Edwards SAPIEN Versus Medtronic Aortic Bioprosthesis in Women Undergoing Transcatheter Aortic Valve Implantation (from the Win-TAVI Registry)

Journal Pre-proof

Edwards SAPIEN Versus Medtronic Aortic Bioprosthesis In Women Undergoing Transcatheter Aortic Valve Implantation (From the Win-TAVI Registry) Cristina Giannini MD, PhD , Anna Sonia Petronio MD , Julinda Mehilli MD , Samantha Sartori PhD , Jaya Chandrasekhar MBBS, MS , Michela Faggioni MD , ` Thierry Lefevre MD , Patrizia Presbitero MD , Piera Capranzano MD , Didier Tchetche MD , Alessandro Iadanza MD , Gennaro Sardella MD , Nicolas M. Van Mieghem MD , Emanuele Meliga MD , Nicolas Dumonteil MD , Chiara Fraccaro MD, PhD , Daniela Trabattoni MD , Ghada W. Mikhail MD , Maria C. Ferrer MD , Christoph Naber MD , Peter Kievit MD , Sabato Sorrentino MD , Marie Claude Morice MD , Alaide Chieffo MD , Roxana Mehran MD , WIN-TAVI Investigators PII: DOI: Reference:

S0002-9149(19)31259-7 https://doi.org/10.1016/j.amjcard.2019.10.056 AJC 24286

To appear in:

The American Journal of Cardiology

Received date: Accepted date:

16 October 2019 28 October 2019

Please cite this article as: Cristina Giannini MD, PhD , Anna Sonia Petronio MD , Julinda Mehilli MD , Samantha Sartori PhD , Jaya Chandrasekhar MBBS, MS , ` Michela Faggioni MD , Thierry Lefevre MD , Patrizia Presbitero MD , Piera Capranzano MD , Didier Tchetche MD , Alessandro Iadanza MD , Gennaro Sardella MD , Nicolas M. Van Mieghem MD , Emanuele Meliga MD , Nicolas Dumonteil MD , Chiara Fraccaro MD, PhD , Daniela Trabattoni MD , Ghada W. Mikhail MD , Maria C. Ferrer MD , Christoph Naber MD , Peter Kievit MD , Sabato Sorrentino MD , Marie Claude Morice MD , Alaide Chieffo MD , Roxana Mehran MD , WIN-TAVI Investigators, Edwards SAPIEN Versus Medtronic Aortic Bioprosthesis In Women Undergoing Transcatheter Aortic Valve Implantation (From the Win-TAVI Registry), The American Journal of Cardiology (2019), doi: https://doi.org/10.1016/j.amjcard.2019.10.056

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.

Edwards SAPIEN Versus Medtronic Aortic Bioprosthesis In Women Undergoing Transcatheter Aortic Valve Implantation (From the Win-TAVI Registry)

Cristina Giannini, MD, PhD1; Anna Sonia Petronio, MD1; Julinda Mehilli, MD2; Samantha Sartori, PhD3; Jaya Chandrasekhar, MBBS, MS3; Michela Faggioni, MD3; Thierry Lefèvre, MD4; Patrizia Presbitero, MD5; Piera Capranzano, MD6; Didier Tchetche, MD7; Alessandro Iadanza, MD8; Gennaro Sardella, MD9; Nicolas M. Van Mieghem, MD10; Emanuele Meliga, MD11; Nicolas Dumonteil, MD7; Chiara Fraccaro, MD, PhD12; Daniela Trabattoni, MD13; Ghada W. Mikhail, MD14; Maria C. Ferrer, MD15; Christoph Naber, MD16; Peter Kievit, MD17; Sabato Sorrentino, MD3; Marie Claude Morice, MD4; Alaide Chieffo, MD18; Roxana Mehran, MD3; WIN-TAVI Investigators

1 Department of Cardiology, AOUP Cisanello, University Hospital, Pisa, Italy; 2 Department of Cardiology, Ludwig-Maximilians-University of Munich, Munich, Germany; 3 The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York; 4 Department of Cardiology, Institut Hospitalier Jacques Cartier, Ramsay Générale de Santé, Massy, France; 5 Department of Cardiology, Istituto Clinico Humanitas, Milan, Italy; 6 Department of Cardiology, University of Catania, Catania, Italy; 7 Department of Cardiology, Clinique Pasteur, Toulouse, France; 8 Department of Cardiology, Azienda Ospedaliera Universitaria Senese, Policlinico Le Scotte, Siena, Italy; 9 Department of Cardiology, Policlinico “Umberto I,” Sapienza University of Rome, Rome, Italy; 10 Department of Cardiology, Erasmus Medical Center, Thoraxcenter, Rotterdam, the Netherlands; 11 Department of Cardiology, Mauriziano Hospital, Turin, Italy; 1

12 Department of Cardiology, University of Padova, Padova, Italy; 13 Department of Cardiology, Centro Cardiologico Monzino, Milan, Italy; 14 Department of Cardiology, Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, United Kingdom; 15 Department of Cardiology, Hospital Universitario Miguel Servet, Zaragoza, Spain; 16 Department of Cardiology, Klinikum Wilhelmshaven Germany; 17 Department of Cardiology, HartKliniek Nederland, theNetherlands; 18 Department of Cardiology, San Raffaele Scientific Institute, Milan, Italy. Word count: 2,437 (excluding title page, abstract, references and tables) Short title: Balloon-expandable versus self-expanding TAVI in women

Corresponding Author Roxana Mehran, MD, FACC Professor of Medicine (Cardiology) Director of Interventional Cardiovascular Research and Clinical Trials The Zena and Michael A. Wiener Cardiovascular Institute, The Icahn School of Medicine at Mount Sinai One Gustave L. Levy Place, Box 1030, New York, NY 10029-6574, USA Tel.: +1 212 659 9691 Fax: +1 646 537 8547 [email protected]

