Author + information
- Received March 20, 2015
- Revision received April 21, 2015
- Accepted May 5, 2015
- Published online July 14, 2015.
- Michael J. Reardon, MD∗∗ (, )
- David H. Adams, MD†,
- Neal S. Kleiman, MD∗,
- Steven J. Yakubov, MD‡,
- Joseph S. Coselli, MD§,
- G. Michael Deeb, MD‖,
- Thomas G. Gleason, MD¶,
- Joon Sup Lee, MD¶,
- James B. Hermiller Jr., MD#,
- Stan Chetcuti, MD‖,
- John Heiser, MD∗∗,
- William Merhi, MD∗∗,
- George L. Zorn III, MD††,
- Peter Tadros, MD††,
- Newell Robinson, MD‡‡,
- George Petrossian, MD‡‡,
- G. Chad Hughes, MD§§,
- J. Kevin Harrison, MD§§,
- Brijeshwar Maini, MD‖‖,
- Mubashir Mumtaz, MD‖‖,
- John V. Conte, MD¶¶,
- Jon R. Resar, MD¶¶,
- Vicken Aharonian, MD##,
- Thomas Pfeffer, MD##,
- Jae K. Oh, MD∗∗∗,
- Hongyan Qiao, PhD††† and
- Jeffrey J. Popma, MD‡‡‡
- ∗Houston Methodist DeBakey Heart & Vascular Center, Houston, Texas
- †Mount Sinai Health System, New York, New York
- ‡Riverside Methodist Hospital, Columbus, Ohio
- §Texas Heart Institute at St. Luke’s Medical Center, Houston, Texas
- ‖University of Michigan Medical Center, Ann Arbor, Michigan
- ¶University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
- #St. Vincent Medical Center, Indianapolis, Indiana
- ∗∗Spectrum Health System, Grand Rapids, Michigan
- ††The University of Kansas Hospital, Kansas City, Kansas
- ‡‡St. Francis Hospital, Roslyn, New York
- §§Duke University Medical Center, Durham, North Carolina
- ‖‖PinnacleHealth, Wormleysburg, Pennsylvania
- ¶¶The Johns Hopkins Hospital, Baltimore, Maryland
- ##Kaiser Permanente–Los Angeles Medical Center, Los Angeles, California
- ∗∗∗Mayo Clinic, Rochester, Minnesota
- †††Medtronic, Inc., Minneapolis, Minnesota
- ‡‡‡Beth Israel Deaconess Medical Center, Boston, Massachusetts
- ↵∗Reprint requests and correspondence:
Dr. Michael J. Reardon, Houston Methodist DeBakey Heart & Vascular Center, 6550 Fannin, Suite 1401, Houston, Texas 77030.
Background The U.S. pivotal trial for the self-expanding valve found that among patients with severe aortic stenosis at increased risk for surgery, the 1-year survival rate was 4.9 percentage points higher in patients treated with a self-expanding transcatheter aortic valve bioprosthesis than in those treated with a surgical bioprosthesis.
Objectives Longer-term clinical outcomes were examined to confirm if this mortality benefit is sustained.
Methods Patients with severe aortic stenosis who were at increased surgical risk were recruited. Eligible patients were randomly assigned in a 1:1 ratio to transcatheter aortic valve replacement with the self-expanding transcatheter valve (transcatheter aortic valve replacement [TAVR] group) or to aortic valve replacement with a surgical bioprosthesis (surgical group). The 2-year clinical and echocardiographic outcomes were evaluated in these patients.
Results A total of 797 patients underwent randomization at 45 centers in the United States. The rate of 2-year all-cause mortality was significantly lower in the TAVR group (22.2%) than in the surgical group (28.6%; log-rank test p < 0.05) in the as-treated cohort, with an absolute reduction in risk of 6.5 percentage points. Similar results were found in the intention-to-treat cohort (log-rank test p < 0.05). The rate of 2-year death or major stroke was significantly lower in the TAVR group (24.2%) than in the surgical group (32.5%; log-rank test p = 0.01).
