ESC Congress 2009 Clinical Trial Summary Slides

AAA Trial design: Patients with no known CV disease, with an ABI ≤0.95, were randomized to enteric coated aspirin 100 mg daily or placebo. Patient follow-up was a mean of 8.2 years. Results Primary outcome (coronary event, stroke, revascularization) similar in aspirin and placebo arms (HR = 1.03, 95% CI 0.84-1.27) Mortality, stroke, MI rates similar Major bleeding requiring hospital admission higher in aspirin arm (2.0% vs. 1.2%, p = NS) (p = NS) (p = NS) 30 30 20 20 % Conclusions % 10.8 10.5 10.5 11.1 In patients without known CAD, with an ABI ≤0.95, no benefit noted with aspirin for primary prevention of vascular events; aspirin was associated with higher risk of bleeding Data on primary prevention of CAD with aspirin are conflicting - some studies (PHS) show a benefit, others (WHS, JPAD, AAA) show negative results 10 10 Primary endpoint All-cause mortality Aspirin (n = 1,675) Placebo (n = 1,675) Presented by Dr. Gary Fowkes at ESC 2009 2

Vascular death, MI, or stroke ACTIVE-I Trial design: Patients with AF were randomized in a double-blind manner to irbesartan titrated to 300 mg (n = 4,518) vs. placebo (n = 4,498). Mean follow-up: 4 years. Results (p = 0.85) Vascular death, MI, or stroke: 5.4% in each group Vascular death, MI, stroke, or hospitalization for HF: 7.3% vs. 7.7% (p = 0.12) Stroke: 2.1% vs. 2.3% Irbesartan resulted in less hospitalization due to HF (p = 0.018) or CV events (p = 0.003) (p = 0.21) % Conclusions Among patients with AF, treatment with irbesartan not associated with a reduction in composite endpoint Irbesartan resulted in less hospitalization due to HF or CV events Vascular death, MI, or stroke Stroke Irbesartan Placebo Presented by Dr. Salim Yusuf at ESC 2009 3

CURRENT OASIS 7 Trial design: Patients presenting with ACS were randomized in a 2 x 2 factorial design to either low-dose or high-dose aspirin, and standard-dose or high-dose clopidogrel. Patients were followed for 30 days. Results No difference in primary endpoint between aspirin arms; benefit noted in high-dose arm on high-dose clopidogrel (p = 0.04) No difference in primary endpoint between clopidogrel arms, but significant interaction with aspirin dose; benefit noted in high-dose arm undergoing PCI (p < 0.05) Major bleeding similar in both aspirin arms, but higher in high-dose clopidogrel arm (p = 0.01) (p = 0.76) (p = 0.37) 30 30 20 20 % % 10 10 4.4 4.2 4.4 4.2 Conclusions High-dose aspirin and high-dose clopidogrel associated with significant clinical benefit at 30 days in ACS patients; more in PCI subgroup Bleeding complications were higher with high-dose clopidogrel, but not with aspirin Important findings; likely to be in future guidelines Primary endpoint (CV death, MI, stroke) ASA 300-325 mg Standard-dose clopidogrel High-dose clopidogrel ASA 75-100 mg Presented by Dr. Shamir Mehta at ESC 2009 4

ISAR-TEST-4 Trial design: Patients with stable coronary disease or ACS were randomized to the biodegradable polymer DES (rapamycin-eluting; n = 1,299) vs. permanent polymer DES (sirolimus-eluting, n = 652 or everolimus-eluting, n = 652). Mean follow-up was 1 year. Results (p for non-inferiority = 0.005) Cardiac death, MI, or TLR at 12 months: 13.8% of the biodegradable polymer group vs. 14.4% of the permanent polymer group Cardiac death: 2.8% vs. 3.2% (p = 0.5) ARC definite/probable stent thrombosis: 1.0% vs. 1.5% (p = 0.29) (p = NS) % Conclusions Among patients with either stable coronary disease or ACS undergoing stent implantation, a biodegradable polymer DES was non-inferior to a permanent polymer-based DES Biodegradable polymer DES associated with similar frequency of the composite endpoint of cardiac death, MI, or TLR at 12 months Cardiac death, MI, or TLR at 12 months Cardiac death Biodegradable polymer group Permanent polymer group Byrne RA, et al. Eur Heart J 2009;Aug 30:[Epub] 5