2

Abstract: We sought to analyze outcomes of women receiving balloon-expandable valves (BEV) or self-expanding valves (SEV) in contemporary transcatheter aortic valve implantation (TAVI). WIN TAVI (Women's INternational Transcatheter Aortic Valve Implantation) is the first all-female TAVI registry to study the safety and performance of TAVI in women. We compared women treated with BEV (n=408, 46.9%) versus those treated with SEV (n = 461, 53.1%). The primary efficacy endpoint was the (VARC-2) composite of 1-year all-cause death, stroke, myocardial infarction, hospitalization for valve-related symptoms or heart failure or valve-related dysfunction. Women receiving SEV had higher surgical risk scores, higher rate of prior stroke and pulmonary hypertension whereas women receiving BEV were more frequently denied surgical valve replacement due to frailty. BEV patients were less likely to require post-dilation and had significantly lower rates of residual aortic regurgitation grade 2 (9.8% vs. 4.7%, p=0.007). At 1-year, the crude incidence and adjusted risk of the primary VARC-2 efficacy endpoint was similar between groups (17.1% with SEV and 14.3% with BEV, p=0.25; HR 1.09, 95% CI 0.68-1.75). Conversely the crude rate and adjusted risk of new pacemaker implantation was higher with SEV than BEV (15% vs. 8.6%, p=0.001; HR 1.97, 95% CI 1.13-3.43). A subanalysis on new generation valves showed no difference in the need for pacemaker implantation between the two devices (10.1% vs. 8.0%, p=0.56). In conclusion, in contemporary TAVI, SEV are used more frequently in women with greater comorbidities. While there were no differences in unadjusted and adjusted risk of 1-year primary efficacy endpoint between the valve types, there was a greater need for permanent pacemakers after SEV implantation. Keywords: transcatheter aortic valve implantation, women, valve type, clinical outcomes

3

Introduction Transcatheter aortic valve implantation (TAVI) represents a safe and efficacious therapeutic strategy for patients with severe aortic stenosis [1-6]. Unlike coronary artery disease trials, women represent a significant proportion of enrolled patients in TAVI studies. The importance of gender on clinical outcomes following TAVI compared to surgical aortic valve replacement (SAVR) has been previously highlighted by the gender sub-analysis of the PARTNER (Placement of AoRTic TraNscathetER valve) trial and US Corevalve trial, demonstrating that for high risk female patients, TAVI is a better option than surgery[7, 8]. However, a patient-centered TAVI risk/ benefit assessment is required, and anatomical characteristics should be taken into account during patient and prosthetic valve selection. Although there are several devices available for TAVI, only two have been widely utilized both in the US and in Europe: the Edwards balloon expandable valve (BEV) and Medtronic self-expandable valve (SEV). Comparative studies evaluating BEV versus SEV have been limited by small sample size, lower female representation and/or indirect comparison [9-12]. While BEV and SEV are known to have specific features and anatomical requirements, potential gender-related differences in procedural and clinical outcomes have not been investigated so far. The aim of this study from the WIN-TAVI registry [13, 14] is 1) to compare the safety and efficacy of SEV and BEV in an all-female population with severe aortic valve stenosis and 2) to compare the effect of new generation SEV versus BEV.

Methods WIN TAVI (Women’s INternational Transcatheter Aortic Valve Implantation) is an international prospective registry comprising all consecutive female patients undergoing TAVI with any approved device in 19 centers in Europe and the US from March 2013 to December 2015, as previously described [13, 14]. All participating sites had institutional approval from the local ethical review board and the study was conducted according to the principles of the Declaration of Helsinki, International Organization for Standardization Guidelines, and Good Clinical Practice Guidelines. All patients who met the 4

eligibility criteria and provided written informed consent were enrolled in the study. Use of multidetector computed tomography (MDCT) of the aorta and iliofemoral axis was recommended to screen patients and direct the heart team’s choice on procedure type.

For the purpose of this analysis, we included all patients receiving an Edwards SAPIEN (Edwards Lifesciences, Irvine, CA, USA) or a Medtronic (Medtronic, Minneapolis, MN, USA) valve. Patients receiving other valve types were excluded from this analysis due to small numbers. Patients were divided based on valve type implanted into two groups: BEV and SEV. Procedural selection access, device type and use of pre and post-dilation was at the discretion of the treating physician. New-generation BEV (SAPIEN 3) and SEV (Evolut R) groups were also compared.

The primary study endpoint was 1-year efficacy endpoint according to the Valve Academic Research Consortium 2 (VARC-2) definition, comprising all-cause death, all stroke, myocardial infarction, hospitalizations for valve-related symptoms or worsening congestive heart failure or valve-related dysfunction (clinical presentation with valve thrombosis or endocarditis) [15]. Additional individual safety endpoints included: 30 day VARC-2 safety endpoint, 1-year all-cause death, cardiovascular death, myocardial infarction, stroke, bleeding (VARC-2 life-threatening or major bleeding), vascular complications, conduction disturbances and cardiac arrhythmias, coronary obstruction, ventricular perforation and conversion to open surgery. The Clinical and Data coordinating center for the study was at the Icahn School of Medicine at Mount Sinai (New York, New York). Adverse clinical events were reported by the centers through the electronic data collection system and were then reviewed and adjudicated by an independent clinical event committee of expert physicians using source documents provided by the sites. An independent core laboratory reviewed all MDCT exams. The study was endorsed by the SCAI-WIN (Society for Cardiovascular Angiography and Interventions - Women In Innovation) initiative.

