Combination of Low Molecular Weight Heparins with Antiplatelet Agents in Non-ST Elevation Acute Coronary Syndromes
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This article reviews the use of low molecular weight heparin (LMWH) and antiplatelet agents in the treatment of unstable angina and non-ST segment elevation myocardial infarction (NSTEMI), which together account for 1 million hospitalisations annually in the US alone. Mortality and recurrent myocardial infarction (MI) in these conditions is currently approximately 8 to 16% at 1 month, and there is a need to optimise treatment further.
Since their introduction, LMWHs have been shown to be successful and well tolerated in the treatment of unstable angina and NSTEMI, but differences have been seen in their efficacy compared with the parent compound, unfractionated heparin (UFH). A meta-analysis of all LMWHs, grouped, versus UFH showed equivalent efficacy and safety. The LMWHs dalteparin sodium and nadroparin calcium have independently been shown to be as effective as UFH. However, enoxaparin sodium has been shown to have greater clinical efficacy than UFH in patients with unstable angina (UA)/NSTEMI.
One area of new research is patients with UA/NSTEMI who later undergo percutaneous coronary interventions (PCI), and early data suggest enoxaparin can be safely used as an anticoagulant instead of UFH in these patients. There is a wealth of data for glycoprotein (GP) IIb/IIIa receptor antagonists (abciximab, eptifibatide, lamifiban, and tirofiban), although some are conflicting. Recent meta-analyses suggest that some benefit is conferred by using these compounds, particularly in patients who undergo PCI.
Recent trials have focussed on combining GP IIb/IIIa antagonists with LMWH, and although data is still scant, the ACUTE (Anti-thrombotic Combination Using Tirofiban and Enoxaparin) and ACUTE II studies indicate the safety and potential clinical benefit of combining enoxaparin with tirofiban in patients with UA/NSTEMI not undergoing PCI, compared with UFH and tirofiban. The NICE (National Investigators Collaborating on Enoxaparin) 4 study collected data on the combination of enoxaparin and abciximab in patients undergoing PCI, and both safety and efficacy data compared well with historical data collected on the use of UFH with abciximab. The more recent NICE 3 study extended this finding to the combination of enoxaparin with abciximab, tirofiban or eptifibatide. The safety of two doses of dalteparin and abciximab had also been investigated, with the higher dose the efficacious, and also with safety, in patients undergoing PCI. In addition, a GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes) IV substudy found that dalteparin had equivalent safety to UFH when co-administered with abciximab in patients not undergoing PCI. The NICE 3 and 4 trials were not randomised comparisons, and as such there results must be interpreted with caution. Recently, the CRUISE (Coronary Revascularisation Utilizing Integrelin [eptifibatide] and Single-bolus Enoxaparin) and INTERACT (Integrelin and Enoxaparin randomised assessment of Acute Coronary Syndromes Treatment) studies have provided evidence for both the safety and efficacy of enoxaparin combined with eptifibatide in non-ST elevation patients with acute coronary syndromes. A further study (SYNERGY [Superior Yield of the New strategy of Enoxaparin, Revascularization and GlYcoprotein IIb/IIIa inhibitors]) will investigate the efficacy of the combination of enoxaparin with abciximab versus that of UFH and abciximab in a large cohort of 8000 patients.
The use of GP IIb/IIIa agents and LMWH in patients with UA/STEMI has led to their use in those with ST-elevation MI, and studies indicate LMWH is efficacious and can be used safely as an adjunct to thrombolysis. New studies will investigate the use of these agents in patients with STEMI not undergoing thrombolysis and we await the results of these studies.
Dr Cohen has received grant and research support from Aventis, Merck and Guident Corporation. This manuscript was supported by Aventis Pharma.
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