Factors Affecting Choice of Non-Vitamin K Antagonist Oral Anticoagulants

The landscape of anticoagulant therapy has changed significantly during the past 5 years with the approval of 4 non-vitamin K antagonist oral anticoagulants (NOACs): the factor Xa inhibitors rivaroxaban and apixaban, and the direct thrombin inhibitors dabigatran and edoxaban. NOACs are a safe and effective alternative to warfarin for preventing stroke in patients with nonvalvular atrial fibrillation (NVAF),^1-5 and their ease of use has been a boon to patients and prescribers. Given the scarcity of head-to-head trials, choosing the most appropriate NOAC for a patient can be challenging. Factors influencing choice include prescriber experience and familiarity, dosage, affordability, drug interactions, reversibility, and patient age and renal function.

Clinical trials have evaluated the safety and efficacy of NOACs vs warfarin in  patients with NVAF.^2-5 In the RE-LY trial, dabigatran 110 mg twice daily was associated with rates of stroke and systemic embolism (SE) similar to those for warfarin, but lower rates of major hemorrhage; 150 mg twice daily was associated with lower rates of stroke and SE but similar rates of major hemorrhage compared with warfarin.² In the ROCKET-AF  trial, rivaroxaban was noninferior to warfarin in preventing stroke and SE; there was no significant between-group difference in the risk of major bleeding, but the frequency of intracranial and fatal bleeding was lower with rivaroxaban.³ In the ARISTOTLE trial, apixaban was superior to warfarin in preventing stroke and SE, resulted in lower mortality, and caused less bleeding.⁴ The ENGAGE-AF TIMI 48 trial demonstrated that edoxaban 30 mg or 60 mg once a day was noninferior to warfarin in preventing stroke or SE and was associated with significantly lower rates of major bleeding and death from cardiovascular causes.^5,6  

Advantages and Disadvantages of NOACs

NOACs offer certain advantages over warfarin, including a more rapid onset and shorter half-life. These attributes simplify periprocedural management and treatment initiation, often eliminating the need for bridging, and reduce the need for reversal in the event of surgery or serious bleeding.⁶ Such advantages can translate to shorter hospital stays. Fixed daily or twice-daily dosing and the elimination of INR monitoring and dietary considerations are other advantages. Unlike with warfarin, inconsistency in the intake of vitamin K-rich foods is not an issue since vitamin K does not reverse the anticoagulant effects of NOACs. 

Robert D. Fishberg, MD, FACC, calls NOACs “revolutionary… [They are] a less difficult, less toxic alternative that saves lives and prevents strokes. They’ve changed the way our practice manages patients.”

A perceived disadvantage of NOAC use has been the absence of specific reversal agents. In October 2015, the US Food and Drug Administration approved idarucizumab, a monoclonal antibody that reverses the effects of dabigatran in emergency situations. Reversal agents for other NOACs are in development. In the meantime, severe bleeding has been managed with prothrombin complex concentrates, recombinant factor VIIa, and factor VIII inhibitor bypass activity.¹

Cost is also an important factor when considering NOAC therapy. Warfarin is a fraction of the price of any NOAC, and this factor may tip the scales in its favor. Coupons for eligible patients can defray the out-of-pocket expense of NOACs. Cost can also play a role in adherence since patients may be more likely to discontinue a drug they cannot afford. Discontinuation of any anticoagulant increases the risk of thrombotic events.¹

Selecting the Right NOAC

Renal status is a factor when choosing a NOAC, as reduced kidney function increases the risk of bleeding with NOACs.⁶ All currently approved NOACs are cleared to some degree by the kidneys. Approximately 77% of dabigatran, 36% of rivaroxaban, 21 to 24% of apixaban, and 50% of edoxaban are eliminated by the kidneys as unchanged drug.⁶ Rivaroxaban and dabigatran require dosage reduction for patients with renal impairment. The dose of apixaban must be reduced if 2 of the following are present: serum creatinine ≥1.5 mg/dL, age ≥80 years, or body weight ≤60 kg. Edoxaban is approved for NVAF only in patients with creatinine clearance (CrCl) ≤95 mL/min. For CrCl 15-50 mL/min, the dose is reduced by half. Warfarin is still the optimal choice for patients with CrCl <15 mL/min. ⁶

