Trial Reference
Bonaca MP, Bauersachs RM, Anand SS, et al. Rivaroxaban in Peripheral Artery Disease after Revascularization. N Engl J Med. 2020 May 21;382(21):1994-2004. doi: 10.1056/NEJMoa2000052.
Expert Comment
Gheorghe-Andrei Dan
Professor of Cardiology and Internal Medicine, Colentina University Hospital, Bucharest, Romania
Background
Different from the traditional belief, the culprit lesion in peripheral artery disease (PAD) with chronic limb ischemia is a thrombotic obstruction accompanied often with insignificant atherosclerosclerosis.1 This fact is the rationale for the observed benefit of rivaroxaban plus aspirin on major limb adverse effects (MALE) and vascular adverse events demonstrated by the analysis of the PAD patients from the COMPASS study.2,3 Among the population with PAD the incidence of MALE is highest for the patients who already suffered revascularization and/or amputation, less in the symptomatic patients with PAD but without history of revascularization or amputation and lowest in the asymptomatic patients with an abnormal ankle-brachial index.4 It is therefore of interest to find out if the global benefit demonstrated in the COMPASS trial translates to patients who suffered revascularization procedures.
The Voyager PAD trial5 randomized 6564 PAD patients who undergone revascularization procedures in a bifactorial design to receive rivaroxaban (2.5mg bid ) plus aspirin (3286 patients) versus placebo plus aspirin (3278 patients). The majority of patients were pre-treated with statin and ACEI. The main efficacy outcome was a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes. The primary safety outcome was the major bleeding as defined by TIMI classification with the major bleeding as defined by ISTH as a secondary endpoint.
The rivaroxaban-aspirin treatment resulted in a highly significant decrease of the hazard ratio for the efficacy outcome of 0.85 (CI:0.76-0.96). As compared to control the combination rivaroxaban plus aspirin resulted in a non-significant increase in the hazard ratio for the primary safety endpoint of 1.43 (CI:0.97-2.10) but in a significant increase of the hazard ratio for the secondary safety endpoint of 1.42 (CI:1.10-1.84).5
A recent substudy of the Voyager PAD trial evaluated the impact of the limited time use of clopidogrel after revascularization procedure on the efficacy and safety of rivaroxaban based therapy.6 The safety of rivaroxaban was consistent regardless of clopidogrel use, however a trend to more ISTH defined bleeding was noticed if clopidogrel was used for more than 30 days.
Conclusions
Rivaroxaban added to aspirin in symptomatic PAD patients who suffered revascularization procedures results in reduced the incidence of the composite outcome of acute limb ischemia, amputation for vascular causes, myocardial infarction, ischemic stroke, or cardiovascular death at the price of increase ISTH defined bleeding
References
1. Narula N, Dannenberg AJ, Olin JW, Bhatt DL, Johnson KW, Nadkarni G, Min J, Torii S, Poojary P, Anand SS, Bax JJ, Yusuf S, Virmani R, Narula J. Pathology of Peripheral Artery Disease in Patients With Critical Limb Ischemia. J Am Coll Cardiol 2018;72:2152–2163.
2. Anand SS, Caron F, Eikelboom JW, Bosch J, Dyal L, Aboyans V, Abola MT, Branch KRH, Keltai K, Bhatt DL, Verhamme P, Fox KAA, Cook-Bruns N, Lanius V, Connolly SJ, Yusuf S. Major Adverse Limb Events and Mortality in Patients With Peripheral Artery Disease: The COMPASS Trial. J Am Coll Cardiol 2018;71:2306–2315.
3. Kaplovitch E, Eikelboom JW, Dyal L, Aboyans V, Abola MT, Verhamme P, Avezum A, Fox KAA, Berkowitz SD, Bangdiwala SI, Yusuf S, Anand SS. Rivaroxaban and Aspirin in Patients with Symptomatic Lower Extremity Peripheral Artery Disease: A Subanalysis of the COMPASS Randomized Clinical Trial. JAMA Cardiol 2020;1–9.
4. Bonaca MP, Creager MA. Antithrombotic Therapy and Major Adverse Limb Events in Peripheral Artery Disease: A Step Forward ∗. J Am Coll Cardiol 2018;71:2316–2318.
5. Bonaca MP, Bauersachs RM, Anand SS, Debus ES, Nehler MR, Patel MR, Fanelli F, Capell WH, Diao L, Jaeger N, Hess CN, Pap AF, Kittelson JM, Gudz I, Mátyás L, Krievins DK, Diaz R, Brodmann M, Muehlhofer E, Haskell LP, Berkowitz SD, Hiatt WR. Rivaroxaban in Peripheral Artery Disease after Revascularization. N Engl J Med 2020;382:1994–2004.
6. Hiatt WR, Bonaca MP, Patel MR, Nehler MR, Debus ES, Anand SS, Capell WH, Brackin T, Jaeger N, Hess C, Pap AF, Berkowitz SD, Muehlhofer E, Haskell L, Brasil D, Madaric J, Sillesen H, Szalay D, Bauersachs R. Rivaroxaban and Aspirin in Peripheral Artery Disease Lower Extremity Revascularization: Impact of Concomitant Clopidogrel on Efficacy and Safety. Circulation 2020;