Author + information
- Received July 21, 2013
- Revision received December 5, 2013
- Accepted January 17, 2014
- Published online April 22, 2014.
- Mathew Williams, MD∗,
- Susheel K. Kodali, MD∗∗ (, )
- Rebecca T. Hahn, MD∗,
- Karin H. Humphries, DS, DSc†,
- Vuyisile T. Nkomo, MD‡,
- David J. Cohen, MD, MS§,
- Pamela S. Douglas, MD||,
- Michael Mack, MD¶,
- Thomas C. McAndrew, MS#,
- Lars Svensson, MD, PhD∗∗,
- Vinod H. Thourani, MD††,
- E. Murat Tuzcu, MD∗∗,
- Neil J. Weissman, MD‡‡,
- Ajay J. Kirtane, MD, SM∗ and
- Martin B. Leon, MD∗
- ∗Herbert and Sandi Feinberg Interventional Cardiology and Heart Valve Center at Columbia University Medical Center/New York Presbyterian Hospital, New York, New York
- †Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada
- ‡Mayo Clinic, Rochester, Minnesota
- §Saint Luke’s Mid-America Heart Institute, Kansas City, Missouri
- ||Duke Clinical Research Institute, Durham, North Carolina
- ¶Baylor Healthcare System, Dallas, Texas
- #Cardiovascular Research Foundation, New York, New York
- ∗∗Cleveland Clinic Foundation, Cleveland, Ohio
- ††Emory University School of Medicine, Atlanta, Georgia
- ‡‡Medstar Research Institute, Washington, DC
- ↵∗Reprint requests and correspondence:
Dr. Susheel Kodali, Columbia University Medical Center, New York-Presbyterian Hospital, 177 Fort Washington Avenue, New York, New York 10032.
Objectives This study sought to examine sex-specific differences in outcomes after surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR) in high-risk patients with severe aortic stenosis.
Background The PARTNER (Placement of Aortic Transcatheter Valve) trial demonstrated similar 2-year survival with SAVR or TAVR for high-risk patients, but sex-specific outcomes are unknown.
Methods In all, 699 patients (300 female) were randomly assigned 1:1 to either SAVR or TAVR with a balloon expandable pericardial tissue valve. Baseline characteristics and 2-year outcomes of TAVR versus SAVR were compared among males and females.
Results Baseline characteristics differed between the sexes. Despite higher Society of Thoracic Surgeons mortality risk scores (11.9 vs. 11.6; p = 0.05), female patients had lower prevalence of coronary artery disease (64.4% vs. 83.7%), prior coronary artery bypass graft surgery (19.8% vs. 61.2%), peripheral vascular disease (36.4% vs. 46.9%), diabetes mellitus (35.6% vs. 45.6%), and elevated creatinine (11.7% vs. 23.9%). Among female patients, procedural mortality trended lower with TAVR versus SAVR (6.8% vs. 13.1%; p = 0.07) and was maintained throughout follow-up (hazard ratio [HR]: 0.67; 95% confidence interval [CI]: 0.44 to 1.00; p = 0.049), driven by the transfemoral arm (HR: 0.55; 95% CI: 0.32 to 0.93; p = 0.02). Among male patients, although procedural mortality was lower with TAVR (6% vs. 12.1%; p = 0.03), there was no overall survival benefit (HR: 1.15; 95% CI: 0.82 to 1.61; p = 0.42).