5

Continuous baseline variables are expressed as mean±SD and were compared with the Student’s t-test. Categorical variables are expressed as percentages and were compared by the chi-square method. Clinical outcomes are reported using Kaplan Meier time-to-event methods and compared using the log-rank test. Hazard ratios (HR) and 95% confidence intervals (CI) were generated using multivariable Cox regression methods for risk of 1-year outcomes with SEV (reference= BEV). Variables for adjustment comprised age, body mass index, prior myocardial infarction, prior percutaneous coronary intervention or coronary artery bypass graft, prior stroke, chronic kidney disease, baseline atrial fibrillation, baseline permanent pacemaker, left ventricular ejection fraction, baseline pulmonary hypertension, surgical risk scores, high surgical risk judged by heart team, surgical aortic valve replacement rejected due to frailty, device size (>26mm vs. <=26mm), device generation, valve pre-dilation, valve post-dilation, post TAVI aortic regurgitation (AR) grade 2 or 3. A sensitivity analysis was carried out in patients receiving SEV or BEV for whom cardiac MDCT data was available (n=461). The sensitivity analysis took into account only MDCT variables that differed between the two groups in addition to the covariates previously listed for the primary analysis. A secondary analysis was carried out to compare new generation SEV Evolut R versus new generation BEV SAPIEN 3 valve (reference=BEV). All analyses were performed using Stata version 14.0 (StataCorp., College Station, Texas) and p-values<0.05 were considered significant.

Results Among 1019 patients enrolled in WIN-TAVI, 408 received an Edwards BEV, either SAPIEN XT or SAPIEN 3, and 461 received a Medtronic SEV, either Corevalve or Evolut R. Table 1 displays the baseline characteristics of patients according to valve type. SEV were more likely used in patients with a history of stroke, higher surgical risk scores and prior pacemaker implantation. Females receiving SEV had higher prevalence of pulmonary hypertension whereas those receiving BEV had high frailty as key reasons for rejecting SAVR (Fig 1). Echocardiographic characteristics were comparable between the two groups, 6

except for larger aortic annulus diameter in women receiving SEV. MDCT aortic root assessment confirmed larger mean annular diameter and circumference in SEV than BEV treated patients, whereas mean annulus area and the mean height from annulus to the left and right coronary ostia were similar between groups.

Procedural data are summarized in Table 2. The majority of BEV and SEV women were treated via the transfemoral route using local anaesthesia or conscious sedation without significant differences between the groups. SEV patients were more likely to receive larger sized valves and were more frequently treated with post-dilatation after implantation compared to BEV patients. No differences in procedural complications were noted between the groups. A significantly lower incidence of post-procedure AR grade ≥2 was observed in the BEV group (9.8% vs. 4.7%, p=0.007).

Clinical outcomes are presented in Table 3. No differences were observed between SEV and BEV in the occurrence of 30 day all-cause (4.3% vs. 3.7%, p=0.62) or cardiovascular death (4.3% vs. 3.4%, p=0.49). In addition, there were no statistically significant differences in the incidence of the VARC-2 combined safety endpoint (14.3% vs. 5.4%, p=0.87) or other secondary endpoints between the two groups. In contrast, the incidence of device failure requiring second valve deployment and new permanent pacemaker implantation was higher for patients treated with SEV. At 1-year, the crude incidence and adjusted risk of the primary VARC-2 efficacy endpoint was similar between BEV and SEV groups (17.1% with SEV and 14.3% with BEV, p=0.25; HR 1.09, 95% CI 0.68-1.75) (Figure 2). Conversely, the risk of new permanent pacemaker implantation was higher with SEV both before and after adjusting for confounders (15% vs. 8.6%, p=0.001; HR 1.97, 95% CI 1.13-3.43). Other secondary endpoints did not significantly differ between SEV and BEV treated women.

7

A sensitivity analysis was performed in those patients for whom cardiac MDCT data were available (n=461) (Figure 3). The sensitivity analysis confirmed that the risk of 1year VARC-2 efficacy endpoint was comparable between SEV and BEV, in keeping with the main analysis. However, once adjusted for MDCT characteristics, no difference was observed in the need for permanent pacemaker implantation (HR 1.25, 95% CI 0.63 - 2.48).

In the secondary analysis on new generation devices, we identified 224 Edwards SAPIEN 3 BEV and 79 Medtronic Evolut R SEV. Notably, the percentage of new generation devices used was significantly higher among the BEV than SEV group (p<0.001). Although the incidence of post procedural AR ≥2 grade was significantly lower for new generation devices (p<0.001), SEV prostheses were associated with a greater rate of AR compared to BEV prostheses (2.7% vs. 8.6%; p=0.04). Of note, no cases of grade 3 AR were recorded in any group. With the limitations of a small sample size, there were no significant differences in the rates of all crude and adjusted 1-year clinical outcomes including permanent pacemaker implantation (Table 4).

Discussion. The WIN-TAVI registry presents the largest observational single arm study to examine the safety and performance of contemporary TAVI in women [13, 14]. The main findings of this analysis by valve type are the following: 1) SEV were used more frequently in females with significant comorbidities and higher surgical risk; 2) there were no differences in crude incidence and adjusted risk of 1-year primary efficacy endpoint between valve types. Moreover, there were no significant differences in incidence and adjusted risk of 30 day or 1-year death between BEV and SEV; 3) the rate of grade 2 or 3 aortic regurgitation post TAVI implantation and new pacemaker implantation were higher with SEV. However, after adjusting for MDCT characteristics, there was no difference in the need for new pacemakers; 4) comparison of new generation devices confirmed no significant differences

8

between BEV and SEV in 1-year clinical outcomes including need for permanent pacemaker implantation.

Gender related studies are of great importance due to their impact on expert consensus statements and societal recommendations for selection of women undergoing TAVI. The current evidence suggests that TAVI is a better option than surgery for high-risk female patients[7, 16-18]. However, women experience greater procedural adverse events compared to men undergoing TAVI regardless of the valve type used [16, 18, 19], which may be due to anatomical differences in annular and left ventricular outflow tract dimension, coronary heights and peripheral vessel sizes [20, 21] . These characteristics should be taken into account during prosthetic valves selection for females undergoing TAVI. Some previous studies have reported a higher use of SEV among females compared with males [10, 19, 22]. In the current analysis from the WIN-TAVI registry, we observed that women receiving SEV prostheses had higher risk baseline profiles including higher surgical risk scores, higher prevalence of prior cerebrovascular events and pulmonary hypertension as well as larger aortic annular circumference on MDCT.

