Holger Thiele, MD on behalf of the SOLVE-TAVI Investigators A 2x2 Randomized Trial of Self-Expandable vs Balloon-Expandable Valves and General vs Local Anesthesia in Patients Undergoing Transcatheter Aortic Valve Implantation Holger Thiele, MD on behalf of the SOLVE-TAVI Investigators

Disclosure Statement of Financial Interest I, Holger Thiele DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation.

Background I TAVR is developing as standard strategy for symptomatic patients with severe aortic stenosis at high to intermediate risk. TAVR device design led to relevant technical and clinical improvements (e.g. pacemaker rates, paravalvular leakage, vascular complications). There is limited evidence for direct valve comparisons (CHOICE, REPRISE III) in particular for latest generation valve designs. Abdel-Wahab et al. JAMA 2014;311:1503-1514 Feldman et al. JAMA. 2018;319:27-37 2

Background II – Anesthesia Strategy - In clinical routine TAVR is performed in ≈50% using general or local anesthesia with conscious sedation. Registry data suggest lower mortality lower morbidity shorter ICU and hospital stay shorter procedure times with local anesthesia. There is a lack of adequately powered randomized trials. Villablanca et al. Catheter Cardiovasc Interv. 2017;1–13 3

Symptomatic Aortic Stenosis with TAVR Indication SOLVE-TAVI Program Symptomatic Aortic Stenosis with TAVR Indication 1:1 CoreValve Evolut R Valve Strategy Edwards Sapien 3 1:1 Local Anesthesia General Anesthesia Anesthesia Strategy

Hypotheses I) Self-expanding CoreValve Evolut R is equivalent to balloon-expandable Sapien 3 (Edwards) valve II) Local anesthesia with conscious sedation is equivalent to general anesthesia in symptomatic aortic stenosis patients undergoing transfemoral TAVR.

Endpoints – Valve Strategy Primary Study Endpoint: 30-day composite of all-cause mortality, stroke, moderate or severe prosthetic valve regurgitation, and permanent pacemaker implantation. Secondary Study Endpoints: Individual components of the primary endpoint at 30 days, 6 and 12 months, 2 and 5 years Device success (VARC-2 criteria*) Early safety at 30 days (VARC-2 criteria*) Clinical efficacy at 30 days (VARC-2 criteria*) Time-related valve safety (VARC-2 criteria*) Cardiovascular mortality at 30 days, 6 and 12 months, 2 and 5 years Mean length of primary hospital stay Quality of life according to the EuroQuol-5 questionnaire (EQ-5D) at 30 days, 6 and 12 months, 2 and 5 years Device time Total procedural time *Kappetein et al. Eur Heart J 2012;33:2403–2418

Endpoints – Anesthesia Strategy Primary Study Endpoint: 30-day composite of all-cause mortality, stroke, myocardial infarction, infection requiring antibiotic treatment, and acute kidney injury. Secondary Study Endpoints: Individual components of the primary endpoint at 30 days, 6 and 12 months, 2 and 5 years Postinterventional occurrence of acute delirium assessed according to CAM-ICU criteria Device time Total procedural time Need and doses of vasopressors and inotropes Mean length of primary hospital stay Mean length of primary stay at the ICU Moderate or severe moderate or severe prosthetic valve regurgitation at 30 days Cardiovascular mortality at 30 days, 6 and 12 months, 2 and 5 years Quality of life according to the EQ-5D-questionnaire at 30 days, 6 and 12 months, 2 and 5 years

Methodology – Sample Size Valve Strategy - Equivalence Testing Postulated event rate for both valves 15% Lower limit - Upper limit + Equivalence zone -D +D -100 -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30 40 50 60 70 80 90 100 Anesthesia Strategy - Equivalence Testing Postulated event rate for both anesthesia strategies 13% Lower limit - Upper limit + Equivalence zone -D +D -100 -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30 40 50 60 70 80 90 100 Sample Size: Valve strategy: 2-sided test Chi2-test; power: 90%, α=0.05 for final analysis → 438 patients Anesthesia strategy: 2-sided test Chi2-test; power: 80%, α=0.05 for final analysis → 388 patients To compensate losses in follow-up → 444 patients