KYOTO Trial design: Hypertensive Japanese patients with one or more CV risk factors were randomized to valsartan titrated to 160 mg daily (n = 1,517) vs. usual therapy without an ACE-I or an ARB (n = 1,514). Results BP at follow-up: 133/76 mm Hg in both groups Composite CV events: 5.5% with valsartan vs. 10.2% with usual therapy Stroke/TIA: 1.5% vs. 3% Angina: 1.5% vs. 2.9% (p = 0.01) New-onset DM: 5.2% vs. 7.7% (p = 0.028) (p < 0.001) (p = 0.015) % Conclusions Among hypertensive Japanese patients with additional CV risk factors, the use of valsartan beneficial Valsartan associated with a reduction in composite CV events, which was driven by fewer strokes/TIA and angina Composite CV events Stroke Valsartan Usual therapy Sawada T, et al. Eur Heart J 2009;Aug 31:[Epub] 6

MADIT-CRT Trial design: Patients with systolic CHF (LVEF ≤30%), QRS ≥120 ms, and NYHA class I or II symptoms were randomized to CRT-D or ICD alone. Patients were followed for a mean of 2 years. Results CRT-D associated with significant reduction in CHF events or death compared with ICD No difference in all-cause mortality Modest improvements noted in LVEF (p < 0.001) and echo LV volumes (p < 0.001) (p = 0.001) (p = 0.99) 100 10 80 7.3 6.8 60 Conclusions 5 % CRT-D was associated with improvement in clinical outcomes compared with ICD alone in patients with class I/II systolic CHF with wide QRS Design considerations, careful evaluation of cost-effectiveness preclude widespread applicability to all patients with systolic CHF and wide QRS; needs further study % 40 25.3 17.2 20 Death or CHF events All-cause mortality CRT-D (n = 1,089) ICD (n = 731) Moss AJ, et al. N Engl J Med 2009;Sep 1:[Epub] 7

NORDISTEMI Trial design: Patients treated with thrombolytic therapy for STEMI with a very long transfer time to a PCI hospital were randomized to immediate transfer for PCI or transfer for rescue PCI only. Patients were followed for 12 months. Results Death, MI, stroke, ischemia ↓ in immediate transfer arm at 30 days (p = 0.03), but not at 1 year (HR 0.72, 95% CI 0.4-1.2) Death, MI, stroke lower in immediate transfer arm at 1 year (15.9% vs. 6.0%, p = 0.01) Total bleeding at 30 days was similar between the two arms (13% vs. 14%) (p = 0.18) (p = 0.68) 30 30 27.3 20.9 20 20 14.0 % 13.0 % Conclusions 10 10 In patients with STEMI treated with thrombolytics at hospitals with very long transfer times for PCI, immediate transfer for PCI associated with better clinical outcomes, without an increase in bleeding Although transfer times in this trial were longer (median 130 minutes), results similar to DANAMI-2 and CARESS-in-AMI Primary endpoint at 1 year Total bleeding at 30 days Immediate transfer Rescue PCI only Presented by Dr. Sigrun Halvorsen at ESC 2009 8

PLATO Trial design: Patients presenting with ACS were randomized to ticagrelor (180 mg loading dose, 90 mg bid thereafter) or clopidogrel (300 mg loading dose, 75 mg daily thereafter). Patients were followed for 12 months. Results Death from vascular cause, MI, stroke lower in ticagrelor arm, including in patients undergoing PCI Mortality, stent thrombosis (p = 0.02) ↓ with ticagrelor; stroke rate similar (p = 0.22) No increase in fatal bleeding or overall major bleeding, but higher rate of non-CABG major bleeding (p = 0.03) (p < 0.001) (p < 0.001) 10 30 20 5.9 % 5 4.5 % 11.7 9.8 10 Conclusions Ticagrelor superior to clopidogrel for several outcomes including death, MI, and stent thrombosis in patients presenting with ACS Very promising results; reduction in CV mortality is particularly notable in the modern era of ACS Primary endpoint All-cause mortality Ticagrelor (n = 9,333) Clopidogrel (n = 9,291) Wallentin L, et al. N Engl J Med 2009;Aug 30:[Epub] 9

Death, re-infarction, stroke PRAGUE-7 Trial design: Patients with cardiogenic shock undergoing primary PCI were randomized to an upfront use of abciximab bolus followed by a 12-hour infusion (n = 40) vs. optional abciximab administration during PCI (n = 40). Primary follow-up was 30 days. Results (p = 0.24) PCI was technically successful: 90% with upfront abciximab vs. 88% with usual care Death, reinfarction, stroke, or new renal failure: 42% vs. 27% Death: 37% vs. 32% (p = 0.82) Stroke: 2.5% vs. 5% % (p = NS) Conclusions Among patients with cardiogenic shock undergoing primary PCI, routine upfront use of the GP IIb/IIIa inhibitor abciximab not superior to optional use Routine upfront abciximab resulted in similar incidence of death, reinfarction, stroke, or new renal failure by 30 days vs. standard therapy with optional abciximab Death, re-infarction, stroke Stroke Upfront abciximab Optional abciximab Presented by Dr. Petr Widimsky at ESC 2009 10