Conclusions In this retrospective subanalysis of high-risk, symptomatic aortic stenosis patients in the PARTNER trial, female subjects had lower late mortality with TAVR versus SAVR. This was especially true among patients suitable for transfemoral access and suggests that TAVR may be preferred over surgery for high-risk female patients. A randomized, controlled trial conducted specifically in female patients is necessary to properly study differences in mortality between treatment modalities. (THE PARTNER TRIAL: Placement of AoRTic TraNscathetER Valve Trial; NCT00530894)
Transcatheter aortic valve replacement (TAVR) improves mortality compared with standard therapy among inoperable patients with severe, symptomatic aortic stenosis (1) and demonstrates similar outcomes as surgical aortic valve replacement (SAVR) among patients at high surgical risk (2). Notably, unlike trials in most other cardiovascular disease states, female patients represent a significant proportion of enrolled patients in TAVR studies. Prior analyses have demonstrated differences between males and females in pre-existing comorbidities as well as the left ventricular response to severe aortic stenosis, potentially explaining improved clinical outcomes for female patients (3–5). The impact of sex on long-term outcomes after SAVR is less certain, as are sex-specific differences after either TAVR or SAVR. Given the importance of identifying subgroups that benefit preferentially from TAVR, we examined the sex-related characteristics and outcomes of high-risk patients undergoing TAVR versus SAVR in the PARTNER (Placement of Aortic Transcatheter Valve) trial.
The PARTNER trial randomly allocated 699 high-risk patients with severe aortic stenosis to TAVR (Edwards SAPIEN valve, Edwards Lifesciences, Irvine, California) or SAVR (Carpentier Edwards pericardial prosthesis), as previously described (2). Randomization was stratified by transapical or transfemoral vascular access. Clinical and echocardiographic follow-up was obtained for ≥2 years; events were adjudicated independently using standardized endpoint definitions (6) and reported by intention-to-treat analysis; echocardiograms were analyzed at an independent core laboratory and analyzed “as treated” (7,8). Categorical variables were compared using Fisher’s exact test, and continuous variables were compared using Student t test. Event rates for procedural outcomes are reported as Kaplan-Meier estimates. Survival curves for time-to-event variables used Kaplan-Meier estimates and were compared using the log-rank test. Cox proportional hazards models were used to calculate hazard ratios (HRs) and to test for interactions between sex and treatment approach. Data were extracted October 9, 2012, using SAS version 9.2 (SAS Institute, Cary, North Carolina).
Of the subjects, 42.9% were female, including 42.2% TAVR and 43.6% SAVR. Among transfemoral patients, 39.3% were female compared with 49% in the transapical arm. Baseline characteristics differed significantly between males and females (Table 1) but not between patients assigned to TAVR versus SAVR. Baseline echocardiographic variables also differed significantly between sexes (Table 2). Although transvalvular gradients were higher in females, there were no differences in valve area after indexing to body size (0.36 cm2/m2 vs. 0.35 cm2/m2; p = 0.55). Annular diameters were smaller in females (1.92 cm vs. 2.07 cm; p < 0.0001), and thus 80% of females received a 23-mm valve (vs. 25.3% of males; p < 0.0001).
Procedural (30-day or in-hospital) outcomes
Among females, procedural mortality trended lower with TAVR compared with SAVR (6.8% vs. 13.1%; p = 0.07) (Table 3), although procedural stroke rates were higher (5.4% vs. 0.7%; p = 0.02) because of differences in the transfemoral arm (Fig. 1). Vascular complications were more common with TAVR (15% vs. 4.6%; p < 0.01) whereas bleeding was more frequent with SAVR (10.9% vs. 21.6%; p = 0.01). TAVR echocardiographic valve areas were larger (1.49 cm2 vs. 1.36 cm2; p = 0.01), and only 3% had moderate-severe paravalvular leak, but there were no differences between TAVR and SAVR in peak gradients (22.72 mm Hg vs. 25 mm Hg; p = 0.06) or mean gradients (11.86 mm Hg vs. 12.91 mm Hg; p = 0.08).
