Howard C. Herrmann, MD University of Pennsylvania Philadelphia Treating the Inoperable – Tools to Make a Decision on Who Will or Will Not Benefit from TAVR Howard C. Herrmann, MD University of Pennsylvania Philadelphia

Disclosure Statement of Financial Interest Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Institutional Grant/Research Support Abbott Vascular Edwards Lifesciences St. Jude Medical Medtronic Gore Bayer Boston Scientific Regado Biosci Corvia Cardiokinetx Univ Laval Claret Medical Consulting Fees/Honoraria Edwards Lifesciences Bayer Leerink Wells Fargo Major Stock Shareholder/Equity Microinterventional Devices Discussion may include unapproved and off-label devices, procedures, and indications

Treating the Inoperable – Tools to Make a Decision on Who Will or Will Not Benefit from TAVR Woody Allen I don’t want to achieve immortality through my work. I want to achieve it by not dying!

More Questions and Issues Than Answers Treating the Inoperable – Tools to Make a Decision on Who Still Benefits from TAVR More Questions and Issues Than Answers Do we know who doesn’t benefit from TAVR? Are there any tools that we can use to determine who doesn’t benefit from TAVR? Do these patients benefit more from SAVR? Are we comparing TAVR to TAVR w/o risk factor or TAVR to MM? What is the proper metric for outcome (survival or QOL)?

Do we know who doesn’t benefit from TAVR? All Cause Mortality (ITT) P1cohort B Crossover Patients Censored at Crossover Do we know who doesn’t benefit from TAVR? Standard Rx HR [95% CI] = 0.53 [0.41, 0.68] p (log rank) < 0.0001 TAVR 80.9% 68.0% 26.8% 50.8% 25.0% All Cause Mortality (%) 54.1% 20.1% 43.0% 30.7% Updated WNA to Oct 9 data Point-in-time at 2 yrs: p < 0.0001 Months Numbers at Risk Standard Rx 179 121 85 62 46 27 17 TAVR 138 124 110 101 88 70

Factors Associated with Poor Outcome NON-CARDIAC CARDIAC PROCEDURAL COPD CKD DM Prior CVA Liver disease Coagulopathy BMI Male Frailty Dementia Low EF Pul HTN Severe MR CAD AKI AR Stroke Vascular CPS Valve re-intervention Rodes-Cabau J Am Coll Cardiol. 2010;55:1080-1090 Moat NE J Am Coll Cardiol. 2011;58:2130-2138 Tamburino C Circulation. 2011;123:299-308 Thomas M Circulation. 2011;124:425-433 Green P JACC Cardiovasc Interv. 2012;5:974-981 Pilgrim T Circ Cardiovasc Interv. 2012;5:856-861 Rodes-Cabau Nat Rev Cardiol. 2012;9:15-29 Dewey TM Ann Thorac Surg. 2010;89:758-767 Beohar et al, TVT presentation, submitted

Frailty Assessment Components ADLs (Activities of Daily Living) 6/6 is normal (not Frail) Dress yourself unassisted Feed unassisted Ambulate unassisted Use the toilet (and clean) unassisted Bath Unassisted Do own hygiene unassisted Serum Albumin Level Normal range: 3.5 – 5.0 g/dL Grip Strength 5MWT (5 meter walk test) Men Cutoff for grip strength (Kg) BMI ≤ 24 ≤ 29 BMI 24.1 – 28 ≤ 30 BMI > 28 ≤ 32 Women Cutoff for grip strength (Kg) BMI ≤ 23 ≤ 17 BMI 23.1 – 26 ≤ 17.3 BMI 26.1 – 29 ≤ 18 BMI > 29 ≤ 21 Men Cutoff time to walk 15 ft. Height ≤ 173 cm ≥ 7 seconds Height > 173 cm ≥ 6 seconds Women Cutoff time to walk 15 ft. Height ≤ 159 cm ≥ 7 seconds Height > 159 cm ≥ 6 seconds

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). Death (%) 20 40 60 Time in Months 3 6 9 12 134 120 114 108 98 110 92 86 75 66 Number at risk: Frailty Score < 6 Frailty Score >= 6 P= 0.004 15.9% 32.7%

