Outcomes in the Randomized CoreValve US Pivotal High Risk Trial in Patients With a Society of Thoracic Surgeons Risk Score of 7% or Less

Key Points

Question  Does the benefit of self-expanding transcatheter aortic valve replacement compared with surgery in patients at increased surgical risk also apply to lower-risk patients?

Findings  This analysis of high-risk patients with a Society of Thoracic Surgeons Predicted Risk of Mortality score of 7% or less from a randomized trial of a self-expanding transcatheter aortic valve shows superior survival, superior echocardiographic flow parameters, significantly less severe patient-prosthesis mismatch, and similar medical benefit for transcatheter aortic valve replacement at 2 years.

Meaning  Although the Society of Thoracic Surgeons Predicted Risk of Mortality has decreased in US trials and the Transcatheter Valve Therapy Registry, the benefit of transcatheter aortic valve replacement in this patient population appears to be preserved.

Importance  Transcatheter aortic valve replacement (TAVR) is now a well-accepted alternative to surgical AVR (SAVR) for patients with symptomatic aortic stenosis at increased operative risk. There is interest in whether TAVR would benefit patients at lower risk.

Objective  The Society of Thoracic Surgeons Predicted Risk of Mortality (STS PROM) has trended downward in US TAVR trials and the STS/American College of Cardiology Transcatheter Valve Therapy Registry. We hypothesized that if the Society of Thoracic Surgeons Predicted Risk of Mortality (STS PROM) alone is sufficient to define decreased risk, the contribution to survival based on the degree of invasiveness of the TAVR procedure will decrease, making it more difficult to show improved survival and benefit over SAVR.

Design, Setting, and Participants  The CoreValve US Pivotal High Risk Trial was a multicenter, randomized, noninferiority trial. This retrospective analysis evaluated patients who underwent an attempted implant and had an STS PROM of 7% or less. The trial was performed at 45 US sites. Patients had severe aortic stenosis and were at increased surgical risk based on their STS PROM score and other risk factors.

Interventions  Eligible patients were randomly assigned (1:1) to self-expanding TAVR or to SAVR.

Main Outcomes and Measures  We retrospectively stratified patients by the overall median STS PROM score (7%) and analyzed clinical outcomes and quality of life using the Kansas City Cardiomyopathy Questionnaire in patients with an STS PROM score of 7% or less.

Results  The mean (SD) ages were 81.5 (7.6) years for the TAVR group and 81.2 years (6.6) for the SAVR group. A little more than half were men (57.9% in the TAVR group and 55.8% in the SAVR group). Of 750 patients who underwent attempted implantation, 383 (202 TAVR and 181 SAVR) had an STS PROM of 7% or less (median [interquartile range]: TAVR, 5.3% [4.3%-6.1%]; SAVR, 5.3% [4.1%-5.9%]). Two-year all-cause mortality for TAVR vs SAVR was 15.0% (95% CI, 8.9-10.0) vs 26.3% (95% CI, 19.7-33.0) (log rank P = .01). The 2-year rate of stroke for TAVR vs SAVR was 11.3% vs 15.1% (log rank P = .50). Quality of life by the Kansas City Cardiomyopathy Questionnaire summary score showed significant and equivalent increases in both groups at 2 years (mean [SD] TAVR, 20.0 [25.0]; SAVR, 18.6 [23.6]; P = .71; both P < .001 compared with baseline). Medical benefit, defined as alive with a Kansas City Cardiomyopathy Questionnaire summary score of at least 60 and a less than 10-point decrease from baseline, was similar between groups at 2 years (TAVR, 51.0%; SAVR, 44.4%; P = .28).

Conclusions and Relevance  Self-expanding TAVR compares favorably with SAVR in high-risk patients with STS PROM scores traditionally considered intermediate risk.

Trial Registration  Clinicaltrials.gov Identifier: NCT01240902.

Transcatheter aortic valve replacement (TAVR) with balloon-expandable and self-expanding valves is now an accepted alternative to surgical aortic valve replacement (SAVR) in the treatment of symptomatic severe aortic stenosis in patients at increased risk for surgery.^1,2 The Society of Thoracic Surgeons Predicted Risk of Mortality (STS PROM), used alone or in part to select patients for TAVR, has decreased over time since the first randomized trial of balloon-expandable TAVR with a study mean of 11.6%,³ to the 2016 study in intermediate-risk patients with a mean of 5.8%.⁴ Transcatheter aortic valve replacement using a self-expanding valve (CoreValve bioprosthesis; Medtronic) has shown superior survival compared with SAVR at 1 year⁵ and 2 years⁶ in patients with a mean STS PROM score of 7.4%.

The STS/American College of Cardiology Transcatheter Valve Therapy Registry provides medical device surveillance of commercial TAVs in the United States. The initial report of 1-year outcomes described patients with a median STS PROM score of 7.1%,⁷ indicating a reduction in STS PROM from randomized trials to US commercial use. Concerns around a creep to lower risk based primarily on the STS PROM score have been raised. We hypothesized that as patient risk decreases, the contribution to survival conferred by the less invasive nature of the TAVR procedure would also decrease because patients at lower risk generally tolerate invasive procedures better than those at higher risk. To test this hypothesis, we evaluated patients in the randomized CoreValve US Pivotal High Risk Trial with an STS PROM score of 7% or less.

