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Influence of Gender on Clinical Outcomes Following Transcatheter Aortic Valve Implantation from the UK Transcatheter Aortic Valve Implantation Registry and the National Institute for Cardiovascular Outcomes Research
Influence of Gender on Clinical Outcomes Following Transcatheter Aortic Valve Implantation from the UK Transcatheter Aortic Valve Implantation Registry and the National Institute for Cardiovascular Outcomes Research Rasha Al-Lamee, MA, MBBSa,*, Christopher Broyd, BSc, MBBSa, Jessica Parker, RGNa, Justin E. Davies, MBBS, PhDa, Jamil Mayet, MBChB, MDa, Nilesh Sutaria, MBChB, MDa, Ben Ariff, MBBS, PhDa, Beth Unsworth, PhDa, Jonathan Cousins, BSc, MBBSa, Colin Bicknell, BSc, MBBSa, Jonathan Anderson, MBChBa, Iqbal S. Malik, MBBCh, PhDa, Andrew Chukwuemeka, MBBS, MDa, Daniel J. Blackman, MBChB, MDc, Neil Moat, MBBSb, Peter F. Ludman, MBBChir, MDd, Darrel P. Francis, MBBChir, MDa, and Ghada W. Mikhail, MBBS, MDa Gender differences exist in outcomes after percutaneous coronary intervention and coronary artery bypass graft surgery but have yet to be fully explored after transcatheter aortic valve implantation. We aimed to investigate gender differences after transcatheter aortic valve implantation in the UK National Institute for Cardiovascular Outcomes Research registry. A retrospective analysis was performed of Medtronic CoreValve and Edwards SAPIEN implantation in 1,627 patients (756 women) from January 2007 to December 2010. Men had more risk factors: poor left ventricular systolic function (11.9% vs 5.5%, p <0.001), 3-vessel disease (19.4% vs 9.2%, p <0.001), previous myocardial infarction (29.5% vs 13.0%, p <0.001), peripheral vascular disease (32.4% vs 23.3%, p <0.001), and higher logistic EuroSCORE (21.8 – 14.2% vs 21.0 – 13.4%, p [ 0.046). Thirty-day mortality was 6.3% (confidence interval 4.3% to 7.9%) in women and 7.4% (5.6% to 9.2%) in men and at 1 year, 21.9% (18.7% to 25.1%) and 22.4% (19.4% to 25.4%), respectively. There was no mortality difference: p [ 0.331 by log-rank test; hazard ratio for women 0.91 (0.75 to 1.10). Procedural success (96.6% in women vs 96.4% in men, p [ 0.889) and 30-day cerebrovascular event rates (3.8% vs 3.7%, p [ 0.962) did not differ. Women had more major vascular complications (7.5% vs 4.2%, p [ 0.004) and less moderate or severe postprocedural aortic regurgitation (7.5% vs 12.5%, p [ 0.001). In conclusion, despite a higher risk profile in men, there was no gender-related mortality difference; however, women had more major vascular complications and less postprocedural moderate or severe aortic regurgitation. Ó 2014 Elsevier Inc. All rights reserved. (Am J Cardiol 2014;113:522e528) Gender differences continue to exist in trials on percutaneous coronary intervention,1e3 coronary artery bypass graft surgery,4,5 and aortic valve surgery6,7 with women having a worse clinical outcome compared with men. This has been explained by a higher level of co-morbidities in women at the time of presentation, specifically older age, more diabetes, hypercholesterolemia, heart failure, and peripheral vascular disease.2,3,5,7 However, women continue to be under-represented in research trials and registries.
a Imperial College Healthcare NHS Trust, London, United Kingdom; Royal Brompton and Harefield NHS Trust, London, United Kingdom; c Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom; and d Queen Elizabeth Hospital, University of Birmingham, Birmingham, United Kingdom. Manuscript received August 12, 2013; revised manuscript received and accepted October 15, 2013. See page 527 for disclosure information. *Corresponding author: Tel: (þ44) 797-627-6923; fax: (þ44) 208-3831342. E-mail address: [email protected] (R. Al-Lamee). b
0002-9149/13/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.10.024
Transcatheter aortic valve implantation (TAVI) differs from these procedures, in that it is applied in broadly equal numbers for men and women.8,9 The United Kingdom (UK) has a national multicenter collaborative database that makes it possible to evaluate gender differences ensuring that the data from every patient in the country are studied. In this study, we report the relation between gender and outcome, for all patients who underwent TAVI in the UK since the procedure’s inception. Methods This is a retrospective analysis of 1,627 patients enrolled in a UK multicenter registry from January 2007 to December 2010. TAVI was conducted through “transfemoral” (TF), transapical (TA), subclavian/axillary (SC), and transaortic access routes with implantation of the Medtronic CoreValve (Medtronic, Santa Rosa, California) and Edwards SAPIEN and SAPIEN XT (Edwards Lifesciences, Irvine, California) devices. www.ajconline.org
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Table 1 Baseline characteristics of study population Variable Age (yrs) Weight (kg) Height (m) Body mass index (kg/m2) Body surface area (m2) Diabetes mellitus Chronic kidney disease Chronic obstructive pulmonary disease Pulmonary hypertension Previous myocardial infarction Previous percutaneous coronary intervention Previous coronary bypass Previous stroke with full recovery Previous stroke with neurologic deficit Peripheral vascular disease Angina Canadian Cardiovascular Society classes I and II Angina Canadian Cardiovascular Society classes III and IV New York Heart Association classes I and II New York Heart Association classes III and IV Poor left ventricular systolic function Three-vessel coronary disease Left main disease Logistic EuroSCORE Peak aortic gradient (mm Hg) Aortic annulus diameter (mm) Aortic valve area (cm2) Aortic valve index (cm2/m2)
