Thrombolysis for Acute Myocardial Infarction: Drug Review

David K. Cundiff

Disclosures
In This Article

Randomized Trials of Thrombolysis Therapy in AMI

In 1985, Yusuf and colleagues[9] published a meta-analysis of 24 randomized trials done over 25 years (more than 6000 patients) comparing intravenous thrombolysis with streptokinase (SK), urokinase (UK), or tissue plasminogen activator (t-PA) vs standard medical treatment. The authors of this meta-analysis found a significant enhanced survival (22% above control) associated with thrombolysis in AMI.[9] However, with such a little difference in AMI mortality from thrombolysis, none of these small studies could stand alone in proving the efficacy of thrombolysis in AMI. Much larger studies were needed.

Nine large randomized controlled trials of thrombolytic drugs,[10,11,12,13,14,15,16,17,18] each with more than 1000 patients for a total of 58,511 evaluable patients, were reported from 1986 to 1992. A meta-analysis of these trials documented a small but highly statistically significant survival advantage in the first 35 days post-AMI.[19] Overall, patients receiving the thrombolytic drug within 6 hours of symptoms had 23/1000 (20.2% odds reduction) fewer deaths in hospital; those beginning the drug 7-12 hours after symptoms began experienced 16/1000 (12.6% odds reduction) fewer deaths; and those starting 13-18 hours later had a statistically insignificant survival advantage of 5/1000 (4.9% odds reduction). The thrombolytic therapy caused about 4 extra strokes per 1000 patients, 2 of which were fatal and 1 of which was disabling.[19]

Methodologic problems with this meta-analysis that cause difficulties in accepting the conclusion of efficacy of thrombolysis in AMI include the following:

  1. The criterion for inclusion into the meta-analysis of N > 1000 excluded smaller published studies that may have been stopped because of lack of efficacy of treatment;

  2. The N > 1000 criterion may have also excluded unpublished negative studies;

  3. This excess of disabling strokes in the thrombolysis group was not included in the calculation of the all-important survival advantage with fibrinolytics;

  4. Aspirin, which itself significantly reduces AMI mortality, was given routinely in only 4 studies and to 50% of patients in "The Second International Study of Infarct" Survival (ISIS-2); and

  5. Incomplete double-blinding allowed a placebo effect potentially favoring thrombolysis.

Interpretation of the conclusions of these 9 randomized clinical studies involving thrombolytics is further complicated by:

  1. The declining hospital mortality from AMI;

  2. The early hazard (ie, increased mortality on day 0 after thrombolysis);

  3. Possible bias introduced by the pharmaceutical company funding of the trials;

  4. Evidence from postdrug US Food and Drug Administration (FDA) approval registry data that thrombolytics may be used inappropriately in a significant number of cases; and

  5. Lack of confirmation from postdrug FDA approval registry data that thrombolytics reduce AMI mortality.

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