Rivaroxaban is the only FDA-approved anticoagulant used in patients with peripheral artery disease and coronary artery disease.
Rivaroxaban (Xarelto) is an anticoagulant approved for multiple conditions such as non-valvular atrial fibrillation, treatment and prevention of venous thromboembolism, and other indications that are subdivided into table 1†
Like other direct factor Xa inhibitors, rivaroxaban is a fixed-dose oral drug that is administered without routine monitoring.1 Although anticoagulants prevent venous thrombosis, rivaroxaban has a unique indication for use. It is the only FDA-approved anticoagulant drug used in patients with peripheral artery disease (PAD) and coronary artery disease (CAD).
In this population, rivaroxaban reduces the risk of heart attack, stroke, cardiovascular death and severe limb adverse reactions (MALE) when taken with 81 mg of aspirin.2
Table 1: Indication/Dosage for Rivaroxaban3
Venous thromboembolism (VTE) occurs when there is endothelial damage, hypercoagulability, or blood stagnation.5 These 3 conditions, known as Virchow’s triad, can lead to deep vein thrombosis or pulmonary embolism.
Rivaroxaban acts by direct inhibition of free and clot-bound factor Xa in a dose-dependent manner. This inhibition prevents the formation of fibrin and reduces the recurrence of VTE.
In a meta-analysis evaluating the recurrence rate of DVT in patients receiving rivaroxaban, 258 of 19,144 (1.35%) patients had VTE within 6 months, demonstrating the efficacy of rivaroxaban in the prevention of venous clots.6 Treating PAD is complex because there are multiple factors that influence atherothrombosis.
Arterial clots occur when exposed plaque interacts with platelet receptors and clotting factors, leading to platelet aggregation.7 Reducing thrombin formation and platelet aggregation with rivaroxaban and aspirin is a proposed mechanism to reduce arterial clots.
Prior to rivaroxaban, the recommended treatment for symptomatic patients on PAD was dual antiplatelet therapy (DAPT). In the PEGASUS study, ticagrelor and aspirin showed an absolute risk reduction of coronary events by 4.1% (NNT 25)9 and a reduction in all-cause mortality; however, it did not significantly reduce the risk of limb ischemia.9
This combination resulted in minimal bleeding episodes and is fairly safe to use in this population.9 DAPT may not be appropriate for all patients. For example, patients with stable PAD, defined as patients with PAD without myocardial infarction or stroke, benefit from single antiplatelet therapy with clopidegral or ticagrelor.
DAPT in chronic stable PAD may lead to a higher risk of bleeding, as found in a study comparing clopidogrel and aspirin to aspirin alone, resulting in significant bleeding [risk ratio (RR) 1.73, P= 0.004]†10 The CAPRIE study evaluated patients with stable PAD.
Clopidogrel was associated with a 22% reduction from aspirin in the relative risk of serious coronary adverse events,11 ticagrelor was also not found to be superior to clopidegral for use in this population based on the EUCLID study.12 DAPT can carry a significant risk of bleeding and determining the right patient population for appropriate use is difficult.
Rivaroxaban is an alternative to DAPT for patients with symptomatic PAD because it reduces the recurrence of cardiovascular events and MALE. Patients taking rivaroxaban 2.5 mg twice daily with aspirin 81 mg had a lower risk of composite death, stroke and myocardial infarction compared to aspirin alone (p<0.001).12 Treatment with rivaroxaban also reduced all-cause mortality by 18%.13
A subgroup study for symptomatic PAD noted an absolute risk reduction of MALE, including amputation at 30 months, by 4.2%.14 Although an increased risk of bleeding was identified with this combination regimen, organ and fatal bleeding rates were low, demonstrating that the benefit of the drug outweighs the risk of bleeding.14
Compared to ticagrelor and aspirin, rivaroxaban and aspirin have the added benefit of reducing MALE. Both drugs are beneficial for patients with co-morbidities such as kidney disease, diabetes, increased age and multi-vessel disease.9,12,14
In short, there are many indications and uses for rivaroxaban. The 2.5 mg dose administered twice daily is beneficial for high-risk patients with PAD and CAD and is a reasonable alternative to DAPT.
- Antoniou S. Rivaroxaban for the treatment and prevention of thromboembolic disorders. Journal of Pharmacy and Pharmacology. 2015;67(8):1119-1132. doi:10.1111/jphp.12387
- Kaplovitch E, Eikelboom JW, Dyal L, et al. Rivaroxaban and aspirin in patients with symptomatic peripheral vascular disease of the lower extremities. JAMA Cardiology. 2020. doi:10.1001/jamacardio.2020.4390
- Xarelto (rivaroxaban) tablets label – food and medicine .https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202439s001lbl.pdf.
- Aursulesei V, Costache II. Anticoagulation in chronic kidney disease: from guidelines to clinical practice. Clinical Cardiology. 2019;42(8):774-782. doi:10.1002/clc.23196
- Aleman MM, Walton BL, Byrnes JR, Wolberg AS. Fibrinogen and red blood cells in venous thrombosis. Thromb res. 2014;133 Supplement 1(0 1):S38-S40. doi:10.1016/j.thromres.2014.03.017
- Aryal MR, Gosain R, Donato A, et al. Systematic review and meta-analysis of the efficacy and safety of apixaban compared to rivaroxaban in real-world acute VTE. Blood Adv. 2019;3(15):2381-2387. doi:10.1182/bloodadvances.2019000572
- Badimon L, Vilahur G. Thrombosis on atherosclerotic lesions and plaque rupture. J Intern Med. 2014;276(6):618-632. doi:10.1111/joim.12296
- Hiatt WR, Fowkes FG, Heizer G, et al. Ticagrelor versus Clopidogrel in symptomatic peripheral artery disease. N Engl J Med. 2017;376(1):32-40. doi:10.1056/NEJMoa1611688
- Bonaca MP, Bhatt DL, Storey RF, et al. Ticagrelor for the prevention of ischemic events after myocardial infarction in patients with peripheral vascular disease. Journal of the American College of Cardiology. 2016;67(23):2719-2728. doi:10.1016/j.jacc.2016.03.524
- Gajulapalli RD, Dias S, Pattanshetty DJ, Athappan G. Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: a network meta-analysis. Anatol J Cardiol. 2017;18(4):251-260. doi:10.14744/AnatolJCardiol.2017.7672
- Create MA. Results of the CAPRIE study: efficacy and safety of clopidogrel. Clopidogrel versus aspirin in patients at risk for ischemic events. Vasc Med. 1998;3(3):257-260
- Hiatt WR, Fowkes FG, Heizer G, et al. Ticagrelor versus clopidogrel in symptomatic peripheral vascular disease. New England Journal of Medicine. 2017;376(1):32-40. doi:10.1056/nejmoa1611688
- Steffel J, Eikelboom JW, Anand SS, Shestakovska O, Yusuf S, Fox KAA. The compass test. Circulation. 2020;142(1):40-48. doi:10.1161/circulationaha.120.046048
- Kaplovitch, E., Eikelboom, JW, et al. Rivaroxaban and aspirin in patients with symptomatic lower extremity peripheral artery disease: a subanalysis of the COMPASS randomized clinical trial. JAMA cardiology, (2021). 6(1), 21-29. https://doi.org/10.1001/jamacardio.2020.4390