is greater than 5.5 cm (113,267,268). (Level of Evidence: B)
In 2 large long-term retrospective cohort studies of patients with bicuspid aortic valves, the incidence of aortic dissection was very low. In a study of 642 patients followed for a mean of 9 years, there were 5 dissections (3 ascending and 2 descending). In another bicuspid aortic valve study of 416 patients followed for a mean of 16 years, there were 2 dissections. In the latter report, the calculated incidence of dissection was higher than the age-adjusted relative risk of the county’s general population (HR: 8.4; 95% CI: 2.1 to 33.5; p=0.003) but was only 3.1 (95% CI: 0.5 to 9.5) cases per 10,000 patient-years. In patients with bicuspid aortic valves, data are limited regarding the degree of aortic dilation at which the risk of dissection is high enough to warrant operative intervention in patients who do not fulfill criteria for AVR on the basis of severe AS or AR. Previous ACC/AHA guidelines have recommended surgery when the degree of aortic dilation is >5.0 cm at any level, including sinuses of Valsalva, sinotubular junction, or ascending aorta. The current writing committee considers the evidence supporting these previous recommendations very limited and anecdotal and endorses a more individualized approach. Surgery is recommended with aortic dilation of 5.1 cm to 5.5 cm only if there is a family history of aortic dissection or rapid progression of dilation. In all other patients, operation is indicated if there is more severe dilation (5.5 cm). The writing committee also does not recommend the application of formulas to adjust the aortic diameter for body size. Furthermore, prior recommendations were frequently ambiguous with regard to the level to which they apply (sinus segment versus tubular ascending aorta) and did not acknowledge the normal difference in diameter at these levels, with the sinus segment 0.5 cm larger in diameter than the normal ascending aorta. In Heart Valve Centers of Excellence, valve-sparing replacement of the aortic sinuses and ascending aorta yields excellent results in patients who do not have severely deformed or dysfunctional valves.
Supporting References: (113,244,245,266–273)
Class IIa1. Operative intervention to repair the aortic sinuses or replace the ascending aorta is reasonable in patients with bicuspid aortic valves if the diameter of the aortic sinuses or ascending aorta is greater than 5.0 cm and a risk factor for dissection is present (family history of aortic dissection or if the rate of increase in diameter is ≥0.5 cm per year). (Level of Evidence: C)
In patients with bicuspid aortic valves, data are limited regarding the degree of aortic dilation at which the risk of dissection is high enough to warrant operative intervention in patients who do not fulfill criteria for AVR on the basis of severe AS or AR. In patients at higher risk of dissection based on family history or evidence of rapid progression of aortic dilation (≥0.5 cm per year), surgical intervention is reasonable when the aortic diameter is >5.0 cm.
Supporting References: (266,268–270,274)
Class IIa2. Replacement of the ascending aorta is reasonable in patients with a bicuspid aortic valve who are undergoing aortic valve surgery because of severe AS or AR (Sections 3.2.3 and 4.3.3) if the diameter of the ascending aorta is greater than 4.5 cm. (Level of Evidence: C)
In patients with bicuspid aortic valves, data are limited regarding the degree of aortic dilation at which the risk of dissection is high enough to warrant replacement of the ascending aorta at the time of AVR. The risk of progressive aortic dilation and dissection after AVR in patients with bicuspid aortic valves has been the subject of several studies, although definitive data are lacking. In patients undergoing AVR because of severe AS or AR, replacement of the ascending aorta is reasonable when the aortic diameter is >4.5 cm. Replacement of the sinuses of Valsalva is not necessary in all cases and should be individualized based on the displacement of the coronary ostia, because progressive dilation of the sinus segment after separate valve and graft repair is uncommon.
Supporting References: (266,268–270,275–279)
6 Mitral Stenosis
6.1 Stages of MS
Medical and interventional approaches to the management of patients with valvular MS depend on accurate diagnosis of the cause and stage of the disease process. Table 13 shows the stages of mitral valve disease ranging from patients at risk of MS (stage A) or with progressive hemodynamic obstruction (stage B) to severe asymptomatic (stage C) and symptomatic MS (stage D). Each of these stages is defined by valve anatomy, valve hemodynamics, the consequences of valve obstruction on the left atrium (LA) and pulmonary circulation, and patient symptoms. The anatomic features of the stages of MS are based on a rheumatic etiology for the disease. There are patients who have a nonrheumatic etiology of MS due to senile calcific disease (Section 6.3) in whom there is a heavily calcified mitral annulus with extension of the calcium into the leaflets. Hemodynamic severity is best characterized by the planimetered mitral valve area and the calculated mitral valve area from the diastolic pressure half-time. The definition of “severe” MS is based on the severity at which symptoms occur as well as the severity at which intervention will improve symptoms. Thus, a mitral valve area ≤1.5 cm2 is considered severe. This usually corresponds to a transmitral mean gradient of >5 mm Hg to 10 mm Hg at a normal heart rate. However, the mean pressure gradient is highly dependent on the transvalvular flow and diastolic filling period and will vary greatly with changes in heart rate. The diastolic pressure half-time is dependent not only on the degree of mitral obstruction but also the compliance of the left ventricle and the LA and other measures of mitral valve area, such as the continuity equation or the proximal isovelocity surface area, may be used if discrepancies exist.
Stages of MS
Supporting References: (280–286)
6.2 Rheumatic MS
See Figure 3 for indications for intervention for rheumatic MS.
Indications for Intervention for Rheumatic MS
AF indicates atrial fibrillation; LA, left atrial; MR, mitral regurgitation; MS, mitral stenosis; MVA, mitral valve area; MVR, mitral valve surgery (repair or replacement); NYHA, New York Heart Association; PCWP, pulmonary capillary wedge pressure; PMBC, percutaneous mitral balloon commissurotomy; and T ½, pressure half-time.
6.2.1 Diagnosis and Follow-Up
6.2.1.1 Diagnostic Testing—Initial Diagnosis: Recommendations
Class I1. TTE is indicated in patients with signs or symptoms of MS to establish the diagnosis, quantify hemodynamic severity (mean pressure gradient, mitral valve area, and pulmonary artery pressure), assess concomitant valvular lesions, and demonstrate valve morphology (to determine suitability for mitral commissurotomy) (8,287–295). (Level of Evidence: B)
Suspicion for MS may arise from a childhood history of rheumatic fever or a characteristic auscultatory finding of an opening snap after the second heart sound and subsequent apical diastolic murmur, but such patients often present with nonspecific complaints of exertional dyspnea with an unrevealing physical examination. In the vast majority of cases, TTE can elucidate the anatomy and functional significance of MS but must be undertaken with great care. Use of 2D scanning from the parasternal long-axis window can identify the characteristic diastolic doming of the mitral valve, whereas short-axis scanning will demonstrate commissural fusion and allow planimetry of the mitral orifice. This must be done carefully to obtain the smallest orifice in space and the largest opening in time. 3D echocardiography (either TTE or TEE) may allow greater accuracy but is not yet routinely used. Doppler hemodynamics are typically obtained from the apical 4–chamber or long-axis view and should include peak and mean transvalvular gradient as calculated by the simplified Bernoulli equation, averaged from 3 to 5 beats in sinus rhythm and 5 to 10 beats in AF. Heart rate should always be included in the report because it greatly affects transvalvular gradient due to the differential impact of tachycardia on diastolic versus systolic duration. Concomitant MR should be sought and quantified as recommended, along with other valve lesions (Section 7.3.1.1). RV systolic pressure is typically estimated by continuous wave Doppler of TR. Mitral valve morphology and feasibility for percutaneous mitral balloon commissurotomy or surgical commissurotomy can be assessed in several ways, most commonly via the Wilkins score, which combines valve thickening, mobility, and calcification with subvalvular scarring in a 16–point scale. Characterization of commissural calcification is also useful. Additional echocardiographic tools for assessment of MS include the mitral pressure half-time, which is inversely related to mitral valve area. However, the mitral pressure half-time is also affected by left atrial and LV compliance. Thus, other methods for calculation of the mitral valve area, such as the continuity method and proximal isovelocity surface area method, could be used if necessary. Left atrial dimension, area, and volume index should be measured, with careful interrogation for possible left atrial thrombus (although full exclusion of thrombus requires TEE). As with any echocardiogram, full characterization of global and regional LV and RV function should be reported.
Supporting References: (8,287–295)
Class I2. TEE should be performed in patients considered for percutaneous mitral balloon commissurotomy to assess the presence or absence of left atrial thrombus and to further evaluate the severity of MR (288,296–298). (Level of Evidence: B)
TEE offers excellent visualization of the mitral valve and LA and is an alternative approach to assessment of MS in patients with technically limited transthoracic interrogation. Three-dimensional datasets may be acquired, from which optimal measurements of minimal orifice area can be obtained offline. However, in the vast majority of patients with MS, valve morphology and lesion severity can be obtained with TTE. A key exception is in patients being considered for percutaneous mitral balloon commissurotomy, in whom left atrial cavity and appendage thrombi must be excluded. Although TTE may identify risk factors for thrombus formation, several studies show that TTE has poor sensitivity for detecting such thrombi, thus mandating a TEE before percutaneous mitral balloon commissurotomy. Although TTE is generally accurate in grading MR, TEE may offer additional quantitation and assurance that MR >2+ is not present, which generally precludes percutaneous mitral balloon commissurotomy.
Supporting References: (288,296–298)
6.2.1.2 Diagnostic Testing—Changing Signs or Symptoms
Patients with an established diagnosis of MS may experience a change in symptoms from progressive narrowing of the mitral valve, worsening of concomitant MR or other valve lesions, or a change in hemodynamic state due to such factors as AF, fever, anemia, hyperthyroidism, or postoperative state. In such cases, a TTE examination should be repeated to quantify the mitral valve gradient and area, as well as other parameters that may contribute to a change in symptoms.
6.2.1.3 Diagnostic Testing—Routine Follow-Up
Rheumatic MS is a slowly progressive disease, characterized by a prolonged latent phase between the initial rheumatic illness and the development of valve stenosis. The latent phase is an interval typically measured in decades in the developed world but considerably shorter periods in the developing world, likely due to recurrent carditis. Once mild stenosis has developed, further narrowing is typical, although the rate of progression is highly variable. In 103 patients with MS followed for 3.3±2 years, valve area decreased at 0.09 cm2 per year, although there was significant interpatient variability. Larger valves decreased in area more rapidly, although the same absolute decrease would be expected to have greater impact in the more stenotic valves. Importantly, progressive enlargement in the right ventricle and rise in RV systolic pressure were observed, even in the absence of a decrease in mitral valve area. Accordingly, repeat TTE at intervals dictated by valve area is an important aspect of disease management, even in patients without symptoms. TTE should be performed to re-evaluate asymptomatic patients with MS and stable clinical findings to assess pulmonary artery pressure and valve gradient (very severe MS with mitral valve area <1.0 cm2 every year, severe MS with mitral valve area ≤1.5 cm2 every 1 to 2 years; and progressive MS with mitral valve area >1.5 cm2 every 3 to 5 years) (Table 4).
Supporting References: (299–301)
6.2.1.4 Diagnostic Testing—Cardiac Catheterization
In the contemporary era, adequate assessment of MS and associated lesions can be obtained in the vast majority of patients by TTE, occasionally supplemented by TEE. However, in those few patients with nondiagnostic studies or whose clinical and echocardiographic findings conflict, it is essential to further characterize MS hemodynamics and catheterization as the next best approach. Catheterization is also the only method available to measure absolute pressures inside the heart, which may be important in clinical decision making. Such studies must be carried out by personnel experienced with catheterization laboratory hemodynamics with simultaneous pressure measurements in the left ventricle and LA, ideally via transseptal catheterization. Although a properly performed mean pulmonary artery wedge pressure is an acceptable substitute for mean LA pressure, the LV to pulmonary wedge gradient will overestimate the true transmitral gradient due to phase delay and delayed transmission of pressure changes. The Gorlin equation is applied for calculation of mitral valve area, using cardiac output obtained via thermodilution (when there is no significant TR) or the Fick method. Ideally, measured oxygen consumption should be used in this calculation. Full right-heart pressures should be reported. In cases where exertional symptoms seem out of proportion to resting hemodynamic severity, data may be obtained during exercise.
Supporting References: (302–304)
6.2.1.5 Diagnostic Testing—Exercise Testing: Recommendation
Class I1. Exercise testing with Doppler or invasive hemodynamic assessment is recommended to evaluate the response of the mean mitral gradient and pulmonary artery pressure in patients with MS when there is a discrepancy between resting Doppler echocardiographic findings and clinical symptoms or signs. (Level of Evidence: C)
Exercise testing with hemodynamics yields a number of data points to help in the management of MS when a patient’s symptoms seem significantly greater or less than would be expected from TTE. Results have been published using both exercise and dobutamine with Doppler echocardiography, although exercise is preferred in general as the more physiological test. Most experience is with treadmill exercise, with images and Doppler obtained immediately after stress, but bicycle exercise allows data acquisition at various stages of exercise. Bicycle or arm ergometry exercise testing during cardiac catheterization can also be performed for direct measurements of pulmonary artery wedge pressure and pulmonary pressures at rest and with exercise. Simple functional capacity is important to help quantify the patient’s symptoms and assess changes over time. Changes in valve gradient are also helpful, as is the presence of exercise-induced pulmonary hypertension. Although exercise-induced pulmonary hypertension does not have a formal place in these guidelines, a rise in RV systolic pressure to >60 mm Hg to 70 mm Hg should prompt the clinician to carefully consider the patient’s symptoms. Most patients can continue to be followed without exercise testing by careful clinical assessment and periodic resting echocardiograms as indicated above.
Supporting References: (305–308)
6.2.2 Medical Therapy: Recommendations
Class I1. Anticoagulation (vitamin K antagonist [VKA] or heparin) is indicated in patients with 1) MS and AF (paroxysmal, persistent, or permanent), 2) MS and a prior embolic event, or 3) MS and a left atrial thrombus (309–315). (Level of Evidence: B)
In the presurgical era, patients with MS were at high risk for arterial embolization, which was further elevated in those with AF and prior embolic events. Anticoagulation with VKA has long been recommended for patients with MS with AF or prior embolism and has been so well accepted that patients with MS have generally been excluded from AF trials examining the utility of anticoagulation. One exception to trials excluding patients with MS is the NASPEAF (National Study for Prevention of Embolism in Atrial Fibrillation) trial. Of the 495 high-risk patients in the cohort, 316 patients had MS. Of these 316 patients, 95 had a prior embolization. Patients in the study were randomized to standard anticoagulation with VKA (international normalized ratio [INR] goal 2 to 3) versus the combination of an antiplatelet agent and VKA anticoagulation with a lower INR goal (0.10 to 2.5). The study demonstrated a highly significant increased risk for embolism among those patients with VHD with prior events versus those without (9.1% versus 2.3% over 3 years; p<0.001). Further larger studies are required to determine if antiplatelet agents should be used in patients with AF and MS. Although no trial evidence exists for anticoagulation when LA or left atrial appendage thrombi are incidentally found (generally by TEE), it is well documented that even in sinus rhythm, such clots are predisposed to embolize, and so anticoagulation with VKA is recommended. Anticoagulation should be given indefinitely to patients with these indications. It is controversial as to whether long-term anticoagulation should be given to patients with MS in normal sinus rhythm on the basis of left atrial enlargement or spontaneous contrast on TEE. The efficacy of the novel oral anticoagulant agents in preventing embolic events has not been studied in patients with MS.
Supporting References: (309–315)
Class IIa1. Heart rate control can be beneficial in patients with MS and AF and fast ventricular response. (Level of Evidence: C)
Patients with MS are prone to developing atrial arrhythmias. Thirty percent to 40% of patients with severe MS will develop AF. Significant detrimental hemodynamic consequences may be associated with the acute development of AF, primarily from the rapid ventricular response, which shortens the diastolic filling period and increases left atrial pressure. The treatment of acute AF is anticoagulation and control of the heart rate response with negative dromotropic agents. If the rate cannot be adequately controlled with medications, cardioversion may be necessary to improve hemodynamics. In the stable patient, the decision for rate control versus rhythm control is dependent on multiple factors, including the duration of AF, hemodynamic response to AF, left atrial size, prior episodes of AF, and a history of embolic events. It is more difficult to achieve rhythm control in patients with MS because the rheumatic process itself may lead to fibrosis of the intermodal and interatrial tracts and damage to the sinoatrial node.
Supporting Reference: (316)
Class IIb1. Heart rate control may be considered for patients with MS in normal sinus rhythm and symptoms associated with exercise (317,318). (Level of Evidence: B)
It is well known that the proportion of the cardiac cycle occupied by diastole decreases with increasing heart rate, thereby increasing the mean flow rate across the mitral valve (assuming constant cardiac output) with a consequent rise in mean mitral gradient in MS in proportion to the square of the flow rate. A study of normal volunteers undergoing bicycle exercise echocardiography demonstrated a reduction in the diastolic interval from 604 milliseconds to 219 milliseconds as the heart rate increased from 60 beats per minute to 120 beats per minute indicating a 63% reduction in total diastolic time. Maintaining the same cardiac output would require a 38% increase in mean flow rate during diastole, which, by squared relation of the Bernoulli equation, requires an increase in mean mitral gradient of approximately 90%. Thus, it is rational to think that limiting tachycardia with beta blockade might be beneficial in patients with MS in normal sinus rhythm. Nevertheless, the only RCT on the impact of beta blockade on exercise duration in MS failed to show this salutary effect. One study looked at 15 patients with an average mitral area of 1.0 cm2 (NYHA class II and III) randomized in crossover fashion to atenolol or placebo. Although the exercise heart rate was significantly reduced and diastolic filling interval increased by 40%, there was no increase in functional capacity, and maximal O2 consumption actually fell by 11%, with cardiac index falling by 20% when patients were treated with beta blockade. One study had more neutral results in a trial of 17 patients with NYHA class I and II MS, and 7 patients had improvement in maximal oxygen consumption, whereas 4 had a deterioration in symptoms. Overall, anaerobic threshold was reduced by 11% with atenolol therapy, so these studies do not support the general use of heart rate control in patients with MS and normal sinus rhythm. Nevertheless, in selected patients whose symptoms worsen markedly with exercise, a trial of beta blockade might be considered. Other negative chronotropic agents have not been evaluated in patients with MS.
Supporting References: (317,318)
6.2.3 Intervention: Recommendations
See Table 14 for a summary of recommendations from this section.
Class I1. Percutaneous mitral balloon commissurotomy is recommended for symptomatic patients with severe MS (mitral valve area ≤1.5 cm2, stage D) and favorable valve morphology in the absence of left atrial thrombus or moderate-to-severe MR (280–284,286,328). (Level of Evidence: A)
Summary of Recommendations for MS Intervention
Several RCTs have established the safety and efficacy of percutaneous balloon mitral commissurotomy compared with surgical closed or open commissurotomy. The technique is generally performed by advancing ≥1 balloon catheters across the mitral valve and inflating them, thereby splitting the commissures. For the percutaneous approach to have optimal outcome, it is essential that the valve morphology be predictive of success, generally being mobile, relatively thin, and free of calcium. This is usually assessed by the Wilkins score, although other risk scores have also shown utility. Clinical factors such as age, NYHA class, and presence or absence of AF are also predictive of outcome. Percutaneous mitral balloon commissurotomy should be performed by experienced operators with immediate availability of surgical backup for potential complications. Percutaneous mitral balloon commissurotomy is also useful in patients with restenosis following prior commissurotomy if restenosis is the consequence of refusion of both commissures.
Supporting References: (280–284,286,292,294,325,328–331)
See Online Data Supplement 13 for a summary of RCTs that have established the safety and efficacy of percutaneous mitral balloon commissurotomy in comparison to surgical closed or open commissurotomy.
Class I2. Mitral valve surgery (repair, commissurotomy, or valve replacement) is indicated in severely symptomatic patients (NYHA class III to IV) with severe MS (mitral valve area ≤1.5 cm2, stage D) who are not high risk for surgery and who are not candidates for or who have failed previous percutaneous mitral balloon commissurotomy (319–324). (Level of Evidence: B)
Mitral valve surgery is an established therapy for MS, predating percutaneous mitral balloon commissurotomy. Surgical options may involve commissurotomy (either closed, where the valve is opened blindly through the LA or left ventricle, or open, which allows more extensive surgery under direct visualization). MVR may be preferred in the presence of severe valvular thickening and subvalvular fibrosis with leaflet tethering. In addition to those who have suboptimal valve anatomy (or failed percutaneous mitral balloon commissurotomy), patients with moderate or severe TR may also have a better outcome with a surgical approach that includes tricuspid valve repair. Because the natural history of MS is one of slow progression over decades and MS does not have long-standing detrimental effects on the left ventricle, surgery should be delayed until the patient has severe limiting symptoms (NYHA class III to IV).
Supporting References: (283,319–324,332–334)
Class I3. Concomitant mitral valve surgery is indicated for patients with severe MS (mitral valve area ≤1.5 cm2, stage C or D) undergoing cardiac surgery for other indications. (Level of Evidence: C)
Studies of the natural history of moderate-to-severe MS demonstrate progressive decrement in valve area of 0.09 cm2 per year. For patients with other indications for open heart surgery, mitral intervention should be undertaken, particularly in those patients with valves amenable to open commissurotomy or valve repair.
