Haemostasis and thrombosis : new developments in treatment strategies

The pivotal studies from 2002 in the field of clinical haemostasis and thrombosis were all about the evaluation of existing or novel antiplatelet and anticoagulant strategies. Most of the new agents are specifically targeted to haemostatic pathways, which have recently been shown to be of importance in vivo and usually have a higher efficacy in comparison with currently available treatment strategies. In some cases this also results in a (relatively modest) increase in the risk of bleeding. The clinical use of the new compounds is often much more convenient than that of the currently available antithrombotic modalities. or aspirin in combination with moderately dosed coumarin (INR 2.5-3.0). Mean follow-up was 26 months and the main outcome parameter was death, acute myocardial infarction or stroke. The incidence of this composite endpoint was significantly lower in the highdose coumarin and moderate-dose coumarin plus aspirin group compared with the aspirin-alone group (5, 5, and 9%, respectively), resulting in a hazard ratio of about 50% (95% confidence interval (CI) 0.3-1.0) of coumarincontaining regimens versus aspirin alone. There was a nonsignificant trend towards a lower mortality in the coumarin group (1%), compared with the coumarin plus aspirin group (3%) and the aspirin-alone group (4%). The incidence of major bleeding was 2% in the group receiving aspirin plus coumarin and 1% in the two other groups. Haemorrhagic stroke only occurred in 1 of 332 patients (0.3%) in the aspirin plus coumarin group. Another salient result in this trial was again the demonstration of the poor regulation of vitamin K antagonist therapy, resulting in only about 50% of patients being in the therapeutic range for only 50% of the time, as had been shown by previous trials as well. L O N G T E R M C L O P I D O G R E L A N D A S P I R I N A F T E R P E R C U T A N E O U S C O R O N A R Y I N T E R V E N T I O N S Clopidogrel belongs to the class of thienopyridine derivatives which act by blocking the adenosine 5’-diphosphate (ADP) receptor on the platelet. A previous study comparing clopidogrel with aspirin as secondary prophylaxis in patients with a myocardial infarction, stroke or peripheral arterial disease demonstrated an equivalent efficacy of these two antiplatelet agents. The combination of clopidogrel and aspirin was shown to be superior to aspirin alone in another study of patients after an acute coronary event (defined as acute myocardial infarction or unstable angina). In this study of over 12,000 patients, the incidence of the combined endpoint of cardiovascular mortality, myocardial infarction or stroke was 9.3% in the clopidogrel plus aspirin group compared with 11.5% in the aspirin-alone group (relative risk 0.8, 95% CI 0.72-0.89). Earlier studies had already shown the superiority of the combination aspirin and clopidogrel in the protection against acute thrombotic occlusion of coronary stents in the first six weeks after placement in comparison with various combinations of anticoagulant agents at relatively high doses. The CREDO (Clopidogrel for Reduction of Events During Observation) trial was designed to answer the question whether the combination clopidogrel plus aspirin would also offer longer-term protection against cardiovascular mortality, myocardial infarction or the need for revascularisation in patients who had been treated with intracoronary stents. More than 2000 patients in 99 different centres participated in the trial. During a 12month follow-up the incidence of the composite endpoint was 8.5% in the clopidogrel plus aspirin group and 11.5% in the aspirin-alone group, a relative risk reduction of 27% (95% CI 3.9-44.4). Major bleeding was somewhat more frequent in the aspirin plus clopidogrel group (8.8%) compared with the aspirin group (6.7%). In previous studies the incidence of major bleeding with the combination aspirin and clopidogrel was comparable with bleeding induced by aspirin alone. Based on these results, it can be concluded that the combination aspirin and clopidogrel is a promising strategy for secondary prophylaxis of atherothrombotic events. Future studies should determine whether the additional protection offered by this combination will also be present at even longer follow-up. D I S A P P O I N T I N G R E S U L T S O F O R A L G L Y C O P R O T E I N I I B / I I I A I N H I B I T I O N The platelet glycoprotein (GP) IIb/IIIa receptor can bind to fibrinogen, which is the pivotal event in platelet aggregation. Competitive inhibition of this receptor is therefore theoretically the most potent antiplatelet therapy available. The prototype of GP IIb/IIIa inhibitors is the humanised monoclonal antibody abciximab. In four large trials with this compound the efficacy of abciximab in patients undergoing (complex) percutaneous intracoronary interventions, with and without stent placement, was confirmed. Based on this success and in view of the potential disadvantages of murine monoclonal antibody therapy, and the relatively high price, a large array of alternative GP IIb/IIIa receptors have been developed. These agents are synthetic peptides, containing the sequence ‘arginine-glycine-aspartamic acid (RGD)’, which is essential for the interaction with the GP IIb/IIIa receptor, or peptidomimetics, which mimic this RGD sequence. Clinical trials again show a superior efficacy in patients with complex coronary revascularisation. Subsequent studies with these agents in patients with acute coronary syndromes (acute myocardial infarction or unstable angina) were more difficult to interpret. It seems that GP IIb/IIIa inhibition is specifically successful in patients who undergo coronary interventions and is less effective, compared with standard therapy, in less complicated situations. Recently, oral formulations of GP IIb/IIIa have become available, which allow long-term treatment. A number of studies have been performed with these compounds, mostly comparing oral GP IIb/IIIa inhibition with aspirin. Disappointingly, most of the studies did not show any benefit of the oral GP IIb/IIIa inhibitors and were prematurely stopped. The reason for this S U P P L E M E N T M A Y 2 0 0 3 , V O L . 6 1 , N O . 5