2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart FailureA Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America
Author + information
- Clyde W. Yancy, MD, MSc, MACC, FAHA, FHFSA, Chair, Writing Committee∗,
- Mariell Jessup, MD, FACC, FAHA, FESC, Vice Chair, Writing Committee∗,
- Biykem Bozkurt, MD, PhD, FACC, FAHA, Writing Committee Member∗,†,
- Javed Butler, MD, MBA, MPH, FACC, FAHA, Writing Committee Member∗,‡,
- Donald E. Casey Jr., MD, MPH, MBA, FACC, Writing Committee Member∗,§,
- Monica M. Colvin, MD, FAHA, Writing Committee Member∗,‖,
- Mark H. Drazner, MD, MSc, FACC, FAHA, Writing Committee Member∗,‡,
- Gerasimos Filippatos, MD, FESC, Writing Committee Member∗,
- Gregg C. Fonarow, MD, FACC, FAHA, FHFSA, Writing Committee Member∗,‡,
- Michael M. Givertz, MD, FACC, FHFSA, Writing Committee Member∗,¶,
- Steven M. Hollenberg, MD, FACC, Writing Committee Member∗,#,
- JoAnn Lindenfeld, MD, FACC, FAHA, FHFSA, Writing Committee Member∗,¶,
- Frederick A. Masoudi, MD, MSPH, FACC, Writing Committee Member∗∗∗,
- Patrick E. McBride, MD, MPH, FACC, Writing Committee Member∗,††,
- Pamela N. Peterson, MD, FACC, Writing Committee Member∗,‡,
- Lynne Warner Stevenson, MD, FACC, Writing Committee Member∗,‡ and
- Cheryl Westlake, PhD, RN, ACNS-BC, FHFSA, Writing Committee Member∗,¶
- ACC/AHA Clinical Practice Guidelines
- angioedema
- angiotensin-converting enzyme inhibitors
- angiotensin receptor blockers
- angiotensin receptor-neprilysin inhibitor
- beta blockers
- focused update
- heart failure
- ivabradine
- natriuretic peptides
ACC/AHA Task Force Members
Jonathan L. Halperin, MD, FACC, FAHA, Chair
Glenn N. Levine, MD, FACC, FAHA, Chair-Elect
Sana M. Al-Khatib, MD, MHS, FACC, FAHA
Kim K. Birtcher, PharmD, MS, AACC
Biykem Bozkurt, MD, PhD, FACC, FAHA
Ralph G. Brindis, MD, MPH, MACC
Joaquin E. Cigarroa, MD, FACC
Lesley H. Curtis, PhD, FAHA
Lee A. Fleisher, MD, FACC, FAHA
Federico Gentile, MD, FACC
Samuel Gidding, MD, FAHA
Mark A. Hlatky, MD, FACC
John Ikonomidis, MD, PhD, FAHA
José Joglar, MD, FACC, FAHA
Susan J. Pressler, PhD, RN, FAHA
Duminda N. Wijeysundera, MD, PhD
Table of Contents
Preamble 1477
Introduction 1479
7.3. Stage C 1479
7.3.2. Pharmacological Treatment for Stage C HF With Reduced Ejection Fraction: Recommendations 1479
7.3.2.10. Renin-Angiotensin System Inhibition With Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker or ARNI: Recommendations 1479
7.3.2.11. Ivabradine: Recommendation 1482
References 1482
Appendix 1
Author Relationships With Industry and Other Entities (Relevant) 1484
Appendix 2
Reviewer Relationships With Industry and Other Entities (Comprehensive) 1486
Preamble
Incorporation of new study results, medications, or devices that merit modification of existing clinical practice guideline recommendations, or the addition of new recommendations, is critical to ensuring that guidelines reflect current knowledge, available treatment options, and optimum medical care. To keep pace with evolving evidence, the American College of Cardiology (ACC)/American Heart Association (AHA) Task Force on Clinical Practice Guidelines (“Task Force”) has issued this focused update to reassess guideline recommendations on the basis of recently published study data. This update has been subject to rigorous, multilevel review and approval, similar to the full guidelines. For specific focused update criteria and additional methodological details, please see the ACC/AHA guideline methodology manual (1).
