Steven P. Dunn, PharmD, BCPS (AQ Cardiology)

Atrial fibrillation (AF) is the most common dysrhythmia experienced in the United States, with more than 2.2 million adults identified with AF in 2008.

 It is expected that the prevalence of AF will increase over the next several decades as the population ages due to its high association with advanced aging and other cardiovascular disease. The major determinant of AF-related morbidity and mortality is typically not the dysrhythmia itself but rather the development of cardioembolic ischemic stroke related to blood stasis within the left atrium. This pathophysiology increases the risk of stroke in patients with AF approximately 4 to 5 times over patients without AF.

 Given the catastrophic consequences of ischemic stroke related to AF, stroke prevention is of significant importance in the overall treatment of a patient with AF. Previously, stroke prophylaxis consisted of either the oral vitamin-K antagonist warfarin or the antiplatelet aspirin. However, the emergence of new classes of oral anticoagulants has added significant complexity to the prevention of stroke in patients with AF. Moreover, the use of these agents will add challenges for health-system pharmacy practices and may complicate existing paradigms for managing anticoagulation within these.

Efficacy and Safety of New Oral Anticoagulants

All of the major evidence-based guidelines recommend the use of anticoagulants in AF patients at high risk for stroke and that anticoagulation be at least considered for patients with intermediate risk.

 Until recently, the only available oral anticoagulant for this use was warfarin, which has become the gold standard. As such, each of the new oral anticoagulants has been compared with warfarin in the prevention of stroke in AF patients.

Ximelagatran was the first approved oral direct thrombin inhibitor internationally, but was rejected by the FDA and eventually withdrawn in 2006 because of hepatotoxicity risks.

 Dabigatran was subsequently approved by the FDA in 2011 for the prevention of stroke and systemic embolism in nonvalvular AF based on the RELY trial,

 which compared dabigatran with warfarin for stroke prevention in patients with AF. Overall, the 110-mg group was noninferior to warfarin in the efficacy end point of stroke or systemic embolism (annual event rate 1.53% vs 1.69%), and the 150-mg group was superior to warfarin (1.11% vs 1.69%, p <0.001). Patients treated with 110 mg had fewer major bleeding events than those treated with warfarin, whereas the 150 mg group had similar overall major bleeding rates but less intracerebral hemorrhage (ICH) and greater gastrointestinal (GI) bleeding. Warfarin management in the trial produced an overall mean time in therapeutic range (TTR) of 64%. When the mean TTR was greater than 65.5%, the risk of stroke, systemic embolism, and rates of major bleeding were the same across all groups. However, the reductions in ICH and increases in GI bleeding noted with dabigatran in the overall study were maintained.

 The FDA only approved the 150-mg dose because of its superiority over the 110-mg dose in the prevention of stroke or systemic embolism and additionally approved a 75-mg dose for patients with a creatinine clearance of 15 to 30 ml/min based on pharmacokinetic extrapolation.

 The FDA has recently added a boxed warning to the dabigatran label regarding the risk of stroke following drug discontinuation.

Rivaroxaban was the first oral factor Xa inhibitor to be approved by the FDA for stroke and systemic embolism prevention in patients with nonvalvular AF. The ROCKET-AF trial was the phase III study that led to the label approval of rivaroxaban for stroke prevention in AF.

 Overall, rivaroxaban was noninferior to warfarin in the prevention of stroke or systemic embolism (annual event rate 1.7% vs 2.2%) and resulted in no difference in major bleeding events. Notably, the ROCKET-AF trial enrolled higher-stroke-risk patients compared with other trials with new oral anticoagulants. Warfarin management in the trial, however, only produced an overall mean TTR of 55%, a lower rate than achieved in comparable trials of new oral anticoagulants. A significantly higher rate of stroke or systemic embolism was identified with rivaroxaban-treated patients when the study drug was discontinued, which has led to a boxed warning in the rivaroxaban product labeling that providers should consider bridging patients with alternative anticoagulation upon discontinuation.

Apixaban is the latest oral factor Xa inhibitor approved by the FDA for the prevention of stroke and systemic embolism in patients with AF secondary to the results of the ARISTOTLE trial.

 Apixaban was superior to warfarin in the prevention of stroke or systemic embolism (annual event rate 1.27% vs 1.60%, p = 0.01), and it had fewer major bleeding events, including ICH. Apixaban was also compared with aspirin alone in patients with AF having moderate to high stroke risk who were deemed unsuitable for anticoagulation with vitamin K antagonists in the AVERROES trial.12 Indeed, apixaban’s clear benefit over aspirin in stroke or systemic embolism resulted in the early termination of the trial. In addition, major bleeding rates between the apixaban and aspirin groups were not significantly different, although minor bleeding was increased in patients taking apixaban.

Typical formulary management practices within health systems seek to avoid duplication within therapeutic classes in order to minimize inventory costs and reduce complexity of therapy. Given the high medication safety risk with anticoagulants and the uniqueness of each therapy, this is not a recommended practice with the new oral anticoagulants at this time and strong consideration should be given to maintaining all three agents on a formulary. If streamlining available agents within therapeutic classes is pursued, this should at minimum be performed in a protocolized manner based on the pharmacology of each agent.

Specific dosing information for each new oral anticoagulant can be found in Online Table 1. Of note, each oral anticoagulant requires adjustment in patients with varying degrees of renal dysfunction. The use of electronic health records (EHRs) and decision support tools for the identification of patients with marginal or fluctuating renal function should be a key element of the adoption of these agents into health-system formularies.

Table 1. Selected Pharmacologic Characteristics of Oral Anticoagulants

				Vitamin K epoxide reductase inhibitor; decreases synthesis of factors II, VII, IX, X

				20 mg once daily with the evening meal

				15 mg once daily with the evening meal

				~66% without food, increased to 80% to 100% with food

Articles

The new oral anticoagulants that have become available in recent years have added significant complexity to the prevention of stroke in patients with atrial fibrillation.