Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

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

ACP J Club. 1994 May-June;120:72. doi:10.7326/ACPJC-1994-120-3-072


Source Citation

LATE Study Group. Late assessment of thrombolytic efficacy (LATE) study with alteplase 6-24 hours after onset of acute myocardial infarction. Lancet. 1993 Sep 25;342:759-66.


Abstract

Objective

To evaluate the effectiveness of alteplase administered 6 to 24 hours after the onset of chest pain and electrocardiographic changes in patients with an acute myocardial infarction (MI).

Design

Randomized, double-blind, placebo-controlled trial with 6 month of complete follow-up.

Setting

230 centers in Australia, Canada, Europe, and the United States.

Patients

5711 patients (mean age 62 y, 72% men) with symptoms and electrocardiographic criteria consistent with acute MI. Exclusion criteria were risk for serious bleeding including overt gastrointestinal or genitourinary bleeding within the last 6 months, history of stroke, history of transient ischemic attack in the last 6 months, major surgery or trauma within the previous month, shock with systolic blood pressure < 80 mm Hg, uncontrolled hypertension (systolic > 200 mm Hg, diastolic > 110 mm Hg), or serious organic or psychiatric illness. All patients were followed for 6 months.

Intervention

2836 patients were allocated to receive intravenous alteplase (recombinant human tissue plasminogen activator [r-tPA]; 10-mg bolus, 50-mg infusion in 1 hour, and then 20 mg in each of the next 2 hours), and 2875 patients were allocated to receive placebo. All patients received aspirin and, for later recruits, intravenous heparin was recommended.

Main outcome measures

Survival and adverse effects.

Main results

397 patients died in the alteplase group compared with 444 patients in the placebo group (P = 0.12) (Table). The 35-day mortality rates were 8.9% for the alteplase group and 10.3% for the placebo group { P = 0.06}* (Table). For patients treated within 12 hours of symptom onset, the 35-day mortality was 8.9% for the alteplase group compared with 12.0% for the placebo group (P = 0.02) (Table). For patients treated after 12 hours, mortality rates were similar (P > 0.2) (Table). More hemorrhagic strokes occurred within the first 48 hours from onset of treatment in the alteplase group compared with placebo but by 6 months this difference disappeared.

Conclusions

Alteplase improved survival if administered within 12 hours after the onset of major symptoms in patients with acute myocardial infarction. This survival benefit was not seen if treatment was delayed 12 to 24 hours after symptom onset.

Sources of funding: Genentech Inc. and Boehringer Ingelheim.

For article reprint: Dr. R.G. Wilcox, Division of Cardiovascular Medicine, University Hospital, Nottingham NG7 2UH, United Kingdom. FAX 44—115-9709384.

* P value calculated from data in article.


Table. Mortality rates for alteplase vs placebo for acute myocardial infarction†

Patient groups Alteplase Placebo RRR (95% CI) NNT (CI)
All patients at 1 y 14% 15% 9.3% (-2.7 to 20) Not significant
All patients at 35 d 8.9% 10% 14% (-1 to 27) Not significant
Patients treated ≤ 12 h after symptom onset, at 35 d 8.9% 12% 26% (4 to 42) 33 (18 to 220)
Patients treated > 12 h after symptom onset, at 35 d 8.7% 9.2% 5.3% (-17 to 23) Not significant

†Abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article


Commentary

Late thrombolysis did not improve survival in suspected acute myocardial infarction

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.