Giuseppe Tarantini MD, PhD Transcatheter Aortic Valve Implantation in Patients With Severe Left Ventricular Dysfunction Giuseppe Tarantini MD, PhD Assistant professor, Interventional cardiology unit Department of Cardiac, Thoracic and Vascular Sciences University of Padua

Background Current guidelines recommend surgical AVR in patients with severe aortic stenosis (SAS) symptomatic or asymptomatic with left ventricular dysfunction (LVD) (class I). Severe LVD is a predictor of increased surgical AVR risk leading to under treatment of these patients. Transcatheter aortic valve implantation (TAVI) is a promising therapy for patients considered inoperable (Partner cohort B) or at high surgical risk (Partner cohort A). However, few data are available on safety and efficacy of TAVI in patients with severe LVD.

Aim To assess early and mid-term outcomes of “real life” AS patients treated by TAVI with or without the presence of severe LVD in term of mortality, morbidity and LV function recovery.

Methods Study Sample and Study Design Study population: 384 inoperable/high risk patients with severe aortic stenosis treated by TAVI after HEART team screening Study design: Retrospective analysis of prospective registries Period of enrollment: June 2007  December 2010 Centers: - Cardiology Clinic - University of Padua - Italy - Scientific Institute San Raffaele – Milan – Italy Devices: Edwards Sapien/Sapien XT and CoreValve Revalving System Vascular approach: transfemoral (75%), transapical (17%), trans-subclavian (7%), transaortic (1%). Follow-up: 9 months (range 1-36 mos). Total TAVI population 384 pts GROUP A (50) LVEF ≤35% GROUP B (334) LVEF ≤35%

Methods Definitions Device success, cardiovascular mortality, myocardial infarction, stroke, life-threatening or disabling bleeding, and vascular complications were defined according to VARC definitions. Procedural success: device success without urgent cardiac surgery or intraprocedural death. Thirty-day mortality: included any death within 30 days from TAVI. In-hospital mortality: any death occurring during index hospitalization, even if the hospitalization length was longer than 30 days. Cumulative late mortality: overall mortality, including deaths within and after 30 days.

Baseline Characteristics Variables Total Sample n=384 Group A n=50 Group B n=334 P Value Male sex 185 (48) 29 (58) 156 (47) 0.14 Age, y, mean±SD 80±7 78±6 81±7 0.039 Body mass index, mean±SD 26.0±4.4 24.9±4.5 26.2±4.4 0.049 NYHA class III/IV 258 (67) 40 (80) 218 (65) Congestive heart failure 152 (40) 21 (42) 131 (39) 0.71 Diabetes 103 (27) 20 (40) 83 (25) 0.024 Previous myocardial infarction 95 (25) 19 (38) 76 (23) 0.020 Previous PCI 98 (26) 15 (30) 0.44 Previous CABG 77 (20) 62 (19) 0.060 Previous stroke 61 (16) 7 (14) 54 (16) 0.70 Chronic kidney disease 183 (48) 28 (56) 155 (46) 0.21 Dialysis 11 (3) 6 (12) 5 (2) <0.0001 Pulmonary insufficiency 132 (34) 18 (36) 114 (34) 0.80 Peripheral vasculopathy 92 (24) 13 (26) 79 (24) 0.72 Pacemaker 32 (8) 11 (22) 21 (6) Multivessels CAD 115 (30) 22 (44) 93 (28) Logistic euroSCORE (%), mean±SD 24.0±15.6 39.6±19.4 21.6±13.4 STS score (%), mean±SD 9.8±8.8 12.8±11.7 10.3±2.4 0.052

Baseline Echo Data Aortic mean gradient (mm Hg), 49.7±17.0 41.6±14.5 Variables Total Sample n=384 Group A n=50 Group B n=334 P Value LVEF (%), mean±SD 52.8±12.8 27.7±6.0 56.5±8.7 <0.0001 Aortic annulus (mm), mean±SD 22.7±2.0 23.3±2.0 22.6±1.9 0.041 AVA (cm2), mean±SD 0.75±0.48 0.71±0.21 0.76±0.51 0.50 AVA (cm2/m2), mean±SD 0.43±0.25 0.41±0.12 0.44±0.27 0.56 Aortic peak gradient (mm Hg), mean±SD 81.3±25.5 67.4±23.2 83.3±25.2 Aortic mean gradient (mm Hg), 49.7±17.0 41.6±14.5 50.9±17.0 <0.001 RVSP (mm Hg), mean±SD 41.9±13.7 48.3±15.2 40.9±13.2 0.001 Aortic regurgitation >2+/4 39 (10) 5 (10) 34 (10) 0.96 Mitral regurgitation >2+/4 23 (6) 18 (5) 0.20

