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Rivaroxaban and Aspirin in Peripheral Artery Disease Lower Extremity Revascularization: Impact of Concomitant Clopidogrel on Efficacy and Safety.

Publication ,  Journal Article
Hiatt, WR; Bonaca, MP; Patel, MR; Nehler, MR; Debus, ES; Anand, SS; Capell, WH; Brackin, T; Jaeger, N; Hess, CN; Pap, AF; Berkowitz, SD ...
Published in: Circulation
December 8, 2020

BACKGROUND: The VOYAGER PAD trial (Vascular Outcomes Study of ASA Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease) demonstrated superiority of rivaroxaban plus aspirin versus aspirin to reduce major cardiac and ischemic limb events after lower extremity revascularization. Clopidogrel is commonly used as a short-term adjunct to aspirin after endovascular revascularization. Whether clopidogrel modifies the efficacy and safety of rivaroxaban has not been described. METHODS: VOYAGER PAD was a phase 3, international, double-blind, placebo-controlled trial in patients with symptomatic PAD undergoing lower extremity revascularization randomized to rivaroxaban 2.5 mg twice daily plus 100 mg aspirin daily or rivaroxaban placebo plus aspirin. The primary efficacy outcome was a composite of acute limb ischemia, major amputation of a vascular cause, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety end point was TIMI (Thrombolysis in Myocardial Infarction) major bleeding, with International Society on Thrombosis and Haemostasis major bleeding a secondary safety outcome. Clopidogrel use was allowed at the discretion of the investigator for up to 6 months after the qualifying revascularization. RESULTS: Of the randomized patients, 3313 (50.6%) received clopidogrel for a median duration of 29.0 days. Over 3 years, the hazard ratio for the primary outcome of rivaroxaban versus placebo was 0.85 (95% CI, 0.71-1.01) with clopidogrel and 0.86 (95% CI, 0.73-1.01) without clopidogrel without statistical heterogeneity (P for interaction=0.92). Rivaroxaban resulted in an early apparent reduction in acute limb ischemia within 30 days (hazard ratio, 0.45 [95% CI, 0.14-1.46] with clopidogrel; hazard ratio, 0.48 [95% CI, 0.22-1.01] without clopidogrel; P for interaction=0.93). Compared with aspirin, rivaroxaban increased TIMI major bleeding similarly regardless of clopidogrel use (P for interaction=0.71). With clopidogrel use >30 days, rivaroxaban was associated with more International Society on Thrombosis and Haemostasis major bleeding within 365 days (hazard ratio, 3.20 [95% CI, 1.44-7.13]) compared with shorter durations of clopidogrel (P for trend=0.06). CONCLUSIONS: In the VOYAGER PAD trial, rivaroxaban plus aspirin reduced the risk of adverse cardiovascular and limb events with an early benefit for acute limb ischemia regardless of clopidogrel use. The safety of rivaroxaban was consistent regardless of clopidogrel use but with a trend for more International Society on Thrombosis and Haemostasis major bleeding with clopidogrel use >30 days than with a shorter duration. These data support the addition of rivaroxaban to aspirin after lower extremity revascularization regardless of concomitant clopidogrel, with a short course (≤30 days) associated with less bleeding. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02504216.

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Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

December 8, 2020

Volume

142

Issue

23

Start / End Page

2219 / 2230

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Rivaroxaban
  • Platelet Aggregation Inhibitors
  • Peripheral Arterial Disease
  • Middle Aged
  • Male
  • Lower Extremity
  • Internationality
  • Humans
  • Female
 

Citation

APA
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MLA
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Hiatt, W. R., Bonaca, M. P., Patel, M. R., Nehler, M. R., Debus, E. S., Anand, S. S., … Bauersachs, R. (2020). Rivaroxaban and Aspirin in Peripheral Artery Disease Lower Extremity Revascularization: Impact of Concomitant Clopidogrel on Efficacy and Safety. Circulation, 142(23), 2219–2230. https://doi.org/10.1161/CIRCULATIONAHA.120.050465
Hiatt, William R., Marc P. Bonaca, Manesh R. Patel, Mark R. Nehler, Eike Sebastian Debus, Sonia S. Anand, Warren H. Capell, et al. “Rivaroxaban and Aspirin in Peripheral Artery Disease Lower Extremity Revascularization: Impact of Concomitant Clopidogrel on Efficacy and Safety.Circulation 142, no. 23 (December 8, 2020): 2219–30. https://doi.org/10.1161/CIRCULATIONAHA.120.050465.
Hiatt WR, Bonaca MP, Patel MR, Nehler MR, Debus ES, Anand SS, et al. Rivaroxaban and Aspirin in Peripheral Artery Disease Lower Extremity Revascularization: Impact of Concomitant Clopidogrel on Efficacy and Safety. Circulation. 2020 Dec 8;142(23):2219–30.
Hiatt, William R., et al. “Rivaroxaban and Aspirin in Peripheral Artery Disease Lower Extremity Revascularization: Impact of Concomitant Clopidogrel on Efficacy and Safety.Circulation, vol. 142, no. 23, Dec. 2020, pp. 2219–30. Pubmed, doi:10.1161/CIRCULATIONAHA.120.050465.
Hiatt WR, Bonaca MP, Patel MR, Nehler MR, Debus ES, Anand SS, Capell WH, Brackin T, Jaeger N, Hess CN, Pap AF, Berkowitz SD, Muehlhofer E, Haskell L, Brasil D, Madaric J, Sillesen H, Szalay D, Bauersachs R. Rivaroxaban and Aspirin in Peripheral Artery Disease Lower Extremity Revascularization: Impact of Concomitant Clopidogrel on Efficacy and Safety. Circulation. 2020 Dec 8;142(23):2219–2230.

Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

December 8, 2020

Volume

142

Issue

23

Start / End Page

2219 / 2230

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Rivaroxaban
  • Platelet Aggregation Inhibitors
  • Peripheral Arterial Disease
  • Middle Aged
  • Male
  • Lower Extremity
  • Internationality
  • Humans
  • Female