Author + information
- Received February 16, 2015
- Revision received July 15, 2015
- Accepted July 16, 2015
- Published online September 22, 2015.
- Steven J. Yakubov, MD∗∗ (, )
- David H. Adams, MD†,
- Daniel R. Watson, MD∗,
- Michael J. Reardon, MD‡,
- Neal S. Kleiman, MD‡,
- David Heimansohn, MD§,
- James Hermiller Jr., MD§,
- G. Chad Hughes, MD‖,
- J. Kevin Harrison, MD‖,
- Joseph Coselli, MD¶,
- Jose Diez, MD¶,
- Theodore Schreiber, MD#,
- Thomas G. Gleason, MD∗∗,
- John Conte, MD††,
- G. Michael Deeb, MD‡‡,
- Jian Huang, MD§§,
- Jae Oh, MD‖‖,
- Timothy Byrne, MD¶¶,
- Michael Caskey, MD¶¶,
- Jeffrey J. Popma, MD##,
- CoreValve United States Clinical Investigators
- ∗Riverside Methodist Hospital, Columbus, Ohio
- †Mount Sinai Health System, New York, New York
- ‡Houston-Methodist-DeBakey Heart and Vascular Center, Houston, Texas
- §St. Vincent’s Heart Center of Indiana, Indianapolis, Indiana
- ‖Duke University Medical Center, Durham, North Carolina
- ¶Texas Heart Institute at St. Luke’s Medical Center, Houston, Texas
- #Detroit Medical Center, Detroit, Michigan
- ∗∗University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
- ††Johns Hopkins Medical Center, Baltimore, Maryland
- ‡‡University of Michigan Medical Center, Ann Arbor, Michigan
- §§Medtronic, Minneapolis, Minnesota
- ‖‖Mayo Clinic Foundation, Rochester, Minnesota
- ¶¶Banner Good Samaritan Hospital, Phoenix, Arizona
- ##Beth Israel Deaconess Medical Center, Boston, Massachusetts
- ↵∗Reprint requests and correspondence:
Dr. Steven J. Yakubov, OhioHealth, Riverside Methodist Hospital, 3705 Olentangy River Road, Columbus, Ohio 43214.
Background We reported favorable 1-year outcomes in patients unsuitable for surgery who underwent self-expanding transcatheter aortic valve replacement (TAVR) compared with an objective performance goal. Longer-term outcomes in these patients are not known.
Objectives This study sought to evaluate the 2-year safety and efficacy in patients with severe aortic stenosis (AS) at extreme risk of surgery treated with self-expanding TAVR.
Methods We performed a prospective, multicenter, controlled, nonrandomized investigation of self-expanding TAVR in patients with severe AS and prohibitive surgical risk. We report the 2-year clinical outcomes in these patients.
Results A total of 489 extreme-risk patients were treated transfemorally with a self-expanding aortic bioprosthesis at 41 centers. The rate of all-cause mortality or major stroke was 38.0% at 2 years (all-cause mortality, 36.5%; major stroke, 5.1%). The rates of all-cause mortality, cardiovascular mortality, and major stroke were 36.6%, 26.2%, and 5.1%, respectively, at 2 years. Between 1 and 2 years, the incremental all-cause mortality, cardiovascular mortality, and major stroke rates were 12.3%, 7.9%, and 0.8%, respectively. Multivariable predictors of all-cause mortality at 2 years included the presence of coronary artery disease and admission from an assisted living center. A Society of Thoracic Surgeons score >15% was also predictive of 2-year all-cause mortality. At 2 years, 94% of patients had New York Heart Association functional class I or II symptoms. The frequency of moderate or severe paravalvular regurgitation (4.3% at 1 year; 4.4% at 2 years) was unchanged between the first and second year.
