PACT Clinical Trial Commentary 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 MUSTT

Plasminogen-activator Angioplasty Compatibility Trial  multicenter, randomized, double-blind trial  606 AMI patients  < 75 years old, low-risk infarctions  50 mg IV bolus of rtPA vs placebo  followed by rescue PTCA if TIMI-3 flow not immediately achieved PACT trial Ross AM, et al. J Amer Coll Cardiol 1999;34:

Reperfusion and LV function: rtPA vs placebo rtPA (n=302) Placebo (n=304) Frequency of TIMI-3 flow immediately following drug treatment 33%15% LVEF immediately following drug treatment 59.4%± %± Frequency of TIMI-3 flow achieved following rescue PTCA 78.6% % 4 1 ventriculograms available for analysis for only 220 patients 2 ventriculograms available for analysis for only 224 patients 3 in 169 patients with TIMI 0, 1, or 2 flow following drug treatment 4 in 231 patients with TIMI 0, 1, or 2 flow following drug treatment PACT trial Ross AM, et al. J Amer Coll Cardiol 1999;34:

Adverse clinical outcomes: rtPA vs placebo rtPA (n=302) Placebo (n=304) Recurrent ischemia*17.9%13.5% Reinfarction3.0%2.6% Reocclusion†5.9% (11/187)3.7% (7/189) Emergent CABG2.0%4.6% Intracerebral hemorrhage0.3% 30-day mortality3.6%3.3% Rate of major hemorrhaging12.9%13.5% * as noted on the patient’s case report form † angiographically defined PACT trial Ross AM, et al. J Amer Coll Cardiol 1999;34:

“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, PACT trial

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:

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:

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 MUSTT results Buxton AE, et al. N Engl J Med 1999;341:

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 MUSTT and implantable defibrillators A second look at the Multicenter UnSustained Tachycardia Trial (MUSTT). Clinical trials. theheart.org. December 7, 1999.

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

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 minimum 2.5 year follow-up

SCD-HeFT endpoints Primary endpoint: overall mortality Secondary endpoints: 1.arrhythmic vs nonarrhythmic cardiac mortality 2.comparison of morbidity 3.comparison of quality of life 4.analysis of cost effectiveness 5.categorizing arrhythmias in ICD arm

“…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, MUSTT trial

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 months Bigger J, et al. New Engl J Med 1997;337:

CABG Patch results Mortality by treatment arm in the CABG Patch trial ICD group (n=446) Control group (n=454) Hazard ratio p value Overall mortality*10195p=0.64 Cardiac deaths7172- * primary endpoint Bigger J, et al. New Engl J Med 1997;337: