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aEnd points measured at 21 d; included patients without STE.

bEnd points measured at 35 d; death = vascular mortality; included patients without STE. Study also included a factorial randomization to aspirin.

cEndpoints measured at 30 d; included patients without STE.

dMajor bleeds and stroke attributed by investigator to SK. Nonfatal stroke at 6 mo was 0.7% in each group (102).

NR = not reported. SK = Streptokinase.

aEnd points measured at 21 d; included patients without STE.

bEnd points measured at 35 d; death = vascular mortality; included patients without STE. Study also included a factorial randomization to aspirin.

cEndpoints measured at 30 d; included patients without STE.

dMajor bleeds and stroke attributed by investigator to SK. Nonfatal stroke at 6 mo was 0.7% in each group (102).

NR = not reported. SK = Streptokinase.

previous MI (RR = 0.75), with Killip class I or II (RR = 0.80), and of age <65 yr (RR = 0.72). A trend also favored treatment in more elderly patients. Thus, GISSI, published in 1986, suggested that iv SK was safe and conferred a significant early survival benefit in AMI (at least among patients presenting within 6 h of symptom onset who generally had STE). Moreover, mortality benefits appeared to be maintained in the long term (102).

Second International Study of Infarct Survival (ISIS-2)

ISIS-2, an even more ambitious test of IV thrombolysis, followed in 1988 (103) and confirmed and extended the observations of GISSI. ISIS-2 used a 2-by-2 factorial design to assess the effects of iv SK (1.5 MU over 1 h), aspirin (162 mg/d on admission and daily for 1 mo), both, or neither in 17,187 patients entering 417 hospitals worldwide with suspected AMI within 24 h of symptom onset. The primary end point was vascular death at 5 wk. In the double placebo group, the mortality rate was 13.2%. The odds of dying were reduced by SK alone (by 25%, p < 0.0001) and also by aspirin alone (by 23%, p < 0.0001). Additive benefit occurred with the combination of SK and aspirin (42% odds reduction, p < 0.00001). When SK and aspirin were given early (within 4 h of symptom onset), a 53% odds reduction in mortality was achieved. Benefits were time-dependent, although less so than in GISSI. Subgroup analyses demonstrated lower mortality rates with thrombolytic therapy in the same subgroups shown to benefit in GISSI and, in addition, in those presenting with bundle-branch block (BBB), with inferior infarction, and at all ages (including those > 70 yr old). A notable exception was the group presenting with ST-segment depression. A small excess (0.1%) of confirmed cerebral hemorrhage was observed with SK, as were larger excesses in hypotension, presumed allergic reactions, and minor bleeds. Overall, therapy was regarded as safe, and IV SK was "established" in a broad group of patients with AMI. Importantly, ISIS-2 also established antiplatelet therapy with aspirin, given on admission and daily thereafter, as a routine part of AMI management.

APSAC Intervention Mortality Study (AIMS)

Contemporary with ISIS-2 (1988), AIMS established a substantial survival benefit of IV APSAC in a multicenter trial from the United Kingdom (104,105). Patients under 70 with STE were entered within 6 h of AMI onset and randomized to APSAC (30 U) or placebo. The primary end points were 30-d and 1-yr mortality. Aspirin was not routinely used, but iv heparin was begun after 6 h. Patients were subsequently given warfarin for at least 3 mo. AIMS was stopped early because of efficacy. In the final analysis of 1258 patients, 30-d mortality was reduced from 12.1% in the placebo group to 6.4% in the APSAC group (odds reduction 51%, 95% CI: 26-67%, p = 0.0006) (105). After 1 yr, mortality reductions persisted (17.8% with placebo, 11.1% with APSAC, odds reduction 43%, CI: 21-59%, p = 0.0007) (105). All subgroups benefited.

The need for adjunctive IV heparin added to aspirin after APSAC was addressed by the first Duke University Clinical Cardiology Study (DUCCS-1) (106). DUCCS-1, of intermediate size, found no difference in clinical end points other than a higher rate of bleeding in AMI patients assigned to IV heparin compared with no heparin. Hence, current recommendations for heparin with APSAC follow those for its parent drug SK (9), derived from a larger experience including GUSTO-1 (95), which demonstrated no advantage of concomitant iv over sc heparin with SK.

Anglo-Scandinavian Study of Early Thrombolysis (ASSET)

Shortly after ISIS-2, ASSET provided evidence of a survival benefit with rtPA (107). ASSET enrolled 5013 patients with suspected AMI (ECG confirmation not required) within 5 h of symptom onset and randomized them to double-blind therapy with rtPA, 100 mg over 3 h together with IV heparin, 5000 U, then 1000 U/h for 1 d, or placebo plus heparin. Aspirin was not routinely given. The primary end points were 1- and 6-mo mortality. Thirty-day mortality was significantly lower in the rtPA than the placebo group (7.2 vs 9.8%, relative risk reduction 26%, 95% CI: 11-39%, p = 0.001). Bleeding complication rates were higher with rtPA (1.4 vs 0.4% for major hemorrhage), but total stroke rates were similar (1.1 vs 1.0%).