All Patients (n ¼ 1,627)
Men (n ¼ 871)
Women (n ¼ 756)
p Value
81.6 7.3 72.5 15.9 1.6 0.1 26.8 5.3 1.8 0.2 351 (21.6%) 87 (5.3%) 366 (22.5%) 190 (11.7%) 354 (21.8%) 238 (14.6%) 452 (27.8%) 92 (5.7%) 50 (3.1%) 436 (26.8%) 313 (19.2%) 280 (17.2%) 1,268 (78.3%) 316 (19.4%) 143 (8.8%) 237 (14.6%) 93 (5.7%) 21.5 13.8 81 26 22.4 2.2 0.65 0.37 0.36 0.18
80.8 7.6 77.8 14.2 1.7 0.1 26.7 4.7 1.9 0.2 207 (23.9%) 59 (3.7%) 214 (20.8%) 89 (10.2%) 256 (29.5%) 157 (18.0%) 356 (40.9%) 52 (6.0%) 27 (3.1%) 267 (32.4%) 177 (19.3%) 166 (17.3%) 683 (78.8%) 165 (19.0%) 102 (11.9%) 168 (19.4%) 69 (8.0%) 21.8 14.2 77 24 23.2 2.0 0.70 0.46 0.37 0.21
82.6 6.8 63.4 15.4 1.6 0.1 26.8 5.9 1.7 0.2 144 (19.2%) 28 (6.8%) 152 (25.1%) 101 (13.4%) 98 (13.0%) 81 (10.7%) 96 (12.7%) 40 (5.3%) 23 (3.0%) 169 (23.3%) 136 (18.1%) 114 (15.1%) 585 (77.8%) 151 (20.1%) 41 (5.5%) 69 (9.2%) 24 (3.2%) 21.0 13.4 85 28 21.3 1.9 0.60 0.21 0.36 0.13
<0.001 <0.001 <0.001 0.736 <0.001 0.021 0.006 0.042 0.130 <0.001 <0.001 <0.001 0.539 0.933 <0.001 0.231 0.033 0.631 0.595 <0.001 <0.001 <0.001 0.046 <0.001 0.354 0.086 0.471
Table 2 Procedural demographics Variable Edwards SAPIEN THV and XT Medtronic CoreValve Transfemoral access Transapical access Subclavian/transaxillary access Transaortic access Transfemoral access: Surgical closure Transfemoral access: device closure Transfemoral access: manual compression
All Patients (n ¼ 1,627) 813 814 1,097 411 96 23 387 700 10
(50.0%) (50.0%) (67.4%) (25.3%) (5.9%) (1.4%) (35.3%) (63.8%) (0.9%)
All patients who underwent TAVI in the UK were enrolled in a UK TAVI multicenter registry from January 2007 to December 2010. All patients had been selected for TAVI after a multidisciplinary team review by a dedicated Heart team at each institution, including interventional cardiologists, cardiothoracic surgeons, imaging cardiologists, and anesthetists. Data were prospectively collected on 1,627 consecutive patients and entered into a central database run by the Central Cardiac Audit Database that became part of the National Institute for Cardiovascular Outcomes Research in 2011 with the Data Management Group of the UK TAVI group acting as custodians of the data set.10 Device selection was based on aortic annulus diameter. The aortic annulus diameter was measured using transthoracic echocardiography, transesophageal echocardiography, cardiac
Men (n ¼ 871) 421 450 580 218 65 8 192 382 6
(48.3%) (51.7%) (67.2%) (25.2%) (7.5%) (1.0%) (33.1%) (65.9%) (1.5%)
Women (n ¼ 756) 392 364 517 193 31 15 195 318 4
(51.9%) (48.1%) (69.8%) (26.0%) (4.2%) (2.0%) (37.7%) (61.5%) (0.8%)
p Value 0.157 0.157 0.271 0.709 0.005 0.069 0.110 0.134 0.650
computerized tomography, invasive aortography, and cardiac magnetic resonance imaging in 29.9% (n ¼ 487), 65.9% (n ¼ 1,073), 1.8% (n ¼ 30), 1.8% (n ¼ 30), and 0.4% (n ¼ 7) patients, respectively, based on routine practice at each center at the time of the procedure. During the study period, the following devices were available: Edwards SAPIEN and Edwards XT devices in 23, 26, and 29 mm and CoreValve device in 23, 26, and 29 mm. A TF first policy was applied in all centers, with alternative access routes considered only when disease, tortuosity, calcification, and/or small caliber vessels prohibited a TF approach. TAVI was performed using conventional techniques as have been previously described.11,12 Patients were preloaded with 300 mg aspirin and 300 mg clopidogrel, and the majority of patients went on to receive 3 to 6 months of dual
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Table 3 Clinical outcomes at 30 days Variables
All Patients (n ¼ 1,627)
Men (n ¼ 871)
Women (n ¼ 756)
p Value
10.7 33.4 1,568 (96.4%) 1,486 (91.3%) 15 (0.9%) 39 (2.4%) 163 (10.0%) 6 (0.4%) 92 (5.7%) 374 (23.0%) 14 (0.9%) 253 (15.6%) 60 (3.7%) 30 (1.8%) 75 (4.6%) 103 (6.3%) 310 (19.1%)
9.8 39.5 838 (96.4%) 806 (92.8%) 6 (0.7%) 26 (3.0%) 107 (12.5%) 3 (0.3%) 36 (4.2%) 191 (21.9%) 9 (1.0%) 132 (15.3%) 32 (3.7%) 16 (1.9%) 41 (4.7%) 59 (6.8%) 160 (18.6%)
11.8 24.4 730 (96.6%) 680 (89.9%) 9 (1.2%) 13 (1.7%) 56 (7.5%) 3 (0.4%) 56 (7.4%) 183 (24.2%) 5 (0.7%) 121 (16.2%) 28 (3.8%) 14 (1.9%) 34 (4.5%) 44 (5.9%) 150 (20.2%)
0.219 0.889 0.044 0.288 0.097 0.001 0.859 0.004 0.388 0.419 0.606 0.962 0.974 0.840 0.446 0.408
Hospital stay, d Procedural success Procedural success without major vascular complication Valve embolization “Valve in valve” AR grades 3 and 4 Major apical access complication Major femoral vascular complication Major bleeding Need for conversion to aortic surgery Need for permanent pacemaker Stroke and transient ischemic attack with residual deficit Major organ failure or sepsis Acute renal failure requiring ultrafiltration All-cause mortality Combined safety end point
All statistical analysis was performed using SPSS version 16.0 statistical software (SPSS Inc., Chicago, Illinois). Parametric tests or nonparametric tests were used to analyze continuous variables according to plausibility of normality and expressed as mean SD or median and interquartile range as appropriate. Categorical variables are expressed as counts and percentages. Survival was assessed by the standard Kaplan-Meier method. Stepwise logistic regression was used to assess potential predictors of dichotomous end points. Statistical significance was defined as p <0.05. Results
Figure 1. Vascular complication rate by body surface area.
