For the past five decades, there has been little progress in the development of oral anticoagulants, with the choices being limited to the vitamin K antagonists (VKAs). The situation is changing with the development of orally active small molecules that directly target thrombin or activated factor X (FXa). The two agents in the most advanced stages of development are dabigatran etexilate and rivaroxaban, which inhibit thrombin and FXa, respectively. Both are approved in the EU and Canada for venous thromboprophylaxis in patients undergoing elective hip- or knee-replacement surgery. Other agents in the early stages of development include several FXa inhibitors (apixaban, DU 176b, LY 517717, YM 150, betrixaban, eribaxaban [PD 0348292] and TAK 442) and one thrombin inhibitor (AZD 0837). With a predictable anticoagulant response and low potential for drug-drug interactions, these new agents can be given in fixed doses without coagulation monitoring. This renders them more convenient than VKAs. While the anticoagulant effect of the new thrombin and FXa inhibitors is similar, differences in the pharmacokinetic and pharmacodynamic parameters may influence their use in clinical practice. Here, we compare the pharmacokinetic and pharmacodynamic features of these new oral agents.

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Background-Randomized trials and meta-analyses have reached conflicting conclusions about the role of thrombolytic therapy for the treatment of acute pulmonary embolism. Methods and Results-We performed a meta-analysis of all randomized trials comparing thrombolytic therapy with heparin in patients with acute pulmonary embolism. Eleven trials, involving 748 patients, were included. Compared with heparin, thrombolytic therapy was associated with a nonsignificant reduction in recurrent pulmonary embolism or death (6.7% versus 9.6%; OR 0.67, 95% CI 0.40 to 1.12, P for heterogeneityϭ0.48), a nonsignificant increase in major bleeding (9.1% versus 6.1%; OR 1.42, 95% CI 0.81 to 2.46), and a significant increase in nonmajor bleeding (22.7% versus 10.0%; OR 2.63, 95% CI 1.53 to 4.54; number needed to harmϭ8). Thrombolytic therapy compared with heparin was associated with a significant reduction in recurrent pulmonary embolism or death in trials that also enrolled patients with major (hemodynamically unstable) pulmonary embolism (9.4% versus 19.0%; OR 0.45, 95% CI 0.22 to 0.92; number needed to treatϭ10) but not in trials that excluded these patients (5.3% versus 4.8%; OR 1.07, 95% CI 0.50 to 2.30), with significant heterogeneity between these 2 groups of trials (Pϭ0.10). Conclusions-Currently available data provide no evidence for a benefit of thrombolytic therapy compared with heparin for the initial treatment of unselected patients with acute pulmonary embolism. A benefit is suggested in those at highest risk of recurrence or death. The number of patients enrolled in randomized trials to date is modest, and further evaluation of the efficacy and safety of thrombolytic therapy for the treatment of high-risk patients with acute pulmonary embolism appears warranted.

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The last decade has seen the evaluation of several new oral anticoagulants that directly target thrombin or activated factor X (FXa). All demonstrate a rapid onset of action, a low potential for food and drug interactions, and a predictable anticoagulant effect that obviates the need for routine coagulation monitoring. Those agents at the most advanced stages of clinical development are a direct thrombin inhibitor, dabigatran, and direct FXa inhibitors, rivaroxaban and apixaban. Dabigatran and rivaroxaban are approved in more than 70 countries for prevention of venous thromboembolism in patients undergoing elective hip or knee arthroplasty, and apixaban is being considered for approval by regulatory agencies for this indication. Dabigatran was shown in a large phase III trial to be more effective and safer than warfarin for the prevention of stroke or systemic embolism in patients with atrial fibrillation and has recently been approved for this indication. Edoxaban, an oral FXa inhibitor, is also being evaluated in phase III clinical trials. This review summarizes the pharmacology, clinical trial results, and future role of the new oral anticoagulants in clinical practice.

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Robust evidence from patients with atrial fibrillation randomized to NOACs or warfarin demonstrates that unmonitored NOAC therapy is at least as effective and safe as monitored warfarin, with lower rates of intracranial hemorrhage and reduced mortality. Further research is required to determine whether routine laboratory monitoring might provide a net benefit for patients. Until such data are available, clinicians should continue to prescribe NOACs in fixed doses without routine monitoring.

In patients who undergo hip or knee replacement and receive short-duration anticoagulant prophylaxis, symptomatic nonfatal venous thromboembolism will occur in about 1 of 32 patients and fatal pulmonary embolism will occur in about 1 of 1000 patients within 3 months of the surgery. Although the prevalence of asymptomatic deep vein thrombosis is more than 2-fold higher after knee replacement than after hip replacement 7 to 10 days after surgery, in the subsequent 3 months, symptomatic venous thromboembolism is more likely to occur after hip replacement.