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
Plasminogen-activator Angioplasty Compatibility Trial
multicenter, randomized, double-blind trial 606 AMI patients lt 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

Ross AM, et al. J Amer Coll Cardiol
1999341954-1962
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PACT trial
Reperfusion and LV function rtPA vs placebo
rtPA (n302) Placebo (n304)
Frequency of TIMI-3 flow immediately following drug treatment 33 15
LVEF immediately following drug treatment 59.413.81 57.714.12
Frequency of TIMI-3 flow achieved following rescue PTCA 78.63 80.54
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 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 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
Ross AM, et al. J Amer Coll Cardiol
1999341954-1962
4
PACT trial
Adverse clinical outcomes rtPA vs placebo
rtPA (n302) Placebo (n304)
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 patients case report form angiographically defined as noted on the patients case report form angiographically defined as noted on the patients case report form angiographically defined
Ross AM, et al. J Amer Coll Cardiol
1999341954-1962
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PACT trial

• The bottom line is that the combination therapy
  did not improve LV function or change
  outcomeEnhancing reperfusion by 10, 15, or 20
  minutes hasnt 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.
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MUSTT trial eligibility criteria

• EF lt 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 19993411882-1890
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MUSTTprotocol
Electrophysiologic studies
Registry (n1435) sustained VT not inducible
Randomization (n704) sustained VT inducible
Conservative therapy (n353) ACE-inhibitors and
beta-blockers
EP-guided therapy (n351) ACE-inhibitors and
beta-blockers
Buxton AE, et al. N Engl J Med 19993411882-1890
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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 19993411882-1890
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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.
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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
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SCD-HeFT eligibility criteria

• EF lt 35
• CHF treatment with ACE-I gt 3 months
• NYHA II and III, ischemic or nonischemic
• Age gt 18 years
• projected enrollment 2 500
• minimum 2.5 year follow-up

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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

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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 groupwhat 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.
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CABG Patch trial eligibility criteria

• EF lt 36
• scheduled for CABG
• abnormalities on signal averaged ECGs
• Age lt 80 years
• patients (n900) randomly assigned to ICD vs
  control
• average follow-up 32 16 months

Bigger J, et al. New Engl J Med 19973371569-75.
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CABG Patch results
Mortality by treatment arm in the CABG Patch trial
ICD group (n446) Control group (n454) Hazard ratio p value
Overall mortality 101 95 p0.64
Cardiac deaths 71 72 -
primary endpoint primary endpoint primary endpoint primary endpoint
Bigger J, et al. New Engl J Med 19973371569-75.