Anticoagulation Service For Health Professionals
Low-Molecular-Weight-Heparin in Acute Coronary Syndromes
Unfractionated Heparin (UFH) is used routinely in the management of non-Q-wave myocardial infarction (NQMI) and unstable angina pectoris (USA). Despite its proven benefits, UFH has several disadvantages that limit its effectiveness. The anticoagulant response to UFH varies widely, which necessitates frequent hemostatic monitoring. Even with optimal heparin dosing protocols, the APTT is outside the therapeutic range in approximately 40% of patients. Low-molecular-weight heparin (LMWH) is derived from UFH by chemical methods. LMWH has several pharmacologic advantages compared to UFH, including reduced susceptibility to inhibition by platelet factor 4 and greater bioavailability due to reduced interaction with endothelial cells and plasma proteins. Therefore, the anticoagulant response to LMWH is much less variable among patients. Because LMWH has relatively high anti-factor Xa activity and relatively low antithrombin activity, it produces only a minimal effect on the APTT, even when administered in full antithrombotic doses. Therefore, monitoring of the APTT (or thrombin time or ACT) is not necessary in patients on LMWH.
Recent studies in patients with NQMI and USA suggest that LMWH is at least as effective as UFH. The FRISC Trial was a Swedish multicenter study of dalteparin (Fragmin) vs. placebo. All patients received beta blockers and aspirin. Compared to placebo, dalteparin 120 U/kg sc BID reduced the combined end points of death, myocardial infarction and recurrent angina by 63%. However, dalteparin administered once daily post discharge was not beneficial. The FRIC Trial was an international study of dalteparin vs. UFH in patients with NQMI and USA. In addition to in-hospital dalteparin 120 U/kg sc BID, patients were discharged on once daily dalteparin (7500 U/kg) for 6 weeks. This trial concluded that dalteparin was as effective as UFH during in-hospital treatment, but that post-discharge dalteparin did not demonstrate a beneficial effect. A borderline statistically significant increase in death was observed during the in-hospital phase in patients on dalteparin. However, this probably resulted from the relatively small numbers of deaths in this study. The ESSENCE trial was a randomized trial of enoxaparin (Lovenox) vs. UFH in patients with USA and NQMI. Patients were randomized in either enoxaparin 1 mg/kg sc q 12 hr for 2-8 days (mean 2.6) or to standard dose UFH. In contrast to FRIC, ESSENCE found a significant reduction in coronary events by 30 days in patients who received enoxaparin vs. standard unfractionated heparin. This reduction in events was maintained at one year follow-up. The TIMI-11B study, yet unpublished, also found that enoxaparin was superior to UFH in patients with USA/NQMI. Endpoints were death, MI, and urgent revascularization. Incidence of death + MI (i.e. excluding the "softer" endpoint of urgent revascularization) did not differ significantly between LMWH and UFH.
The reasons for the superiority of LMWH in ESSENCE (enoxaparin), but a lack of superiority in the FRIC (dalteparin) are not known. It is possible that enoxaparin is a superior drug to dalteparin. However, it is also possible that standard unfractionated heparin, the "denominator" in both trials, was administered more effectively in FRIC than in ESSENCE. Also, the adverse event rates for both LMWH and UFH were lower in FRIC than in ESSENCE, suggesting that ESSENCE patients may have been a higher risk group than FRIC patients. More studies are necessary to determine if one brand of LMWH is superior to another in patients with acute CAD. At this time, enoxaparin has been used more extensively in the United States for USA/NQMI and is the only LMWH that is FDA approved for this indication. Therefore, the accompanying guidelines suggest enoxaparin