Similar to females, procedural mortality among males was lower with TAVR compared with SAVR (6% vs. 12.1%; p = 0.03), but there was no difference in stroke rates (4% vs. 4%; p = 0.98) (Table 3, Fig. 1). Vascular complications were more frequent with TAVR (8% vs. 2.5%; p = 0.02) whereas bleeding was more common with SAVR (9.5% vs. 21.2%; p = 0.001). Also similar to females, TAVR echocardiographic valve areas were larger (1.71 cm2 vs. 1.55 cm2; p < 0.01), but there were no differences in peak transaortic gradients (19.60 mm Hg vs. 22.04 mm Hg; p = 0.08) or mean transaortic gradients (10.13 mm Hg vs. 11.13 mm Hg; p = 0.17). Moderate-severe paravalvular leak was present in 10.3% of male TAVR patients (Table 4).
Among females, all-cause mortality was significantly lower with TAVR compared with SAVR at 6 months (12.2% vs. 25.8%; p < 0.01) and 2-year follow-up (28.2% vs. 38.2%; HR: 0.67; 95% confidence interval [CI]: 0.44 to 1.00; p = 0.049) (Fig. 2A). Although there was no interaction between access site (transfemoral vs. transapical) and treatment group (p = 0.13), differences in late mortality were driven by the transfemoral cohort (23.4% vs. 36.9%; HR: 0.55; 95% CI: 0.32 to 0.93; p = 0.02), with no mortality difference in the transapical cohort (Fig. 3A and B).
Among males, mortality in TAVR and SAVR was similar at 6 months (15% vs. 19.8%; p = 0.17) and at 2 years (37.7% vs. 32.3%; HR: 1.15; 95% CI: 0.82 to 1.61; p = 0.42) (Fig. 2B), with no reduction in either arm (Figs. 3C and 3D). Excluding procedural deaths, mortality was higher with TAVR than SAVR (HR: 1.58; 95% CI: 1.06 to 2.36; p = 0.02).
Among male and female patients in the randomized PARTNER trial evaluating TAVR versus SAVR we found the following: 1) significant differences in important comorbid conditions that may account for differences in late mortality; 2) a survival benefit for female, but not for male patients, with TAVR compared with SAVR, especially using a transfemoral approach; and 3) higher stroke risk for female patients with TAVR but no differences among male patients.
The impact of sex on outcomes after SAVR is unclear although the STS risk model includes female sex as a significant risk factor for mortality (HR: 1.23) (9). Although adjusted procedural outcomes do not differ by sex (10,11), long-term survival is better among women undergoing SAVR (12,13), particularly if a bioprosthesis is implanted (13). Others have shown that despite no difference in survival, women respond differently to SAVR with a greater improvement in ejection fraction after intervention (10).
Although the PARTNER trial demonstrated similar mortality for SAVR and TAVR, outcomes differ according to the patient’s sex (2). In the current study, a modest difference in procedural mortality favoring TAVR in female patients continues to increase over time so that at 6 months and 2 years, SAVR mortality was significantly higher. Conversely, there was no mortality difference between TAVR and SAVR among men. Although male patients experienced lower procedural mortality with TAVR versus SAVR, 2-year mortality actually tended to be higher among men treated with TAVR as compared with SAVR.
These differences in late outcomes may be driven by differences in baseline characteristics. Women were less likely to have important comorbidities including coronary artery disease, peripheral vascular disease, diabetes mellitus, and renal dysfunction. Once a female patient survives the procedural period, the initial benefit of lower mortality with TAVR is sustained. Among male patients, however, the early benefit of lower procedural mortality with TAVR appears to be overwhelmed by competing risks (baseline factors as well as post-implant complications), leading to higher mortality in follow-up.
Another interesting finding from this study is the sex-related difference in outcomes in the transfemoral and transapical arms of the trial. Among women, late mortality was dramatically lower with TAVR as compared with SAVR among patients who were suitable for transfemoral access (23.4% vs. 36.9%; p = 0.02), whereas among patients without suitable transfemoral access (in whom TAVR was performed by a transapical approach), 2-year mortality was similar with TAVR and SAVR (37.3% vs. 41.7%; p = 0.62). For male patients, however, there was no significant difference in late outcomes between TAVR and SAVR in either the transfemoral or transapical arm. It is important to note that the study was not powered to detect mortality differences in each access stratum. The transapical population had increased rates of important comorbidities such as previous coronary artery bypass grafting, cerebrovascular disease, and peripheral vascular disease that may have influenced mortality.
