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					Clinical Trial Commentary

                          PACT             MUSTT

 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
                                                        PACT trial

            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




Ross AM, et al. J Amer Coll Cardiol 1999;34:1954-1962
                                                               PACT trial
   Reperfusion and LV function:
   rtPA vs placebo
                                                  rtPA              Placebo
                                                  (n=302)           (n=304)
    Frequency of TIMI-3 flow
                                         33%                        15%
    immediately following drug treatment
    LVEF immediately following drug
                                                  59.4%±13.81 57.7%±14.12
    treatment
    Frequency of TIMI-3 flow achieved
                                                  78.6%3            80.5%4
    following rescue PTCA

    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 1999;34:1954-1962
                                                        PACT trial
    Adverse clinical outcomes:
    rtPA vs placebo
                                      rtPA            Placebo
                                      (n=302)         (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



Ross AM, et al. J Amer Coll Cardiol 1999;34:1954-1962
                                              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.
         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                   Randomization
      (n=1435)                   (n=704)
      sustained VT               sustained VT
      not inducible              inducible



     Conservative                EP-guided therapy
     therapy (n=353)             (n=351)
     ACE-inhibitors and          ACE-inhibitors and
     beta-blockers               beta-blockers


Buxton AE, et al. N Engl J Med 1999;341:1882-1890
                                  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
    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.
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
    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
        mortality
     2. comparison of morbidity
     3. comparison of quality of life
     4. analysis of cost effectiveness
     5. categorizing arrhythmias in ICD arm
                                               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.
      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    Control group   Hazard ratio
                          (n=446)      (n=454)         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.

				
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