With respect to clinical outcomes between BEV and SEV treated females we observed no significant differences in the crude incidence and adjusted risk of the primary 1year efficacy endpoint or 1-year mortality. To date, the only randomized trial comparing the safety and efficacy of BEV and SEV, is the “Comparison of Transcatheter Heart Valves in High Risk Patients With Severe Aortic Stenosis: Medtronic CoreValve vs Edwards SAPIEN XT” (CHOICE) trial, limited by small sample size and the use of only first generation devices[9]. This trial did not find significant differences in the rate of all-cause mortality and cardiovascular mortality between BEV and SEV treated patients. Other studies including a meta-analysis comprising 35,347 patients have also confirmed similar survival after TAVI with both devices [9, 11, 12, 23]. However, in several studies, the risk of aortic regurgitation ≥2+, valve embolization, and, permanent pacemaker implantation was significantly higher 9

with SEV [9, 11, 23]. Notably, the percentage of males in the meta-analysis by Agarwal et al. was over 80% in both valve groups, making the results potentially difficult to apply to female patients [23]. Nevertheless, we also observed that overall SEVs were associated with a greater risk of post procedural aortic regurgitation ≥2+ (4.7% vs. 9.8%; p=0.007) and higher permanent pacemaker implantation rate (8.6% vs. 15.6%; p=0.001) compared to BEVs in women. Several factors may be implicated in this difference between valve types for paravalvular leak, including lower radial strength of the nitinol frame of SEV, an increased angulation between the left ventricular outflow tract and the ascending aorta in treated patients and deep implantation [9, 21]. Some data suggest that women undergoing TAVI experience less frequent undersizing than men who have larger annuli [7, 19]. Accordingly, females achieve a higher valve cover index and consequently lower incidence of residual severe AR [16], albeit this may occur predominantly with BEV [19]. Therefore, the larger annular dimensions observed in women receiving SEV in our study, might in part explain the higher rate of AR in this group compared to BEV treated women. Residual clinically significant paravalvular leak is rare with second generation TAVI devices, both balloon expandable S3 and Evolut R [24, 25]. In line with previous results, we found a reduced rate of postprocedural AR ≥2+ in females treated with newer generation prostheses. However, despite the higher incidence of post-dilation, new generation SEV were still associated with a greater rate of AR compared to new generation BEV.

Current evidence indicates that, age, pre-existent and procedure-induced conduction abnormalities together with the use of SEV are predictive of need for permanent pacemaker implantation with early-generation prostheses [26-28]. The large TAVI meta-analysis demonstrated more than three times higher incidence of new pacemaker after SEV compared to BEV at 30 days and 1 year [23]. We also observed significant differences in the frequency of permanent pacemaker implantation favoring BEVs among females undergoing TAVI. The rates were reduced with the new generation of SEVs and remained low with new 10

generation BEV. This has been correlated to the repositionable capability enabling more precise valve placement in the device landing zone thereby avoiding conduction disturbances associated with deep implantation [29, 30]. Aligned with these results, we noted comparable risk of pacemaker implantation with new generation SEV versus BEV.

The findings of our study may have important clinical implications for selection of female patients undergoing TAVI. Nevertheless, long term differences in device outcomes will drive physician choice of valve type for women. Our study has some limitations. First, this was an observational study without a control arm of males. Second, valve selection was at operator’s discretion, thus our analyses are subject to selection bias. Third, the majority of devices implanted in the study period were of the first generation. Fourth, despite the high rate of follow-up, lack of mandatory 1-year echocardiography led to missed opportunity for follow-up of paravalvular leak and may have led to underdiagnosis of TAVI dysfunction.

In conclusion, in a large group of women with severe aortic stenosis undergoing contemporary TAVI, SEV are more commonly used in women with severe comorbidities and higher surgical risk. Nevertheless, 1-year hard outcomes did not differ between SEV and BEV treated patients after adjustment. The risk of new pacemaker implantation after TAVI was higher with SEV, although the risk was mitigated with new generation valves.

11

References 1.

Smith CR, Leon MB, Mack MJ, Miller DC, Moses JW, Svensson LG, Tuzcu EM, Webb JG, Fontana GP, Makkar RR, Williams M, Dewey T, Kapadia S, Babaliaros V, Thourani VH, Corso P, Pichard AD, Bavaria JE, Herrmann HC, Akin JJ, Anderson WN, Wang D, Pocock SJ, and Investigators PT. Transcatheter versus surgical aorticvalve replacement in high-risk patients. N Engl J Med 2011;364:2187-2198.

2.

Adams DH, Popma JJ, Reardon MJ, Yakubov SJ, Coselli JS, Deeb GM, Gleason TG, Buchbinder M, Hermiller J, Jr., Kleiman NS, Chetcuti S, Heiser J, Merhi W, Zorn G, Tadros P, Robinson N, Petrossian G, Hughes GC, Harrison JK, Conte J, Maini B, Mumtaz M, Chenoweth S, Oh JK, and Investigators USCC. Transcatheter aorticvalve replacement with a self-expanding prosthesis. N Engl J Med 2014;370:17901798.

3.

Leon MB, Smith CR, Mack MJ, Makkar RR, Svensson LG, Kodali SK, Thourani VH, Tuzcu EM, Miller DC, Herrmann HC, Doshi D, Cohen DJ, Pichard AD, Kapadia S, Dewey T, Babaliaros V, Szeto WY, Williams MR, Kereiakes D, Zajarias A, Greason KL, Whisenant BK, Hodson RW, Moses JW, Trento A, Brown DL, Fearon WF, Pibarot P, Hahn RT, Jaber WA, Anderson WN, Alu MC, Webb JG, and Investigators P. Transcatheter or Surgical Aortic-Valve Replacement in Intermediate-Risk Patients. N Engl J Med 2016;374:1609-1620.