Investigator-initiated German multicenter trial; 1:1 randomization SOLVE-TAVI Trial Investigator-initiated German multicenter trial; 1:1 randomization Leipzig Berlin Rostock Kiel Lübeck Bremen Giessen PI: Holger Thiele Study Coordination: Suzanne de Waha-Thiele University Heart Center Lübeck: Thomas Kurz, Roza Meyer-Saraei Ingo Eitel, Matthias Heringlake Klinikum Links der Weser Bremen: Rainer Hambrecht, Harm Wienbergen Heart Center Leipzig: Hans-Josef Feistritzer, Steffen Desch Marcus Sandri, Mohamed Abdel-Wahab David Holzhey, Michael Borger Yvonne Rückert, Jörg Ender University of Giessen: Holger Nef, Oliver Dörr Charité Berlin: Alexander Lauten, Sascha Treskatsch University of Rostock: Hüseyin Ince, Mohamed Sherif University Schleswig-Holstein, Campus Kiel: Norbert Frey, Derk Frank Funding: CROs: 9

Study Flow Chart - Valve Strategy Primary endpoint analysis 447 randomized Allocation 225 randomized to Evolut R 4 withdrawal of informed consent 1 death prior to TAVI procedure 1 medical treatment (no aortic stenosis) 222 randomized to Sapien 3 2 withdrawal of informed consent 1 death prior to TAVI procedure Intervention 219 undergoing TAVI procedure 216 Evolut R as allocated 1 cross-over Sapien 3 1 conventional AVR 1 balloon valvuloplasty only 219 undergoing TAVI procedure 218 Sapien 3 as allocated 1 cross-over Corevalve Evolut R Follow-up 219 eligible for 30-day follow-up 2 missing data for primary endpoint 219 eligible for 30-day follow-up 1 withdrawal of informed consent 3 missing data for primary endpoint Primary endpoint analysis 217 primary endpoint analysis 215 primary endpoint analysis

Baseline Characteristics – Valve Strategy Evolut R (n=219) Sapien 3 Age (years); mean ±SD 81.7 ± 5.3 81.5 ± 5.7 Male sex; n/total (%) 105/219 (47.9) 109/219 (49.8) Risk scores STS score (%); mean ±SD 7.7 ± 7.2 7.6 ± 7.4 Log. EuroScore I (%), mean ±SD 18.4 ± 12.1 18.3 ± 13.1 EuroScore II (%), mean ±SD 6.1 ± 5.5 5.4 ± 4.9 Frailty; n/total (%) 93/216 (43.1) 80/217 (36.9) Peripheral arterial disease; n/total (%) 28/219 (12.8) 27/219 (12.3) Prior myocardial infarction; n/total (%) Prior PCI; n/total (%)  Prior CABG; n/total (%) Atrial fibrillation; n/total (%) Pacemaker/ICD; n/total (%) 19/219 (8.7) 84/219 (38.4) 26/219 (11.9) 103/219 (47.0) 24/218 (11.0) 22/219 (10.1) 79/219 (36.1) 18/219 (8.2) 93/219 (42.5) 23/219 (10.5) Prior stroke; n/total (%) 25/219 (11.4) 26/218 (11.9) Renal insufficiency; n/total (%) 177/216 (81.9) 184/214 (86.0) Pulmonary hypertension; n/total (%) 106/216 (49.1) 105/218 (48.2) COPD; n/total (%) 30/219 (13.7) 29/217 (13.4) Cardiovascular risk factors Diabetes; n/total (%) Arterial hypertension; n/total (%) HLP; n/total (%) Current smoking; n/total (%) 79/218 (36.2)  193/219 (88.1) 118/218 (54.1) 8/218 (3.7) 68/219 (31.1)  204/219 (93.2) 10/219 (4.6)