Conclusions In patients with severe aortic stenosis who are at increased surgical risk, the higher rate of survival with a self-expanding TAVR compared with surgery was sustained at 2 years. (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)
Two-year outcome reports have confirmed the superiority of balloon-expandable transcatheter aortic valve replacement (TAVR) compared with medical therapy in patients deemed unsuitable for surgery (1) and noninferior survival compared with surgery in patients at high surgical risk (2). We previously confirmed a survival advantage with a self-expanding transcatheter bioprosthesis in patients not suitable for surgery (3) and observed a significantly lower 1-year mortality rate compared with surgery in patients at increased risk for surgery (4). The suggestion of a survival advantage in patients at increased risk for surgery treated with self-expanding aortic valve bioprostheses is provocative (5,6) and requires confirmation with longer term follow-up. The present study examined these longer term clinical outcomes to confirm if this mortality benefit is sustained.
This multicenter, randomized, noninferiority trial was performed at 45 sites in the United States; the trial design and 1-year clinical outcomes have been reported previously (4). An independent clinical events committee adjudicated all major clinical events, and an independent data and safety monitoring board provided study oversight. All patients provided written informed consent for follow-up evaluations up to 5 years.
Patient selection has been described previously in detail (4). Patients with severe aortic stenosis and New York Heart Association (NYHA) functional class II or worse symptoms were judged eligible for the trial if they were considered at increased risk for open heart surgery by both the local heart team and a national screening committee. Severe aortic stenosis was defined as an aortic valve area (AVA) ≤0.8 cm2 or an AVA index ≤0.5 cm2/m2 and either a mean gradient >40 mm Hg or peak aortic velocity >4 m/s. Increased risk was defined as an expected 30-day risk of mortality ≥15% but <50%. Detailed inclusion and exclusion criteria can be found in the Online Table. The Society of Thoracic Surgeons predictors of mortality score (7) and other factors previously described were used in assessing this risk (8,9). The selection process has been fully described elsewhere (4).
The CoreValve self-expanding transcatheter bioprostheses (Medtronic, Inc., Minneapolis, Minnesota) and the TAVR procedure have been previously described in detail (4). Surgical aortic valve replacements were performed by using site-specific standard techniques with valve type chosen by the cardiac surgeon. Transcatheter heart valve size selection was performed by using multidetector computed tomography angiography. At each site, 3 roll-in cases were allowed, and the implant team was required to have an independent proctor present for at least the first 5 cases (inclusive of the roll-in cases). For the TAVR group, dual antiplatelet therapy with aspirin and clopidogrel was recommended for 3 months after the procedure.
There were 390 patients initially reported in the TAVR group and 357 in the surgical group. Since the publication of the initial report, 2 additional patients enrolled in the ongoing 23-mm valve randomized arm reached the 2-year follow-up, and 1 patient who was included in the previous intention-to-treat analysis but not in the as-treated analysis due to missing procedural information had these forms completed. Accordingly, 3 additional patients were included in the as-treated analysis and 2 additional patients in the intention-to-treat analysis.
All-cause mortality was evaluated at 2 years. Other clinical endpoints included a composite of major adverse cardiovascular and cerebrovascular events, defined as death from any cause, myocardial infarction, any stroke or reintervention at 2 years on the basis of Valve Academic Research Consortium–1 criteria (10), new-onset atrial fibrillation, and the requirement for new pacemaker placement. An independent echocardiography core laboratory (Mayo Clinic, Rochester, Minnesota) assessed the echocardiographic evaluation of aortic hemodynamics and paravalvular regurgitation.
The analysis cohort for this report was the as-treated population, which included all patients who underwent an attempted implantation. All-cause mortality is also reported for the intention-to-treat population, which included all patients who underwent randomization.