antiplatelet therapy in the form of 75 mg/day aspirin and 75 mg/day clopidogrel. Intravenous heparin was administered to achieve an activated clotting time of between 250 and 300 seconds. All procedures conducted through the transapical and transaortic routes were performed under general anesthesia, whereas devices implanted through the TF or the SC routes were done under general anesthesia or sedation with local anesthesia at the team’s discretion. The degree of postoperative aortic regurgitation (AR) was assessed using transesophageal echocardiography. Routine follow-up was obtained at 1 year. The primary end points of this study were procedural success, all-cause mortality at 30 days, and the combined safety end point at 30 days. Procedural success was defined as stable device placement and adequate function (significant reduction in transaortic valve gradient 20 mm Hg) without severe AR grade 3, valve embolization, or need for a second valve. The combined safety end point was a composite of all-cause mortality, major stroke, life-threatening bleeding, stage 3 acute kidney injury, periprocedural myocardial infarction, major vascular complication, and repeat procedure for valve-related dysfunction.
TAVI was performed in 1,627 patients with the CoreValve Revalving System implanted in 814 (50.0%) patients and the Edwards SAPIEN THV and XT System implanted in 813 (50.0%) patients. The baseline clinical demographics of the patients are presented in Table 1. Of the 1,627 patients, 871 were men and 756 were women. Men had a higher rate of risk factors than women, with a higher prevalence of diabetes, previous myocardial infarction, previous percutaneous coronary intervention, previous coronary artery bypass graft surgery, peripheral vascular disease, poor left ventricular systolic function, 3-vessel coronary artery disease, left main coronary artery disease, and a higher logistic EuroSCORE. However, there were 3 characteristics in which the male patients had potentially favorable status. The men were younger and had lower rates of chronic kidney disease and chronic obstructive pulmonary disease. The men were taller and, therefore, had a greater body surface area. There was no difference in body mass index between the 2 groups. Women had a higher peak aortic gradient and a smaller aortic valve area. However, there was no difference between the groups in the aortic valve area when corrected for body surface area (aortic valve index) or the aortic annulus diameter. The procedural characteristics are presented in Table 2. Equivalent numbers of men and women had implantation of the Edwards and the CoreValve devices. The SC route was
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Figure 2. (A) Vascular complication rate by body surface area in men. (B) Vascular complication rate by body surface area in women.
Figure 3. Postprocedural AR by aortic annulus diameter in whole group. mod ¼ moderate.
used more commonly in men than in women, although the corresponding values for the other routes did not individually show any statistically significant differences between sexes. Clinical outcomes are listed in Table 3. In the whole group, procedural success was achieved in 96.4% with no gender difference. There was no difference in the incidence of stroke, conduction abnormalities leading to permanent pacemaker implantation, major organ failure, sepsis, or acute kidney injury requiring renal replacement therapy. All-cause mortality rates at 30 days were the same in men and women, despite their different risk profiles. However, women had a higher rate of vascular complications but no difference in major bleeding rate. On stepwise logistic regression analysis, vascular complications were associated with female gender (odds ratio [OR] 2.23, confidence interval [CI] 1.23 to 4.04, p ¼ 0.009) but not with height, weight, body surface area or body mass index (Figures 1 and 2), peripheral vascular disease, or body surface area (p ¼ 0.232 and p ¼ 0.950, respectively). The men had a higher rate of moderate or severe AR than women after the procedure. The rates of moderate or severe AR are shown in Figures 3e5 in relation to annulus diameter. Rates of moderate or severe AR rose from 9.8% for annulus diameter of 18 to 20 mm to 37.5% for annulus diameter of 27 to 30 mm. On multivariate analysis, the
severity of postprocedural AR was not related to gender (p ¼ 0.101). However, the degree of AR was strongly related to aortic annulus diameter (t ¼ 4.0, p <0.0001) as shown in Figures 4 and 5. Additionally, there were higher rates of postprocedural AR of moderate grade after implantation of the CoreValve device when compared with the Edwards device (12.1% vs 6.7%, p <0.001), although there was no statistically significant difference in the rate of severe AR between the 2 devices, p ¼ 0.244 (Figure 5). Survival status was obtained in 1,625 patients (99.9%). For the survivors, median follow-up was 475 (interquartile range 377 to 820) days. For the 433 patients who died, median time to death was 140 (interquartile range 28 to 382) days. Of these, 237 (55.0%) were men and 196 (45.0%) were women. There was no difference in survival between the sexes, as shown in Figure 6 (p ¼ 0.331). Mortality in men and women, respectively, was 7.4% (CI 5.6% to 9.2%) and 6.3% (4.3% to 7.9%) at 30 days; 16.6% (14.0% to 16.6%) and 14.1% (11.5% to 16.7%) at 6 months; and 22.4% (19.4% to 25.4%) and 21.9% (18.7% to 25.1%) at 1 year. On Cox proportional hazards analysis, female gender gave a hazard ratio of 0.911 (0.754 to 1.100). The combined safety end point at 30 days, which was 19.1% adverse events in the whole group, was not different between men and women (18.6% vs 20.2%, p ¼ 0.408). Discussion This study is an analysis of a large national database assessing the effect of gender on outcomes of TAVI. There was no difference in 30-day or l-year mortality rates between men and women. Despite having a lower vascular risk profile than men, women had a higher incidence of vascular complications. This does not seem to be explained by their smaller body. AR was a more common complication in men and may have been because some men had large aortic annular diameters. Vascular complications are common in TAVI and are associated with increased morbidity and mortality.8,9,12 In our analysis, vascular complications were almost twice as common in women as in men. Furthermore, on multivariable analysis, female gender was independently associated with the risk of vascular complications. This is consistent with the findings of Humphries et al13 (12.4% in women vs 5.4% in men), the ADVANCE CoreValve registry (14.1% in women vs 7.1% in men),14 the Observational Study of
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Figure 4. (A) Postprocedural AR by aortic annulus diameter in men. (B) Postprocedural AR by aortic annulus diameter in women.
