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Randomized Controlled Trial
. 2022 May;20(5):1193-1205.
doi: 10.1111/jth.15673. Epub 2022 Mar 7.

Prevention of arterial and venous thrombotic events in symptomatic peripheral arterial disease patients after lower extremity revascularization in the VOYAGER PAD trial: Dual anticoagulant/antiplatelet regimen vs antiplatelet therapy alone

Scott D Berkowitz  1   2 , Rupert M Bauersachs  3   4 , Michael Szarek  1   5   6 , Mark R Nehler  1   7 , E Sebastian Debus  8 , Manesh R Patel  9   10 , Sonia S Anand  11   12 , Warren H Capell  1   13 , Connie N Hess  1   5 , Judy Hsia  1   5 , Nicholas J Leeper  14 , David Brasil  15 , Lajos Mátyás  16 , Rafael Diaz  17 , Marianne Brodmann  18 , Eva Muehlhofer  19 , Lloyd P Haskell  20 , Marc P Bonaca  1   5
Affiliations
Randomized Controlled Trial

Prevention of arterial and venous thrombotic events in symptomatic peripheral arterial disease patients after lower extremity revascularization in the VOYAGER PAD trial: Dual anticoagulant/antiplatelet regimen vs antiplatelet therapy alone

Scott D Berkowitz et al. J Thromb Haemost. 2022 May.

Abstract

Background: Vascular disease burden after lower extremity revascularization (LER) comprises more than the first event, more vascular beds than the local arteries, and more than one clinical event type.

Objectives: Assess total arterial and venous thrombotic burden after LER for symptomatic peripheral artery disease (PAD) and effect of low-dose anticoagulation added to low-dose antiplatelet therapy.

Patients/methods: VOYAGER PAD randomized 6564 symptomatic PAD patients undergoing LER to rivaroxaban 2.5 mg twice-daily or placebo on aspirin background. Marginal proportional-hazards models used to generate treatment hazard ratios and associated 95% CIs for first and total events; non-thrombotic deaths treated as competing terminal events. Incidence rates calculated as number of events per 100 patient-years follow-up.

Results: Over 2.5 years (median), first and total thrombotic event rates: 7.1 and 10.3 events/100 patient-years, respectively, in placebo group. Two-thirds (925/1372) of total thrombotic events (arterial 95%, venous 5%) were nonfatal first events. Nearly one-third of patients with first event had a second arterial or venous thrombotic event. Rivaroxaban plus aspirin reduced first and total arterial and venous thrombotic events to 5.4 and 7.9 events/100 patient-years, respectively, a reduction in total thrombotic events over aspirin of 23% (HR: 0.77, 95%CI: 0.67-0.89, p = .0005), preventing 6.1 total arterial and venous thrombotic events at 3 years.

Conclusions: Assessing total arterial and venous thrombotic events, not just first events, provides more complete information about disease burden and absolute on-treatment impact. Following LER, judicious modulation of more than one coagulation pathway can provide broader benefit than intensifying inhibition of one hemostatic system component.

Keywords: anticoagulants; atherosclerosis; peripheral arterial disease; rivaroxaban; thrombosis; venous thromboembolism.

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Conflict of interest statement

  1. Drs. Berkowitz, Nehler, Hsia, Capell, Hess, Hsia, and Bonaca report that their University of Colorado salary is partially supported through funds to the University from the Colorado Prevention Center, a non‐profit academic research organization affiliated with the University of Colorado, that receives research grant/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 Co, Esperion Therapeutics, Everly Health, Faraday, Fortress Biotech, HDL Therapeutics, Heartflow, Hummingbird Bioscience, Insmed, Janssen, Kowa Research, Lexicon, Merck, MedPace, Medtronic, Moderna, Novate Medical, NovoNordisk, Pfizer, PhaseBio, PPD Development, Prairie Education and Research, Prothena Biosciences, Regeneron, Regio Biosciences, Sanifit Therapeutics, Sanofi, Smith and Nephew, Stealth BioTherapeutics, University of Colorado, University of Pittsburgh, Worldwide Clinical Trials, Wraser, Yale Cardiovascular Research Group.

  2. Dr. Bauersachs reports consultation and speaker´s honoraria from Aspen, Bayer, Bristol Myers Squibb and Pfizer.

  3. Dr. Szarek reports grant support from Resverlogix, Baxter, and Janssen; Personal fees from CiVi and Esperion; Grant support, personal fees, and non‐financial support from Sanofi; and grant support and non‐financial support from Regeneron.

  4. Dr. Debus reports grants and personal fees from Bayer AG, grants from Cook LTD, grants from Terumo Aortic, during the conduct of the study.

  5. Dr. Patel reports receiving Advisory Board/Consultant Fees: Bayer, Janssen, Heartflow, Novartis, Phillips and Research Grants from Bayer, Janssen, and Heartflow.

