Thrombolysis for Acute Myocardial Infarction: Drug Review

David K. Cundiff

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In This Article

Declining Overall AMI Hospital Mortality Rates

The decline in the AMI death rates in the control groups in the later thrombolysis for AMI studies creates an issue in interpreting the results of the international trials. The deaths from AMI in the control groups in Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-1) and ISIS-2 were 13.0% and 13.2%, respectively, greatly exceeding death rates in the control groups of other studies that had more difficulty showing a statistically significant reduction in mortality with thrombolysis. For instance, the trial titled Intravenous Streptokinase in Acute Myocardial Infarction(ISAM), from Germany (N = 1741), shows a nonsignificant beneficial trend of SK on mortality (6.3% vs 7.1% mortality in the SK and placebo groups, respectively) at 21 days.[12] Follow-up data at 7 months showed the mortality in the 2 groups was practically indistinguishable (10.9% and 11.1% for SK and placebo, respectively).[13] Before the implementation of ISAM, statisticians and clinicians estimated that the control group death rate in the first 21 days would be about 18%, so the low control group death rate probably led to the loss of statistical significance of the study.

Similarly, Rossi and Bolognese,[14] from Italy, reported on a controlled trial (N = 2201) of thrombolytic therapy titled Urochinasi per via Sistemica nell'Infarto Miocardico (USIM), which demonstrated a remarkable reduction of mortality that was also not accounted for by thrombolysis. Data analysts for this study had estimated a mortality in the control arm of the study of about 12%. However, due in part to the low death rate in the control group, this study found no significant difference in the overall hospital mortality (8.0% vs 8.3% with urokinase + heparin and heparin alone, respectively).

The randomized studies with low mortality in the control arms generally had no statistically significant difference in survival with thrombolysis. The lower AMI hospital death rate in the control patients probably reflects improvements in overall management of AMI in recent years, a higher frequency of hospitalization for milder AMI cases due to public awareness campaigns, biases in the selection of patients for the studies, or a combination of these factors. The AMI 30-day hospital mortality rate in the 1990s was less than 10% compared with 16% in the 1980s, when most of the thrombolysis trials were done.[22,23,24] The NRMI-2 found those patients eligible for thrombolysis from 1994-1997 had a mortality of 7.9%.[25] This is 25% below the overall mortality of the FTT Collaborative Group meta-analysis (10.5%).[19] This low overall AMI death rate would make it virtually impossible for placebo-controlled thrombolysis in AMI trials today to show statistically significant reduction in mortality.

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