Modernization
Processes have evolved over time in response to published reports from the Institute of Medicine (2,3) and ACC/AHA mandates (4–7), leading to adoption of a “knowledge byte” format. This process entails delineation of a recommendation addressing a specific clinical question, followed by concise text (ideally <250 words) and hyperlinked to supportive evidence. This approach better accommodates time constraints on busy clinicians, facilitates easier access to recommendations via electronic search engines and other evolving technology, and supports the evolution of guidelines as “living documents” that can be dynamically updated as needed.
Guideline-Directed Evaluation and Management
The term guideline-directed evaluation and management (GDEM) refers to care defined mainly by ACC/AHA Class I recommendations. For these and all recommended drug treatment regimens, the reader should confirm dosage with product insert material and carefully evaluate for contraindications and interactions. Recommendations are limited to treatments, drugs, and devices approved for clinical use in the United States.
Class of Recommendation and Level of Evidence
The Class of Recommendation (COR) and Level of Evidence (LOE) are derived independently of each other according to established criteria. The COR indicates the strength of recommendation, encompassing the estimated magnitude and certainty of benefit of a clinical action in proportion to risk. The LOE rates the quality of scientific evidence supporting the intervention on the basis of the type, quantity, and consistency of data from clinical trials and other sources (Table 1). Recommendations in this focused update reflect the new 2015 COR/LOE system, in which LOE B and C are subcategorized for the purpose of increased granularity (1,5,8).
Applying Class of Recommendation and Level of Evidence to Clinical Strategies, Interventions, Treatments, or Diagnostic Testing in Patient Care∗ (Updated August 2015)
Relationships With Industry and Other Entities
The ACC and AHA exclusively sponsor the work of guideline writing committees without commercial support, and members volunteer time for this activity. Selected organizations and professional societies with related interests and expertise are invited to participate as partners or collaborators. The Task Force makes every effort to avoid actual, potential, or perceived conflicts of interest that might arise through relationships with industry or other entities (RWI). All writing committee members and reviewers are required to fully disclose current industry relationships or personal interests, beginning 12 months before initiation of the writing effort. Management of RWI involves selecting a balanced writing committee and requires that both the chair and a majority of writing committee members have no relevant RWI (see Appendix 1 for the definition of relevance). Members are restricted with regard to writing or voting on sections to which RWI apply. Members of the writing committee who recused themselves from voting are indicated and specific section recusals are noted in Appendix 1. In addition, for transparency, members’ comprehensive disclosure information is available as an Online Supplement, and reviewers’ RWI disclosures are included in Appendix 2. Comprehensive disclosure information for the Task Force is also available online. The Task Force strives to avoid bias by selecting experts from a broad array of backgrounds representing different geographic regions, genders, ethnicities, intellectual perspectives, and scopes of clinical activities.
Intended Use
Guidelines provide recommendations applicable to patients with or at risk of developing cardiovascular disease. The focus is on medical practice in the United States, but guidelines developed in collaboration with other organizations may have a broader target. Although guidelines may be used to inform regulatory or payer decisions, the intent is to improve quality of care and align with patients’ interests. The guidelines are reviewed annually by the Task Force and are official policy of the ACC and AHA. Each guideline is considered current unless and until it is updated, revised, or superseded by a published addendum.
Related Issues
For additional information pertaining to the methodology for grading evidence, assessment of benefit and harm, shared decision making between the patient and clinician, structure of evidence tables and summaries, standardized terminology for articulating recommendations, organizational involvement, peer review, and policies regarding periodic assessment and updating of guideline documents, we encourage readers to consult the ACC/AHA guideline methodology manual (1).