Figure 5. Postprocedural AR by aortic valve device.
Figure 6. Impact of gender on survival.
Appropriateness, Efficacy, and Effectiveness of AVR-TAVI procedures for the treatment of severe symptomatic aortic stenosis (OBSERVANT) trial,15 Van Mieghem et al,16 and the trend seen in the Milan registry17 and the findings of d’Ascenzo et al.18 A number of factors have been reported to be predictors of vascular complications after TF TAVI including introducer sheath size, sheath-to-femoral artery ratio, and femoral artery calcium score.19,20 Additionally, the rate of
vascular complications has been shown to improve as centers gain more experience.8 However, iliofemoral diameters were not routinely collected in the UK nationwide database; therefore, we cannot assess the plausible link between vascular complications and the likelihood of smaller iliofemoral diameters in women. Notably, in our study, women had lower rates of peripheral vascular disease than men, indicating that this did not explain their higher vascular complication rate. Subgroup analysis of vascular complication rates by body surface area showed a trend toward higher rates in the smallest body surface area groups. However, body surface was not found to be a predictor of vascular complication rates after logistic regression analysis. We found no difference in the bleeding rate in the major bleeding rate between the 2 groups. This is similar to the findings of Buja et al.21 However, other studies have shown higher rates of blood transfusions15,17 and higher rates of life-threatening and major bleeding in women.13,16,18 AR is a frequent complication of TAVI.22e24 It is more common in men, but the driving factor for this may be because of a difference in aortic annulus diameter. Although there was no sex difference in the mean aortic annulus diameter, the distribution of aortic annulus diameters differed between the genders with only men having measurements in the largest annulus diameter group (27 to 30 mm). Notably, the highest level of severe AR was present in this group. Once aortic annulus diameter was adjusted for, there was no difference between the genders. This is in keeping with the physicoanatomical concept that AR arises from incomplete apposition of the device with the aortic wall. Other studies have also shown larger aortic annulus diameters in men and higher rates of moderate to severe AR after TAVI.15,25 The present study reflects outcomes during the era when devices were available in 23, 26, and 29 mm. The advent of a wider range of device sizes and newer devices may help reduce this problem in future years as the technology continues to mature. Mortality in our study was similar between men and women, with the hazard ratio for women being 0.91 (CI 0.75 to 1.10). Mortality data appear to vary with some studies showing better survival rates in women than men after TAVI13,26 and others showing no gender difference in mortality.15,18,21,27 Our data showed a higher baseline risk
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profile in men that is consistent with the Canadian analysis,13 the TAVI cohort of the OBSERVANT study,15 and the Italian registry data.21 The stroke rate in our study was similar between men and women, with an OR for men being 0.99 (0.59 to 1.66). Data on stroke rates appear to be somewhat variable that may reflect underpowering because of small event numbers. Women had higher stroke rates in the gender analysis of a high-risk subset of cohort A of the Placement of Aortic Transcatheter Valves (PARTNER) trial (30-day stroke rate of 0.7% in men vs 6.8% in women)28 and the ADVANCE trial with the OR for stroke rates in men being 0.37 (0.17 to 0.81).14 However, the findings of d’Ascenzo et al,18 Hayashida et al,26 and the Italian registry21 were consistent with our findings with no gender difference in the incidence of stroke. This is a retrospective study, albeit from a prospectively acquired data set, which brings with it limitations. However, the principal comparison is being made between genders (which are fixed) and not between therapies (which are allocated by clinicians), and so there is less risk of erroneous conclusions from allocation bias.29 As a multicenter database, this study could only address data that were systematically collected from all the sites. Some information, such as iliofemoral diameter, was not collected and, therefore, cannot be explored for explanatory value. Logistic EuroSCORE was the only risk score measurement collected, postoperative AR was not divided into paravalvular or valvular regurgitation in the original data set, and no specific data were collected regarding the antiplatelet regimen. Also, clinical practice varied across the centers within the study, and in particular, aortic annulus diameter was measured using a variety of modalities that may have led to inaccuracies in terms of device selection. As the data protocol was laid out in January 2007, 3 years before the VARC definitions were published,30 rates reported here may not be directly comparable with VARC-based reports from other studies. Additionally, although total patient-months of follow-up are substantial, the length of follow-up in individual patients was variable as this data set represented a real-world cohort of patients in multiple centers with different protocols for outpatient care. Some patients were lost to follow-up, which is a common finding in multicenter cohorts that systematically include every patient receiving intervention.
