Rivaroxaban and Risk of Venous Thromboembolism in Patients With Symptomatic Peripheral Artery Disease After Lower Extremity Revascularization

TY - JOUR

T1 - Rivaroxaban and Risk of Venous Thromboembolism in Patients With Symptomatic Peripheral Artery Disease After Lower Extremity Revascularization

AU - Hess, Connie N

AU - Szarek, Michael

AU - Anand, Sonia S

AU - Bauersachs, Rupert M

AU - Patel, Manesh R

AU - Debus, E Sebastian

AU - Nehler, Mark R

AU - Capell, Warren H

AU - Beckman, Joshua A

AU - Piazza, Gregory

AU - Henkin, Stanislav

AU - Bura-Rivière, Alessandra

AU - Lawall, Holger

AU - Roztocil, Karel

AU - Hsia, Judith

AU - Muehlhofer, Eva

AU - Berkowitz, Scott D

AU - Haskell, Lloyd P

AU - Bonaca, Marc P

PY - 2022/6/1

Y1 - 2022/6/1

N2 - IMPORTANCE: Prior studies have observed an association between the burden of atherosclerotic vascular disease and the risk of venous thromboembolism (VTE). The association is not well described in peripheral artery disease (PAD) after lower extremity revascularization (LER).OBJECTIVE: To describe the risk of, factors associated with, and outcomes after VTE, as well as the association of low-dose rivaroxaban plus antiplatelet therapy with VTE after LER.DESIGN, SETTING, AND PARTICIPANTS: This global, multicenter cohort study used data from the Vascular Outcomes Study of ASA (acetylsalicylic acid) Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD (VOYAGER PAD) randomized clinical trial, which enrolled patients from 2015 to 2018 with median follow-up of 28 months. Participants included patients with PAD undergoing LER. Patients with an indication for therapeutic anticoagulation were excluded. Data were analyzed from September 2020 to September 2021.EXPOSURE: Randomization to rivaroxaban 2.5 mg twice daily or placebo on a background of aspirin 100 mg daily; short-term clopidogrel was used at the discretion of the treating physician.MAIN OUTCOMES AND MEASURES: Symptomatic VTE was a prespecified secondary outcome and prospectively collected.RESULTS: Among 6564 patients (median [IQR] age, 67 [61-73] years; 4860 [74.0%] men), 66 patients had at least 1 VTE. The 3-year rate of VTE in patients receiving placebo was 1.7%, and the pattern of risk was linear (year 1: 0.5%; year 2: 1.1%). After multivariable modeling, weight (hazard ratio [HR], 3.04; 95% CI, 1.09-8.43), hypertension (HR, 2.11; 95% CI, 0.91-4.89), prior amputation (HR, 2.07; 95% CI, 0.95-4.53), and older age (HR, 1.81; 95% CI, 1.06-3.11) were associated with increased risk of VTE. VTE was associated with risk of subsequent mortality (HR, 7.22; 95% CI, 4.66-11.19). Compared with aspirin alone, rivaroxaban plus aspirin was associated with lower VTE risk (HR, 0.61; 95% CI, 0.37-0.998; P = .047), with benefit apparent early and sustained over time. This association was not modified by use of clopidogrel at randomization (without clopidogrel: HR, 0.55; 95% CI, 0.29-1.07; with clopidogrel: HR, 0.69; 95% CI, 0.32-1.48; P for interaction = .67).CONCLUSIONS AND RELEVANCE: In this cohort study, there was continuous risk for VTE after LER in patients with PAD, with greater risk in patients who were older and had obesity and those with more severe PAD, as reflected by prior amputation. Low-dose rivaroxaban plus aspirin was associated with lower VTE risk compared with aspirin alone, with benefits apparent early and continued over time. The spectrum of venous and arterial thrombotic events and overall benefits of more potent antithrombotic strategies for prevention should be considered after LER for PAD.

AB - IMPORTANCE: Prior studies have observed an association between the burden of atherosclerotic vascular disease and the risk of venous thromboembolism (VTE). The association is not well described in peripheral artery disease (PAD) after lower extremity revascularization (LER).OBJECTIVE: To describe the risk of, factors associated with, and outcomes after VTE, as well as the association of low-dose rivaroxaban plus antiplatelet therapy with VTE after LER.DESIGN, SETTING, AND PARTICIPANTS: This global, multicenter cohort study used data from the Vascular Outcomes Study of ASA (acetylsalicylic acid) Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD (VOYAGER PAD) randomized clinical trial, which enrolled patients from 2015 to 2018 with median follow-up of 28 months. Participants included patients with PAD undergoing LER. Patients with an indication for therapeutic anticoagulation were excluded. Data were analyzed from September 2020 to September 2021.EXPOSURE: Randomization to rivaroxaban 2.5 mg twice daily or placebo on a background of aspirin 100 mg daily; short-term clopidogrel was used at the discretion of the treating physician.MAIN OUTCOMES AND MEASURES: Symptomatic VTE was a prespecified secondary outcome and prospectively collected.RESULTS: Among 6564 patients (median [IQR] age, 67 [61-73] years; 4860 [74.0%] men), 66 patients had at least 1 VTE. The 3-year rate of VTE in patients receiving placebo was 1.7%, and the pattern of risk was linear (year 1: 0.5%; year 2: 1.1%). After multivariable modeling, weight (hazard ratio [HR], 3.04; 95% CI, 1.09-8.43), hypertension (HR, 2.11; 95% CI, 0.91-4.89), prior amputation (HR, 2.07; 95% CI, 0.95-4.53), and older age (HR, 1.81; 95% CI, 1.06-3.11) were associated with increased risk of VTE. VTE was associated with risk of subsequent mortality (HR, 7.22; 95% CI, 4.66-11.19). Compared with aspirin alone, rivaroxaban plus aspirin was associated with lower VTE risk (HR, 0.61; 95% CI, 0.37-0.998; P = .047), with benefit apparent early and sustained over time. This association was not modified by use of clopidogrel at randomization (without clopidogrel: HR, 0.55; 95% CI, 0.29-1.07; with clopidogrel: HR, 0.69; 95% CI, 0.32-1.48; P for interaction = .67).CONCLUSIONS AND RELEVANCE: In this cohort study, there was continuous risk for VTE after LER in patients with PAD, with greater risk in patients who were older and had obesity and those with more severe PAD, as reflected by prior amputation. Low-dose rivaroxaban plus aspirin was associated with lower VTE risk compared with aspirin alone, with benefits apparent early and continued over time. The spectrum of venous and arterial thrombotic events and overall benefits of more potent antithrombotic strategies for prevention should be considered after LER for PAD.

KW - Aged

KW - Aspirin/adverse effects

KW - Clopidogrel/therapeutic use

KW - Cohort Studies

KW - Female

KW - Humans

KW - Lower Extremity/blood supply

KW - Male

KW - Peripheral Arterial Disease/complications

KW - Platelet Aggregation Inhibitors/adverse effects

KW - Rivaroxaban/adverse effects

KW - Venous Thromboembolism/epidemiology

U2 - 10.1001/jamanetworkopen.2022.15580

DO - 10.1001/jamanetworkopen.2022.15580

M3 - SCORING: Journal article

C2 - 35731517

VL - 5

JO - JAMA NETW OPEN

JF - JAMA NETW OPEN

SN - 2574-3805

IS - 6

M1 - e2215580

ER -