JACC: CARDIOVASCULAR INTERVENTIONS VOL. 6, NO. 5, PUBLISHED BY ELSEVIER INC.

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1 JACC: CARDIOVASCULAR INTERVENTIONS VOL. 6, NO. 5, BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN /$36.00 PUBLISHED BY ELSEVIER INC. MINI-FOCUS ON CLINICAL RESEARCH A 3-Center Comparison of 1-Year Mortality Outcomes Between Transcatheter Aortic Valve Implantation and Surgical Aortic Valve Replacement on the Basis of Propensity Score Matching Among Intermediate-Risk Surgical Patients Nicolo Piazza, MD, PHD,* Bindu Kalesan, PHD, Nicolas van Mieghem, MD, Stuart Head, MSC, Peter Wenaweser, MD, Thierry P. Carrel, MD,# Sabine Bleiziffer, MD,* Peter P. de Jaegere, MD, PHD, Brigitta Gahl,# Robert H. Anderson, MD, PHD,** Arie-Pieter Kappetein, MD, PHD, Ruediger Lange, MD, PHD,* Patrick W. Serruys, MD, PHD, Stephan Windecker, MD, Peter Jüni, MD Munich, Germany; Bern, Switzerland; Rotterdam, the Netherlands; Montreal, Canada; and Newcastle-Upon-Tyne, United Kingdom Objectives This study sought to compare all-cause mortality in patients at intermediate surgical risk undergoing transcatheter aortic valve implantation () or surgical aortic valve replacement (). Background Physicians are selecting lower surgical risk patients to undergo. No clinical data exist about the clinical outcomes of versus among intermediate-surgical-risk patients. Methods We prospectively enrolled symptomatic patients with severe aortic stenosis who underwent or. Propensity-score matched pairs of and patients with Society of Thoracic Surgeons (STS) scores between 3% and 8% made up the study population. Primary endpoint was all-cause mortality at 1 year. Results Between November 2006 and January 2010, 3,666 consecutive patients underwent either (n 782) or (n 2,884). Four hundred five patients were matched to 405 patients. Of matched patients, 99 (24%) patients had STS scores 3%, 255 (63%) had scores between 3% and 8%, and 51 (13%) had scores 8%. Among patients with STS scores between 3% and 8%, 20 (7.8%) versus 18 (7.1%) patients had died up to 30 days (hazard ratio: 1.12, 95% confidence interval: 0.58 to 2.15, p 0.74) and 42 (16.5%) versus 43 (16.9%) patients had died up to 1 year (hazard ratio: 0.90, 95% confidence interval: 0.57 to 1.42, p 0.64) after and, respectively. Effects of treatment on 1-year mortality were similar across all subgroups except for sex, with some evidence for a beneficial effect of in women but not in men (test for interaction p 0.024). Conclusions Cumulative all-cause mortality at 30 days and 1 year was similar among propensityscore matched and patients at intermediate surgical risk. (Surgical Replacement and Transcatheter Aortic Valve Implantation [SUR]; NCT ) (J Am Coll Cardiol Intv 2013; 6:443 51) 2013 by the American College of Cardiology Foundation From the *Department of Cardiovascular Surgery, German Heart Center, Munich, Germany; Department of Cardiology, McGill University Health Center, Royal Victoria Hospital, Montreal, Canada; Institute of Social and Preventive Medicine and Clinical Trials Unit, University of Bern, Bern, Switzerland; Department of Cardiology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Cardiovascular Surgery, Erasmus Medical Center, Rotterdam, the Netherlands; Department of

2 444 JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 6, NO. 5, 2013 Recent evidence suggests that European centers undertaking transcatheter aortic valve implantation () are selecting patients deemed to be at lower surgical risk than specified for the original CE mark label or those enrolled in the PARTNER (Placement of Aortic Transcatheter Valves) US Cohort A trial. It is unclear, however, whether offlabel treatment of patients considered being at intermediatesurgical-risk would modify the effectiveness and safety of compared with surgical aortic valve replacement (). The SUR (Surgical Replacement and Transcatheter Aortic Valve Implantation) trial is an investigator-initiated trial designed to randomize intermediate surgical risk patients with severe aortic stenosis, defined by Society of Thoracic Surgeons (STS) scores between 3% and 8%, to either a self-expanding transcatheter aortic valve or. Currently, there are no data about the clinical outcomes of compared with among such Abbreviations and Acronyms CI confidence interval EuroSCORE European System for Cardiac Operative Risk Evaluation HR hazard ratio LVEF left ventricular ejection fraction NYHA New York Heart Association OR odds ratio surgical aortic valve replacement STS Society of Thoracic Surgeons transcatheter aortic valve implantation Methods patients. To inform the design and implementation of the SUR