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The American Journal of Cardiology (www.ajconline.org) Tamburino C, Sheiban I. Gender differences in patients undergoing TAVI: a multicentre study. EuroIntervention 2013;9:367e372. Hayashida K, Lefevre T, Chevalier B, Hovasse T, Romano M, Garot P, Mylotte D, Uribe J, Farge A, Donzeau-Gouge P, Bouvier E, Cormier B, Morice MC. Transfemoral aortic valve implantation new criteria to predict vascular complications. JACC Cardiovasc Interv 2011;4:851e858. Vavuranakis M, Kariori M, Voudris V, Kalogeras K, Vrachatis D, Aznaouridis C, Moldovan C, Masoura C, Thomopoulou S, Lazaros G, Stefanadis C. Predictive factors of vascular complications after transcatheter aortic valve implantation in patients treated with a default percutaneous strategy. Cardiovasc Ther 2013;31:e46ee54. Buja P, Napodano M, Tamburino C, Petronio AS, Ettori F, Santoro G, Ussia GP, Klugmann S, Bedogni F, Ramondo A, Maisano F, Marzocchi A, Poli A, Gasparetto V, Antoniucci D, Colombo A, Tarantini G. Italian Multicenter CoreValve Registry I, Comparison of variables in men versus women undergoing transcatheter aortic valve implantation for severe aortic stenosis (from Italian Multicenter CoreValve registry). Am J Cardiol 2013;111:88e93. Gilard M, Eltchaninoff H, Iung B, Donzeau-Gouge P, Chevreul K, Fajadet J, Leprince P, Leguerrier A, Lievre M, Prat A, Teiger E, Lefevre T, Himbert D, Tchetche D, Carrie D, Albat B, Cribier A, Rioufol G, Sudre A, Blanchard D, Collet F, Dos Santos P, Meneveau N, Tirouvanziam A, Caussin C, Guyon P, Boschat J, Le Breton H, Collart F, Houel R, Delpine S, Souteyrand G, Favereau X, Ohlmann P, Doisy V, Grollier G, Gommeaux A, Claudel JP, Bourlon F, Bertrand B, Van Belle E, Laskar M, Investigators F. Registry of transcatheter aortic-valve implantation in high-risk patients. N Engl J Med 2012;366:1705e1715. Unbehaun A, Pasic M, Buz S, Dreysse S, Kukucka M, Hetzer R, Drews T. Transapical aortic valve implantation in patients with severely depressed left ventricular function. J Thorac Cardiovasc Surg 2012;143: 1356e1363. Kodali SK, Williams MR, Smith CR, Svensson LG, Webb JG, Makkar RR, Fontana GP, Dewey TM, Thourani VH, Pichard AD, Fischbein M, Szeto WY, Lim S, Greason KL, Teirstein PS, Malaisrie SC, Douglas PS,
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Hahn RT, Whisenant B, Zajarias A, Wang D, Akin JJ, Anderson WN, Leon MB, Investigators PT. Two-year outcomes after transcatheter or surgical aortic-valve replacement. N Engl J Med 2012;366:1686e1695. Unbehaun A, Pasic M, Dreysse S, Drews T, Kukucka M, Mladenow A, Ivanitskaja-Kuhn E, Hetzer R, Buz S. Transapical aortic valve implantation: incidence and predictors of paravalvular leakage and transvalvular regurgitation in a series of 358 patients. J Am Coll Cardiol 2012;59:211e221. Hayashida K, Morice MC, Chevalier B, Hovasse T, Romano M, Garot P, Farge A, Donzeau-Gouge P, Bouvier E, Cormier B, Lefevre T. Sexrelated differences in clinical presentation and outcome of transcatheter aortic valve implantation for severe aortic stenosis. J Am Coll Cardiol 2012;59:566e571. Finkelstein A, Havakuk O, Steinvil A, Arbel Y, Halkin A, Bazan S, Abramowitz Y, Keren G, Banai S. Gender differences and clinical outcome in patients undergoing trans-femoral aortic valve implantation. Int J Cardiol 2013;168:4854e4855. Williams M, Kodali S, Humphries K, Nkomo V, Svensson LG, Weissman N, Cohen DJ, Thourani VH, Mack M, Tuzcu EM, Hueter I, Alu M, Kirtane A, Leon MB. Outcomes of transcatheter vs. surgical aortic valve replacement in women: insights from the randomized PARTNER trial. J Am Coll Cardiol 2012;60; TCT-95. Sen S, Davies JE, Malik IS, Foale RA, Mikhail GW, Hadjiloizou N, Hughes A, Mayet J, Francis DP. Why does primary angioplasty not work in registries? Quantifying the susceptibility of real-world comparative effectiveness data to allocation bias. Circ Cardiovasc Qual Outcomes 2012;5:759e766. Leon MB, Piazza N, Nikolsky E, Blackstone EH, Cutlip DE, Kappetein AP, Krucoff MW, Mack M, Mehran R, Miller C, Morel MA, Petersen J, Popma JJ, Takkenberg JJ, Vahanian A, van Es GA, Vranckx P, Webb JG, Windecker S, Serruys PW. Standardized endpoint definitions for transcatheter aortic valve implantation clinical trials: a consensus report from the Valve Academic Research Consortium. Eur Heart J 2011;32:205e217.
a Imperial College Healthcare NHS Trust, London, United Kingdom; Royal Brompton and Harefield NHS Trust, London, United Kingdom; c Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom; and d Queen Elizabeth Hospital, University of Birmingham, Birmingham, United Kingdom. Manuscript received August 12, 2013; revised manuscript received and accepted October 15, 2013. See page 527 for disclosure information. *Corresponding author: Tel: (þ44) 797-627-6923; fax: (þ44) 208-3831342. E-mail address: [email protected] (R. Al-Lamee). b
0002-9149/13/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.10.024
Transcatheter aortic valve implantation (TAVI) differs from these procedures, in that it is applied in broadly equal numbers for men and women.8,9 The United Kingdom (UK) has a national multicenter collaborative database that makes it possible to evaluate gender differences ensuring that the data from every patient in the country are studied. In this study, we report the relation between gender and outcome, for all patients who underwent TAVI in the UK since the procedure’s inception. Methods This is a retrospective analysis of 1,627 patients enrolled in a UK multicenter registry from January 2007 to December 2010. TAVI was conducted through “transfemoral” (TF), transapical (TA), subclavian/axillary (SC), and transaortic access routes with implantation of the Medtronic CoreValve (Medtronic, Santa Rosa, California) and Edwards SAPIEN and SAPIEN XT (Edwards Lifesciences, Irvine, California) devices. www.ajconline.org