Procedural complications also varied by sex. Unlike prior reports (13,14), our study showed lower procedural strokes among female subjects versus male subjects in the SAVR group (0.7% vs. 4%; p = 0.08), but similar to prior reports (4), there was no difference in the TAVR group (4.8% vs. 4%; p = 0.73) despite having less vascular disease, suggesting that embolic risk with TAVR is due to liberation of debris from the aortic valve. Vascular complications were also more frequent among female patients in the TAVR group (23.8% vs. 13.9%; p = 0.02), a finding seen in some studies (4,15), but not all (3). Despite more vascular and neurologic complications, the better outcomes after TAVR for women offer further support for the importance of other comorbidities as drivers of late mortality in men. Smaller, next-generation devices with lower vascular and bleeding complications may further improve outcomes with TAVR over SAVR in women.
Echocardiographic outcomes differed, with moderate or severe paravalvular aortic regurgitation being more frequent in men versus women undergoing TAVR (10.3% vs. 3%; p = 0.03), perhaps because of more frequent undersizing of valves. Because of the association of paravalvular aortic regurgitation with increased mortality (16–20), that may contribute to the lack of TAVR benefit seen for men and may be remedied by next-generation valves and better sizing algorithms.
As a retrospective subanalysis of the PARTNER trial, the current study is not adequately powered to evaluate mortality outcomes. This study represents an early experience with TAVR. With increased procedural expertise and device iterations, outcomes will likely improve. Finally, these results only apply to high-risk patients and cannot be extrapolated to moderate-risk patients with aortic stenosis.
Despite higher incidences of vascular complications and strokes, women had better late mortality with TAVR than with SAVR. That was especially true in the transfemoral arm and suggests that for high-risk female patients, TAVR is a better option than surgery. Because the study was not powered for this subgroup analysis, the results should be considered hypothesis generating and a randomized, controlled trial in female subjects is necessary to properly study differences in outcomes.
The authors thank Maria Alu for editorial support and Ke Xu for statistical support.
The PARTNER trial was funded by Edwards Lifesciences and designed collaboratively by the Steering Committee and the sponsor. The present analysis was carried out by academic investigators with no additional funding. Dr. Williams is a consultant for the PARTNER Trial Steering Committee and Edwards Lifesciences, and Medtronic. Dr. Kodali is a consultant for the PARTNER Trial Steering Committee, Edwards Lifesciences; and is on the Scientific Advisory Board of Thubrikar Aortic Valve, Inc. Dr. Cohen has received research grant support from Edwards Lifesciences, Medtronic, and Boston Scientific; and is a consultant for Medtronic. Dr. Douglas has received institutional grant support from Edwards Lifesciences. Dr. Svensson has received travel reimbursements from Edwards Lifesciences related to his work as an unpaid member of the PARTNER Trial Executive Committee; holds equity in Cardiosolutions and ValvXchange; and has Intellectual Property Rights/Royalties from Posthorax. Drs. Mack, Tuzcu, and Leon have received travel reimbursements and are unpaid members of the PARTNER Trial Executive Committee and Edwards Lifesciences. Dr. Thourani is a consultant for the PARTNER Trial Steering Committee and Edwards Lifesciences; and is a consultant for Sorin Medical, St. Jude Medical, and DirectFlow. Dr. Weissman has received research grants from Edwards Lifesciences, St. Jude Medical, Boston Scientific, Sorin Medical, Direct Flow, and MitralAlign. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Williams and Kodali contributed equally to this work.
- Abbreviations and Acronyms
- surgical aortic valve replacement
- transcatheter aortic valve replacement
- Received July 21, 2013.
- Revision received December 5, 2013.
- Accepted January 17, 2014.
- American College of Cardiology Foundation
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