By Omar Khalid Pharm.D. Candidate c/o 2014
The outpour of a multitude of new oral anticoagulants in recent years has health care professionals questioning whether they should switch the patients over, and what new agents should be used. With the recent addition of dabigatran (Pradaxa®) in October 2010, rivaroxaban (Xarelto®) in November 2011, and apixaban (Eliquis®) in December 2012, there are now many alternatives to warfarin for stroke prevention in atrial fibrillation. Direct factor Xa inhibitors edoxaban and betrixaban are also in the pipeline and may be approved in the next few years.
Anticoagulants are categorized by their mechanism of action. Apixaban and rivaroxaban are direct factor Xa inhibitors, dabigatran is a direct thrombin inhibitor, and warfarin is a VKORC1 inhibitor. Warfarin inhibits the formation of vitamin-K dependent clotting factors II, VII, IX, and X. Both apixaban and dabigatran are only approved for thromboembolism prevention in non-valvular atrial fibrillation. They are dosed at twice a day. On the other hand, rivaroxaban is approved for more treatments including venous thromboembolism (VTE) prevention, deep vein thrombosis (DVT) and pulmonary embolism (PE) treatment and prevention. Rivaroxaban is used once daily. Until recently, warfarin was used for most of these conditions.
Compared to warfarin which requires extensive INR monitoring, the new antithrombotics such as apixaban, dabigatran, and rivaroxaban have the major advantage of not requiring routine coagulation tests. In addition, apixaban seems to yield better patient outcomes in clinical trials: for every 1000 patients with atrial fibrillation treated annually, apixaban prevented three more strokes and prevented four deaths when compared to warfarin. Patients on apixaban also avoided ten major bleeds.3 Dabigatran prevented five more strokes per year in every 1000 patients treated for atrial fibrillation, with comparable overall bleeding risk to warfarin.4 Lastly, rivaroxaban was found to be comparable to warfarin in preventing strokes in atrial fibrillation.5 However, it is important to keep in mind that the newer agents are harder to control, lack long-term research data, and needs more post-marketing surveillance.
Regardless of these advantages, practitioners are tempted to switch their patients to the newer agents because of the inconvenient aspects of warfarin. Warfarin is highly protein bound (99%), works against vitamin K, and is heavily metabolized (92%). In addition, warfarin metabolism is carried out by cytochrome P450 2C9 and 3A4. Competition for protein binding and for 2C9 and 3A4 metabolism with other drugs, CYP450 2C9 polymorphism, and varying intake of vitamin K all leave the anticoagulant bare to numerous drug and food interactions. Genomic variations in 2C9 may reduce warfarin clearance, increasing the risk of bleeding. On the other hand, foods rich in vitamin K such as dark leafy vegetables may inhibit anticoagulant effects of warfarin, meaning that patients have to restrict their diet. Additionally, because the onset of warfarin is 48-72 hours and the full therapeutic effect may not be seen for 5-7 days, supplemental anticoagulation is needed for at least the first five days.
Even though warfarin has many shortcomings, it still holds some advantage over the newer agents. The new agents do not have antidotes while warfarin has Vitamin K. In addition the newer agents are not approved for use in patients with prosthetic heart valves, most likely needs renal function monitoring, and cost over $230 every month (the cost for warfarin is $80 monthly including the cost for INR monitoring). Due to these disadvantages, switching patients already on warfarin to the newer agents is not recommended at this time, especially if the patients’ INR is stable.
- The approval of Eliquis will intensify the marketing war among the new oral anticoagulants.” Pharmacists Letter. Volume 29 Number 2, n.d. Web. 13 Feb 2013. <http://pharmacistsletter.therapeuticresearch.com/ pl/Sample.aspx?cs=&s=PL.
- “Comparison of Oral Antithrombotics.” Pharmacists Letter. 29.2 (2013): Feb. Web. 13 Feb. 2013. <http://pharmacistsletter.therapeuticresearch.com/ pl/ArticleDD.aspx?nidchk=1&cs=student&s=PL&pt=2&fpt=56&dd=290201&pb=PL&segment=5249>.
- Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-92.
- Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009 ;361 :1139-51.
- Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med2011;365:883-91.