Dyspnea improvement at 24 & 48 hours Persistent renal impairment PROTECT Trial design: Patients with AHF were randomized in a double-blind manner to rolofylline 30 mg/day (n = 1,356) or placebo (n = 677). Treatment was administered as a 4-hour daily infusion and repeated for 3 days. Results (p = NS) Moderate or marked dyspnea improvement at 24 and 48 hours: 51.2% with rolofylline vs. 44.5% with placebo Death by 7 days: 1.7% vs. 2.1% HF readmission by 7 days: 0.4% vs. 0.6% Persistent renal impairment: 12.7% vs. 11.1% (p = NS) % Conclusions Among patients with acute heart failure, composite outcomes were similar with rolofylline vs. placebo Due to lack of efficacy, research on rolofylline has been discontinued by the study sponsor Dyspnea improvement at 24 & 48 hours Persistent renal impairment Rolofylline Placebo Presented by Dr. Marco Metra at ESC 2009 11

RE−LY Trial design: Patients with AF were randomized to either dabigatran 110 mg, 150 mg, or open-label warfarin. Patients were followed for a mean of 2 years. *Dabigatran 150 mg vs. warfarin; †Dabigatran 110 mg vs. warfarin Results (p <0.001*, p = 0.34†) (p = 0.31*, p = 0.03†) Dabigatran 150 mg superior to warfarin for stroke/systemic embolism; dabigatran 110 mg was non-inferior Stroke ↓ in dabigatran 150 mg arm (p < 0.001) Major bleeding was higher in warfarin arm compared with dabigatran 110 mg, but was similar to dabigatran 150 mg 10 10 %/year 5 %/year 5 Conclusions Dabigatran 150 mg superior to warfarin in reducing stroke or systemic embolism, with a similar bleeding profile. The 110 mg dose was non-inferior for efficacy, associated with lower bleeding compared with warfarin Could prove to be alternative to warfarin for chronic anticoagulation; further data are awaited 1.69 1.53 3.11 3.36 1.11 2.71 Stroke/systemic embolism Major bleeding Dabigatran 110 mg Dabigatran 150 mg Warfarin Connolly SJ, et al. N Engl J Med 2009;Aug 30:[Epub] 12

Primary efficacy endpoint SEPIA-ACS1 TIMI 42 Trial design: Patients with NSTE-ACS were randomized to direct factor Xa inhibitor otamixaban (0.035, 0.070, 0.105, 0.140, 0.175 mg/kg/h) or heparin plus eptifibatide (control). Patients were followed for a mean of 6 months. Results (p = 0.34) Primary efficacy endpoint (Death, MI, revascularization, bailout GP IIb/IIIa inhibitor use) similar in otamixaban and control arms Non-CABG TIMI major or minor bleeding was dose-related for otamixaban (p = 0.001 for trend) Overall TIMI major bleeding was similar 10 7.2 6.2 4.6 4.3 % 5 3.8 3.6 Conclusions Phase II dose ranging trial, which demonstrates that intermediate doses of otamixaban (0.105-0.140 mg/kg/h) are associated with best balance between safety and efficacy Further phase III trials are awaited Primary efficacy endpoint 0.035 0.070 0.105 0.140 0.175 Control Sabatine MS, et al. Lancet 2009;Aug 28:[Epub] 13

Death, reinfarction, or stroke TRIANA Trial design: STEMI patients ≥75 years of age were randomized to fibrinolytic therapy with TNK (n = 134) vs. primary angioplasty (n = 132). Primary follow-up was 30 days. Results Median time from symptoms to treatment: 195 minutes with fibrinolytic therapy vs. 245 minutes with primary angioplasty Death, reinfarction, or disabling stroke: 25.4% vs. 18.9% Death: 17.2% vs. 13.6% (p = 0.43) Stroke: 3.0% vs. 0.8% (p = 0.21) (p = 0.18) 25.4 % 18.9 Conclusions 3.0 In elderly STEMI patients, composite outcomes were similar with fibrinolysis vs. primary angioplasty Trial terminated early due to slow enrollment Composite and individual outcomes trended toward being reduced with primary angioplasty 0.8 Death, reinfarction, or stroke Stroke Primary angioplasty Fibrinolysis Presented by Dr. H. Bueno at ESC 2009 14