Conclusions Patients with severe AS at extreme surgical risk treated with self-expanding TAVR continued to show good clinical outcomes and hemodynamic valve performance at 2 years. The presence of comorbid conditions rather than valve performance affected 2-year outcomes in these patients. (Safety and Efficacy Study of the Medtronic CoreValve System in the Treatment of Symptomatic Severe Aortic Stenosis in High Risk and Very High Risk Subjects Who Need Aortic Valve Replacement; NCT01240902)
Patients with severe symptomatic aortic stenosis (AS) deemed unsuitable for surgery have an estimated 50.0% mortality at 1 year without valve replacement (1). Transcatheter aortic valve replacement (TAVR) using balloon-expandable (1) and self-expanding (2) bioprostheses has become standard of care in these patients, who often have significant comorbidities, frailties, and disabilities that affect their long-term prognosis (3). Late outcomes after TAVR have been reported (4–7), but there is limited information about late survival in patients deemed to be at extreme risk of surgery (8,9).
The CoreValve US Extreme Risk Pivotal Trial evaluated patients deemed unsuitable for surgery by 2 cardiac surgeons and 1 interventional cardiologist (2). A total of 489 patients underwent implantation with self-expanding TAVR by means of an iliofemoral access approach (2). Despite significant concomitant morbidities, the rate of 1-year all-cause mortality and major stroke at 1 year was superior to a rigorously defined objective performance goal (2). The self-expanding aortic bioprosthesis provided sustained improvement in the aortic valve effective orifice area, a reduction in the aortic valve gradient, and an overall improvement in New York Heart Association (NYHA) functional class (2). Our objective in this study was to evaluate the 2-year clinical outcomes in these patients.
Patient enrollment and study design
Detailed patient enrollment criteria, inclusion and exclusion criteria, and study methods have been reported elsewhere (2). In brief, patients with severe symptomatic AS defined as having at least NYHA functional class II symptoms, an aortic valve area ≤0.8 cm2 (or aortic valve index ≤0.5 cm2/m2), and a mean aortic valve gradient >40 mm Hg or a peak aortic valve velocity >4.0 m/s were eligible. Patients were considered to be at extreme risk if they were determined to have a 50.0% or greater risk for mortality or irreversible morbidity at 30 days with surgical replacement (2). Baseline assessment included calculation of risk using the Society of Thoracic Surgery Predictors of Mortality (STS-PROM) (10) and logistic euroSCORE (European System for Cardiac Operative Risk Evaluation) (11), the Charlson Comorbidity Index (12), and assessments of frailty using 5-m gait speed (13) and disability using the Katz Activities of Daily Living (14).
The CoreValve US Extreme Risk Pivotal Trial was a prospective, multicenter, controlled, nonrandomized, single-arm clinical study performed at 41 clinical sites in the United States (2). The responsible institutional review boards approved the study protocol, and written informed consent was obtained from all patients. The sponsor (Medtronic, Minneapolis, Minnesota), funded the study and, along with the study Steering Committee, designed the study. The study sponsor was responsible for selection of the clinical sites, monitoring of the data, and management of the case report forms and statistical analyses. An independent Clinical Events Committee adjudicated all major adverse clinical events. The primary author (S.J.Y.) and Co-Principal Investigators of the CoreValve US Pivotal Trials (J.J.P. and D.H.A.) drafted the initial manuscript. All authors contributed to this manuscript and made the decision to submit it for publication.
The attempted iliofemoral implant population was the primary analysis group (2). All-cause mortality or stroke was assessed at 2 years. Major and minor strokes were defined using Valve Academic Research Consortium 1 criteria (15). Valve Academic Research Consortium 1 criteria also were used to define major adverse cardiovascular and cerebral events that comprised all-cause death, myocardial infarction, all stroke, and reintervention to alter, adjust, or replace a previously implanted valve (15). Symptom status at 2 years was assessed using the NYHA functional classification system.
