Risk of bleeding with dabigatran in atrial fibrillation

Abstract

Importance: It remains unclear whether dabigatran etexilate mesylate is associated with higher risk of bleeding than warfarin sodium in real-world clinical practice.

Objective: To compare the risk of bleeding associated with dabigatran and warfarin using Medicare data.

Design, setting, and participants: In this retrospective cohort study, we used pharmacy and medical claims in 2010 to 2011 from a 5% random sample of Medicare beneficiaries. We identified participants as those newly diagnosed as having atrial fibrillation from October 1, 2010, through October 31, 2011, and who initiated dabigatran or warfarin treatment within 60 days of initial diagnosis. We followed up patients until discontinued use or switch of anticoagulants, death, or December 31, 2011.

Exposures: Dabigatran users (n = 1302) and warfarin users (n = 8102).

Main outcomes and measures: We identified any bleeding events and categorized them as major and minor bleeding by anatomical site. Major bleeding events included intracranial hemorrhage, hemoperitoneum, and inpatient or emergency department stays for hematuria, gastrointestinal, or other hemorrhage. We used a propensity score weighting mechanism to balance patient characteristics between 2 groups and Cox proportional hazards regression models to evaluate the risk of bleeding. We further examined the risk of bleeding for 4 subgroups of high-risk patients: those 75 years or older, African Americans, those with chronic kidney disease, and those with more than 7 concomitant comorbidities.

Results: Dabigatran was associated with a higher risk of bleeding relative to warfarin, with hazard ratios of 1.30 (95% CI, 1.20-1.41) for any bleeding event, 1.58 (95% CI, 1.36-1.83) for major bleeding, and 1.85 (95% CI, 1.64-2.07) for gastrointestinal bleeding. The risk of intracranial hemorrhage was higher among warfarin users, with a hazard ratio of 0.32 (95% CI, 0.20-0.50) for dabigatran compared with warfarin. Dabigatran was consistently associated with an increased risk of major bleeding and gastrointestinal hemorrhage for all subgroups analyzed. The risk of major bleeding among dabigatran users was especially high for African Americans and patients with chronic kidney disease.

Conclusions and relevance: Dabigatran was associated with a higher incidence of major bleeding (regardless of the anatomical site), a higher risk of gastrointestinal bleeding, but a lower risk of intracranial hemorrhage. Thus, dabigatran should be prescribed with caution, especially among high-risk patients.

Figure 1.

Association between Bleeding Events, Treatment and Patient Characteristics. NOTES: Abbreviations: TIA= Transient Ischemic Attack; CMS= Centers for Medicare and Medicaid Services; NSAIDs=Non-Steroidal Anti-inflammatory Drug. Hazard rates estimated by Cox Proportional Hazards models with propensity score weighting. The number of other comorbidities has been calculated as the sum of previous history of acute myocardial infarction, Alzheimer’s disease, related disorders or senile dementia, anemia, asthma, benign prostatic hyperplasia, cataract, chronic obstructive pulmonary disease, congestive heart failure, depression, diabetes, ischemic heart disease, hip or pelvic fracture, glaucoma, hyperlipidemia, osteoporosis, rheumatoid arthritis or osteoarthritis, breast cancer, colorectal cancer, prostate cancer, lung cancer and endometrial cancer. NSAIDs include diclofenac, ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen, piroxicam, meloxicam, mefenamic acid and indomethacin and antiplatelet agents include aspirin, clopidogrel, prasugrel, dipyridamol, ticlopidine and ticagrelor. Prospective risk score was calculated with the use of an algorithm as described in the text, higher scores predict greater medical spending.

Figure 2.

Hazard Rates for Bleeding Events, by Anatomical Site and Treatment. NOTES: Abbreviations: NOS=Not Otherwise Specified. Hazard rates estimated by Cox Proportional Hazards models with propensity score weighting controlling for age, gender, race, chronic kidney disease, history of stroke or TIA, hypertension, acquired hypothyroidism, history of bleeding in the year before treatment initiation, history of hospitalization in the year before treatment initiation, use of non-steroidal inflammatory drugs, use of antiplatelet agents, number of other CMS priority comorbidities and annual prospective risk score.

Figure 3.

Hazard Rates for Bleeding Events, by Anatomical Site, Subgroup, and Treatment. NOTES: Abbreviations: CKD=Chronic Kidney Disease. Hazard rates estimated by Cox Proportional Hazards models with propensity score weighting. The general model controlled for age, gender, race, chronic kidney disease, history of stroke or TIA, hypertension, acquired hypothyroidism, number of other CMS priority comorbidities, history of bleeding in the year before treatment initiation, history of hospitalization in the year before treatment initiation, use of non-steroidal inflammatory drugs, use of antiplatelet agents and annual prospective risk score. Subgroup analyses controlled for the same covariates except for the one defining the subgroup. For example, age-stratified analysis controlled for the same covariates except for age. The number of comorbidities used to define the subgroup with ≥7 comorbidities was calculated as the sum of all CMS priority comorbidities but atrial fibrillation (previous history of acute myocardial infarction, Alzheimer’s disease, related disorders or senile dementia, anemia, asthma, benign prostatic hyperplasia, cataract, chronic obstructive pulmonary disease, congestive heart failure, depression, diabetes, ischemic heart disease, hip or pelvic fracture, glaucoma, hyperlipidemia, osteoporosis, rheumatoid arthritis or osteoarthritis, breast cancer, colorectal cancer, prostate cancer, lung cancer and endometrial cancer, history of stroke or transient ischemic attack, hypertension, acquired hypothyroidism, chronic kidney disease).