Procedural Outcome CoreValve Edwards Valve 1790 (47) 205 (53) 28 (56) Variables Total Sample n=384 Group A n=50 Group B n=334 P Value CoreValve Edwards Valve 1790 (47) 205 (53) 28 (56) 22 (44) 151 (45) 183 (55) 0.2 Aortic regurgitation >2+/4 at the end of procedure 16 (4) 5 (10) 11 (3) 0.027 Coronary flow obstruction 1 (<1) 0 (0) 1.00 Device embolization 12 (3) 1 (2) 0.62 Conversion to surgery 8 (2) 7 (2) 0.97 Valve-in-valve 3 (6) 13 (4) 0.49 Tamponade 0.60 Aortic dissection 2 (<1) Vascular complications 86 (22) 11 (22) 75 (23) 0.94 Major vascular complications 47 (12) 42 (13) Major bleeding 35 (9) 7 (14) 28 (8) 0.20 Device success 344 (90) 41 (82) 303 (91) 0.060 Procedural success 339 (88) 298 (89) 0.14 Complete AV block 34/352 (10) 2/39 (5) 32/313 (10) Ventricular fibrillation 15 (4) 12 (4) 0.41

In Hospital Outcome and Events Variables Total Sample n=384 Group A n=50 Group B n=334 P Value Stroke 2 (<1) 0 (0) 1.00 Acute myocardial infarction 6 (2) 2 (4) 4 (1) 0.14 AKI requiring ultrafiltration 20/373 (5) 3/44 (7) 17/329 (5) 0.65 Sepsis 16 (4) 14 (4) Permanent pacemaker 63/352 (18) 10/39 (26) 53/313 (17) 0.18 30-d mortality 5 (10) 9 (3) 0.010 In hospital mortality 21 (6) 7 (14) 0.004 Hospital stay, d, 10.9±11.3 12.6±16.0 10.6±10.4 0.25 At 30 days 94% of patients in NYHA I/II (p<0.0001 versus baseline value).

Changes in LVEF in group A and group B Panel A shows the changes in left ventricular ejection fraction (LVEF) over time in group A and group B. Panel B shows the LVEF at the same temporal steps in patients with low-flow, low-gradient aortic stenosis (group A1: LVEF ≤35% and mean aortic gradient <40 mm Hg) and in those with low-flow, high-gradient aortic stenosis (group A2: LVEF ≤35% and mean aortic gradient ≥40mm Hg). Fraccaro C et al. Circ Cardiovasc Interv 2012;5:253-260 Copyright © American Heart Association

Changes in LVEF in AS pts with severe: LVD with low-gradient (A1) or high-gradient (A2) A1: LVEF ≤35%; mean Ao grad <40 mm Hg A2: LVEF ≤35%; mean Ao grad ≥40 mm Hg Panel A shows the changes in left ventricular ejection fraction (LVEF) over time in group A and group B. Panel B shows the LVEF at the same temporal steps in patients with low-flow, low-gradient aortic stenosis (group A1: LVEF ≤35% and mean aortic gradient <40 mm Hg) and in those with low-flow, high-gradient aortic stenosis (group A2: LVEF ≤35% and mean aortic gradient ≥40mm Hg). Fraccaro C et al. Circ Cardiovasc Interv 2012;5:253-260 Copyright © American Heart Association

1-year follow up (278 eligible pts) Group A Group B p All cause death 29% 12% 0.012 Cardiovascular death 10% 6% 0.434

Estimated total survival by Kaplan Meier according to basal left ventricular ejection fraction (group A, solid line; group B, dotted line). Estimated total survival by Kaplan Meier according to basal left ventricular ejection fraction (group A, solid line; group B, dotted line). Fraccaro C et al. Circ Cardiovasc Interv 2012;5:253-260 Copyright © American Heart Association

Independent predictors of cumulative late mortality Variable HR 95% CI p Congestive heart failure 2.69 1.64–4.40 <0.0001 Logistic euroSCORE 1.02 1.01–1.04 0.002 Moderate-to-severe periprosthetic leakage after TAVI 2.19 1.02– 4.67 0.043

Conclusions TAVI appear to be a safe and effective procedure, even in “real life” patients with severe LV dysfunction leading to procedural success rates with an acceptable rate of complications and 30-day mortality. TAVI leads to clinical improvement with a rapid partial recovery of their LV function. Although these results are encouraging, randomized trials data are needed to determine whether this therapeutic approach is able also to improve long-term survival rates in this subgroup of patients.

Study Limitations Small, non-randomized, retrospective analysis. Post-hoc analyses regarding low LVEF and/or low gradient are unpowered, therefore just hypothesis generating No systematic evaluation of contractile reserve in pts with low gradient. No “frailty index” was used, and it is possible that this may have affected the outcomes.

WHAT THE STUDY ADDS The presence of severe left ventricular dysfunction is not infrequent, being 13% of our TAVI treated population. Despite the fact that patients with left ventricular dysfunction were sicker and had more comorbidities, TAVI seems to be a safe and effective procedure providing a prompt and sustained improvement in clinical and left ventricular ejection function. The presence of severe left ventricular dysfunction is not to be considered a contraindication to TAVI.