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

Oct 23, 2023
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Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC; Kim A. Eagle, MD, MACC
Trial Sponsor:
Bayer and Janssen Pharmaceuticals
Date Presented:
05/16/2021
Date Published:
10/18/2023
Date Updated:
10/23/2023
Original Posted Date:
03/28/2020
References

Contribution To Literature:

Highlighted text has been updated as of October 23, 2023.

The VOYAGER PAD trial showed that rivaroxaban/aspirin was superior to aspirin alone 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)
  • Primary outcome for rivaroxaban/aspirin versus placebo/aspirin among those who underwent lower extremity revascularization for critical limb ischemia: HR 0.85, 95% CI 0.69-1.05, and among those who underwent lower extremity revascularization for noncritical limb ischemia: HR 0.86, 95% CI 0.74-0.99 (p for interaction 0.94)

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).

Long-term safety of drug-coated devices (n = 1,342; drug-coated stent, drug-coated balloon, and both):

  • Weighted all-cause mortality: 12.1% in the drug-coated device group vs. 12.6% in the nondrug-coated device group (p = 0.66)
  • Weighted all-cause mortality for drug-coated balloon vs. PTA: 7.4% in the drug-coated device group vs. 9.7% in the nondrug-coated device group (p = not significant)
  • Weighted all-cause mortality for drug-eluting stent vs. bare-metal stent: 8.2% in the drug-coated device group vs. 9.9% in the nondrug-coated device group (p = not significant)

Effect of rivaroxaban vs. placebo on cardiovascular death, acute limb ischemia, major amputation of vascular etiology, myocardial infarction, or ischemic stroke according to drug-coated devices:

  • Drug-coated device: 13.5% in the rivaroxaban group vs. 15.0% in the nondrug-coated device group
  • Nondrug-coated device: 14.4% in the rivaroxaban group vs. 16.0% in the nondrug-coated device group (p for interaction = 0.88)

Outcomes among subjects who underwent endovascular lower extremity revascularization (67% endovascular revascularization):

  • Among the endovascular revascularization group, the primary efficacy outcome of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death: 14.0% in the rivaroxaban group vs. 15.7% in the placebo group (p = 0.12; p for interaction vs. surgical revascularization group = 0.43)
  • Among the endovascular revascularization group, the primary safety outcome of TIMI major bleeding: 2.3% in the rivaroxaban group vs. 1.4% in the placebo group (p = 0.02; p for interaction vs. surgical revascularization group = 0.17)

Outcomes among subjects who underwent surgical lower extremity revascularization (of the total randomized, 33% underwent surgical revascularization):

  • Among the surgical revascularization group, the primary efficacy outcome of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death: 18.4% in the rivaroxaban group vs. 22.0% in the placebo group (p = 0.026; p for interaction vs. endovascular revascularization group = 0.43)
  • Among the surgical revascularization group, the primary safety outcome of TIMI major bleeding: 1.0% in the rivaroxaban group vs. 1.2% in the placebo group (p = 0.75; p for interaction vs. endovascular revascularization group = 0.17)

Total events (considers first and subsequent events):

  • Total primary endpoints, rivaroxaban vs. placebo: (HR 0.86, 95% CI 0.75-0.98; p = 0.02)
  • Total vascular events, rivaroxaban vs. placebo: (HR 0.86, 95% CI 0.79-0.95; p = 0.003)

Treatment effects in older patients (participants >75 years [20%]):

  • Efficacy of rivaroxaban vs. placebo (p for interaction = 0.83)
  • Safety of rivaroxaban vs. placebo (p for interaction = 0.38)

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. Benefit for rivaroxaban/aspirin versus placebo/aspirin was similar for endovascular and surgical lower extremity revascularization, and for revascularization of critical limb ischemia and noncritical limb ischemia. 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. Rivaroxaban/aspirin was beneficial without excess harm among participants >75 years.

Drug-coated devices were not associated with an increase (or decrease) in mortality compared with non-drug-coated devices. Rivaroxaban was beneficial at reducing major adverse cardiac and limb events, irrespective of drug-coated device use.

References:

Rymer J, Anand SS, Debus ES, et al. Rivaroxaban Plus Aspirin Versus Aspirin Alone After Endovascular Revascularization for Symptomatic PAD: Insights From VOYAGER PAD. Circulation 2023;Oct 18:[Epub ahead of print].

Krantz MJ, Debus SE, Hsia J, et al. Low-dose rivaroxaban plus aspirin in older patients with peripheral artery disease undergoing acute limb revascularization: insights from the VOYAGER PAD trial. Eur Heart J 2021;42:4040-8.

Debus ES, Nehler MR, Govsyeyev N, et al. Effect of Rivaroxaban and Aspirin in Patients With Peripheral Artery Disease Undergoing Surgical Revascularization: Insights From the VOYAGER PAD Trial. Circulation 2021;144:1104-16.

Bauersachs RM, Szarek M, Brodmann M, et al. Total Ischemic Event Reduction With Rivaroxaban After Peripheral Arterial Revascularization in the VOYAGER PAD Trial. J Am Coll Cardiol 2021;78:317-26.

Presented by Dr. Rupert Bauersachs at the American College of Cardiology Virtual Annual Scientific Session (ACC 2021), May 16, 2021.

Presented by Dr. Marc P. Bonaca at the American Heart Association Virtual Scientific Sessions, November 14, 2020.

Presented by Dr. Manesh R. Patel at the American Heart Association Virtual Scientific Sessions, November 14, 2020.

Presented by Dr. Connie N. Hess at the Transcatheter Cardiovascular Therapeutics Virtual Meeting (TCT Connect), October 18, 2020.

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: ACC21, ACC Annual Scientific Session, AHA20, AHA Annual Scientific Sessions, acc20, Anticoagulants, Amputation, Ankle Brachial Index, Aspirin, Cardiac Surgical Procedures, Endovascular Procedures, ESC20, ESC Congress, Geriatrics, Hemorrhage, Intracranial Hemorrhages, Myocardial Infarction, Myocardial Ischemia, Myocardial Revascularization, Peripheral Arterial Disease, Secondary Prevention, Stroke, Thrombosis, Vascular Diseases, TCT20, Transcatheter Cardiovascular Therapeutics


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