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Table 1 Baseline characteristics of study population Variable Age (yrs) Weight (kg) Height (m) Body mass index (kg/m2) Body surface area (m2) Diabetes mellitus Chronic kidney disease Chronic obstructive pulmonary disease Pulmonary hypertension Previous myocardial infarction Previous percutaneous coronary intervention Previous coronary bypass Previous stroke with full recovery Previous stroke with neurologic deficit Peripheral vascular disease Angina Canadian Cardiovascular Society classes I and II Angina Canadian Cardiovascular Society classes III and IV New York Heart Association classes I and II New York Heart Association classes III and IV Poor left ventricular systolic function Three-vessel coronary disease Left main disease Logistic EuroSCORE Peak aortic gradient (mm Hg) Aortic annulus diameter (mm) Aortic valve area (cm2) Aortic valve index (cm2/m2)
All Patients (n ¼ 1,627)
Men (n ¼ 871)
Women (n ¼ 756)
p Value
81.6 7.3 72.5 15.9 1.6 0.1 26.8 5.3 1.8 0.2 351 (21.6%) 87 (5.3%) 366 (22.5%) 190 (11.7%) 354 (21.8%) 238 (14.6%) 452 (27.8%) 92 (5.7%) 50 (3.1%) 436 (26.8%) 313 (19.2%) 280 (17.2%) 1,268 (78.3%) 316 (19.4%) 143 (8.8%) 237 (14.6%) 93 (5.7%) 21.5 13.8 81 26 22.4 2.2 0.65 0.37 0.36 0.18
80.8 7.6 77.8 14.2 1.7 0.1 26.7 4.7 1.9 0.2 207 (23.9%) 59 (3.7%) 214 (20.8%) 89 (10.2%) 256 (29.5%) 157 (18.0%) 356 (40.9%) 52 (6.0%) 27 (3.1%) 267 (32.4%) 177 (19.3%) 166 (17.3%) 683 (78.8%) 165 (19.0%) 102 (11.9%) 168 (19.4%) 69 (8.0%) 21.8 14.2 77 24 23.2 2.0 0.70 0.46 0.37 0.21
82.6 6.8 63.4 15.4 1.6 0.1 26.8 5.9 1.7 0.2 144 (19.2%) 28 (6.8%) 152 (25.1%) 101 (13.4%) 98 (13.0%) 81 (10.7%) 96 (12.7%) 40 (5.3%) 23 (3.0%) 169 (23.3%) 136 (18.1%) 114 (15.1%) 585 (77.8%) 151 (20.1%) 41 (5.5%) 69 (9.2%) 24 (3.2%) 21.0 13.4 85 28 21.3 1.9 0.60 0.21 0.36 0.13
<0.001 <0.001 <0.001 0.736 <0.001 0.021 0.006 0.042 0.130 <0.001 <0.001 <0.001 0.539 0.933 <0.001 0.231 0.033 0.631 0.595 <0.001 <0.001 <0.001 0.046 <0.001 0.354 0.086 0.471
Table 2 Procedural demographics Variable Edwards SAPIEN THV and XT Medtronic CoreValve Transfemoral access Transapical access Subclavian/transaxillary access Transaortic access Transfemoral access: Surgical closure Transfemoral access: device closure Transfemoral access: manual compression
All Patients (n ¼ 1,627) 813 814 1,097 411 96 23 387 700 10
(50.0%) (50.0%) (67.4%) (25.3%) (5.9%) (1.4%) (35.3%) (63.8%) (0.9%)
All patients who underwent TAVI in the UK were enrolled in a UK TAVI multicenter registry from January 2007 to December 2010. All patients had been selected for TAVI after a multidisciplinary team review by a dedicated Heart team at each institution, including interventional cardiologists, cardiothoracic surgeons, imaging cardiologists, and anesthetists. Data were prospectively collected on 1,627 consecutive patients and entered into a central database run by the Central Cardiac Audit Database that became part of the National Institute for Cardiovascular Outcomes Research in 2011 with the Data Management Group of the UK TAVI group acting as custodians of the data set.10 Device selection was based on aortic annulus diameter. The aortic annulus diameter was measured using transthoracic echocardiography, transesophageal echocardiography, cardiac
Men (n ¼ 871) 421 450 580 218 65 8 192 382 6
(48.3%) (51.7%) (67.2%) (25.2%) (7.5%) (1.0%) (33.1%) (65.9%) (1.5%)
Women (n ¼ 756) 392 364 517 193 31 15 195 318 4
(51.9%) (48.1%) (69.8%) (26.0%) (4.2%) (2.0%) (37.7%) (61.5%) (0.8%)
p Value 0.157 0.157 0.271 0.709 0.005 0.069 0.110 0.134 0.650
computerized tomography, invasive aortography, and cardiac magnetic resonance imaging in 29.9% (n ¼ 487), 65.9% (n ¼ 1,073), 1.8% (n ¼ 30), 1.8% (n ¼ 30), and 0.4% (n ¼ 7) patients, respectively, based on routine practice at each center at the time of the procedure. During the study period, the following devices were available: Edwards SAPIEN and Edwards XT devices in 23, 26, and 29 mm and CoreValve device in 23, 26, and 29 mm. A TF first policy was applied in all centers, with alternative access routes considered only when disease, tortuosity, calcification, and/or small caliber vessels prohibited a TF approach. TAVI was performed using conventional techniques as have been previously described.11,12 Patients were preloaded with 300 mg aspirin and 300 mg clopidogrel, and the majority of patients went on to receive 3 to 6 months of dual
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Table 3 Clinical outcomes at 30 days Variables
All Patients (n ¼ 1,627)
Men (n ¼ 871)
Women (n ¼ 756)
p Value
10.7 33.4 1,568 (96.4%) 1,486 (91.3%) 15 (0.9%) 39 (2.4%) 163 (10.0%) 6 (0.4%) 92 (5.7%) 374 (23.0%) 14 (0.9%) 253 (15.6%) 60 (3.7%) 30 (1.8%) 75 (4.6%) 103 (6.3%) 310 (19.1%)
9.8 39.5 838 (96.4%) 806 (92.8%) 6 (0.7%) 26 (3.0%) 107 (12.5%) 3 (0.3%) 36 (4.2%) 191 (21.9%) 9 (1.0%) 132 (15.3%) 32 (3.7%) 16 (1.9%) 41 (4.7%) 59 (6.8%) 160 (18.6%)
11.8 24.4 730 (96.6%) 680 (89.9%) 9 (1.2%) 13 (1.7%) 56 (7.5%) 3 (0.4%) 56 (7.4%) 183 (24.2%) 5 (0.7%) 121 (16.2%) 28 (3.8%) 14 (1.9%) 34 (4.5%) 44 (5.9%) 150 (20.2%)
0.219 0.889 0.044 0.288 0.097 0.001 0.859 0.004 0.388 0.419 0.606 0.962 0.974 0.840 0.446 0.408
Hospital stay, d Procedural success Procedural success without major vascular complication Valve embolization “Valve in valve” AR grades 3 and 4 Major apical access complication Major femoral vascular complication Major bleeding Need for conversion to aortic surgery Need for permanent pacemaker Stroke and transient ischemic attack with residual deficit Major organ failure or sepsis Acute renal failure requiring ultrafiltration All-cause mortality Combined safety end point
All statistical analysis was performed using SPSS version 16.0 statistical software (SPSS Inc., Chicago, Illinois). Parametric tests or nonparametric tests were used to analyze continuous variables according to plausibility of normality and expressed as mean SD or median and interquartile range as appropriate. Categorical variables are expressed as counts and percentages. Survival was assessed by the standard Kaplan-Meier method. Stepwise logistic regression was used to assess potential predictors of dichotomous end points. Statistical significance was defined as p <0.05. Results
Figure 1. Vascular complication rate by body surface area.