Supporting Reference: (300)
Class IIa1. Percutaneous mitral balloon commissurotomy is reasonable for asymptomatic patients with very severe MS (mitral valve area ≤1.0 cm2, stage C) and favorable valve morphology in the absence of left atrial thrombus or moderate-to-severe MR (293,325–327). (Level of Evidence: C)
Although it is a general rule in VHD not to intervene before the onset of symptoms, there are patients who will clearly benefit from intervention while still ostensibly asymptomatic. Most patients with mitral valve area ≤1.0 cm2 will manifest a true reduction in functional capacity even if the gradual onset is not obvious. In addition, numerous studies have demonstrated a greater likelihood of successful percutaneous mitral balloon commissurotomy when the valve is less thickened and calcified, indicating intervention before this state. Furthermore, it is preferable to intervene before the development of severe pulmonary hypertension, because those patients with near systemic pulmonary pressure show reduced RV function and persistent pulmonary hypertension following percutaneous mitral balloon commissurotomy or MVR.
Supporting References: (293,325–327)
Class IIa2. Mitral valve surgery is reasonable for severely symptomatic patients (NYHA class III to IV) with severe MS (mitral valve area ≤1.5 cm2, stage D), provided there are other operative indications (e.g., aortic valve disease, CAD, TR, aortic aneurysm). (Level of Evidence: C)
A situation may arise in which a patient who is otherwise a candidate for percutaneous mitral balloon commissurotomy (favorable valve anatomy, no atrial thrombus or significant MR) has other cardiac conditions that should be addressed surgically. These patients should undergo a comprehensive operation to address all lesions, including MS. However, as percutaneous intervention has evolved, particularly that involving the coronary arteries and aortic valve, there will be circumstances in which an all-percutaneous approach will be favored. This decision should take into account the local expertise at the treating facility.
Class IIb1. Percutaneous mitral balloon commissurotomy may be considered for asymptomatic patients with severe MS (mitral valve area ≤1.5 cm2, stage C) and valve morphology favorable for percutaneous mitral balloon commissurotomy in the absence of left atrial thrombus or moderate-to-severe MR who have new onset of AF. (Level of Evidence: C)
Patients with mild and asymptomatic MS may develop AF as an isolated event that can be managed without mitral valve intervention for many years. However, in many patients, the onset of AF may be a harbinger of a more symptomatic phase of the disease. Percutaneous mitral balloon commissurotomy may be considered in such cases, particularly if rate control is difficult to achieve or if the mitral valve area is ≤1.5 cm2. Lowering the left atrial pressure by percutaneous mitral balloon commissurotomy may be useful if a rhythm control approach is taken for AF.
Class IIb2. Percutaneous mitral balloon commissurotomy may be considered for symptomatic patients with mitral valve area greater than 1.5 cm2 if there is evidence of hemodynamically significant MS based on pulmonary artery wedge pressure greater than 25 mm Hg or mean mitral valve gradient greater than 15 mm Hg during exercise. (Level of Evidence: C)
It is recognized that there are patients with genuine symptoms from MS, even with mitral valve area between 1.6 cm2 and 2.0 cm2, who would benefit from percutaneous mitral balloon commissurotomy. This may occur for several reasons. First, given the vagaries of clinical imaging, it is possible that the valve is actually smaller than the reported area. Second, for a given valve area, the transmitral gradient will be higher in persons with a large body surface area or those with other reasons to have an elevated cardiac output (e.g., arteriovenous fistulae). Third, there is a variable relation of pulmonary vascular resistance in comparison to mitral valve area. Thus, patients may experience clinical improvement in such cases. This procedure may be performed for these indications in patients with valve morphology suitable for percutaneous mitral balloon commissurotomy.
Supporting Reference: (335)
Class IIb3. Percutaneous mitral balloon commissurotomy may be considered for severely symptomatic patients (NYHA class III to IV) with severe MS (mitral valve area ≤1.5 cm2, stage D) who have a suboptimal valve anatomy and who are not candidates for surgery or at high risk for surgery. (Level of Evidence: C)
Both the Wilkins score and the presence of commissural calcification predict successful percutaneous mitral balloon commissurotomy. However in all such series, this predictive ability is not absolute, with 42% of patients with a Wilkins score >8 having an optimal outcome (25% increase in mitral valve area to >1.5 cm2) and 38% of patients with commissural calcium having event-free survival at 1.8 years. Accordingly, severely symptomatic patients who are poor surgical candidates may benefit from percutaneous mitral balloon commissurotomy even with suboptimal valve anatomy. Patients who refuse surgery may also be considered for percutaneous mitral balloon commissurotomy after discussion about the potential complications associated with this procedure when performed in patients with suboptimal valve anatomy.
Supporting References: (292–294)
Class IIb4. Concomitant mitral valve surgery may be considered for patients with moderate MS (mitral valve area 1.6 cm2 to 2.0 cm2) undergoing cardiac surgery for other indications. (Level of Evidence: C)
Consideration of concomitant MVR at the time of other heart surgery must balance several factors, including the severity of MS (based on mitral valve area, mean pressure gradient, and pulmonary arterial pressure); rate of progression; history of AF; skill of the surgeon; and perceived risk of repeat cardiac surgery if the MS progresses to a symptomatic state. Consideration should also include the suitability of the valve for subsequent percutaneous mitral balloon commissurotomy (echocardiogram score and presence of MR), as this might be a preferable method for treating worsening MS.
Class IIb5. Mitral valve surgery and excision of the left atrial appendage may be considered for patients with severe MS (mitral valve area ≤1.5 cm2, stages C and D) who have had recurrent embolic events while receiving adequate anticoagulation. (Level of Evidence: C)
A large prospective study of patients with MS shows an elevated risk of recurrent embolism among patients with prior embolic events irrespective of the presence or absence of AF. The risk is reduced, but not eliminated, by percutaneous mitral balloon commissurotomy. Another study of 205 patients who underwent mitral valve surgery, 58 with ligation of the left atrial appendage, demonstrated that lack of ligation was significantly associated with future embolic events (odds ratio [OR]: 6.7). This study also noted that in 6 of the 58 ligation patients, communication of the left atrial appendage and LA cavity was still present. Residual communication between the left atrial appendage and LA cavity was noted in 60% of patients undergoing left atrial appendage ligation in a subsequent study, suggesting that left atrial appendage excision and not ligation may be the preferred approach in selected patients.
Supporting References: (336,337)
See Online Data Supplements 14 and 15 for more information on the outcomes of percutaneous mitral balloon commissurotomy.
6.3 Nonrheumatic MS
Although the vast majority of MS in the world results from rheumatic heart disease, senile calcific MS is found with increasing frequency in the elderly population in North America. This is due to calcification of the mitral annulus and calcification that extends into the leaflets, which cause both a narrowing of the annulus and rigidity of the leaflets without commissural fusion. Mitral annular calcification has been associated with decreased renal function and inflammatory markers like C-reactive protein; however, senile calcific MS is common in the elderly population with normal renal function and is associated with senile AS. Data are relatively sparse on the natural history of senile calcific MS. A small study of 32 patients observed over a mean of 2.6 years demonstrated progression in mean mitral valve gradient in only half of the subjects. However, in those with progression, the rate of change averaged 2 mm Hg per year and changed as rapidly as 9 mm Hg per year. More rapid progression was found in younger patients, but surprisingly this was not predicted by a reduced glomerular filtration rate. Although the mean pressure gradient from Doppler echocardiography is accurate, the use of a mitral valve area from diastolic half-time is uncertain in this population. Indications for intervention in patients with senile calcific MS are different from those for rheumatic MS for the following reasons. First, because calcification involves the annulus and base of the leaflets without commissural fusion, there is no role for percutaneous mitral balloon or surgical commissurotomy. Second, the presence of severe mitral annular calcification can be quite challenging for the surgeon because it causes problems in securely attaching the prosthetic valve and narrowing of the orifice. Supra-annular insertion and other innovative techniques can be used, such as placement of a felt patch around the valve orifice to anchor the prosthesis; however, this only works if the mitral orifice is adequate. If the annular calcification narrows the orifice, it has to be debrided. The other alternative is left atrial to ventricular bypass with a valved conduit in extreme cases of calcification both of the leaflet and the annulus. Finally, patients with calcification are often elderly and debilitated, have multiple comorbidities, and are at high risk for surgery. For these reasons, intervention should be delayed until symptoms are severely limiting and cannot be managed with diuresis and heart rate control.
A subset of patients have mitral inflow obstruction due to other causes, such as congenital malformations, tumors, or other masses. Congenital MS usually takes the form of a parachute mitral valve, where the mitral chordae are attached to a single or dominant papillary muscle and often form a component of the Shone complex, which can include supramitral rings, valvular or subvalvular AS, and aortic coarctation. For MS caused by tumors or other obstructive lesions, intervention is aimed at reducing or removing the mass, with efforts made to preserve the valve.
Supporting References: (338–352)
7 Mitral Regurgitation
7.1 Acute MR
Acute MR may be due to disruption of different parts of the mitral valve apparatus. IE may cause leaflet perforation or chordal rupture. Spontaneous chordal rupture may occur in patients with degenerative mitral valve disease. Rupture of the papillary muscle occurs in patients who have an acute ST-segment elevation MI usually associated with an inferior infarction. The acute volume overload on the left ventricle and LA results in pulmonary congestion and low forward cardiac output. Diagnosis of the presence and etiology of acute MR and urgent intervention may be lifesaving.
7.1.1 Diagnosis and Follow-Up
TTE is useful in patients with severe acute primary MR for evaluation of LV function, RV function, pulmonary artery pressure, and mechanism of MR. The patient with severe acute MR, which might occur from chordal rupture, usually experiences acute decompensation with hemodynamic embarrassment. The sudden volume overload increases left atrial and pulmonary venous pressure, leading to pulmonary congestion and hypoxia, whereas decreased blood delivery to the aorta causes reduced cardiac output, hypotension, or even shock. The rapid systolic rise in LA pressure with a concomitant fall in LV systolic pressure limits the pressure gradient driving MR to early systole. Thus, the murmur may be short and unimpressive. Some patients with severe torrential MR have no murmur due to equalization of the LV and left atrial pressures. TTE can usually clarify the diagnosis by demonstrating the presence of severe MR, the mechanism causing MR, and a hyperdynamic instead of a depressed left ventricle as would be present in many other causes of hemodynamic compromise. Likely mechanisms of acute MR detected by TTE include valve disruption or perforation from IE, chordal rupture, and/or papillary muscle rupture. If the diagnosis of IE as the cause of acute MR is made, therapy that includes antibiotic administration and early surgery must be considered.
It may be difficult to diagnose severe acute MR with TTE due to narrow eccentric jets of MR, tachycardia, and early equalization of LV and LA pressures. In cases where TTE is nondiagnostic but the suspicion of severe acute MR persists, enhanced mitral valve imaging with TEE usually clarifies the diagnosis. TEE can be especially helpful in detecting valvular vegetations and annular abscesses that may further accentuate the need for a more urgent surgical approach. In the presence of sudden acute and hemodynamic instability after MI with hyperdynamic LV function by TTE and no other cause for the deterioration, TEE should be performed as soon as possible, looking for severe MR due either to a papillary muscle or chordal rupture.
7.1.2 Medical Therapy
Vasodilator therapy can be useful to improve hemodynamic compensation in acute MR. The premise of use of vasodilators in acute MR is reduction of impedance of aortic flow, thereby preferentially guiding flow away from the left ventricle to the left atrial regurgitant pathway, decreasing MR while simultaneously increasing forward output. This is usually accomplished by infusion of an easily titratable agent such as sodium nitroprusside or nicardipine. Use of vasodilators is often limited by systemic hypotension that is exacerbated when peripheral resistance is decreased.
Intra-aortic balloon counterpulsation can be helpful to treat acute severe MR. By lowering systolic aortic pressure, intra-aortic balloon counterpulsation decreases LV afterload, increasing forward output while decreasing regurgitant volume. Simultaneously, intra-aortic balloon counterpulsation increases diastolic and mean aortic pressure, thereby supporting the systemic circulation. In almost every case, intra-aortic balloon counterpulsation is a temporizing measure for achieving hemodynamic stability until definitive mitral surgery can be performed. The use of a percutaneous circulatory assist device may also be effective to stabilize a patient with acute hemodynamic compromise before operation.
Supporting References: (353,354)
7.1.3 Intervention
Prompt mitral valve surgery is recommended for treatment of the symptomatic patient with acute severe primary MR. The severity of acute primary MR is variable, and some patients with more moderate amounts of MR may develop compensation as LV dilation allows for lower filling pressure and increased forward cardiac output. However, most patients with acute severe MR will require surgical correction for re-establishment of normal hemodynamics and for relief of symptoms. This is especially true for a complete papillary muscle rupture that causes torrential MR, which is poorly tolerated. Even if there is a partial papillary muscle rupture with hemodynamic stability, urgent surgery is indicated because this can suddenly progress to complete papillary muscle rupture. In cases of ruptured chordae tendineae, mitral repair is usually feasible and preferred over MVR, and the timing of surgery can be determined by the patient’s hemodynamic status. If IE is the cause of severe symptomatic MR, earlier surgery is generally preferred because of better outcomes over medical therapy. However, this strategy should also be tempered by the patient’s overall condition.
Supporting Reference: (355)
7.2 Stages of Chronic MR
In assessing the patient with chronic MR, it is critical to distinguish between chronic primary (degenerative) MR and chronic secondary (functional) MR, as these 2 conditions have more differences than similarities.
In chronic primary MR, the pathology of ≥1 of the components of the valve (leaflets, chordae tendineae, papillary muscles, annulus) causes valve incompetence with systolic regurgitation of blood from the left ventricle to the LA (Table 15). The most common cause of chronic primary MR in developed countries is mitral valve prolapse, which has a wide spectrum of etiology and presentation. Younger populations present with severe myxomatous degeneration with gross redundancy of both anterior and posterior leaflets and the chordal apparatus (Barlow’s valve). Alternatively, older populations present with fibroelastic deficiency disease, in which lack of connective tissue leads to chordal rupture. The differentiation between these 2 etiologies has important implications for operative intervention. Other less common causes of chronic primary MR include IE, connective tissue disorders, rheumatic heart disease, cleft mitral valve, and radiation heart disease. If the subsequent volume overload of chronic primary MR is prolonged and severe, it causes myocardial damage, HF, and eventual death. Correction of the MR is curative. Thus, MR is “the disease.”
Stages of Primary MR
In chronic secondary MR, the mitral valve is usually normal (Table 16). Instead, severe LV dysfunction is caused either by CAD, related MI (ischemic chronic secondary MR), or idiopathic myocardial disease (nonischemic chronic secondary MR). The abnormal and dilated left ventricle causes papillary muscle displacement, which in turn results in leaflet tethering with associated annular dilation that prevents coaptation. Because MR is only 1 component of the disease (severe LV dysfunction, coronary disease, or idiopathic myocardial disease are the others), restoration of mitral valve competence is not by itself curative; thus, the best therapy for chronic secondary MR is much less clear than it is for chronic primary MR. The data are limited, and there is greater difficulty in defining the severity of MR in patients with secondary MR than in those with primary MR. In patients with secondary MR, adverse outcomes are associated with a smaller calculated effective regurgitant orifice compared to primary MR due to multiple reasons. The MR will likely progress because of the associated progressive LV systolic dysfunction and adverse remodeling. In addition, there is an underestimation of effective regurgitant orifice area by the 2D echocardiography−derived flow convergence method due to the crescentic shape of the regurgitant orifice. There are the additional clinical effects of a smaller amount of regurgitation in the presence of compromised LV systolic function and baseline elevated filling pressures.
Stages of Secondary MR
7.3 Chronic Primary MR
7.3.1 Diagnosis and Follow-Up
7.3.1.1 Diagnostic Testing—Initial Diagnosis: Recommendations
Class I1. TTE is indicated for baseline evaluation of LV size and function, RV function and left atrial size, pulmonary artery pressure, and mechanism and severity of primary MR (stages A to D) in any patient suspected of having chronic primary MR (5,21,39,356–371). (Level of Evidence: B)
Images provided by TTE generate most of the diagnostic data needed for clinical decision making in chronic primary MR. The outcome of the patient with chronic primary MR is determined by lesion severity and the presence or absence of negative prognostic features that include the presence of symptoms, onset of LV dysfunction, and presence of pulmonary hypertension; usually only severe MR leads to these negative sequelae. Favorable loading conditions in MR (increased preload and usually normal afterload) increase ejection phase indexes of LV function, such as LVEF, but do not affect the extent of shortening. Thus, a “normal” LVEF in MR is approximately 70%. In turn, the onset of LV dysfunction is inferred when LVEF declines toward 60% or when the left ventricle is unable to contract to <40 mm diameter at end systole. It is clear that properly obtained and validated chamber volumes give more information about detrimental cardiac remodeling than simple chamber dimensions, as suggested by angiographically obtained volume data. These techniques have been replaced by newer noninvasive imaging techniques, which initially used chamber dimensions for measurement of LV size and function. Until more prognostic volumetric data are available, most current prognostic data rely on chamber dimensions. Pulmonary artery systolic pressure approaching 50 mm Hg also worsens prognosis. Thus, when the murmur of MR is first discovered, the clinician needs to know the severity of the MR (Table 15) and the size and function of the left ventricle, pulmonary artery pressure, and valve pathoanatomy from which valve reparability can be predicted. Determination of the severity of MR should be made on the basis of measurements of effective orifice area, regurgitant volume, and regurgitant fraction using the proximal isovelocity surface area or quantitative Doppler flow measurements. However, there are limitations to this technique, and multiple Doppler parameters, including color jet area, vena contracta, continuous wave Doppler intensity, and transmitral jet velocity curve should be used to correlate with the quantitative measurements. Once 1 of the above “triggers” is reached, indicating severe MR and LV dysfunction, the patient should be considered for mitral valve surgery. TTE serves to give this information in most cases and also generates baseline data that can be used to compare the patient’s progress on subsequent examinations. Three-dimensional echocardiography, strain imaging, or CMR may add more accurate assessment of the LV response in the future. Symptom presence is a key determinant of outcome, yet symptom status is highly subjective. Studies have demonstrated a correlation between B-type natriuretic peptide and outcome in MR. Although the data are preliminary, the finding of a rising B-type natriuretic peptide could be helpful as another factor in deciding the optimal timing of mitral surgery.
Supporting References: (5,21,39,356–371)
Class I2. CMR is indicated in patients with chronic primary MR to assess LV and RV volumes, function, or MR severity and when these issues are not satisfactorily addressed by TTE (366,372,373). (Level of Evidence: B)
In most cases, TTE provides the data needed for adequate evaluation of the MR patient. However, in cases where TTE image quality is poor, CMR may be of value in MR evaluation. CMR produces highly accurate data on LV volumes, RV volumes, and LVEF, and an estimation of MR severity, but outcome data using CMR volumes is pending. CMR is less helpful in establishing mitral pathoanatomy.
Supporting References: (366,372,373)
Class I3. Intraoperative TEE is indicated to establish the anatomic basis for chronic primary MR (stages C and D) and to guide repair (374,375). (Level of Evidence: B)
Intraoperative TEE is a standard imaging modality for the surgical therapy of MR. Before the operative incision, TEE may give the surgeon a better understanding of the valve anatomy and type of repair that will likely be performed, although this decision is ultimately made when the valve is inspected visually. Three-dimensional TEE may be helpful in further visualizing the abnormal mitral valve anatomy. Because anesthesia lessens afterload, preload, and mitral valve closing force, it is important that decisions about severity of MR not be re-evaluated under these artificial conditions, in which MR severity could be underestimated.
Intraoperative TEE is especially helpful in gauging the adequacy of repair. Because even mild residual MR after repair increases the likelihood of later repair failure necessitating reoperation, surgeons strive for near-perfect operative repair. If MR is detected in the operating room following repair, it is often an indication that the repair should be revised. This assessment should be made during conditions that approach those of normal physiology. The left ventricle should be well filled and systemic BP should be brought well into the normal range. A low preload with underfilling of the left ventricle can lead to 1) systolic anterior leaflet motion with outflow obstruction or 2) underestimation of degree of residual MR. Thus, information obtained by TEE when the ventricle is underfilled can lead to an unneeded revision in the former case while overlooking a needed revision in the latter. Intraoperative TEE is also useful for diagnosing mitral inflow obstruction or LV outflow obstruction as a result of the mitral valve repair.
Supporting References: (374,375)
Class I4. TEE is indicated for evaluation of patients with chronic primary MR (stages B to D) in whom noninvasive imaging provides nondiagnostic information about severity of MR, mechanism of MR, and/or status of LV function. (Level of Evidence: C)
TEE is not recommended for routine evaluation and follow-up of patients with chronic primary MR but is indicated in specific situations. Because TEE provides excellent imaging of the mitral valve, it should be performed when TTE images are inadequate. TEE is especially useful in cases of MR due to IE, where additional information about other potentially infected structures can be fully evaluated by that technique. TEE allows more precise quantitation of regurgitant severity and provides a better estimate of the likelihood of a successful surgical valve repair. Three-dimensional TEE may be helpful in further visualizing the abnormal mitral valve anatomy. Mitral valve repair is preferable to valve replacement because of lower operative mortality and avoidance of the complications inherent to prosthetic valves that accrue over time. Thus, if repair can be accomplished, it might be performed earlier in the course of disease. Alternatively, if replacement is likely, strategy shifts toward performing surgery later to avoid unwanted exposure time to prosthetic-related complications.