trial, we conducted an analysis at 3 centers by matching patients undergoing and based on propensity scores with the aim of determining, first, the proportion of patients undergoing who are potentially eligible for the SUR trial in present-day clinical practice; second, any differences in the effect of treatment between patients undergoing and for allcause 30-day and 1-year mortality; and third, whether such effects vary across subgroups of patients as suggested by the PARTNER US Cohort A trial. Patient selection and identification of the study population. Between November 2006 and January 2010 we prospectively enrolled over 3,500 consecutive symptomatic patients with severe aortic stenosis who underwent either or at Bern University Hospital, Bern, Switzerland; the German Heart Center, Munich, Germany; and Erasmus Medical Center, Rotterdam, the Netherlands. Patients were included if they had symptomatic severe aortic stenosis defined as an aortic valvular orifice area of 1.0 cm 2, a mean gradient across the aortic valve of 40 mm Hg or more, or a peak aortic-jet velocity of 4.0 m/s or more. Criteria for exclusion included: sepsis; hematologic disorders, such as bleeding or coagulopathy; estimated life expectancy of 1 year; a primary diagnosis of aortic valvular regurgitation; aortic valvular endocarditis; and the need for surgery on multiple valves or additional procedures involving the aortic root. We used propensity scores to match each patient undergoing to a comparable patient having (see the Statistical Methods section for further details). Matched pairs featuring patients with STS scores between 3% and 8% comprised the study population. The local ethical committees in all 3 centers approved the prospective collection of data, and all subjects gave written informed consent. Study device and procedures. The was performed with standard techniques as previously described. Suitability for was confirmed by a combination of transesophageal echocardiography, multislice computed tomography, and angiography. Details of the anatomic criteria for selection of patients, the device, and procedural techniques are described in detail elsewhere (1). The site of interventional access was determined by anatomical characteristics, whereas was performed through a sternotomy or right lateral thoracotomy and followed standard routines, with single-mattressed sutures passed circumferentially through the valvular annulus to fix the bioprosthesis in a supra-annular position. Concomitant coronary revascularization was performed by either percutaneous or surgical techniques according to the discretion of the operator. Data collection and study endpoints. We collected data on baseline characteristics for all patients, including the logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE). The STS scores were prospectively collected for patients undergoing but not for those submitted for. Attempts retrospectively to calculate STS scores for those undergoing proved unreliable, because of incomplete collection of data at baseline. The Cardiology, Bern University Hospital, Bern, Switzerland; #Department of Cardiovascular Surgery, Bern University Hospital, Bern, Switzerland; and the **Institute of Genetic Medicine, Newcastle University, Newcastle-Upon-Tyne, United Kingdom. Dr. Piazza has served as consultant for Medtronic, HighLife, and CardiaAQ; and steering committee member for the SUR trial. Dr. van Mieghem has served as study chair and steering committee member for the SUR trial. Dr. Wenaweser has served as proctor for Medtronic and Edwards Lifesciences; is a consultant for Biotronik; has received honoraria/lecture fees from Medtronic and Edwards Lifesciences; and has received honoraria from Biotronik. Dr. Bleiziffer has served as consultant for Medtronic and Edwards Lifesciences; and as a proctor for Medtronic and JenaValve. Dr. de Jaegere has served as consultant for Medtronic. Dr. Kappetein has served as principal investigator for the SUR trial. Dr. Lange has served on the advisory board and as consultant for Medtronic; and principal investigator for the SUR trial. Dr. Serruys has served as Study Chair for the SUR trial. Dr. Windecker has served as principal investigator for the SUR trial; been supported by grants to the institution from Medtronic, Edwards Lifesciences, Abbott, Cordis, Biotronik, Boston Scientific, Biosensors, and St. Jude; and has received lecture fees from Edwards Lifesciences and Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Dr. Piazza and Dr. Kalesan contributed equally to this work. Manuscript received November 26, 2012; revised manuscript received January 8, 2013, accepted January 23, 2013.