Treatment – Valve Strategy Characteristic Evolut R (n=219) Sapien 3 P Pre echo data AVA; cm2 AVA index; cm2/m2 Mean gradient; mmHg Peak gradient; mmHg TAPSE; mm LVEF >55%; n/total (%) LVEF 45-54%; n/total (%) LVEF 35-44%; n/total (%) LVEF <35%; n/total (%) 0.76 ± 0.19 0.41 ± 0.12 39.5 ± 14.4 63.9 ± 22.9 20.6 ± 4.6 114/203 (56.2) 56/203 (27.6) 21/203 (10.3) 12/203 (5.9) 0.77 ± 0.20 0.43 ± 0.12 64.2 ± 26.4 19.9 ± 5.7 114/201 (56.7) 52/201 (25.9) 16/201 (8.0) 19/201 (9.5) 0.60 0.39 0.52 0.37 0.49 Valve size 23 mm; n/total (%) 1/215 (0.5) 51/218 (23.4) 26 mm; n/total (%) 56/215 (26.2) 120/218 (55.1) 29 mm; n/total (%) 108/215 (50.2) 47/218 (21.6) 34 mm; n/total (%) 50/215 (23.3) Pre dilatation; n/total (%) 83/219 (37.9) 86/216 (39.8) 0.68 Post dilatation; n/total (%) 77/219 (35.2) 50/218 (22.9) 0.006 Recapturing; n/total (%) 55/204 (27.0) <0.001 Contrast agent, ml 119 ± 44 98 ± 33 Fluoroscopy time, min 14.2 ± 12.8 12.0 ± 6.1 0.02

Primary Endpoint – Valve Strategy All-cause mortality, stroke, moderate or severe prosthetic valve regurgitation, permanent pacemaker implantation at 30 days Rate difference -1.14 90%CI -8.15 – 5.87 Pequivalence=0.02 Psuperiority=0.83 27.2% 26.1% %

Endpoints – Valve Strategy Individual components primary endpoint % Pacemaker implantation Moderate/severe valve regurgitation Pequivalence<0.001 Psuperiority=0.77 2.8% 2.3% Pequivalence=0.003 Psuperiority=0.01 0.5% 4.7% Psuperiority>0.99 1.9% 1.4% Pequivalence=0.06 Psuperiority=0.34 22.9% 19.0% ■ Evolut R ■ Sapien 3

Secondary Endpoints – Valve Strategy Evolut R (n=219) Sapien 3 Rate difference Pequivalence Psuperiority Device time, min 63 ± 32 64 ± 43 0.80 Total procedural time, min 118 ± 48 117 ± 52 0.40 Cardiovascular mortality, n (%) 1/216 (0.5) 4/218 (1.8) 1.37 (-2.27 ─ 5.01) <0.001 0.37 Hospital stay, days 9 ± 7 0.97 VARC-2 criteria: Device success, n (%) 203/216 (94.0) 200/218 (91.7) -2.24 (-6.91 ─ 2.43) 0.002 0.46 Early safety, n (%) 24/217 (11.1) 33/219 (15.1) 4.01 (-1.57 ─ 9.59) 0.03 0.26 Clinical efficacy, n (%) 74/216 (34.3) 80/217 (36.9) 2.61 (-4.94 ─ 10.15) 0.05 0.61 Time-related safety, n (%) 41/217 (18.9) 58/219 (26.5) 7.59 (0.91-14.27) 0.27 0.07