7.3.1.2 Diagnostic Testing—Changing Signs or Symptoms
TTE is indicated in patients with primary MR (stages B to D) to evaluate the mitral valve apparatus and LV function after a change in signs or symptoms. The onset of symptoms (dyspnea on exertion, orthopnea, or declining exercise tolerance) is by itself a negative prognostic event even if LV function is preserved. Symptoms are the culmination of the pathophysiology of MR and may indicate changes in LV diastolic function, left atrial compliance, LV filling pressure and/or increases in pulmonary artery pressure, and decreases in RV function or the coexistence of TR. Therefore, symptoms add pathophysiological data not readily available from imaging. Further, there is no evidence that treatment with diuretics or other therapies that might relieve symptoms changes the prognostic effect of symptom onset. Once symptoms have occurred, the patient should be considered for mitral valve operation even if medication has led to improvement. Repeat TTE at the time of symptom onset is indicated to confirm that symptoms are likely due to MR or its effect on the left ventricle, which in turn supports surgical correction. The new onset of AF is also an indication for repeat TTE to look for changes in severity of MR and the status of the left ventricle.
Supporting References: (365,376)
7.3.1.3 Diagnostic Testing—Routine Follow-Up
TTE should be performed on an annual or semiannual basis for surveillance of LV function (estimated by LVEF and end-systolic dimension) and pulmonary artery pressure in asymptomatic patients with severe primary MR (stage C1). Chronic severe MR is tolerated poorly, reaching a trigger for surgery at an average rate of about 8% per year. Because this progression varies from patient to patient and because prognosis worsens if correction of MR is delayed beyond the onset of these triggers, either referral to a Heart Valve Center of Excellence for early repair or very careful surveillance is mandatory. If a watchful waiting approach is pursued, periodic TTE is critical to examine the patient for changes in LV function and pulmonary pressure in determining the proper timing of surgery. For patients approaching the above benchmarks, semiannual TTE is recommended. It should be noted that echocardiographic measurements are variable, and management decisions that rest on these measurements should be confirmed by repeat TTE if the patient is approaching or has reached the important triggers for surgery noted above.
In patients with chronic primary MR that is less than severe (stages A and B), TTE is indicated periodically to evaluate for changes in MR severity. MR is a progressive disease. The LV volume overload induced by chronic primary MR causes eccentric cardiac remodeling with progressively increasing chamber volume, tending to reduce valve leaflet coaptation. Advancing valve pathology leads to further worsening of MR. This process may develop slowly without dramatic changes in symptoms or physical examination. Thus, MR could become severe and even lead to LV dysfunction without the patient or clinician being aware of it. Accordingly, periodic repeat TTE to examine for changes in severity of MR and LV size and function when baseline disease is less than severe is advisable. For mild MR, follow-up every 3 to 5 years is adequate unless the results of the physical examination or symptoms change. For moderate MR, follow-up every 1 to 2 years is recommended, again unless clinical status suggests a worsening in severity (Table 4).
Supporting Reference: (39)
7.3.1.4 Diagnostic Testing—Cardiac Catheterization
Left ventriculography and/or hemodynamic measurements are indicated when clinical assessment and/or noninvasive tests are inconclusive or discordant regarding 1) severity of MR, 2) LV function, or 3) the need for surgery. Imaging with these techniques is adequate for evaluation of MR in the majority of cases. However, invasive hemodynamic evaluation may be necessary in some cases, especially when there is a clinical discrepancy between symptomatic status and noninvasive testing. Elevated filling pressures support a cardiac cause for dyspnea and/or may indicate severely abnormal pathophysiology even when the patient claims to be asymptomatic. Conversely, a normal invasive hemodynamic examination in a symptomatic patient with what appears to be less than severe MR suggests a noncardiac cause for the symptoms. Hemodynamic evaluation can be especially helpful in patients with concomitant lung disease. Normal left atrial (or wedge) pressure and a large transpulmonary gradient suggest pulmonary hypertension due to lung disease rather than mitral valve disease. Patients usually complain of dyspnea with exertion, yet noninvasive evaluation is usually made at rest. Hemodynamic measurement made during either handgrip or dynamic exercise may be very revealing. Increased load with exercise may bring out severely disordered hemodynamics explaining the patient’s exercise-related symptoms. Left ventriculography may also be of diagnostic benefit. Whereas echo-Doppler interrogation of the mitral valve measures flow velocity, ventriculography uses the density of contrast to determine the amount of blood flow from the left ventricle to LA. Although only semiquantitative, a carefully performed ventriculogram can add significantly to the diagnostic data pool.
Supporting Reference: (42)
7.3.1.5 Diagnostic Testing—Exercise Testing: Recommendations
Class IIa1. Exercise hemodynamics with either Doppler echocardiography or cardiac catheterization is reasonable in symptomatic patients with chronic primary MR where there is a discrepancy between symptoms and the severity of MR at rest (stages B and C) (377,378). (Level of Evidence: B)
The symptoms of chronic primary MR usually occur during exercise. Thus, evaluation during exercise may be very informative when resting TTE and symptomatic status are discordant or when the magnitude of LV and LA enlargement seem out of proportion to the severity of resting MR. In such cases, severity of MR and/or pulmonary artery pressure may increase during exercise, both helping to explain exercise-induced symptoms and indicating that mitral surgery may be in order. The change in pulmonary artery wedge pressure and LV diastolic pressure during exercise can be obtained during cardiac catheterization, which may further aid in determining the etiology of symptoms.
Supporting References: (42,377,378)
Class IIa2. Exercise treadmill testing can be useful in patients with chronic primary MR to establish symptom status and exercise tolerance (stages B and C). (Level of Evidence: C)
The onset of symptoms represents a key development in severe MR. However, some patients may not recognize their symptoms, may deny them, or may alter their lifestyle to remain asymptomatic. A formal treadmill exercise test can establish true exercise tolerance and can also form the baseline for future symptom assessment. Additional information about a cardiac or noncardiac limitation can be obtained using oxygen consumption measurements during exercise. Exercise echocardiography may add additional prognostic value beyond conventional exercise treadmill testing in patients with asymptomatic moderate or severe chronic primary MR.
Supporting References: (378–381)
7.3.2 Medical Therapy: Recommendations
Class IIa1. Medical therapy for systolic dysfunction is reasonable in symptomatic patients with chronic primary MR (stage D) and LVEF less than 60% in whom surgery is not contemplated (382–386). (Level of Evidence: B)
Patients with MR and LV dysfunction experience myocardial damage and HF. With onset of LV systolic dysfunction, surgery is usually indicated. However, in those patients in whom surgery is not performed or will be delayed, medical therapy for systolic dysfunction should be implemented. Although there are sparse data available specific to patients with MR with LV dysfunction, it seems reasonable to treat such patients with the standard regimen for HF, including beta-adrenergic blockade, ACE inhibitors or ARBs, and possibly aldosterone antagonists. Perhaps the best data exist for the use of beta blockers, which reverse LV dysfunction in experimental MR. Patients who are receiving beta blockers may have better surgical outcomes and delayed onset of LV dysfunction compared with those not taking these medications. ACE inhibition has not been effective in experimental MR with LV dysfunction but has caused reverse remodeling in a study with a small number of patients. Because aldosterone antagonism is thought to work in part by inhibiting fibrosis, its role in MR where little fibrosis occurs is unclear.
Supporting References: (382–386)
Class III: No Benefit1. Vasodilator therapy is not indicated for normotensive asymptomatic patients with chronic primary MR (stages B and C1) and normal systolic LV function (386–391). (Level of Evidence: B)
Because vasodilator therapy appears to be effective in acute severe symptomatic MR, it seems reasonable to attempt afterload reduction in chronic asymptomatic MR with normal LV function in an effort to forestall the need for surgery. However, the results from the limited number of trials addressing this therapy have been disappointing, demonstrating little or no clinically important benefit. Conversely, because vasodilators decrease LV size and mitral closing force, they may increase mitral valve prolapse, worsening rather than decreasing severity of MR. The foregoing does not apply to patients with concomitant hypertension. Hypertension must be treated because of the well-known morbidity and mortality associated with that condition and because increased LV systolic pressure by itself increases the systolic transmitral gradient and worsens severity of MR.
Supporting References: (386–391)
7.3.3 Intervention: Recommendations
See Table 17 for a summary of recommendations from this section.
Summary of Recommendations for Chronic Primary MR
Intervention for patients with primary MR consists of either surgical mitral valve repair or MVR. Mitral valve repair is preferred over MVR if a successful and durable repair can be achieved. Repair success is dependent on the mitral valve morphology as well as surgical expertise. Percutaneous mitral valve repair provides a less invasive alternative to surgery but is not approved for clinical use in the United States.
Supporting Reference: (426)
Class I1. Mitral valve surgery is recommended for symptomatic patients with chronic severe primary MR (stage D) and LVEF greater than 30% (365,376). (Level of Evidence: B)
Primary MR is a mechanical problem of the leaflets that has only a mechanical solution—that of mitral valve surgery. The onset of symptoms that results from severe MR worsens prognosis even when LV function appears to be normal, and negative prognosis extends even to mild symptoms. Thus, the onset of symptoms is an indication for prompt mitral valve surgery.
Supporting References: (365,376)
Class I2. Mitral valve surgery is recommended for asymptomatic patients with chronic severe primary MR and LV dysfunction (LVEF 30% to 60% and/or LVESD ≥40 mm, stage C2) (359–362,392–394). (Level of Evidence: B)
The goal of therapy in MR is to correct it before the onset of LV systolic dysfunction and the subsequent adverse effect on patient outcomes. Ideally, mitral valve surgery should be performed when the patient’s left ventricle approaches but has not yet reached the parameters that indicate systolic dysfunction (LVEF ≤60% or LVESD ≥40 mm). Because symptoms do not always coincide with LV dysfunction, imaging surveillance is used to plan surgery before severe dysfunction has occurred. If moderate LV dysfunction is already present, prognosis is reduced following mitral valve operation. Thus, further delay (even though symptoms are absent) will lead to greater LV dysfunction and a still worse prognosis. Because the loading conditions in MR allow continued late ejection into a lower-impedance LA, a higher cutoff for “normal” LVEF is used in MR than in other types of heart disease. Although it is clearly inadvisable to allow patients’ LV function to deteriorate beyond the benchmarks of an LVEF ≤60% and/or LVESD ≥40 mm, some recovery of LV function can still occur even if these thresholds have been crossed.
Supporting References: (359–362,392–394)
Class I3. Mitral valve repair is recommended in preference to MVR when surgical treatment is indicated for patients with chronic severe primary MR limited to the posterior leaflet (87,364,395–409). (Level of Evidence: B)
Mitral competence is only 1 function of the mitral valve apparatus. The mitral valve apparatus is an integral part of the left ventricle. It aids in LV contraction and helps maintain the efficient prolate ellipsoid shape of the left ventricle. Destruction of the mitral apparatus causes immediate LV dysfunction. Mitral valve repair is favored over MVR for 3 reasons:
1. Mitral valve repair is performed at a lower operative mortality rate than MVR. Although no RCTs exist, virtually every clinical report, including data from the STS database, indicates that operative risk (30–day mortality) for repair is about half that of MVR.
2. LV function is better preserved following repair preserving the integrity of the mitral valve apparatus versus following MVR.
3. Repair avoids the risks inherent to prosthetic heart valves, that is, thromboembolism or anticoagulant-induced hemorrhage for mechanical valves or structural deterioration for bioprosthetic valves.
Because the success of repair increases with surgical volume and expertise, repair (which is the preferred treatment) is more likely to be accomplished in centers with surgeons who have expertise in this type of surgery. Mitral valve repair over MVR is indicated even in patients >65 years of age. When in doubt, MVR is preferable to a poor repair. The results of a minimally invasive approach performed via minithoracotomy/port access using direct vision, thoracoscopic, or robotic assistance versus a conventional sternotomy approach may be similar when performed by highly experienced surgeons.
Surgical repair of MR has been remarkably successful in the treatment of primary MR. When leaflet dysfunction is sufficiently limited so that only annuloplasty and repair of the posterior leaflet are necessary, repair of isolated degenerative mitral disease has led to outcomes distinctly superior to biological or mechanical valve replacement: an operative mortality of <1%; long-term survival equivalent to that of the age-matched general population; approximately 95% freedom from reoperation; and >80% freedom from recurrent moderate or severe (≥3+) MR at 15 to 20 years after operation. As much as one half of the posterior leaflet may be excised, plicated, or resuspended. Posterior leaflet repair has become sufficiently standardized so that valve repair rather than valve replacement is the standard of care in this situation. Execution of this procedure with a success rate ≥90% should be the expectation of every cardiac surgeon who performs mitral valve procedures.
Supporting References: (87,364,395–409,427–432)
Class I4. Mitral valve repair is recommended in preference to MVR when surgical treatment is indicated for patients with chronic severe primary MR involving the anterior leaflet or both leaflets when a successful and durable repair can be accomplished (86,407–413). (Level of Evidence: B)
Degenerative mitral valve disease consisting of more than posterior leaflet disease requires a more complex and extensive repair. When the anterior leaflet or both leaflets require repair, durability of the repair is less certain, with a freedom from reoperation of approximately 80% and a freedom from recurrent moderate or severe MR of 60% at 15 to 20 years. These results are superior to the results of MVR, even in elderly patients. Repair should also be attempted if possible with other causes of severe MR, such as papillary muscle rupture, IE, and cleft mitral valve. As the repair becomes more complex, however, results of very complex repair in younger patients may be matched by results of durable mechanical MVR with careful management of anticoagulation.
More complex repair is not well standardized and is more surgically demanding. The Heart Valve Team should assign complex repairs to more experienced mitral valve surgeons with established outcomes, including acute success rate as well as long-term durability. The probability of mitral valve repair rather than MVR correlates with surgeon-specific mitral volumes. In a 2007 analysis, hospitals that performed <36 mitral operations per year had a 48% repair rate, whereas hospitals that performed >140 mitral operations per year had a 77% repair rate. Hospital mortality was also 50% lower, on average, in the highest-volume hospitals. There was, however, considerable overlap in specific hospital outcomes, with >25% of low-volume hospitals outperforming the median high-volume hospitals. This overlap suggests that hospital or surgeon-specific volumes should not be used as a surrogate for actual surgeon-specific repair rates and outcomes.
Supporting References: (86,407–413)
Class I5. Concomitant mitral valve repair or MVR is indicated in patients with chronic severe primary MR undergoing cardiac surgery for other indications (414). (Level of Evidence: B)
During coronary revascularization and in cases of IE or other conditions where multiple valves may be involved, it is prudent to correct severe primary MR at the time of surgery. This is especially true when mitral repair can be performed in conjunction with AVR because operative risk is lower than that of double valve replacement.
Supporting Reference: (414)
Class IIa1. Mitral valve repair is reasonable in asymptomatic patients with chronic severe primary MR (stage C1) with preserved LV function (LVEF >60% and LVESD <40 mm) in whom the likelihood of a successful and durable repair without residual MR is greater than 95% with an expected mortality rate of less than 1% when performed at a Heart Valve Center of Excellence (39,86,415–419). (Level of Evidence: B)
The onset of symptoms, LV dysfunction, or pulmonary hypertension worsens the prognosis for MR. Careful intensive surveillance may result in timing of valve surgery before these negative sequelae occur. However, an attractive alternative strategy for treating severe chronic primary MR is to perform early mitral repair before these triggers are reached. Early mitral repair avoids the need for intensive surveillance and also obviates the possibility that patients might become lost to follow-up or delay seeing their clinician until advanced LV dysfunction has already ensued. This strategy requires expertise in clinical evaluation and cardiac imaging to ensure that MR is severe. For this strategy to be effective, a durable repair must be provided. An unwanted valve replacement, exposing the patient to the unneeded risks accrued from prosthetic valve replacement, or a repair that fails, necessitating reoperation, should be considered complications of this approach. Thus, there must be a high degree of certainty that a durable repair can be performed. In this regard, posterior leaflet repair is usually more durable than anterior leaflet repair, especially in less experienced hands, and high surgical volume is also associated with better repair rates and more durable outcomes. These operations on the asymptomatic patient should be performed in Heart Valve Centers of Excellence by experienced surgeons with expertise in mitral valve repair. When performed by experienced surgeons in a Heart Valve Center of Excellence, there is a lower risk of patients developing HF and lower mortality rates in patients with severe MR from flail leaflets who undergo early operation as opposed to watchful waiting.
Supporting References: (39,86,415–419)
Class IIa2. Mitral valve repair is reasonable for asymptomatic patients with chronic severe nonrheumatic primary MR (stage C1) and preserved LV function (LVEF >60% and LVESD <40 mm) in whom there is a high likelihood of a successful and durable repair with 1) new onset of AF or 2) resting pulmonary hypertension (pulmonary artery systolic arterial pressure >50 mm Hg) (363,415,420–425). (Level of Evidence: B)
In nonrheumatic MR, the onset of AF is in part due to enlarging left atrial size, and its presence worsens surgical outcome. Furthermore, the longer AF is present, the more likely it is to persist. Thus, it may be reasonable to restore mitral competence by low-risk repair with the hope that the ensuing reduction in left atrial size will help restore and maintain sinus rhythm. However, restoration of sinus rhythm following valve surgery is uncertain, and concomitant AF ablation surgery may be warranted (Section 14.2.2). This strategy does not apply to rheumatic MR, where active atrial inflammation may make restoration of sinus rhythm less likely and valve scarring reduces the likelihood of a successful repair. The presence of pulmonary arterial hypertension due to MR is associated with poorer outcome after valve surgery. Thus, it is reasonable to consider surgery in these patients if there is a high likelihood of a successful and durable repair.
Supporting References: (363,420–425)
Class IIa3. Concomitant mitral valve repair is reasonable in patients with chronic moderate primary MR (stage B) when undergoing cardiac surgery for other indications. (Level of Evidence: C)
Because MR is a progressive lesion, it is reasonable to address it at the time of other cardiac surgery. This is especially true if the mitral valve can be repaired. However, the added risk of mitral valve surgery must be weighed against the potential for progression of MR. In such cases, increased operative mortality might not be justified in treating moderate MR.
Supporting Reference: (433)
Class IIb1. Mitral valve surgery may be considered in symptomatic patients with chronic severe primary MR and LVEF less than or equal to 30% (stage D). (Level of Evidence: C)
Most patients with decompensated MR and an LVEF ≤30% have secondary rather than primary MR. However in the rare cases where valve pathology indicates a clear primary cause in a patient with far-advanced LV dysfunction, surgery might be beneficial, especially in patients without severe comorbidities. Repair seems reasonable in such patients because of the likelihood of continued deterioration in LV function if surgery is not performed. However, data regarding surgery in patients with primary MR and a low LVEF are lacking.
Class IIb2. Mitral valve repair may be considered in patients with rheumatic mitral valve disease when surgical treatment is indicated if a durable and successful repair is likely or when the reliability of long-term anticoagulation management is questionable (86,406,413). (Level of Evidence: B)
Rheumatic mitral valve disease is less suitable for mitral repair than complex degenerative disease. Durability of the repair is limited by thickened or calcified leaflets, extensive subvalvular disease with chordal fusion and shortening, and progression of rheumatic disease. Freedom from reoperation at 20 years, even in experienced hands, is in the 50% to 60% range. In a large series from Korea, repair was accomplished in 22% of patients operated on for rheumatic disease. One third of these patients who underwent repair had significant stenosis or regurgitation at 10 years. Repair of rheumatic mitral valve disease should be limited to patients with less advanced disease in whom a durable repair can be accomplished or to patients in whom a mechanical prosthesis cannot be used because of anticoagulation management concerns.
Supporting References: (434,435)
Class IIb3. Transcatheter mitral valve repair may be considered for severely symptomatic patients (NYHA class III to IV) with chronic severe primary MR (stage D) who have favorable anatomy for the repair procedure and a reasonable life expectancy but who have a prohibitive surgical risk because of severe comorbidities and remain severely symptomatic despite optimal GDMT for HF (426). (Level of Evidence: B)
An RCT of percutaneous mitral valve repair using the MitraClip device versus surgical mitral repair was conducted in the United States. The clip was found to be safe but less effective than surgical repair because residual MR was more prevalent in the percutaneous group. However, the clip reduced severity of MR, improved symptoms, and led to reverse LV remodeling. Percutaneous mitral valve repair should only be considered for patients with chronic primary MR who remain severely symptomatic with NYHA class III to IV HF symptoms despite optimal GDMT for HF and who are considered inoperable.
Supporting References: (426,436,437)
Class III: Harm1. MVR should not be performed for the treatment of isolated severe primary MR limited to less than one half of the posterior leaflet unless mitral valve repair has been attempted and was unsuccessful (87,407–409). (Level of Evidence: B)
Surgical repair of MR has been remarkably successful, particularly in the treatment of chronic primary MR. Repair of isolated degenerative mitral disease, when leaflet dysfunction is sufficiently limited that only annuloplasty and repair of the posterior leaflet are necessary, has led to outcomes distinctly superior to biological or mechanical MVR: operative mortality of <1%; long-term survival equivalent to that of age-matched general population; approximately 95% freedom from reoperation; and >80% freedom from recurrent moderate or severe (≥3+) MR at 15 to 20 years after operation. As much as one half of the posterior leaflet may be excised, plicated, or resuspended. Posterior leaflet repair has become sufficiently standardized in this situation that repair rather than MVR is the standard of care. Execution of this procedure with a success rate ≥90% should be the expectation of every cardiac surgeon who performs mitral valve procedures.