The CoreValve US Pivotal High Risk Trial was a multicenter, randomized (1:1), noninferiority trial performed at 45 sites in the United States. The trial design and outcomes through 3 years have been previously reported.^2,5,6 Each institutional review board approved the study protocol, and all patients provided written informed consent. The formal trial protocols can be found in Supplement 1.

Patient selection and detailed inclusion and exclusion criteria have been described.⁵ A patient’s surgical risk was based on the STS PROM score and other factors (eTable 1 in Supplement 2). Increased risk was defined as an expected 30-day risk of mortality of at least 15% but less than 50%. Each site calculated the STS PROM using the STS calculator and submitted the form to the screening committee. The sponsor ensured the accuracy of the documentation.

The primary end points for this report were all-cause mortality and quality of life based on the Kansas City Cardiomyopathy Questionnaire overall summary score through 2 years. A good medical benefit was defined as having a Kansas City Cardiomyopathy Questionnaire summary score of at least 60 and with less than a 10-point decrease from baseline, and an acceptable outcome was alive without meeting these criteria.⁸

Categorical variables were compared using the Fisher exact test or the χ² test. Continuous variables are presented as mean (SD) and compared with the use of the t test. Kaplan-Meier estimates were used to construct survival curves based on all available follow-up data for the time-to-event analysis. Differences in event rates between groups were evaluated using the log-rank test. Death rates for the quality of life analysis were calculated as straight rates for patients with available Kansas City Cardiomyopathy Questionnaire data. All testing used a 2-sided α level of .05. Statistical analyses were performed with the use of SAS software, version 9.2 (SAS Institute).

Of the 750 patients (391 TAVR; 359 SAVR) in the trial, 383 (202 TAVR; 181 SAVR) had an STS PROM score of 7% or less (eFigure 1 in Supplement 2). The median STS PROM score for each group was 5.3%. The only significant baseline differences between groups were that more patients with SAVR had diabetes mellitus and more patients with SAVR had New York Heart Association class III or IV symptoms. Although more patients with TAVR had a hostile mediastinum at baseline, there were no differences in the other indicators of risk not included in the STS PROM (eTable 2 in Supplement 2). Patients were followed up at least 2 years.

Figure 1 shows all-cause mortality and cardiovascular mortality at 2 years. The Kansas City Cardiomyopathy Questionnaire summary score increased significantly from baseline in both the TAVR and SAVR groups but did not differ between the groups at 2 years (mean [SD] TAVR, 70.3 [23.4] vs SAVR, 69.7 [23.1]; P = .85) (eFigure 2 in Supplement 2).

Good medical benefit was similar for both groups (TAVR 51.0% vs SAVR 44.4%, P = .28), as shown in Figure 2.

Forward flow hemodynamics were superior for TAVR vs SAVR at each follow-up postimplant. At 2 years, the mean (SD) effective orifice areas were 1.83 (0.47) vs 1.52 (0.46), P < .001, and the mean (SD) aortic valve gradients were 8.55 (3.52) vs 12.54 (6.82), P < .001, with similar results at each follow-up (eFigure 3 in Supplement 2). The rates of severe patient-prosthesis mismatch at 2 years also favored TAVR (8.1% vs 25.6%; P < .001), with similar results at each follow-up (eTable 3 in Supplement 2).

Major vascular complications and a new pacemaker were more common in patients with TAVR. Life-threatening or disabling bleeding, new atrial fibrillation, and acute kidney injury were all more common in patients with SAVR (Table).

Concern has been raised that risk creep is occurring owing to lower STS PROM scores seen over time in the US trials and the Transcatheter Valve Therapy Registry and that this may change the potential benefit of TAVR in this population. In this subanalysis of the randomized CoreValve US Pivotal High Risk Trial, we observed superior survival, equivalent stroke rates, equivalent improvement in quality of life and similar medical benefit for TAVR vs SAVR at 2 years in high-risk patients with STS PROM scores of 7% or less.

Survival is also affected by procedural complications. Transcatheter aortic valve replacement was associated with more major vascular complications and paravalvular leak,⁹ both of which have been associated with higher mortality, and increased need for pacemakers, which has not been associated with higher short-term mortality.¹⁰ Surgical aortic valve replacement was associated with more life-threatening bleeding,¹¹ atrial fibrillation,¹² acute kidney injury,¹³ and patient-prosthesis mismatch,¹⁴ all of which have been associated with increased early and longer-term mortality. Survival is influenced by the balance of these effects, which appear to favor TAVR in this analysis.