Echocardiograms were collected at 1 and 2 years and were interpreted by a central laboratory (Mayo Echocardiography Core Laboratory, Rochester, Minnesota). Prosthetic valve dysfunction and periprocedural aortic regurgitation were determined using Valve Academic Research Consortium 1 criteria (15). Aortic valve orifice area and mean gradient were compared at 1 and 2 years.
Categorical variables were compared using the Fisher exact test. Continuous variables were presented as mean ± SD and compared with the Student t test. The Kaplan-Meier estimate and its 95% confidence interval were summarized for each subgroup. The difference between subgroups was compared using Cox regression with subgroup as a factor and the time to event endpoint as the outcome. All testing used a 2-sided alpha level of 0.05. Multivariable predictors of 2-year all-cause mortality were identified from univariable predictors with p < 0.05. Stepwise multivariable analyses were performed. The significance-level thresholds for entry and exit of independent variables were set at 0.10. All statistical analyses were performed with SAS software, version 9.2 (SAS Institute, Cary, North Carolina).
Patient flow and demographics
A total of 489 patients underwent attempted iliofemoral self-expanding TAVR at 41 U.S. centers between February 2011 and August 2012; 486 patients were implanted with a self-expanding bioprosthesis (2). Between 1 and 2 years, 58 patients died, and 2 patients withdrew from the study. Two-year follow-up was available for 289 of 307 patients (94.1%).
Clinical characteristics for the attempted implant population are shown in Table 1. The mean age was 83.2 ± 8.7 years; 47.9% were men; 81.8% had coronary artery disease, and 27.6% were in an assisted living facility. The mean STS-PROM was 10.3% ± 5.5% and >15% in 17.2% of patients. Nearly 92% of patients experienced NYHA functional class III or IV symptoms.
Two-year clinical outcomes are shown in Table 2. The Kaplan-Meier rate of 2-year all-cause mortality or major stroke in the attempted iliofemoral implant population was 38.0% with a 2-sided upper 95% confidence interval of 42.6%. Two-year Kaplan-Meier rates were 36.6% for all-cause mortality and 26.2% for cardiovascular mortality (Central Illustration); the incremental rates between year 1 and year 2 were 12.3% for all-cause mortality and 7.9% for cardiovascular mortality. Causes of death during year 2 are listed in the Online Table 1. The rate of major stroke at 2 years was 5.1% (Figure 1), with a difference in the rates at 1 and 2 years of 0.8%. Univariable predictors for 2-year all-cause mortality are shown in Table 3 (Figures 2A to 2C). Multivariable predictors of all-cause mortality at 2 years included the presence of coronary artery disease (p = 0.002), and admission from an assisted living center (p = 0.0001). An STS-PROM score >15% was also predictive of 2-year all-cause mortality (p = 0.07). Coronary artery disease was defined as the presence of at least 1-vessel disease or having previous coronary artery bypass grafting or a previous percutaneous coronary intervention.
Improvement in symptom status was still present at 2 years after self-expanding TAVR. Compared with baseline symptoms, 92.0% of patients improved at 2 years by at least 1 NYHA functional class, and 58.0% improved by at least 2 classes (Figure 3). An additional 8 patients (2.4%) required a permanent pacemaker between the first and second year after TAVR (Table 2). There was no effect on 2-year survival for patients with or without a pacemaker (38.5% vs. 35.0%; log-rank p = 0.55).
Aortic valve orifice area (1.88 cm2 at 1 year and 1.86 cm2 at 2 years; p = 0.43) and mean gradient (8.86 mm Hg at 1 year and 8.70 mm Hg at 2 years; p = 0.13) were unchanged at 2 years (Figure 4). The rates of moderate paravalvular aortic regurgitation were similar at 1 and 2 years (Figure 5).
