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Therapeutics

Low-molecular-weight heparin prevented new cardiac events in unstable angina

ACP J Club. 1996 July-Aug;125:1. doi:10.7326/ACPJC-1996-125-1-001


Source Citation

Fragmin during Instability in Coronary Artery Disease (FRISC) Study Group. Low-molecular-weight heparin during instability in coronary artery disease. Lancet. 1996 Mar 2;347:561-8.


Abstract

Objective

To evaluate the effectiveness of subcutaneous low-molecular-weight heparin (LMWH) in preventing new cardiac events in patients with unstable coronary artery disease.

Design

150-day randomized, double-blind, placebo-controlled trial.

Setting

23 hospitals in Sweden.

Patients

1506 patients who were > 40 years of age (median age 70 y, 64% men) and who had been admitted to the hospital because of chest pain in the previous 72 hours. Inclusion criteria were new onset or increased angina or angina at rest in the previous 2 months or persisting chest pain, and at least 1 of either transient or persistent pathologic ST depression of ≥ 0.1 mV or T-wave inversion of ≥ 0.1 mV in at least 2 adjacent leads without pathologic Q-waves in the ischemic leads. Exclusion criteria included increased risk for bleeding, Q-waves or bundle branch block, planned revascularization, uncontrolled hypertension or hypotension, or other cardiac or serious disease. Follow-up was > 99%.

Intervention

Patients were allocated to injections of dalteparin sodium (n = 746) or placebo (sodium chloride, 9 g/L) (n = 760). Patients received dalteparin, 120 IU/kg of body weight (maximum 10 000 IU), or placebo every 12 hours for 6 days followed by dalteparin, 7500 IU, or placebo once per day for 35 to 40 days (at home).

Main outcome measures

The primary end point was death or new myocardial infarction (MI) at 6 days. Secondary end points were death or new MI at 40 and 150 days.

Main results

6 days of treatment with dalteparin led to a lower rate of death or new MI than did placebo (1.8% vs 4.8%, P = 0.001). {This absolute risk reduction (ARR) of 3% means that 33 patients would need to be treated (NNT) with dalteparin (compared with placebo) for 6 days to prevent 1 additional death or new MI, 95% CI 20 to 80; the relative risk reduction (RRR) was 63%, CI 32% to 80%.}* The groups did not differ for death or new MI at 40 or 150 days. When revascularization was included in the end point, patients who received dalteparin had a lower rate of death, new MI, or revascularization at 40 days than did patients who received placebo (18% vs 24%, P = 0.005) {ARR 6%, NNT 18, CI 10 to 64; RRR 24%, CI 7% to 38%}* but did not have a lower rate at 150 days (41% vs 44%, P = 0.18).

Conclusions

Low-molecular-weight heparin was effective in preventing new cardiac events in patients with unstable coronary artery disease. Its effectiveness was most apparent in the first 6 days of treatment.

Sources of funding: Pharmacia, Stockholm, Sweden, and the Swedish National Association against Heart and Lung Diseases.

For article reprint: Professor L. Wallentin, Department of Cardiology, University Hospital, S-781 85 Uppsala, Sweden. FAX 46-18-50-66-38.

*Numbers calculated from data in article.


Commentary

Unstable angina and non-Q-wave MI are characterized by varying degrees of plaque rupture and coronary arterial thrombosis (1, 2). They are among the most common causes of hospitalization in industrialized nations.

The study bears good news for clinicians but reminds us that much work lies ahead. LMWH was effective in preventing new cardiac events during the first 6 days of treatment. Differences persisted at 40 days, particularly in high-risk patients, but were strongly influenced by revascularization rates. By 150 days, no differences existed between groups for any of the primary or secondary outcome measures.

How should we interpret these findings? Atherosclerotic coronary artery disease is a dynamic process and plaque activity persists after initial clinical stabilization (3, 4). LMWH (combined with low-dose aspirin) appears to be more effective than low-dose aspirin alone during the early phase of treatment.

The benefits, however, were short-lived, and the benefits compared with intravenous unfractionated heparin and either higher-dose aspirin or more potent platelet inhibitors (glycoprotein IIb/IIIa antagonists) are unknown and await the results of ongoing clinical trials.

LMWH may offer the advantage of convenience and applicability compared with existing therapies and adds an important dimension to the management of low- and intermediate-risk patients. Early identification of high-risk patients is of vital importance, and treatment strategies that directly address the underlying pathologic substrate must be developed and studied if further improvement in patient care is to be realized.

Richard C. Becker, MD
University of Massachusetts Medical SchoolWorcester, Massachusetts, USA


References

1. Davies MJ, Thomas AC. Br Heart J. 1985;53:363-73.

2. Farrell M, Fuster V. In: Becker RC, ed. The Modern Era of Coronary Thrombolysis. Boston: Kluwer Academic Publishers; 1994:1-13.

3. Rho R, Tracy RP, Bovill EG, Ball SP, Becker RC. Journal of Thrombosis and Thrombolysis. 1995;2:239-43.

4. Becker RC, Bovill EG, Corrao JM, et al. Journal of Thrombosis and Thrombolysis. 1995;2:57-64.