VOYAGER-PAD

Published

Bonaca M, et al. "Rivaroxaban in Peripheral Artery Disease after Revascularization". The New England Journal of Medicine. 2020. 382(21):1994-2004.
PubMed • Full text • PDF • ClinicalTrials.gov

Clinical Question

Among patients undergoing lower limb revascularization for PAD, does addition of low dose rivaroxaban (2.5mg twice daily) to aspirin±clopidogrel lower risk of acute limb ischemia, major amputation for vascular causes, MI, ischemic stroke, or CV mortality or increase bleeding, when compared to placebo?

Bottom Line

Among patients undergoing lower limb revascularization for PAD, the addition of low dose rivaroxaban (2.5mg twice daily) to aspirin±clopidogrel is associated with lower risk of acute limb ischemia, major amputation for vascular causes, MI, ischemic stroke, or CV mortality when compared to placebo. Rivaroxaban is associated with greater risk of some (but not all) definitions of major bleeding.

Major Points

PAD is an important contributor to ASCVD events in the US and abroad, and persons with PAD are at greater risk for other types of ASCVD events, including stroke and MI. Contemporary management of symptomatic PAD includes lifestyle and risk factor modification revascularization for disease of greater severity, and the use of agents affecting hemostasis. In the 2010s, this was primarily antiplatelet drugs, such as aspirin or clopidogrel alone or DAPT (ie, aspirin+clopidogrel). There was less clear evidence for the use of anticoagulation add-on therapy for PAD management. For example, the 2007 WAVE trial found no benefit for adding warfarin targeting an INR of 2-3 to aspirin therapy among persons with PAD. Whether newer anticoagulation agents might lower ASCVD events among individuals with PAD was unknown.

The 2017 COMPASS trial studied the anti-Xa DOAC, rivaroxaban, among individuals with stable ASCVD. Importantly, the dosing of rivaroxaban (2.5 mg PO BID) differed greatly from the doses approved by the FDA at that time (10 mg and 20 mg PO daily for chronic anticoagulation therapy, depending on indication). COMPASS reported a 1.3% absolute risk reduction of ASCVD events, but a 1.2% increased risk of bleeding. A 2021 subgroup analysis of COMPASS found rivaroxaban to be associated with a lower risk of ASCVD events and major limb events among persons with symptomatic lower extremity PAD. A larger, dedicated trial was needed to confirm this observation among persons with PAD.

Published in 2020, the Vascular Outcomes Study of ASA Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD (VOYAGER-PAD) trial enrolled 6,564 persons with clinically-relevant PAD who underwent a lower extremity revascularization procedure in the prior 10 days. Participants were randomized to rivaroxaban 2.5 mg PO BID or placebo in addition to low-dose aspirin±clopidogrel. Participants randomized to rivaroxaban experienced fewer CVD events (17.3% vs. 19.9%; P=0.009). The primary major bleeding definition was TIMI, and there was no difference in bleeding by that definition (2.65% vs. 1.87%; P=0.07) or the secondary bleeding definition of BARC major bleeding (3.86% vs. 2.92%; P=0.10). There was more ISTH major bleeding, however (5.94% vs. 4.06%; P=0.007). As detailed in Figure S6, the authors estimated that 181 primary efficacy events were prevented for each 10,000 patients treated with rivaroxaban for 1 year.

Taken together, COMPASS and VOYAGER-PAD provides some evidence for the use of low-dose rivaroxaban in PAD.

Guidelines

As of April 2023, no guidelines have been published that reflect the results of this trial.

Design

• Placebo controlled, randomized controlled trial
• N=6564
  • Rivaroxaban (n=3286)
  • Placebo (n=3278)
• Location: 542 sites in 34 countries
• Recruitment: 2015-2018
• Median follow-up: 28 months
• Analysis: Intention-to-treat
• Primary outcomes:
  • Efficacy: Acute limb ischemia, major amputation for vascular causes, MI, ischemic stroke, or CV mortality
  • Safety: TIMI major bleeding

Population

Inclusion Criteria

Full details on page 19 of the supplemental appendix.

• Aged ≥50 years
• Mod-severe atherosclerosis-related PAD, with all of the following:
  • Clinical disease (impairment in walking, ischemic pain at rest, or ischemic ulcers)
  • Imaging showing PAD distal to external iliac artery in affected leg within 1 year of revascularization event
  • ABI in either leg:
    • No prior revascularization - ABI ≤0.80 or TBI ≤0.60
    • Prior revascularizatoin - ABI ≤0.85 or TBI ≤0.65
• Successful surgical or endovascular revascularization distal to the external iliac artery for symptomatic PAD in prior 10 days
• Informed consent, willing to participate, negative pregnancy test in women of childbearing potential & on high-quality contraception

Exclusion Criteria

• Minimal disease (ie asymptomatic PAD or mild claudication) at baseline or as indication for index event
• If the qualifying revascularization occurred within 10 days of prior revascularization
• Acute limb ischemia in 2 weeks prior to revascularization
• Major tissue loss in either leg
• Requiring treatment with aspirin at doses >100 mg/day
• Planned DAPT (clopidogrel+aspirin specifically) use for >6 months after event
  • Use of other antiplatelet agent
• Other indication for anticoagulation
• Hypersensitivity or use of strong CYP540 inhibitors or inducers
• History of bleeding or at high risk for bleeding (eg, certain GI conditions, bleeding disorders, aneurysms, hepatic coagulopathy)
• eGFR <15 mL/min/1.73 m²
• ACS or major trauma in prior 30 days
• Known cancer, other than BCC or SCC of skin
• Poorly controlled diabetes or hypertension
• <1 year life expectancy
• Breast feeding

Baseline Characteristics

From rivaroxaban group.

