Apixaban for Extended Treatment of Venous Thromboembolism

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Abstract

Apixaban, an oral factor Xa inhibitor that can be administered in a simple, fixed-dose regimen, may be an option for the extended treatment of venous thromboembolism. In this randomized, double-blind study, we compared two doses of apixaban (2.5 mg and 5 mg, twice daily) with placebo in patients with venous thromboembolism who had completed 6 to 12 months of anticoagulation therapy and for whom there was clinical equipoise regarding the continuation or cessation of anticoagulation therapy. The study drugs were administered for 12 months. A total of 2486 patients underwent randomization, of whom 2482 were included in the intention-to-treat analyses. Symptomatic recurrent venous thromboembolism or death from venous thromboembolism occurred in 73 of the 829 patients (8.8%) who were receiving placebo, as compared with 14 of the 840 patients (1.7%) who were receiving 2.5 mg of apixaban (a difference of 7.2 percentage points; 95% confidence interval [CI], 5.0 to 9.3) and 14 of the 813 patients (1.7%) who were receiving 5 mg of apixaban (a difference of 7.0 percentage points; 95% CI, 4.9 to 9.1) (P<0.001 for both comparisons). The rates of major bleeding were 0.5% in the placebo group, 0.2% in the 2.5-mg apixaban group, and 0.1% in the 5-mg apixaban group. The rates of clinically relevant nonmajor bleeding were 2.3% in the placebo group, 3.0% in the 2.5-mg apixaban group, and 4.2% in the 5-mg apixaban group. The rate of death from any cause was 1.7% in the placebo group, as compared with 0.8% in the 2.5-mg apixaban group and 0.5% in the 5-mg apixaban group. Extended anticoagulation with apixaban at either a treatment dose (5 mg) or a thromboprophylactic dose (2.5 mg) reduced the risk of recurrent venous thromboembolism without increasing the rate of major bleeding. (Funded by Bristol-Myers Squibb and Pfizer; AMPLIFY-EXT ClinicalTrials.gov number, NCT00633893.).

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Venous thromboembolism and subsequent hospitalisation due to acute arterial cardiovascular events: a 20-year cohort study.

Henrik T Sørensen, Lars Henning Pedersen, Erzsébet Horváth-Puhó … (2007)

In some studies, venous thromboembolism has been associated with atherosclerosis and with the risk of arterial cardiovascular events such as myocardial infarction and stroke. Other studies, however, do not show this association. To help clarify these discrepant findings, we aimed to investigate the risk of arterial cardiovascular events in patients who were diagnosed with venous thromboembolism. We undertook a 20-year population-based cohort study using data from nationwide Danish medical databases. After excluding those with known cardiovascular disease, we assessed the risk of myocardial infarction and stroke in 25,199 patients with deep venous thrombosis, 16,925 patients with pulmonary embolism, and 163,566 population controls. For patients with deep venous thrombosis, the relative risks varied from 1.60 for myocardial infarction (95% CI 1.35-1.91) to 2.19 (1.85-2.60) for stroke in the first year after the thrombotic event. For patients with pulmonary embolism, the relative risks in that year were 2.60 (2.14-3.14) for myocardial infarction and 2.93 (2.34-3.66) for stroke. The relative risks were also raised, though less markedly, during the subsequent 20 years of follow-up, with 20-40% increases in risk for arterial cardiovascular events. Relative risks were similar for those with provoked and unprovoked deep venous thrombosis and pulmonary embolism. Patients with venous thromboembolism have a substantially increased long-term risk of subsequent arterial cardiovascular events.

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Idraparinux versus standard therapy for venous thromboembolic disease.

F Piovella, Peter Gent, Alexander T. Cohen … (2007)

Venous thromboembolism is treated with unfractionated heparin or low-molecular-weight heparin, followed by a vitamin K antagonist. We investigated the potential use of idraparinux, a long-acting inhibitor of activated factor X, as a substitute for standard therapy. We conducted two randomized, open-label noninferiority trials involving 2904 patients with deep-vein thrombosis and 2215 patients with pulmonary embolism to compare the efficacy and safety of idraparinux versus standard therapy. Patients received either subcutaneous idraparinux (2.5 mg once weekly) or a heparin followed by an adjusted-dose vitamin K antagonist for either 3 or 6 months. The primary efficacy outcome was the 3-month incidence of symptomatic recurrent venous thromboembolism (nonfatal or fatal). In the study of patients with deep venous thrombosis, the incidence of recurrence at day 92 was 2.9% in the idraparinux group as compared with 3.0% in the standard-therapy group (odds ratio, 0.98; 95% confidence interval [CI], 0.63 to 1.50), a result that satisfied the prespecified noninferiority requirement. At 6 months, the hazard ratio for idraparinux was 1.01. The rates of clinically relevant bleeding at day 92 were 4.5% in the idraparinux group and 7.0% in the standard-therapy group (P=0.004). At 6 months, bleeding rates were similar. In the study of patients with pulmonary embolism, the incidence of recurrence at day 92 was 3.4% in the idraparinux group and 1.6% in the standard-therapy group (odds ratio, 2.14; 95% CI, 1.21 to 3.78), a finding that did not meet the noninferiority requirement. In patients with deep venous thrombosis, once-weekly subcutaneous idraparinux for 3 or 6 months had an efficacy similar to that of heparin plus a vitamin K antagonist. However, in patients with pulmonary embolism, idraparinux was less efficacious than standard therapy. (ClinicalTrials.gov numbers, NCT00067093 [ClinicalTrials.gov] and NCT00062803 [ClinicalTrials.gov].). Copyright 2007 Massachusetts Medical Society.

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Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran.

Karin F.C. Wåhlander, , Sam Schulman … (2003)

For many patients with venous thromboembolism, secondary prevention with vitamin K antagonists is not extended beyond six months, since the risk of recurrence may be outweighed by the risk of major bleeding. In a double-blind, multicenter trial, we randomly assigned 1233 patients with venous thromboembolism who had undergone six months of anticoagulant therapy to extended secondary prevention with the oral direct thrombin inhibitor ximelagatran (24 mg) or placebo, taken twice daily, for 18 months without monitoring of coagulation. At base line, bilateral ultrasonography of the legs and perfusion lung scanning were performed. Data from 612 patients in the ximelagatran group and 611 in the placebo group were analyzed. The occurrence of the primary end point, symptomatic recurrent venous thromboembolism, was confirmed in 12 patients assigned to ximelagatran and 71 patients assigned to placebo (hazard ratio, 0.16; 95 percent confidence interval, 0.09 to 0.30; P<0.001). Death from any cause occurred in 6 patients in the ximelagatran group and 7 patients in the placebo group, and bleeding occurred in 134 patients and 111 patients, respectively (hazard ratio, 1.19; 95 percent confidence interval, 0.93 to 1.53; P=0.17). The incidence of major hemorrhage was low (six events in the ximelagatran group and five in the placebo group), and none of these hemorrhages were fatal. The cumulative risk of a transient elevation of the alanine aminotransferase level to more than three times the upper limit of normal was 6.4 percent in the ximelagatran group, as compared with 1.2 percent in the placebo group (P<0.001). Oral ximelagatran was superior to placebo for the extended prevention of venous thromboembolism. There was no significant increase in the frequency of bleeding complications, but there was an increase in the number of patients with a transient elevation in the alanine aminotransferase level. Copyright 2003 Massachusetts Medical Society