Our study shows that the good survival and low stroke rates at 1 year associated with the self-expanding TAVR in patients deemed unsuitable for surgery were sustained 2 years after the procedure (Central Illustration, Figure 1). Our study also showed that the improvement in aortic valve effective orifice area and reduction in the aortic valve gradient was maintained and that improvement in functional class persisted in patients undergoing self-expanding TAVR. We also found that the degree of paravalvular regurgitation remained unchanged over the second year after the procedure. Longer-term mortality was most influenced by the presence of coronary artery disease and disability requiring assisted living.
Mortality and major stroke
Left untreated in patients deemed unsuitable for surgery, severe AS is associated with an all-cause mortality rate of 50.0% at 1 year (1) and 68.0% at 2 years (8). Both balloon-expandable (1) and self-expanding bioprostheses (2) improve survival in these patients. We previously reported a rate of 1-year all-cause mortality and major stroke of 26.0% (95% upper confidence bound: 29.9%) in extreme-risk patients undergoing self-expanding TAVR, which was significantly lower than an objective performance goal of patients with medical therapy alone (43.0%; p < 0.0001) (2). We now report an increase in all-cause mortality from 24.3% at 1 year to 36.6% at 2 years with an incremental increase in all-cause mortality in the second year of 12.3%, similar to the second-year mortality rate in the PARTNER B (Placement of Aortic Transcatheter Valve Trial B) of 18.2% (6). Late deaths in the PARTNER B were attributable to extensive comorbidities, as reflected in a worsened outcome in patients with an STS-PROM >15.0% (8). Our study also found a relationship between STS-PROM >15% and late mortality, and we identified that severe disability, as assessed by admission from an assisted living facility also worsened prognosis with a untoward 2-year mortality rate (50.5% vs. 33.3% in patients admitted from home for TAVR: p < 0.001).
Strokes occur in approximately 3.0% to 4.0% of patients after TAVR (16). With careful neurological examination before and after TAVR, we reported low major stroke rates at 30 days (2.3%) and 1 year (4.3%) (2). The current study also found a low (1.6%) stroke rate in the second year after TAVR, similar to the 2.6% increase in stroke in the second year in PARTNER B (6). Although we did not characterize the type of stroke in our study, hemorrhagic strokes occurred most often after 30 days in the PARTNER B (8). Due to the occasional occurrence of atrial fibrillation after TAVR and the higher risk of bleeding complications in the elderly population, a careful balance is needed to optimize anticoagulation in this population of patients.
We observed a durable improvement in symptom status associated with self-expanding TAVR in our patients, with 94.0% of patients reporting NYHA functional class I or II symptoms at 2 years. This symptomatic improvement at 2 years in inoperable patients treated with TAVR was also found in the PARTNER B with 83.1% of patients having NYHA functional class I or II symptoms (8).
Paravalvular aortic regurgitation
Significant residual paravalvular regurgitation is an important prognostic finding after TAVR (17,18). Predictors of paravalvular regurgitation include implantation depth, aortic valve area (17), annular size (17–19), presence of severe calcification (17,20,21), and the use of computed tomography imaging to guide valve sizing (22,23). We previously reported paired analyses that showed a reduction in the frequency of moderate or severe paravalvular regurgitation during the first year after self-expanding TAVR (from 10.7% at discharge to 4.2% at 1 year; p = 0.004) (2). We hypothesized that the mechanism of this improvement resulted from annular remodeling due to appropriate valve sizing on the basis of multidetector computed tomography imaging (19,24). In the current report, we found that the frequency of moderate paravalvular regurgitation remained stable from 1 to 2 years (4.3% to 4.4%, respectively) (Figure 5). Longer-term studies in a larger number of patients are needed to understand the complex relationship between moderate paravalvular regurgitation and late mortality.
We found no evidence of valve degeneration in the second year after self-expanding TAVR in our study, and there were no cases of valve thrombosis. There was no significant change in the aortic valve effective orifice area or increase in the aortic valve gradients in the second year after self-expanding TAVR. This is similar to hemodynamic reports by others (4,8). Although the 2-year timeframe is short for the identification of structural deterioration of the self-expanding bioprosthesis, it is reassuring that there is no evidence of early failure in this population of patients.
