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Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: population based cohort study

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      Abstract

      Objective To determine the real world risk of gastrointestinal bleeding associated with the use of the novel oral anticoagulants dabigatran and rivaroxaban compared with warfarin.Design Retrospective, propensity matched cohort study.Setting: Optum Labs Data Warehouse, a large database including administrative claims data on privately insured and Medicare Advantage enrollees.Participants New users of dabigatran, rivaroxaban, and warfarin from 1 November 2010 to 30 September 2013.Main outcome measures Incidence rates (events/100 patient years) and propensity score matched Cox proportional hazards models were used to estimate rates of total gastrointestinal bleeds, upper gastrointestinal bleeds, and lower gastrointestinal bleeds for the novel oral anticoagulants compared with warfarin in patients with and without atrial fibrillation. Heterogeneity of treatment effect related to age was examined using a marginal effects model.Results The incidence of gastrointestinal bleeding associated with dabigatran was 2.29 (95% confidence interval 1.88 to 2.79) per 100 patient years and that associated with warfarin was 2.87 (2.41 to 3.41) per 100 patient years in patients with atrial fibrillation. In non-atrial fibrillation patients, the incidence of gastrointestinal bleeding was 4.10 (2.47 to 6.80) per 100 patient years with dabigatran and 3.71 (2.16 to 6.40) per 100 patient years with warfarin. With rivaroxaban, 2.84 (2.30 to 3.52) gastrointestinal bleeding events per 100 patient years occurred in atrial fibrillation patients (warfarin 3.06 (2.49 to 3.77)/100 patient years) and 1.66 (1.23 to 2.24) per 100 patient years in non-atrial fibrillation patients (warfarin 1.57 (1.25 to 1.99)/100 patient years). In propensity score matched models, the risk of gastrointestinal bleeding with novel oral anticoagulants was similar to that with warfarin in atrial fibrillation patients (dabigatran v warfarin, hazard ratio 0.79 (0.61 to 1.03); rivaroxaban v warfarin, 0.93 (0.69 to 1.25)) and in non-AF patients (dabigatran v warfarin, hazard ratio 1.14 (0.54 to 2.39); rivaroxaban v warfarin, 0.89 (0.60 to 1.32)). The risk of gastrointestinal bleeding increased after age 65, such that by age 76 the risk exceeded that with warfarin among atrial fibrillation patients taking dabigatran (hazard ratio 2.49 (1.61 to 3.83)) and patients with and without atrial fibrillation taking rivaroxaban (2.91 (1.65 to 4.81) and 4.58 (2.40 to 8.72), respectively).Conclusions: The risk of gastrointestinal bleeding related to novel oral anticoagulants was similar to that for warfarin. Caution should be used when prescribing novel oral anticoagulants to older people, particularly those over 75 years of age.

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      Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases

       R Deyo (1992)
      Administrative databases are increasingly used for studying outcomes of medical care. Valid inferences from such data require the ability to account for disease severity and comorbid conditions. We adapted a clinical comorbidity index, designed for use with medical records, for research relying on International Classification of Diseases (ICD-9-CM) diagnosis and procedure codes. The association of this adapted index with health outcomes and resource use was then examined with a sample of Medicare beneficiaries who underwent lumbar spine surgery in 1985 (n = 27,111). The index was associated in the expected direction with postoperative complications, mortality, blood transfusion, discharge to nursing home, length of hospital stay, and hospital charges. These associations were observed whether the index incorporated data from multiple hospitalizations over a year's time, or just from the index surgical admission. They also persisted after controlling for patient age. We conclude that the adapted comorbidity index will be useful in studies of disease outcome and resource use employing administrative databases.
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        Dabigatran versus warfarin in patients with atrial fibrillation.

