Impact of Low-molecular-weight Heparin (Reviparin) on Mortality, Reinfarction, and Stroke in Patients with Acute MI

1. CREATE-ECLA - Reviparin Impact of Low-molecular-weight Heparin (Reviparin) on Mortality, Reinfarction, and Stroke in Patients with Acute MI Presented at: American Heart Association Scientific Sessions 2004 Presented by: Dr. S.D. Yusuf

2. CREATE-ECLA - Reviparin 15,570 acute MI patients presenting within 12 hours of symptom onset Enrolled exclusively in India and China 6% received PCI, 73% thrombolytic therapy (primarily streptokinase and urokinase) 97% Aspirin, 72% ACE inhibitors, 66% beta-blockers, 66% lipid-lowering therapy, 55% clopidogrel Also randomized to GIK or control – results presented separately • Reviparin • (low-molecular-weight heparin) • Subcutaneous injections for 7 days • Weight-adjusted doses: • <50 kg 3436 IU • 50-75 kg 5153 IU • >75 kg 6871 IU • n=7,780 Mean onset-to-treatment = 4.9 hr • Placebo • n=7,790 Mean onset-to-treatment = 4.8 hr Primary Endpoints: Death, MI, or stroke at 7 days; death, MI, stroke, or recurrent ischemia with ECG changes at 7 days. Secondary Endpoints: above endpoints at 30 days Presented at AHA 2004

3. CREATE-ECLA –Reviparin: 7-day results Death/MI/stroke and Death/MI/stroke/ischemia at 7 days • The primary composite endpoints of 7-day death/MI/stroke and death/MI/stroke/ischemia were significantly lower in the Reviparin group compared to the placebo group p=0.0039 p=0.0049 % Presented at AHA 2004

4. CREATE-ECLA –Reviparin 7-day results Treatment with Reviparin was associated with a significant reduction in the individual primary endpoints of death and recurrent MI at 7 days. The two treatments were not significantly different in the occurrence of stroke. p=0.0357 p=0.018 p= NS % Presented at AHA 2004

5. CREATE-ECLA –Reviparin: 30-day results Death/MI/stroke and Death/MI/stroke/ischemia at 30 days • The secondary composite endpoints of 30-day death/MI/stroke and death/MI/stroke/ischemia were significantly lower in the Reviparin group compared to the placebo group. • The individual endpoints of Death and MI were also significantly lower in the Reviparin group at 30 days. p=0.0016 p=0.0014 % Presented at AHA 2004

6. CREATE-ECLA –Reviparin: Safety Bleeding at 7 days p=<0.001 • Life-threatening bleeding and major bleeding and life-threatening bleeding alone at 7 days were both significantly higher with Reviparin compared with placebo p=<0.001 % Presented at AHA 2004

7. CREATE-ECLA –Reviparin: Summary • Among acute MI patients presenting within 12 hours of onset of symptoms, treatment with the low-molecular-weight heparin reviparin was associated with a significant reduction in the primary composite endpoints of 7-day death/MI/stroke and death/MI/stroke/ischemia compared with placebo. The results were maintained at 30-days • The reduced primary composite endpoints at both 7 and 30 days were due to lower individual endpoints of death and recurrent MI in the reviparin group; the two treatments were not significantly different in incidence of stroke • Small but significant increases in 7-day life-threatening bleeding/major bleeding and life-threatening bleeding alone occurred in the reviparin arm • There was a significant association between time-to-treatment and efficacy, with no effect seen in patients treated after 8 hours from symptom onset. • Treatment occurred entirely in India and China and differed from standard Western practice in several ways, including a reduced number of patients receiving primary PCI and reliance on thrombolytics not often used in the US (streptokinase and urokinase) • The study is the first large randomized trial to show a significant reduction in mortality with a low molecular weight heparinoid drug when given in addition to reperfusion therapy and aspirin in patients with acute MI • The ongoing EXTRACT trial is looking for a similar reduction in mortality in acute MI patients treated with another low-molecular-weight heparin, enoxaparin