Late Assessment of Thrombolytic Efficacy (LATE) Study

Earlier studies had conclusively demonstrated the benefit of IV thrombolytic therapy begun within 6 h of onset of symptoms. The LATE study aimed to assess the more controversial question of treatment effects of a randomized double-blind comparison of iv rtPA (100 mg over 3 h) with matching placebo in patients with symptoms of 6-24 h duration and ECG criteria consistent with AMI (108). A total of 5711 patients were entered and randomized to rtPA or placebo plus oral aspirin. iv heparin was recommended for 48 h. The primary end point, 35-d mortality, was reduced by 14.1% (95% CI: 0-28%). Mortality reductions occurred primarily in the prespecified patient group given treatment within 12 h of symptom onset (8.9 vs 12.0%, RR reduction 26%, CI: 6-45%, p = 0.023). The results of LATE suggested that the time window for throm-bolysis (with rtPA) should be extended to at least 12 h from symptom onset for patients with AMI. An overview of "late" studies with SK also supported a survival benefit up to 12 h (109,110).

Fig. 4. Thrombolytic therapy effect on mortality (lives saved/1000 treated) as reported in the FTT Collaborative Group (using SK, APSAC, UK, and 3-h tPA), by admission ECG. Patients presenting with BBB and anterior segment elevation derived the most benefit from thrombolytic therapy. Patients with inferior STE derived much less benefit, whereas those with ST-segment depression or with normal or nonspecific ECG showed trends toward harm. Adapted from ref. 110.

Fig. 4. Thrombolytic therapy effect on mortality (lives saved/1000 treated) as reported in the FTT Collaborative Group (using SK, APSAC, UK, and 3-h tPA), by admission ECG. Patients presenting with BBB and anterior segment elevation derived the most benefit from thrombolytic therapy. Patients with inferior STE derived much less benefit, whereas those with ST-segment depression or with normal or nonspecific ECG showed trends toward harm. Adapted from ref. 110.

Fibrinolytic Therapy Trialists' (FTT) Collaborative Group Report

By 1990, the benefit of IV thrombolytic therapy in appropriate AMI patients was regarded as established, ending the era of placebo (or nonthrombolytic)-controlled trials (110,111). To maximize information gained from these trials, the FTT collaborative group pooled the nine major trials that had randomized 1000 or more patients (110). The FTT database included 58,600 patients. Overall, an 18% reduction in 5-wk mortality (from 11.5 to 9.6%) was observed with fibrinolytic therapy, a highly significant result (p < 0.0001). Most patients (approx 45,000) presented with STE or BBB on ECG, and benefit was concentrated in these groups. Within the group with BBB on admission ECG, 49 lives were saved per 1000 patients treated. Within the STE group, greater benefit was observed in those with anterior (37 saved/1000) than with inferior STE only (8 saved/1000). Combined or other site STE showed intermediate benefit (27 saved/1000). No mortality benefit was observed for patients presenting with normal ECGs or ST depression; indeed, thrombolysis caused a slight adverse trend (7 and 14 more deaths/1000 treatments, respectively) (Fig. 4). The mortality reductions seen in the STE and BBB groups showed time dependence: absolute benefits declined from about 40 lives saved/1000 for treatment within the first h, to 20-30 for h 2-12, to 7 for h 13-24.

When other studies that evaluated very early therapy (i.e., emergency ward or paramedic-based) are included, even greater benefits are observed. Boersma et al. (112) reappraised very early therapy based on a database of 50,246 patients derived from all randomized trials of 100 or more patients published between 1983 and 1993. Overall, a nonlinear relation of treatment delay to benefit was observed (Fig. 5). These results clearly demonstrated a time dependency of benefit, particularly when large numbers of patients are treated within the first 1 or 2 "golden hours".

The FTT collaborative group analysis provides important information on therapy for patients over age 75, for whom relatively few data are available in single randomized

Fig. 5. Absolute reduction in 35-d mortality decreased as time-to-treatment increases. Small closed dots represent data from trials included in the FTT analysis, open dots represent information from additional trials, and small squares represent trials with absolute benefit >80 lives/1000 treated. The linear and nonlinear regression lines are fitted within these data and weighted by the inverse of the variance of the absolute benefit for each data point. The six black squares represent the average effect by time-to-treatment at six different time points (area of the squares are inversely proportional to the variance of the absolute benefit). Reproduced with permission from ref. 112.

trials. For these patients, proportionate mortality reductions were less (the trend to benefit was not significant) although the absolute mortality reduction was still preserved.

Mortality reductions were little influenced by systolic blood pressure or heart rate except at their extremes. Hypotension (systolic blood pressure < 100 mmHg on presentation) was associated with greater AMI risk overall, but also with greater absolute mortality reductions with therapy (60 lives saved/1000 treated; p < 0.001). During persistent hypotension (cardiogenic shock), the effectiveness of thrombolytic therapy is unclear (113). Intra-aortic balloon pumps are associated with lower mortality in the presence of thrombolytic therapy during cardiogenic shock (114); however, emergent revascularization is preferred when available.

Benefits of thrombolytic therapy also were confirmed by FTT for other high-risk groups, including those with prior MI (absolute reduction of1.6 vs 2.0% for those without prior MI) and diabetes (absolute reduction of 3.7 vs 1.5% for those without diabetes). The absolute benefit of thrombolytics in the currently era may be even greater, as the FTT data are derived primarily from SK, APSAC, and 3-h tPA infusions, which have been shown inferior to accelerated tPA, and these trials have included patients with ECG criteria now known to not benefit from thrombolytic therapy.

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