Categorical variables were compared by using the Fisher exact test or the chi-square test. Continuous variables were presented as mean ± SD and compared by using the Student t test. Kaplan-Meier estimates were used to construct the survival curves on the basis of all available follow-up data for the time-to-event analysis. Differences in event rates between the TAVR group and the surgical group were evaluated by using log-rank testing. All echocardiographic measurements were evaluated by using a 2-sample Student t test or the Wilcoxon rank-sum test for continuous variables and the Mantel-Haenszel test for categorical variables, as appropriate. All testing used a 2-sided alpha level of 0.05, and all statistical analyses were performed by using SAS version 9.2 (SAS Institute, Inc., Cary, North Carolina).
Patient flow and baseline characteristics
There were 750 patients in the as-treated population; 391 patients were treated with TAVR, and 359 patients underwent surgery (4). Patients were followed up for a median of 24.4 months in the transcatheter group (interquartile range: 21.7 to 26.3 months) and 24.2 months in the surgical group (interquartile range: 14.0 to 26.1 months). Figure 1 illustrates the study group assignment and patient flow through 2 years.
Baseline clinical features for as-treated patients are displayed in Table 1. The patient population had a mean age of 83.2 ± 6.7 years, and 53% were men. Patients were highly symptomatic, with NYHA III or IV symptoms in 86.1% of patients. The overall mean Society of Thoracic Surgeons predictors of mortality score was 7.4 ± 3.2%. Diabetes mellitus occurred less often in the TAVR group (34.8%) than in the surgical group (45.1%; p = 0.004); however, there were no significant differences between groups according to insulin requirements. A Charlson Comorbidity Index score ≥5 was recorded in 55.8% of patients. Five-meter gait speed was >6 s in 79.7% of patients, and 10.3% did not live independently.
All-cause mortality and stroke
Table 2 presents the 2-year clinical events. The rate of 2-year all-cause mortality was significantly lower in the TAVR group (22.2%) than in the surgical group (28.6%; log-rank test p < 0.05) in the as-treated cohort, with an absolute reduction in risk of 6.5 percentage points (Central Illustration). Similar results were found in the intention-to-treat cohort (p < 0.05). All stroke tended to be lower at 2 years in the TAVR group compared with the surgical group (p = 0.05). Of these strokes, major stroke occurred through 2 years in 6.8% of the TAVR group and in 9.8% of the surgical group (p = 0.25). The rate of 2-year death or major stroke was significantly lower in the TAVR group (24.2%) than in the surgical group (32.5%; log-rank test p = 0.01). No significant interactions were observed between treatment and any of 9 subgroups with respect to 2-year all-cause mortality (Figure 2).
Other clinical events
The occurrence of 2-year major adverse cardiovascular or cerebrovascular events was lower in the TAVR group (29.7%) than in the surgical group (38.6%; log-rank test p = 0.01) (Central Illustration). Life-threatening or major bleeding, acute kidney injury, and new-onset atrial fibrillation were more common in the surgical group, whereas vascular complications, reintervention, and the need for new permanent pacemakers were more common in the transcatheter group (Table 2).
Endocarditis was uncommon in both groups (Table 3). The rate of 2-year aortic valve hospitalization was 24.2% in the TAVR group and 18.2% in the surgical group (p = 0.08). There were no differences in the frequency of NYHA functional class I or II in the TAVR group (92.1%) and in the surgical group (90.5%) at 2 years (Figure 3).
Echocardiographic parameters of effective orifice area and mean aortic valve gradient remained stable over the 2-year period after transcatheter or surgical valve replacement. The aortic valve hemodynamics were significantly improved, however, in the TAVR group compared with the surgical group (Figure 4). Moderate to severe paravalvular regurgitation (Figure 5) was higher in the TAVR group (6.1%) compared with the surgical group (0.6%; p < 0.001).