3 JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 6, NO. 5, primary and secondary endpoints were all-cause 1-year and 30-day mortality, respectively. For patients with a suspected event, we systematically collected any relevant medical records, discharge letters, and documentation of hospital stay from the hospitals providing treatment and physicians in private practice. Statistical methods. We compared the baseline characteristics of all patients with a chi-square test for categorical variables and unpaired Student t test for continuous variables. Variables associated with treatment selection varied by center. For example, we found that chronic obstructive pulmonary disease was associated with in Rotterdam (odds ratio [OR]: 2.26, 95% confidence interval [CI]: 1.09 to 4.70) but not in Bern (OR: 1.48, 95% CI: 0.86 to 2.53) or Munich (OR: 0.88, 95% CI: 0.58 to 1.31). Therefore, we derived propensity scores with separate multivariable probit models for each center, including age and sex along with center-specific pre-treatment variables that were associated at p 0.10 in a multivariable model of all variables. The pre-treatment variables for Bern were logistic EuroSCORE, New York Heart Association (NYHA) functional class, hypertension, peripheral vascular disease, and pulmonary hypertension. Those for Munich were logistic EuroSCORE, NYHA, hypertension, left ventricular ejection fraction (LVEF), and pulmonary hypertension. In Rotterdam, we used logistic EuroSCORE, LVEF, peripheral vascular disease, chronic obstructive pulmonary disease, and history of cerebrovascular accident. Propensity scores were then matched with a caliper range of 0.05 to obtain matched pairs of patients. We derived standardized differences between groups before and after propensity score matching by dividing differences in proportions and differences in means by the pooled SD, hence expressing all differences in SD units. A 0.20 SD unit corresponds to a small difference between groups (2), a 0.10 SD unit might indicate the smallest potentially meaningful difference (3). From the pairs created, those patients undergoing with STS scores between 3% and 8% were deemed potentially eligible for the SUR trial. Hazard ratios (HRs) of overall mortality at 30 days and 1 year were calculated with Cox proportional hazards models. In view of the results from the PARTNER US Cohort A trial, we performed pre-specified analyses stratified by the following variables: age ( 80 vs. 80 years), sex, logistic EuroSCORE ( 20% vs. 20%), STS score ( 4% vs. 4%), diabetes, LVEF ( 30% vs. 30%), cerebrovascular event, peripheral vascular disease, pulmonary hypertension, and prior coronary arterial bypass graft surgery. Main Assessed for eligibility (n= 3,666) = 782 (21.3%) = 2,884 (87.7%) Unmatched: n= 2,856 = 377 = 2,479 PS matched patients with (n= 405) Loss to follow-up (n=4) PS matched patients with (n= 405) Loss to follow-up (n=10) Patient declined (n=2) Ineligible for SUR trial and excluded: n= 150 STS <3: n= 99 STS >8: n= 51 Ineligible for SUR trial and excluded: n= 150 STS <3: n= 99 STS >8: n= 51 PS matched patients with eligible for SUR trial (n= 255) Lost to follow-up (n=3) PS matched patients with eligible for SUR trial (n= 255) Loss to follow-up (n=8) Figure 1. Patient Flow Chart A total of 255 transcatheter aortic valve implantation () and 255 surgical aortic valve replacement () patients were included in the main analysis. CI confidence interval; STS Society of Thoracic Surgeons.