antiplatelet therapy in the form of 75 mg/day aspirin and 75 mg/day clopidogrel. Intravenous heparin was administered to achieve an activated clotting time of between 250 and 300 seconds. All procedures conducted through the transapical and transaortic routes were performed under general anesthesia, whereas devices implanted through the TF or the SC routes were done under general anesthesia or sedation with local anesthesia at the team’s discretion. The degree of postoperative aortic regurgitation (AR) was assessed using transesophageal echocardiography. Routine follow-up was obtained at 1 year. The primary end points of this study were procedural success, all-cause mortality at 30 days, and the combined safety end point at 30 days. Procedural success was defined as stable device placement and adequate function (significant reduction in transaortic valve gradient 20 mm Hg) without severe AR grade 3, valve embolization, or need for a second valve. The combined safety end point was a composite of all-cause mortality, major stroke, life-threatening bleeding, stage 3 acute kidney injury, periprocedural myocardial infarction, major vascular complication, and repeat procedure for valve-related dysfunction.
TAVI was performed in 1,627 patients with the CoreValve Revalving System implanted in 814 (50.0%) patients and the Edwards SAPIEN THV and XT System implanted in 813 (50.0%) patients. The baseline clinical demographics of the patients are presented in Table 1. Of the 1,627 patients, 871 were men and 756 were women. Men had a higher rate of risk factors than women, with a higher prevalence of diabetes, previous myocardial infarction, previous percutaneous coronary intervention, previous coronary artery bypass graft surgery, peripheral vascular disease, poor left ventricular systolic function, 3-vessel coronary artery disease, left main coronary artery disease, and a higher logistic EuroSCORE. However, there were 3 characteristics in which the male patients had potentially favorable status. The men were younger and had lower rates of chronic kidney disease and chronic obstructive pulmonary disease. The men were taller and, therefore, had a greater body surface area. There was no difference in body mass index between the 2 groups. Women had a higher peak aortic gradient and a smaller aortic valve area. However, there was no difference between the groups in the aortic valve area when corrected for body surface area (aortic valve index) or the aortic annulus diameter. The procedural characteristics are presented in Table 2. Equivalent numbers of men and women had implantation of the Edwards and the CoreValve devices. The SC route was
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Figure 2. (A) Vascular complication rate by body surface area in men. (B) Vascular complication rate by body surface area in women.
Figure 3. Postprocedural AR by aortic annulus diameter in whole group. mod ¼ moderate.
used more commonly in men than in women, although the corresponding values for the other routes did not individually show any statistically significant differences between sexes. Clinical outcomes are listed in Table 3. In the whole group, procedural success was achieved in 96.4% with no gender difference. There was no difference in the incidence of stroke, conduction abnormalities leading to permanent pacemaker implantation, major organ failure, sepsis, or acute kidney injury requiring renal replacement therapy. All-cause mortality rates at 30 days were the same in men and women, despite their different risk profiles. However, women had a higher rate of vascular complications but no difference in major bleeding rate. On stepwise logistic regression analysis, vascular complications were associated with female gender (odds ratio [OR] 2.23, confidence interval [CI] 1.23 to 4.04, p ¼ 0.009) but not with height, weight, body surface area or body mass index (Figures 1 and 2), peripheral vascular disease, or body surface area (p ¼ 0.232 and p ¼ 0.950, respectively). The men had a higher rate of moderate or severe AR than women after the procedure. The rates of moderate or severe AR are shown in Figures 3e5 in relation to annulus diameter. Rates of moderate or severe AR rose from 9.8% for annulus diameter of 18 to 20 mm to 37.5% for annulus diameter of 27 to 30 mm. On multivariate analysis, the
severity of postprocedural AR was not related to gender (p ¼ 0.101). However, the degree of AR was strongly related to aortic annulus diameter (t ¼ 4.0, p <0.0001) as shown in Figures 4 and 5. Additionally, there were higher rates of postprocedural AR of moderate grade after implantation of the CoreValve device when compared with the Edwards device (12.1% vs 6.7%, p <0.001), although there was no statistically significant difference in the rate of severe AR between the 2 devices, p ¼ 0.244 (Figure 5). Survival status was obtained in 1,625 patients (99.9%). For the survivors, median follow-up was 475 (interquartile range 377 to 820) days. For the 433 patients who died, median time to death was 140 (interquartile range 28 to 382) days. Of these, 237 (55.0%) were men and 196 (45.0%) were women. There was no difference in survival between the sexes, as shown in Figure 6 (p ¼ 0.331). Mortality in men and women, respectively, was 7.4% (CI 5.6% to 9.2%) and 6.3% (4.3% to 7.9%) at 30 days; 16.6% (14.0% to 16.6%) and 14.1% (11.5% to 16.7%) at 6 months; and 22.4% (19.4% to 25.4%) and 21.9% (18.7% to 25.1%) at 1 year. On Cox proportional hazards analysis, female gender gave a hazard ratio of 0.911 (0.754 to 1.100). The combined safety end point at 30 days, which was 19.1% adverse events in the whole group, was not different between men and women (18.6% vs 20.2%, p ¼ 0.408). Discussion This study is an analysis of a large national database assessing the effect of gender on outcomes of TAVI. There was no difference in 30-day or l-year mortality rates between men and women. Despite having a lower vascular risk profile than men, women had a higher incidence of vascular complications. This does not seem to be explained by their smaller body. AR was a more common complication in men and may have been because some men had large aortic annular diameters. Vascular complications are common in TAVI and are associated with increased morbidity and mortality.8,9,12 In our analysis, vascular complications were almost twice as common in women as in men. Furthermore, on multivariable analysis, female gender was independently associated with the risk of vascular complications. This is consistent with the findings of Humphries et al13 (12.4% in women vs 5.4% in men), the ADVANCE CoreValve registry (14.1% in women vs 7.1% in men),14 the Observational Study of
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Figure 4. (A) Postprocedural AR by aortic annulus diameter in men. (B) Postprocedural AR by aortic annulus diameter in women.
