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; Rupert M Bauersachs; Michael Szarek; Mark R Nehler; E Sebastian Debus; Manesh R Patel; Sonia S Anand; Warren H Capell; Connie N Hess; Judy Hsia; Nicholas J Leeper; David Brasil; Lajos Mátyás; Rafael Diaz; Marianne Brodmann; Eva Muehlhofer; Lloyd P Haskell; Marc P Bonaca

doi:10.1111/jth.15673

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

J Thromb Haemost. 2022 May;20(5):1193-1205. doi: 10.1111/jth.15673. Epub 2022 Mar 7.

Authors

Scott D Berkowitz^{1

2}, Rupert M Bauersachs^{3

4}, Michael Szarek^{1

5

6}, Mark R Nehler^{1

7}, E Sebastian Debus⁸, 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 Leeper¹⁴, David Brasil¹⁵, Lajos Mátyás¹⁶, Rafael Diaz¹⁷, Marianne Brodmann¹⁸, Eva Muehlhofer¹⁹, Lloyd P Haskell²⁰, Marc P Bonaca^{1

5}

Affiliations

¹ Colorado Prevention Center Clinical Research, Aurora, Colorado, USA.
² Divisions of Cardiology and Hematology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA.
³ Cardiovascular Center Bethanien CCB, Frankfurt, Germany.
⁴ Center of Thrombosis and Hemostasis, University of Mainz, Mainz, Germany.
⁵ Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA.
⁶ State University of New York Downstate Health Sciences University, Brooklyn, New York, USA.
⁷ Division of Vascular Surgery, Department of Surgery, University of Colorado School of Medicine, Aurora, Colorado, USA.
⁸ Department of Vascular Medicine, Vascular Surgery-Angiology-Endovascular Therapy, University of Hamburg-Eppendorf, Hamburg, Germany.
⁹ Duke Clinical Research Institute, Durham, North Carolina, USA.
¹⁰ Division of Cardiology, Duke University Medical Center, Durham, North Carolina, USA.
¹¹ Department of Medicine & Epidemiology, McMaster University, Hamilton, Ontario, Canada.
¹² Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada.
¹³ Division of Endocrinology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA.
¹⁴ Division of Vascular Surgery, Department of Surgery, Stanford University, Stanford, California, USA.
¹⁵ FELUMA-Faculdade de Ciencias Medicas de Minas Gerais School of Medicine, Belo Horizonte, Brazil.
¹⁶ B-A-Z Central University Teaching County Hospital Vascular and Endovascular Surgery, Miskolc, Hungary.
¹⁷ Estudios Clínicos Latinoamérica - Instituto Cardiovascular de Rosario, Rosario, Argentina.
¹⁸ Division of Angiology, Medical University of Graz, Graz, Austria.
¹⁹ Bayer AG, Research & Development, Wuppertal, Germany.
²⁰ Janssen Research and Development, Raritan, New Jersey, USA.

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.

Publication types

Randomized Controlled Trial

MeSH terms

Anticoagulants / therapeutic use
Arteries
Aspirin / therapeutic use
Endovascular Procedures* / adverse effects
Humans
Lower Extremity / blood supply
Peripheral Arterial Disease* / drug therapy
Peripheral Arterial Disease* / surgery
Platelet Aggregation Inhibitors / therapeutic use
Rivaroxaban
Thrombosis* / etiology
Thrombosis* / prevention & control

Substances

Anticoagulants
Platelet Aggregation Inhibitors
Rivaroxaban
Aspirin