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


Therapeutics

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

ACP J Club. 1991 Sept-Oct;115:42. doi:10.7326/ACPJC-1991-115-2-042


Source Citation

Califf RM, Topol EJ, Stack RS, et al. Evaluation of combination thrombolytic therapy and timing of cardiac catheterization in acute myocardial infarction. Results of thrombolysis and angioplasty in myocardial infarction—Phase 5 randomized trial. Circulation. 1991 May;83:1543-56.


Abstract

Objective

To compare 3 thrombolytic treatment strategies (tissue-type plasminogen activator [t-PA], urokinase, or both) and 2 coronary angiographic strategies (immediate or deferred) in patients with acute myocardial infarction.

Design

Randomized, 3 × 2 factorial trial, with unblinded interventions but blinded assessment of end points.

Setting

7 regional cardiac referral centers and 29 community hospitals.

Patients

Patients had symptomatic acute myocardial infarction of ≥ 2 contiguous electrocardiographic leads), were < 76 years old, and had no contraindication to thrombolytic therapy. 575 patients were included in intention-to-treat analyses.

Intervention

The 3 intravenous drug regimens were urokinase (3 million U over 90 min, 190 patients); t-PA (100 mg over 3 h, 191 patients); or a combination using separate lines (n = 194). Patients were also randomized to either immediate coronary angiography, as soon as possible after 90 minutes from initiation of thrombolytic therapy (with rescue angioplasty of appropriate lesions when thrombolysis had failed) (n = 287) or to deferred angiography 5 to 10 days after admission (n = 288). All patients received aspirin, heparin, and diltiazem, and other drugs and transfusions when needed.

Main outcome measures

Left ventricular function, composite clinical end point (death, stroke, reinfarction, heart failure, and recurrent ischemia), and reocclusion.

Main results

No difference existed among the groups for left ventricular ejection fraction (mean 54%, P = 0.98). The combination of t-PA and urokinase produced a lower reocclusion rate (2%) than either drug alone (12% with t-PA and 7% with urokinase, P = 0.04), and led to fewer composite clinical end points: 32% with the combination, 40% with t-PA {95% CI for the 8% difference, -2% to 17%}* and 45% with urokinase {CI for the 13% difference, 4% to 23%}*. (P = 0.013 for overall difference). Early angiography and angioplasty of appropriate lesions also produced a lower rate of the composite clinical end points (33%) than deferred angiography (45%) {CI for the 12% difference, 4% to 20%}*. Mean predischarge artery patency was ≥ 90% for all treatment groups.

Conclusion

Combination thrombolytic therapy with urokinase and tissue-type plasminoger activator, coupled with an aggressive angiographic strategy, was more successful than monotherapy and deferred angiography in avoiding composite adverse clinical end points among hospitalized patients with myocardial infarction.

Sources of funding: Abbott Laboratories; Agency for Health Care Policy and Research; National Heart, Lung, and Blood Institute.

Address for article reprint: Dr. R.M. Califf, Duke University Medical Center, Box 31123, Durham, NC 27710, USA.

*Numbers calculated from data in article.


Commentary

Continuing heparin beyond 24 hours after rt-PA was not better than oral aspirin-dipyridamole for acute 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 for any intervention requires a large number of patients or the use of surrogate end points for mortality. For this reason, both studies 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 study 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, the 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