        Warfarin reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage and is difficult to use. Dabigatran is a new oral direct thrombin inhibitor. In this noninferiority trial, we randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive, in a blinded fashion, fixed doses of dabigatran--110 mg or 150 mg twice daily--or, in an unblinded fashion, adjusted-dose warfarin. The median duration of the follow-up period was 2.0 years. The primary outcome was stroke or systemic embolism. Rates of the primary outcome were 1.69% per year in the warfarin group, as compared with 1.53% per year in the group that received 110 mg of dabigatran (relative risk with dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P<0.001 for noninferiority) and 1.11% per year in the group that received 150 mg of dabigatran (relative risk, 0.66; 95% CI, 0.53 to 0.82; P<0.001 for superiority). The rate of major bleeding was 3.36% per year in the warfarin group, as compared with 2.71% per year in the group receiving 110 mg of dabigatran (P=0.003) and 3.11% per year in the group receiving 150 mg of dabigatran (P=0.31). The rate of hemorrhagic stroke was 0.38% per year in the warfarin group, as compared with 0.12% per year with 110 mg of dabigatran (P<0.001) and 0.10% per year with 150 mg of dabigatran (P<0.001). The mortality rate was 4.13% per year in the warfarin group, as compared with 3.75% per year with 110 mg of dabigatran (P=0.13) and 3.64% per year with 150 mg of dabigatran (P=0.051). In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. (ClinicalTrials.gov number, NCT00262600.) 2009 Massachusetts Medical Society
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          Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.

          The use of warfarin reduces the rate of ischemic stroke in patients with atrial fibrillation but requires frequent monitoring and dose adjustment. Rivaroxaban, an oral factor Xa inhibitor, may provide more consistent and predictable anticoagulation than warfarin. In a double-blind trial, we randomly assigned 14,264 patients with nonvalvular atrial fibrillation who were at increased risk for stroke to receive either rivaroxaban (at a daily dose of 20 mg) or dose-adjusted warfarin. The per-protocol, as-treated primary analysis was designed to determine whether rivaroxaban was noninferior to warfarin for the primary end point of stroke or systemic embolism. In the primary analysis, the primary end point occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 in the warfarin group (2.2% per year) (hazard ratio in the rivaroxaban group, 0.79; 95% confidence interval [CI], 0.66 to 0.96; P<0.001 for noninferiority). In the intention-to-treat analysis, the primary end point occurred in 269 patients in the rivaroxaban group (2.1% per year) and in 306 patients in the warfarin group (2.4% per year) (hazard ratio, 0.88; 95% CI, 0.74 to 1.03; P<0.001 for noninferiority; P=0.12 for superiority). Major and nonmajor clinically relevant bleeding occurred in 1475 patients in the rivaroxaban group (14.9% per year) and in 1449 in the warfarin group (14.5% per year) (hazard ratio, 1.03; 95% CI, 0.96 to 1.11; P=0.44), with significant reductions in intracranial hemorrhage (0.5% vs. 0.7%, P=0.02) and fatal bleeding (0.2% vs. 0.5%, P=0.003) in the rivaroxaban group. In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. (Funded by Johnson & Johnson and Bayer; ROCKET AF ClinicalTrials.gov number, NCT00403767.).
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            Author and article information

            Affiliations
            [1 ]Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ, 85259, USA
            [2 ]Division of Health Care Policy and Research, Department of Health Services Research, Mayo Clinic, Rochester, MN, USA
            [3 ]Mayo Clinic Robert D and Patricia E Kern Center for the Science of Health Care Delivery, Rochester, MN, USA
            [4 ]Division of General Internal Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
            [5 ]Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health and Center for Drug Safety and Effectiveness, Baltimore, MD, USA
            [6 ]Optum Labs, Cambridge, MA, USA
            Author notes
            Correspondence to: N S Abraham  abraham.neena@ 123456mayo.edu
            Contributors
            Role: professor of medicine
            Role: assistant professor of medicine
            Role: associate professor of epidemiology and medicine
            Role: senior health services analyst
            Role: senior health services analyst
            Role: chief scientific officer
            Role: associate professor of health services research
            Journal
            BMJ
            BMJ
            bmj
            BMJ : British Medical Journal
            BMJ Publishing Group Ltd.
            0959-8138
            1756-1833
            2015
            24 April 2015
            : 350
            25910928
            4413863
            abrn023104
            10.1136/bmj.h1857
            © Abraham et al 2015

            This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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