4 446 JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 6, NO. 5, 2013 Table 1. Baseline Characteristics Before and After PS Matching Before PS Matching After PS Matching (n 782) (n 2,884) Diff p Value (n 405) (n 405) Diff p Value Age (yrs) Female 457 (58.4) 1,106 (38.4) (56.8) 226 (55.8) Logistic EuroSCORE (%) NYHA I 22 (3.4) 128 (5.2) (3.4) 13 (3.7) II 59 (9.2) 295 (11.9) (9.4) 33 (9.4) III 346 (54.0) 1,665 (67.2) (65.1) 222 (63.4) IV 214 (33.4) 391 (15.8) (22.0) 82 (23.4) Diabetes mellitus 183 (23.4) 618 (21.4) (27.4) 98 (25.7) Hypertension 522 (66.8) 1,881 (65.2) (86.0) 286 (81.7) Coronary artery disease 216 (59.7) 589 (50.4) (56.6) 96 (57.8) LVEF % 431 (55.1) 1,762 (61.1) (65.2) 237 (58.5) % 50% 239 (30.6) 997 (34.6) (25.4) 130 (32.1) % 112 (14.3) 125 (4.3) (9.4) 38 (9.4) Cerebrovascular accident 58 (7.4) 75 (2.6) (9.9) 30 (7.4) Peripheral vascular disease 109 (13.9) 165 (5.7) (8.2) 41 (10.1) Chronic obstructive pulmonary disease 131 (16.8) 328 (11.4) (17.8) 64 (15.8) Pulmonary hypertension 187 (23.9) 315 (10.9) (21.0) 93 (23.0) Creatinine (mg/dl) Values are mean SD or n (%). The p values are from paired Student t test for continuous data and conditional logistic regression for dichotomous and ordinal data. Diff standardized difference between transcatheter aortic valve implantation and surgical aortic valve replacement patients; EuroSCORE European System for Cardiac Operative Risk Evaluation; LVEF left ventricular ejection fraction; NYHA New York Heart Association functional class; PS propensity score; surgical aortic valve replacement; transcatheter aortic valve implantation. analysis and all stratified analyses included stratification by pairs to account for propensity score matching. This required that pairs be maintained in case of residual variation in a baseline variable that resulted in discordant classification of patients within a pair. Therefore, we gave precedence to the characteristics of the patient in case of discordance. For example, if a patient was 79.9 years old and the matched patient was 80.1 years old, we classified the matched pair in accordance with the age of the patient as 80 years. Because STS scores were unavailable for patients, we used the same approach and classified matched pairs according to the STS score of patients. Stratified analyses were accompanied by tests for interaction between treatment and patient characteristics from Cox models. Statistical analyses were performed with Stata (version 11.2, StataCorp, College Station, Texas). Results Between November 2006 and January 2010, 3,666 consecutive patients with severe aortic stenosis underwent (n 782) or (n 2,884) (Fig. 1). The patients undergoing were older, more likely to be in NYHA functional class III or IV, had higher logistic EuroSCORE, and featured more comorbidities, such as hypertension, left ventricular dysfunction, cerebral and peripheral vascular disease, and pulmonary hypertension (Table 1, left), with 13 of 18 standardized differences above From this cohort, we were able to propensity score match 405 patients undergoing with 405 patients undergoing, resulting in similar baseline characteristics between groups (Fig. 1, Table 1, right), with 3 of 18 standardized differences above Of these, 99 patients had STS scores 3%, 255 (65%) had scores between 3% and 8%, and 51 had scores 8%. In Table 2, we present baseline characteristics of the propensity score-matched cohort ( and ) according to the stratification by STS scores, with significant trends across ordered groups for age, logistic Euro- SCORE, NYHA, diabetes, left ventricular function, peripheral vascular disease, chronic obstructive pulmonary disease, pulmonary hypertension, and levels of creatinine. The STS score of propensity score-matched patients decreased from 6% (95% CI: 5.2% to 6.8%) to 4.3% (95% CI: 3.8% to 4.7%) from the first to the last quartile of the period of enrollment, respectively (p value for trend 0.001) (Fig. 2). Characteristics of patients potentially eligible for SUR. The intermediate risk-matched cohort (STS score 3% to 8%) potentially eligible for the SUR trial consisted of 255 pairs, again with comparable baseline characteristics as

