1. ACC 2015 | San Diego, CA | March 14-16 2015 Relation Between Frailty and Outcomes After Transcatheter Aortic Valve Replacement Philip Green, MD Columbia University on behalf of The PARTNER Trial Investigators and The PARTNER Publications Office From the PARTNER Trial

2. Background TAVR is a worthwhile treatment for symptomatic severe AS patients who cannot have surgery (inoperable/extreme risk) or are at high-risk for surgeryTAVR is a worthwhile treatment for symptomatic severe AS patients who cannot have surgery (inoperable/extreme risk) or are at high-risk for surgery However, after TAVR, the intermediate and long- term (thru 5 years) mortality is still high (>50%)However, after TAVR, the intermediate and long- term (thru 5 years) mortality is still high (>50%) Therefore, improving patient selection for TAVR is an important priorityTherefore, improving patient selection for TAVR is an important priority

3. Frailty A syndrome of impaired physiologic reserve and decreased resistance to stressors which is associated with a poor prognosis…A syndrome of impaired physiologic reserve and decreased resistance to stressors which is associated with a poor prognosis…  In the general population  In the elderly with CAD  In the elderly after general or cardiac surgery  After TAVR (small single center studies)

4. Physical Frailty Cardiovascular Health Study Self Reported Unintentional 10 pound weight loss Subjective exhaustion Low physical activity (survey estimated Kcal per week) Objective Measures Low grip strength Lowest 20% population BMI and gender based cut point Slow walking / gait speed Lowest 20% population Height and gender based cut point Fried LP, J Gerontol A Biol Sci Med Sci. 2001 Mar;56(3):M146

5. Objective To evaluate the prognostic value of frailty among older adults who received TAVR in the PARTNER TrialTo evaluate the prognostic value of frailty among older adults who received TAVR in the PARTNER Trial We hypothesized that frail patients who undergo TAVR would experience:We hypothesized that frail patients who undergo TAVR would experience:  increased mortality  a higher likelihood of poor clinical outcomes

6. Methods All patients in PARTNER (cohorts A & B) randomized to TAVR and who received baseline frailty assessmentAll patients in PARTNER (cohorts A & B) randomized to TAVR and who received baseline frailty assessment High enrolling sites who performed objective frailty assessment prior to TAVR in consecutive patientsHigh enrolling sites who performed objective frailty assessment prior to TAVR in consecutive patients  Baylor Healthcare System, Dallas, TX (n=35)  Mayo Clinic, Rochester, MN (n=83)  Columbia University, New York, NY (n=126)

7. Primary Predictor Frailty Score Frailty DomainMeasureFrailty Score Slowness15 foot walk gait speed (m/s)Quartiles (0-3) WeaknessGrip strength (kg)Gender based quartiles (0-3) Wasting and malnutrition Serum albumin (g/dl)Quartiles (0-3) InactivityKatz ADLs (dress, bath, transfer, feed, toilet, continence) Any dependence=3, Independence=0 Score range 0-12 12 = most frail 0 = least frail Green, Am Coll Cardiol Intv. 2012;5(9):974

8. Outcomes 1 year death from any cause Poor outcome (Arnold et al)   Considers mortality and quality of life   Success is defined as alive with acceptable or improved QOL   Poor outcome is defined as dead or with significant reduction in QOL (KCCQ reduced by 10 ~ 1 NYHA functional class) or KCCQ < 40 (class IV CHF) Arnold SV. Circ Cardiovasc Qual Outcomes. 2013 Sep 1;6(5):591 Arnold SV. Circulation. 2014 Jun 24;129(25):2682

9. Poor Outcome Arnold SV. Circ Cardiovasc Qual Outcomes. 2013 Sep 1;6(5):591

10. Baseline Frailty Markers Non-frail (n=134) Score >= 6 Frail (n=110) Score < 6 Independent in ADLs134 (100%)38 (35%) Albumin, g/dL median (IQR)4.1 [3.8, 4.4]3.7 [3.4, 4.0] Gait speed, m/s median (IQR)0.51 [0.30, 0.76]0.27 [0.00, 0.45] Grip strength, kg (men) median (IQR)27.0 [21.3, 31.7]18.7 [13.2, 23.2] Grip strength kg (women) median (IQR)14.0 [10.9, 16.9]11.0 [9.0, 14.0]

