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Older age, lighter weight, female sex, African ancestry, and invasive procedures were associated with bleeding after thrombolytic therapy

ACP J Club. 1998 Jan-Feb;128:17. doi:10.7326/ACPJC-1998-128-1-017

Source Citation

Berkowitz SD, Granger CB, Pieper KS, et al., for the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) I Investigators. Incidence and predictors of bleeding after contemporary thrombolytic therapy for myocardial infarction. Circulation. 1997 Jun 3;95:2508-16.



To determine the risk factors for bleeding after thrombolytic therapy for acute myocardial infarction.


Univariate and multivariate analysis of participants in the GUSTO-I trial.


1081 hospitals in 15 countries participating in the GUSTO-I trial.


40 903 patients (median age 62 y) who presented to the hospital within 6 hours of symptom onset, had chest pain lasting ≥ 20 minutes, and showed signs of ≥ 0.1 mV of ST-segment elevation in ≥ 2 leads on electrocardiography. Exclusion criteria were active bleeding, recent trauma or major surgery, history of stroke, noncompressible vascular punctures, or previous treatment with streptokinase (SK) or anistreplase.

Assessment of risk factors

Patients were allocated to 1 of 4 thrombolytic regimens: SK plus subcutaneous (SQ) heparin; SK plus intravenous (IV) heparin; accelerated tissue plasminogen activator (t-PA) plus IV heparin; or the combination of IV t-PA, SK, and IV heparin. Data on baseline characteristics, outcomes, and incidence of bleeding by location, severity, and treatment were collected.

Main outcome measures

Severe bleeding (substantial hemodynamic compromise that required intervention or treatment) and moderate bleeding (bleeding that required transfusion but did not lead to hemodynamic compromise that required intervention). Intracerebral hemorrhages were excluded.

Main results

Thrombolytic regimens were strongly related to bleeding. Moderate or severe hemorrhage occurred less often in patients who received SK plus SQ heparin or t-PA plus IV heparin than in patients who received SK plus IV heparin (P < 0.001) or combination therapy (P < 0.001). Bleeding occurred more often in patients who were older, female, lighter, shorter, of African ancestry, and living in the United States. The 3 most powerful independent predictors of hemorrhage were older age (odds ratio [OR] 1.30, 95% CI 1.26 to 1.35), lighter body weight (100 kg vs 90 kg, OR 0.83, CI 0.73 to 0.95; 85 kg vs 75 kg, OR 0.81, CI 0.78 to 0.85), and female sex (OR 1.42, CI 1.31 to 1.53). Bleeding events were strongly related to invasive procedures. Age, weight, and sex remained the 3 most important predictors of bleeding when the analysis was done on patients who did not have invasive procedures.


Older age, lighter weight, female sex, African ancestry, and invasive procedures were associated with risk for bleeding after thrombolytic therapy.

Sources of funding: In part, Bayer; CIBA-Corning; Genentech; ICI Pharmaceuticals; Sanofi Pharmaceuticals.

For article reprint: Dr. S.D. Berkowitz, Divisions of Hematology/Coagulation and Cardiology, Department of Medicine, Box 3471, Duke University Medical Center, Durham, NC 27710, USA. FAX 919-681-7791.


The retrospective analysis of the GUSTO-I trial by Berkowitz and colleagues confirms the similar safety of the most widely used thrombolytic regimens for myocardial infarction. Of particular importance, in this and in a previous analysis of the GUSTO-I data, is that a strong correlation was seen between excessively prolonged activated partial thromboplastin times 12 hours after treatment and increased bleeding complications and mortality, regardless of the type of thrombolytic therapy used (1). Accordingly, the activated partial thromboplastin time should be maintained in a range of 50 to 70 seconds in patients treated with thrombolytic agents and IV heparin. However, Berkowitz and colleagues found that for any given activated partial thromboplastin time, the risk for bleeding was higher in patients assigned to SK than in those assigned to t-PA.

This study confirms that the risk for bleeding is markedly increased in patients who have invasive procedures. Surprisingly, increased bleeding was seen in patients who had coronary artery bypass surgery, even though this intervention occurred a median of 7 days after study enrollment (2). Although the mechanism is unclear, this phenomenon suggests that elective invasive procedures should be avoided or delayed as long as possible after treatment with thrombolytic agents. The other important predictors of bleeding (increased age, lighter weight, female sex, and African ancestry) have been previously identified. The authors provide tables based on risk factors for estimating the risk for bleeding in individual patients that clinicians may find useful in triaging patients to primary angioplasty as an alternative reperfusion strategy.

Paul R. Eisenberg, MD, MPH
Washington University School of MedicineSt. Louis, Missouri, USA


1. Granger CB, Hirsch J, Califf RM, et al. Activated partial thromboplastin time and outcome after thrombolytic therapy for acute myocardial infarction: results from GUSTO-I trial. Circulation. 1996;93:870-8.

2. Tardiff BE, Califf RM, Morris D, et al. Coronary revascularization surgery after myocardial infarction: impact of bypass surgery on survival after thrombolysis. GUSTO investigators. Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries. J Am Coll Cardiol. 1997;29:2409.