Ross, Joseph S.

Background: Stroke prevention using warfarin is challenging in AF patients with CKD, due to high bleeding risk and difficulties in the INR control. NOACs provide alternative options, but all have greater degrees of renal clearance. This study aimed to compare the outcomes of apixaban, dabigatran, rivaroxaban, and warfarin across the range of kidney function in patients with AF. Methods: Using a US administrative database including private insurance or Medicare Advantage patients with linked claims and laboratory data, we identified 34,569 new users of oral anticoagulants with AF and eGFR ≥15 between 10/1/2010-11/29/2017. Stabilized IPTW balanced four treatment groups on 66 baseline characteristics. The primary outcomes included stroke, major bleeding, and mortality. Weighted Cox proportional hazards models compared treatments in the overall population and in each eGFR subgroup, with mortality as a competing risk for stroke and major bleeding. Results: The proportion of patients using warfarin increased as the kidney function declined - 26.5%, 30.4%, 34.6%, 40.5%, and 55.0% of patients were prescribed warfarin in eGFR ≥90, 60-90, 45-60, 30-45, 15-30 groups, respectively. In comparison to warfarin, apixaban was associated with a lower risk of stroke, major bleeding, and mortality; dabigatran was associated with a similar risk of stroke, and a lower risk of major bleeding and mortality; rivaroxaban was associated with a lower risk of stroke, major bleeding, and mortality (Figure). When comparing one NOAC to another NOAC, apixaban and dabigatran were associated with a lower risk of major bleeding than rivaroxaban (HR 0.61 [0.51-0.73], p<0.001 for apixaban versus rivaroxaban; HR 0.67 [0.50-0.90], p=0.007 for dabigatran versus rivaroxaban); dabigatran was associated with a higher risk of stroke than apixaban (HR 1.65 [1.11-2.46], p=0.01); there was no difference in mortality. There was no significant interaction between treatment and eGFR categories for any outcome, but the number of patients with low eGFR was small. Conclusions: In practice, relative to warfarin, NOACs are progressively less commonly used with increasing degree of renal dysfunction. However, each NOAC was consistently associated with at least equivalent effectiveness and safety compared with warfarin across the range of kidney function.

The cost of prescription drugs in the United States continues to be a source of concern for patients, caregivers, and policymakers. Drug prices typically decline rapidly once generic drugs receive US Food and Drug Administration (FDA) approval and enter the market, but the past decade has witnessed rising costs and shortages of generic drugs. We describe the strategies used by brand‐name manufacturers to undermine generic competition and the reasons underlying the price increases of off‐patent drugs, some of which continue to lack any competition from generic versions, and others that have increased in price despite having generic versions. We discuss the FDA's role in addressing drug prices and promoting competition, including recent agency policies to modify its process of reviewing generic drug applications and to prioritize applications for off‐patent drugs with few competitors. We also examine proposed policy solutions and research areas that could help address the price increases of off‐patent drugs.