Jonathan L. Halperin, MD, FACC, FAHA
Chair, ACC/AHA Task Force on Clinical Practice Guidelines
Introduction
The ACC, the AHA, and the Heart Failure Society of America (HFSA) recognize that the introduction of effective new therapies that potentially affect a large number of patients presents both opportunities and challenges. The introduction of an angiotensin receptor–neprilysin inhibitor (ARNI) (valsartan/sacubitril) and a sinoatrial node modulator (ivabradine), when applied judiciously, complements established pharmacological and device-based therapies and represents a milestone in the evolution of care for patients with heart failure (HF). Accordingly, the writing committees of the “2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure” and the “2016 ESC Guideline on the Diagnosis and Treatment of Acute and Chronic Heart Failure” concurrently developed recommendations for the incorporation of these therapies into clinical practice. Working independently, each writing committee surveyed the evidence, arrived at similar conclusions, and constructed similar, but not identical, recommendations. Given the concordance, the respective organizations simultaneously issued aligned recommendations on the use of these new treatments to minimize confusion and improve the care of patients with HF.
Members of the ACC/AHA/HFSA writing committee without relevant RWI voted on the final recommendations. These were subjected to external peer review by 25 official, organizational, and content reviewers before approval by the Task Force and the leadership of the ACC, AHA, and HFSA, as well as endorsement by the American College of Chest Physicians and the International Society for Heart and Lung Transplantation. The statements issued by the European Society of Cardiology writing committee went through a similarly rigorous process of external review before endorsement by the societal leadership.
No single clinical trial answers all pertinent questions, nor can trial results be perfectly replicated in clinical practice. Several critical questions remain unanswered, and further experience in both ongoing trials and clinical therapeutics may require modification of these initial recommendations. On the basis of the currently available evidence, however, the recommendations that follow reflect our assessment of how best to proceed today.
7.3 Stage C
7.3.2 Pharmacological Treatment for Stage C HF With Reduced Ejection Fraction: Recommendations
7.3.2.10 Renin-Angiotensin System Inhibition With Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker or ARNI: Recommendations
See the Online Data Supplement for evidence supporting these recommendations.
| COR | LOE | Recommendations |
|---|---|---|
| I | ACE: A ARB: A | The clinical strategy of inhibition of the renin-angiotensin system with ACE inhibitors (Level of Evidence: A) (9–14), OR ARBs (Level of Evidence: A) (15–18), OR ARNI (Level of Evidence: B-R) (19) in conjunction with evidence-based beta blockers (20–22), and aldosterone antagonists in selected patients (23,24), is recommended for patients with chronic HFrEF to reduce morbidity and mortality. |
| ARNI: B-R | ||
| See Online Data Supplements 1, 2, 18–20. | Angiotensin-converting enzyme (ACE) inhibitors reduce morbidity and mortality in heart failure with reduced ejection fraction (HFrEF). Randomized controlled trials (RCTs) clearly establish the benefits of ACE inhibition in patients with mild, moderate, or severe symptoms of HF and in patients with or without coronary artery disease (9–14). ACE inhibitors can produce angioedema and should be given with caution to patients with low systemic blood pressures, renal insufficiency, or elevated serum potassium. ACE inhibitors also inhibit kininase and increase levels of bradykinin, which can induce cough but also may contribute to their beneficial effect through vasodilation. Angiotensin receptor blockers (ARBs) were developed with the rationale that angiotensin II production continues in the presence of ACE inhibition, driven through alternative enzyme pathways. ARBs do not inhibit kininase and are associated with a much lower incidence of cough and angioedema than ACE inhibitors; but like ACE inhibitors, ARBs should be given with caution to patients with low systemic blood pressure, renal insufficiency, or elevated serum