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Therapeutics

Late thrombolysis did not improve survival in suspected acute myocardial infarction

ACP J Club. 1994 May-June;120:73. doi:10.7326/ACPJC-1994-120-3-073


Source Citation

EMERAS (Estudio Multicéntrico Estreptoquinasa Repúblicas de América del Sur) Collaborative Group. Randomised trial of late thrombolysis in patients with suspected acute myocardial infarction. Lancet. 1993 Sep 25;342:767-72.


Abstract

Objective

To evaluate the effectiveness of streptokinase administered up to 24 hours after the onset of pain in patients with suspected acute myocardial infarction (MI).

Design

Randomized, placebo-controlled trial with 1-year follow-up.

Setting

236 hospitals in 6 South American countries.

Patients

4534 patients (56% between the age of 55 and 74 y, 77% men) presenting to the hospital up to 24 hours after the onset of suspected acute MI with no clear indication for, or contraindication to, streptokinase. {This sample size is large enough to detect, with about 80% power, a reduction of 25 to 30 deaths per 1000 patients treated.}* After the results of the Second International Study of Infarct Survival (ISIS-2) were known, only patients presenting to the hospital > 6 hours after symptom onset were included. Exclusion criteria were history of stroke, gastrointestinal hemorrhage, or ulcer within the past 6 months. Completeness of follow-up for mortality at 1 year was 90%.

Intervention

2257 patients were allocated to receive streptokinase (1.5 million units) and 2277 were allocated to receive placebo. Streptokinase or placebo was infused intravenously over 1 hour in 100 mL of saline.

Main outcome measures

Mortality, stroke, and adverse effects.

Main results

In-hospital mortality was similar in the 2 groups (11.9% in the streptokinase group vs 12.4% in the placebo group) { P = 0.12}*. Among the 2080 patients presenting with symptoms between 7 to 12 hours after the onset, 11.7% died in the streptokinase group compared with 13.2% in the placebo group { P = 0.2}*(Table). Among the 1791 patients presenting between 13 to 24 hours after symptom onset, 11.4% died in the streptokinase group compared with 10.7% in the placebo group { P > 0.2}* (Table). No significant differences, overall or in defined delay-from-symptom-onset subgroups, were seen with further follow-up to 35 days or to 1 year. Overall, the treatment groups did not differ for the incidence of total stroke (Table). Adverse effects of streptokinase were similar to those in previous studies.

Conclusions

Streptokinase did not improve survival when administered 6 to 24 hours after the onset of symptoms in patients with suspected acute myocardial infarction.

Source of funding: Hoechst and Sterling Drugs (donation of aspirin).

For article reprint: Dr. E. Paolasso, ECLA Collaborative Study Group, Bv Orono 500, 2000 Rosario, Argentina. FAX 54-341-4242071.

*Numbers calculated from data in article.


Table. Streptokinase vs placebo in suspected acute myocardial infarction†

Outcomes Patient groups Streptokinase Placebo RRR (95% CI) NNT
In-hospital mortality rates Patients with symptoms 7 to 12 h after onset 11.7% 13.2% 12% (-11 to 30) Not significant
RRI (CI) NNH
Patients with symptoms 13 to 24 h after onset 11.4% 10.7% 7% (-18 to 39) Not significant
Stroke at 1 y All 1.5% 1.1% 38% (-17 to 128) Not significant

†Abbreviations defined in Glossary: RRR, RRI, NNT, NNH, and CI calculated from data in article.


Commentary

Late thrombolysis improved survival only if given within 12 hours of onset of acute myocardial infarction symptoms

At least 30% of patients with acute MI admitted to hospitals (participating in thrombolytic trials) are excluded from receiving thrombolysis because of symptom duration > 6 hours. Some clinicians do not treat patients beyond the 3- or 4-hour limit within which myocardial salvage can be achieved. Yet, increasing data suggest that mortality reduction caused by mechanisms other than myocardial salvage can occur for hours after symptom onset if infarction artery patency can be restored. Limitation of left ventricular dilatation and aneurysm formation, improved healing, better electrical stability, reduced mural thrombus formation, and potential collateral circulation to a remote ischemic zone are possible mechanisms that collectively constitute the "open artery hypothesis."