4.

Reardon MJ, Van Mieghem NM, Popma JJ, Kleiman NS, Sondergaard L, Mumtaz M, Adams DH, Deeb GM, Maini B, Gada H, Chetcuti S, Gleason T, Heiser J, Lange R, Merhi W, Oh JK, Olsen PS, Piazza N, Williams M, Windecker S, Yakubov SJ, Grube E, Makkar R, Lee JS, Conte J, Vang E, Nguyen H, Chang Y, Mugglin AS, Serruys PW, Kappetein AP, and Investigators S. Surgical or Transcatheter Aortic-Valve Replacement in Intermediate-Risk Patients. N Engl J Med 2017;376:1321-1331.

5.

Mack MJ, Leon MB, Thourani VH, Makkar R, Kodali SK, Russo M, Kapadia SR, Malaisrie SC, Cohen DJ, Pibarot P, Leipsic J, Hahn RT, Blanke P, Williams MR, McCabe JM, Brown DL, Babaliaros V, Goldman S, Szeto WY, Genereux P, Pershad 12

A, Pocock SJ, Alu MC, Webb JG, Smith CR, and Investigators P. Transcatheter Aortic-Valve Replacement with a Balloon-Expandable Valve in Low-Risk Patients. N Engl J Med 2019;380:1695-1705. 6.

Popma JJ, Deeb GM, Yakubov SJ, Mumtaz M, Gada H, O'Hair D, Bajwa T, Heiser JC, Merhi W, Kleiman NS, Askew J, Sorajja P, Rovin J, Chetcuti SJ, Adams DH, Teirstein PS, Zorn GL, 3rd, Forrest JK, Tchetche D, Resar J, Walton A, Piazza N, Ramlawi B, Robinson N, Petrossian G, Gleason TG, Oh JK, Boulware MJ, Qiao H, Mugglin AS, Reardon MJ, and Evolut Low Risk Trial I. Transcatheter Aortic-Valve Replacement with a Self-Expanding Valve in Low-Risk Patients. N Engl J Med 2019;380:1706-1715.

7.

Williams M, Kodali SK, Hahn RT, Humphries KH, Nkomo VT, Cohen DJ, Douglas PS, Mack M, McAndrew TC, Svensson L, Thourani VH, Tuzcu EM, Weissman NJ, Kirtane AJ, and Leon MB. Sex-related differences in outcomes after transcatheter or surgical aortic valve replacement in patients with severe aortic stenosis: Insights from the PARTNER Trial (Placement of Aortic Transcatheter Valve). J Am Coll Cardiol 2014;63:1522-1528.

8.

Skelding KA, Yakubov SJ, Kleiman NS, Reardon MJ, Adams DH, Huang J, Forrest JK, and Popma JJ. Transcatheter Aortic Valve Replacement Versus Surgery in Women at High Risk for Surgical Aortic Valve Replacement (from the CoreValve US High Risk Pivotal Trial). Am J Cardiol 2016;118:560-566.

9.

Abdel-Wahab M, Neumann FJ, Mehilli J, Frerker C, Richardt D, Landt M, Jose J, Toelg R, Kuck KH, Massberg S, Robinson DR, El-Mawardy M, Richardt G, and CHOICE Investigators. 1-Year Outcomes After Transcatheter Aortic Valve Replacement With Balloon-Expandable Versus Self-Expandable Valves: Results From the CHOICE Randomized Clinical Trial. J Am Coll Cardiol 2015;66:791-800.

10.

Chieffo A, Buchanan GL, Van Mieghem NM, Tchetche D, Dumonteil N, Latib A, van der Boon RM, Vahdat O, Marcheix B, Farah B, Serruys PW, Fajadet J, Carrié D, de Jaegere PP, and Colombo A. Transcatheter aortic valve implantation with the 13

Edwards SAPIEN versus the Medtronic CoreValve Revalving system devices: a multicenter collaborative study: the PRAGMATIC Plus Initiative (Pooled-RotterdAmMilano-Toulouse In Collaboration). J Am Coll Cardiol 2013;61:830-836. 11.

Osman M, Ghaffar YA, Saleem M, Kheiri B, Osman K, Munir MB, and Alkhouli M. Meta-Analysis Comparing Transcatheter Aortic Valve Implantation With Balloon Versus Self-Expandable Valves. Am J Cardiol 2019. 10.1016/j.amjcard.2019.07.028

12.

Moretti C, D'Ascenzo F, Mennuni M, Taha S, Brambilla N, Nijhoff F, Fraccaro C, Barbanti M, Tamburino C, Tarantini G, Rossi ML, Presbitero P, Napodanno M, Stella P, Bedogni F, Omedè P, Conrotto F, Montefusco A, Giordana F, Biondi Zoccai G, Agostoni P, D'Amico M, Rinaldi M, Marra S, and Gaita F. Meta-analysis of comparison between self-expandable and balloon-expandable valves for patients having transcatheter aortic valve implantation. Am J Cardiol 2015;115:1720-1725.

13.

Chieffo A, Petronio AS, Mehilli J, Chandrasekhar J, Sartori S, Lefèvre T, Presbitero P, Capranzano P, Tchetche D, Iadanza A, Sardella G, Van Mieghem NM, Meliga E, Dumonteil N, Fraccaro C, Trabattoni D, Mikhail GW, Sharma S, Ferrer MC, Naber C, Kievit P, Faggioni M, Snyder C, Morice MC, Mehran R, and Investigators W -T. Acute and 30-Day Outcomes in Women After TAVR: Results From the WIN-TAVI (Women's INternational Transcatheter Aortic Valve Implantation) Real-World Registry. JACC Cardiovasc Interv 2016;9:1589-1600.