potassium. Long-term therapy with ARBs produces hemodynamic, neurohormonal, and clinical effects consistent with those expected after interference with the renin-angiotensin system and have been shown in RCTs (15–18) to reduce morbidity and mortality, especially in ACE inhibitor–intolerant patients. In ARNI, an ARB is combined with an inhibitor of neprilysin, an enzyme that degrades natriuretic peptides, bradykinin, adrenomedullin, and other vasoactive peptides. In an RCT that compared the first approved ARNI, valsartan/sacubitril, with enalapril in symptomatic patients with HFrEF tolerating an adequate dose of either ACE inhibitor or ARB, the ARNI reduced the composite endpoint of cardiovascular death or HF hospitalization significantly, by 20% (19). The benefit was seen to a similar extent for both death and HF hospitalization and was consistent across subgroups. The use of ARNI is associated with the risk of hypotension and renal insufficiency and may lead to angioedema, as well. | |
| I | ACE: A | The use of ACE inhibitors is beneficial for patients with prior or current symptoms of chronic HFrEF to reduce morbidity and mortality (9–14,25). |
| See Online Data Supplement 18. | ACE inhibitors have been shown in large RCTs to reduce morbidity and mortality in patients with HFrEF with mild, moderate, or severe symptoms of HF, with or without coronary artery disease (9–14). Data suggest that there are no differences among available ACE inhibitors in their effects on symptoms or survival (25). ACE inhibitors should be started at low doses and titrated upward to doses shown to reduce the risk of cardiovascular events in clinical trials. ACE inhibitors can produce angioedema and should be given with caution to patients with low systemic blood pressures, renal insufficiency, or elevated serum potassium (>5.0 mEq/L). Angioedema occurs in <1% of patients who take an ACE inhibitor, but it occurs more frequently in blacks and women (26). Patients should not be given ACE inhibitors if they are pregnant or plan to become pregnant. ACE inhibitors also inhibit kininase and increase levels of bradykinin, which can induce cough in up to 20% of patients but also may contribute to beneficial vasodilation. If maximal doses are not tolerated, intermediate doses should be tried; abrupt withdrawal of ACE inhibition can lead to clinical deterioration and should be avoided. Although the use of an ARNI in lieu of an ACE inhibitor for HFrEF has been found to be superior, for those patients for whom ARNI is not appropriate, continued use of an ACE inhibitor for all classes of HFrEF remains strongly advised. | |
| I | ARB: A | The use of ARBs to reduce morbidity and mortality is recommended in patients with prior or current symptoms of chronic HFrEF who are intolerant to ACE inhibitors because of cough or angioedema (15–18,27,28). |
| See Online Data Supplements 2 and 19. | ARBs have been shown to reduce mortality and HF hospitalizations in patients with HFrEF in large RCTs (15–18). Long-term therapy with ARBs in patients with HFrEF produces hemodynamic, neurohormonal, and clinical effects consistent with those expected after interference with the renin-angiotensin system (27,28). Unlike ACE inhibitors, ARBs do not inhibit kininase and are associated with a much lower incidence of cough and angioedema, although kininase inhibition by ACE inhibitors may produce beneficial vasodilatory effects. Patients intolerant to ACE inhibitors because of cough or angioedema should be started on ARBs; patients already tolerating ARBs for other indications may be continued on ARBs if they subsequently develop HF. ARBs should be started at low doses and titrated upward, with an attempt to use doses shown to reduce the risk of cardiovascular events in clinical trials. ARBs should be given with caution to patients with low systemic blood pressure, renal insufficiency, or elevated serum potassium (>5.0 mEq/L). Although ARBs are alternatives for patients with ACE inhibitor–induced angioedema, caution is advised because some patients have also developed angioedema with ARBs. Head-to-head comparisons of an ARB versus ARNI for HF do not exist. For those patients for whom an ACE inhibitor or ARNI is inappropriate, use of an ARB remains advised. | |
