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.
N1 - Funding Information:
Conflict of Interest Disclosures: Dr Szarek reported receiving grants from Baxter and Resverlogix; personal fees from CiVi and Esperion; grants, personal fees, and nonfinancial support from Sanofi; and grants and nonfinancial support from Regeneron outside the submitted work. Dr Anand reported receiving personal fees from Bayer and Janssen outside the submitted work. Dr Bauersachs reported receiving personal fees from Bayer during the conduct of this study and personal fees from Bristol Myers Squibb, Daiichi Sankyo, Leo Pharma, and Pfizer outside the submitted work. Dr Patel reported receiving personal fees from Bayer and Heartflow during the conduct of the study and grants and personal fees from AstraZeneca and Heartflow and grants from Heartflow, Janssen, Medtronic, Novartis, and Philips Healthcare outside the submitted work. Dr Debus reported receiving grants from Cook and Terumo Aortic outside the submitted work. Dr Beckman reported receiving personal fees from Amgen, Bayer, JanOne, Janssen, Novartis, and VIVA and grants from Bristol Myers Squibb outside the submitted work. Dr Piazza reported receiving grants from Alexion, Amgen, Bayer, Boston Scientific, Bristol Myers Squibb/Pfizer Alliance, and Janssen (paid to his institution), and personal fees from Amgen, Boston Scientific, Brazilian Clinical Research Institute, Bristol Myers Squibb, Janssen, Pfizer, Prairie Education and Research Cooperative, and Syntactx outside the submitted work. Dr Henkin reported receiving personal fees from Pfizer outside the submitted work. Dr. Bura-Rivière reported serving as a paid consultant for Bayer. Dr Lawall reported receiving personal fees from Bayer Vital during the conduct of the study. Dr Roztocil reported serving as a national coordinator for Vascular Outcomes Study of ASA (acetylsalicylic acid) Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD (VOYAGER PAD) trial. Dr Hsia reported receiving personal fees from the University of Pittsburgh and owning stock in AstraZeneca. Dr Muehlhofer reported being employed by Bayer during the conduct of this study. Dr Berkowitz reported being employed by Bayer during the conduct and operationalization of VOYAGER PAD. Dr Haskell reported being employed by Janssen Pharmaceuticals and owning stock in Johnson & Johnson outside the submitted work. Drs Hess, Szarek, Nehler, Capell, Hsia, Berkowitz, and Bonaca reported receiving salary support from CPC Clinical research, a nonprofit academic research organization affiliated with the University of Colorado, that receives grants and consulting funding from Abbott, Agios, Alexion Pharma, Alnylam, Amgen, Angionetics, ARCA Biopharma, Array, AstraZeneca, Atentiv, Audentes, Bayer, Better Therapeutics, Brigham and Women’s Hospital, Bristol Myers Squibb, Cardiol Therapeutics, CellResearch, Cook Medical, Cook, CSL Behring, Eidos Therapeutics, EP Trading, Esperion Therapeutics, EverlyWell, Faraday, Fortress Biotech, HDL Therapeutics, Heartflow, Hummingbird Bioscience, Insmed, Janssen, Kowa Research, Lexicon, Merck, Medtronic, Moderna, Novate Medical, Novo Nordisk, Pfizer, PhaseBio, PPD Development, Prairie Education and Research, Prothena Ciosciences, Regeneron, Regio Biosciences, Sanifit Therapeutics, Sanofi, Smith and Nephew, Stealth BioTherapeutics, University of Colorado, Worldwide Clinical Trials, Wraser, and Yale Cardiovascular Research Group. No other disclosures were reported.
Funding Information:
Funding/Support: The VOYAGER PAD trial was funded by Bayer and Janssen Pharmaceuticals. Dr Bonaca was supported by the American Heart Association Strategically Focused Research Network in Vascular Disease under award No. 18SFRN3390085 (Brigham and Women’s Hospital [BWH]–Dartmouth-Hitchcock [DH] Medical Center Strategically Focused Research Networks Center) and 18SFRN33960262 (BWH-DH Clinical Project). The content is solely the responsibility of the authors and does not necessarily represent the official views of the American Heart Association.
Publisher Copyright:
© 2022 American Medical Association. All rights reserved.
PY - 2022/6/22
Y1 - 2022/6/22
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..
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U2 - 10.1001/jamanetworkopen.2022.15580
DO - 10.1001/jamanetworkopen.2022.15580
M3 - Article
C2 - 35731517
AN - SCOPUS:85133100906
SN - 2574-3805
VL - 5
SP - E2215580
JO - JAMA network open
JF - JAMA network open
IS - 6
ER -