14.

Chieffo A, Petronio AS, Mehilli J, Chandrasekhar J, Sartori S, Lefèvre T, Presbitero P, Capranzano P, Tchetche D, Iadanza A, Sardella G, Van Mieghem NM, Meliga E, Dumonteil N, Fraccaro C, Trabattoni D, Mikhail G, Sharma S, Ferrer MC, Naber C, Kievit P, Baber U, Snyder C, Sharma M, Morice MC, Mehran R, and Investigators WT. 1-Year Clinical Outcomes in Women After Transcatheter Aortic Valve Replacement: Results From the First WIN-TAVI Registry. JACC Cardiovasc Interv 2018;11:1-12.

15.

Kappetein AP, Head SJ, Genereux P, Piazza N, van Mieghem NM, Blackstone EH, Brott TG, Cohen DJ, Cutlip DE, van Es GA, Hahn RT, Kirtane AJ, Krucoff MW, Kodali 14

S, Mack MJ, Mehran R, Rodes-Cabau J, Vranckx P, Webb JG, Windecker S, Serruys PW, Leon MB, and Valve Academic Research C. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. J Thorac Cardiovasc Surg 2013;145:6-23. 16.

Chandrasekhar J, Dangas G, Yu J, Vemulapalli S, Suchindran S, Vora AN, Baber U, Mehran R, and Registry SAT. Sex-Based Differences in Outcomes With Transcatheter Aortic Valve Therapy: TVT Registry From 2011 to 2014. J Am Coll Cardiol 2016;68:2733-2744.

17.

Forrest JK, Adams DH, Popma JJ, Reardon MJ, Deeb GM, Yakubov SJ, Hermiller JB, Jr., Huang J, Skelding KA, and Lansky A. Transcatheter Aortic Valve Replacement in Women Versus Men (from the US CoreValve Trials). Am J Cardiol 2016;118:396-402.

18.

Kodali S, Williams MR, Doshi D, Hahn RT, Humphries KH, Nkomo VT, Cohen DJ, Douglas PS, Mack M, Xu K, Svensson L, Thourani VH, Tuzcu EM, Weissman NJ, Leon M, and Kirtane AJ. Sex-Specific Differences at Presentation and Outcomes Among Patients Undergoing Transcatheter Aortic Valve Replacement: A Cohort Study. Ann Intern Med 2016;164:377-384.

19.

O'Connor SA, Morice MC, Gilard M, Leon MB, Webb JG, Dvir D, Rodés-Cabau J, Tamburino C, Capodanno D, D'Ascenzo F, Garot P, Chevalier B, Mikhail GW, and Ludman PF. Revisiting Sex Equality With Transcatheter Aortic Valve Replacement Outcomes: A Collaborative, Patient-Level Meta-Analysis of 11,310 Patients. J Am Coll Cardiol 2015;66:221-228.

20.

Naoum C, Blanke P, Dvir D, Pibarot P, Humphries K, Webb J, and Leipsic J. Clinical Outcomes and Imaging Findings in Women Undergoing TAVR. JACC Cardiovasc Imaging 2016;9:483-493.

21.

Hamdan A, Barbash I, Schwammenthal E, Segev A, Kornowski R, Assali A, Shaviv E, Fefer P, Goitein O, Konen E, and Guetta V. Sex differences in aortic root and

15

vascular anatomy in patients undergoing transcatheter aortic valve implantation: A computed-tomographic study. J Cardiovasc Comput Tomogr 2017;11:87-96. 22.

Rogers T, Steinvil A, Buchanan K, Alraies MC, Koifman E, Gai J, Torguson R, Okubagzi P, Ben-Dor I, Pichard A, Satler L, and Waksman R. Contemporary transcatheter aortic valve replacement with third-generation balloon-expandable versus self-expanding devices. J Interv Cardiol 2017;30:356-361.

23.

Agarwal S, Parashar A, Kumbhani DJ, Svensson LG, Krishnaswamy A, Tuzcu EM, and Kapadia SR. Comparative meta-analysis of balloon-expandable and selfexpandable valves for transcatheter aortic valve replacement. Int J Cardiol 2015;197:87-97.

24.

Nijhoff F, Abawi M, Agostoni P, Ramjankhan FZ, Doevendans PA and Stella PR. Transcatheter aortic valve implantation with the new balloon-expandable Sapien 3 versus Sapien XT valve system: a propensity score-matched single-center comparison. Circ Cardiovasc Interv 2015;8:e002408.

25.

Grube E, Van Mieghem NM, Bleiziffer S, Modine T, Bosmans J, Manoharan G, Linke A, Scholtz W, Tchétché D, Finkelstein A, Trillo R, Fiorina C, Walton A, Malkin CJ, Oh JK, Qiao H, Windecker S, and Investigators FS. Clinical Outcomes With a Repositionable Self-Expanding Transcatheter Aortic Valve Prosthesis: The International FORWARD Study. J Am Coll Cardiol 2017;70:845-853.

26.

Siontis GC, Jüni P, Pilgrim T, Stortecky S, Büllesfeld L, Meier B, Wenaweser P, and Windecker S. Predictors of permanent pacemaker implantation in patients with severe aortic stenosis undergoing TAVR: a meta-analysis. J Am Coll Cardiol 2014;64:129-140.

27.

De Carlo M, Giannini C, Bedogni F, Klugmann S, Brambilla N, De Marco F, Zucchelli G, Testa L, Oreglia J, and Petronio AS. Safety of a conservative strategy of permanent pacemaker implantation after transcatheter aortic CoreValve implantation. Am Heart J 2012;163:492-499.