The PARTNER II trial that randomized patients with an STS PROM score of 4% to 8% to TAVR with a balloon-expandable TAV or SAVR reported a mean STS PROM score of 5.8% for each group, which was similar in our study (5.3% for TAVR and SAVR).⁴ Although comparable with our study in STS PROM score, other patient conditions outside of the STS could contribute to risk assessment. This trial reported similar rates of all-cause mortality at 2 years of 16.7% for TAVR vs 18.0% for SAVR (P = .45) and disabling stroke rates of 6.2% for TAVR and 6.4% for SAVR (P = .83).⁴

In our study, we chose to stratify patients based on the median STS PROM of 7% or less reported from the TVT Registry.⁷ The results show that as the risk profile defined by STS score is lowered, the benefit seen with TAVR persists. However, it is important to note that the patients in this analysis were deemed to be at high surgical risk based on screening committee assessment despite their STS scores.

Although the data are drawn from a prospective, randomized trial, this was a retrospective, post hoc subgroup analysis. We did not perform any matching procedures to account for the few baseline differences.

This analysis of high-risk patients with an STS PROM of 7% or less from a randomized trial of a self-expanding TAV shows superior survival, superior echocardiographic flow parameters, significantly less severe patient-prosthesis mismatch, and similar medical benefit for TAVR compared with SAVR at 2 years.

Corresponding Author: Michael J. Reardon, MD, Houston Methodist DeBakey Heart and Vascular Center, 6550 Fannin, Ste 1401, Houston, TX 77030 (mreardon@houstonmethodist.org).

Accepted for Publication: June 2, 2016.

Published Online: August 17, 2016. doi:10.1001/jamacardio.2016.2257

Author Contributions: Dr Reardon had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Reardon, Kleiman, Adams, Deeb, Gleason, Hermiller, Maini, Popma.
Acquisition, analysis, or interpretation of data: Reardon, Yakubov, Coselli, Deeb, O'Hair, Gleason, Lee, Chetcuti, Heiser, Merhi, Zorn, Tadros, Robinson, Petrossian, Hughes, Harrison, Maini, Mumtaz, Conte, Resar, Aharonian, Pfeffer, Oh, Huang, Popma.
Drafting of the manuscript: Reardon, Deeb.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Deeb, Huang, Popma.
Administrative, technical, or material support: Kleiman, Yakubov, Coselli, Gleason, Merhi, Robinson, Pfeffer, Popma.
Study supervision: Reardon, Adams, Yakubov, O'Hair, Gleason, Lee, Hermiller, Chetcuti, Heiser, Merhi, Zorn, Tadros, Robinson, Harrison, Maini, Conte, Resar, Popma.
Other—Echo Core Lab: Oh.
Other: Hughes.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Drs Reardon and Kleiman have received fees from Medtronic for providing educational services. Dr Adams has received grant support from Medtronic and has royalty agreements through Mount Sinai School of Medicine with Medtronic and with Edwards Lifesciences. Dr Yakubov has received grant support and served on advisory boards for Medtronic and Boston Scientific and has received grant support from Direct Flow Medical. Dr Coselli has consulted with and participated in clinical research trials sponsored by Medtronic; has consulted with St. Jude Medical, Inc; and has participated in clinical research trials sponsored by Edwards Lifesciences. Dr O’Hair has received fees from Medtronic for providing educational services. Dr Gleason receives institutional grant support from Medtronic but receives no personal income. Dr Hermiller has received fees for educational services from Medtronic. Dr Chetcuti has received grant support from Edwards Lifesciences, Boston Scientific, and Medtronic and has received proctoring fees from Medtronic. Dr Zorn has received consulting/proctoring fees from Medtronic and Edwards Lifesciences. Dr Tadros has received consulting fees, proctoring fees, and research support from Medtronic and St. Jude Medical. Dr Maini has received fees for service on speakers’ bureaus, advisory boards, proctor, and has conducted contracted research for Medtronic, Abbott Vascular, Boston Scientific, ABIOMED, Siemens, and St. Jude Medical. Dr Mumtaz has received consulting fees, proctoring fees, honoraria, and research support from Atricure, Abbott, Edwards Lifesciences, Medtronic, and Direct Flow Medical. Dr Resar has received proctoring fees from Medtronic. Dr Oh has received core laboratory and consulting funding from Medtronic. Dr Huang is an employee of Medtronic. Dr Popma has received grants from Medtronic, Boston Scientific, and Direct Flow Medical. No other disclosures are reported.

Funding/Support: The CoreValve US Pivotal High Risk Trial was funded by Medtronic, Minneapolis, Minnesota.

Role of the Funder/Sponsor: The study sponsor was responsible for study design, selection of the clinical sites, monitoring of the data, management of the case report forms, and statistical analyses but had no role in the preparation, review, or approval of the manuscript and decision to submit the manuscript for publication.

Previous Presentation: Portions of this manuscript were presented as a poster at the 65th Scientific Session of the American College of Cardiology, April 2, 2016; Chicago, Illinois.

Additional Contributions: Jane Moore, MS, ELS, drafted the study methods, created all tables and figures, and provided technical review of the manuscript. Julie A. Linick, ELS, provided copyediting assistance. We also thank Joleen Perkins, BS, and Eric Vang, PhD, for overall trial management. All are employees of Medtronic. All persons listed in this section are employees of the study sponsor and made the contributions acknowledged here as part of their usual responsibilities of employment.