• Demographics: Age 67 years, 26% female
• BMI: 26 kg/m²
• Race: White 81%, Asian 15%, Black 3%, other 2%
• Region: N America 11%, W Europe 28%, E Europe 40%, Asia/Pacific 15%, S America 7%
• Medical comorbidies: Hypertension 81%, HLD 60%, current smoker 35%, DM 40%, eGFR <60 21%, symptomatic CAD 32%, MI 11%, known carotid artery disease 9%
• PAD details: Median ABI 0.56; prior amputation 6%, claudication 95%, critical limb ischemia 30%, prior revascularization 36%
• Qualifying revascularization details: For claudication 77%, for critical limb ischemia 23%, endovascular 65%, surgical 34%
• Medications: Statin 79%, ACE/ARB 64%, ASA 99%, clopidogrel 50%

Interventions

Published elsewhere.

• Eligible participants were randomized to a group, within 10 days of revascularization:
  • Rivaroxaban 2.5mg PO BID
  • Placebo
• All participants received aspirin 100 mg PO daily; clopidogrel could be administered up to 6 months, at the discretion of the investigator.

Outcomes

Presented as rivaroxaban vs. placebo. Percentages are from the Kaplan-Meier estimate at 3 years.

Primary Outcomes

Components of the primary outcome are presented here for readability.

Efficacy

Acute limb ischemia, major amputation for vascular causes, MI, ischemic stroke, or CV mortality

17.3% vs. 19.9% (HR 0.85; 95% CI 0.76-0.96; P=0.009)

Acute limb ischemia: 5.2% vs. 7.8% (0.67; 95% CI 0.55-0.82)

Major amputation for vascular causes: 3.4% vs. 3.9% (HR 0.89; 95% CI 0.68-1.16)

MI: 4.6% vs. 5.2% (HR 0.88; 95% CI 0.70-1.12)

Ischemic stroke: 2.7% vs. 3.0% (HR 0.87; 95% CI 0.63-1.19)

CV mortality: 7.1% vs. 6.4% (HR 1.14; 95% CI 0.93-1.40)

Safety

TIMI major bleeding

2.65% vs. 1.87% (HR 1.43; 0.97-2.10; P=0.07)

ICH: 0.60% vs. 0.90% (HR 0.78; 95% CI 0.38-1.61)

Bleeding mortality: 0.21% vs. 0.21% (HR 1.02; 95% CI 0.33-3.15)

ICH or bleeding mortality: 0.74% vs. 0.97% (HR 0.91; 9% CI 0.47-1.76)

Secondary Outcomes

Acute limb ischemia, major amputation for a vascular cause, MI, ischemic stroke, or CHD mortality

14.7% vs. 18.2% (HR 0.80; 95% CI 0.71-0.91; P<0.001)

Recurrent limb ischemia leading to unplanned index-limb revascularization

20.0% vs. 22.5% (HR 0.88; 95% CI 0.79-0.99; P=0.03)

Thrombotic coronary or PAD-related hospitalization

8.7% vs. 12.1% (HR 0.72; 9% CI 0.62-0.85; P<0.001)

Acute limb ischemia, major amputation for a vascular cause, MI, ischemic stroke, or all-cause mortality

20.6% vs. 23.2% (HR 0.89; 95% CI 0.79-0.99; P=0.03)

Acute limb ischemia, major amputation for a vascular cause, MI, all-cause stroke, or all-cause mortality

17.5% vs. 20.1% (HR 0.86; 95% CI 0.76-0.96; P=0.01)

All-cause mortality

11.1% vs. 10.9% (HR 1.08; 95% CI 0.92-1.27; P=0.34)

VTE

0.8% vs. 1.7% (HR 0.61; 95% CI 0.37-1.00)

ISTH major bleeding

5.94% vs. 4.06% (HR 1.42; 95% CI 1.10-1.84; P=0.007)

BARC major bleeding

3.86% vs. 2.92% (HR 1.29; 95% CI 0.95-1.76; P=0.10)

Subgroup Analysis

Detailed in Figures S4 & S5 on PDF page 39 & 40 of the supplemental appendix. In general, the primary efficacy and safety endpoints were similar by age, sex, region, BMI, eGFR, DM, HTN, HLD, smoking, CAD, HF, index ABI, indication of critical limb ischemia, revascularization type, and clopidogrel use (ie aspirin monotherapy vs. DAPT). The WJC editors were surprised that bleeding did not seem to vary by clopidogrel use.

Criticisms

• Bleeding incidence differed depending on the definition of major bleeding - significant on ISTH, but not significant on TIMI.
• High discontinuation rates of therapy in both groups (14%), though the authors note that the on-treatment analysis presented in supplemental table S3 observed similar findings.
• Somewhat unclear benefit when compared to dual antiplatlet therapy (aspirin/clopidogrel) which is a common practice, especially in the setting of endovascular intervention

Funding

Bayer, who sells Xarelto, the brand name for rivaroxaban.