Patients with Chronic Lung Disease (CLD) Have Higher Mortality After TAVR (data from Partner and NCAR) Independent predictors of mortality: Short 6MWT* Oxygen dependency* Renal disease Lower BMI* Higher PAP* Lower AoV gradient * Included in the PBOSS score Dvir et al, JACC 2014;63:269-79

TAVR vs Std Therapy TAVR vs SAVR Cohort B: Cohort A: TAVR vs Std Therapy TAVR vs SAVR Dvir et al, JACC 2014;63:269-79

Dvir et al, JACC 2014;63:269-79

Survival After the Initial Diagnosis of Alzheimer Disease Larson et al, Ann Int Med 2004;140:501 Greta Rait et al. BMJ 2010;341:bmj.c3584 Dementia and TAVR Despite the high incidence of microemboli with TAVR, most studies have generally shown cognitive improvement or preservation! Rodes-Cabau et al, JACC TAVR made me smarter

Difficult to use binary risk factors as a litmus test TAVR NO TAVR

All-Cause Mortality Stratified by STS Score (ITT) Months STS < 5 STS 5-15 STS > 15 100% 55.9% 93.3% 73.7% 75.2% 93.4% p (log rank) = 0.0012 p (log rank) = 0.0002 p (log rank) = 0.0749 Standard Rx (n = 123) TAVR (n = 113) Standard Rx (n = 12) TAVR (n = 28) Standard Rx (n = 43) TAVR (n = 38)

Problems with the STS DataBase Voluntary data submission Operated patients only Morbidity also important Doesn’t include all risk factors: Porcelain Aorta Previous Mediastinal Radiation (Lymphoma) Multiple Previous Sternotomies With Open Grafts Advanced Liver Disease/ Cirrhosis Frailty/ Debility/ Immobility Dementia

ACC/AHA Guideline – Risk Levels

FRANCE 2: Risk Factors for TAVR Early Mortality 3,833 patients analyzed to develop, validate a risk score for 30-day and in-hospital mortality using patient-specific variables. . Data from 2,552 patients were used to identify predictive factors and develop the score; the rest provided validation Low BMI, critical state, respiratory insufficiency, transapical approach among most important predictors of early mortality Overall, score showed moderate discrimination with a c-index of 0.67 in the developmental cohort, 0.59 in validation cohort Implications: In prognostic scoring, low body mass, comorbidities contributed significantly to risk of 30-day mortality after TAVR. Iung B, et al. Heart. 2014;Epub ahead of print.

Case Presentation 74 yo with RHD 1996: s/p #23 SJM AVR 2013: OLT c/b renal failure 2014: recurrent ascites, pul htn, mitral stenosis redo MVR (#27 bio), TV repair Now, pleural mass -> bx HCC (metastatic) Referred for off-label TMVR with VIV Oncologist: “Median survival 24 mos, but hard to prognosticate beyond 6 mos at this time” “Why not just do it for symptomatic benefit?”

Poor outcome should include both a mortality and a QOL component Poor outcome was defined in 463 Partner patients as any of the following at 6 months after TAVR : Death (19%) KCCQ score <45 (≈NYHA Class IV) or Decrease ≥10 points in KCCQ score Poor outcome occurred in 35% 16% Circ Cardiovasc Qual Outcomes 2013;6:591-7

Overall, 62% alive with reasonable QOL 38% had poor 1-year outcome: Kansas City Cardiomyopathy Score –overall score (0-100, higher scores indicate less symptom burden and better QOL) Overall, 62% alive with reasonable QOL 38% had poor 1-year outcome: 19% mortality 17% persistent poor QOL (<50) 5% decline in score JAMA Cardiol. Published online February 01, 2017. doi:10.1001/jamacardio.2016.5302

Conclusions Mortality in extreme risk patients is high even after “successful” TAVR Societal/economic perspective (cost-effectiveness) Life expectancy ~3 years (cost per life-year gained = $50,000) Mortality alone may not be the best indicator of acceptable outcome (include QOL) – “TAVR only treats symptoms that are due to AS” Individual patient perspective No single risk factor is sufficient to identify futility or serve as a litmus test Combination of risk factors (STS and new TAVR scores) improve prediction, but have limitations and still may not be sufficient. Need to not only improve patient selection, but optimize post procedure care to get the best QOL possible in survivors The heart team approach is best suited to balancing patient risk, the role of evolving technology, and QOL. It may be the best reason we have for keeping the heart valve team intact in the future.