  6. Dr. Anand discloses receiving lecture fees from Bayer and Janssen.

  7. Dr. Leeper reports having has received consulting fees from Janssen within the last 2 years.

  8. Dr. Brasil reports the following:

    1. o

      Employee at:

      1. ▪

        Assistant Professor of Medicine, Faculdade de Ciências Médicas de Minas Gerais FCMMG/FELUMA School of Medicine. Principal Investigator in the Centro de Investigacao Clinica (CIC) at Hospital Universitario Ciencias Medicas (HUCM). Belo Horizonte ‐ MG, Brazil.

      2. ▪

        Assistant Professor of Medicine, Faculdade de Ciências da Saúde (FCS), Departamento de Medicina (DME), Universidade Federal de Lavras (UFLA) School of Medicine. Lavras ‐ MG, Brazil.

    2. o

      His institution Faculdade de Ciencias Medicas de Minas Gerais FCMMG/FELUMA School of Medicine received payments to conduct Voyager‐PAD from the sponsor (Bayer). DPB served as the NLI for Brazil during Voyager‐PAD.

    3. o

      Institutional grants from BAYER during the conduct of the Voyager PAD study.

    4. o

      Personal fees outside the submitted work from:

      1. ▪

        LIBBS (Brazil) and SERVIER (Brazil) to write scientific educational materials and speak in meetings organized by those pharmaceutical companies.

      2. ▪

        LIBBS (Brazil) to function as member of consulting boards in hypertension, hyperlipidemias, diabetes, and peripheral artery disease.

      3. ▪

        VIATRIS (Brazil) and BIOLAB (Brazil) to function as speaker in scientific meetings.

      4. ▪

        SERVIER (Brazil) to serve as a scientific consultant, deliver interview, and function as member of a consulting board in hypertension.

    5. o

      Sponsored in transport and/or hotel accommodations to attend national or international scientific congresses by SERVIER.

    6. o

      Dr. Brasil does not hold any patents, whether planned, pending or issued, broadly relevant to this work.

  9. Dr. Lajos Mátyás notes no conflicts of interest to declare.

  10. Dr. Diaz reports Bayer support via a grant for a trial in Argentina.

  11. Dr. Brodmann reports no conflicts of interest to declare.

  12. Dr. Muehlhofer reports being employed a Bayer AG employee.

  13. Dr. Haskell, being employed by Janssen Pharmaceuticals and owning stock in Johnson & Johnson.

Figures

FIGURE 1
FIGURE 1
Independent determinants of total thrombotic events. Baseline patient and procedural characteristics associated with arterial and venous thrombotic risk after multivariate modeling are shown. Candidate variables shown in Figure S1. ABI, ankle‐brachial index; BP, blood pressure; CAD, coronary artery disease; CI, confidence interval; CLI, chronic limb ischemia; eGFR, estimated glomerular filtration rate; HR, hazard ratio
FIGURE 2
FIGURE 2
First and total arterial and venous thrombotic events, per 100 patient‐years. The first and total arterial and venous thrombotic events per 100 patient years in the Placebo and Rivaroxaban groups, respectively, are provided. ARR, absolute risk reduction; CI, confidence interval; HR, hazard ratio; p, p‐value; p‐y, patient‐yearsNote: arterial and venous events include acute limb ischemia, major amputation of vascular cause, MI, ischemic stroke, and symptomatic VTE (deep vein thrombsis and pulmonary embolism).
FIGURE 3
FIGURE 3
Second Arterial and Venous Thrombotic Events by Type of First Nonfatal Event. The number of second thrombotic events by type of first nonfatal event, categorized by arterial and venous and by treatment group, are presentedNote: Of the 929 patients with first events, all but 4 were nonfatal. Arterial and venous events include acute limb ischemia, major amputation of vascular cause, MI, ischemic stroke, and symptomatic VTE (deep vein thrombsis and pulmonary embolism).
FIGURE 4
FIGURE 4
Distribution of total (first and subsequent) arterial and venous thrombotic events. The distribution of first, second, and third and subsequent arterial and venous thrombotic events within the placebo and rivaroxaban‐treated groups is shown, along with the occurrence of the nonfatal outcome components and fatal events
FIGURE 5
FIGURE 5
Effect of rivaroxaban on arterial and venous thrombotic events. Shown are the cumulative incidence curves for the composite first and total arterial and venous thrombotic events, defined as acute limb ischemia, major amputation of vascular etiology, myocardial infarction, ischemic stroke, or symptomatic VTE, in patients randomized to placebo versus rivaroxaban. The treatment hazard ratios (HRs) for first and total events and associated 95% confidence intervals (CIs) are provided, along with the estimated rates at 3 years and associated 95% CIs, and the absolute risk reductions (ARR) in terms of the number of thrombotic events per 100 patients prevented with associated 95% CIs. p, p‐value
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