Hemorrhagic and thrombotic events associated with generic substitution of warfarin in patients with atrial fibrillation: a retrospective analysis.

BACKGROUND: Substitution of generic warfarin for imprint warfarin (Coumadin; DuPont/Bristol-Myers Squibb) has been a controversial issue due to bioavailability and bioequivalence concerns. OBJECTIVE: To assess the risk of thrombotic and hemorrhagic events following substitution of warfarin formulations in patients with atrial fibrillation (AF). METHODS: Historical cohort analysis was performed using a commercial insurance claims database. Adults with a diagnosis of AF between January 2003 and December 2007, with 16 or more months of continuous eligibility, a warfarin prescription within 30 days after index AF diagnosis, and at least 3 warfarin prescription fills during the follow-up period were included. Individuals with AF diagnosis or warfarin prescription during the pre-index period were excluded. Cox proportional hazard regression models controlling for sex and baseline comorbidities (Charlson comorbidity index, CCI) were used to evaluate the risks of thrombotic and hemorrhagic events following warfarin formulation switches. RESULTS: Of 37,756 subjects included in the analysis (mean age 70.96 years, 42.3% females), 12,996 (34.4%) switched warfarin formulations, 20,292 (53.7%) used only 1 generic product, and 4468 (11.8%) used only Coumadin during follow-up. Compared with continued use of Coumadin, switching from that product to the generic formulation was associated with a significantly higher risk of thrombotic events (HR = 1.81; 95% CI 1.42 to 2.31). Similar findings were observed for switching from generic warfarin to Coumadin (HR = 1.76; 95% CI 1.35 to 2.30), and from 1 generic to another generic product (HR = 1.89; 95% CI 1.57 to 2.29). Similarly, switching from Coumadin to generic warfarin (HR = 1.51; 95% CI 1.17 to 1.93), generic warfarin to Coumadin (HR = 1.60; 95% CI 1.23 to 2.1), and from 1 generic to another generic product (HR = 1.74; 95% CI 1.45 to 2.11) were associated with significantly higher risk of hemorrhage than remaining on Coumadin. CONCLUSIONS: Switching warfarin formulations exposed patients with AF to a higher risk of bleeding events compared to remaining on a single product. Maintaining patients on a product with consistent bioavailability may optimize the risk-benefit balance of anticoagulation therapy.

Anticoagulation therapy for patients with non-valvular atrial fibrillation: comparison of decision analytic model recommendations and real-world warfarin prescription use.

BACKGROUND: Anticoagulation in patients with atrial fibrillation (AF) is challenging because stroke-risk reduction must be balanced against increased bleeding risk. OBJECTIVE: We developed a decision model integrating both stroke and bleeding risk schemes to guide optimal use of anticoagulation in AF, and compared model recommendations with warfarin use in a real-world database. METHODS: A Markov model based on demographics, CHADS(2) (Congestive Heart Failure, Hypertension, Age of 75 years and greater, Diabetes Mellitus and History of Stroke) stroke and ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) bleed risk scores, and anticoagulation treatment effects from clinical trials simulated health state transitions for recently diagnosed AF patients. The model recommended the treatment with greater quality-adjusted life expectancy. Model recommendations were contrasted with actual warfarin use recorded in the Thomson Reuters MarketScan database (N = 64,946). RESULTS: 74.8% (n = 48,548) of the Marketscan AF cohort had CHADS(2) ≥1, of whom 14.3% had moderate/high (≥4) ATRIA bleeding risk. While the model recommended warfarin for almost all patients with CHADS(2) ≥1 who are at low bleeding risk, it recommended warfarin for fewer patients as bleeding risk increased. Of the 44,611 patients recommended warfarin, 63.4% of patients were considered warfarin exposed (concordant with model recommendation), and of the 20,335 patients recommended aspirin (acetylsalicylic acid), 59.7% received warfarin (discordant with model recommendations). Actual warfarin use decreased modestly with higher stroke risk (p < 0.0001) and with higher bleeding risk (p < 0.0001). CONCLUSION: High discordance between actual warfarin use and model recommendations suggests that anticoagulation decisions are not based on systematic evaluation of stroke and bleeding risks. Model-based clinical decision aids may improve oral anticoagulation decisions by more systematically weighing bleed and stroke risk.