5 JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 6, NO. 5, Table 2. Baseline Characteristics After PS Matching According to STS Score STS <3 (n 198) STS 3 8 (n 510) STS >8 (n 102) p Value Age (yrs) Female 47 (47.5) 156 (61.2) 27 (52.9) Logistic EuroSCORE (%) NYHA I 5 (3.1) 17 (3.7) 3 (3.5) II 13 (8.1) 51 (11.2) 2 (2.3) III 114 (71.3) 284 (62.6) 52 (60.5) IV 28 (17.5) 102 (22.5) 29 (33.7) Diabetes mellitus 14 (14.1) 79 (31.0) 18 (35.3) Hypertension 134 (83.8) 381 (83.9) 72 (83.7) Coronary artery disease 36 (50.0) 137 (61.2) 17 (47.2) LVEF % 132 (66.7) 318 (62.4) 51 (50.0) 30% 50% 55 (27.8) 144 (28.2) 34 (33.3) 30% 11 (5.6) 48 (9.4) 17 (16.7) Cerebrovascular accident 10 (10.1) 26 (10.2) 26 (51.0) Peripheral vascular disease 5 (5.1) 17 (6.7) 11 (21.6) Chronic obstructive 8 (8.1) 48 (18.8) 16 (31.4) pulmonary disease Pulmonary hypertension 16 (16.2) 52 (20.4) 17 (33.3) Creatinine, mg/dl Treatment type (50.0) 255 (50.0) 51 (50.0) 99 (50.0) 255 (50.0) 51 (50.0) Values are mean SD or n (%). The p Values are for trend across ordered groups. STS Society of Thoracic Surgeons; other abbreviations as in Table 1. shown in Table 3. The mean age of and patients was 80.6 and 79.7 years, respectively. At baseline, 83.7% of patients undergoing and 86.3% of those undergoing were in NYHA functional class III or IV. The logistic EuroSCORE was 17.3% (SD 9.1%) for those undergoing and 17.6% (SD 11.7%) in the group submitted for. Severe left ventricular dysfunction, defined as an ejection fraction of 30%, was noted in one-tenth or less of patients. Among the 255 matched cases, 3 patients after and 8 after were lost to follow-up (Fig. 1). Mortality in patients potentially eligible for SUR. A- mong the 255 propensity score-matched pairs with STS scores between 3% and 8%, 20 patients (7.8%) and 18 patients (7.1%) had died up to 30 days (HR: 1.12, 95% CI: 0.58 to 2.15, p 0.74) (Fig. 3). At 1 year, death had occurred in 42 patients undergoing (16.5%) and 43 patients undergoing (16.9%, HR: 0.90, 95% CI: 0.57 to 1.42, p 0.64). Results from stratified analyses are shown in Figure 4. Treatment effects in terms of 1-year mortality were similar across all subgroups except for sex, with being more beneficial in women than in men (p for interaction 0.027). Mortality in overall cohort of propensity score-matched patients. In the overall cohort of 405 propensity scorematched pairs, 33 patients and 25 patients died up to 30 days (HR: 1.29, 95% CI: 0.76 to 2.20, p 0.35). At 1-year follow-up, there were 71 deaths in and 67 deaths in patients (HR: 1.02, 95% CI: 0.71 to 1.46, p value 0.93). When we stratified the overall cohort by STS score, we found little evidence for differences in HRs between the 191 pairs with STS scores 4% (HR: 0.75, 95% CI: 0.43 to 1.32) and the 214 pairs with STS scores 4% (HR: 1.26, 95% CI: 0.79 to 2.02, p for interaction 0.17). In the subset of the 99 propensity score-matched pairs ineligible for the SUR trial because of STS scores 3%, HR were 0.75 (95% CI: 0.17 to 3.35, p 0.71) at 30 days and 0.76 (95% CI: 0.34 to 1.75, p 0.53) at 1 year. When stratifying the overall cohort by logistic EuroSCORE, we found an HR of 0.92 in the 279 pairs with a logistic EuroSCORE 20% (95% CI: 0.58 to 1.46) and an HR of 1.19 in the 126 pairs with a logistic EuroSCORE 20% (95% CI: 0.67 to 2.13), again with little evidence for a difference between groups (p for interaction 0.50). Discussion Our major findings are as follows: one-third of the patients undergoing in our current cohort had STS scores between 3% and 8% and were therefore potentially qualify for enrollment in the randomized SUR trial. The proportion of such patients increased progressively over the enrollment period. The cumulative allcause rates of mortality at 30 days and 1 year were comparable among the matched pairs of and patients deemed to be at intermediate risk. Finally, analysis of pre-specified subgroups showed that produced significantly was associated with improved outcomes for female but not for male patients. In our study, we were able to match just over one-half of the overall cohort undergoing with patients submitted for with propensity score