Supporting References: (87,407–409)
See Online Data Supplements 16 and 17 for more information on intervention.
7.4 Chronic Secondary MR
7.4.1 Diagnosis and Follow-Up: Recommendations
Class I1. TTE is useful to establish the etiology of chronic secondary MR (stages B to D) and the extent and location of wall motion abnormalities and to assess global LV function, severity of MR, and magnitude of pulmonary hypertension. (Level of Evidence: C)
In general, the presence of chronic secondary MR worsens the prognosis of patients with LV systolic dysfunction and symptoms of HF, and most patients with secondary MR have severe global LV dysfunction. However, in some patients, a limited but strategically placed wall motion abnormality may also cause chronic secondary MR, and prognosis may be better in such patients. An initial TTE helps establish the cause of chronic secondary MR and also serves as a baseline for future comparisons. In patients with secondary MR, outcome studies have shown poorer prognosis with effective regurgitant orifice ≥20 mm2. It is recognized that there is difficulty assessing secondary MR in patients with reduced LV systolic function and low forward flow.
Supporting References: (438,439)
Class I2. Noninvasive imaging (stress nuclear/positron emission tomography, CMR, or stress echocardiography), cardiac CT angiography, or cardiac catheterization, including coronary arteriography, is useful to establish etiology of chronic secondary MR (stages B to D) and/or to assess myocardial viability, which in turn may influence management of functional MR. (Level of Evidence: C)
Prognosis is poor for both ischemic and nonischemic MR, but ischemic MR lends itself to the possibility of revascularization and potential improvement in LV function if CAD has led to large areas of hibernating viable myocardium. CT angiography is usually adequate to rule out significant CAD and thus rule out ischemic MR. If CAD is detected and noninvasive testing demonstrates areas of viability, coronary arteriography is pursued to better define the anatomy for potential revascularization.
Supporting Reference: (440)
7.4.2 Medical Therapy: Recommendations
Class I1. Patients with chronic secondary MR (stages B to D) and HF with reduced LVEF should receive standard GDMT therapy for HF, including ACE inhibitors, ARBs, beta blockers, and/or aldosterone antagonists as indicated (310,441–445). (Level of Evidence: A)
Chronic secondary MR usually develops as a result of severe LV dysfunction. Thus, standard GDMT for HF forms the mainstay of therapy. Diuretics, beta blockers, ACE inhibition or ARBs, and aldosterone antagonists help improve symptoms and/or prolong life in HF in general and probably do so even when HF is complicated by chronic secondary MR.
Supporting References: (310,441–445)
Class I2. Cardiac resynchronization therapy with biventricular pacing is recommended for symptomatic patients with chronic severe secondary MR (stages B to D) who meet the indications for device therapy (446,447). (Level of Evidence: A)
Wall motion abnormalities are a common cause of chronic secondary MR, and their presence worsens the condition. The presence of conduction system abnormalities, especially left bundle-branch block, causes disordered LV contraction that exacerbates or is the primary cause of wall motion abnormalities. Electrical resynchronization may reduce or even eliminate wall motion abnormalities. Cardiac resynchronization therapy may also improve LV function and mitral valve closing force, which in turn leads to a reduction in chronic secondary MR in some cases. Thus, cardiac resynchronization therapy should be considered in symptomatic patients with chronic secondary MR who meet the indications for device therapy as outlined in the ACC/AHA guidelines for device-based therapy.
Supporting References: (446,447)
7.4.3 Intervention: Recommendations
See Table 18 for a summary of recommendations for this section and Figure 4 for indications for surgery for MR.
Indications for Surgery for MR
*Mitral valve repair is preferred over MVR when possible.
AF indicates atrial fibrillation; CAD, coronary artery disease; CRT, cardiac resynchronization therapy; ERO, effective regurgitant orifice; HF, heart failure; LV, left ventricular; LVEF, left ventricular ejection fraction; LVESD, left ventricular end-systolic dimension; MR, mitral regurgitation, MV, mitral valve; MVR, mitral valve replacement; NYHA, New York Heart Association; PASP, pulmonary artery systolic pressure; RF, regurgitant fraction; RVol, regurgitant volume; and Rx, therapy.
Summary of Recommendations for Chronic Severe Secondary MR
Chronic severe secondary MR adds volume overload to a decompensated left ventricle and worsens prognosis. However, there are only sparse data to indicate that correcting MR prolongs life or even improves symptoms over an extended time. The benefits of performing mitral valve repair over MVR are also unclear in this subset of patients. Percutaneous mitral valve repair provides a less invasive alternative to surgery but is not approved for clinical use in the United States.
Supporting References: (426,436,459)
Class IIa1. Mitral valve surgery is reasonable for patients with chronic severe secondary MR (stages C and D) who are undergoing CABG or AVR. (Level of Evidence: C)
There is no proof that correction of chronic secondary MR at the time of AVR or CABG is effective in prolonging life or relieving symptoms, but it seems wise to address the mitral valve during those operations. Although it may be hoped that the revascularization will recruit hibernating myocardium and reduce chronic secondary MR or that LV pressure reduction from relief of AS or volume reduction from relief of AR might improve chronic secondary MR, such hopes may not be realized. Failing to correct chronic secondary MR may leave the patient with severe residual MR.
Class IIb1. Mitral valve repair or replacement may be considered for severely symptomatic patients (NYHA class III to IV) with chronic severe secondary MR (stage D) who have persistent symptoms despite optimal GDMT for HF (439,448–458). (Level of Evidence: B)
Although it is clear that chronic severe secondary MR adds to the burden of HF by imposing volume overload on an already compromised left ventricle and worsens prognosis, there is remarkably little evidence that correcting chronic severe secondary MR prolongs life or even improves symptoms for a prolonged period. This paradox may result from the fact that mitral surgery in ischemic MR does not prevent CAD from progressing, nor does it prevent the continued idiopathic myocardial deterioration in nonischemic chronic secondary MR. Furthermore, when chronic severe secondary MR is addressed surgically, it is not clear that repair, so valuable in treating primary MR, is even preferred over MVR in chronic severe secondary MR. Small RCTs have demonstrated that mitral valve surgery reduces chamber size and improves peak oxygen consumption in chronic severe secondary MR. Deciding which patients with chronic severe secondary MR will benefit from mitral surgery awaits the results of larger RCTs. Ischemic or dilated cardiomyopathy presents different challenges for mitral repair. Regurgitation is caused by annular dilation as well as apical and lateral displacement of the papillary muscles. New techniques have facilitated mitral repair in this situation, but durability of the repair is primarily dependent on regression or progression of ventricular dilation. If the heart continues to dilate, long-term durability of the repair is moot; the survival of the patient is limited.
Supporting References: (434,435,439,448–458)
Class IIb2. Mitral valve repair may be considered for patients with chronic moderate secondary MR (stage B) who are undergoing other cardiac surgery. (Level of Evidence: C)
Because MR tends to be a progressive disease, it may be helpful to address moderate MR when other cardiac surgery is being performed. Because adding MVR to other valve surgery increases surgical risk, it seems logical that repair would be preferred in such instances; however, there are sparse data available at the time of publication to support this concept.
Supporting Reference: (433)
See Online Data Supplement 18 for more information on intervention.
8 Tricuspid Valve Disease
8.1 Stages of TR
Trace-to-mild degrees of TR of no physiological consequence are commonly detected on TTE in subjects with anatomically normal valves. Primary disorders of the tricuspid apparatus that can lead to more significant degrees of TR include rheumatic disease, prolapse, congenital disease (Ebstein’s), IE, radiation, carcinoid, blunt chest wall trauma, RV endomyocardial biopsy−related trauma, and intra-annular RV pacemaker or implantable cardioverter-defibrillator leads. Approximately 80% of cases of significant TR are functional in nature and related to tricuspid annular dilation and leaflet tethering in the setting of RV remodeling due to pressure and/or volume overload. The tricuspid annulus is a saddle-shaped ellipsoid that becomes planar and circular as it dilates in an anterior-posterior direction and will often not return to its normal size and configuration after relief of RV overload. Table 19 shows the stages (A through D) of primary and functional TR as defined for other valve lesions. Severe TR (stages C and D) is associated with poor prognosis independent of age, LV and RV function, and RV size. Patients with signs or symptoms of right HF would fit into the stage D category even if they do not meet other hemodynamic or morphological criteria.
Stages of TR
Supporting Reference: (460)
8.2 Tricuspid Regurgitation
See Figure 5 for indications for surgery.
Indications for Surgery
*See Table 19 for definition of stages. TA dilation is defined by >40 mm on TTE (>21 mm/m2) or >70 mm on direct intraoperative measurement.
LV indicates left ventricular; PHTN, pulmonary hypertension; RV, right ventricular; TA, tricuspid annular; TR, tricuspid regurgitation; TTE, transthoracic echocardiogram; TV, tricuspid valve; and TVR, tricuspid valve replacement.
8.2.1 Diagnosis and Follow-Up: Recommendations
Class I1. TTE is indicated to evaluate severity of TR, determine etiology, measure sizes of right-sided chambers and inferior vena cava, assess RV systolic function, estimate pulmonary artery systolic pressure, and characterize any associated left-sided heart disease. (Level of Evidence: C)
Most TR is clinically silent. Advanced degrees of TR may be detected on physical examination by the appearance of elevated “c-V” waves in the jugular venous pulse, a systolic murmur at the lower sternal border that increases in intensity with inspiration, and a pulsatile liver edge. In many patients, characteristic findings in the jugular venous pulse are the only clues to the presence of advanced TR, because a murmur may be inaudible even with severe TR. Symptoms include fatigue from low cardiac output, abdominal fullness, edema, and palpitations, particularly if AF is also present. Progressive hepatic dysfunction may occur due to the elevated right atrial pressure, and thus assessment of liver function is useful in patients with advanced degrees of TR.
TTE can distinguish primary from functional TR, define any associated left-sided valvular and/or myocardial disease, and provide an estimate of pulmonary artery systolic pressure. Characterization of severity of TR (Table 19) relies on an integrative assessment of multiple parameters as recommended by the ASE and EAE. In cases of functional TR, the tricuspid annular diameter should be measured in the apical 4–chamber view. There is a linear relationship between annular diameter and tricuspid regurgitant volume. A diastolic diameter >40 mm (or >21 mm/m2) indicates significant annular dilation and an increased risk of persistent or progressive TR after isolated mitral valve surgery. With RV remodeling, tricuspid valve leaflet tethering height and area also contribute to functional TR and may predict the need for repair techniques other than annuloplasty to achieve an effective and durable operative result. Pulmonary artery systolic pressure is estimated from the maximal tricuspid valve regurgitant velocity using the modified Bernoulli equation. The accuracy of this technique can be compromised in severe TR due to the difficulty in assessing right atrial pressure as well as potential inaccuracies of applying the simplified Bernoulli equation to lesions with laminar flow. Assessment of RV systolic function is challenged by geometric and image acquisition constraints, as well as by variability in RV loading conditions. Normal RV systolic function is defined by several parameters, including tricuspid annular plane systolic excursion >16 mm, tricuspid valve annular velocity (S’) >10.0 cm per second, and RV end-systolic area <20.0 cm2 or fractional area change >35%. TEE for tricuspid valve assessment can be considered when TTE images are inadequate, although visualization of the tricuspid valve with TEE can also be suboptimal.
Supporting References: (5,461–469,469–471)
Class IIa1. Invasive measurement of pulmonary artery pressures and pulmonary vascular resistance can be useful in patients with TR when clinical and noninvasive data regarding their values are discordant. (Level of Evidence: C)
When physical examination, ECG, and TTE data regarding estimated pulmonary artery systolic pressure are either discordant or insufficient, including when the TR jet velocity signal is inadequate or may underestimate pulmonary artery systolic pressure, invasive measurement of pulmonary artery pressures and pulmonary vascular resistance can be helpful to guide clinical decision making in individual patients. Invasive data are essential for accurate diagnosis of the cause of pulmonary hypertension and for the assessment of pulmonary vascular reactivity following vasodilator challenge. Direct measurements of right atrial pressure may also be useful for clinical decision making. Right ventriculography may further aid in the evaluation of the severity of TR and the status of the right ventricle. Thermodilution cardiac output measurements may be inaccurate with severe TR, and thus a Fick cardiac output should be measured to apply to the calculation of pulmonary resistance.
Class IIb1. CMR or real-time 3D echocardiography may be considered for assessment of RV systolic function and systolic and diastolic volumes in patients with severe TR (stages C and D) and suboptimal 2D echocardiograms. (Level of Evidence: C)
Assessment of RV systolic function in patients with TR is a critical component of preoperative planning, especially in the context of reoperative isolated tricuspid valve repair or replacement years after left-sided valve surgery. Impaired RV systolic function negatively impacts early functional, late functional, and survival outcomes following tricuspid valve surgery. Evaluation with TTE or TEE may be suboptimal in some patients, due to poor acoustic windows, the technical limitations of standard echocardiographic and Doppler techniques, and dynamic changes in RV loading conditions. Both CMR and real-time 3D echocardiography may provide more accurate assessment of RV volumes and systolic function, as well as annular dimension and the degree of leaflet tethering. CMR may be the ideal modality in young asymptomatic patients with severe TR to assess initial and serial measurements of RV size and systolic function. In addition, echocardiographic strain imaging or CT scanning may be useful in assessing RV function. These imaging modalities are not widely used at the time of guideline publication, and outcome data are needed to determine the incremental utility of these tests.
Supporting References: (472–481)
Class IIb2. Exercise testing may be considered for the assessment of exercise capacity in patients with severe TR with no or minimal symptoms (stage C). (Level of Evidence: C)
Patients with severe functional TR usually report symptoms referable to the responsible left-sided valve or myocardial abnormality. However, in some patients with primary TR, symptoms may not emerge until relatively late in the course of the disease. As is the case for left-sided valve lesions, treadmill or bicycle testing may uncover limitations to exercise not previously recognized by the patient and prompt earlier evaluation for surgery. Although some clinical experience has been reported for patients with Ebstein’s anomaly, the effect on clinical outcomes of any exercise-induced changes in RV size/function or pulmonary artery pressures in patients with severe TR (stage C) has not been prospectively studied.
Supporting Reference: (482)
8.2.2 Medical Therapy: Recommendations
Class IIa1. Diuretics can be useful for patients with severe TR and signs of right-sided HF (stage D). (Level of Evidence: C)
Patients with severe TR usually present with signs or symptoms of right HF, including peripheral edema and ascites. Diuretics can be used to decrease volume overload in these patients. Loop diuretics are typically provided and may relieve systemic congestion, but their use can be limited by worsening low-flow syndrome. Aldosterone antagonists may be of additive benefit, especially in the setting of hepatic congestion, which may promote secondary hyperaldosteronism.
Class IIb1. Medical therapies to reduce elevated pulmonary artery pressures and/or pulmonary vascular resistance might be considered in patients with severe functional TR (stages C and D). (Level of Evidence: C)
Medical therapies for management of severe TR (stages C and D) are limited. Attention should be focused on the causative lesion in patients with functional TR. Reduction of pulmonary artery pressures and pulmonary vascular resistance with specific pulmonary vasodilators may be helpful to reduce RV afterload and functional TR in selected patients with pulmonary hypertension who demonstrate acute responsiveness during invasive testing. Medical treatment of conditions that elevate left-sided filling pressures, such as systemic hypertension, should be optimized.
Supporting References: (483,484)
8.2.3 Intervention: Recommendations
Class I1. Tricuspid valve surgery is recommended for patients with severe TR (stages C and D) undergoing left-sided valve surgery. (Level of Evidence: C)
The indications for surgical correction of TR are most often considered at the time of mitral or aortic valve surgery. Severe TR of either a primary or functional nature may not predictably improve after treatment of the left-sided valve lesion and reduction of RV afterload; as such, severe TR should be addressed as part of the index procedure. Reoperation for severe, isolated TR after left-sided valve surgery is associated with a perioperative mortality rate of 10% to 25%. Tricuspid valve repair does not add appreciably to the risks of surgery and can be accomplished with a clinically insignificant increase in ischemic time. There has been a significant increase in the number of tricuspid valve repairs performed for this indication over the past decade. Tricuspid valve repair is preferable to replacement. When replacement is necessary for primary, uncorrectable tricuspid valve disease, the choice of prosthesis is individualized, with the usual trade-offs between thrombosis/anticoagulation with a mechanical valve and durability with a tissue valve. Meta-analysis has shown no difference in overall survival between mechanical and tissue valves for patients undergoing tricuspid valve replacement. The risks and benefits of tricuspid valve operation should be carefully considered in the presence of severe RV systolic dysfunction or irreversible pulmonary hypertension, due to the possibility of RV failure after operation.
Supporting References: (485–494)
Class IIa1. Tricuspid valve repair can be beneficial for patients with mild, moderate, or greater functional TR (stage B) at the time of left-sided valve surgery with either 1) tricuspid annular dilation or 2) prior evidence of right HF (464–466,495–501). (Level of Evidence: B)
Left uncorrected at the time of left-sided valve surgery, mild or moderate degrees of functional TR may progress over time in approximately 25% of patients and result in reduced long-term functional outcome and survival. Risk factors for persistence and/or progression of TR include tricuspid annulus dilation (>40 mm diameter or 21 mm/m2 diameter indexed to body surface area on preoperative TTE; >70 mm diameter on direct intraoperative measurement); degree of RV dysfunction/remodeling; leaflet tethering height; pulmonary artery hypertension; AF; nonmyxomatous etiology of MR; and intra-annular RV pacemaker or implantable cardioverter-defibrillator leads. The cut-off of >70 mm diameter on direct intraoperative measurement originated from a single center, performed with the patient on cardiopulmonary bypass using a supple ruler, taken from the anteroseptal commissure to the anteroposterior commissure. Echocardiography is usually performed on the beating heart and examines a different plane of the tricuspid annulus. Numerous observational studies and 1 prospective RCT attest to the benefit on several echocardiographic and functional parameters of tricuspid repair at the time of mitral valve surgery for mild-to-moderate TR (stage B) with tricuspid annulus dilation. When surgery is performed for isolated severe primary MR due to a degenerative etiology, less than moderate TR is unlikely to progress if left untreated. A prior recent history of right HF is also an indication for tricuspid valve repair at the time of left-sided valve surgery. A survival benefit with tricuspid repair in this setting has not been demonstrated. Management of indwelling pacemaker or implantable cardioverter-defibrillator leads may require their removal with epicardial placement in selected patients. Other approaches, such as sequestering the leads in a commissure or placing them in an extra-annular position, may be used. Following repair with ring annuloplasty, residual TR is present in approximately 10% of patients at 5 years.
Supporting References: (463–466,495–504)
Class IIa2. Tricuspid valve surgery can be beneficial for patients with symptoms due to severe primary TR that are unresponsive to medical therapy (stage D). (Level of Evidence: C)
Correction of symptomatic severe primary TR (stage D) in patients without left-sided valve disease is preferentially performed before onset of significant RV dysfunction. Replacement may be required because of the extent and severity of the underlying pathology (e.g., carcinoid, radiation, Ebstein’s anomaly). Reduction or elimination of the regurgitant volume load can alleviate systemic venous and hepatic congestion and decrease reliance on diuretics. Patients with severe congestive hepatopathy may also benefit from surgery to prevent irreversible cirrhosis of the liver. Quality and duration of long-term survival are related to residual RV function.
Class IIb1. Tricuspid valve repair may be considered for patients with moderate functional TR (stage B) and pulmonary artery hypertension at the time of left-sided valve surgery. (Level of Evidence: C)
When pulmonary artery hypertension is caused predominantly by left-sided valve disease, effective surgery on the left-sided valve lesions usually leads to a fall in RV afterload and improvement in functional TR, especially in the absence of significant (i.e., >40 mm on TEE) tricuspid annulus dilation. This observation dates to the early years of mitral valve surgery. Prediction rules that account for the relative contributions of pulmonary hypertension and only mild-to-moderate degrees of tricuspid annulus enlargement for the risk of progressive TR are lacking. The benefit of routine tricuspid valve repair in this context is less clear across broad populations but may be considered on an individual basis.
Supporting References: (503,505,506)
Class IIb2. Tricuspid valve surgery may be considered for asymptomatic or minimally symptomatic patients with severe primary TR (stage C) and progressive degrees of moderate or greater RV dilation and/or systolic dysfunction. (Level of Evidence: C)
The optimal timing of tricuspid valve surgery for asymptomatic or minimally symptomatic, severe primary TR has not been established. Extrapolation from limited experiences reported for patients with stable carcinoid heart disease and patients with a flail tricuspid leaflet and application of the management principles adopted for patients with severe MR suggest that serial assessments of RV size and function might trigger consideration of corrective surgery in selected patients with severe, primary TR when a pattern of continued deterioration can be established and the risks of surgery are considered acceptable. In otherwise healthy patients without other comorbidities, such as the patient with severe TR due to trauma, the risk of tricuspid valve operation is low (<1% to 2%) in the absence of RV dysfunction or pulmonary hypertension.
