1. GENDER DISPARITIES AMONG PATIENTS UNDERGOING TRANSCATHETER AORTIC VALVE REPLACEMENT Michael A. Gaglia, Jr.; Michael J. Lipinski; Rebecca Torguson; Jiaxiang Gai; Itsik Ben-Dor; Lowell F. Satler; Augusto D. Pichard; Ron Waksman Medstar Heart and Vascular Institute Washington, DC

2. Background Studies regarding mortality after SAVR are conflicting, although high-risk female patients appear to have worse outcomes than male In PARTNER, Williams et al reported women had lower rates of late mortality with TAVR vs. SAVR – Driven by females with transfemoral access Recent meta-analysis by O’Connor et al of 11,310 TAVR patients: – Long-term mortality: female lower (no diff at 30d) – Stroke, major bleed, vascular complications: female higher Heart 2010;96:539; J Thorac Cardiovasc Surg 2014;147:1529; JACC 2014;63:1522; JACC 2015;66:221

3. Hypothesis Women undergoing TAVR, compared to men, will have lower mortality rates at 1 year Women undergoing TAVR, compared to men, will have higher rates of major bleeding and vascular complications

4. Methods – Cohort Selection Database of 752 patients undergoing TAVR for severe, symptomatic AS at Washington Hospital Center (study and commercial patients) Includes both balloon-expandable and self- expanding valves In-hospital, 30 day and 1 year outcomes stratified by gender, access route, and valve type – Outcomes defined according to VARC 2

5. Methods - Statistics Categorical variables compared using Fisher’s exact test Continuous variables compared using Student t test Survival curves used Kaplan-Meier estimates and compared using log-rank test Multivariable Cox regression for mortality at 1 year

6. Results – Baseline Characteristics Female (n=382)Male (n=372)p value Caucasian81.3%88.0%0.02 African American15.6%9.0%0.009 Age83.5 ± 7.782.4 ± 7.70.049 Hypertension92.4%95.4%0.09 Diabetes mellitus31.1%35.4%0.22 COPD35.0%34.1%0.80 Current smoking0.3%3.9%0.002 Atrial fib/flutter36.5%46.0%0.01 GFR <60 or dialysis41.8%53.0%0.003 Hx CABG19.1%48.3%<0.001 Hx PCI24.9%36.9%<0.001 Hx MI13.9%23.8%<0.001 PVD28.4%41.9%<0.001

7. Results – Baseline Measurements Female (n=382)Male (n=372)p value STS score9.8 ± 4.68.0 ± 4.4<0.001 MLD Right6.7 ± 1.17.6 ± 1.3<0.001 MLD Left6.7 ± 1.17.6 ± 1.4<0.001 AVA (cm 2 )0.63 ± 0.130.70 ± 0.13<0.001 LVEF ≤40%16.2%30.1%<0.001 Mean AV gradient50.1 ± 13.344.9 ± 11.5<0.001 LVEDD (cm)4.20 ± 0.684.70 ± 0.75<0.001 LV septal thickness1.30 ± 0.221.35 ± 0.250.006 LVPW1.20 ± 0.201.25 ± 0.190.002 PASP45.6 ± 16.644.2 ± 15.50.31

8. Results – Procedural Characteristics Female (n=382)Male (n=372)p value Transfemoral76.2%82.0%0.052 Transapical19.3%16.4%0.30 Commercial34.3%36.9%0.46 Sapien46.9%43.7%0.38 Sapien XT21.6%17.1%0.12 CoreValve18.9%27.2%0.007 23 mm valve67.0%15.7%<0.001 26 mm20.1%50.9%<0.001 29 mm8.6%19.7%<0.001 31 mm1.1%12.5%<0.001 Post moderate or worse AR2.4%3.9%0.29 Post mean AV gradient12.6 ± 5.310.7 ± 4.4<0.001 Post AVA (cm 2 )1.43 ± 0.301.71 ± 0.550.29

9. 30 days: F 9.4% vs. M 5.4%, p=0.035 1 year: F 20.6% vs. M 21.5%, p=0.87 Mortality up to 1 Year post-TAVR: Female vs. Male