11. Baseline characteristics (1) VariableNon-frail (n = 134)Frail (n = 110)p-value Age (yrs)85.4 [79.4, 89.5]87.1 [82.7, 90.3]0.11 Male gender55%47%0.22 Body mass index (kg/m2)25.8 [22.2, 29.6]24.8 [21.9, 28.3]0.46 Transfemoral TAVR46%52%0.39 STS Score (%)10.5 [8.8, 12.4]11.3 [9.6, 13.8]0.07 NYHA Class IV27%29%0.7 6-Minute Walk Test Could Not Perform17%35%0.002 Total Distance Walked (m)*192 [122, 297]146 [77, 238]0.01 11

12. Baseline characteristics (2) VariableNon-frail (n = 134)Frail (n = 110)p-value Diabetes mellitus32%26%0.26 CAD85%83%0.62 Peripheral vascular disease 41%42%0.89 Renal disease14% 0.9 Liver disease2%8%0.03 COPD43%42%0.91 AV area (cm2)0.63 [0.50, 0.83]0.62 [0.51, 0.72]0.2 12

13. 30 day outcomes Non-Frail (n=134)Frail (n=110)p-value Death Any cause8%10%0.49 Cardiovascular cause6%7%0.68 Repeat hospitalization*7%4%0.29 Major stroke2%1%0.68 Major bleeding5%9%0.24 Major vascular complications 5%6%0.51 Permanent pacemaker9% 0.97 Renal failure (dialysis required) 5%8%0.36 *Due to aortic stenosis or complications of the valve procedure.

14. Kaplan-Meier Survival Estimates Stratified by Frailty Score After adjusting for important clinical and demographic characteristics, frailty remained independently associated with… 2.5-fold increased hazard of 1-year mortality after TAVR (95% CI 1.40-4.35, p=0.002).

15. Poor Clinical Outcome Dead, decrease in KCCQ > 10, or KCCQ 10, or KCCQ < 40 OR 2.2 (1.1 - 4.5) p = 0.03 15 OR 2.4 (1.1 - 5.1) p = 0.02

16. Poor Clinical Outcome Separating death and Poor QOL (KCCQ 10) 6 months 16 12 months P=0.13

17. Markers of Frailty and Mortality at 1 year 17 VariableHR (95% CI)p-value Gait speed (m/s)*1.37 [0.53-3.45]0.51 Grip strength (kg)*1.02 [0.99-1.05]0.28 Albumin (g/dL)*1.25 [0.88-1.79]0.21 Any ADL limitation1.59 [0.93, 2.70]0.09 Score (continuous)*1.12 [1.02, 1.22]0.01 Score (≥ 6 versus < 6)2.18 [1.27, 3.75]0.005 * Hazard ratio is per unit decrease

18. Limitations Secondary analysis of a subgroup from the PARTNER randomized trials Frailty composite in this analysis is a departure from well established epidemiologic definitions of frailty Very early TAVR experience with first generation device and patients at highest risk for poor outcomes No surgical or standard therapy comparisons

19. Conclusion Frailty as assessed by a composite of gait speed, grip strength, ADLs, and serum albumin is not associated with adverse 30-day outcomes, but is associated with increased mortality and a higher rate of poor clinical outcomes 1 year after TAVR. Frailty measurement is an essential component of the risk assessment in older adults considering therapy for AS

20. Thank you to the dedicated study teams at all the PARTNER Sites! Special thanks to the participants in this writing group Suzanne Arnold David J Cohen Ajay Kirtane Susheel Kodali David Brown Charanjit Rihal Ke Xu Yang Lei Marian Hawkey Rebeca Kim Maria Alu Martin Leon Michael Mack

22. Supplemental Material

23. Poor Outcome At 6-months after TAVR: occurred in 41.9% of frail participants and 27.6% of non-frail participants. – –unadjusted OR for frailty 1.89, 95% CI 1.03-3.46, p=0.04 – –After multivariable adjustment OR 2.21, 95% CI 1.09-4.46, p = 0.03 At 12 months, a poor outcome occurred in 50.0% of frail participants and 31.5% of non-frail participants – –unadjusted OR for frailty 2.17, 95% CI 1.16-4.07, p=0.02). – –After multivariable adjustment year OR 2.40, 95% CI 1.14- 5.05, p = 0.02