Supporting References: (507,508)
Class IIb3. Reoperation for isolated tricuspid valve repair or replacement may be considered for persistent symptoms due to severe TR (stage D) in patients who have undergone previous left-sided valve surgery and who do not have severe pulmonary hypertension or significant RV systolic dysfunction. (Level of Evidence: C)
Isolated tricuspid valve surgery for severe TR has historically been performed relatively late in the natural history of the disease and once patients have become symptomatic with signs of right HF. Unadjusted mortality rates for isolated tricuspid valve surgery have therefore exceeded those reported for isolated aortic or mitral valve surgery, and this trend has been even more pronounced following reoperative tricuspid surgery late after left-sided valve surgery. This high mortality is likely related to the advanced nature of RV failure encountered at the time of the second procedure, residual pulmonary hypertension, LV dysfunction, and other valve abnormalities. Two Heart Valve Centers of Excellence have reported perioperative mortality rates with tricuspid valve reoperation of 4.2% and 13.2%, respectively. Thus, the hazards imposed by reoperation have influenced decision making for repair of functional TR initially at the time of left-sided valve surgery. The sobering results seen with tricuspid valve repair at reoperation inject a note of caution into the recommendations for its performance and may encourage replacement with an age-appropriate (mechanical or biological) prosthesis. The presence of either severe and uncorrectable pulmonary hypertension or significant RV dysfunction constitutes a relative contraindication to reoperation.
Supporting References: (485–489,509–512)
See Online Data Supplement 19 for more information on outcomes following tricuspid valve surgery.
8.3 Stages of Tricuspid Stenosis
See Table 20 for the stages of severe tricuspid stenosis (TS).
Stages of Severe TS
8.4 Tricuspid Stenosis
8.4.1 Diagnosis and Follow-Up: Recommendations
Class I1. TTE is indicated in patients with TS to assess the anatomy of the valve complex, evaluate severity of stenosis, and characterize any associated regurgitation and/or left-sided valve disease. (Level of Evidence: C)
Rheumatic disease is the most common etiology of TS. Its clinical manifestations are far overshadowed by those attributable to the associated left-sided (particularly mitral) valve disease. Because TS is often not detected during bedside examination, TTE is essential for diagnosis and characterization. TS is usually accompanied by TR of varying severity. When valve and/or chordal thickening and calcification are evident, additional findings indicative of severe TS include mean pressure gradient >5 mm Hg, pressure half-time ≥190 milliseconds, valve area ≤1.0 cm2 (continuity equation), and associated right atrial and inferior vena cava enlargement. It is recognized that assessment of TS severity with TTE is limited by several technical factors; thus, these values are less well validated than those reported for MS.
Supporting Reference: (8)
Class IIb1. Invasive hemodynamic assessment of severity of TS may be considered in symptomatic patients when clinical and noninvasive data are discordant. (Level of Evidence: C)
Hemodynamic assessment of TS is rarely undertaken for patients with acquired disease but may be performed in selected patients at the time of invasive study for another indication, such as MS with pulmonary hypertension. Direct assessment of the absolute right atrial and RV diastolic pressure may be useful in determining the contribution of TS to the patient’s signs or symptoms.
8.4.2 Medical Therapy
As for patients with severe TR, loop diuretics may be useful to relieve systemic and hepatic congestion in patients with severe, symptomatic TS, although their use may be limited by worsening low-flow syndrome. Attention to left-sided valve disease and AF, when present, is also important.
8.4.3 Intervention: Recommendations
Class I1. Tricuspid valve surgery is recommended for patients with severe TS at the time of operation for left-sided valve disease. (Level of Evidence: C)
Surgery for severe TS is most often performed at the time of operation for left-sided valve disease, chiefly rheumatic MS/MR. If repair is not adequate or feasible due to valve destruction or multiple levels of pathological involvement, replacement may be necessary. The choice of prosthesis should be individualized. Perioperative mortality rates are higher for mitral plus tricuspid versus either isolated mitral or tricuspid surgery alone.
Supporting Reference: (489)
Class I2. Tricuspid valve surgery is recommended for patients with isolated, symptomatic severe TS. (Level of Evidence: C)
Relief of severe stenosis should lower elevated right atrial and systemic venous pressures and alleviate associated symptoms. Tricuspid valve surgery is preferred over percutaneous balloon tricuspid commissurotomy for treatment of symptomatic severe TS because most cases of severe TS are accompanied by TR (rheumatic, carcinoid, other), and percutaneous balloon tricuspid commissurotomy may either create or worsen regurgitation. There is also a relative lack of long-term follow-up data on patients managed with percutaneous balloon tricuspid commissurotomy for this indication. Outcomes with surgery are dependent on RV function.
Supporting References: (513,514)
Class IIb1. Percutaneous balloon tricuspid commissurotomy might be considered in patients with isolated, symptomatic severe TS without accompanying TR. (Level of Evidence: C)
Isolated, symptomatic severe TS without accompanying TR is an extremely rare condition for which percutaneous balloon tricuspid commissurotomy might be considered, recognizing its short-term limitations and the lack of long-term outcome data.
See Online Data Supplement 19 for more information on outcomes following tricuspid valve surgery.
9 Pulmonic Valve Disease
9.1 Stages of Pulmonic Regurgitation
See Table 21 for the stages of severe pulmonic regurgitation (PR).
Stages of Severe PR
Mild-to-moderate PR seen on echocardiography is common and does not require further follow-up or intervention if asymptomatic with normal RV size and function. Significant PR in patients is uncommon. Primary PR that follows in the wake of childhood surgery for tetralogy of Fallot or other congenital lesions may progress insidiously and reach severe proportions that threaten RV function without adequate clinical recognition. Its evaluation and management, including indications for valve replacement, are comprehensively reviewed in the “2008 ACC/AHA Guidelines for the Management of Patients With Congenital Heart Disease.” The pulmonic valve is rarely involved by IE or rheumatic disease but is susceptible to carcinoid accretion because it also affects the tricuspid valve and results in varying degrees of stenosis and regurgitation. Surgery is considered when symptoms or signs of RV dysfunction have intervened and PR is severe. Secondary PR from long-standing pulmonary hypertension and annular dilation is encountered less frequently in the modern era. Treatment should focus on the cause(s) of elevated pulmonary artery pressures.
Supporting Reference: (516)
9.2 Stages of Pulmonic Stenosis
See Table 22 for the stages of severe pulmonic stenosis.
Stages of Severe Pulmonic Stenosis
Pulmonic stenosis is essentially a congenital disorder. Less common etiologies include carcinoid and obstructing vegetations or tumors. Assessment with TTE alone is usually sufficient for diagnosis and clinical decision making. Indications for percutaneous balloon pulmonic valve commissurotomy and valve replacement are contained in the “2008 ACC/AHA Guidelines for the Management of Patients With Congenital Heart Disease.”
Supporting Reference: (516)
10 Mixed Valve Disease
10.1 Mixed VHD
10.1.1 Diagnosis and Follow-Up
For the majority of patients with mixed valve disease, there is usually a predominant valve lesion (i.e., stenosis or regurgitation); further, the symptoms and pathophysiology resemble those of a pure dominant lesion. However, the presence of mixed valve disease poses limitations for noninvasive and invasive techniques used to determine severity. These limitations should be strongly considered in the evaluation of patients with mixed valve disease. For patients with mixed aortic disease and predominant AS, a high gradient and small valve area will be present. Pressure overload results in concentric LV myocardial hypertrophy, usually without chamber enlargement except in late stages of the disease. Symptoms may be present in patients with predominant AS with or without alterations in chamber morphology. Conversely, for patients with mixed aortic disease and predominant AR, the aortic velocity and gradient may be significantly elevated due to regurgitation in the setting of AS, but the aortic valve area is relatively large. Patients with predominant AR will have both pressure and volume overload, resulting in marked increases in LV volume. In these patients, symptoms may be relatively latent due to preload recruitment with compensatory hypertrophy. For patients with mixed mitral disease and predominant MS, a high transmitral gradient and small valve area will be present. Left atrial enlargement occurs with relative preservation of the LV chamber size. Conversely, in patients with mixed mitral disease and predominant MR, LV remodeling will occur in addition to left atrial enlargement. These patients frequently have high transmitral gradients due to the regurgitant flow, but the valve area may be relatively large.
For patients with mixed valve disease, there is a paucity of data on the natural history of such coexistent conditions. Consequently, the appropriate timing for serial evaluations of these patients remains uncertain. For patients with predominant lesions (i.e., stenosis or regurgitation), serial evaluations in accordance with recommendations for the predominant valve lesion are generally recommended. Nonetheless, it is important to recognize that the coexistence of stenosis and regurgitation may have pathological consequences that are incremental to the effects of either of these disease states alone. As a result, patients with mixed disease may require serial evaluations at intervals earlier than recommended for single valve lesions.
Supporting References: (517–521)
10.1.2 Medical Therapy
Recommendations for medical therapy follow those for single valve disease when there is a predominant valve lesion and other management recommendations for concomitant LV dysfunction. There are no other recommendations for medical therapy specific to patients with mixed valve disease.
10.1.3 Timing of Intervention
For patients with mixed valve disease and a predominant lesion, the need for intervention should generally follow recommendations for a pure dominant lesion. This consideration should be undertaken with attention to symptoms, lesion severity, chamber remodeling, operative risk, and the expected surgical outcome. Timing of intervention must be individualized because coexistence of stenosis and regurgitation may have pathological consequences that are incremental to the effects of either lesion alone. For example, patients with mixed aortic disease will have increased afterload due to both the regurgitant volume and the relatively small aortic valve area. Thus, patients with dominant AR may develop symptoms and require surgery before severe LV enlargement develops. For patients with dominant AS, coexistent regurgitation may be poorly tolerated by a ventricle that is noncompliant due to pressure hypertrophy. An elevated left atrial pressure results from both MS and regurgitation in patients with mixed mitral disease. Thus, patients with mixed mitral disease may develop symptoms or pulmonary hypertension at earlier intervals than has been demonstrated in patients with pure stenosis or regurgitation. The alterations in loading conditions due to mixed valve disease may also lead to cardiac symptoms and chamber remodeling in patients when there is not a predominant lesion (i.e., mixed moderate valve disease). Patients with mixed moderate valve disease present a special management challenge, as there is a paucity of data to guide timing of intervention in these patients.
For those patients with symptoms of uncertain origin, valve intervention may be considered when there are clinical findings or data supportive of significant pathological consequences of the mixed valve lesion. Supportive abnormalities include objective evidence of functional limitation (e.g., severely reduced peak myocardial oxygen consumption attributable to impaired cardiac output) and significantly elevated atrial or ventricular pressures. Exercise hemodynamic studies should be considered for those patients with symptoms that are out of proportion to hemodynamic findings at rest. For example, patients with mixed mitral disease and a relatively low mitral gradient may be particularly susceptible to developing functional MS at higher transvalvular flow rates due to the concomitant regurgitant volume. In patients with mixed aortic disease, the pathological contribution of aortic regurgitant volume may lessen with exercise due to shortening of diastole. Given the potential limitations of noninvasive assessments, direct pressure measurement with cardiac catheterization may be needed for assessing ventricular filling abnormalities at rest and with exercise in patients with mixed valve disease. Because the indications for intervention have not been well studied in this patient population, the decision to pursue surgical therapy should be individualized, with consideration of patient symptoms, severity of hemodynamic abnormalities, and risk of surgery.
Supporting References: (517–521)
10.1.4 Choice of Intervention
For patients with mixed valve disease, the appropriate interventional therapy is determined by guidelines for the predominant valve lesion with consideration of the severity of the concomitant valve disease. For example, in a patient with predominant AS, TAVR may be considered in patients with moderate but not severe AR, whereas conventional AVR may be a therapeutic option regardless of severity of mixed valve disease. Similarly, percutaneous balloon mitral commissurotomy is a therapeutic option in patients with MS and suitable anatomy if there is mild but not moderate or severe regurgitation. Percutaneous aortic balloon dilation should not be performed if there is moderate or severe regurgitation due to the potential for worsening of the regurgitation with the procedure.
11 Prosthetic Valves
11.1 Evaluation and Selection of Prosthetic Valves
11.1.1 Diagnosis and Follow-Up: Recommendations
Patients who have undergone valve replacement are not cured but still have serious heart disease. Patients have exchanged native valve disease for prosthetic valve disease and must be followed with the same care as those with native valve disease. The clinical course of patients with prosthetic heart valves is influenced by several factors, including LV dysfunction; progression of other valve disease; pulmonary hypertension; concurrent coronary, myocardial, or aortic disease; and complications of prosthetic heart valves. The interval between routine follow-up visits depends on the patient’s valve type, residual heart disease, comorbid conditions, and other clinical factors. Management of anticoagulation should be supervised and monitored frequently by an experienced healthcare professional.
The asymptomatic uncomplicated patient is usually seen at 1–year intervals for a cardiac history and physical examination. ECG and chest x-ray examinations are not routinely indicated but may be appropriate in individual patients. Additional tests that may be considered include hemoglobin and hematocrit in patients receiving chronic anticoagulation. No further echocardiographic testing is required after the initial postoperative evaluation in patients with mechanical valves who are stable and who have no symptoms or clinical evidence of prosthetic valve or ventricular dysfunction or dysfunction of other heart valves.
Class I1. An initial TTE study is recommended in patients after prosthetic valve implantation for evaluation of valve hemodynamics (522–525). (Level of Evidence: B)
An echocardiographic examination performed 6 weeks to 3 months after valve implantation is an essential component of the first postoperative visit because it allows for an assessment of the effects and results of surgery and serves as a baseline for comparison should complications or deterioration occur later. Doppler TTE provides accurate measurements of transvalvular velocities and pressure gradients as well as detection and quantitation of valvular and paravalvular regurgitation. Normal Doppler transvalvular velocities and gradients vary among different types and sizes of prosthetic valves but are also affected by patient-specific factors, including body size and cardiac output. The postoperative study, recorded when the patient is asymptomatic and in a stable hemodynamic state, provides the normal Doppler flow data for that valve in that patient. In addition to imaging and Doppler flow data for the prosthetic valve, TTE provides assessment of other valve disease(s), pulmonary hypertension, atrial size, LV and RV hypertrophy, LV and RV size and function, and pericardial disease.
Supporting References: (291,526,527)
Class I2. Repeat TTE is recommended in patients with prosthetic heart valves if there is a change in clinical symptoms or signs suggesting valve dysfunction. (Level of Evidence: C)
Bioprosthetic valves are prone to tissue degeneration or pannus formation with development of valve regurgitation and/or stenosis. Bioprosthetic valve dysfunction typically presents with the insidious onset of exertional dyspnea or with a louder systolic murmur (MR or AS) or a new diastolic murmur (AR or MS) on physical examination. More abrupt and severe symptoms may occur with bioprosthetic valve endocarditis or with degenerative rupture of a valve cusp.
Patients with mechanical valve dysfunction present with symptoms of HF, systemic thromboembolism, hemolysis, or a new murmur on auscultation. Mechanical valve dysfunction may be due to thrombosis, pannus formation, or IE. Signs or symptoms of mechanical valve dysfunction are often acute or subacute because of more abrupt impairment of leaflet occluder opening or closing by thrombus or pannus. Acute or chronic paravalvular regurgitation may also be seen due to IE or suture dehiscence.
TTE allows evaluation of valve dysfunction based on imaging of leaflet structure and motion, vegetations, and thrombus and Doppler evaluation for prosthetic valve stenosis or regurgitation. Comparison with the baseline postoperative echocardiogram is particularly helpful for detection of prosthetic valve dysfunction.
Supporting References: (528,529)
Class I3. TEE is recommended when clinical symptoms or signs suggest prosthetic valve dysfunction. (Level of Evidence: C)
TTE is the preferred approach for initial assessment of suspected prosthetic valve dysfunction because it allows correct alignment of the Doppler beam with transvalvular flow for measurement of velocity, gradient, and valve area. TTE also allows quantitation of LV volumes and LVEF, an estimate of pulmonary pressures, and evaluation of right heart function. However, the left atrial side of a prosthetic mitral valve is obscured by acoustic shadowing from the TTE approach, resulting in a low sensitivity for detection of prosthetic MR and prosthetic mitral valve thrombus, pannus, or vegetation. TEE provides superior images of the left atrial side of the mitral prosthesis and is accurate for diagnosis of prosthetic mitral valve dysfunction. However, both TTE and TEE are needed for complete evaluation in a patient with suspected prosthetic valve dysfunction, particularly for those with prosthetic aortic valves in whom the posterior aspect of the valve is shadowed on the TTE approach and the anterior aspect of the valve is shadowed on the TEE approach. With suspected mechanical valve stenosis, fluoroscopy or CT imaging of valve occluder motion is also helpful for detection of reduced motion due to pannus or thrombus.
Supporting References: (530,531)
Class IIa1. Annual TTE is reasonable in patients with a bioprosthetic valve after the first 10 years, even in the absence of a change in clinical status. (Level of Evidence: C)
The incidence of bioprosthetic valve dysfunction is low within 10 years of valve implantation but increases markedly after that point; as such, routine annual evaluation is a reasonable approach. Earlier evaluation may also be prudent in selected patients at increased risk of early bioprosthetic valve degeneration, including those with renal impairment, diabetes mellitus, abnormal calcium metabolism, systemic inflammatory disease, and in patients <60 years of age. Patients typically remain asymptomatic until valve dysfunction is severe enough to result in adverse hemodynamic consequences, such as LV dilation and systolic dysfunction, pulmonary hypertension, or AF. It may be challenging to distinguish a murmur due to prosthetic MR or AS from the normal postoperative flow murmur, and the diastolic murmurs of prosthetic AR and MS often are very soft and difficult to hear on auscultation. Depending on the valve type and mechanism of regurgitation, some patients with asymptomatic significant prosthetic valve regurgitation may require surgical intervention. For example, if prosthetic regurgitation is due to a bioprosthetic leaflet tear, more severe acute regurgitation may suddenly occur and cause clinical decompensation. Other asymptomatic patients with less severe prosthetic valve regurgitation or with stable valve anatomy can be monitored for evidence of progressive LV dilation and systolic dysfunction with the same criteria for timing of surgical intervention as those for native valve regurgitation. With prosthetic valve stenosis, echocardiographic diagnosis while the patient is asymptomatic alerts the clinician to the need for more frequent follow-up. Patients with asymptomatic prosthetic valve stenosis should be educated about symptoms, the likely need for repeat valve intervention, and the importance of promptly reporting new symptoms.
In patients with mechanical valve prostheses, routine annual echocardiographic evaluation is not needed if the postoperative baseline study is normal in the absence of signs or symptoms of valve dysfunction. However, many of these patients require TTE for other indications, such as residual LV systolic dysfunction, pulmonary hypertension, aortic disease, or concurrent valve disease.
Supporting References: (532,533)
11.1.2 Intervention: Recommendations
See Table 23 for a summary of recommendations for prosthetic valve choice.
Class I1. The choice of valve intervention, that is, repair or replacement, as well as type of prosthetic heart valve, should be a shared decision-making process that accounts for the patient’s values and preferences, with full disclosure of the indications for and risks of anticoagulant therapy and the potential need for and risk of reoperation. (Level of Evidence: C)
Summary of Recommendations for Prosthetic Valve Choice
The choice of valve prosthesis in an individual patient is based on consideration of several factors, including valve durability, expected hemodynamics for a specific valve type and size, surgical or interventional risk, the potential need for long-term anticoagulation, and patient preferences. Specifically, the tradeoff between risk of reoperation for bioprosthetic valve degeneration and the risk associated with long-term anticoagulation should be discussed in detail with the patient. Surgical or interventional risk for an individual patient is estimated by using the STS PROM score with the online calculator (Section 3.2.4). This information is discussed with the patient and family to allow for shared decision making about the timing and type of intervention. In a patient with a small aortic annulus, patient-prosthesis mismatch of the implanted prosthetic aortic valve may be avoided or reduced by consulting tables of prosthetic valve hemodynamics for the valve types and sizes being considered. Aortic annular enlarging procedures may be used when patient-prosthesis mismatch cannot be avoided with any available valve substitute.
Bioprosthetic valves avoid the need for long-term anticoagulation with VKA, such as warfarin, but have limited durability. The risk of need for reoperation with a bioprosthetic valve is inversely related to the patient’s age at the time of implantation, with a rate of structural deterioration 15 to 20 years after implantation of only 10% in patients 70 years of age at the time of implantation compared with 90% in those 20 years of age at the time of implantation. Mechanical valves are durable in patients of any age with a low risk of reoperation, and current VKA therapeutic management strategies are associated with a low risk of thromboembolism and bleeding. Some patients prefer to avoid repeat surgery and are willing to accept the risks and inconvenience of lifelong anticoagulant therapy. A mechanical valve might be prudent for patients in whom a second surgical procedure would be high risk; for example, those with prior radiation therapy or a porcelain aorta. Other patients are unwilling to consider long-term VKA therapy due to the inconvenience of monitoring, the attendant dietary and medication interactions, and the need to restrict participation in some types of athletic activity. In women who desire subsequent pregnancy, the issue of anticoagulation during pregnancy is a consideration (Section 13).
In patients who are being treated with long-term VKA anticoagulation before valve surgery, a mechanical valve may be appropriate, given its greater durability compared with a bioprosthetic valve and the need for continued VKA anticoagulation even if a bioprosthetic valve is implanted. However, if interruption of VKA therapy is necessary for noncardiac procedures, bridging therapy with other anticoagulants may be needed if a mechanical valve is present, whereas stopping and restarting VKA therapy for other indications may be simpler. Specific clinical circumstances, comorbid conditions, and patient preferences should be considered when deciding between a bioprosthetic and mechanical valve in patients receiving VKA therapy for indications other than the prosthetic valve itself.
