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March 29, 2020

Clopidogrel With Rivaroxaban and Aspirin Shows No Added Benefit After PAD Revascularization in VOYAGER PAD Subgroup Analysis

March 29, 2020—The American College of Cardiology (ACC) announced that results from a subgroup analysis of the VOYAGER PAD trial suggest that concomitant use of clopidogrel along with a regimen of rivaroxaban and aspirin provides no added benefit after revascularization for peripheral artery disease (PAD). The data were presented at the virtual conference of ACC's Annual Scientific Session Together with World Congress of Cardiology (ACC.20/WCC).

The results of VOYAGER PAD, which were presented at ACC.20/WCC on March 28, found that patients with PAD who took rivaroxaban with aspirin after undergoing lower extremity revascularization had a significant reduction in the risk of major adverse limb and cardiovascular events when compared with those receiving aspirin alone. Data also showed that patients taking rivaroxaban had higher rates of bleeding, but there was no excess in severe bleeding events such as intracranial or fatal bleeds.

Adding clopidogrel at the time of revascularization did not offer any added clinical benefit and, when added to rivaroxaban and aspirin, appeared to increase International Society on Thrombosis and Hemostasis (ISTH) major bleeding early in treatment.

As summarized in the ACC press release, in this prespecified subgroup analysis, half of the 6,564 randomized patients enrolled in VOYAGER PAD (median age, 67 years) also received clopidogrel at the time of their lower extremity revascularization procedure, which was at the discretion of their treating physician and was allowed for up to 6 months. Patients receiving clopidogrel were more likely to undergo endovascular procedures (90.7%) than undergo surgery (9.3%); the use of clopidogrel is common in endovascular procedures.

Dr. Hiatt reported that after a median follow-up of 28 months, there was a 15% reduction in the risk of major limb or cardiovascular complications among those taking rivaroxaban, which was unaffected by the addition of clopidogrel.

For the main safety endpoint, Thrombolysis in Myocardial Infarction (TIMI) major bleeding was reported in 2.7% of those taking clopidogrel along with rivaroxaban and aspirin compared with 2.6% of patients who were taking rivaroxaban and aspirin and did not receive clopidogrel.

In addition, ISTH major bleeding, a secondary bleeding scale, occurred in 6.5% of patients taking clopidogrel plus rivaroxaban and aspirin versus 5.4% in those taking rivaroxaban and aspirin without clopidogrel. Minor TIMI bleeding events occurred in 1.67% of the clopidogrel group and 1.26% of those who were not taking it. Intracranial bleeds were infrequent and similar among those taking and not taking clopidogrel, respectively.

Dr. Hiatt explained in the ACC announcement, “This was a prespecified subgroup analysis to look at whether the use of clopidogrel modified the benefits seen with rivaroxaban and aspirin or increased the risks [of bleeding]. We found that in this [clinical] setting, where we are treating patients with symptomatic PAD with lower extremity revascularization procedures, the addition of clopidogrel [atop] rivaroxaban and aspirin does not provide any further benefit, but did increase bleeding risks, so there doesn’t seem to be a compelling reason to use it.”

Dr. Hiatt continued, “People with PAD tend to be undertreated, yet they are at very high risk. I hope that these data will lead to more education and improve how we care for these patients. From these unique data we see the benefit and risks of rivaroxaban plus aspirin were consistent regardless of concomitant use of clopidogrel. However, with higher rates of bleeding when clopidogrel is added to rivaroxaban and aspirin, these findings do not support the routine use of clopidogrel after lower extremity revascularization in these patients if they are on rivaroxaban and aspirin.”

The study is limited in that use of clopidogrel was not controlled and was allowed at the discretion of the treating physician. How increased bleeding with clopidogrel, particularly in the first 6 months of use, may affect other outcomes is being explored, noted the ACC announcement.

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