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• W2029192829 abstract "Over the last decade, significant advances have been made in the pharmacotherapy of acute coronary syndromes (ACS). Although aspirin and unfractionated heparin have been the primary agents in fighting ACS, additional approaches have been necessary to combat the intense inflammatory and thrombotic cascades invoked by ACS. In particular, dual antiplatelet therapy with clopidogrel [1], low-molecular-weight heparins (LMWH) [2], and direct thrombin inhibitors [3, 4] have shown great promise in quelling the storm. Another promising reinforcement arrives in the form of factor (F)Xa inhibitors. FXa is the ‘gatekeeper’ of the coagulation cascade, mediating the entry of the extrinsic and intrinsic coagulation pathways to the final common pathway—the conversion of prothrombin to thrombin. Inhibiting this central component has had great appeal from a mechanistic perspective; indeed, LMWHs, in particular enoxoparin, have greater anti-FXa activity than unfractionated heparin and appear to be superior in limiting thrombosis [5]. Similarly, the indirect FXa inhibitor fondaparinux has equivalent or greater efficacy than enoxaparin in preventing venous thromboembolism after orthopedic surgery [6-10], treating pulmonary embolism [11], and treating patients with acute coronary syndromes [12]. In this issue of Journal of Thrombosis and Haemostasis, Alexander and colleagues increase the appeal of FXa inhibition with their phase II trial of DX-9065a—a direct, selective FXa inhibitor—in patients with non-ST-elevation acute coronary syndromes (XaNADU-ACS trial). Patients with ACS were randomized to unfractionated heparin, low-dose DX-9065a or high-dose DX-9065a. The primary end-point was a composite of death, myocardial infarction, urgent revascularization, or ischemia on continuous ST-segment monitoring. This trial was well designed. Its first strength was the population studied; these patients were representative of a high-risk ACS population, with approximately 25% having diabetes, 35% having baseline ST-segment depression, and over 80% with myocardial infarction on admission. Second, patients had excellent medical therapy, with almost 100% receiving aspirin, over 75% receiving a thienopyridine, over 60% receiving glycoprotein IIb/IIIa inhibitors, and over 80% receiving lipid-lowering therapy. Finally, these patients received both optimal medical therapy and aggressive intervention, with almost 100% undergoing angiography, more than 50% undergoing percutaneous coronary intervention (PCI), and almost 20% undergoing coronary artery bypass grafting. Thus, these patients not only mirrored a realistic ACS population, but they also received ‘state-of-the-art’ care. These strengths, of course, increase the credibility of the investigators' findings. Although the primary end-point did not differ between groups (which is not surprising for a small, phase II study), the trial had strong signals suggesting that DX-9065a might be more efficacious and safer than unfractionated heparin for treating ACS. Specifically, patients treated with high-dose DX-9065a had a statistical trend for lower rates of urgent revascularization and symptomatic ischemia, and the composite end-point of death, myocardial infarction, or urgent revascularization was lower in the high-dose group compared with placebo (11.9% of high-dose patients compared with 19.3% of heparin patients, P = 0.125). Importantly, these trends occurred even though the high-dose group was higher risk despite randomization (43% of these patients had ST-segment depression at baseline compared with 29% of patients who received placebo, P = 0.069) The investigators also measured drug concentrations in all patients and demonstrated an inverse linear relationship between probability of an ischemic event and drug concentration (see Table 5a); this was statistically significant (P = 0.03). Finally, a strong trend existed for lower transfusion rates in patients treated with high-dose DX-9065a (0.7% compared with 1.4% for low-dose DX-9065a and 3.1% for heparin, P = 0.078). These findings may be preliminary, but they are very encouraging and merit further investigation in a larger, phase III trial. It will take time, however, to discern exactly how FXa inhibitors will fit in the increasingly complex treatment of patients with ACS, and in the adjunctive therapy of patients undergoing PCI. Fortunately, investigation of other FXa inhibitors is moving rapidly, and several trials have begun (see Table 1). For example, the SEPIA-PCI trial will compare the direct FXa inhibitor otamixaban with unfractionated heparin in patients undergoing non-urgent PCI [13]. The MICHELANGELO-OASIS-5 trial will randomize approximately 16 000 patients with unstable angina and non-ST-elevation myocardial infarction to enoxaparin or fondaparinux [14]. The MICHELANGELO-OASIS-6 trial will randomize approximately 10 000 patients with ST-elevation myocardial infarction to unfractionated heparin or fondaparinux [14]. In addition to this extraordinary clinical trial activity, development of other FXa inhibitors continues unabated, including potent, orally active FXa inhibitors such as DPC423 (Phase I), BAY-59–7939 (Phase I), and DPC602 (preclinical) [15-17]. All of this research is exciting and timely. Despite advances in anticoagulant therapy and interventional techniques, patients with acute coronary syndromes still experience high rates of death or reinfarction. A multifaceted attack is not just attractive theoretically; it is essential clinically. Given the prominence of FXa in the coagulation system, FXa inhibitors are compelling actors to lead the charge. In several years, it is likely that this will be no idle myth." @default.
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• W2029192829 title "Factor Xa inhibitors in acute coronary syndromes: moving from mythology to reality" @default.
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