Supporting References: (532,533,543–545)
Class I2. A bioprosthesis is recommended in patients of any age for whom anticoagulant therapy is contraindicated, cannot be managed appropriately, or is not desired. (Level of Evidence: C)
Anticoagulant therapy with VKA is necessary in all patients with a mechanical valve to prevent valve thrombosis and thromboembolic events. If anticoagulation is contraindicated or if the patient refuses VKA therapy, an alternate valve choice is appropriate.
Class IIa1. A mechanical prosthesis is reasonable for AVR or MVR in patients less than 60 years of age who do not have a contraindication to anticoagulation (534–536). (Level of Evidence: B)
In a prospective randomized study of 575 patients undergoing older-generation mechanical versus bioprosthetic valve replacement, overall survival was similar at 15 years in both groups. However, in patients <65 years of age undergoing AVR, primary valve failure occurred in 26% of those with a bioprosthetic valve compared with 0% of patients with a mechanical valve. Similarly, in those <65 years of age undergoing MVR, primary valve failure occurred in 44% of patients with a bioprosthetic mitral valve compared with 4% with a mechanical mitral valve (p=0.0001). In a propensity score−matched comparison of 103 patients <60 years of age undergoing mechanical versus biological AVR, those with a mechanical valve had lower mortality rates (HR: 0.243; 95% CI: 0.054 to 0.923; p=0.038) despite similar rates of valve-related complications. This is possibly related to better valve hemodynamics and the beneficial effects of anticoagulant therapy in those with a mechanical valve.
Overall, patients <60 years of age at the time of valve implantation have a higher incidence of primary structural deterioration and a reoperation rate as high as 40% for patients 50 years of age, 55% for patients 40 years of age, 75% for patients 30 years of age, and 90% for patients 20 years of age. Anticoagulation with VKA has an acceptable risk of complications in patients <60 years of age, particularly in compliant patients with appropriate monitoring of INR levels. Thus, the balance between valve durability versus risk of bleeding and thromboembolic events favors the choice of a mechanical valve in patients <60 years of age.
Supporting References: (533,536,546)
Class IIa2. A bioprosthesis is reasonable in patients more than 70 years of age (537–540). (Level of Evidence: B)
In patients >70 years of age at the time of bioprosthetic valve implantation, the likelihood of primary structural deterioration at 15 to 20 years is only about 10%. In addition, older patients are at higher risk of bleeding complications related to VKA therapy and more often require interruption of VKA therapy for noncardiac surgical and interventional procedures. In the United States, the expected number of remaining years of life at 70 years of age is 13.6 years for a man and 15.9 years for a woman; at 80 years of age the expected number of remaining years of life is 7.8 years for men and 9.3 years for women. Thus, it is reasonable to use a bioprosthetic valve in patients >70 years of age to avoid the risks of anticoagulation because the durability of the valve exceeds the expected years of life. Data from 41,227 patients in the Society for Cardiothoracic Surgery in the Great Britain and Ireland National database between 2004 and 2009 show that the proportion of patients >70 years of age who receive a biological prosthesis at the time of valve replacement has increased from 87% to 96%, with no evidence for an increase in adverse events.
Supporting References: (41,533,546)
Class IIa3. Either a bioprosthetic or mechanical valve is reasonable in patients between 60 and 70 years of age (541,542). (Level of Evidence: B)
Outcomes are similar with implantation of either a bioprosthetic or mechanical valve for patients between 60 and 70 years of age at the time of surgery. In the Edinburgh Heart Valve Study of 533 patients (mean age 54.4±10.4 years) undergoing valve surgery, there was no difference in long-term survival between those randomized to a Bjork-Shiley mechanical prosthesis or a porcine prosthesis (log-rank test: p=0.39). In a prospective randomized Italian study of 310 patients between 55 and 70 years of age, there was no difference in overall survival at 13 years between those receiving a mechanical valve compared with those who received a bioprosthetic valve. The linearized rates of thromboembolism, bleeding, IE, and major adverse prosthesis-related events were no different between the 2 valve types, but valve failures and reoperations were more frequent in the bioprosthetic valve group compared with the mechanical valve group (p=0.0001 and p=0.0003, respectively).
Although the evidence supports the use of either a mechanical or bioprosthetic valve in patients 60 to 70 years of age, patient preferences should also be considered. According to data on 41,227 patients in the Society for Cardiothoracic Surgery in the Great Britain and Ireland National database collected between 2004 and 2009, the proportion of patients 60 to 65 years of age who received a bioprosthesis at the time of valve replacement increased from 37% to 55%; in those 65 to 70 years of age, the proportion increased from 62% to 78%.
Supporting References: (532,533,543,546)
Class IIb1. Replacement of the aortic valve by a pulmonary autograft (the Ross procedure), when performed by an experienced surgeon, may be considered in young patients when VKA anticoagulation is contraindicated or undesirable. (Level of Evidence: C)
Replacement of the aortic valve with a pulmonary autograft (the Ross procedure) is a complex operation intended to provide an autologous substitute for the patient’s diseased aortic valve by relocating the pulmonic valve into the aortic position and subsequently replacing the pulmonic valve with a homograft. It is a surgical challenge and requires an experienced surgical team with exceptional surgical expertise. In the most experienced hands, hospital mortality can be similar to mortality for a simple bioprosthetic or mechanical valve replacement. Expansion of the Ross procedure to a broader group of surgeons with less focused experience has been difficult. The failure mode of the Ross procedure is most often due to regurgitation of the pulmonary autograft (the neoaortic valve) in the second decade after the operation. Regurgitation typically is due to leaflet prolapse if the autograft is implanted in the subcoronary position or to aortic sinus dilation if the autograft is implanted starting at the aortic sinuses. Surgical reinforcement techniques have been used to prevent dilation of the neoaortic sinuses. Some surgeons have advocated placing the pulmonic valve within a Dacron conduit. Still others have returned to placing the neoaortic valve in a subcoronary position with a reinforced native aorta. The outcome of these new procedures, with data extending into the second decade after operation, is not yet available.
In a small (n=228) RCT comparing pulmonary autografts with aortic valve allografts, the HR for death at 10 years was 4.61 (p=0.006) in those receiving an allograft compared with those with a pulmonary autograft AVR, with survival in the autograft group similar to an age-matched general population. Freedom from reoperation for the aortic sinuses and ascending aorta was 99% in the autograft group and 82% in the allograft group. Freedom from severe regurgitation of the neoaortic valve was 94% at 10 years. However, these outstanding results have not been generally replicated. In addition, an allograft valve is not the ideal comparator, given current outcomes with bioprosthetic valves.
In addition to reoperation for neoaortic valve regurgitation, at least half of the new pulmonic homograft valve implants will require intervention during the second decade. This is obviously a concern for young patients who began with single valve disease and then face a lifetime of dealing with both pulmonic homograft and neoaortic valve disease. Calcification of the homograft and adhesions between the homograft and neoaorta may increase the difficulty of reoperation.
The Ross procedure is an effective procedure in the hands of a small group of focused and experienced surgeons. It is a risky procedure in the hands of surgeons who perform it only occasionally. The procedure should be reserved for patients in whom anticoagulation is either contraindicated or very undesirable, and it should be performed only by surgeons experienced in complex surgery involving the aortic valve, sinuses, and ascending aorta.
Supporting References: (547–549)
See Online Data Supplement 20 for more information on choice of valve prosthesis.
11.2 Antithrombotic Therapy for Prosthetic Valves
11.2.1 Diagnosis and Follow-Up
Effective antithrombotic therapy in patients with mechanical heart valves requires continuous effective VKA anticoagulation with an INR in the target range. It is preferable to specify a single INR target in each patient, recognizing that the acceptable range is 0.5 INR units on each side of this target; this is preferable because it avoids patients having INR values consistently near the upper or lower edge of the range. In addition, fluctuations in INR are associated with increased incidence of complications in patients with prosthetic valves, so patients and caregivers should strive to attain the single INR value. The effects of VKA anticoagulation vary with the specific medication, absorption of medication, effects of various foods and medications, and changes in liver function. Most of the published studies on VKA therapy used warfarin, although other coumarin agents are used on a worldwide basis. In clinical practice, a program of patient education and close surveillance by an experienced healthcare professional with periodic monitoring of the INR is necessary. Patient monitoring by hospital-based anticoagulation clinics results in lower complication rates compared with standard care and is cost-effective due to lower rates of bleeding and hemorrhagic complications. Periodic direct patient contact and telephone encounters with the anticoagulation clinic pharmacists are equally effective in reducing complication rates. Self-monitoring with home INR measurement devices is another option for educated and motivated patients.
Supporting References: (550–555)
11.2.2 Medical Therapy: Recommendations
Class I1. Anticoagulation with a VKA and INR monitoring is recommended in patients with a mechanical prosthetic valve (556–558). (Level of Evidence: A)
All patients with mechanical valves require anticoagulant therapy. In addition to the thrombogenicity of the intravascular prosthetic material, mechanical valves impose abnormal flow conditions, with zones of low flow within their components, as well as areas of high-shear stress, which can cause platelet activation, leading to valve thrombosis and embolic events. Life-long therapy with an oral VKA at an INR goal appropriate for the comorbidity of the patient and the type and position of the mechanical valve prosthesis is recommended to decrease the incidence of thromboembolism and the associated morbidity (e.g., ischemic stroke, cerebrovascular accident, and peripheral systemic embolism). Cumulative data show that anticoagulation with a VKA is protective against valve thrombosis (OR: 0.11; 95% CI: 0.07 to 0.2) and thromboembolic events (OR: 0.21; 95% CI: 0.16 to 0.27).
Many centers initiate heparin early after surgery for anticoagulation until the INR reaches the therapeutic range. Bridging anticoagulation is typically started once postoperative bleeding is no longer an issue. Some centers use subcutaneous low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH), whereas other centers continue to prefer intravenous UFH.
Supporting References: (12,556,559,560)
Class I2. Anticoagulation with a VKA to achieve an INR of 2.5 is recommended in patients with a mechanical AVR (bileaflet or current-generation single tilting disc) and no risk factors for thromboembolism (561–563). (Level of Evidence: B)
The intensity of anticoagulation in a patient with a mechanical aortic valve prosthesis should be optimized so that protection from thromboembolism and valve thrombosis is achieved without excess risk of bleeding. The rate of thromboembolism in patients with bileaflet mechanical AVR on VKA and antiplatelet regimen is estimated to be 0.53% per patient-year over the INR range of 2.0 to 4.5. In a large retrospective study, adverse events increased if the INR was >4.0 in patients with mechanical AVR. In patients with the new-generation AVR without other risk factors for thromboembolism, the risk of thromboembolic events was similar, but the risk of hemorrhage was lower in the group with an INR of 2.0 to 3.0 versus the group with an INR of 3.0 to 4.5 (p<0.01). In a study comparing an INR target of 1.5 to 2.5 with the conventional 2.0 to 3.0 in 396 patients with low-risk mechanical aortic prosthetic valves and no other risk factors, the lower INR target was noninferior, but the quality of the evidence was low. Thus, for bileaflet and current-generation single tilting disc valve prostheses in the aortic position, an INR of 2.5 (between 2.0 and 3.0) provides a reasonable balance between optimal anticoagulation and a low risk of bleeding for mechanical aortic valves with a low thromboembolic risk.
Supporting Reference: (12)
Class I3. Anticoagulation with a VKA is indicated to achieve an INR of 3.0 in patients with a mechanical AVR and additional risk factors for thromboembolic events (AF, previous thromboembolism, LV dysfunction, or hypercoagulable conditions) or an older-generation mechanical AVR (such as ball-in-cage) (564). (Level of Evidence: B)
In patients with an aortic mechanical prosthesis who are at higher risk of thromboembolic complications, INR should be maintained at 3.0 (range 2.5 to 3.5). These patients include those with AF, previous thromboembolism, and a hypercoagulable state. Many would also include patients with severe LV dysfunction in this higher-risk group.
Supporting Reference: (12)
Class I4. Anticoagulation with a VKA is indicated to achieve an INR of 3.0 in patients with a mechanical MVR (564,565). (Level of Evidence: B)
In patients with mechanical prostheses, the incidence of thromboembolism is higher for the mitral than the aortic position, and the rate of thromboembolism is lower in patients with a higher INR goal compared with those with a lower target INR. In the GELIA (German Experience With Low Intensity Anticoagulation) study of patients with a mechanical mitral prosthesis, a lower INR (2.0 to 3.5) was associated with lower survival rates than a higher target INR range (2.5 to 4.5) in those with a second mechanical valve. Patient compliance may be challenging with higher INR goals. In 1 study, patients with a target INR between 2.0 and 3.5 were within that range 74.5% of the time. In contrast, patients with a target INR of 3.0 to 4.5 were within range only 44.5% of the time. An INR target of 3.0 (range 2.5 to 3.5) provides a reasonable balance between the risks of under- or overanticoagulation in patients with a mechanical mitral valve.
Supporting References: (12,562)
Class I5. Aspirin 75 mg to 100 mg daily is recommended in addition to anticoagulation with a VKA in patients with a mechanical valve prosthesis (566,567). (Level of Evidence: A)
Aspirin is recommended for all patients with prosthetic heart valves, including those with mechanical prosthetic valves receiving VKA therapy. Even with the use of VKA, the risk of thromboemboli is 1% to 2% per year.
The addition of aspirin 100 mg daily to oral VKA anticoagulation decreases the incidence of major embolism or death (1.9% versus 8.5% per year; p<0.001), with the stroke rate decreasing to 1.3% per year versus 4.2% per year (p<0.027) and overall mortality to 2.8% per year versus 7.4% per year (p<0.01). The addition of low-dose aspirin (75 mg to 100 mg per day) to VKA therapy (INR 2.0 to 3.5) also decreases mortality due to other cardiovascular diseases. The combination of low-dose aspirin and VKA is associated with a slightly increased risk of minor bleeding such as epistaxis, bruising, and hematuria, but the risk of major bleeding does not differ significantly between those who received aspirin (8.5%) versus those who did not (6.6%; p=0.43). The risk of GI irritation and hemorrhage with aspirin is dose dependent over the range of 100 mg to 1,000 mg per day, but the antiplatelet effects are independent of dose over this range. The addition of aspirin (75 mg to 100 mg per day) to VKA should be strongly considered unless there is a contraindication to the use of aspirin (i.e., bleeding or aspirin intolerance). This combination is particularly appropriate in patients who have had an embolus while on VKA therapy with a therapeutic INR, those with known vascular disease, and those who are known to be particularly hypercoagulable.
Supporting References: (12,568–571)
Class IIa1. Aspirin 75 mg to 100 mg per day is reasonable in all patients with a bioprosthetic aortic or mitral valve (572–575). (Level of Evidence: B)
The risk of a clinical thromboembolism is on average 0.7% per year in patients with biological valves in sinus rhythm; this figure is derived from several studies in which the majority of patients were not undergoing therapy with VKA. Among patients with bioprosthetic valves, those with mitral prostheses have a higher rate of thromboembolism than those with aortic prostheses in the long term (2.4% per patient-year versus 1.9% per patient-year, respectively). In a prospective study of bioprosthetic valves in patients with AVR who were in sinus rhythm and had no other indications for anticoagulation, the incidence of thromboembolic events, bleeding, and death was similar between those who received aspirin or aspirin-like antiplatelet agents only versus those who received VKA. There are no studies examining the long-term effect of antiplatelet agents in patients with bioprosthetic MVR or mitral valve repair, but the beneficial effects seen with bioprosthetic aortic valves are presumed to apply to mitral valves as well.
Supporting Reference: (12)
Class IIa2. Anticoagulation with a VKA is reasonable for the first 3 months after bioprosthetic MVR or repair to achieve an INR of 2.5 (576). (Level of Evidence: C)
The risk of ischemic stroke after all types of mitral valve surgery is about 2% at 30 days, 3% at 180 days, and 8% at 5 years. This is observed even with routine use of early heparin followed by VKA in patients with a mechanical valve or other indications for long-term anticoagulant therapy. The risk of ischemic stroke at 5 years is lower with mitral valve repair (6.1%±0.9%) compared with bioprosthetic (8.0%±2.1%) and mechanical valve replacement (16.1%±2.7%). In 1 study, patients with a bioprosthetic MVR who received anticoagulation had a lower rate of thromboembolism than those who did not receive therapy with VKA (2.5% per year with anticoagulation versus 3.9% per year without anticoagulation; p=0.05). However, another study showed that even with routine anticoagulation early after valve surgery, the incidence of ischemic stroke within the first 30 postoperative days was higher after replacement with a biological prosthesis (4.6%±1.5%; p<0.0001) than after mitral valve repair (1.5%±0.4%) or replacement with a mechanical prosthesis (1.3%±0.8%; p<0.001). Thus, anticoagulation with a target INR of 2.5 (range 2.0 to 3.0) is reasonable early after bioprosthetic mitral valve implantation.
Many centers start heparin as soon as the risk of surgical bleeding is acceptable (usually within 24 to 48 hours), with maintenance of a therapeutic partial thromboplastin time. After an overlap of heparin and VKA for 3 to 5 days, heparin may be discontinued when the INR reaches 2.5. After 3 months, the tissue valve can be treated like native valve disease, and VKA can be discontinued in more than two thirds of patients with biological valves. In the remaining patients with associated risk factors for thromboembolism, such as AF, previous thromboembolism, or hypercoagulable condition, lifelong VKA therapy is indicated to achieve an INR of 2 to 3.
Supporting References: (572–574,577–582)
Class IIb1. Anticoagulation, with a VKA, to achieve an INR of 2.5 may be reasonable for the first 3 months after bioprosthetic AVR (583). (Level of Evidence: B)
Patients with a bioprosthetic aortic valve are at a higher risk of ischemic stroke or peripheral embolism than the normal population, particularly in the first 90 days after valve replacement. Anticoagulation early after valve implantation is intended to decrease the risk of thromboembolism until the prosthetic valve is fully endothelialized. The potential benefit of anticoagulation therapy must be weighed against the risk for bleeding, particularly in patients who are at low risk for thromboembolism (e.g., those in sinus rhythm with normal LV function, no history of thromboembolism, or history of hypercoagulable conditions). Small RCTs have not established benefit for anticoagulation after implantation of a bioprosthetic AVR; however, a large observational registry demonstrated benefit without a significantly increased bleeding risk. In 4,075 patients undergoing isolated bioprosthetic AVR with a median duration of follow-up of 6.57 person-years, the estimated rate of strokes per 100 person-years was 7.00 (95% CI: 4.07 to 12.06) in patients not treated with VKA versus 2.69 (95% CI: 1.49 to 4.87) in those treated with VKA (HR: 2.46; 95% CI: 1.09 to 5.55). The lower event rates in those on VKA persisted at 6 months, with a cardiovascular death rate of 6.50 per 100 person-years (95% CI: 4.67 to 9.06) in those not on VKA therapy compared with 2.08 (95% CI: 0.99 to 4.36) in those on VKA therapy (adjusted internal rate of return: 3.51; 95% CI: 1.54 to 8.03) for events within 90 to 179 days after surgery. Thus, anticoagulation with an INR target of 2.5 (range 2.0 to 3.0) may be reasonable for at least 3 months, and perhaps as long as 6 months, after bioprosthetic AVR.
Supporting References: (572,574,583–586)
Class IIb2. Clopidogrel 75 mg daily may be reasonable for the first 6 months after TAVR in addition to life-long aspirin 75 mg to 100 mg daily. (Level of Evidence: C)
During TAVR, a biological prosthesis mounted on a metallic expandable frame is inserted transcutaneously within the native aortic valve with stenosis. In prospective RCTs of balloon-expandable TAVR for treatment of AS, the research protocol included dual antiplatelet therapy with aspirin and clopidogrel for the first 6 months to minimize the risk of thromboembolism. The current recommendation is based on outcomes in these published studies, although the issue of antiplatelet therapy was not assessed. A small prospective, RCT, single-center study of 79 patients receiving self-expanding TAVR did not show a difference in the composite of major adverse cardiac and cerebrovascular events, defined as death from any cause, MI, major stroke, urgent or emergency conversion to surgery, or life-threatening bleeding between aspirin and clopidogrel versus aspirin alone at both 30 days (13% versus 15%; p=0.71) and 6 months (18% versus 15%; p=0.85).
Supporting References: (79,170,587,588)
Class III: Harm1. Anticoagulant therapy with oral direct thrombin inhibitors or anti-Xa agents should not be used in patients with mechanical valve prostheses (589–591). (Level of Evidence: B)
The U.S. Food and Drug Administration has approved new anticoagulants that are direct thrombin inhibitors or factor Xa inhibitors (dabigatran, apixaban, and rivaroxaban) for anticoagulant prophylaxis in patients with AF not caused by VHD. Several case reports have demonstrated thrombosis on mechanical heart valves despite therapeutic dosing with dabigatran. The RE-ALIGN (Randomized, Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients after Heart Valve Replacement) trial was stopped prematurely for excessive thrombotic complications in the dabigatran arm. After enrollment of 252 patients, ischemic or unspecified stroke occurred in 9 patients (5%) randomized to dabigatran compared with no patients treated with warfarin. In the dabigatran group, 15 patients (9%) reached the composite endpoint of stroke, transient ischemic attack, systemic embolism, MI, or death compared with 4 patients (5%) in the warfarin group (HR in the dabigatran group: 1.94; 95% CI: 0.64 to 5.86; p=0.24). In addition, a major bleeding episode occurred in 7 patients (4%) in the dabigatran group and 2 patients (2%) in the warfarin group, and bleeding of any type occurred in 45 patients (27%) and 10 patients (12%), respectively (HR: 2.45; 95% CI: 1.23 to 4.86; p=0.01). The Food and Drug Administration has issued a specific contraindication for use of this product in patients with mechanical heart valves. These agents are also not recommended, due to lack of data on their safety and effectiveness, in patients with bioprosthetic valves who require anticoagulation.