The traditional 6-hour time window for thrombolytic benefit originated from the statistical analysis of the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI-I) study (1). Although a similar mortality reduction was found for patients with 6 to 9 hours of symptoms, the results were not statistically significant, probably because of the small sample size. Subsequent trials, all of which added adjunctive aspirin to thrombolytic therapy, supported treating patients who present later to the hospital. The ISIS-2 trial (2) showed a survival benefit for treated patients both 6 to 12 hours (10.4% vs 12.1%) and 12 to 24 hours (8.7% vs 10.8%) after symptom onset. The third ISIS trial (ISIS-3) (3) also showed a mortality benefit for treated patients 6 to 12 hours after symptom onset (12.6% vs 14.6%). The Late Assessment of Thrombolytic Efficacy (LATE) and the Estudio Multicéntrico Estreptoquinasa Repúblicas de América del Sur (EMERAS) trials amplify these previous observations.

The LATE trial showed a mortality benefit for patients treated 6 to 12 hours after symptom onset (8.9% vs 12.0%) but not for those treated with 12 to 24 hours of symptoms (8.7% vs 9.2%). The EMERAS results were supportive (11.7% vs 13.2% for 6 to 12 hours, 11.4% vs 10.7% for 12 to 24 hours). The results from all of these trials justify extending the thrombolytic treatment window from 6 hours to at least 12 hours after symptom onset. Saving 2 to 3 lives per 100 patients treated by giving thrombolysis within 12 hours after the onset of symptoms is a greater clinical benefit than that achieved by adjunctive therapy with either intravenous β-blockers or angiotensin-converting enzyme inhibitors (0.5 lives saved per 100 patients) for < 6 hours of symptoms!

Does the 26% mortality reduction in LATE compared with the 12% reduction in the EMERAS suggest that r-tPA is superior to streptokinase for late therapy? 90-minute patency rates after treatment are higher for r-tPA than for streptokinase but the importance of this observation is not known for the 6- to 12-hour time period. 2 comparative mortality trials using similar thrombolytic dosing showed no difference between agents in patients with < 6 hours of symptoms. No data exist on the superior strategy of front-loaded, weight-adjusted r-tPA with monitored heparin for late therapy.

The LATE and EMERAS trials treated a large proportion of patients without ST-segment elevation or chest pain. Moreover, no mortality benefit was noted for patients with inferior infarction in the LATE trial. (Personal communication with Dr. R. Wilcox.) Until further data are available, I would favor limiting treatment for the 6- to 12-hour group to patients with persistent ST-segment elevation, ongoing chest pain, and moderate-to-large estimated infarction size because of the risk for intracerebral hemorrhage. Expanding the thrombolytic treatment window from 3 to 6 hours up to 12 hours would double the number of patients who might benefit from the reduction in morbidity and mortality associated with thrombolytic therapy.

The FTT Collaborative Study (4) pooled later trials of thrombolytic therapy in acute MI and reported reduced mortality for patients with ST elevation or bundle-branch block presenting 7 to 12 hours after onset of symptoms (P > 0.005). This is consistent with 20 lives saved per 1000 patients treated. For patients presenting after 12 hours from symptom onset, there may still be a benefit of about 10 lives saved per 1000 patients treated, but such a benefit has been less well documented (fewer patients studied) and any potential treatment advantage has to be considered within the context of possible side effects of therapy.

Eric R. Bates, MD
University of MichiganAnn Arbor, Michigan, USA


References

1. Gruppo Italiano per lo Studio della Streptochinasi nell' Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet. 1986;1:397-402.

2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet. 1988;2:349-60.

3. ISIS-3 (Third International Study of Infarct Survival) Collaborative Group. ISIS-3: a randomised comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41,299 cases of suspected acute myocardial infarction. Lancet. 1992;339:753-70.

4. Fibrinolytic Therapy Trialists' (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Lancet. 1994;343:311-22.