Subgroup Analysis – Valve Strategy Primary Endpoint Event Rate difference P Value for Corevalve Evolut R Sapien 3 (90% CI) Interaction No. of patients with event/total no. (%) Sex Female 28/113 (24.8) 33/107 (30.8) 6.1 (-3.9 ─ 16.0) 0.08 Male 31/104 (29.8) 23/108 (21.3) -8.5 (-18.4 ─ 1.4) Age <80 years 18/69 (26.1) 16/73 (21.9) -4.2 (-16.0 ─ 7.7) 0.59 ≥80 years 41/148 (27.7) 40/142 (28.2) 0.5 (-8.2 ─ 9.2) Coronary artery disease Yes 34/126 (27.0) 34/115 (29.6) 2.6 (-7.0 ─ 12.2) 0.37 No 22/80 (27.5) 21/94 (22.3) -5.2 (-16.0 ─ 5.7) Frailty Mild 52/202 (25.7) 53/204 (26.0) 0.2 (-6.9 ─ 7.4) 0.99 Moderate 4/12 (33.3) 3/9 (33.3) 0.0 (-34.3 ─ 34.4) Chronic renal failure 49/175 (28.0) 46/182 (25.3) -2.7 (-10.4 ─ 5.0) 0.44 10/39 (25.6) 9/28 (32.1) 6.5 (-12.1 ─ 25.1) Left ventricular ejection fraction <35 % 3/12 (25.0) 4/19 (21.1) -4.0 (-30.1 ─ 22.2) 0.86 ≥35 % 52/189 (27.5) 47/179 (26.3) -1.3 (-8.9 ─ 6.4) Body mass index <25 kg/m² 25/69 (36.2) 22/76 (29.0) -7.3 (-20.1 ─ 5.5) 0.57 25-30 kg/m² 20/95 (21.1) 22/90 (24.4) 3.4 (-6.8 ─ 13.6) ≥30 kg/m² 13/52 (25.0) 12/49 (24.5) -0.5 (-14.7 ─ 13.7) STS score <10% 43/149 (28.9) 36/157 (22.9) -5.9 (-14.2 ─ 2.3) 0.02 ≥10% 9/49 (18.4) 18/50 (36.0) 17.6 (2.8 ─ 32.5) Logistic EuroScore <20% 36/142 (25.4) 33/141(23.4) -2.0 (-10.4 ─ 6.5) 0.71 ≥20% 22/74 (29.7) 23/74 (31.1) 1.4 (-11.1 ─ 13.8) Aortic stenosis Normal flow, high gradient 23/98 (23.5) 0.0 (-10.0 ─ 10.0) 0.29 Low flow, low gradient 19/50 (38.0) 13/50 (26.0) - 12.0 (-27.4 ─ 3.4) Paradoxical low flow low gradient 7/32 (21.9) 13/41 (31.7) 9.8 (-7.8 ─ 27.4) ScO2 prior to intervention <50% 42/158 (26.6) 45/165 (27.3) 0.7 (-7.5 ─ 8.8) 1.00 ≥50% 5/15 (33.3) 0.0 (-30.2 ─ 30.2) Mode of anesthesia General anesthesia 32/111 (28.8) 22/107 (20.6) -8.3 (-18.0 ─ 1.5) 0.09 Local anesthesia 27/106 (25.5) 34/108 (31.5) 6.0 (-4.2 ─ 16.2) Equivalence margin Corevalve Evolut R better -20 -15 -10 -5 5 10 15 20 Sapien 3 better

Study Flow Chart - Anesthesia Strategy 222 randomized to local anesthesia 3 withdrawal of informed consent 1 death prior to TAVI procedure 447 randomized 225 randomized to general anesthesia 1 medical treatment (no aortic stenosis) 218 undergoing TAVI procedure 217 local anesthesia 13 bailout general anesthesia 1 elective cross over general anesthesia 220 undergoing TAVI procedure 219 general anesthesia 1 elective cross-over to local anesthesia 218 eligible for 30-day follow-up 1 withdrawal of informed consent 2 missing data for primary endpoint 220 eligible for 30-day follow-up 215 primary endpoint analysis 220 primary endpoint analysis Intervention Follow-up Primary endpoint analysis Allocation

Baseline Characteristics – Anesthesia Strategy Local Anesthesia (n=218) General Anesthesia (n=220) Age (years); mean ±SD 81.8 ± 5.3 81.4 ± 5.7 Male sex; n/total (%) 107/218 (49.1) 107/220 (48.6) Risk scores STS score (%); mean ±SD 6.9 ± 6.2 8.3 ± 8.2 Log. EuroScore I (%), mean ±SD 17.8 ± 12.6 18.9 ± 12.5 EuroScore II (%), mean ±SD 5.5 ± 4.8 6.0 ± 5.6 Frailty; n/total (%) 91/214 (42.5) 82/219 (37.4) Peripheral arterial disease; n/total (%) 29/218 (13.3) 26/220 (11.8) Prior myocardial infarction; n/total (%) Prior PCI; n/total (%)  Prior CABG; n/total (%) Atrial fibrillation; n/total (%) Pacemaker/ICD; n/total (%) 24/218 (11.0) 92/218 (42.2) 22/218 (10.1) 98/218 (45.0) 13/218 (6.0) 17/220 (7.7) 71/220 (32.3) 22/220 (10.0) 98/220 (44.6) 20/220 (9.1) Prior stroke; n/total (%) 24/217 (11.1) 27/220 (12.3) Renal insufficiency; n/total (%) 179/213 (84.0) 182/217 (83.9) Pulmonary hypertension; n/total (%) 100/216 (46.3) 111/218 (50.9) COPD; n/total (%) 27/216 (12.5) 32/220 (14.6) Cardiovascular risk factors Diabetes; n/total (%) Arterial hypertension; n/total (%) HLP; n/total (%) Current smoking; n/total (%) 70/218 (32.1)  199/218 (91.3) 92/216 (42.6) 9/218 (4.1) 77/219 (35.2)  198/220 (90.0) 88/219 (40.2) 9/219 (4.1)