Supporting References: (591–594)
11.3 Bridging Therapy for Prosthetic Valves
11.3.1 Diagnosis and Follow-Up
The management of patients with mechanical heart valves in whom interruption of anticoagulation therapy is needed for diagnostic or surgical procedures should take into account the type of procedure, risk factors, and type, location, and number of heart valve prosthesis(es).
11.3.2 Medical Therapy: Recommendations
Class I1. Continuation of VKA anticoagulation with a therapeutic INR is recommended in patients with mechanical heart valves undergoing minor procedures (such as dental extractions or cataract removal) where bleeding is easily controlled. (Level of Evidence: C)
Management of antithrombotic therapy must be individualized, but some generalizations apply. Antithrombotic therapy should not be stopped for procedures in which bleeding is unlikely or would be inconsequential if it occurred (i.e., surgery on the skin, dental cleaning, or simple treatment for dental caries). Eye surgery, particularly for cataracts or glaucoma, is usually associated with very little bleeding and thus is frequently performed without alterations to antithrombotic treatment.
Class I2. Temporary interruption of VKA anticoagulation, without bridging agents while the INR is subtherapeutic, is recommended in patients with a bileaflet mechanical AVR and no other risk factors for thrombosis who are undergoing invasive or surgical procedures. (Level of Evidence: C)
The risk of increased bleeding during a procedure performed with a patient receiving antithrombotic therapy has to be weighed against the increased risk of a thromboembolism caused by stopping the therapy. In patients with a bileaflet mechanical aortic valve and no other risk factors for thromboembolism, the risk of stopping VKA is relatively slight if the drug is withheld for only a few days. In these low-risk patients, the inconvenience and expense of bridging anticoagulation can be avoided. When it is necessary to interrupt VKA therapy, VKA is stopped 2 to 4 days before the procedure (so the INR falls to <1.5 for major surgical procedures) and restarted as soon as bleeding risk allows, typically 12 to 24 hours after surgery.
Supporting References: (595,596)
Class I3. Bridging anticoagulation with either intravenous UFH or subcutaneous LMWH is recommended during the time interval when the INR is subtherapeutic preoperatively in patients who are undergoing invasive or surgical procedures with a 1) mechanical AVR and any thromboembolic risk factor, 2) older-generation mechanical AVR, or 3) mechanical MVR. (Level of Evidence: C)
In patients at higher risk of thromboembolism during interruption of VKA anticoagulation, the risk of an adverse event can be minimized by anticoagulation with alternative agents that can be stopped right before and restarted right after the surgical procedure (e.g., “bridging therapy”). Patients at high risk of thrombosis include all patients with mechanical MVR or tricuspid valve replacements and patients with an AVR and any risk factors for thromboembolism. Such risk factors include AF, previous thromboembolism, hypercoagulable condition, older-generation mechanical valves, LV systolic dysfunction (LVEF <30%), or >1 mechanical valve.
When interruption of VKA therapy is needed, VKA is stopped 2 to 4 days before the procedure (so the INR falls to <1.5 for major surgical procedures) and restarted as soon as bleeding risk allows, typically 12 to 24 hours after surgery. Bridging anticoagulation with intravenous UFH or subcutaneous LMWH is started when INR is <2.0 (usually about 48 hours before surgery) and stopped 4 to 6 hours (for intravenous UFH) or 12 hours (for subcutaneous LMWH) before the procedure. When LMWH is used, therapeutic weight-adjusted doses are given twice daily. One study of bridging therapy for interruption of VKA included 215 patients with mechanical valves. In the total group of 650 patients, the risk of thromboembolism (including possible events) was 0.62%, with 95% CI: 0.17% to 1.57%. Major bleeding occurred in 0.95% (0.34% to 2.0%). Most studies using LMWH used enoxaparin for therapy. The use of bridging heparin after surgery must be individualized, depending on risk of bleeding and risk of thrombosis.
The acceptable level of anticoagulation in patients undergoing cardiac catheterization depends on the specific procedure being performed. For procedures with a low bleeding risk, such as coronary angiography from the radial approach, only slight modification in VKA dosing is needed. With interventional procedures at higher risk, many clinicians prefer to stop VKA anticoagulation and use bridging therapy as is done for other surgical procedures.
Supporting References: (597–599)
Class IIa1. Administration of fresh frozen plasma or prothrombin complex concentrate is reasonable in patients with mechanical valves receiving VKA therapy who require emergency noncardiac surgery or invasive procedures. (Level of Evidence: C)
Because VKA inhibits production of several proteins involved in the coagulation cascade, the anticoagulant effect persists until adequate levels of these proteins are achieved after stopping warfarin therapy, a process that takes at least 48 to 72 hours. In patients with mechanical valves on long-term warfarin therapy who require emergency surgery or invasive procedures, anticoagulation can be reversed by administration of fresh frozen plasma or intravenous prothrombin complex concentrate. Administration of low-dose (1 mg to 2 mg) oral vitamin K may be added because the effect of fresh frozen plasma or prothrombin complex has a shorter half-life than the effects of VKA therapy. Higher doses of vitamin K are discouraged to avoid difficulty in achieving a therapeutic INR after the procedure.
Supporting References: (600–602)
See Online Data Supplement 21 for more information on bridging therapy.
11.4 Excessive Anticoagulation and Serious Bleeding With Prosthetic Valves: Recommendation
See Figure 6 for anticoagulation for prosthetic valves.
Class IIa1. Administration of fresh frozen plasma or prothrombin complex concentrate is reasonable in patients with mechanical valves and uncontrollable bleeding who require reversal of anticoagulation (601,602). (Level of Evidence: B)
Anticoagulation for Prosthetic Valves
Risk factors include AF, previous thromboembolism, LV dysfunction, hypercoagulable condition, and older-generation mechanical AVR.
AF indicates atrial fibrillation; ASA, aspirin; AVR, aortic valve replacement; INR, international normalized ratio; LMWH, low-molecular-weight heparin; MVR, mitral valve replacement; PO, by mouth; QD, every day; SC, subcutaneous; TAVR, transcatheter aortic valve replacement; UFH, unfractionated heparin; and VKA, vitamin K antagonist.
Excessive anticoagulation (INR ≥5) greatly increases the risk of hemorrhage. However, a rapid decrease in the INR that leads to INR falling below the therapeutic level increases the risk of thromboembolism. High-dose vitamin K should not be given routinely, because this may create a hypercoagulable condition. In most patients with an INR of 5 to 10, excessive anticoagulation can be managed by withholding VKA and monitoring the level of anticoagulation with serial INR determinations. In patients with an INR >10 who are not bleeding, it is prudent to administer 1 mg to 2.5 mg of oral vitamin K1 (phytonadione) in addition to holding VKA therapy. When the INR falls to a safe level, VKA therapy is restarted with the dose adjusted as needed to maintain therapeutic anticoagulation. In emergency situations, such as uncontrollable bleeding, administration of fresh frozen plasma or prothrombin complex concentrate is reasonable because the onset of action of vitamin K is very slow.
Supporting References: (600,603)
11.5 Thromboembolic Events With Prosthetic Valves
11.5.1 Diagnosis and Follow-Up
The annual risk of thromboembolic events in patients with a mechanical heart valve is 1% to 2% versus 0.7% with a bioprosthetic valve, even with appropriate antithrombotic therapy. Many complications are likely related to suboptimal anticoagulation; even in clinical trials, the time in therapeutic range for patients on VKA varies from only 60% to 70%. However, embolic events do occur even in patients who are in the therapeutic range at every testing interval. Annual follow-up in patients with prosthetic heart valves should include review of the adequacy of anticoagulation and any issues related to compliance with medical therapy. Screening questions for symptoms that may be related to embolic events are especially important if anticoagulation has been suboptimal. Patients should be educated about symptoms related to embolic events and instructed to promptly report to a healthcare provider should symptoms occur. TTE is the first step in evaluation of suspected prosthetic valve thromboembolism to evaluate valve hemodynamics in comparison to previous studies, and TEE often is needed, particularly for mitral prosthetic valves. However, the prosthetic valve should be considered the source of thromboembolism even if echocardiographic findings are unchanged.
11.5.2 Medical Therapy
In patients on VKA anticoagulation and aspirin 75 mg to 100 mg daily for a mechanical valve who have a definite embolic episode, it is important to document the adequacy of the anticoagulation, including the time within therapeutic range. If there have been periods in which the INR has been documented to be subtherapeutic, appropriate steps to ensure adequate anticoagulation should be taken. If embolic events have occurred despite a therapeutic INR when other contraindications are not present, a prudent approach to antithrombotic therapy is:
• Increase the INR goal from 2.5 (range 2.0 to 3.0) to 3.0 (range 2.5 to 3.5) for patients with an AVR; or, increase the INR goal from 3.0 (range 2.5 to 3.5) to 4.0 (range 3.5 to 4.5) for patients with an MVR.
In patients with a bioprosthetic valve with embolic events who are only on aspirin 75 mg to 100 mg daily, a possible approach includes consideration of anticoagulation with a VKA.
11.5.3 Intervention
Embolic events in patients with prosthetic heart valves should be managed by ensuring optimal anticoagulation and antiplatelet therapy. Measures to improve patient compliance, including patient education and more frequent monitoring, should be instituted. Studies show that patients on anticoagulation with VKA who are managed by a dedicated pharmacist-led anticoagulation clinic have lower rates of bleeding and thromboembolism compared with conventional monitoring by a clinician’s office. Surgical intervention is rarely needed for recurrent thromboembolic events but might be considered in some situations. In patients with degenerated bioprosthetic valves, calcific emboli may complicate thrombotic embolism, often in association with prosthetic valve stenosis and/or regurgitation. In patients with mechanical valves who have recurrent serious adverse effects of over- or underanticoagulation despite all efforts to improve compliance, replacement of the mechanical valve with a bioprosthetic valve might be considered after a discussion of the potential risks and benefits of this approach.
11.6 Prosthetic Valve Thrombosis
See Figure 7 for evaluation and management of suspected valve thrombosis.
Evaluation and Management of Suspected Prosthetic Valve Thrombosis
*See text for dosage recommendations.
CT indicates computed tomography; IV, intravenous; NYHA, New York Heart Association; Rx, therapy; TEE, transesophageal echocardiography; and TTE, transthoracic echocardiography.
11.6.1 Diagnosis and Follow-Up: Recommendations
Class I1. TTE is indicated in patients with suspected prosthetic valve thrombosis to assess hemodynamic severity and follow resolution of valve dysfunction (604,605). (Level of Evidence: B)
Obstruction of prosthetic heart valves may be caused by thrombus formation, pannus ingrowth, or a combination of both. Mechanical prosthetic heart valve thrombosis has a prevalence of only 0.3% to 1.3% per patient-year in developed countries but is as high as 6.1% per patient-year in developing countries. Bioprosthetic valve thrombosis is less common. Differentiation of valve dysfunction due to thrombus versus fibrous tissue ingrowth (pannus) is challenging because the clinical presentations are similar. Thrombus is more likely when there is a history of inadequate anticoagulation and with more acute onset of valve dysfunction and symptoms. Although fluoroscopy or CT imaging can be used to evaluate the leaflet motion of an obstructed mechanical prosthesis, the etiology and hemodynamic impact are best evaluated by echocardiography. TTE allows evaluation of valve hemodynamics and detection of valve stenosis or regurgitation. Leaflet motion and thrombus may be visualized in some patients, but TEE is more sensitive for detection of valve thrombosis, especially of the mitral valve. Transthoracic imaging also allows measurement of LV size and systolic function, left atrial size, right heart function, and an estimation of pulmonary pressures.
Clinical evaluation, including auscultation of diminished or abolished clicks together with new systolic or diastolic murmurs, is the first step in the routine assessment of patients with a prosthetic heart valve but is unreliable for detection of valve thrombosis. TTE allows detection of prosthetic valve dysfunction and quantitation of stenosis and regurgitation but is inadequate for evaluation of the presence and size of thrombus or valve occluder motion.
Class I2. TEE is indicated in patients with suspected prosthetic valve thrombosis to assess thrombus size and valve motion (605–607). (Level of Evidence: B)
TEE allows direct imaging of mechanical valve thrombosis, particularly for thrombi on the left atrial side of the mitral valve, which is obscured by shadowing on TTE imaging. Compared with chronic fibrous ingrowth or pannus, thrombi tend to be larger, less dense, and more mobile than pannus on ultrasound imaging. Thrombus size, measured on TEE, is a significant independent predictor of outcome after thrombolysis of an obstructed prosthetic heart valve. Multivariate analysis of 107 patients with thrombosed heart valve prostheses revealed that prior history of stroke (OR: 4.55; 95% CI: 1.35 to 15.38) and thrombus area by TEE (OR: 2.41 per 1.0 cm2; CI: 1.12 to 5.19) were independent predictors of complications after thrombolysis. A thrombus area <0.8 cm2 identified patients at lower risk for complications from thrombolysis, irrespective of NYHA classification. TEE should be used to identify lower-risk patients for thrombolysis.
Supporting References: (605–607)
Class IIa1. Fluoroscopy or CT is reasonable in patients with suspected valve thrombosis to assess valve motion. (Level of Evidence: C)
Fluoroscopy and CT are alternative imaging techniques for evaluation of mechanical valve “leaflet” motion, particularly in patients with prosthetic aortic valves, which are difficult to image by either TTE or TEE. CT is best suited for measurement of valve opening angles because 3D image acquisition allows postacquisition analysis from multiple views. CT imaging may also allow visualization of pannus or thrombus in patients with mechanical or bioprosthetic valves.
11.6.2 Medical Therapy: Recommendations
Class IIa1. Fibrinolytic therapy is reasonable for patients with a thrombosed left-sided prosthetic heart valve, recent onset (<14 days) of NYHA class I to II symptoms, and a small thrombus (<0.8 cm2) (605,608). (Level of Evidence: B)
Although fibrinolytic therapy of a left-sided obstructed prosthetic heart valve is associated with an overall rate of thromboembolism and bleeding of 17.8%, the degree of risk is directly related to thrombus size. When thrombus area is measured in the 2D TEE view showing the largest thrombus size, an area of 0.8 cm2 provides a useful breakpoint for clinical decision making. A mobile thrombus or a length >5 mm to 10 mm is also associated with increased embolic risk. Patients with a small thrombus (<1.0 cm in diameter or 0.8 cm2 in area) have fewer thrombolysis-related complications, whereas those with a large thrombus (>1.0 cm diameter or 0.8 cm2 in area) have a 2.4–fold higher rate of complications per 1.0 cm2 increase in size. Factors that identify patients at risk for adverse outcomes of fibrinolytic therapy include active internal bleeding, history of hemorrhagic stroke, recent cranial trauma or neoplasm, diabetic hemorrhagic retinopathy, large thrombi, mobile thrombi, systemic hypertension (>200 mm Hg/120 mm Hg), hypotension or shock, and NYHA class III to IV symptoms.
With mild symptoms due to aortic or mitral valve thrombosis with a small thrombus burden, it is prudent to reassess after several days of intravenous UFH. If valve thrombosis persists, fibrinolysis with a recombinant tissue plasminogen activator dose of a 10 mg IV bolus followed by 90 mg infused IV over 2 hours is reasonable. Heparin and glycoprotein IIb/IIIa inhibitors are held, but aspirin can be continued. A lower tissue plasminogen activator dose of a 20 mg IV bolus followed by 10 mg per hour for 3 hours may be appropriate in some situations. Alternatively, streptokinase may be used with a loading dose of 500,000 IU in 20 minutes followed by 1,500,000 IU over 10 hours. Urokinase is less effective than tissue plasminogen activator or streptokinase. If fibrinolytic therapy is successful, it is followed by intravenous UFH until VKA achieves an INR of 3.0 to 4.0 for aortic prosthetic valves and 3.5 to 4.5 for mitral prosthetic valves. A structured institutional protocol with indications, contraindications, and a specific timeline for medication administration and patient monitoring is recommended.
After treatment of the acute thrombotic event, it is important to always determine the adequacy of anticoagulation before the event and ensure that there is meticulous follow-up after the event. The anticoagulation regimen can be increased as outlined in Section 11.5.2.
Supporting References: (609,610)
Class IIa2. Fibrinolytic therapy is reasonable for thrombosed right-sided prosthetic heart valves (611,612). (Level of Evidence: B)
In nonrandomized, retrospective cohorts of thrombosed mechanical or biological tricuspid valve prostheses, fibrinolysis was as successful in normalization of hemodynamics as surgical intervention. With fibrinolysis of right-sided valve thrombosis, the resultant small pulmonary emboli appear to be well tolerated and systemic emboli are uncommon.
See Online Data Supplement 22 for more information on fibrinolytic therapy.
11.6.3 Intervention: Recommendations
Class I1. Emergency surgery is recommended for patients with a thrombosed left-sided prosthetic heart valve with NYHA class III to IV symptoms (610,611,613). (Level of Evidence: B)
Prompt surgical treatment of a thrombosed prosthetic heart valve is an effective treatment to ameliorate clinical symptoms and restore normal hemodynamics, with a success rate close to 90% in patients who do not have a contraindication to surgical intervention. In contrast, a meta-analysis of 7 studies that included 690 episodes of left-sided prosthetic valve thrombosis showed a success rate for restoring normal valve function of only about 70% in 244 cases treated with fibrinolytic therapy. There was no difference in mortality between surgical and fibrinolytic therapy for left-sided prosthetic valve thrombosis, but in addition to a higher success rate for restoring normal valve function, surgery was associated with lower rates of thromboembolism (1.6% versus 16%), major bleeding (1.4% versus 5%), and recurrent prosthetic valve thrombosis (7.1% versus 25.4%). Although RCTs have not been performed, the weight of the evidence favors surgical intervention for left-sided prosthetic valve thrombosis unless the patient is asymptomatic and the thrombus burden is small.
Supporting References: (605,613,614)
Class IIa1. Emergency surgery is reasonable for patients with a thrombosed left-sided prosthetic heart valve with a mobile or large thrombus (>0.8 cm2) (605,607,610). (Level of Evidence: C)
Prompt surgical treatment of a thrombosed prosthetic heart valve is associated with a relatively low rate of mortality. In a retrospective study of 106 surgeries for obstructed left-sided prosthetic heart valves, the mortality rate was 17.5% for patients with NYHA class IV symptoms and 4.7% in those patients with NYHA class I to III symptoms. Mortality was similar for removing the thrombus or replacing the entire prosthetic valve. Patients with large, mobile clots that extend beyond the prosthesis are better suited for surgical intervention than fibrinolysis, which is associated with significant risk of systemic embolism. In 1 report, in which patients with small thrombus burden (<0.8 cm2 on TEE imaging) had minimal thrombolysis-related complications, those with large thrombus burden (≥0.8 cm2) had a 2.4–fold higher rate of complications per 1.0 cm2 increase in size, making surgery the optimal intervention. In patients with recent hemorrhagic stroke, surgery is a better choice because of the bleeding risks associated with fibrinolysis.
11.7 Prosthetic Valve Stenosis
11.7.1 Diagnosis and Follow-Up
Reoperation to replace a prosthetic heart valve is a serious clinical event. It is usually required for moderate-to-severe prosthetic dysfunction (structural and nonstructural), dehiscence, and prosthetic valve endocarditis (PVE). Causes of prosthetic valve stenosis that might require reoperation with a mechanical valve include chronic thrombus or pannus impinging on normal leaflet occluder motion; for a bioprosthetic valve, leaflet fibrosis and calcification are the most common causes. Reoperation may also be needed for recurrent thromboembolism, severe intravascular hemolysis, severe recurrent bleeding from anticoagulant therapy, and thrombosed prosthetic valves.
In some patients, the size of the prosthetic valve that can be implanted results in inadequate blood flow to meet the metabolic demands of the patient, even when the prosthetic valve itself is functioning normally. This situation, called “patient-prosthesis mismatch” (defined as an indexed effective orifice area ≤0.85 cm2/m2 for aortic valve prostheses), is a predictor of a high transvalvular gradient, persistent LV hypertrophy, and an increased rate of cardiac events after AVR. The impact of a relatively small valve area is most noticeable with severe patient-prosthesis mismatch, defined as an orifice area <0.65 cm2/m2. Patient-prosthesis mismatch is especially detrimental in patients with reduced LVEF and may decrease the likelihood of resolution of symptoms and improvement in LVEF. Patient-prosthesis mismatch can be avoided or reduced by choosing a valve prosthesis that will have an adequate indexed orifice area, based on the patient’s body size and annular dimension. In some cases, annular enlargement or other approaches may be needed to allow implantation of an appropriately sized valve or avoidance of a prosthetic valve. With bileaflet mechanical valves, patterns of blood flow are complex and significant pressure recovery may be present; this may result in a high velocity across the prosthesis that should not be mistaken for prosthetic valve stenosis or patient-prosthesis mismatch.
In patients with bioprosthetic valves who show evidence of prosthetic valve stenosis, TTE is used to monitor the appearance of the valve leaflets, valve hemodynamics, LV size, and systolic function, and to estimate pulmonary pressures. Transthoracic imaging is usually adequate, with TEE imaging reserved for patients with poor-quality images. In patients with mechanical valves, fluoroscopy or CT imaging can be helpful for showing disc motion. CT may also visualize paravalvular pannus formation with either bioprosthetic or mechanical valves.
