New Questions About Triple Therapy After PAD Revascularization: VOYAGER PAD Substudy

The addition of clopidogrel to rivaroxaban (Xarelto; Bayer/Janssen) and aspirin in patients with a recent lower limb revascularization does not provide increased protection against acute limb ischemia, amputation, or CV events and is associated with higher bleeding risk, according to a prespecified subanalysis of VOYAGER PAD.

During a presentation on March 28, 2020, at the virtual American College of Cardiology 2020 Scientific Session, William R. Hiatt, MD (University of Colorado School of Medicine, Aurora), said the study results suggest that clopidogrel should be minimized or avoided in this setting, even when stents are used.

“It appears the longer the duration of clopidogrel, the higher the risk of bleeding,” he said. “[M]ore bleeding with background clopidogrel, even if not severe by adjudication, may be associated with broad consequences, including discontinuation of therapies.”

At follow-up out to 36 months, there were no significant differences in the primary endpoint of acute limb ischemia, major amputation for vascular causes, MI, ischemic stroke, or CV death between PAD patients on twice-daily rivaroxaban plus aspirin or placebo plus aspirin, regardless of whether clopidogrel was or was not given after revascularization (P for interaction = 0.91). However, numerically higher differences in ISTH bleeding between the on- versus no-clopidogrel groups suggest that there is some degree of higher bleeding risk conferred by being on clopidogrel.

Discussing the results, Tyler J. Gluckman, MD (Providence Heart and Vascular Institute, Portland, OR), called the trial “practice-changing” but also noted that clopidogrel patients appeared to have more risk factors and greater burdens of atherosclerotic cardiovascular disease that need to be taken into consideration on an individual basis.

“When you look at patients that got triple antithrombotic therapy, whether in the rivaroxaban arm or not, they had lower absolute rates of events,” he noted. In that context, Gluckman asked Hiatt if there might be subgroups for whom triple therapy, whether after surgical or endovascular revascularization, would be advisable.

We’re not suggesting that you shouldn’t use DAPT. But . . . patients receiving three drugs—rivaroxaban, clopidogrel, and aspirin—are at much higher risk of bleeding than [those] receiving two drugs. William Hiatt

“These are challenging results to interpret clinically because they contradict some of the dogma that has been out there in this field for several decades,” Hiatt observed, referencing the use of clopidogrel after stent implantation. However, since clopidogrel use was at the discretion of the operator and not controlled in VOYAGER PAD, “I would emphasize that comparing the outcomes [in] patients with and without clopidogrel should be taken cautiously,” he added.

Hiatt reiterated that the results suggest that clopidogrel exposure should be kept to a short period of time. “We’re not suggesting that you shouldn’t use [dual antiplatelet therapy (DAPT)]. But these data would suggest that patients receiving three drugs—rivaroxaban, clopidogrel, and aspirin—are at much higher risk of bleeding than [those] receiving two drugs. Also, this protocol would suggest that if you want to use this regimen, [it’s best] to start rivaroxaban as soon as the procedure is completed and not delay its use until after a DAPT course.”

Consistent Risk Reduction

For the main VOYAGER PAD study, researchers enrolled 6,564 symptomatic PAD patients from 34 countries who had undergone a limb revascularization in the previous 10 days. Patients were randomly assigned to receive rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily or to receive placebo plus aspirin 100 mg daily.

Rivaroxaban plus aspirin resulted in fewer cases of acute limb ischemia compared with aspirin alone, a difference that was apparent as early as 3 months after randomization, and an approximate sixfold increase in the number of ischemic events prevented relative to bleeds caused. However, since 51% of the study population received clopidogrel at the discretion of their treating physician, the VOYAGER PAD investigators conducted the subanalysis to determine what effect, if any, the background clopidogrel had on the main results.

Of those treated with clopidogrel (n = 3,313), 91% had undergone an endovascular as opposed to a surgical procedure. Those who had undergone a prior limb revascularization were more likely than those who had not to receive clopidogrel (40% vs 31%; P < 0.0001). Other patient groups more likely to receive clopidogrel were Caucasians, women, and those with hypertension, diabetes, hyperlipidemia, CAD, or a prior coronary intervention.

The median duration of clopidogrel use was similar, at approximately 29 days, regardless of whether patients were on concomitant rivaroxaban and aspirin or aspirin plus placebo. As Hiatt showed, there was a slight excess of events in the first few days in clopidogrel patients, but the curves began to separate thereafter. By 6 months, the absolute risk difference between the placebo and rivaroxaban groups for the occurrence of the primary endpoint was 1.6% with clopidogrel use versus 1.5% without clopidogrel.

Similarly, the individual components of the primary endpoint were all relatively consistent, with no effect modification from the use of clopidogrel. The only exception was CV death, for which there was a higher risk in the clopidogrel group (HR 1.27; 95% CI 0.94-1.72 vs HR 1.06; 95% CI 0.80-1.39).

“That’s something that we are looking into, but overall we think that rivaroxaban plus aspirin is relatively neutral for cardiovascular death,” Hiatt noted.

For the principal safety outcome of TIMI major bleeding, there was a numerical increase in the rivaroxaban-treated patients relative to those on placebo in both the on-clopidogrel and no-clopidogrel groups, but this finding was not statistically significant (P for interaction = 0.69). Intracranial hemorrhage or fatal bleeding, which were rare events, also were not statistically different between on-clopidogrel and no-clopidogrel groups (P for interaction = 0.12). The investigators also analyzed patients by ISTH bleeding criteria, finding no difference between the on-clopidogrel and no-clopidogrel groups (P for interaction = 0.70). However, numerically higher differences in ISTH bleeding between the on-clopidogrel vs no clopidogrel groups suggest that there is some degree of higher bleeding risk conferred by being on clopidogrel, Hiatt observed.

Guideline Considerations

In an online press conference, Sahil Parikh, MD (NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY), said that the results raise important clinical questions.

“Whereas with COMPASS a year ago, we were wondering when was the right time to switch from dual antiplatelet therapy after an intervention to aspirin plus rivaroxaban 2.5 mg twice daily, now I think as an interventionalist, I'm going to wonder about whether I would send the patient home from the procedure on aspirin and rivaroxaban as opposed to dual antiplatelet therapy,” he said.

Parikh also implied that VOYAGER PAD may provide an opportunity for developing a bleeding score to aid in risk-stratifying patients at higher bleeding risk, for whom a more cautious approach that includes clopidogrel might be warranted.  

“I would implore the guidelines committees now to really look hard at updating our guidelines for the use of oral anticoagulants in the management of PAD, both with and without intervention,” he concluded.