A comparison of continuous infusion of alteplase with double-bolus administration for acute myocardial infarction

N Engl J Med. 1997 Oct 16;337(16):1124-30. doi: 10.1056/NEJM199710163371604.


Background: Accelerated infusion of alteplase (tissue plasminogen activator) over a period of 90 minutes induces more rapid lysis of coronary-artery thrombi than a 3-hour infusion. With two bolus doses of alteplase, further shortening the duration of administration, complete reperfusion was achieved in more than 85 percent of the patients in initial angiographic studies. We tested the hypothesis that double-bolus alteplase is at least as effective as accelerated infusion.

Methods: In 398 hospitals, 7169 patients with acute myocardial infarction were randomly assigned to weight-adjusted, accelerated infusion of 100 mg of alteplase or to a bolus of 50 mg of alteplase over a period of 1 to 3 minutes followed 30 minutes later by a second bolus of 50 mg (or 40 mg for patients who weighed less than 60 kg). The primary end point was death from any cause at 30 days. The trial was stopped prematurely because of concern about the safety of the double-bolus injection.

Results: Thirty-day mortality was higher in the double-bolus group than in the accelerated-infusion group: 7.98 percent as compared with 7.53 percent. The absolute difference was 0.44 percent, with a one-sided 95 percent upper boundary of 1.49 percent, which exceeded the prespecified upper limit of 0.40 percent to indicate equivalence in 30-day mortality between the two regimens. The respective rates of any stroke and of hemorrhagic stroke were 1.92 and 1.12 percent after double-bolus alteplase, as compared with 1.53 and 0.81 percent after an accelerated infusion of alteplase (P=0.24 and P=0.23, respectively).

Conclusions: Double-bolus alteplase was not shown to be equivalent, according to the prespecified criteria, to accelerated infusion with regard to 30-day mortality. There was also a slightly higher rate of intracranial hemorrhage with the double-bolus method. Therefore, accelerated infusion of alteplase over a period of 90 minutes remains the preferred regimen.

Publication types

  • Clinical Trial
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Cerebrovascular Disorders / chemically induced
  • Female
  • Hemorrhage / chemically induced
  • Humans
  • Infusions, Intravenous
  • Injections, Intravenous
  • Male
  • Middle Aged
  • Myocardial Infarction / complications
  • Myocardial Infarction / drug therapy*
  • Myocardial Infarction / mortality
  • Plasminogen Activators / administration & dosage*
  • Plasminogen Activators / adverse effects
  • Survival Analysis
  • Therapeutic Equivalency
  • Tissue Plasminogen Activator / administration & dosage*
  • Tissue Plasminogen Activator / adverse effects
  • Treatment Outcome


  • Plasminogen Activators
  • Tissue Plasminogen Activator