Studies supporting the addition of a parental anticoagulant to aspirin in patients with NSTE-ACS were performed primarily on patients with a diagnosis of “unstable angina” in the era before dual anti-platelet therapy and early catheterization and revascularization. In general, those studies found a strong trend for reduction in composite adverse events with the addition of parenteral unfractionated heparin to aspirin therapy – AHA/ACC Guidelines 2014 0
1988 Threoux et al. Aspirin, heparin, or both to treat acute unstable angina.
1990 RISC Group. Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease.
1990 Cohen et al. Usefulness of antithrombotic therapy in resting angina pectoris or non-Q-wave myocardial infarction in preventing death and myocardial infarction (a pilot study from the antithrombotic therapy in acute coronary syndromes study group).
1994 Holdright et al. Comparison of the effect of heparin and aspirin versus aspirin alone on transient myocardial ischemia and in-hospital prognosis in patients with unstable angina.
1994 Cohen et al. Combination antithrombotic therapy in unstable rest angina and non-Q-wave infarction in nonprior aspirin users. Primary end points analysis from the ATACS trial.
1995 Gurfinkel et al. Low molecular weight heparin versus regular heparin or aspirin in the treatment of unstable angina and silent ischemia.
1996 FRISC group. Low-molecular-weight heparin during instability in coronary artery disease
1996 Oler et al. Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina.
Because the anticoagulant effects of heparin are brief, any benefit of therapy is unlikely to last beyond the duration of treatment. Consistent with this theory, we found no reduction in the risk of MI or death between 2 and 12 weeks following randomization in patients with unstable angina who received heparin and aspirin compared to those who received aspirin alone. This result underscores that heparin is a short-acting, temporizing therapy, and not an intervention that alters underlying atherosclerotic disease. – Oler et al. 1996
Synthesis of the data
- Holdright 1994 used a 48-hour heparin infusion and evaluated event-free survival at 30 days. Since this study had plenty of time to evaluate the rebound of events following withdrawal of heparin, the results were negative. Note that the heparin group was doing better at day two, but this benefit promptly disappeared.
- Cohen 1994 used heparin followed by warfarin throughout the entire study period. These authors didn't observe a sharp rebound in event rates because they continued anticoagulation throughout the entire study.
- Gurfinkel 1995 found a benefit of low molecular-weight heparin, but not unfractionated heparin. This may reflect that unfractionated heparin wears off more quickly, leading to a faster rebound in infarction rate. The FRISC study showed that after stopping low molecular-weight heparin the rebound in reinfarction rate occurs over several days. The Gurfinkel study may not have followed patients long enough to observe this.
Implications for management of NSTEMI today
What do the European Society of Cardiology guidelines say?
Recurrence of events after interruption of unfractionated heparin explains why this benefit is not maintained over time, unless the patient is revascularized before the interruption of unfractionated heparin” – European Society of Cardiology guidelines 2011
What does the Cochrane Database say?
Limitations of the data
- AHA/ACC recommends anticoagulation with heparin as a Class I recommendation despite no proven benefit (the AHA/ACC bases this on a “strong trend for reduction in composite adverse events”).
- Heparin causes a temporary reduction in ischemic events, with a rebound in events following discontinuation. No placebo-controlled study has ever shown a sustained benefit from heparin.
- For NSTEMI patients treated with an invasive strategy, heparin makes sense as a temporary bridge to definitive revascularization with stenting or CABG surgery. However, this has never been proven in a prospective placebo-controlled RCT.
- For NSTEMI patients treated with a noninvasive strategy, heparin carries a significant risks of hemorrhage without offering any long-term benefit. In particular, the practice of using a 48-hour heparin infusion for patients treated with a noninvasive approach is not supported by evidence and should be abandoned (Holdright 1994).
(1) It is unclear exactly how long patients were on study therapy, given the multiple indications to stop study therapy.