New Support for Paclitaxel Balloon, Stent Safety in PAD: SWEDEPAD

December 10, 2020

The safety evidence for paclitaxel-coated devices in peripheral interventions has received another boost with publication of a clinical trial interim analysis that found no associated mortality hazard, compared with uncoated balloons and stents.

The findings expand on other research that has helped to ease concerns raised by a December 2018 meta-analysis from Katsanos and colleagues that identified excess mortality among patients with femoropopliteal disease treated with the paclitaxel-based devices.

A similar adverse signal emerged in other reports, notably an evidence review by the US Food and Drug Administration, but some other mostly observational studies subsequently failed to find such a risk from the devices used in peripheral artery disease (PAD).

Still, the controversy upended the field and prompted several ongoing peripheral intervention clinical trials to suspend enrollment for several months. The new findings further supporting the safety of the coated devices are based on continued follow-up in one of those studies, the Swedish Drug-Elution Trial in Peripheral Arterial Disease (SWEDEPAD).

SWEDEPAD, which wasn't originally designed to compare drug-coated and uncoated devices for mortality, features two parallel cohorts of patients with femoropopliteal or infrapopliteal disease: one with critical limb ischemia and a smaller one with intermittent claudication. They had been separately assigned to endovascular therapy using either paclitaxel-coated balloons or stents or uncoated balloons or stents.

No mortality differences, either at 1 year or across the entire follow-up, which averaged more than 2 years, were seen overall or among the two cohorts individually.

"We believe it is safe to use paclitaxel-coated devices in the PAD population," SWEDEPAD principal investigator Mårten Falkenberg, MD, PhD, told theheart.org | Medscape Cardiology.

Remaining questions, which the trial was originally designed to address, include "whether these devices actually improve lives for patients with PAD in terms of decreased risk for amputation and improved quality of life," said Falkenberg, from Sahlgrenska University Hospital and Gothenburg University, Sweden.

The multicenter SWEDEPAD launched in November 2014 with a projected enrollment of about 3800, and separate primary end points for the two cohorts: amputation for those with critical limb ischemia and quality of life for patients with claudication. All-cause mortality was a secondary end point in both randomizations.

Enrollment halted right after the December 2018 meta-analysis publication but resumed in 2019. The current unplanned interim analysis for all-cause mortality, published December 9 in the New England Journal of Medicine, is based on the 2289 patients entered before enrollment was suspended.

"As we've moved further away from the initial Katsanos meta-analysis, there have been a lot of observational studies. And for the most part, none have reproduced the finding that was of concern," Herbert D. Aronow, MD, MPH, cardiac cath lab director at Rhode Island & The Miriam Hospitals and Alpert Medical School of Brown University, Providence, told theheart.org | Medscape Cardiology.

"So I think that there's less concern today within the vascular and cardiovascular community that this signal may be real. That said, nothing we've seen to date has been definitive, so it's not possible to say we know there's no longer a risk. I don't know that we'll ever be able to say that with certainty."

Still, said Aronow, who was not part of the SWEDEPAD trials, "I think it's great to have a randomized trial, not an observational study, say that there was no difference as far out as two and a half years."

Concerns after the Katsanos meta-analysis "created a lot of hesitancy in the PAD world," observed Marc P. Bonaca, MD, MPH, University of Colorado School of Medicine, Aurora, in an interview. "So there have been efforts to try to resolve the issue with real-world data that have provided some reassurance."

Earlier clinical trial evidence supporting the safety of paclitaxel-coated devices in PAD include a prespecified retrospective comparison of patients in the VOYAGER PAD trial treated with drug-coated vs uncoated balloons and stents, observed Bonaca, who was a principal investigator.

Primarily a test of a direct oral anticoagulant on top of aspirin in patients undergoing lower-extremity revascularization, VOYAGER PAD also showed an adjusted mortality of about 12% over about 3.5 years, regardless of whether revascularization used paclitaxel-coated or uncoated balloons or stents, as previously reported.

