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Abbreviations: SK, streptokinase; tPA, tissue-type plasminogen activator (alteplase); APSAC, anisoy-lated plasminogen streptokinase activator complex.

Abbreviations: SK, streptokinase; tPA, tissue-type plasminogen activator (alteplase); APSAC, anisoy-lated plasminogen streptokinase activator complex.

cally significant in-hospital 6% reduction in mortality (from 9.1 to 8.6%, p = 0.03) and 9% reduction in reinfarction (from 3.3 to 3.0%, p = 0.04) (Fig. 12). Again, treatment with heparin was also associated with an increased major bleeding rate (1.0 vs 0.7%).

Most of the data come from the GISSI-2 trial (138,139) and the ISIS-3 trial (140). During the actual period of heparin treatment in these trials there was a 7% relative reduction in mortality (from 7.3 to 6.8%), but at 35 d, the difference in mortality was no longer statistically significant (2% relative reduction, from 10.2 to 10.0%). There is, however, concern that these two megatrials may have underestimated the beneficial effects of heparin because of the way in which the heparin was administered. In GISSI-2, the heparin was started 12 h after the initiation of fibrinolytic therapy, and in ISIS-3, it was started 4 h after the initiation of fibrinolytic therapy. Moreover, in both trials, the heparin was administered subcutaneously, which further delayed the achievement of an anticoagulated state.

Trials with IV Heparin. Given the fact that patients enrolled in GISSI-2 and ISIS-3 accounted for greater than 95% of the patients included in the above meta-analysis and that there are concerns regarding the efficacy of the heparin regimens in those two mega-trials, it is reasonable to undertake a separate inspection of trials that have used intravenous heparin. There have been six randomized controlled trials (136,137,141-144) that have directly examined the effect of iv heparin in patients receiving thrombolytic therapy for acute myocardial infarction (Table 3). A meta-analysis of these trials (145) revealed a statistically nonsignificant 9% reduction in mortality (from 5.6 to 5.1%) (Fig. 13). There was no significant difference in the rates of reinfarction or recurrent ischemia. There was, however, a statistically nonsignificant 42% increase in the rate of severe bleeding with double the rates of stroke and intracranial hemorrhage.

The above trials, however, are a heterogeneous group. None of the patients in the study by Bleich and colleagues (136), half of the patients in the ISIS-2 pilot study (137), and only those patients who did not receive heparin in Heparin-Aspirin Reperfusion Trial (HART) (144) received aspirin, whereas all of the patients in European Cooperative Study Group (eCSG)-6 (141), OSIRIS (142), and Duke University Clinical Cardiology Study (DUCCS)-1 (143) received aspirin. An analysis of the subgroup of patients in these six trials who were given aspirin revealed that heparin had no effect on mortality. In con-

Outcome Death

Reinfarction Recurrent Ischemia Stroke ICH

Any Bleeding Any Bleeding

Heparin-allocated Control-allocated n = 857

45 (5.1%) 29 (3.5%)* 111 (16.6%)t 12(1.4%) 4 (0.6%)+ 26 (4.7%)** 199 (22.7%)

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