Introduction and methods

Subgroup analysis VOYAGER PAD Trial: Efficacy and Safety of Rivaroxaban in Patients with PAD undergoing Revascularization with and without Clopidogrel

Presented at ACC.20 by William Hiatt, MD (Aurora, CO, USA)

The VOYAGER PAD (Vascular Outcomes Study of ASA Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease) trial demonstrated that low dose rivaroxaban plus aspirin reduced CV risk in PAD patients who had undergone lower-extremity revascularization (LER). In addition, TIMI major bleeding was numerically increased and incidence of ISTH major bleeding was significantly higher after rivaroxaban treatment compared to placebo, but no difference in ICH and fatal bleeding was observed between rivaroxaban and placebo.

The present study was a subgroup analysis of the VOYAGER PAD trial. The subgroup analysis evaluated whether background clopidogrel therapy modified efficacy and/or safety of rivaroxaban plus aspirin versus aspirin alone. Clopidogrel was allowed up to 6 months after LER at the discretion of the investigator. Actual clopidogrel use for this analysis was determined at baseline (50.5% of the participants used clopidogrel, a total of n=3313 used clopidogrel and a total of n=3234 did not use clopidogrel). The primary composite endpoint included CV death, MI, ischemic stroke (MACE), acute limb ischemia or major amputation for vascular cause (MALE). In addition, safety was assessed by looking at temporal patterns of bleeding (principal safety outcome TIMI major bleeding, ISTH major bleeding, ICH and fatal bleeding).

Main results

• After 3 years follow-up, there was no difference in the primary endpoint between those on clopidogrel compared to those without (with clopidogrel: HR 0.85, 95% CI: 0.71-1.01; without clopidogrel: HR 0.86, 95% CI: 0.73-1.01, P-interaction=0.9163).
• After 3 years follow-up, overall, bleeding was not different between the clopidogrel group and the non-clopidogrel group (for ISHT major bleeding: with clopidogrel: HR 1.36, 95% CI: 0.96-1.91; without clopidogrel: HR 1.50, 95% CI: 1.02-2.20; P-interaction=0.7002). Also no differences were found between treatment groups for TIMI major bleeding (with clopidogrel: HR 1.32, 95% CI: 0.78-2.24; without clopidogrel: HR 1.55, 95% CI: 0.88-2.73; P-interaction=0.69) or ICH/fatal bleeding (with clopidogrel: HR 0.44, 95% CI: 0.71-1.43; without clopidogrel: HR 1.35, 95% CI: 0.59-3.07; P-interaction=0.1261).
• Clopidogrel use added to rivaroxaban plus aspirin lead to a higher rate of increase from baseline of risk of ISTH major bleeding as compared to clopidogrel use added to aspirin alone, visable at 6 months. After 1 year, absolute risk increase (ARI) with clopidogrel was 1.4% for ISTH major bleeding (3.0% for those on rivaroxaban and aspirin and 1.6% for those on placebo and aspirin). For those not taking clopidogrel, ARI was 0.7% (2.5% for those on rivaroxaban and aspirin and 1.8% for those on placebo and aspirin).
• When comparing those >30 days on clopidogrel to those ≤30 days, ARI was 2.1% after 6 months in those on clopidogrel and ARI was 0.7% in those without clopidogrel.

Conclusion

In patients with symptomatic PAD undergoing LER, rivaroxaban added to aspirin significantly reduced limb and CV risk with consistent benefits regardless of clopidogrel use. Furthermore, the addition of clopidogrel to rivaroxaban plus aspirin was associated with higher early rates of ISTH bleeding. In conclusion, in the absence of clear benefit, added use of clopidogrel to rivaroxaban plus aspirin should be minimized or avoided to reduce risk in these patients.

Discussion

Discussant Sahil Parikh, MD (New York, NY, USA) emphasized that VOYAGER PAD was the largest vascular intervention trial ever conducted, where even the subgroups were an order of magnitude larger than any of the prior trials for device approval. He thinks the VOYAGER PAD trial is practice-changing, making the results especially interesting for vascular interventionalists and surgeons. The hazard reduction with rivaroxaban is clear for these patients according to him, and he thinks of switching his own patients to rivaroxaban if they’re not already taking it. With regard to the present subgroup analysis, he mentioned that an important question is how bleeding hazard changes with DAPT in patients, and that in this regard the data suggest that the benefit of clopidogrel is questionable, but its bleeding hazard is not. He further mentions that bleeding risk scores of patients might help decide in which patients caution is needed with DAPT. He also mentioned that the results may help understand if (drug-eluting) stents can be used without clopidogrel and DAPT for a period of time. Finally, in light of the results, Parikh implored that the guideline committees look hard at updating guidelines for use of oral anticoagulants in managing PAD with and without interventions.

– Our coverage of ACC.20 is based on the information provided during the congress –