Treatment – Anesthesia Strategy Characteristic Local Anesthesia (n=218) General Anesthesia (n=220) P O2 saturation at start of anesthesia; % 92.7 ± 25.0 91.6 ± 27.3 0.08 Minimal O2 saturation during anesthesia; % 88.0 ± 27.4 93.3 ± 21.8 <0.001 O2 saturation at end of anesthesia; % 83.2 ± 36.7 81.9 ± 38.2 0.42 Conversion to general anesthesia Agitation; ; n/total (%) Emergency surgery; n/total (%) Respiratory insufficiency; n/total (%) Hemodynamic reasons; n/total (%) 13/218 (5.9) 3/13 (23.1) 5/13 (38.5) 2/13 (15.4) Transesophageal echocardiography; n/total (%) 8/210 (3.8) 73/217 (33.6) Anesthesia medication Remifentanyl; n/total (%) Propofol; n/total (%) Dexmedetomidine; n/total (%) Sufentanyl; n/total (%) Fentanyl; n/total (%) Piritramide; n/total (%) Other non-benzodiazepine drugs; n/total (%) 18/218 (8.3) 56/218 (25.7) 111/218 (50.9) 63/218 (28.9) 13/218 (6.0) 7/218 (3.2) 213/220 (96.8) 198/220 (90.0) 3/220 (1.4) 7/220 (3.2) 9/220 (4.1) 6/220 (2.7) 0.39 0.79 Zahlen bei agitation und emergency.

Primary Endpoint – Anesthesia Strategy All-cause mortality, stroke, myocardial infarction, infection requiring antibiotic treatment, acute kidney injury at 30 days Rate difference -1.52 90%CI -8.47 – 5.42 Pequivalence=0.02 Psuperiority=0.74 27.0% 25.5% %

Endpoints – Anesthesia Strategy Individual components primary endpoint % ■ Local anesthesia ■ General anesthesia Pequivalence=0.005 Psuperiority>0.99 21.0% 21.0% Pequivalence<0.001 Psuperiority>0.99 Pequivalence<0.001 Psuperiority=0.77 Pequivalence=0.002 Psuperiority>0.99 Pequivalence<0.001 Psuperiority>0.99 8.9% 9.2% 2.8% 2.3% 2.4% 2.8% 0.5% 0.5% Myocardial infarction Infection requiring antibiotics Acute kidney injury

Secondary Endpoints – Anesthesia Strategy Local Anesthesia (n=218) General Anesthesia (n=220) Rate difference Pequivalence Psuperiority Cardiovascular mortality, n (%) 2/214 (0.9) 3/220 (1.4) 0.43 (-3.16 ─ 4.02) <0.001 >0.99 Moderate/severe valve 4/209 (1.9) 3/212 (1.4) -0.5 (-4.20 ─ 3.20) 0.72 Delirium, n (%) 28/211 (13.3) 32/215 (14.9) 1.61 (-4.13 ─ 7.36) 0.007 0.68 Device time, min 61 ± 27 65 ± 45 0.76 Total procedural time, min 116 ± 50 119 ± 49 0.43 Need for catecholamines, n (%) 137/218 (62.8) 214/220 (97.3) 34.43 (27.84 ─41.02) 1.00 Hospital stay, days 9 ± 7 0.74 ICU stay, hours 51 ± 84 47 ± 65 0.59 regurgitation, n (%)