We have previously shown that TAVR was associated with improved survival at 1 year compared with surgery in patients at increased risk for surgery (4). This benefit was achieved without an increase in stroke and with favorable aortic valve hemodynamics (4). In the present analysis, we showed that this mortality benefit was sustained at 2 years. Furthermore, the significant reduction in major adverse clinical and cerebrovascular events seen at 1 year persisted at 2 years. We also reported a sustained improvement in aortic valve hemodynamics with no structural valve deterioration associated with the self-expanding transcatheter bioprostheses.
TAVR has become the standard of care in patients who are poor candidates for surgery (3,11). Current American Heart Association/American College of Cardiology guidelines recognize that TAVR is a reasonable alternative approach to surgical valve replacement in patients at high surgical risk (12). Our randomized trial of transcatheter or surgical valve replacement further clarifies these recommendations related to the treatment of severe aortic stenosis in this population. We enrolled patients with symptomatic severe aortic stenosis who were deemed at increased risk as determined by a multidisciplinary heart team. We previously reported a lower rate of all-cause mortality at 1 year in patients treated with self-expanding transcatheter valve therapy compared with surgery without an increase in stroke (4). The present results demonstrate a sustained survival benefit at 2 years with transcatheter replacement (77.8%) compared with surgery (71.4%; p < 0.05). The absolute difference in all-cause mortality between transcatheter and surgical therapy increased from 4.9% at 1 year to 6.5% at 2 years. Furthermore, the frequency of major adverse cardiovascular or cerebrovascular events was significantly lower at 2 years (p = 0.01), with the absolute difference in major adverse cardiac and cerebral events increasing from 6.5% at 1 year to 8.9% at 2 years. The combined endpoint of all-cause mortality or major stroke was also significantly reduced at 2 years in patients treated with transcatheter therapy (24.2%) compared with surgery (32.5%; p < 0.01). We believe that the results of this randomized study suggest that self-expanding transcatheter valve therapy should be considered standard of care and preferred over surgery in this patient population.
There are a number of potential reasons why TAVR resulted in improved survival at 2 years. There was an absolute increase in the mortality difference between transcatheter replacement and surgical replacement between 1 and 2 years, potentially due to persistent adverse outcomes associated with higher rates of bleeding, transfusion, and acute kidney injury at the time of surgery; worse long-term valve performance; and more episodes of atrial fibrillation in patients treated with surgery. Although there were higher rates of permanent pacemakers, paravalvular regurgitation, and vascular complications in the transcatheter group, on balance, they may not have affected long-term mortality in this group.
We also found that the occurrence of all stroke at 2 years also tended to be lower in the TAVR group compared with the surgical group (Central Illustration). In our study, National Institutes of Health Stroke Scale evaluations by trained observers were required before treatment, immediately after treatment, and during all follow-up visits; abnormalities in the neurological evaluation triggered a neurology consultation and imaging. As a result, we believe that the lower observed rates of stroke at 2 years compared with surgery are reassuring for patients undergoing TAVR. Although the etiology of the higher stroke rate in surgical patients is not clearly defined, the higher frequency of atrial fibrillation in patients treated with surgery may also have contributed to these differences (13,14).
Similar to previous reports (15,16), AVAs and aortic valve mean gradients remained stable over 2 years with TAVR and were superior to surgical replacement (Figure 4). We also found no evidence of early structural valve deterioration at 2 years. The rate of moderate or severe paravalvular regurgitation was higher in patients treated with a transcatheter valve, although the overall frequency was low at 2 years (6.1%) (Figure 5). Longer term follow-up will provide more insight into the late term durability of transcatheter bioprostheses. The small number of patients with moderate to severe paravalvular regurgitation prevents a detailed analysis of the association of paravalvular regurgitation and 2-year mortality (17).
This trial was a randomized trial between TAVR with the self-expanding prosthesis and surgical AVR. All sites were experienced centers for surgical AVR, and all surgeons were required to have at least 5 years of experience with surgical AVR. All sites were new to TAVR and were implanting their first TAVR prosthesis in this trial. In the surgical arm of the trial there were more withdrawals for patient preference than in the TAVR arm.