methodology. Of the 405 matched patients undergoing, 255 (63%) had STS scores between 3% and 8% and would therefore potentially qualify for enrollment in the randomized SUR trial. Looked at from a different perspective, this would account for just over one-third of all our patients undergoing, specifically 255 of a total of 782 patients. Once anatomical criteria and discussions within the heart team are taken into account, however, it is likely that less than one-third of the patients undergoing would be eligible for the SUR trial. The STS scores for our surgical patients were not available, and these scores could not be calculated retrospectively from the existing databases. According to the STS database for the period 2006 through 2010, one-quarter of

6 448 JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 6, NO. 5, 2013 STS score p for trend< st Quartile 2nd Quartile 3rd Quartile 4th Quartile Enrollment Period Mean STS (95% CI): 6.0 (5.2 to 6.8) 6.1 (5.3 to 6.9) 4.5 (4.0 to 5.0) 4.3 (3.8 to 4.7) Figure 2. Mean STS of Patients by Enrollment Period Mean Society of Thoracic Surgeons (STS) scores (95% confidence interval [CI]) of propensity score-matched transcatheter aortic valve implantation () patients (n 405) across enrollment period quartiles. The mean STS score decreased from 6% to 4.3% from the first to the fourth quartile. patients undergoing isolated surgical replacement of the aortic valve and 45% of those undergoing such replacement combined with coronary arterial bypass grafting have STS scores between 3% and 8%, respectively (Michael Mack, MD, personal communication, August 9, 2011). We estimate, therefore, that approximately one-third of the patients undergoing in the United States would be eligible for enrollment in the SUR trial. From the first to the fourth quartile of our current enrollment period, the STS scores for propensity scorematched patients decreased from 6% to 4.3%. This points to an important shift in selection of patients and corroborates recent studies suggesting that increasingly younger patients, at lower surgical risk, are undergoing in Europe (4). The randomized SUR trial will provide valuable information with regard to the safety and efficacy of as compared with among patients deemed to be at intermediate risk and will either confirm or refute current European practice for. Inspection of the characteristics of our patients reveals that the matched cohort with STS scores between 3% and 8% differs considerably from the patients at high surgical risk enrolled in the PARTNER I US Cohort A (5). In fact, the characteristics of those enrolled in the PARTNER I US Cohort A more closely resemble our matched cohort with STS scores of 8%. The SUR trial will enroll elderly patients of similar age but with less comorbidity, when compared with the PARTNER I study. Such a tendency toward the enrollment of healthier elderly patients seems sensible, given the clinical uncertainties that still surround issues of, such as paravalvular aortic regurgitation, stroke, and the durability of valves inserted transcutaneously. The similar mortality outcomes not only mirror the results of the PARTNER I US Cohort A among patients at high surgical risk but also provide preliminary evidence of the lack of difference in mortality between patients at Table 3. Baseline Characteristics of PS-Matched Patients With STS Scores 3% to 8% (n 255) (n 255) Diff p Value Age (yrs) Female 156 (61.2) 151 (59.2) Logistic EuroSCORE (%) NYHA I 7 (3.1) 10 (4.4) II 24 (10.6) 27 (11.9) III 145 (63.9) 139 (61.2) IV 51 (22.5) 51 (22.5) Diabetes mellitus 79 (31.0) 60 (24.4) Hypertension 198 (87.2) 183 (80.6) Coronary artery disease 69 (61.6) 68 (60.7) LVEF % 166 (65.1) 152 (59.6) % 50% 68 (26.7) 76 (29.8) % 21 (8.2) 27 (10.6) Cerebrovascular accident 26 (10.2) 17 (6.7) Peripheral vascular disease 17 (6.7) 29 (11.7) Chronic obstructive pulmonary disease 48 (18.8) 41 (16.1) Pulmonary hypertension 52 (20.4) 57 (22.4) Creatinine (mg/dl) Values are mean SD or n (%). The p values are from paired t test for continuous data and conditional logistic regression for dichotomous and ordinal data. Abbreviations as in Tables 1 and 2.