Drug interaction is a consideration when choosing a NOAC and may preclude the use of certain agents or necessitate dosage adjustment. Significant interaction can occur with the concomitant use of NOACs and strong inhibitors or inducers of P-glycoprotein and/or CYP3A4, including verapamil, dronedarone, quinidine, carbamazepine, phenobarbital, phenytoin, rifampin, ketoconazole, clarithromycin, St John’s wort, and others.⁶ Interactions and their likelihood differ for each NOAC and are explained in the prescribing literature. Renal dysfunction can increase the magnitude of drug interactions.⁶      

Dosing frequency and adverse effects may also factor into NOAC choice. To prevent stroke in NVAF, apixaban and dabigatran are given twice a day, while rivaroxaban and edoxaban are given once a day. Patients may prefer once-a-day dosing, which may also prevent missed doses. Patients taking medication for NVAF are more likely to adhere to a once-a-day than a twice-a-day regimen.⁷ One adverse effect that can influence adherence is gastrointestinal upset, which is more like to occur with dabigatran; dyspepsia occurs in up to 10% of patients taking dabigatram.⁶ A study by Ninshino and colleagues found that the incidence of dyspepsia was higher in dabigatran than rivaroxiban patients.⁷

Maureen Ruckel, RN, explains that patients [with AF] in her practice are instructed to “take dabigatran twice a day after a full meal, apixaban twice a day with or without food, and rivaroxaban once a day with dinner.” The newest NOAC, edoxaban, is taken once a day with or without food.  

Dabigatran has the advantage of being the only NOAC with an approved reversal agent, and this may influence NOAC choice. Another factor that may affect selection is prescriber familiarity. Prescribers may be reluctant try a new drug, particularly if it offers no clear advantage over a drug they have been using successfully.

A Look Ahead

All 4 NOACs are also approved for treatment of venous thromboembolism (VTE), and rivaroxaban and apixaban are indicated for VTE prophylaxis in hip and knee surgery. NOAC use during catheter ablation and cardioversion,⁹ as well as in patients receiving antiplatelet drugs, is currently being studied.^9,10 Additional data from real-world comparisons with warfarin are needed,^10,11 as are head-to-head comparisons of the efficacy, safety, and cost-effectiveness of the various NOACs.

References

1. Bauer KA. Pros and cons of new oral anticoagulants. Hematology. Am Soc Hematol Educ Program. 2013;2013:464-470. doi:10.1182/asheducation-2013.1.464.
2. Connolly SJ, Ezekowitz, MD, Yusuf S, et al. Dabigatran versus warfarin in patient with atrial fibrillation. N Engl J Med. 2009; 361:1139-1151. doi: 10.1056/NEJMoa0905561.
3. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-891. doi: 10.1056/NEJMoa1009638.
4. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-992. doi: 10.1056/NEJMoa1107039.
5. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban  versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013; 369:2093-2104. doi: 10.1056/NEJMoa1310907.
6. Weitz JI, Eikelboom J. Incorporating edoxaban into the choice of anticoagulants for atrial fibrillation. Thromb Haemost. 2015;115.  http://dx.doi.org/10.1160/TH15-02-0181.
7. Nishino M, Okamoto N, Tanaka A, et al. Different risk factors for bleeding and discontinuation between dabigatran and rivaroxaban. J Cardiol. 2015. doi: 10.1016/j.jjcc.2015.08.019.
8. Laliberte F, Nelson WW, Lefebvre P, et al. Impact of daily dosing frequency on adherence to chronic medications among nonvalvular atrial fibrillation patients. Adv Ther. 2012;29:675-690. doi: 10.1007/s12325-012-0040-x.
9. Rillig A, Lin T, Plesman J, et al. Apixaban, rivaroxaban and dabigatran in patients undergoing atrial fibrillation ablation. J Cardiovasc Electrophysiol. 2015. doi: 10.1111/jce.12856.
10. Laliberte F, Cloutier M, Nelson WW, et al. Real-world comparative effectiveness and safety of rivaroxaban and warfarin in nonvalvular atrial fibrillation patients. Curr Med Res Opin. 2014;30:1317-1325. doi:  10-1185/03007995.2014.907140.
11. Verhamme P, Heidbuchel H. Organizing patient-centered anticoagulant therapy. Acta Cardiol. 2013;68:413-415.