Challenges associated with widespread use of newer oral anticoagulants in the United States.

Rivaroxaban was recently approved by the US Food and Drug Administration (FDA) for use in the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and to reduce the risk of recurrence of DVT and PE following initial treatment. This drug has already been approved for use in the prevention of DVT and PE occurring after hip or knee surgery and in stroke prevention in patients with nonvalvular atrial fibrillation. The FDA had approved dabigatran to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. These drugs selectively block factor Xa (rivaroxaban and apixaban) and factor IIa (dabigatran) in the coagulation pathway to cause their anticoagulant effect. Warfarin has been the drug of choice for the last 60 years in such indications but requires frequent monitoring and has significant food and drug interactions that require frequent dosing adjustments. The newer oral anticoagulants do not require routine laboratory monitoring and also provide easy-to-use profile due to fixed dosing regimens. However, due to relatively shorter experience and the high cost of these newer agents, their acceptance has been slow. Recent studies have used indices including the number of strokes prevented, life years gained, and quality-adjusted life years (QALY) gained to compare costs. These studies suggest that these drugs might be cost comparable to warfarin. Whether these outcomes can be applied universally or specifically to the patients in the United States may not be a simple task. Many patients in the United States rely on state run Medicaid programs, while there are others with no insurance at all. Warfarin has been added to the ‘‘4-$ list’’ for many US-based pharmacies and thus costs 4$ for a months supply. This makes it an obvious cheap option in comparison to some of the newer oral anticoagulants that may cost as much or more for daily out-of-pocket expense for the uninsured. The insured patients have their own challenges. Sometimes these drugs are not a part of the formulary of the insurance provider, and at other times, patients have to meet with large deductibles. Frequently, when cheaper options are available, doctors have to get preauthorization and justify the use of the more expensive medication to insurance providers prior to prescribing the drug. A study of patients in the United States, performed by Shah and Gage, suggested dabigatran to be cost-effective (based on QALY) for stroke prevention in patients with atrial fibrillation in comparison to warfarin. However, the study group used the average price of warfarin to be 15$ per month and the price of dabigatran to be 9$ per day. As may be expected, the variation in drug prices will significantly affect outcomes of data analysis. Another challenge is the absence of data for the newer oral anticoagulants in special situations such as pregnancy and in children. Special attention is also needed for patients who have renal dysfunction. Dosing adjustments are indicated for newer agents based on creatinine clearance both in chronic therapy and bridging with warfarin or parenteral anticoagulants. Lack of reversal agents is also of concern. Bleeding associated with newer agents may be life threatening and usually requires blood products for reversal. Patient’s compliance is another important factor in maintaining adequate anticoagulation with these newer agents, since they have shorter half-lives and require up to twice daily dosing. The developments in the world of thrombosis have provided more choices to the clinician for oral anticoagulation. As we gain more experience with these drugs, we will continue to learn more about their drug–drug interactions. We may find out about each drug’s distinctive niche patient population (and specific indication) that obtains the most benefit from them and the ones that should not have these newer agents at all. Graded approaches for complications such as bleeding are being suggested, and these may need to be addressed more definitively for the clinician based on broader experience. The studies that are listed here compare newer agents with warfarin based on QALY indices in patients with stroke. Real-life quality indicators in patient population with DVT and PE may also be needed to determine comparative effectiveness and cost efficacy. Addressing these factors may help in shifting the paradigm toward more frequent use of these new oral anticoagulants.