7 JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 6, NO. 5, A Cumulative incidence (%) 20 HR (95% CI): 1.12 ( ); p= No. at risk B Cumulative incidence (%) No. at risk Days after procedure HR (95% CI): 0.90 ( ); p= Months after procedure Figure 3. Cumulative Incidence of All-Cause Mortality (A) Cumulative incidence (%) of all-cause 30-day mortality in (black line) and (blue line) patients. No difference in 30-day mortality between groups. (B) Cumulative incidence (%) of all-cause 1-year mortality in (black line) and (blue line) patients. No difference in 1-year mortality between groups. HR hazard ratio; other abbreviations as in Figure 2. intermediate surgical risk. That said, measured and unmeasured confounders might continue to limit observational comparisons and provide the rationale for planned randomized comparisons between these 2 treatment strategies. The death rate at 30 days in our population was somewhat higher than previously reported for the patients in the PARTNER US Cohort A trial, at 7.9% as opposed to 3.4% for, and 7.1% versus 6.5% for. Our results, however, are well in line with those reported from other registries, including the recent experience from the FRANCE 2 (French Aortic National CoreValve and Edwards) registry, with a 30-day mortality of 9.7% (6). By contrast, our mortality rates at 1 year are 5% to 10% lower than those of the PARTNER US I Cohort A ( 18.8% vs. 24.2%, 17% vs. 26.8%), which can be expected, given the lower long-term risk related to coexisting comorbidities. In this context, Grossi et al. (7) reported mortality at 30 days of 7.8% for 731 patients undergoing with a mean logistic EuroSCORE of 17.2%, which is directly comparable to the mortality of surgically treated patients in this study with a mean logistic EuroSCORE of 17.5%. Other studies based on propensity score matching have also reported similar outcomes in terms of mortality at 30 days and during longer-term follow-up extending to 3 years (8 14). Our study extends these observations to patients at intermediate risk and justifies the pursuit to perform randomized clinical trials. Lower transvalvular aortic gradients, larger effective orifice area, and lower rates of patient-prosthesis mismatch have been demonstrated in patients undergoing when compared with, even though paravalvular aortic regurgitation is more frequent after, with deleterious effect on survival (15,16). Nonetheless, is suggested to result in greater recovery of left ventricular function among those with reduced LVEF at baseline (17). A recent cost-effectiveness study using a Markov model, with data derived from real-world registry studies, noted a slightly increased cost of over, which was offset by a slightly higher gain in quality-adjusted life years (18). The authors concluded that satisfies current standards of cost-effectiveness relative to. (18). Our study now extends these inferences to patients at intermediate risk. We found no differences in treatment effects across subgroups, except for sex. In women, however, appeared more beneficial than in men, endorsing the findings from the PARTNER US Cohort A trial. In surgical series, female sex is often associated with worse outcomes (19). Women tend to have smaller body surface area, a smaller chest cavity, smaller (and more calcified) aortic annulus and root, and a more pronounced concentric remodeling. These conditions might predispose to worse outcomes in the context of but not (or to a lesser extent) in the context of. Furthermore, women might be more prone to prosthesis-patient mismatch after (20). It has been observed that results in a lesser incidence of patient prosthesis mismatch compared with, particularly in those