Supporting References: (527,528,544,615,616)
11.7.2 Medical Therapy
There are no medical therapies known to prevent bioprosthetic valve degeneration other than those integrated into the valve design. Medical therapy is not effective for treatment of symptoms due to significant prosthetic valve stenosis, except with valve thrombosis, but standard medical therapy may help stabilize patients before surgical intervention and may be used for palliative care in patients who are not surgical candidates.
11.7.3 Intervention: Recommendation
Class I1. Repeat valve replacement is indicated for severe symptomatic prosthetic valve stenosis. (Level of Evidence: C)
The indications for surgical intervention for prosthetic valve stenosis are the same as those for native stenosis of the aortic or mitral valve. Surgery is primarily needed for bioprosthetic valve degeneration. In this situation, the choice of a new valve prosthesis depends on the same factors as those for patients undergoing a first valve replacement. The use of transcatheter valve prostheses to treat bioprosthetic valve stenosis with a “valve-in-valve” approach is promising but not yet fully validated.
Mechanical valve stenosis is rare and typically due to valve thrombosis or pannus formation. If patient noncompliance contributed to valve thrombosis, it is prudent to consider a bioprosthetic valve at the time of reoperation. With attention to optimal valve selection, a second surgical procedure for significant patient-prosthesis mismatch is rarely needed and should be considered only if a larger prosthetic valve or a valve type with better hemodynamics can be implanted.
11.8 Prosthetic Valve Regurgitation
11.8.1 Diagnosis and Follow-Up
In patients with bioprosthetic valves who show evidence of prosthetic valve regurgitation, TTE is used to monitor the appearance of the valve leaflets, valve hemodynamics, LV size, and systolic function, and to estimate pulmonary pressures. The initial approach is TTE for evaluation of antegrade valve velocities and pressure gradients. However, TEE is essential for evaluation of suspected or known prosthetic mitral valve regurgitation. On TTE imaging, the LA is shadowed by the valve prosthesis, obscuring evidence of prosthetic regurgitation. TEE imaging provides clear images of the left atrial side of the mitral prosthesis and is particularly useful for delineation of the site and severity of paravalvular regurgitation, evaluation of suitability for a percutaneous approach, and guidance during percutaneous closure procedures.
11.8.2 Medical Therapy
Bioprosthetic valve regurgitation is typically due to leaflet degeneration and calcification. There are no medical therapies known to prevent bioprosthetic valve degeneration other than those integrated into the valve design. Pathological regurgitation of a mechanical prosthetic valve is typically due to a paravalvular leak or pannus limiting normal occluder closure. Medical therapy is not effective for treatment of symptoms due to significant prosthetic valve regurgitation, but standard approaches may help stabilize patients before surgical intervention and may be used for palliative care in patients who are not surgical candidates.
11.8.3 Intervention: Recommendations
Class I1. Surgery is recommended for operable patients with mechanical heart valves with intractable hemolysis or HF due to severe prosthetic or paraprosthetic regurgitation (617,618). (Level of Evidence: B)
The indications for surgical intervention for prosthetic valve regurgitation include the same indications for native regurgitation of the aortic or mitral valve. Specifically, indicators are evidence of LV systolic dysfunction, including a low LVEF or progressive LV dilation; the same cut-off points should be used as defined for native valve disease. Paravalvular regurgitation may also result in hemolytic anemia; often this is mild and is managed medically but may be refractory in some patients. Paravalvular regurgitation may be treated by replacing the dysfunctional valve with a new valve or by repairing the paravalvular defect.
Supporting Reference: (619)
Class IIa1. Surgery is reasonable for operable patients with severe symptomatic or asymptomatic bioprosthetic regurgitation. (Level of Evidence C)
Bioprosthetic valve degeneration results in regurgitation due to leaflet calcification and noncoaptation or leaflet degeneration with a tear or perforation. Even in asymptomatic patients with severe bioprosthetic regurgitation, valve replacement is reasonable due to the risk of sudden clinical deterioration if further leaflet tearing occurs. The choice of type of valve prosthesis in a patient undergoing reoperation depends on the same factors as those for patients undergoing a first valve replacement. The use of transcatheter valve prostheses to treat bioprosthetic valve regurgitation with a “valve-in-valve” approach is promising but is not yet fully validated. Paravalvular regurgitation can also occur with a bioprosthetic valve. New paravalvular regurgitation may be due to IE or suture disruption from mechanical causes. Blood cultures should be obtained when new paravalvular regurgitation is detected.
Class IIa2. Percutaneous repair of paravalvular regurgitation is reasonable in patients with prosthetic heart valves and intractable hemolysis or NYHA class III/IV HF who are at high risk for surgery and have anatomic features suitable for catheter-based therapy when performed in centers with expertise in the procedure (620–622). (Level of Evidence B)
Surgery is a viable therapeutic option in many patients with symptomatic paravalvular prosthetic regurgitation. However, in some patients, surgery to replace a prosthetic valve with significant paravalvular regurgitation may carry significant operative risk due to the need for reoperation and patient comorbidity. Recent studies have demonstrated clinical success with percutaneous approaches, in which operators use complex catheter techniques and a variety of occluder devices to reduce paravalvular regurgitation. Procedural success rates with percutaneous closure, typically defined by no more than mild residual regurgitation and the absence of death and major complications, have been reported to be 80% to 85% in centers with expertise in the procedure. Major complications, nonetheless, occur in 9% of patients, mainly due to vascular injury, cardiac perforation, and bleeding (procedural death, <2%). The degree of residual regurgitation directly affects symptom improvement and survival free of adverse events. Treatment of HF symptoms is more successful than treatment of hemolysis. Due to the complexity of these procedures, consideration should be given to their performance in centers of expertise under the guidance of a multidisciplinary team.
Supporting References: (620–629)
See Online Data Supplement 23 for more information on paravalvular regurgitation.
12 Infective Endocarditis
See Online Data Supplement 24 for more information on surgical outcomes.
12.1 IE: Overview
IE has a high mortality rate, even with appropriate antibiotic therapy and surgical intervention, with an in-hospital mortality rate of 15% to 20% and a 1–year mortality rate approaching 40%. The overall incidence of IE is 3 to 10 per 100,000 patient-years, with a higher prevalence in older patients. In underdeveloped countries, IE is most often associated with rheumatic heart disease. In developed countries, IE is increasingly associated with prosthetic valve and intracardiac devices, with a risk of IE 50 times higher in patients with a prosthetic valve compared with the general population. IE also may be associated with intravenous drug use, diabetes mellitus, or immunosuppression. Despite differences in associated risk factors and clinical outcomes, there are few differences in the recommendations for diagnosis and treatment of NVE versus PVE. In this guideline, there is 1 set of recommendations for diagnosis and management of all types of IE. Recommendations for prevention of IE are included in Section 2.
Antimicrobial therapy is the cornerstone of therapy for IE. The specific antimicrobial agents and duration of therapy should be guided by the susceptibility profile of the causative organism. Temporal and geographic variability in causative organisms and antimicrobial susceptibility profiles mandate concomitant management with an infectious disease specialist. Details of specific antimicrobial regimens have previously been published by the AHA, European Society of Cardiology, and British Society for Antimicrobial Chemotherapy and are not repeated in this guideline.
In addition to antibiotic therapy, early surgical intervention is often needed for effective treatment of infection and to manage the sequelae of valve leaflet and paravalvular tissue destruction. Decisions about whether surgical intervention is needed and the optimal timing of intervention are complex. Most of the indications for surgical intervention are the same for NVE and PVE and are included in 1 recommendation for both when possible. Appropriate management of patients with IE requires a Heart Valve Team approach, initiated as soon as a diagnosis of probable or definite IE is confirmed, with specialists in cardiology, cardiothoracic surgery, and infectious disease all involved in patient care and decision making.
Supporting References: (52,278,630–635)
12.2 Infective Endocarditis
See Online Data Supplement 24 for more information on surgical outcomes.
12.2.1 Diagnosis and Follow-Up: Recommendations
See Figure 8 for recommendations for imaging studies in NVE and PVE.
Class I1. At least 2 sets of blood cultures should be obtained in patients at risk for IE (e.g., those with congenital or acquired VHD, previous IE, prosthetic heart valves, certain congenital or heritable heart malformations, immunodeficiency states, or injection drug users) who have unexplained fever for more than 48 hours (636) (Level of Evidence: B) or patients with newly diagnosed left-sided valve regurgitation. (Level of Evidence: C)
Recommendations for Imaging Studies in NVE and PVE
*Repeat TEE and/or TTE re-commended for re-evaluation of patients with IE and a change in clinical signs or symptoms and in patients at high risk of complications.
CT indicates computed tomography; IE, infective endocarditis; NVE, native valve endocarditis; PVE, prosthetic valve endocarditis; S. aureus, Staphylococcus aureus; TEE, transesophageal echocardiography; and TTE, transthoracic echocardiography.
Blood cultures are positive in 90% of patients with IE. In patients with a chronic (or subacute) presentation, 3 sets of blood cultures should be drawn >6 hours apart at peripheral sites before initiation of antimicrobial therapy. However, this is not feasible or safe in patients with severe sepsis or septic shock. In this situation, ≥2 cultures at separate times should allow for a secure microbiological diagnosis before initiation of antimicrobial therapy. More important than the time interval of the cultures is the observance of strict aseptic technique, avoiding sampling from intravascular lines, and ensuring adequate volume of blood for culture sample. Routine incubation of blood cultures for >7 days is no longer necessary in the era of continuous-monitoring blood culture systems and nonculture-based technology. In the 10% of patients with culture-negative endocarditis, serologic testing to identify the etiologic agent is appropriate.
Supporting References: (52,637–641)
Class I2. The Modified Duke Criteria should be used in evaluating a patient with suspected IE (Tables 24 and 25) (642–645). (Level of Evidence: B)
Diagnosis of IE According to the Proposed Modified Duke Criteria
Major and Minor Criteria in the Modified Duke Criteria for the Diagnosis of IE
The Modified Duke Criteria (Tables 24 and 25) have been well validated in comparison to surgical or autopsy findings and in clinical outcomes in numerous studies in a wide spectrum of patients, including children, the elderly, prosthetic valve recipients, injection drug users, and nondrug users, as well as patients in both primary and tertiary care settings. Clinical judgment and infectious disease specialty guidance are essential when deciding on the type and duration of antibiotic therapy when these criteria suggest possible IE and in patients with unusual clinical presentations or culture-negative endocarditis. About three fourths of patients with IE are diagnosed within 30 days of the onset of infection, so classic clinical features, such as embolic or vasculitic skin lesions, renal disease due to immune complex deposition, and immunologic abnormalities of IE, are often absent. In these cases, maintaining a high level of clinical suspicion to the possibility of IE in patients who are susceptible is paramount.
Supporting References: (644,646–650)
Class I3. Patients with IE should be evaluated and managed with consultation of a multispecialty Heart Valve Team including an infectious disease specialist, cardiologist, and cardiac surgeon. In surgically managed patients, this team should also include a cardiac anesthesiologist (651). (Level of Evidence: B)
The diagnosis of IE can still be difficult and is frequently delayed, which may cause progressive and potentially irreparable structural damage to the heart and other organ systems secondary to vascular-embolic and immunologically mediated events. The in-hospital mortality rate for patients with IE remains high (15% to 20%), with 1–year mortality, even in the current therapeutic era, approaching 40%. Additionally, stroke (16.9%), embolization other than stroke (22.6%), HF (32.3%), intracardiac abscess (14.4%), and the need for surgical therapy (48.2%) remain common.
The optimal treatment and potential timing of invasive strategies in these patients can be quite challenging in the individual patient. Patients with suspected IE are most optimally managed in an environment that coordinates management of specialists well attuned to various organ systems, pathological processes, and potential treatment modalities involved. Cardiologists provide expertise in diagnosis, imaging, and clinical management; infectious disease specialists provide expertise in identification of the causative organism and the choice and duration of antimicrobial therapy; cardiac surgeons are essential for decisions about timing of surgical intervention as well as the procedure itself; and anesthesiologists are essential for peri- and intraoperative diagnosis and management. Because the urgent/emergency need for surgical intervention can arise rapidly, it is strongly recommended that these patients be cared for in centers with immediate access to cardiac surgery during the initial observation stages of the disease. With the emerging use of telemedicine, it may be reasonable to manage patients with lower-acuity IE in a center without on-site multispecialty care by telecommunication with a Heart Valve Team and infectious disease specialists. Rapid transfer of the patient should also be available if the need arises. IE is a disease that is continually changing with new high-risk patients, new diagnostic procedures, the involvement of new micro-organisms, and new therapeutic approaches. Despite knowledge of these changes and considerable improvements in diagnostic and therapeutic strategies, IE is still a potentially debilitating or fatal disease. Patients affected by the disease are often older and sicker, and the comorbidity rate is high.
Supporting References: (652–654)
Class I4. TTE is recommended in patients with suspected IE to identify vegetations, characterize the hemodynamic severity of valvular lesions, assess ventricular function and pulmonary pressures, and detect complications (655–659). (Level of Evidence: B)
The presence of valvular vegetation is a major criterion in the diagnosis of IE. TTE has a sensitivity of between 50% and 90% and a specificity >90% for detection of vegetations in NVE. TTE has a sensitivity of only 36% to 69% in PVE, but TTE still has a role in these patients for detection and quantitation of valve dysfunction (even in the challenging situation of regurgitation in the mechanical prosthetic mitral valve, for which a proximal convergence zone may provide important evidence for a paravalvular leak), evaluation of ventricular size and systolic function, and estimation of pulmonary pressures. TTE exhibits superior imaging over TEE for the anterior aspect of a prosthetic aortic valve, which is commonly shadowed by the valve on TEE. TTE also allows measurement of aortic transvalvular velocity/gradient, which is not always possible on TEE. Although TTE will not definitely exclude vegetations or abscesses in IE, it can identify very high-risk patients and establish the diagnosis as well as guide early treatment decisions (Figure 8).
Supporting References: (655,660–664)
Class I5. TEE is recommended in all patients with known or suspected IE when TTE is nondiagnostic, when complications have developed or are clinically suspected, or when intracardiac device leads are present (662,665–672). (Level of Evidence: B)
The sensitivity of TEE in NVE ranges from 90% to 100%, with sensitivity ranges slightly lower in PVE. The positive predictive value for TEE in both NVE and PVE is 90%. TEE is superior to TTE in the visualization of both vegetations and perivalvular complications, which can be anatomic or hemodynamic in nature. Examples of such complications include valve perforation, abscesses, and pericardial effusion. Hemodynamic complications may include valve regurgitation, fistulae, and intracardiac thrombi. TEE is now considered the most reliable noninvasive test for defining this disease. However, it may not differentiate between active and healed vegetations and may not discriminate between thickened valves or valvular nodules and vegetations. TTE and TEE are complementary for the comprehensive evaluation of hemodynamics and anatomy in patients with IE. Because TEE has a higher sensitivity in detecting anatomic complications, it should be used as an adjunct in patients with echocardiographic features of IE on TTE to rule out the presence of findings such as abscesses, which may alter the therapeutic approach to the management of the patient. TEE also serves a vital role in reassessment of patients with known IE with suspected clinical complications as well as a guiding tool in the intraoperative assessment and management of the IE patient.
The number, type, and timing of repeat examinations depend on the clinical presentation and course as well as the virulence of the microorganism. Vegetation size at diagnosis has clearly identified a higher risk of death in prospective studies. Additionally, 1 study has shown that failure to decrease vegetation size with antibiotic treatment was associated with an increased risk of embolism. Another study demonstrated that most vegetations (83.8%) remain constant in size under therapy and that this does not worsen prognosis. In this study, both increase of vegetation size under antibiotic therapy (observed in 10.5% of patients with IE) and reduction of vegetation size under therapy were associated with an increased embolic risk. Thus, increasing vegetation size under therapy must be considered a risk factor for new embolic events, whereas unchanged or reduced vegetation size under therapy may be more difficult to interpret.
Compared with TTE, TEE is more sensitive for detection of vegetations and thrombi associated with device leads. There are emerging data that intracardiac echocardiography may be an increasingly useful tool to diagnose vegetations that may be present on right-sided pacemaker leads. It has shown superior sensitivity over TEE in identifying these lesions.
Supporting References: (664,670,673–681)
Class I6. TTE and/or TEE are recommended for re-evaluation of patients with IE who have a change in clinical signs or symptoms (e.g., new murmur, embolism, persistent fever, HF, abscess, or atrioventricular heart block) and in patients at high risk of complications (e.g., extensive infected tissue/large vegetation on initial echocardiogram or staphylococcal, enterococcal, fungal infections) (679,682). (Level of Evidence: B)
HF, perivalvular extension, and embolic events represent the 3 most frequent and severe complications of IE. They are also the 3 main indications for early surgery, which is performed in almost 50% of cases. If signs or symptoms consistent with any of these complications exist, there should be a very low threshold for repeat imaging in these patients. TEE may miss initial paravalvular abscesses, particularly when the study is performed early in the patient’s illness. In such cases, the incipient abscess may be seen only as nonspecific paravalvular thickening, which on repeat imaging across several days may become recognizable as it expands and cavitates. Similarly, paravalvular fistulae and pseudoaneurysms develop over time, and negative early TEE images do not exclude the potential for their development. For patients who have IE that was diagnosed by clinical, microbiological, or surgical criteria but for whom results of initial TEE were false-negative, repeated TEE has often demonstrated vegetative IE. Thus, it appears that a single negative TEE study cannot rule out underlying IE and that a repeat TEE study should be performed when a suspicion of persistence of infection remains or if complications ensue. Conversely, in the absence of clinical deterioration or new signs/symptoms, routine follow-up echocardiography is probably of only limited clinical utility.
Supporting References: (52,630,665,683–685)
Class I7. Intraoperative TEE is recommended for patients undergoing valve surgery for IE (686,687). (Level of Evidence: B)
Intraoperative TEE during cardiac surgery plays an important role in the evaluation and quality control of a large variety of pathologies. Clinical and echocardiographic characteristics may change during an episode of IE because of the prolonged active phase and fluctuating course of this disease. Even if preoperative TEE has been performed, the possibility of vegetation change/embolization or extension of the infectious process beyond the valve tissue may occur. In addition, other valves may become involved as the disease timeline progresses. Intraoperative TEE has been invaluable for baseline reassessment of anatomical/hemodynamic changes that may occur in the interval between the diagnostic echocardiogram and the time of surgery. TEE is also an important monitoring tool for evaluation of operative complications such as air emboli and an important adjunct to ensure the quality of the intended surgical result.
Supporting References: (688,689)
Class IIa1. TEE is reasonable to diagnose possible IE in patients with Staphylococcal aureus (S. aureus) bacteremia without a known source (690–692). (Level of Evidence: B)
IE in patients with S. aureus bacteremia frequently involves normal cardiac valves and is seldom accompanied by the physical stigmata of IE, rendering the diagnosis of the disease difficult. Reliance on physical examination findings and clinical stigmata is likely to result in underdiagnosis of S. aureus IE in a large number of cases. TEE is cost-effective to guide duration of therapy in patients with intravascular catheter-associated S. aureus bacteremia, patients with intracardiac electronic devices, or other patients at higher risk for IE (including those with previous prosthetic valve surgery) or associated complications.
Despite early diagnosis and appropriate therapy, IE following S. aureus bacteremia is frequently associated with disabling and life-threatening sequelae. The overall mortality of S. aureus IE ranges from 19% to 65%. Other complications include HF (20% to 50%), paravalvular cardiac abscesses (30% to 40%), neurological manifestations (30%), and systemic embolization (40%).
Supporting References: (652,677,693,694)
Class IIa2. TEE is reasonable to diagnose IE of a prosthetic valve in the presence of persistent fever without bacteremia or a new murmur (695,696). (Level of Evidence: B)
When compared with NVE, PVE is characterized by a lower incidence of vegetations (especially in mechanical prostheses) and a higher incidence of annular abscess and other paravalvular complications. Because cardiac auscultation may also be less revealing in PVE and because ordinarily less virulent organisms may cause more anatomic destruction before culture or serological detection, it is important to use TEE early in these high-risk patients. TEE has a lower sensitivity in detecting prosthetic IE when compared with TEE detection rates in NVE, so the importance of comparing serial echocardiographic studies is paramount to making the diagnosis.
Supporting References: (697,698)
Class IIa3. Cardiac CT is reasonable to evaluate morphology/anatomy in the setting of suspected paravalvular infections when the anatomy cannot be clearly delineated by echocardiography (678,699–701). (Level of Evidence: B)
Electrocardiographic-synchronized, multidetector-row CT is emerging as an important tool for noninvasive cardiac assessment and may be helpful in evaluating complications of IE. CT may also be indicated in right-sided IE to demonstrate the presence of septic pulmonary infarcts and abscesses. Although CT is less accurate than TTE and TEE for identifying valvular vegetation and valvular perforations, CT is useful for evaluating patients with equivocal findings on TEE and for evaluating complications in patients with suspected myocardial, pericardial, and coronary sinus extension of the infectious process. CT can also more sensitively detect paravalvular abscess involvement and evaluate extent and anatomic consequences of pseudoaneurysms and their relationship to adjacent structures. CT imaging is particularly useful in preoperative evaluation of patients with aortic valve IE to evaluate coronary artery and aortic