16

28.

van Rosendael PJ, Delgado V and Bax JJ. Pacemaker implantation rate after transcatheter aortic valve implantation with early and new-generation devices: a systematic review. Eur Heart J 2018;39:2003-2013.

29.

Petronio AS, Sinning JM, Van Mieghem N, Zucchelli G, Nickenig G, Bekeredjian R, Bosmans J, Bedogni F, Branny M, Stangl K, Kovac J, Schiltgen M, Kraus S, and de Jaegere P. Optimal Implantation Depth and Adherence to Guidelines on Permanent Pacing to Improve the Results of Transcatheter Aortic Valve Replacement With the Medtronic CoreValve System: The CoreValve Prospective, International, Post-Market ADVANCE-II Study. JACC Cardiovasc Interv 2015;8:837-846.

30.

Giannini C, De Carlo M, Tamburino C, Ettori F, Latib AM, Bedogni F, Bruschi G, Presbitero P, Poli A, Fabbiocchi F, Violini R, Trani C, Giudice P, Barbanti M, Adamo M, Colombo P, Benincasa S, Agnifili M, and Petronio AS. Transcathether aortic valve implantation with the new repositionable self-expandable Evolut R versus CoreValve system: A case-matched comparison. Int J Cardiol 2017;243:126-131.

17

Figures Fig 1. Main reasons patients were not eligible for SAVR. COPD, chronic obstructive pulmonary disease; HTN, pulmonary hypertension; LVEF, left ventricular ejection fraction. Fig 2. Adjusted 1-year risk of cardiovascular outcomes in patients treated with selfexpandable valves compared to those treated with balloon expandable valves. VARC, Valve Academic Research Consortium. Fig 3. Sensitivity analysis of 1 year outcomes in patients treated with self-expandable valves compared to those treated with balloon expandable valves. VARC, Valve Academic Research Consortium.

18

FIGURES Fig 1. Main reasons patients were not eligible for SAVR

19

Fig 2. Adjusted 1-year risk of cardiovascular outcomes in patients treated with selfexpandable valves compared to those treated with balloon expandable valves

20

Fig 3. Sensitivity analysis of 1-year outcomes in patients treated with self-expandable valves compared to those treated with balloon expandable valves. VARC, Valve Academic Research Consortium

21

Table 1. Baseline characteristics of BEV and SEV treated women Balloon Expandable valves (Edwards) (N = 408)

Self-Expandable valves (Medtronic) (N = 461)

P-value

82.4 ± 6.2 25.9 ± 5.2 103 (25.3%) 337 (83.8%) 38 (9.3%) 84 (20.6%) 22 (5.4%) 22 (5.4%) 36 (8.9%) 118 (29.4%) 24 (5.9%) 16.9 ±10.5

82.7± 6.4 26.1 ± 5.8 122 (26.7%) 362 (79.9%) 45 (9.8%) 114 (24.9%) 29 (6.3%) 41 (8.9%) 37 (8.2%) 150 (33.5%) 52 (11.3%) 18.6 ±12.5

0.59 0.69 0.64 0.14 0.82 0.13 0.56 0.04 0.72 0.19 0.005 0.03

8.0±7.1

8.9±7.7

0.007

Echocardiography Aortic annulus diameter, (mm) Peak aortic valve gradient, (mmHg) Mean aortic valve gradient, (mmHg) Effective aortic valve area, (cm 2) LV Ejection fraction, (%)

22.5 ± 1.9 77.7 ± 22.7 48.8 ± 15.1 0.66 ± 0.23 56.3±10.2

22.0 ± 2.2 79.1 ± 24.6 49.9 ± 16.5 0.60 ± 0.20 55.1 ±11.2

0.01 0.44 0.36 0.40 0.09

Multidetector computed tomography Aortic annulus diameter, (mm) Annulus circumference, (mm) Aortic annulus area, (mm2) Height right coronary artery, (mm) Height left coronary ostium, (mm) Total valve calcium volume (mm3)

n=208 22.4±2.2 72.1 ± 5.8 404.8±65.7 17.3 ± 2.8 14.2 ± 3.0 700.0 ± 481

n=253 22.8±1.7 73.1 ± 5.3 395.8±81.3 16.9 ± 2.9 14.3 ± 3.3 689.4 ± 530

0.03 0.02 0.15 0.08 0.63 0.42

Variable Age, (years) BMI, (kg/m2) Diabetes mellitus Hypertension Prior myocardial infarction Previous PCI Previous coronary bypass Prior stroke Prior PAD Chronic kidney disease Permanent pacemaker EuroSCORE I, (%) Society of Thoracic Surgeons’ score, (%)

Values are shown as n (%) or mean ± SD. BMI, body mass index; PAD, peripheral artery disease; PCI, percutaneous coronary intervention; LV, left ventricle.

22

Table 2: Procedural characteristics of BEV and SEV treated women

Variable Procedural access  Transfemoral  Trans-subclavian  Transapical  Transaortic  General anesthesia Prosthesis size (mm) - 23 - 26 - 29 -31 Post-dilation Post-TAVI AI grade 0 1 2 3 Post TAVI AR grade ≥2 Valve embolization Annulus or aortic rupture Pericardiocentesis Ventricular perforation Coronary obstruction Surgical conversion Values are shown as n (%)

Balloon Expandable valves (Edwards) (N = 408)

Self-Expandable valves (Medtronic) (N = 461)

366 (89.7%) 1 (0.25%) 23 (5.6%) 18 (1.4%) 122 (31.0%)

419 (90.9%) 22 (4.8%) -20 (4.3%) 160 (36.7%)

279 (69.1%) 115 (28.5%) 10 (2.5%) -35 (8.6%)

66 (14.5%) 241(52.9%) 144 (31.6%) 5 (1.1%) 100 (22.0%)

219 (60.8%) 124 (34.4%) 16 (4.4%) 1 (0.3%) 17 (4.7%) 4 (1.0%) 5 (1.2%) 5 (1.2%) 5 (1.2%) 3 (0.7%) 4 (1.0%)

