PACT

Clinical Trial Commentary

Dr Eric TopolChairman and Professor, Department of Cardiology Director of the Joseph J Jacobs Center for Thrombosis and Vascular Biology at the Cleveland Clinic

Dr Robert CaliffProfessor 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;34:1954-1962

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%±13.81 57.7%±14.12

Frequency of TIMI-3 flow achieved following rescue PTCA

78.6%3 80.5%4

1 ventriculograms available for analysis for only 220 patients2 ventriculograms available for analysis for only 224 patients3 in 169 patients with TIMI 0, 1, or 2 flow following drug treatment4 in 231 patients with TIMI 0, 1, or 2 flow following drug treatment

PACT trial

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

Adverse clinical outcomes: rtPA vs placebo

rtPA (n=302)

Placebo(n=304)

Recurrent ischemia* 17.9% 13.5%

Reinfarction 3.0% 2.6%

Reocclusion† 5.9% (11/187) 3.7% (7/189)

Emergent CABG 2.0% 4.6%

Intracerebral hemorrhage 0.3% 0.3%

30-day mortality 3.6% 3.3%

Rate of major hemorrhaging 12.9% 13.5%* as noted on the patient’s case report form† angiographically defined

PACT trial

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

“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.

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;341:1882-1890

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

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;341:1882-1890

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 2 500

• minimum 2.5 year follow-up

SCD-HeFT endpoints

Primary endpoint: overall mortality

Secondary endpoints:1. arrhythmic vs nonarrhythmic cardiac

mortality2. comparison of morbidity 3. comparison of quality of life4. analysis of cost effectiveness5. 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, 1999.

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 32 + 16 months

Bigger J, et al. New Engl J Med 1997;337:1569-75.

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* 101 95 p=0.64

Cardiac deaths 71 72 -

* primary endpoint

Bigger J, et al. New Engl J Med 1997;337:1569-75.