Alexander T Cohen1, Robert A Harrington1, Samuel Z Goldhaber1, Russell D Hull1, Brian L Wiens1, Alex Gold1, Adrian F Hernandez1, C Michael Gibson1. 1. From Guy's and St. Thomas' Hospitals, London (A.T.C.); the Department of Medicine, Stanford University, Stanford (R.A.H.), and Portola Pharmaceuticals, South San Francisco (B.L.W., A.G.) - both in California; the Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School (S.Z.G.), and Beth Israel Deaconess Medical Center (C.M.G.) - both in Boston; the Faculty of Medicine, University of Calgary, Calgary, AB, Canada (R.D.H.); and the Division of Cardiology, Duke University and Duke Clinical Research Institute, Durham, NC (A.F.H.).
Abstract
BACKGROUND: Patients with acute medical illnesses are at prolonged risk for venous thrombosis. However, the appropriate duration of thromboprophylaxis remains unknown. METHODS: Patients who were hospitalized for acute medical illnesses were randomly assigned to receive subcutaneous enoxaparin (at a dose of 40 mg once daily) for 10±4 days plus oral betrixaban placebo for 35 to 42 days or subcutaneous enoxaparin placebo for 10±4 days plus oral betrixaban (at a dose of 80 mg once daily) for 35 to 42 days. We performed sequential analyses in three prespecified, progressively inclusive cohorts: patients with an elevated d-dimer level (cohort 1), patients with an elevated d-dimer level or an age of at least 75 years (cohort 2), and all the enrolled patients (overall population cohort). The statistical analysis plan specified that if the between-group difference in any analysis in this sequence was not significant, the other analyses would be considered exploratory. The primary efficacy outcome was a composite of asymptomatic proximal deep-vein thrombosis and symptomatic venous thromboembolism. The principal safety outcome was major bleeding. RESULTS: A total of 7513 patients underwent randomization. In cohort 1, the primary efficacy outcome occurred in 6.9% of patients receiving betrixaban and 8.5% receiving enoxaparin (relative risk in the betrixaban group, 0.81; 95% confidence interval [CI], 0.65 to 1.00; P=0.054). The rates were 5.6% and 7.1%, respectively (relative risk, 0.80; 95% CI, 0.66 to 0.98; P=0.03) in cohort 2 and 5.3% and 7.0% (relative risk, 0.76; 95% CI, 0.63 to 0.92; P=0.006) in the overall population. (The last two analyses were considered to be exploratory owing to the result in cohort 1.) In the overall population, major bleeding occurred in 0.7% of the betrixaban group and 0.6% of the enoxaparin group (relative risk, 1.19; 95% CI, 0.67 to 2.12; P=0.55). CONCLUSIONS: Among acutely ill medical patients with an elevated d-dimer level, there was no significant difference between extended-duration betrixaban and a standard regimen of enoxaparin in the prespecified primary efficacy outcome. However, prespecified exploratory analyses provided evidence suggesting a benefit for betrixaban in the two larger cohorts. (Funded by Portola Pharmaceuticals; APEX ClinicalTrials.gov number, NCT01583218.).
BACKGROUND: Patients with acute medical illnesses are at prolonged risk for venous thrombosis. However, the appropriate duration of thromboprophylaxis remains unknown. METHODS: Patients who were hospitalized for acute medical illnesses were randomly assigned to receive subcutaneous enoxaparin (at a dose of 40 mg once daily) for 10±4 days plus oral betrixaban placebo for 35 to 42 days or subcutaneous enoxaparin placebo for 10±4 days plus oral betrixaban (at a dose of 80 mg once daily) for 35 to 42 days. We performed sequential analyses in three prespecified, progressively inclusive cohorts: patients with an elevated d-dimer level (cohort 1), patients with an elevated d-dimer level or an age of at least 75 years (cohort 2), and all the enrolled patients (overall population cohort). The statistical analysis plan specified that if the between-group difference in any analysis in this sequence was not significant, the other analyses would be considered exploratory. The primary efficacy outcome was a composite of asymptomatic proximal deep-vein thrombosis and symptomatic venous thromboembolism. The principal safety outcome was major bleeding. RESULTS: A total of 7513 patients underwent randomization. In cohort 1, the primary efficacy outcome occurred in 6.9% of patients receiving betrixaban and 8.5% receiving enoxaparin (relative risk in the betrixaban group, 0.81; 95% confidence interval [CI], 0.65 to 1.00; P=0.054). The rates were 5.6% and 7.1%, respectively (relative risk, 0.80; 95% CI, 0.66 to 0.98; P=0.03) in cohort 2 and 5.3% and 7.0% (relative risk, 0.76; 95% CI, 0.63 to 0.92; P=0.006) in the overall population. (The last two analyses were considered to be exploratory owing to the result in cohort 1.) In the overall population, major bleeding occurred in 0.7% of the betrixaban group and 0.6% of the enoxaparin group (relative risk, 1.19; 95% CI, 0.67 to 2.12; P=0.55). CONCLUSIONS: Among acutely ill medical patients with an elevated d-dimer level, there was no significant difference between extended-duration betrixaban and a standard regimen of enoxaparin in the prespecified primary efficacy outcome. However, prespecified exploratory analyses provided evidence suggesting a benefit for betrixaban in the two larger cohorts. (Funded by Portola Pharmaceuticals; APEX ClinicalTrials.gov number, NCT01583218.).
Authors: Holly Guy; Vicki Laskier; Mark Fisher; W Richey Neuman; Iwona Bucior; Steven Deitelzweig; Alexander T Cohen Journal: Pharmacoeconomics Date: 2019-05 Impact factor: 4.981
Authors: Megan K Yee; Tarek Nafee; Yazan Daaboul; Serge Korjian; Fahad AlKhalfan; Mathieu Kerneis; Cara Wiest; Samuel Z Goldhaber; Adrian F Hernandez; Russell D Hull; Alexander T Cohen; Robert A Harrington; C Michael Gibson Journal: J Thromb Thrombolysis Date: 2018-01 Impact factor: 2.300
Authors: Holger J Schünemann; Mary Cushman; Allison E Burnett; Susan R Kahn; Jan Beyer-Westendorf; Frederick A Spencer; Suely M Rezende; Neil A Zakai; Kenneth A Bauer; Francesco Dentali; Jill Lansing; Sara Balduzzi; Andrea Darzi; Gian Paolo Morgano; Ignacio Neumann; Robby Nieuwlaat; Juan J Yepes-Nuñez; Yuan Zhang; Wojtek Wiercioch Journal: Blood Adv Date: 2018-11-27
Authors: Gerald Chi; James L Januzzi; Serge Korjian; Yazan Daaboul; Samuel Z Goldhaber; Adrian F Hernandez; Russell D Hull; Alex Gold; Alexander T Cohen; Robert A Harrington; C Michael Gibson Journal: J Thromb Thrombolysis Date: 2017-11 Impact factor: 2.300