Jenna Matelske, Pharm.D. candidate 2019, Ferris State University
College of Pharmacy
Rivaroxaban (Xarelto®) is a factor Xa inhibitor regularly referred to as a "NOAC" meaning "new" or "novel" oral anticoagulant. Until recently, rivaroxaban was indicated for treatment/prevention of deep vein thrombosis and pulmonary embolism in addition to reduction of stroke risk in patients with atrial fibrillation. In October 2018, rivaroxaban gained a new indication for use in combination with aspirin to reduce the risk of major cardiovascular (CV) events (CV death, myocardial infarction, and stroke) in patients with chronic coronary artery disease (CAD) or peripheral artery disease (PAD).1,2 This additional indication stems from the investigations of the COMPASS trial published in 2017.3
Eikelboom and colleagues evaluated the efficacy of rivaroxaban alone and in combination with aspirin compared to the use of aspirin alone for secondary cardiovascular prevention. This multinational, double blind, double dummy, randomized trial was terminated early due to the demonstrated superiority of the rivaroxaban plus aspirin group compared to aspirin alone. The primary outcome of major CV events occurred in 4.1 percent of patients receiving the combination of aspirin and rivaroxaban versus 5.4 percent with aspirin alone (hazard ratio, 0.76; P<0.001). The trial conclusion led to the recommendation of adding rivaroxaban 2.5 mg twice daily to low dose aspirin for the prevention of secondary CV outcomes in patients with stable atherosclerotic vascular disease.3
As pharmacists, there are several major considerations of this new indication. First, the indication is only for the prevention of secondary CV events in CAD and PAD; primary prevention of CV events was not evaluated in the COMPASS trial. Uniquely, the trial evaluated adherence through the use of a 14 day run-in phase that identified patients who were unwilling or unable to adhere to the regimen.3 The recommended regimen does require the patient to take two different tablets on a different schedule (one twice daily and the other only once daily). The increased complexity of the regimen - from historical use of one aspirin tablet once daily - did not seem to be a barrier to efficacy. Recognition of the new dosage associated with this indication is vital. Rivaroxaban previously was only available as brand name Xarelto® in 10, 15, and 20 mg tablets.4 Following the most recent recommendation. a 2.5 mg tablet has come to the market - which is 25 percent the strength of the previous lowest available strength. The recommended regimen is also dosed twice daily, unlike the most common once daily dosing strategy for other rivaroxaban indications.4 These changes require vigilance as pharmacists to ensure safe and proper use. Finally, the major side effect of bleeding must be considered. The combination of rivaroxaban with aspirin did result in more major bleeding events (defined as events that led to patient presentation to an acute facility or hospitalization) than aspirin alone, 3.1 percent versus 1.9 percent respectively (hazard ratio, 1.70; P<0.001).3
Health system pharmacies also have important considerations regarding this new indication. At any given time, hospitals may have patients meeting the criteria for initiation of this indication as well as patients continuing home therapy of the combination. Health system pharmacists must work with multidisciplinary teams to evaluate the implementation of the new rivaroxaban indication. Cost of the addition of the 2.5 mg dosage to hospital formulary will have to be evaluated. Maintaining one patient on aspirin alone costs approximately $0.05/day, but with the addition of rivaroxaban 2.5 mg twice daily the price increases by $16.76/day based on average wholesale price. 4,5 The cost of rivaroxaban to the patient should also be considered as pharmacists may be involved in insurance and discount programs. Lastly, as many health systems are incorporating pharmacists in programs focused on educating patients initiated on oral anticoagulants, there is reason to include this new low dose indication in education programs.
Rivaroxaban is the only NOAC with an indication for secondary CV prevention in patients with CAD/PAD. We look to the future to see upcoming trials and evaluation of efficacy of the other oral anticoagulants in the pursuit of a similar indication.
1. Global Janssen [Internet]. Titusville: Janssen Global Services, LLC. c2012-2019. U.S. FDA approves Xarelto (rivaroxaban) to reduce the risk of major cardiovascular events in patients with chronic coronary artery disease (CAD) or peripheral artery disease (PAD); 2018 Oct. 11 [cited 2019 Jan. 14]; [about 3 screens]. Available from: https://www.janssen.com/us-fda-approves-xareltor-rivaroxaban-reduce-risk-major-cardiovascular-events-patients-chronic
2. Xarelto® [packet insert]. Titusville, NJ: Janssen; 2018.
3. Eikelboom JW, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med [Internet]. 2017 Aug. 27 [cited 2019 Jan. 14];377:1319-30. Available from: https://www.nejm.org/doi/full/10.1056/NEJMoa1709118
4. Lexicomp Online [Internet]. Indianapolis: Wolters Kluwer Clinical Drug Information, Inc. 2013. Rivaroxaban; [cited 2019 Jan. 14]; Available from: http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/1275239#f_preparations
5. Lexicomp Online [Internet]. Indianapolis: Wolters Kluwer Clinical Drug Information, Inc. 2013. Aspirin; [cited 2019 Jan. 14]; Available from: http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6388#fee