Vascular Outcomes Study of ASA Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease - VOYAGER PAD

Contribution To Literature:

The VOYAGER PAD trial showed that rivaroxaban/aspirin was superior to aspirin at preventing major adverse limb and cardiovascular events.

Description:

The goal of the trial was to evaluate rivaroxaban/aspirin compared with placebo/aspirin among patients with lower extremity peripheral artery disease (PAD) undergoing revascularization.

Study Design

  • Randomized
  • Parallel
  • Stratified

Patients with lower extremity PAD undergoing revascularization were randomized to rivaroxaban 2.5 mg twice daily/aspirin (n = 3,286) versus placebo/aspirin (n = 3,278).

  • Total number of enrollees: 6,564
  • Duration of follow-up: median 28 months
  • Median patient age: 67 years
  • Percentage female: 26%
  • Percentage with diabetes: 40%

Inclusion criteria:

  • Age ≥50 years
  • Lower extremity PAD (documented by ischemic symptoms, imaging evidence of disease, and abnormal ankle-brachial index)
  • Successful lower extremity revascularization

Exclusion criteria:

  • Revascularization for asymptomatic disease
  • Recent revascularization (<10 days), acute limb ischemia (<2 weeks), or acute coronary syndrome (<30 days)
  • Current major tissue loss
  • Need for antiplatelet or anticoagulation therapy other than aspirin and/or clopidogrel
  • Need for long-term dual antiplatelet therapy
  • High-risk for bleeding

Other salient features/characteristics:

  • Indication for revascularization; claudication = 77%, critical limb ischemia = 23%
  • Type of revascularization: surgical = 35%, endovascular or hybrid = 66%
  • Median ankle-brachial index = 0.56

Principal Findings:

The primary efficacy outcome, cardiovascular death, acute limb ischemia, major amputation, myocardial infarction, or stroke, occurred in 17.3% of the rivaroxaban/aspirin group compared with 19.9% of the placebo/aspirin group (p = 0.0085). This association was similar among various tested subgroups.

The primary safety outcome, Thrombolysis in Myocardial Infarction (TIMI) major bleeding, occurred in 2.7% of the rivaroxaban/aspirin group compared with 1.9% of the placebo/aspirin group (p = 0.069). Among diabetics, TIMI major bleeding occurred in 2.4% of the rivaroxaban/aspirin group compared with 1.0% of the placebo/aspirin group (p for interaction = 0.033).

Secondary outcomes:

  • Acute limb ischemia: 5.2% of the rivaroxaban/aspirin group compared with 7.8% of the placebo/aspirin group (p < 0.05)
  • International Society on Thrombosis and Haemostasis (ISTH) major bleeding: 5.9% of the rivaroxaban/aspirin group compared with 4.1% of the placebo/aspirin group (p = 0.0068)
  • Intracranial hemorrhage: 0.6% of the rivaroxaban/aspirin group compared with 0.9% of the placebo/aspirin group (p = 0.5)

Study medication and baseline clopidogrel use:

  • Baseline clopidogrel: primary efficacy outcome for rivaroxaban plus aspirin vs. aspirin alone, hazard ratio = 0.85
  • No baseline clopidogrel: primary efficacy outcome for rivaroxaban plus aspirin vs. aspirin alone, hazard ratio = 0.86 (p for interaction = 0.92)

Coronary artery disease (CAD) subgroups:

  • PAD without CAD: Cardiovascular death, acute limb ischemia, major amputation, myocardial infarction, or stroke occurred in 16.1% of the rivaroxaban group compared with 17.9% of the placebo group (absolute risk reduction [ARR] 1.8%, p = not significant).
  • PAD with CAD: Cardiovascular death, acute limb ischemia, major amputation, myocardial infarction, or stroke occurred in 18.9% of the rivaroxaban group compared with 24.3% of the placebo group (ARR 5.4%, p < 0.05, p for interaction = 0.29).
  • PAD without CAD: TIMI major bleeding occurred in 1.7% of the rivaroxaban group compared with 1.5% of the placebo group (p = nonsignificant).
  • PAD with CAD: TIMI major bleeding occurred in 2.4% of the rivaroxaban group compared with 1.1% of the placebo group (p for interaction = 0.13).

Interpretation:

Among patients with lower extremity PAD undergoing revascularization, rivaroxaban/aspirin was associated with a reduction in major adverse limb and cardiovascular events compared with placebo/aspirin. Rivaroxaban/aspirin was associated with a 2.6% absolute risk reduction in cardiovascular death, acute limb ischemia, major amputation, myocardial infarction, or stroke compared with placebo/aspirin at 3 years. Although the benefit of rivaroxaban/aspirin was consistent regardless of CAD status, the absolute benefit of this regimen appeared to be greater among those with both PAD and CAD. Benefit of rivaroxaban/aspirin was observed regardless of baseline clopidogrel use. Rivaroxaban/aspirin was associated with a similar frequency of TIMI major bleeding; however, there was an increased incidence of ISTH major bleeding compared with placebo/aspirin. Intracranial hemorrhage was similar between treatment groups.

References:

Presented by Dr. William Hiatt at the European Society of Cardiology Virtual Congress, August 30, 2020.

Bonaca MP, Bauersachs RM, Anand SS, et al. Rivaroxaban in Peripheral Artery Disease After Revascularization. N Engl J Med 2020;382:1994-2004.

Editorial: Creager MA. A Bon VOYAGER for Peripheral Artery Disease. N Engl J Med 2020;382:2047-8.

Presented by Dr. William R. Hiatt at the American College of Cardiology Virtual Annual Scientific Session Together With World Congress of Cardiology (ACC 2020/WCC), March 29, 2020.

Presented by Marc P. Bonaca at the American College of Cardiology Virtual Annual Scientific Session Together With World Congress of Cardiology (ACC 2020/WCC), March 28, 2020.

Clinical Topics: Anticoagulation Management, Cardiac Surgery, Geriatric Cardiology, Invasive Cardiovascular Angiography and Intervention, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Aortic Surgery, Cardiac Surgery and Arrhythmias, Interventions and Vascular Medicine

Keywords: ESC20, ESC Congress, acc20, ACC Annual Scientific Session, Anticoagulants, Amputation, Ankle Brachial Index, Aspirin, Cardiac Surgical Procedures, Endovascular Procedures, Geriatrics, Hemorrhage, Intracranial Hemorrhages, Myocardial Infarction, Myocardial Ischemia, Myocardial Revascularization, Peripheral Arterial Disease, Secondary Prevention, Stroke, Thrombosis, Vascular Diseases


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