10. Mortality at 1 year post-TAVR by Gender and Access Overall p for trend=0.027

11. Mortality at 1 year post-TAVR by Gender and Access Overall p for trend=0.027 Women TF vs. Women TA: p=0.056

12. Mortality at 1 year post-TAVR by Gender and Access Overall p for trend=0.027 p= Women TF vs. Men TF: p=0.87

13. Mortality at 1 year post-TAVR by Gender and Access Overall p for trend=0.027 p= Women TF vs. Men TF: p=0.87 Women TA vs. Men TA: p=0.94 Men TF vs. Men TA: p=0.07

14. Mortality at 1 Year by Gender and Valve Type

15. Women SE vs. Women BE: p=0.62

16. Mortality at 1 Year by Gender and Valve Type Women SE vs. Men SE: p=0.84

17. Mortality at 1 Year by Gender and Valve Type Women BE vs. Men BE: p=0.23 Men SE vs. Men BE: p=0.03

18. In-Hospital Outcomes (VARC 2) p=0.02 p=0.06

19. Results – In-Hospital Bleeding and Vascular Complications Female (n=383)Male (n=372)p value Hb drop >128.1%7.6%0.83 Any transfusion43.7%29.0%<0.001 AV fistula0.6%0.3%1.0 Access site hematoma15.3%13.8%0.58 Pseudoaneurysm5.2%3.5%0.30 Retroperitoneal bleed5.5%2.6%0.06 Lower extremity ischemia2.2%1.3%0.40 Arterial perforation6.2%3.5%0.12 Arterial dissection8.0%2.9%0.004 Surgical repair access site8.4%3.6%0.01 Endovascular repair access site 12.1%6.5%0.02 Cardiac tamponade1.8%0.3%0.07

20. Results: Multivariable Logistic Regression for All-Cause Mortality at 30 Days Hazard Ratio95% CIp value Female1.560.89-2.750.12 Age (per 5 years)1.060.88-1.290.53 Chronic Renal Insufficiency1.580.91-2.760.11 Transfemoral Access0.350.20-0.60<0.0001

21. Results: Multivariable Cox Regression for All-Cause Mortality at 1 Year Hazard Ratio95% CIp value Female0.850.59-1.220.37 Transfemoral access0.630.42-0.950.027 Chronic renal insufficiency1.491.04-2.140.028 Age (per 5 years)1.000.89-1.120.97 Peripheral vascular disease1.030.71-1.500.89 History of myocardial infarction 1.220.80-1.880.36 LVEF ≤40%1.160.78-1.740.45 Self-expanding valve0.900.55-1.450.66

22. Mortality at 1 Year Among Patients with Stroke AliveDeadTotal Female11415 Male6915 p value for Fisher’s exact test = 0.14

23. Limitations No data regarding FEV1 (to assess severity of pulmonary disease) – known to be associated with mortality after TAVR Multivariable adjustment limited by number of events Retrospective registry with highly variable patient population, and evolving technology – Both very early and recent experience with TAVR

24. Conclusion Females have higher rates of short term (30 day) all- cause mortality after TAVR – Mortality rates at 1 year, however, are similar to males – Trend for higher mortality after stroke in male patients may contribute Females at higher risk for life-threatening bleeding and most vascular complications Unlike some previous studies, females did not have increased risk for stroke Significant trend for improved survival with transfemoral access, regardless of gender

25. Early Hazard of TAVR in Women Linked to higher rates of bleeding and vascular complications – Does hazard exist with smaller devices and improved strategies for mitigating access complications? Lower overall rates of major bleeding and vascular complications in meta-analysis by O’Connor et al – Rates of mortality at 30 days no different between men and women, better for women at 1 year Is long-term survival trend in women driven by lower burden of comorbidities, or TAVR itself?

26. Discussion Women overall have longer life expectancy than men – Does this account for similar survival despite higher complication rate? Women have higher STS scores despite having less comorbidities than men – Is STS score really valid in women undergoing TAVR? Women with AS have higher levels of interstitial fibrosis than men with AS, and more rapid reversal of LVH post AVR – Does LV respond differently to TAVR in women vs. men? If women have worse outcomes than men post SAVR, should TAVR be preferred in women?