Clinical Trial Commentary

1. Clinical Trial Commentary MUSTT PACT Dr Eric Topol Chairman and Professor, Department of Cardiology Director of the Joseph J Jacobs Center for Thrombosis and Vascular Biology at the Cleveland Clinic Dr Robert Califf Professor of Cardiology Associate Vice Chancellor for Clinical Research at Duke University

2. PACT trial Ross AM, et al. J Amer Coll Cardiol 1999;34:1954-1962

3. PACT trial Reperfusion and LV function: rtPA vs placebo Ross AM, et al. J Amer Coll Cardiol 1999;34:1954-1962

4. PACT trial Adverse clinical outcomes: rtPA vs placebo Ross AM, et al. J Amer Coll Cardiol 1999;34:1954-1962

5. PACT trial “The bottom line is that the combination therapy did not improve LV function or change outcome…Enhancing reperfusion by 10, 15, or 20 minutes hasn’t proven to be an added benefit. So why would you adopt that type of therapy?” Dr Cindy Grines William Beaumont Hospital, Detroit PACT trial ignites clash of opinions… heartwire. theheart.org. December 2, 1999.

6. MUSTT trial eligibility criteria • EF < 40% • CAD • spontaneous nonsustained ventricular tachycardia (VT-NS) • Eligible patients randomized to • electrophysiologic (EP)-guided • antiarrhythmic therapy • no antiarrhythmic therapy Buxton AE, et al. N Engl J Med 1999;341:1882-1890

7. MUSTT:protocol Electrophysiologic studies Registry (n=1435) sustained VT not inducible Randomization(n=704) sustained VT inducible Conservative therapy (n=353) ACE-inhibitors and beta-blockers EP-guided therapy (n=351) ACE-inhibitors and beta-blockers Buxton AE, et al. N Engl J Med 1999;341:1882-1890

8. MUSTT results • EP guided therapy showed a reduction in primary endpoints • 27% reduction in arrhythmic death and cardiac arrest • trend toward overall reduction in mortality (20% risk reduction) • entire benefit derived from EP-guided therapy was due to treatment with implantable defibrillators Buxton AE, et al. N Engl J Med 1999;341:1882-1890

9. MUSTT and implantable defibrillators Benefit was derived from implantable defibrillators, however: • trial was not designed to test efficacy of ICD therapy • patients were not randomized to receive ICD implantation • ICD was only undertaken after patients failed antiarrhythmic drug therapy A second look at the Multicenter UnSustained Tachycardia Trial (MUSTT). Clinical trials. theheart.org. December 7, 1999.

10. Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT): randomization Control group Heart failure Rx Blinded placebo Amiodarone group Heart failure Rx Blinded amiodarone ICD group Heart failure Rx Single-lead, pectoral ICD

11. SCD-HeFT eligibility criteria • EF < 35% • CHF treatment with ACE-I > 3 months • NYHA II and III, ischemic or nonischemic • Age > 18 years • projected enrollment 2 500 • minimum 2.5 year follow-up

12. SCD-HeFT endpoints • Primary endpoint: • overall mortality • Secondary endpoints: • arrhythmic vs nonarrhythmic cardiac mortality • comparison of morbidity • comparison of quality of life • analysis of cost effectiveness • categorizing arrhythmias in ICD arm

13. MUSTT trial “…it is an implantable device. But if we had these results in a study looking at aspirin, do you really think we'd be sitting here arguing over would I withhold aspirin therapy from a defined sub-risk group…what we're really talking about here is economics, that's the bottom line.” Dr Eric Prystowski St Vincent Hospital A second look at the Multicenter UnSustained Tachycardia Trial (MUSTT). Clinical trials. theheart.org. December 7, 1999.

14. CABG Patch trial eligibility criteria • EF < 36% • scheduled for CABG • abnormalities on signal averaged ECG’s • Age < 80 years • patients (n=900) randomly assigned to ICD vs control • average follow-up 32 + 16 months Bigger J, et al. New Engl J Med 1997;337:1569-75.

15. CABG Patch results Mortality by treatment arm in the CABG Patch trial Bigger J, et al. New Engl J Med 1997;337:1569-75.