Curriculum in CardiologyPersistence of the prothrombotic state after acute coronary syndromes: Implications for treatment☆,☆☆,★
Section snippets
Aspirin
The recommendation for aspirin to be given as soon as possible in all patients with ACS is based largely on the treatment's efficacy reported in the second International Study of Infarct Survival (ISIS-2) trial.27 Nearly half the 23% reduction in mortality observed in aspirin-treated patients occurred between 2 and 35 days after the acute event. Long-term aspirin treatment conclusively reduces the incidence of subsequent MI, stroke, and vascular death among patients after ACS, as shown by 4
LMWHs
LMWHs have several advantages compared with standard heparin. For example, they bind less strongly to inhibitory plasma proteins such as platelet factor 4. This characteristic, combined with the longer half-lives and high bioavailability when administered subcutaneously, results in longer and more predictable anticoagulant effects without the need for laboratory monitoring. By nature of the high anti-Xa to anti-IIa activity, they are more effective than unfractionated heparin (UFH) at
Warfarin
The efficacy of warfarin therapy for MI patients has been documented. Several trials indicate that moderate-intensity warfarin is both effective (35% to 40% relative risk reduction in major vascular events) and reasonably safe, but these studies were small and conducted without aspirin in the control arms.42, 43 Investigators comparing anticoagulants with antiplatelet therapy have not found a significant benefit in reducing death or reinfarction, but a higher risk of bleeding.
Two trials have
Clopidogrel
Clopidogrel was compared with aspirin in the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial.51 More than 19,000 patients were enrolled. Clopidogrel resulted in a small reduction in the primary end point of ischemic stroke, MI, or vascular death (8.7%, 95% CI 0.3-16.5). In subgroup analyses, the point estimate of benefit was greater among patients with peripheral arterial disease or cerebrovascular disease than with coronary syndromes. This study showed that
Oral GP IIb/IIIa inhibitors
On the basis of the proved benefits of the intravenous GP IIb/IIIa inhibitors in the acute setting and aspirin in the subacute setting, there was great anticipation that oral GP IIb/IIIa inhibitors would be highly effective in reducing subacute events. However, 5 phase III trials investigating oral GP IIb/IIIa antagonists have failed to demonstrate benefit.54
The Evaluation of Oral Xemilofiban in Controlling Thrombotic Events (EXCITE) trial tested xemilofiban in patients undergoing percutaneous
Antithrombotic treatment effect in subgroups
As a general principle, the benefit with respect to relative risk reduction of a therapy is similar across various subgroups of patients who share a common disease. The absolute benefit of a therapy, therefore, can best be estimated by the absolute risk of a particular patient, with patients at higher risk deriving greater absolute benefit.62 Two subgroups of patients with ACS may warrant special consideration when estimating treatment effect of longer-term antithrombotic therapy: patients with
Ongoing research
Further trials are being conducted to evaluate warfarin given to achieve a higher INR. A large number of additional targets for longer antithrombotic therapy have been identified and currently are being developed, such as oral direct thrombin inhibitors, factor Xa inhibitors, and VIIa/tissue factor inhibitors.
Conclusions
In spite of major improvements in recent years in the early management of ACS, there is a major need to develop and apply therapies to reduce the incidence of recurrent ischemic events in the weeks after ACS. In addition to aspirin and clopidogrel, the only antithrombotic treatment that has been shown to reduce ischemic events during this time period is with LMWHs. Longer-term treatment with LMWH may be important for patients with elevated troponin and for those who have not yet undergone
Acknowledgements
We thank Vic Hasselblad for the statistical support.
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Supported by an unrestricted educational grant from Pharmacia & Upjohn, Peapack, NJ.
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Guest Editor for this manuscript was Richard C. Becker, MD, University of Massachusetts Medical Center, Worcester, Mass.
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Reprint requests: Maria Cecilia Bahit, MD, Duke Clinical Research Institute, PO Box 17969, Durham, NC 27715. E-mail: [email protected]