Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Hess CN

PROVIDER: S-EPMC9218845 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportancePatients with symptomatic lower extremity peripheral artery disease (LE-PAD) experience an increased risk of major vascular events. There is limited information on what clinical features of symptomatic LE-PAD prognosticate major vascular events and whether patients at high risk have a greater absolute benefit from low-dose rivaroxaban and aspirin.ObjectiveTo quantify the risk of major vascular events and investigate the response to treatment with low-dose rivaroxaban and aspirin among patients with symptomatic LE-PAD based on clinical presentation and comorbidities.Design, setting, and participantsThis is a subanalysis of a previously reported subgroup of patients with symptomatic LE-PAD who were enrolled in a large, double-blind, placebo-controlled randomized clinical trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies [COMPASS]) in 602 centers in 33 countries from March 2013 to January 2020. Data analysis was completed from May 2016 to June 2020.InterventionsA combination of low-dose rivaroxaban and aspirin compared with aspirin alone.Main outcomes and measuresThirty-month incidence risk of myocardial infarction, stroke and cardiovascular death (MACE), major adverse limb events (MALE) including major vascular amputation, and bleeding.ResultsThe COMPASS trial enrolled 4129 patients with symptomatic LE-PAD (mean [SD] age, 66.8 [8.8] years; 2932 men [71.0%]). The 30-month Kaplan-Meier incidence risk of MACE or MALE, including major amputation, was 22.6% in those with prior amputation (this outcome was observed in 54 patients), 17.6% (n = 15) in those with Fontaine III or IV symptoms, and 11.8% (n = 142) in those with previous peripheral artery revascularization, classifying these features as high-risk limb presentations. The 30-month incidence risk of MACE or MALE, including major amputation, was 14.1% (n = 118) in those with kidney dysfunction, 13.5% (n = 67) in those with heart failure, 13.4% (n = 199) in those with diabetes, and 12.8% (n = 222) in those with polyvascular disease, classifying these features as high-risk comorbidities. Among patients with either high-risk limb presentations or high-risk comorbidities, treatment with rivaroxaban and aspirin compared with aspirin alone was associated with an estimated 4.2% (95% CI, 1.9%-6.2%) absolute risk reduction for MACE or MALE, including major amputation, at 30 months. Although the estimated absolute risk increase of major bleeding was higher with rivaroxaban and aspirin in combination than aspirin alone (2.0% [95% CI, 0.5%-3.9%]) for patients with either high-risk limb presentation or high-risk comorbidity, the estimated absolute risk increase of fatal or critical organ bleeding was low in this high-risk group (0.4% [95% CI, 0.2%-1.8%]), such that the net clinical benefit was estimated to be 3.2% (95% CI, 0.6%-5.3%).Conclusions and relevancePatients with LE-PAD with high-risk limb presentations or high-risk comorbidities had a high incidence of major vascular events. For these patients, treatment with rivaroxaban and aspirin in combination compared with aspirin alone led to a large absolute reduction in vascular risk.

Project description:BACKGROUND:The global EINSTEIN DVT and PE studies compared rivaroxaban (15 mg twice daily for 3 weeks followed by 20 mg once daily) with enoxaparin/vitamin K antagonist therapy and demonstrated non-inferiority for efficacy and superiority for major bleeding. Owing to differences in targeted anticoagulant intensities in Japan, Japanese patients were not enrolled into the global studies. Instead, a separate study of deep vein thrombosis (DVT) and/or pulmonary embolism (PE) in Japanese patients was conducted, which compared the Japanese standard of care with a reduced dose of rivaroxaban. METHODS:We conducted an open-label, randomized trial that compared 3, 6, or 12 months of oral rivaroxaban alone (10 mg twice daily or 15 mg twice daily for 3 weeks followed by 15 mg once daily) with activated partial thromboplastin time-adjusted intravenous unfractionated heparin (UFH) followed by warfarin (target international normalized ratio 2.0; range 1.5-2.5) in patients with acute, objectively confirmed symptomatic DVT and/or PE. Patients were assessed for the occurrence of symptomatic recurrent venous thromboembolic events or asymptomatic deterioration and bleeding. RESULTS:Eighty-one patients were assigned to rivaroxaban and 19 patients to UFH/warfarin. Three patients were excluded because of serious non-compliance issues. The composite of symptomatic venous thromboembolic events or asymptomatic deterioration occurred in 1 (1.4%) rivaroxaban patient and in 1 (5.3%) UFH/warfarin patient (absolute risk difference, 3.9% [95% confidence interval, -3.4-23.8]). No major bleeding occurred during study treatment. Clinically relevant non-major bleeding occurred in 6 (7.8%) patients in the rivaroxaban group and 1 (5.3%) patient in the UFH/warfarin group. CONCLUSIONS:The findings of this study in Japanese patients with acute DVT and/or PE suggest a similar efficacy and safety profile with rivaroxaban and control treatment, consistent with that of the worldwide EINSTEIN DVT and PE program. TRIAL REGISTRATION:Clinicaltrials.gov: NCT01516840 and NCT01516814.