Peripheral artery disease (PAD) commonly coexists with atherosclerosis in other vascular beds and is associated with higher risks of myocardial infarction (MI), cerebrovascular accident (CVA), and acute limb ischemia (ALI) or chronic limb-threatening ischemia (CLTI).^1,2 However, PAD may also be associated with higher risk of venous thromboembolism (VTE) and vice versa. These vascular entities may be mediated by shared risk factors such as age and obesity, and underlying mechanisms like chronic inflammation or thrombophilia. In a combined analysis of two antiplatelet trials, the reported VTE rate was approximately 0.3%/year in patients with atherosclerosis regardless of vascular territory. Meanwhile, polyvascular atherosclerotic disease was associated with increased 3-year VTE rates (0.76% for 1, 1.53% for 2, and 2.45% for 3 territories).³ Recently, a post-hoc analysis of VOYAGER-PAD by Hess and colleagues evaluated the rates and risk factors of VTE in patients with PAD undergoing lower extremity revascularization.⁴

The VOYAGER-PAD trial is an international, randomized controlled trial which evaluated the role of low-dose rivaroxaban in patients with PAD undergoing lower extremity revascularization.⁵ In this study conducted between 2015 and 2018, 6,564 individuals with PAD undergoing lower extremity revascularization for claudication or CLTI were randomized to a combination of rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily versus aspirin 100 mg daily alone. At 3 years, individuals receiving combination therapy had significantly lower rates of the primary composite outcome of ALI, major amputation, MI, ischemic stroke, or death from cardiovascular cause (hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.76-0.96). Symptomatic VTE was a pre-specified exploratory outcome in the clinical trial design. Combination of low-dose rivaroxaban and aspirin was associated with 39% relative risk reduction of VTE.

The post-hoc analysis of VOYAGER-PAD evaluated the rates and risk factors of VTE in patients with PAD undergoing lower extremity revascularization. The overall incidence of VTE was 1% (0.6% per year, 0.42 per 100 patient-years) and VTE was associated with a higher risk of all-cause mortality (HR 7.22, 95% CI 4.66-11.2). Factors associated with higher risk of developing a VTE included weight ≥60 kg (HR 3.04, 95% CI 1.09-8.43), age ≥75 years (HR 1.81, 95% CI 1.06-3.11), hypertension (HR, 2.11, 95% CI, 0.91-4.89), and a history of prior amputation suggestive of a higher burden of atherosclerotic disease (HR, 2.07; 95% CI, 0.95-4.53). The investigators found that low-dose rivaroxaban plus aspirin was associated with a 39% reduction in VTE (HR 0.61, 95% CI 0.37-1.0). The risk reduction was similar to that observed in the COMPASS trial for patients receiving low dose rivaroxaban plus aspirin (HR 0.61, 95% CI 0.37-1.0).⁶ The 3-year VTE rate in the placebo group was 1.7% with an observed linear pattern of continuous risk (year 1: 0.5%; year 2: 1.1%). These rates of VTE over time suggest that the overall burden of atherosclerotic disease may be a more important risk factor for the development of a VTE than the risks associated with the post-procedural period.

Overall, the data from these studies suggest that a dual pathway inhibition strategy with low dose rivaroxaban plus aspirin may be useful to reduce the risk of both arterial and venous thrombotic complications after lower extremity revascularization. In patients with polyvascular atherosclerotic disease, a more intensive antiplatelet regimen has also been shown to be beneficial in risk reduction for VTEs (HR 0.71; CI 0.56-0.89; p=0.003).³

Additional research is needed to determine the optimal combination therapy for VTE risk reduction, as a means of leading to new guidelines for antiplatelet and/or antithrombotic therapies after lower extremity revascularization in patients with PAD.

References

1. Kumbhani DJ, Steg PG, Cannon CP, et al. Statin therapy and long-term adverse limb outcomes in patients with peripheral artery disease: insights from the REACH registry. Eur Heart J 2014;35:2864-72.
2. Bonaca MP, Bhatt DL, Storey RF, et al. Ticagrelor for prevention of ischemic events after myocardial infarction in patients with peripheral artery disease. J Am Coll Cardiol 2016;67:2719-28.
3. Cavallari I, Morrow DA, Creager MA, et al. Frequency, predictors, and impact of combined antiplatelet therapy on venous thromboembolism in patients with symptomatic atherosclerosis. Circulation 2018;137:684-92.
4. Hess CN, Szarek M, Anand SS, et al. Rivaroxaban and risk of venous thromboembolism in patients with symptomatic peripheral artery disease after lower extremity revascularization. JAMA Netw Open 2022;5:e2215580.
5. Bonaca MP, Bauersachs RM, Anand SS, et al. Rivaroxaban in peripheral artery disease after revascularization. N Engl J Med 2020;382:1994-2004.
6. Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017;377:1319-30.

Clinical Topics: Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Interventions and Vascular Medicine

Keywords: Rivaroxaban, Venous Thromboembolism, Myocardial Revascularization, Peripheral Arterial Disease, Aspirin, Fibrinolytic Agents, Ischemic Stroke, Confidence Intervals, Lower Extremity, Thrombophilia, Risk Factors, Ischemia, Inflammation, Infarction, Myocardial Infarction

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