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Therapeutics

Continuing heparin beyond 24 hours after rt-PA was not better than oral aspirin-dipyridamole for acute myocardial infarction

ACP J Club. 1991 Sept-Oct;115:43. doi:10.7326/ACPJC-1991-115-2-043


Source Citation

Thompson PL, Aylward PE, Federman J, et al., for the National Heart Foundation of Australia Coronary Thrombolysis Group. A randomized comparison of intravenous heparin with oral aspirin and dipyridamole 24 hours after recombinant tissue-type plasminogen activator for acute myocardial infarction. Circulation. 1991 May;83:1534-42.


Abstract

Objective

To assess the need for continued heparin administration beyond 24 hours after recombinant tissue-type plasminogen activator (rt-PA) infusion, by comparing it with an oral antiplatelet regimen of aspirin and dipyridamole.

Design

Randomized controlled trial lasting until patient discharge at 7 to 10 days.

Setting

Coronary care units in 10 Australian centers during 1988.

Patients

523 of 1464 patients admitted for suspected acute myocardial infarction initially fulfilled inclusion criteria of age ≤ 75 years, no history of previous myocardial infarction, admission to the hospital within 4 hours of symptom onset, typical cardiac pain, and electrocardiographic evidence of infarction. 248 patients were excluded (mostly for having contraindications to thrombolytic therapy) and 17 patients refused to participate. Of 241 patients who began rt-PA and heparin, 20 were not randomized because of adverse events in the first 24 hours (including 9 deaths), and 19 were excluded for protocol violations.

Intervention

Patients received a 5000-U heparin bolus and 100 mg of rt-PA intravenously over 3 hours, followed by 1000 U of heparin/h for 24 hours. 99 patients were then randomized to continue intravenous heparin at a rate adjusted to maintain activated partial thromboplastin time at 2 to 2.5 times the normal range and 103 patients were allocated to oral aspirin, 300 mg/d, and dipyridamole, 100 mg 3 times daily.

Main outcome measures

Death, reinfarction, coronary artery patency, stroke, chest pain, and bleeding complications. All randomized patients were included in the analysis.

Main results

No differences existed between the 2 groups in the timing or number of episodes of chest pain, in the distribution of extent of narrowing of infarct-related arteries before discharge, or in bleeding complications. 10 major in-hospital events (10%) occurred in the heparin group (5 deaths and 5 reinfarctions) and 5 major in-hospital events (5%) in the aspirin-dipyridamole group (2 deaths, 2 reinfarctions, and 1 stroke) {95% CI for the difference in proportions of 5%, -2% to 13%} (P = 0.09).

Conclusion

Patients who survived 24 hours of rt-PA and heparin therapy after myocardial infarction did not do better on continued treatment with heparin than on oral aspirin-dipyridamole antiplatelet therapy.

Sources of funding: The National Heart Foundation of Australia and Boehringer Ingelheim Pty. Ltd.

Address for article reprint: Dr. P.L. Thompson, Department of Cardiovascular Medicine, Sir Charles Gairdner Hospital, Verdun Street, Nedlands, Perth, WA 6009, Australia.


Commentary

Thrombolytic therapy plus an aggressive angiographic strategy were more effective than monotherapy for reducing complications after myocardial infarction

Randomized trials have established that thrombolytic therapy improves survival after acute myocardial infarction but several questions remain unresolved. These 2 studies address 3 of them: whether a combination of thrombolytic agents may be better than any single agent alone; how catheterization should be used after thrombolysis; and whether patients should continue to receive intravenous heparin or antiplatelet agents after thrombolysis. Although these reports suggest possible answers to these questions, their small sizes render their conclusions tentative.

The good news in these and other reports is the low in-hospital mortality (< 10%) associated with acute myocardial infarction. The resulting bad news for researchers is that detecting survival benefits as a result of any intervention therefore requires a large number of patients or the use of surrogate end points for mortality. For this reason, both papers relied on combinations of outcomes such as chest pain, coronary patency, left ventricular function, and others. Whether differences in outcomes such as "improved regional wall motion in the infarct region" will be translated into improved survival or quality of life is far from certain.

Nevertheless, these reports are being read with interest by physicians responsible for managing patients with acute myocardial infarction. The paper by Califf and colleagues supports the hypothesis that a combination of a "fast," fibrin-specific agent (rt-PA) with a "slow," nonspecific agent (urokinase) may be better than either drug alone because one drug opens the vessel quickly and the other helps prevent reocclusion. This study also suggests that early catheterization strategies may improve patient outcomes, although the techniques of intravascular intervention are evolving so rapidly that trials such as this are more useful as a benchmark than as a summary of the state of the art. Moreover, this study's statistically significant results relied on combined, intermediate end points, and the previous caution about extrapolation to mortality and quality of life applies in this case.

The second study, from Thompson and colleagues, suggests that intravenous heparin can give way to oral antiplatelet therapy 24 hours after thrombolysis. It should be noted that the ability of this latter study to detect benefits from continued heparin therapy was limited by the small sample size (202 patients). As a result, the 95% confidence interval on the difference in composite clinical end points was very wide.

Clinicians will continue to seek answers to questions such as those posed in these trials. Larger studies, of sufficient size and power to determine the effects of these interventions on survival and quality of life, are awaited with keen interest.

Thomas H. Lee, MD
Brigham and Women's HospitalBoston, Massachusetts, USA.