We compared TAVR with the CoreValve self-expanding prosthesis with surgical aortic valve replacement in patients with symptomatic severe aortic stenosis who were at increased surgical risk. The rate of death from any cause at 2 years was significantly reduced with TAVR performed with the self-expanding bioprosthesis.
COMPETENCY IN MEDICAL KNOWLEDGE: Aortic stenosis is a disease that increases with age. A number of patients, particularly the elderly population, are at increased risk of mortality after surgical aortic valve replacement. Self-expanding TAVR can provide superior survival compared with surgical aortic valve replacement in this patient group.
COMPETENCY IN PATIENT CARE: Superior survival, less overall stroke, a superior major adverse cardiac and cerebrovascular event rate, and improved valve hemodynamics are all possible with the self-expanding TAVR system compared with surgical aortic valve replacement and should be considered in patients at increased risk.
TRANSLATIONAL OUTLOOK: Paravalvular leak is still higher in TAVR than in surgical aortic valve replacement, and future efforts should be aimed at decreasing this result.
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 (they are employees of Medtronic).
This study was sponsored by Medtronic. Dr. Reardon serves on a medical advisory board for Medtronic. Dr. Adams has received institutional grants and institutional royalties for patents with Medtronic; and institutional royalties for patents with Edwards Lifesciences. Dr. Kleiman has received grants from Medtronic outside of the current work. Dr. Yakubov has received institutional research grants from Medtronic, Direct Flow Medical, and Boston Scientific; and serves on a medical advisory board for Medtronic and Boston Scientific. Dr. Coselli has received remuneration and other fees from Medtronic and Edwards Lifesciences outside of the submitted work. Dr. Deeb has received grants from Medtronic; and serves on a medical advisory board and on the screening committees for the reported trial, and the SURTAVI and Evolut R trials, but receives no personal income. Dr. Gleason has received institutional grants from Medtronic. Dr. Hermiller serves on the steering committee for the reported trial and the speakers bureau for Medtronic. Dr. Chetcuti has received grants from Medtronic, Edwards Lifesciences, and Boston Scientific; and personal fees from Medtronic and Edwards Lifesciences outside of the submitted work. Dr. Zorn serves as a consultant to Medtronic and Edwards Lifesciences. Dr. Tadros serves as a consultant to Medtronic and St. Jude Medical outside of the submitted work. Dr. Hughes serves as a consultant and speaker for Medtronic. Dr. Harrison has received institutional grants from Medtronic, Boston Scientific, Direct Flow Medical, St. Jude Medical, and Edwards Lifesciences; serves on a medical advisory board for Direct Flow Medical; and serves on the Data and Safety Monitoring Board for CardiAQ. Dr. Maini serves as a speaker and proctor for Medtronic, Boston Scientific, and Abbott Vascular; and has received institutional research grants from Medtronic, Boston Scientific, Direct Flow Medical, and Abbott Vascular. Dr. Mumtaz has received personal fees from Medtronic outside of the submitted work. Dr. Conte serves on a surgical advisory board for Medtronic and Sorin; and has received research support from Boston Scientific, Medtronic, and St. Jude Medical. Dr. Resar has received institutional research grants from Medtronic, Boston Scientific, and St. Jude Medical; has received proctor fees from Medtronic; and serves on a medical advisory board for Boston Scientific. Dr. Oh has received institutional research grants from Medtronic. Dr. Qiao is an employee and shareholder of Medtronic. Dr. Popma has received institutional research grants from Medtronic, Boston Scientific, and Direct Flow Medical; 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.
- Abbreviations and Acronyms
- aortic valve area
- New York Heart Association
- transcatheter aortic valve replacement
- Received March 20, 2015.
- Revision received April 21, 2015.
- Accepted May 5, 2015.
- American College of Cardiology Foundation
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