"I think if you take the weight of evidence, the observational data and VOYAGER PAD and SWEDEPAD together, it shows me that there's really no compelling risk," Bonaca said.

"You never want to dismiss a safety issue. I think it gave us all pause, but it was never biologically plausible" he noted. "I never really believed the signal from the Katsanos meta-analysis."

Because VOYAGER PAD was not randomized according to whether the endovascular devices were drug-coated, Falkenberg said, it "cannot answer the question of paclitaxel safety with the same scientific reliability" offered by SWEDEPAD.

The latter trial is well positioned to demonstrate the safety of drug-coated balloons and stents in the periphery, he noted. "We believe the SWEDEPAD population is representative of PAD patients who receive drug-coated devices in everyday clinical practice." Their demographics "match that of all patients treated in Sweden very well."

Its population also closely resembles those featured in the 2018 Katsanos report combined with a second meta-analysis from the same group published in January, he said. About 90% of patients in the first report had intermittent claudication. The second meta-analysis, which also showed more deaths with paclitaxel-coated devices, focused on patients with critical limb ischemia.

The SWEDEPAD interim results also have limitations. The study was randomized by whether the balloons and stents were coated with paclitaxel; "therefore, we're not as worried about potential confounding," Bonaca said. But, "a downside is that the numbers are so small. There are just a handful of events," especially in the cohort with intermittent claudication.

"So, I am not sure that it answers the question in the claudicants. It's just underpowered for that."

The overall SWEDEPAD trial entered adults with symptomatic PAD caused by a femoral, popliteal, or infrapopliteal artery stenosis of 50% or greater. Researchers randomly assigned 1149 of them to treatment with paclitaxel-coated devices and 1140 to intervention with uncoated balloons or stents.

There were 574 deaths overall in the interim analysis, for statistically similar intention-to-treat mortality of 25.5% in the paclitaxel-device group and 24.6% for those treated with uncoated devices over a mean follow-up of 2.5 years.

Nor were there significant differences between treatment groups by disease severity. Mortality was 33.4% for those treated with paclitaxel-coated devices vs 33.1% in the uncoated-device group among those with critical limb ischemia. It was 10.9% vs 9.4%, respectively, among the patients with intermittent claudication.

Overall 1-year mortality was 10.2% in the drug-coated device and 9.9% in the uncoated-device group.

Adjusted Hazard Ratio (HR) for All-Cause Mortality in SWEDEPAD, Paclitaxel-Coated vs Uncoated Devices
  HR (95% CI)
Follow-up Duration Overall, n = 2289 Chronic Limb-Threatening Ischemia, n = 1480 Intermit Claudication, n = 809
1 year 1.03 (0.77–1.37) 1.00 (0.75–1.35) 1.26 (0.49–3.24)
Mean 2.5 years 1.06 (0.92–1.22) 1.04 (0.90–1.21) 1.18 (0.72–1.93)

"I don't think this will arrest the debate," Bonaca said about the interim analysis. "I think that it is overall reassuring, but I don't think it completely answers the questions."

It's reassuring, Aronow agreed, every time another study shows no excess mortality risk associated with paclitaxel-coated balloons and stents in the periphery. But "I think that practitioners in the end will continue to be faced with a situation where we need to have a very honest and candid conversation with our patients about the potential for risk, and engage in shared decision-making. Because I don't think we'll ever be able to say that we know for sure there's no risk."

Falkenberg reports receiving grants from the Swedish Research Council, Swedish Heart Lung Foundation, and Region Vastra Gotaland. Disclosures for the other authors are at NEJM.org. Aronow discloses that he is on the data safety monitoring board for the ILLUMENATE studies sponsored by Philips Spectranetics. Bonaca had disclosed receiving grant support or a research contract from AstraZenca, Bayer, Medtronic, Merck/Schering Plough, Sanofi-Aventis, Amgen, and Janssen.

N Engl J Med. Published online December 9, 2020. Full text

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