Continuing Education (continued from page 34) Only within the last three years have new oral anticoagulants been made available; dabigatran (2010), rivaroxaban (2011) and apixaban (2012). Table 4 outlines each agent’s mechanism of action and Food and Drug Administration (FDA) approved indications for use. It is important to note that all agents are approved for use in nonvalvular AF, but warfarin is the only agent with approval for use in patients with AF in the setting of rheumatic heart disease, mitral stenosis, or prosthetic heart valves. Dabigatran (Pradaxa®) Dabigatran is a prodrug that received FDA approval for prevention of stroke and systemic embolism in nonvalvular AF.8 Dabigatran is usually dosed at 150 mg twice daily, but has a reduced dosage of 75 mg twice daily recommended for patients with CrCl of 15 to 30 mL/ min. It is important to note that this FDA approved dose of 75 mg had not been studied in clinical trials but was instead based on pharmacokinetic extrapolations. Dabigatran use is contraindicated in patients with CrCl < 15 mL/min and those with CrCl < 30 mL/min who are also taking strong P-glycoprotein (Pgp) inhibitors (e.g. dronedarone or oral ketoconazole). It is also recommended to consider a reduced dose of 75 mg twice daily in patients with CrCl 30 to 50 mL/min who are on concomitant p-gp inhibitors. It is recommended to avoid concomitant use of p-gp inducers (e.g. rifampin) and dabigatran as it may reduce dabigatran efficacy. The American Geriatric Society has listed dabigatran in the 2012 Beers criteria.12 Due to a greater risk of bleeding as compared to warfarin in those who are over 75 years of age as well as a lack of evidence for efficacy and safety in those with CrCl < 30 mL/min, the Beers criteria expert panel recommends that dabigatran be used with caution in those who are < 75 years of age or have a CrCl <30 mL/min. Table 5 details the pharmacology of dabigatran. The most common adverse effects associated with dabigatran are generally gastrointestinal (GI) related, bleeding, gastritis, dyspepsia, and are thought to be due to the coating. The pellet coating of dabigatran is formulated with tartaric acid that is specially designed to acidify the stomach environment and increase dabigatran absorption. It should be noted that the use of proton pump inhibitors in clinical trials did not affect the efficacy of dabigatran compared with warfarin.13 However, given the over-the-counter availability of both histamine antagonists and proton pump inhibitors, the potential exists for higher doses than those that were clinically evaluated in clinical trials. It remains to be seen if these higher doses will affect dabigatran efficacy. The Randomized Evaluation of LongTerm Anticoagulation Therapy (RE-LY) trial was a phase III study that compared dabigatran with warfarin for stroke prevention in patients with AF.13 Table 6 summarizes the details from the RE-LY trial. The trial found that the dabigatran 110 mg group was noninferior to warfarin in regards to the primary endpoint of stroke or systemic embolism (annual rate 1.53% vs. 1.69%, hazard ratio, 0.91 (0.74-1.11); noninferiority p<0.001) while the 150 mg group was superior to warfarin (1.11% vs. 1.69%, hazard ratio, 0.66 (0.53-0.82); superiority p < 0.001). Bleeding rates were similar between warfarin and the 150 mg group, while the 110 mg group had fewer major and nonmajor bleeding events. In the 150 mg group, the incidence of GI bleeding was higher when compared to warfarin (annual rate 1.51 vs. 1.02, p < 0.001), while intracranial bleeding was lower (annual rate 0.30 vs. 0.75, p<0.001). The rate of myocardial infarction (MI) was higher with the dabigatran 110 mg group (annual rate 0.72% vs. 0.53%, p=0.07) and 150 mg group (annual rate 0.74% vs. 0.53%, p=0.048) compared to warfarin. It is noteworthy to mention that warfarin management in the trial produced an overall mean TTR of 64%.14 However, in patients with a mean TTR greater than 65.5%, there was no significant difference in the risk of stroke or systemic embolism compared with the 110 mg or 150 mg dabigatran groups, and rates of major bleeding events were similar. Rivaroxaban (Xarelto®) Rivaroxaban has FDA approval for use in DVT/PE prophylaxis and treatment, DVT prophylaxis in orthopedics and stroke prevention in nonvalvular AF. Rivaroxaban for the prevention of stroke in AF is dosed 20 mg daily with a dose reduction to 15 mg daily if CrCl is 15 – 50 mL/min. Rivaroxaban use is contraindicated in patients with CrCl < 15 mL/min and in patients with moderate to severe hepatic impairment (Child- Pugh class B and C). Rivaroxaban doses ≥ 15 mg per day should be taken with food as it increases bioavailability.9 Table 5 details the pharmacology of rivaroxaban. Rivaroxaban should not be used concurrently with strong cytochrome P450 (CYP) 3A4 and P-gp inducers or inhibitors. The most common adverse effects associated with rivaroxaban are bleeding events. The Rivaroxaban Once-Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial was a phase III study that ultimately led to rivaroxaban approval for stroke prevention in AF.15 Table 6 summarizes the details from the ROCKET-AF trial. The trial found that rivaroxaban was noninferior to warfarin in stroke or systemic embolism prevention (annual rate 2.1% vs. 2.4%, hazard ratio, 0.88 (0.74 - 1.03); noninferiority p<0.001). Both rivaroxaban and warfarin had similar major and nonmajor clinically relevant bleeding rates, with less intracerebral hemorrhage (0.5% vs. 0.7%, p=0.02) and fatal bleeding (0.2% vs. 0.5%, p=0.003) with rivaroxaban. Of note warfarin management in this trial produced an overall mean TTR of 55%, which is lower than in other trials with new oral anticoagulants. The trial also observed an increased rate of stroke or systemic embolism following discontinuation of rivaroxaban (81 events vs. 66 events in warfarin, p=0.58), which led to a black box warning and a recommendation to bridge patients with alternative anticoagulation upon discontinuation of rivaroxaban. Apixaban (Eliquis®) Apixaban, the most recently FDA approved oral anticoagulant, is approved for stroke and systemic embolism prevention in nonvalvular AF.10 The approved dose of apixaban is 5 mg twice daily with a dose reduction to 2.5 mg twice daily in patients with any two of the following: weight ≤ 60kg, Scr ≥ 1.5 mg/ dL or ≥ 80 years old. Also recommended is a dose of 2.5 mg twice daily when used concomitantly with strong CYP3A4 and p-gp inhibitors. It is not recommended in severe hepatic impairment (Child-Pugh class C) or in patients with CrCl < 15 mL/ min. Table 5 details the pharmacology of apixaban. The most common adverse Summer 2013 • Arizona Journal of Pharmacy • 35

AJP Summer 2013