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


Therapeutics

Discontinuation of heparin in patients with angina resulted in reactivation of ischemia

ACP J Club. 1993 Jan-Feb;118:5. doi:10.7326/ACPJC-1993-118-1-005


Source Citation

Théroux P, Waters D, Lam J, Juneau M, McCans J. Reactivation of unstable angina after the discontinuation of heparin. N Engl J Med. 1992 Jul 16;327:141-5.


Abstract

Objective

To monitor the occurrence of reactivation of unstable angina and myocardial infarction after the discontinuation of heparin in patients with unstable angina.

Design

Unexpected observation during the post-treatment period of a randomized, double-blind, placebo-controlled trial.

Setting

Hospital in Canada.

Patients

479 patients (mean age 58 y) hospitalized with unstable angina. 403 of the original 479 patients who had completed 6 days of therapy without refractory angina or myocardial infarction had all study medication discontinued and were followed for 96 hours in the hospital.

Intervention

Patients were assigned to 1 of 4 groups: aspirin, 325 mg twice daily, plus placebo heparin (n = 121); intravenous heparin, 5000 units, followed by a continuous infusion to maintain the activated partial-thromboplastin time at 1.5 to 2 times the baseline values plus placebo aspirin (n = 118); a combination of aspirin and heparin (n = 122); and placebo aspirin plus placebo heparin (n = 118). Study drugs were stopped abruptly after coronary arteriography. Patients with end-point events occurring before arteriography were excluded from subsequent follow-up.

Main outcome measures

Refractory angina (defined as recurrent chest pain with ST-T changes) and new myocardial infarction.

Main results

Reactivation of unstable angina occurred in more patients who had been in the heparin-alone group than in the aspirin and heparin group, the aspirin-alone group, and the placebo group (P < 0.01) (Table). 4 of the 6 myocardial infarctions occurred in the heparin-alone group. The reactivations were more likely to be severe in the heparin-alone group with 11 patients requiring urgent intervention compared with only 2 patients in the other 3 treatment groups combined (P < 0.01). Reactivation occurred within a median of 9.5 hours after the discontinuation of the study drugs in the heparin-alone group compared with a median of 28 hours in the other 3 groups (P < 0.05). Logistic regression analysis identified therapy with heparin-alone as the most powerful predictor of reactivation (P = 0.009).

Conclusion

The discontinuation of heparin therapy a mean of 6 days after initiation in patients with acute unstable angina resulted in reactivation of ischemia within hours, manifested by recurrent unstable angina, myocardial infarction, or both.

Source of funding: Not stated.

For article reprint: Dr. R. Théroux, Montreal Heart Institute, 5000 Belanger Street, Montreal, Quebec H1T 1C8, Canada. FAX 514-593-2540.


Table. Reactivation of unstable angina with aspirin plus heparin, aspirin-alone, or placebo vs heparin alone at 96 hours*

Treatment EER Heparin-alone CER RRR (95% CI) NNT (CI)
Aspirin plus heparin 5% 13% 65% (9 to 86) 12 (6 to 107)
Aspirin-alone 4% 13% 70% (16 to 89) 11 (6 to 61)
Placebo 5% 13% 65% (3 to 88) 12 (6 to 317)

*Abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.


Commentary

In the initial trial by Théroux and colleagues, treatment with intravenous heparin, aspirin, or both significantly reduced the incidence of myocardial infarction compared with placebo (1). Patients randomized to treatment with intravenous heparin, either with or without aspirin, were less likely to have refractory angina during the first 6 days of the study than patients treated with aspirin alone or placebo. Théroux (1) and others (2) also have shown that treatment with intravenous heparin in patients hospitalized with unstable angina is more effective than aspirin alone in the initial 5 to 7 days (1, 2). The results of the current study, however, suggest that anticoagulation alone may not result in prolonged inhibition of the procoagulant factors that promote coronary thrombosis, but treatment with aspirin in conjunction with heparin appears to provide a more prolonged benefit.

This study provides additional important insights into the use of heparin and aspirin in patients with unstable angina. Conjunctive treatment with aspirin during the early management of patients with unstable angina may confer additional benefit (3), but at the risk of a slightly greater increase in serious bleeding complications (1). The results of the current study suggest that aspirin should be started before heparin is discontinued to avoid recurrence of ischemic symptoms and should be continued long term, which appears to reduce the incidence of myocardial infarction in these patients (4, 5).

Rebound was also observed with hirudin and low-molecular-weight heparin (6, 7). The phenomenon of rebound is important and should be studied further. The effect of new drugs on rebound should also be examined.

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


References

1. Théroux P, Ouimet HJ, McCans J, et al. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med. 1988;319:1105-11.

2. Neri Serneri GG, Gensini GF, Poggesi L, et al. Effect of heparin, aspirin, or alteplase in reduction of myocardial ischaemia in refractory unstable angina. Lancet. 1990;335:615-8.

3. The RISC Group. Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. Lancet. 1990;336:827-30.

4. Cairns JA, Gent M, Singer J, et al. Aspirin, sulfinpyrazone, or both in unstable angina. Results of a Canadian multicenter trial. N Engl J Med. 1985;313:1369-75.

5. Lewis HD Jr, Davis JW, Archibald DG, et al. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study. N Engl J Med. 1983;309:396-403.

6. Fragmin during Instability in Coronary Artery Disease (FRISC) study group. Low-molecular-weight heparin during instability in coronary artery disease. Lancet. 1996;347: 561-8

7. The Global Use of Strategies to Open Ocluded Coronary Arteries (GUSTO) IIb Investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl J Med. 1996;335:775-82.