| I | ARNI: B-R | In patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACE inhibitor or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality (19). |
| See Online Data Supplements 1 and 18. | Benefits of ACE inhibitors with regard to decreasing HF progression, hospitalizations, and mortality rate have been shown consistently for patients across the clinical spectrum, from asymptomatic to severely symptomatic HF. Similar benefits have been shown for ARBs in populations with mild-to-moderate HF who are unable to tolerate ACE inhibitors. In patients with mild-to-moderate HF (characterized by either 1) mildly elevated natriuretic peptide levels, BNP [B-type natriuretic peptide] >150 pg/mL or NT-proBNP [N-terminal pro-B-type natriuretic peptide] ≥600 pg/mL; or 2) BNP ≥100 pg/mL or NT-proBNP ≥400 pg/mL with a prior hospitalization in the preceding 12 months) who were able to tolerate both a target dose of enalapril (10 mg twice daily) and then subsequently an ARNI (valsartan/sacubitril; 200 mg twice daily, with the ARB component equivalent to valsartan 160 mg), hospitalizations and mortality were significantly decreased with the valsartan/sacubitril compound compared with enalapril. The target dose of the ACE inhibitor was consistent with that known to improve outcomes in previous landmark clinical trials (10). This ARNI has recently been approved for patients with symptomatic HFrEF and is intended to be substituted for ACE inhibitors or ARBs. HF effects and potential off-target effects may be complex with inhibition of the neprilysin enzyme, which has multiple biological targets. Use of an ARNI is associated with hypotension and a low-frequency incidence of angioedema. To facilitate initiation and titration, the approved ARNI is available in 3 doses that include a dose that was not tested in the HF trial; the target dose used in the trial was 97/103 mg twice daily (29). Clinical experience will provide further information about the optimal titration and tolerability of ARNI, particularly with regard to blood pressure, adjustment of concomitant HF medications, and the rare complication of angioedema (30). | |
| III: Harm | B-R | ARNI should not be administered concomitantly with ACE inhibitors or within 36 hours of the last dose of an ACE inhibitor (31,32). |
| See Online Data Supplement 3. | Oral neprilysin inhibitors, used in combination with ACE inhibitors, can lead to angioedema and concomitant use is contraindicated and should be avoided. A medication that represented both a neprilysin inhibitor and an ACE inhibitor, omapatrilat, was studied in both hypertension and HF, but its development was terminated because of an unacceptable incidence of angioedema (31,32) and associated significant morbidity. This adverse effect was thought to occur because both ACE and neprilysin break down bradykinin, which directly or indirectly can cause angioedema (32,33). An ARNI should not be administered within 36 hours of switching from or to an ACE inhibitor. | |
| III: Harm | C-EO | ARNI should not be administered to patients with a history of angioedema. |
| N/A | Omapatrilat, a neprilysin inhibitor (as well as an ACE inhibitor and aminopeptidase P inhibitor), was associated with a higher frequency of angioedema than that seen with enalapril in an RCT of patients with HFrEF (31). In a very large RCT of hypertensive patients, ompatrilat was associated with a 3-fold increased risk of angioedema as compared with enalapril (32). Blacks and smokers were particularly at risk. The high incidence of angioedema ultimately led to cessation of the clinical development of omapatrilat (34,35). In light of these observations, angioedema was an exclusion criterion in the first large trial assessing ARNI therapy in patients with hypertension (36) and then in the large trial that demonstrated clinical benefit of ARNI therapy in HFrEF (19). ARNI therapy should not be administered in patients with a history of angioedema because of the concern that it will increase the risk of a recurrence of angioedema. | |
Recommendations for Renin-Angiotensin System Inhibition With ACE Inhibitor or ARB or ARNI
7.3.2.11 Ivabradine: Recommendation
See the Online Data Supplement for evidence supporting this recommendation.
The remainder of the “2016 ACC/AHA/HFSA Focused Update on the Management of Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure” will be forthcoming.
