New antithrombotic drugs: beyond aspirin and heparin.

Abstract

Low-molecular-weight heparins (LMWHs) have been rigorously evaluated in the management of acute coronary ischaemia. The results of clinical trials suggest that the LMWHs (enoxaparin, dalteparin and nadroparin) are effective and safe in the treatment of unstable angina and non-Q-wave myocardial infarction. Two studies have shown enoxaparin to be more effective than unfractionated heparin in this setting. Furthermore, the pharmacologic and pharmacokinetic characteristics of LMWHs result in them having practical and economic advantages. Data on the benefits of long-term therapy with LMWHs are conflicting. Copyright © 1999 S. Karger AG, Basel Antithrombotic therapy with or without revascularization has been extensively studied in patients with acute coronary ischaemic syndromes. The role of aspirin in reducing both fatal and non-fatal myocardial infarction (MI) in the acute phase of unstable angina is well established. Furthermore, the long-term risk of death or MI in patients with acute coronary syndromes is reduced by approximately 50% with regular aspirin use [1]. In acute transmural MI, aspirin alone reduces mortality by 25% [1]. Anticoagulants such as heparin play a key role in inhibiting the generation of thrombin, the enzyme that is central for the formation of fibrin. In patients with unstable angina and non-Q-wave MI, heparin has been shown to decrease the frequency of MI and to reduce overall mortality, particularly when used in combination with aspirin [2–6]. Standard heparin has a number of limitations, however. Gurfinkel et al. [8] Low-Molecular-Weight Heparins in Acute Unstable Coronary Artery Disease Haemostasis 1999;29(suppl 1):72–75 73 Table 1. Summary of LMWH studies/trials Study Year Drug used Compared with 1995 Nadroparin Aspirin or standard aspirin and heparin Wallentin et al. (FRISC) [9] 1996 Dalteparin Aspirin Klein et al. (FRIC) [10] 1997 Dalteparin Intravenous unfractionated heparin Cohen et al. (ESSENCE) [11] 1997 Enoxaparin Standard heparin Antman (TIMI 11B) [12] 1997 Enoxaparin Heparin Leizorovicz (FRAXIS) [13] 1998 Nadroparin Heparin FRISC II [14] 1999 Dalteparin Placebo Invasive versus non-invasive strategy ESSENCE = Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events; FRAXIS = Fraxiparine in Ischaemic Syndromes; FRIC = Fragmin in Unstable Coronary Artery Disease; FRISC = Fragmin During Instability in Coronary Artery Disease; TIMI = Thrombolysis in Myocardial Infarction. In particular, its anticoagulant effect is unpredictable and it has a poor bioavailability when given subcutaneously. Low-molecular-weight heparins (LMWHs) offer a number of pharmacologic and pharmacokinetic advantages over standard heparin: a predictable anticoagulant response, a high bioavailability and a long plasma half-life, which together result in a therapeutic anticoagulant effect with onceor twice-daily subcutaneous injections at fixed, weight-adjusted doses [7]. A number of LMWHs – enoxaparin, dalteparin and nadroparin – have been evaluated in patients with unstable angina and non-Qwave MI (table 1). In a small open trial, nadroparin reduced the risk of ischaemic outcomes, as compared with aspirin alone or a combination of aspirin and standard heparin, in the acute phase [8]. Two large trials have evaluated dalteparin in the management of unstable angina and non-Q-wave MI [9, 10]. In the placebo-controlled FRISC trial (Fragmin During Instability in Coronary Artery Disease), dalteparin (120 units/kg subcutaneously twice daily) resulted in a 63% reduction in the risk of death or acute MI, as compared with aspirin alone, in the acute phase, and was associated with a significant reduction in cardiac events at 42 days when it was continued at a dose of 7,500 units subcutaneously once daily [9]. The FRIC trial (Fragmin in Unstable Coronary Artery Disease), which directly compared dalteparin with intravenous unfractionated heparin, demonstrated that dalteparin, administered at the same therapeutic dose, was not significantly different from heparin in the acute phase. Furthermore, this trial, unlike FRISC, showed no benefit of continued treatment with dalteparin at a low dose once daily [10]. In the ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events) study [11], involving 3,171 patients, enoxaparin (1 mg/kg subcutaneously twice daily) resulted in a statistically significant 16% reduction in the combined outcome