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


Therapeutics

Aspirin plus low-molecular-weight heparin was effective for unstable angina

ACP J Club. 1996 Mar-April;124:39. doi:10.7326/ACPJC-1996-124-2-039


Source Citation

Gurfinkel EP, Manos EJ, MejaĆ­l RI, et al. Low molecular weight heparin versus regular heparin or aspirin in the treatment of unstable angina and silent ischemia. J Am Coll Cardiol. 1995 Aug;26:313-8.


Abstract

Objective

To compare low-molecular-weight heparin (LMWH) combined with aspirin, regular heparin (RH) plus aspirin, and aspirin alone for unstable angina.

Design

Randomized, single-blind, placebo-controlled trial.

Setting

Coronary care unit in Argentina.

Patients

211 patients (mean age 63 y, 76% men) who were aged > 21 years and had recent onset or prolonged unstable angina, spontaneous rest pain 24 hours before randomization, and evidence of ischemic heart disease. Exclusion criteria included acute or recent myocardial infarction (MI); left bundle-branch block; angina caused by pulmonary edema, status after acute or subacute MI, thyrotoxicosis, hypertension, or anemia; angioplasty within 3 months; contraindications to anticoagulants or nonsteroidal anti-inflammatory drugs; use of anticoagulants; terminal disease; pregnancy; and implanted pacemaker. Follow-up was complete.

Intervention

Patients were allocated to aspirin, 200 mg/d, plus LMWH, 214 units Institute Choay/kg anti-Xa subcutaneously twice daily (n = 68); aspirin, 200 mg/d, plus RH, 400 IU/kg body weight per day intravenously, with adjustment based on activated partial thromboplastin time measurements (n = 70); or aspirin, 200 mg/d, plus saline placebo, unblinded (n = 73).

Main Outcome Measures

Primary outcomes were recurrent angina, acute MI, urgent intervention (coronary angioplasty or bypass surgery), major bleeding, and death.

Main Results

Analysis was by intention to treat. Patients in the aspirin plus LMWH group had a lower rate of recurrent angina than did patients in the aspirin plus RH group (21% vs 44%, P = 0.003) and patients in the aspirin alone group (21% vs 37%, P = 0.03). {For the first comparison, this absolute risk reduction (ARR) of 23% means that 4 patients would need to be treated (NNT) to prevent 1 patient from having recurrent angina, 95% CI 3 to 12; the relative risk reduction (RRR) was 54%, CI 22% to 73%; and for the second comparison, ARR 16%; NNT 6, CI 3 to 70; RRR 44%, CI 4.7% to 68%.}* No patients who received aspirin plus LMWH had an acute MI compared with 7 patients (9.5%) who received aspirin alone (ARR 9.5%, P = 0.01). 1 patient (1.5%) who received aspirin plus LMWH required revascularization compared with 9 patients (12%) who received aspirin alone (P = 0.01) {ARR 11%; NNT 9, CI 5 to 34; RRR 88%, CI 30% to 98%}*.

Conclusion

In patients with unstable angina, aspirin plus low-molecular-weight heparin was superior to aspirin plus regular heparin for reducing the occurrence of acute myocardial infarction and the need for revascularization, and it was superior to both aspirin plus regular heparin and aspirin alone for reducing recurrent angina.

Source of funding: Not stated.

For article reprint: Dr. E. Gurfinkel, Institute of Cardiology and Cardiovascular Surgery, University Institute of Biomedical Sciences, Favaloro Foundation, Belgrano 1746 (1093), Buenos Aires, Argentina. FAX 54-1-381-1001.

*Numbers calculated from data in article.


Commentary

The study by Gurfinkel and colleagues is one of the first to evaluate LMWH for thrombotic arterial diseases on the basis of previous studies of LMWH in the prevention and treatment of venous thrombosis and thromboembolism. LMWH has several important theoretical advantages over unfractionated heparin for treating unstable angina, but this trial had predominantly clinical end points and thus does not advance mechanistic insight.

The study is weakened by its unblinded design. Because the end points most affected by LMWH are subjective (angina recurrence) or subjectively pursued (subsequent infarction, need for revascularization), bias may have influenced the results. Nonetheless, the favorable safety profile and preliminary efficacy data provide a strong rationale for the large-scale trials recently completed or currently under way but not for the adoption of LMWH as standard treatment for unstable angina at present.

An issue that is not resolved by this study and is unlikely to be resolved by other studies is the comparative effects of different LMWH preparations. The results of this study, which evaluated nadroparin calcium, may not be directly generalizable to enoxaparin or other LMWH formulations currently being investigated. The study also suggests that the addition of unfractionated heparin to aspirin had similar efficacy and increased bleeding similar to that seen with aspirin alone, as was found in another recent, small trial (1). Thus, the limitations of unfractionated heparin are underscored, as is the potential for LMWH and other new antithrombins and antiplatelet agents to further reduce the rate of events. Clinical trials must assess whether this can be done without excessive hemorrhage in patients with unstable angina and MI.

Steven Borzak, MD
Henry Ford HospitalDetroit, Michigan, USA


References

1. Holdright D, Patel D, Cunningham D, et al. J Am Coll Cardiol. 1994;24:39-45.

2. Ridker PM, O'Donnell CJ, Hennekens CH, et al. Journal of Thrombosis and Thrombolysis. 1995;1:119-24.