| COR | LOE | Recommendation |
|---|---|---|
| IIa | B-R | Ivabradine can be beneficial to reduce HF hospitalization for patients with symptomatic (NYHA class II-III) stable chronic HFrEF (LVEF ≤35%) who are receiving GDEM, including a beta blocker at maximum tolerated dose, and who are in sinus rhythm with a heart rate of 70 bpm or greater at rest (37–40). |
| See Online Data Supplement 4. | Ivabradine is a new therapeutic agent that selectively inhibits the If current in the sinoatrial node, providing heart rate reduction. One RCT demonstrated the efficacy of ivabradine in reducing the composite endpoint of cardiovascular death or HF hospitalization (38). The benefit of ivabradine was driven by a reduction in HF hospitalization. The study included patients with HFrEF (New York Heart Association [NYHA] class II-IV, albeit with only a modest representation of NYHA class IV HF) and left ventricular ejection fraction (LVEF) ≤35%, in sinus rhythm with a resting heart rate of ≥70 bpm. Patients enrolled included a small number with paroxysmal atrial fibrillation (<40% of the time) but otherwise in sinus rhythm and a small number experiencing ventricular pacing but with a predominant sinus rhythm. Those with a myocardial infarction within the preceding 2 months were excluded. Patients enrolled had been hospitalized for HF in the preceding 12 months and were on stable GDEM for 4 weeks before initiation of ivabradine therapy. The target of ivabradine is heart rate slowing (the presumed benefit of action), but only 25% of patients studied were on optimal doses of beta-blocker therapy (20–22,38). Given the well-proven mortality benefits of beta-blocker therapy, it is important to initiate and up titrate these agents to target doses, as tolerated, before assessing the resting heart rate for consideration of ivabradine initiation (38). | |
Recommendation for Ivabradine
Presidents and Staff
American College of Cardiology
Richard A. Chazal, MD, FACC, President
Shalom Jacobovitz, Chief Executive Officer
William J. Oetgen, MD, MBA, FACC, Executive Vice President, Science, Education, Quality, and Publications
Amelia Scholtz, PhD, Publications Manager, Science, Education, Quality, and Publishing
American College of Cardiology/American Heart Association
Melanie Stephens-Lyman, MSc, Director, Guideline Operations and Strategy
Lisa Bradfield, CAE, Director, Guideline Methodology and Policy
Abdul R. Abdullah, MD, Associate Science and Medicine Advisor
Morgane Cibotti-Sun, MPH, Project Manager, Clinical Practice Guidelines
American Heart Association
Mark A. Creager, MD, FACC, FAHA, President
Nancy Brown, Chief Executive Officer
Rose Marie Robertson, MD, FAHA, Chief Science and Medical Officer
Gayle R. Whitman, PhD, RN, FAHA, FAAN, Senior Vice President, Office of Science Operations
Comilla Sasson, MD, PhD, FACEP, Vice President, Science and Medicine
Jody Hundley, Production Manager, Scientific Publications, Office of Science Operations
Appendix 1 Author Relationships With Industry and Other Entities (Relevant)—2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure (December 2015)
Appendix 2 Reviewer Relationships With Industry and Other Entities (Comprehensive)—2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure (March 2016)
Footnotes
↵∗ Writing committee members are required to recuse themselves from voting on sections to which their specific relationships with industry may apply; see Appendix 1 for detailed information.
↵† ACC/AHA Task Force on Clinical Practice Guidelines Liaison.
↵‡ ACC/AHA Representative.
↵§ ACP Representative.
↵‖ ISHLT Representative.
↵¶ HFSA Representative.
↵# CHEST Representative.
↵∗∗ ACC/AHA Task Force on Performance Measures Representative.
↵†† AAFP Representative.
Developed in Collaboration With the American College of Chest Physicians and International Society for Heart and Lung Transplantation
This document was approved by the American College of Cardiology Board of Trustees and Executive Committee, the American Heart Association Science Advisory and Coordinating Committee and Executive Committee, and the Heart Failure Society of America Executive Committee in April 2016.
The American College of Cardiology requests that this document be cited as follows: Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM, Drazner MH, Filippatos G, Fonarow GC, Givertz MM, Hollenberg SM, Lindenfeld J, Masoudi FA, McBride PE, Peterson PN, Stevenson LW, Westlake C. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol 2016;68:1476–88; http://dx.doi.org/10.1016/j.jacc.2016.05.011.
This article has been copublished in Circulation and the Journal of Cardiac Failure.
Copies: This document is available on the World Wide Web sites of the American College of Cardiology (www.acc.org), the American Heart Association (professional.heart.org), and the Heart Failure Society of America (www.hfsa.org). For copies of this document, please contact Elsevier Reprint Department, fax (212) 633-3820 or e-mail reprints{at}elsevier.com.
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- 2016 American College of Cardiology Foundation, the American Heart Association, Inc., and the Heart Failure Society of America