191 (45.7%) 186 (44.5%) 39 (9.3%) 2 (0.5%) 41 (9.8%) 9 (2.0%) 3 (0.7%) 5 (1.1%) 8 (1.8%) 4 (0.9%) 4(0.9%)

P-value <0.001

0.08 <0.0001

<0.0001 <0.0001

0.007 0.27 0.48 0.87 0.51 1.000 1.000

AR, aortic regurgitation; TAVI, Transcatheter aortic valve implantation

23

Table 3: Clinical outcomes during 1-year follow-up of BEV and SEV treated women Balloon Expandable valves (Edwards)

Self-Expandable valves (Medtronic)

(N = 408)

(N = 461)

P-value

Balloon Expandable valves (Edwards)

Self-Expandable valves (Medtronic)

(N = 408)

(N = 461)

0-30 days VARC-2 Safety Endpoint* VARC-2 Efficacy Endpoint°

22 (5.4%)

26 (14.3%)

P-value

0-1year 0.87

--- ---

---

---

53 (14.3%)

68 (17.1%)

0.25

Secondary endpoints All-cause death

15 (3.7%)

20 (4.3%)

0.62

42 (10.3%)

60 (13.2%)

0.19

Cardiovascular death

14 (3.4%)

20 (4.3%)

0.49

35 (8.7%)

53 (11.7%)

0.14

Myocardial infarction

1 (0.25%)

1 (0.22%)

0.93

5 (1.2%)

5 (1.1%)

0.85

Stroke

4 (1.0%)

5 (1.1%)

0.88

10 (2.5%)

7 (1.5%)

0.32

Major vascular complication

26 (6.4%)

42 (9.1)

0.12

26 (6.4%)

44 (9.6%)

0.09

VARC-2 Life threatening bleeding

17 (4.2%)

20 (4.3%)

0.91

17 (4.2%)

20 (4.3%)

0.89

Acute Kidney injury, stage 2 or 3

6 (1.5%)

6 (1.30%)

0.83

7 (1.7%)

6 (1.3%)

0.61

TAV in TAV

0 (0.0%)

16 (3.5%)

<0.0001

1 (0.2%)

16 (3.5%)

0.0006

Other endpoints VARC-2 major bleeding

30 (7.4%)

43 (9.3%)

0.29

30 (7.4%)

45 (9.8%)

0.21

BARC 3 or 5 major bleeding

47(11.5%)

63 (13.7%)

0.34

47 (11.5%)

65 (14.1)

0.25

Any Arrhythmia or conduction disturbance

70 (17.2%)

96 (20.8%)

0.17

74 (18.1%)

97 (21.1%)

0.28

24

New pacemaker implantation

31 (7.6%)

69 (15.0%)

0.001

35 (8.6%)

72 (15.6%)

0.001

Composite all-cause death or stroke

18 (4.4%)

23 (5.0%)

0.68

48 (11.8%)

65 (14.3%)

0.29

Composite all-cause death, MI, or stroke

19 (4.7%)

23 (5.0%)

0.82

53 (13.0%)

68 (14.9%)

0.43

26 (6.4%)

35 (7.6%)

0.48

60 (14.7%)

80 (17.5%)

0.27

Composite all-cause death, MI, stroke, or VARC-2 life-threatening bleeding

Values are shown as n (Kaplan-Meier %) *Composite of 30-day all-cause death, stroke, myocardial infarction, major vascular complication, VARC life-threatening bleeding, coronary obstruction, reintervention for valve related dysfunction, or stage 2 or 3 acute kidney injury. °Composite of 1 year all-cause death, stroke, myocardial infarction, hospitalization for valve related symptoms or heart failure, or valve-related dysfunction (clinical presentation with valve thrombosis or endocarditis). TAV, transcatheter aortic valve; VARC, Valve Academic Research Consortium; BARC, Bleeding Academic Research consortium.

25

Table 4. Crude estimates and adjusted risk of 1-year clinical outcomes in women treated with new generation BEV and SEV BEV SAPIEN 3

SEV Evolut R

(N = 224)

(N=79)

VARC 2 efficacy endpoint*

29 (13.0%)

All-cause death

21 (9.4%)

Stroke

#

p-value

HR [95% CI]

p-value

11 (13.9%)

0.80

1.44 [0.49-4.17]

0.51

8 (10.1%)

0.83

2.12 [0.58-7.75]

0.25

4 (1.8%)

1 (1.3%)

0.75

0.71 [0.08-6.35]

0.75

Major vascular complications

13 (5.8%)

4 (5.1%)

0.80

1.43 [0.18-11.10]

0.73

VARC-2 life threatening bleeding

5 (2.2%)

2 (2.5%)

0.87

1.64 [0.29-9.40]

0.57

New pacemaker implantation

18 (8.0%)

8 (10.1%)

0.56

2.11 [0.62-7.19]

0.23

Any Arrhythmia or conduction disturbance

46 (20.5%)

10 (12.7%)

0.12

0.94 [0.39-2.28]

0.89

Composite all-cause death or stroke

24 (10.7%)

9 (11.4%)

0.83

1.93 [0.61-6.13]

0.26

Composite all-cause death, MI, or stroke

26 (11.6%)

9 (11.4%)

0.99

1.48 [0.47-4.71]

0.50

Composite all-cause death, MI, stroke, or VARC-2 life-threatening bleeding

27 (12.05%)

10 (10.7%)

0.84

10.7 [0.52-2.22]

0.84

Values are shown as n (Kaplan-Meier %) # Reference = BEV *Composite of 1-year all-cause death, stroke, myocardial infarction, hospitalization for valve related symptoms or heart failure, or valve-related dysfunction (clinical presentation with valve thrombosis or endocarditis). VARC, Valve Academic Research Consortium.

26