Subgroup Analysis – Anesthesia Strategy Primary Endpoint Event Rate difference P Value for Local anesthesia General anesthesia 3 (90% CI) Interaction No. of patients with event/total no. (%) Sex Female 30/109 (27.5) 32/113 (28.3) 0.8 (-9.1 ─ 10.7) 0.56 Male 28/106 (26.4) -4.0 (-13.7 ─ 5.8) Age <80 years 19/71 (26.8) 13/72 (18.1) -8.7 (-20.3 ─ 2.9) 0.21 ≥80 years 39/144 (27.1) 43/148 (29.1) 2.0 (-6.7 ─ 10.6) Coronary artery disease Yes 36/124 (29.0) 33/118 (28.0) -1.1 (-10.6 ─ 8.5) 0.89 No 20/80 (25.0) 22/96 (22.9) -2.1 (-12.8 ─ 8.7) Frailty Mild 53/201 (26.4) 49/208 (23.6) -2.8 (-9.9 ─ 4.2) 0.20 Moderate 3/10 (30.0) 6/11 (54.6) 24.6 (-10.9 ─ 60.0) Chronic renal failure 54/176 (30.7) 50/182 (27.5) -3.2 (-11.1 ─ 4.7) 0.41 4/34 (11.8) 6/35 (17.1) 5.4 (-9.2 ─ 20.0) Left ventricular ejection fraction <35 % 5/15 (33.3) 3/16 (18.8) -14.6 (-40.6 ─ 11.5) 0.37 ≥35 % 48/186 (25.8) 48/185 (26.0) 0.1 (-7.4 ─ 7.6) Body mass index <25 kg/m² 22/78 (28.2) 20/68 (29.4) 1.2 (-11.2 ─ 13.6) 25-30 kg/m² 22/87 (25.3) 22/100 (22.0) -3.3 (-13.6 ─ 7.0) ≥30 kg/m² 14/50 (28.0) 14/51 (27.5) -0.6 (-15.2 ─ 14.1) STS score <10% 44/159 (27.7) 37/150 (24.7) -3.0 (-11.3 ─ 5.3) 0.97 ≥10% 13/42 (31.0) 16/57 (28.1) -2.9 (-18.3 ─ 12.5) Logistic EuroScore <20% 37/147 (25.1) 32/138 (23.2) -2.0 (-10.4 ─ 6.4) 0.91 ≥20% 21/68 (30.9) 24/81 (29.6) -1.3 (-13.7 ─ 11.2) Aortic stenosis Normal-flow, high-gradient 30/85 (31.6) 27/103 (26.2) -5.4 (-16.0 ─ 5.2) 0.71 Low-flow, low-gradient 15/49 (30.6) 15/51 (29.4) -1.2 (-16.3 ─ 13.9) Paradoxical low-flow, low-gradient 7/38 (18.4) 8/35 (22.9) 4.4 (-11.3 ─ 20.1) ScO2 prior to intervention <50% 49/167 (29.3) 41/159 (25.8) -3.6 (-11.7 ─ 4.6) 0.87 ≥50% 3/10 (30) 4/17 (23.5) -6.5 (-36.0 ─23.0) Type of valve Sapien 3 28/110 (25.5) 25/108 (23.2) -2.3 (-11.9 ─ 7.3) 0.85 Corevalve Evolut R 30/105 (28.6) 31/112 (27.7) -0.9 (-11.0 ─ 9.2) Equivalence margin General anesthesia better -20 -15 -10 -5 5 10 15 20 Local anesthesia better

Summary and Conclusions I In patients with symptomatic aortic stenosis undergoing transfemoral TAVR the self-expanding Corevalve Evolut R valve is equivalent to the balloon-expandable Edwards Sapien 3 with respect to the composite of all-cause mortality, stroke, moderate or severe prosthetic valve regurgitation, and permanent pacemaker implantation at 30 days. The rate of relevant valve regurgitation was low whereas permanent pacemaker rates are still relatively high. There may be a higher stroke rate with the balloon-expandable valve.

Summary and Conclusions II Local anesthesia with conscious sedation is equivalent to general anesthesia with respect to the composite of all-cause mortality, stroke, myocardial infarction, infection requiring antibiotic treatment, and acute kidney injury. General anesthesia is associated with a higher rate of catecholamine use but does not affect procedure times, valve-related outcome, or clinical outcome.

Acknowledgement and Thank You SOLVE-TAVI Patients and Investigators Steering Committee Holger Thiele, MD (Chair) Steffen Desch, MD Suzanne de Waha-Thiele, MD Thomas Kurz, MD Holger Nef, MD Rainer Hambrecht, MD Norbert Frey, MD Alexander Lauten, MD Hüseyin Ince, MD Michael Borger, MD David Holzhey, MD Matthias Heringlake, MD Jörg Ender, MD DSMB Gerhard Schuler, MD Steffen Schneider, PhD Bernd Böttiger, MD Funding German Heart Research Foundation Echo Core lab Heart Center Leipzig:: Georg Stachel, MD Suzanne de Waha-Thiele, MD CRO Leipzig Heart Institute: Yvonne Rückert Anne-Kathrin Funkat, PhD Ina Wagner IMBS Lübeck Inke König, PhD Reinhard Vonthein, PhD Jördis Stolpmann ZKS Lübeck: Arne Schreiber, PhD Alicia Illen