A post hoc analysis of the large VOYAGER-PAD randomized trial presented Sunday showed no difference in mortality rate between study patients who were treated with paclitaxel-coated devices and those treated with non-paclitaxel-coated devices.
Connie N. Hess, MD, of the University of Colorado School of Medicine, Aurora, presented the results at the TCT Connect virtual conference. Panelists at a press conference announcing the analysis said this should end the controversy surrounding whether paclitaxel-coated devices cause an increase in mortality among peripheral artery disease (PAD) patients.
Paclitaxel-coated devices have been shown to improve the patency of lower-extremity revascularization. However, there has been controversy and concern surrounding whether these devices might increase mortality based on a December 2018 meta-analysis by Konstantinos Katsanos, MD, PhD, MSc, of Patras University Hospital, Greece, and colleagues.
Meanwhile, observational studies have not shown this signal for excess mortality, but these studies have been limited by short-term follow-up and lack of clinical details.
VOYAGER-PAD was a double-blind, placebo-controlled trial of PAD patients undergoing revascularization who were randomized to receive 2.5 mg of rivaroxaban twice daily or a placebo. Patients in both arms also received 100 mg of aspirin daily, and clopidogrel was given at operator discretion.
The primary outcome of this analysis of the randomized trial was all-cause mortality, which was a prespecified secondary outcome in the original trial. Inverse-probability treatment weighting was used to create a weighted population accounting for each patient’s propensity for paclitaxel drug-coated devices (DCDs) as opposed to non-paclitaxel DCDs.
Among 6,564 randomized patients, 67% (n=4,379) underwent index revascularization and were followed for a median of 31 months. Complete ascertainment of vital status was available in 99.6% of patients in the analysis.
During the index revascularization, DCDs were used in 31% (n=1,358) of patients. These patients more frequently had prior lower-extremity revascularization, higher baseline use of dual antiplatelet therapy and statins, and were more often treated for claudication than were non-DCD patients. Among these patients, 78% (n=1,053) received a drug-coated balloon, 17% (n=235) received a drug-eluting stent, and 5% (n=70) received both.
In the unweighted analysis, the mortality rate in the DCD arm was lower than in the non-DCD arm (2.9 vs. 3.9 per 100 patient-years; 3.5-year Kaplan-Meier cumulative incidence, 10.2% vs. 13.8%). After weighting, there was no association between DCD use and mortality (3.5-year cumulative incidence 12.1% vs. 12.6%; hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.83-1.09; p=0.49).
The original VOYAGER-PAD trial showed that rivaroxaban resulted in a lower rate of the primary composite efficacy endpoint (acute limb ischemia, major amputation of vascular etiology, myocardial infarction, ischemic stroke or cardiovascular death) than placebo (17.3% vs. 19.9%; HR, 0.85; 95% CI, 0.75-0.96; p=0.0085).
The analysis showed no difference in the main trial’s primary endpoint for either the DCD or non-DCD subgroups (DCD: rivaroxaban 13.2% vs. placebo 15%; HR, 0.87; 95% CI, 0.65-1.15. Non-DCD: rivaroxaban 14.4% vs. placebo 16%; HR, 0.89; 95% CI, 0.74-1.07; p-interaction = 0.88).
Robert Lookstein, MD, of the Icahn School of Medicine at Mount Sinai, New York, who was not involved in the analysis, said this trial’s results should help the peripheral vascular community move beyond the paclitaxel controversy.
“I think the entire vascular community has been waiting for a prospective, independently adjudicated trial to try and make determinations of whether we can put this behind us, and I think this trial is it,” he said.
Peter A. Schneider, MD, of the University of California San Francisco, who also was not involved in the analysis, said the original randomized trials concerning paclitaxel were missing follow-up data, introducing ascertainment bias, and strict control of periprocedural and follow-up medications, introducing a treatment bias.
“Those were eliminated here, and now under (randomized controlled trial) conditions, we see no effect on mortality of paclitaxel,” he said. “So I think it’s actually supporting some of the thoughts we’ve had about how we could have gotten the result we got in the first place from the initial meta-analysis showing increased mortality and the potential that it could have been trial design all along.”
The analysis received research grants from Bayer and Janssen.