Figure 5. Postprocedural AR by aortic valve device.
Figure 6. Impact of gender on survival.
Appropriateness, Efficacy, and Effectiveness of AVR-TAVI procedures for the treatment of severe symptomatic aortic stenosis (OBSERVANT) trial,15 Van Mieghem et al,16 and the trend seen in the Milan registry17 and the findings of d’Ascenzo et al.18 A number of factors have been reported to be predictors of vascular complications after TF TAVI including introducer sheath size, sheath-to-femoral artery ratio, and femoral artery calcium score.19,20 Additionally, the rate of
vascular complications has been shown to improve as centers gain more experience.8 However, iliofemoral diameters were not routinely collected in the UK nationwide database; therefore, we cannot assess the plausible link between vascular complications and the likelihood of smaller iliofemoral diameters in women. Notably, in our study, women had lower rates of peripheral vascular disease than men, indicating that this did not explain their higher vascular complication rate. Subgroup analysis of vascular complication rates by body surface area showed a trend toward higher rates in the smallest body surface area groups. However, body surface was not found to be a predictor of vascular complication rates after logistic regression analysis. We found no difference in the bleeding rate in the major bleeding rate between the 2 groups. This is similar to the findings of Buja et al.21 However, other studies have shown higher rates of blood transfusions15,17 and higher rates of life-threatening and major bleeding in women.13,16,18 AR is a frequent complication of TAVI.22e24 It is more common in men, but the driving factor for this may be because of a difference in aortic annulus diameter. Although there was no sex difference in the mean aortic annulus diameter, the distribution of aortic annulus diameters differed between the genders with only men having measurements in the largest annulus diameter group (27 to 30 mm). Notably, the highest level of severe AR was present in this group. Once aortic annulus diameter was adjusted for, there was no difference between the genders. This is in keeping with the physicoanatomical concept that AR arises from incomplete apposition of the device with the aortic wall. Other studies have also shown larger aortic annulus diameters in men and higher rates of moderate to severe AR after TAVI.15,25 The present study reflects outcomes during the era when devices were available in 23, 26, and 29 mm. The advent of a wider range of device sizes and newer devices may help reduce this problem in future years as the technology continues to mature. Mortality in our study was similar between men and women, with the hazard ratio for women being 0.91 (CI 0.75 to 1.10). Mortality data appear to vary with some studies showing better survival rates in women than men after TAVI13,26 and others showing no gender difference in mortality.15,18,21,27 Our data showed a higher baseline risk
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profile in men that is consistent with the Canadian analysis,13 the TAVI cohort of the OBSERVANT study,15 and the Italian registry data.21 The stroke rate in our study was similar between men and women, with an OR for men being 0.99 (0.59 to 1.66). Data on stroke rates appear to be somewhat variable that may reflect underpowering because of small event numbers. Women had higher stroke rates in the gender analysis of a high-risk subset of cohort A of the Placement of Aortic Transcatheter Valves (PARTNER) trial (30-day stroke rate of 0.7% in men vs 6.8% in women)28 and the ADVANCE trial with the OR for stroke rates in men being 0.37 (0.17 to 0.81).14 However, the findings of d’Ascenzo et al,18 Hayashida et al,26 and the Italian registry21 were consistent with our findings with no gender difference in the incidence of stroke. This is a retrospective study, albeit from a prospectively acquired data set, which brings with it limitations. However, the principal comparison is being made between genders (which are fixed) and not between therapies (which are allocated by clinicians), and so there is less risk of erroneous conclusions from allocation bias.29 As a multicenter database, this study could only address data that were systematically collected from all the sites. Some information, such as iliofemoral diameter, was not collected and, therefore, cannot be explored for explanatory value. Logistic EuroSCORE was the only risk score measurement collected, postoperative AR was not divided into paravalvular or valvular regurgitation in the original data set, and no specific data were collected regarding the antiplatelet regimen. Also, clinical practice varied across the centers within the study, and in particular, aortic annulus diameter was measured using a variety of modalities that may have led to inaccuracies in terms of device selection. As the data protocol was laid out in January 2007, 3 years before the VARC definitions were published,30 rates reported here may not be directly comparable with VARC-based reports from other studies. Additionally, although total patient-months of follow-up are substantial, the length of follow-up in individual patients was variable as this data set represented a real-world cohort of patients in multiple centers with different protocols for outpatient care. Some patients were lost to follow-up, which is a common finding in multicenter cohorts that systematically include every patient receiving intervention.
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Disclosures The authors have no conflicts of interest to disclose. 1. Mikhail GW. Coronary heart disease in women. BMJ 2005;331: 467e468. 2. Morice MC, Mikhail GW, Mauri i Ferre F, Modena MG, Strasser RH, Grinfeld L, Sudhir K, Stuteville M, Papeleu P, Li D, Rutledge D, Windecker S. SPIRIT Women, evaluation of the safety and efficacy of the XIENCE V everolimus-eluting stent system in female patients: referral time for coronary intervention and 2-year clinical outcomes. EuroIntervention 2012;8:325e335. 3. Mikhail GW, Gerber RT, Cox DA, Ellis SG, Lasala JM, Ormiston JA, Stone GW, Turco MA, Joshi AA, Baim DS, Colombo A. Influence of sex on long-term outcomes after percutaneous coronary intervention
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