We did not pre-specify an objective performance goal for the composite of all-cause mortality or major stroke in our study beyond 1 year, and there is no active control group for our extreme-risk patients. Our predictor model for later term mortality was not pre-specified, and identified predictors should be considered exploratory for larger analyses. The presence of coronary artery disease was based on a simple definition and did not include detailed ischemia scoring or specific vessel stenosis.
In patients with AS at extreme risk with surgical aortic valve replacement, iliofemoral placement of a self-expanding transcatheter bioprosthesis was shown to safe and effective through 2 years. Longer-term mortality was most influenced by the presence of coronary artery disease and disability. Hemodynamic improvements in aortic valve area and mean gradients were maintained at 2 years, and the rates of moderate or severe paravalvular regurgitation remained unchanged over the second year after the procedure. We conclude that self-expanding TAVR is beneficial in patients with AS without surgical options.
COMPETENCY IN MEDICAL KNOWLEDGE: Patients with severe AS facing a high risk of death or major complications with surgical valve replacement who undergo TAVR with self-expanding prostheses exhibit sustained improvement in valve function and clinical outcomes after 2 years.
COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: The main determinants of clinical outcomes during the first 2 years after TAVR in patients with severe, symptomatic AS at high risk of early operative mortality are comorbid medical conditions.
TRANSLATIONAL OUTLOOK: More work is needed to define the specific diseases, conditions, and other factors contributing to frailty and disability as they relate to long-term outcomes after TAVR. These efforts could lead to the development and validation of a clinical risk prediction instrument to guide selection of patients for this procedure.
The authors thank Jane Moore, MS, ELS, for help in reviewing the manuscript for technical accuracy, and Gloria Toledo, MBA, and Eric Vang, PhD, for overall trial management. All are employees of Medtronic.
Medtronic, Minneapolis, Minnesota, sponsored this study. Dr. Yakubov has received institutional research grants from Boston Scientific, Direct Flow Medical, and Medtronic; and serves on an Advisory Board for Boston Scientific and Medtronic. Dr. Adams has received institutional grants and institutional royalties for patents from Medtronic; and institutional royalties for patents from Edwards Lifesciences. Dr. Reardon serves on an Advisory Board for Medtronic. Dr. Kleiman provides educational services to Medtronic. Dr. Heimansohn serves as a proctor for Sorin Biomedical. Dr. Hermiller has received institutional research grants from Medtronic. Dr. Hughes serves as a consultant and speaker for Medtronic. Dr. Harrison has received institutional research grants from Boston Scientific, Direct Flow Medical, Edwards Lifesciences, and Medtronic; serves on an Advisory Board for St. Jude Medical; and is on a DSMB for CardiAQ. Dr. Coselli serves as an advisor to Medtronic. Dr. Gleason has received institutional research grants from Medtronic. Dr. Conte serves on the Surgery Advisory Board for Medtronic and Sorin; and has received research support from Boston Scientific, Medtronic, and St. Jude Medical. Dr. Deeb serves as a consultant for Edwards Lifesciences; and as an advisor and consultant for Medtronic. Dr. Huang is an employee of and shareholder in Medtronic. Dr. Oh has received institutional research grants from Medtronic. Dr. Caskey serves as a consultant for Medtronic. Dr. Popma has received institutional research grants from Boston Scientific, Direct Flow Medical, and Medtronic; and serves on a Medical Advisory Board for Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Antonio Colombo, MD, served as Guest Editor for this paper.
- Abbreviations and Acronyms
- aortic stenosis
- New York Heart Association
- Society for Thoracic Surgery Predicted Risk of Mortality
- transcatheter aortic valve replacement
- Received February 16, 2015.
- Revision received July 15, 2015.
- Accepted July 16, 2015.
- American College of Cardiology Foundation
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