patients with small aortic annuli (15). Also, women undergoing have higher LVEF, and men have more pronounced left ventricular fibrosis, possibly making men less able to recover left ventricular function after (21,22). Single-arm observational studies have also suggested that women have better shortand long-term survival after (23,24). Other data from the PARTNER I US trial showed that the risk of neurological events, such as transient ischemic attacks or stroke, was slightly higher at 30 days in those undergoing as opposed to, but this difference disappeared after 2 years of follow-up (16). The primary outcome measure in the SUR trial will be a combined endpoint that includes all-cause mortality and major stroke. Notwithstanding its importance, we did not include stroke as an outcome measure in our present

8 450 JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 6, NO. 5, 2013, n (IR), n (IR) HR (95% CI) P Interaction Overall 42 (17.5) 43 (17.3) 0.90 ( ) Age (17.5) 17 (17.0) 0.87 ( ) >80 25 (17.5) 26 (17.6) 0.92 ( ) Gender Male 22 (23.9) 15 (15.7) 1.67 ( ) Female 20 (13.6) 28 (18.4) 0.56 ( ) Logistic EuroSCORE (16.1) 27 (15.8) 0.88 ( ) >20 16 (20.7) 16 (20.7) 0.93 ( ) STS score (17.9) 17 (18.9) 0.73 ( ) > (17.4) 26 (16.5) 1.00 ( ) Diabetes mellitus 0.22 No 32 (19.1) 29 (17.1) 1.08 ( ) Yes 10 (14.0) 14 (18.0) 0.57 ( ) Left ventricular function 0.20 <30% 6 (30.9) 2 (9.5) 2.50 ( ) 30% 36 (16.3) 41 (18.1) 0.82 ( ) Cerebrovascular accident 0.93 No 35 (16.2) 35 (15.7) 0.91 ( ) Yes 7 (30.6) 8 (33.0) 0.86 ( ) Peripheral vascular disease 0.48 No 40 (17.9) 39 (16.9) 0.94 ( ) Yes 2 (12.5) 4 (23.6) 0.50 ( ) Pulmonary hypertension 0.42 No 33 (17.1) 36 (18.1) 0.89 ( ) Yes 9 (18.1) 7 (14.4) 1.33 ( ) Prior CABG No 40 (18.2) 40 (17.7) 0.92 ( ) 0.74 Yes 2 (10.0) 3 (13.6) 0.67 ( ) Figure 4. Stratified Analyses of All-Cause Mortality at 1 Year There was a significant treatment by gender interaction for cumulative 1-year survival favoring over in women but not in men. CABG coronary artery bypass graft surgery; EuroSCORE European System for Cardiac Operative Risk Evaluation; other abbreviations as in Figures 1 and 2. study, because of the heterogeneity in clinical endpoint definitions across the 3 centers. Data on frailty and on comorbidities such as porcelain aorta and radiation disease, which might be associated with treatment decision and with prognosis were neither collected in our study nor incorporated in STS and logistic EuroSCORE. Therefore, we cannot rule out residual confounding by these unmeasured characteristics. However, frailty is probably an infrequent finding in our matched-intermediate-risk cohort, whereas comorbidities such as radiation disease and porcelain aorta are typically found in 5% of patients undergoing. Conclusions Our results show that patients with severe aortic stenosis considered at intermediate surgical risk have similar overall mortality at 30 days and 1 year, irrespective of whether they are treated with or, and point to the need for dedicated randomized trials. The currently observed differences in treatment effects in men as opposed to women warrant further study. Reprint requests and correspondence: Dr. Peter Jüni, Institute of Social and Preventive Medicine and Clinical Trials Unit, University of Bern, 3012 Bern, Switzerland. juni@ispm.unibe.ch. REFERENCES 1. Bleiziffer S, Ruge H, Mazzitelli D, et al. Results of percutaneous and transapical transcatheter aortic valve implantation performed by a surgical team. Eur J Cardiothorac Surg 2009;35:615 20; discussion Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd edition. Hillsdale, New Jersey: Lawrence Erlbaum Associates, 1988.

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