NEW ORLEANS — A balloon angioplasty device coated with sirolimus yielded significant reductions in major adverse events, including limb amputation, in the first phase 3 trial to associate any balloon with an impact on hard outcomes rather than simply improved patency or other surrogate measures of benefit.

Angioplasty with the sirolimus-coated balloon relative to an uncoated balloon “not only reduced the need for intervention, as previously shown with paclitaxel-coated balloons, but also improves clinically relevant limb outcomes,” said Stefano Barco, MD, Department of Vascular Medicine, University Hospital Zurich, Zurich, Switzerland.

A Reduction in Hard Outcomes

In this study, called SirPAD, improved outcomes included complications stemming from lesions below the knee, a location that drives events particularly hard to prevent.

The open-label noninferiority trial was presented during a late-breaking clinical trial session at the American College of Cardiology (ACC) Scientific Session 2026 and published simultaneously in The New England Journal of Medicine.

The study, conducted in Switzerland, enrolled 1252 patients with infrainguinal peripheral artery disease and randomized them in a 1:1 manner to balloon angioplasty with the sirolimus-coated balloon (MagicTouch, Concept Medical) or to an uncoated balloon. In each group, the balloon was inflated at a nominal pressure for 120 seconds.

The primary endpoint was a composite of major adverse limb events, including unplanned major target-limb amputation and target lesion revascularization for critical limb ischemia, Barco reported. Lesions considered responsible for symptoms with a stenosis of ≥ 50% were targeted.

A primary outcome event occurred after 1 year of follow-up in 8.8% of those randomized to the experimental arm and 15.0% of those in the control arm. The risk reduction achieved with the sirolimus-coated balloon easily confirmed statistically significant noninferiority (P < .001), but it also conferred significant superiority (P = .009).

Data on the key composite secondary endpoint, which included noncritical limb ischemia along with the primary major adverse limb endpoints, also significantly favored the sirolimus-coated device (23.0% vs 30.8%; P = .002).

Lesion severity was advanced, according to Barco. He noted that more than half of patients in both groups had total occlusions. The median length of the target lesion approached 150 mm. Approximately 30% were below the knee. More than 40% met criteria for Rutherford stage IV or above. And about one third were in Fontaine classification stage III or IV.

Use of additional devices in the two arms was comparable. Bailout stents were placed in 35.5% of those in the experimental arm and 39.9% in the control arm. For the experimental vs the control arm, the use of mechanical catheter-directed thrombectomy (12.3% vs 12.8%), catheter-based rotational atherectomy (5.4% vs 5.0%), and intravascular lithotripsy (2.6% vs 2.1%) were not statistically different.

The relative advantage of sirolimus-coated balloons was consistent across sex, age, multiple target lesion lengths, chronic occlusion vs de novo or non-de novo lesions, and Fontaine stage.

The advantage of the sirolimus-coated device was also consistent across the two components of the primary outcome — unplanned major target-limb amputation (1.3% vs 2.7%) and target lesion revascularization for critical limb ischemia (8.3% vs 13.3%) — when assessed individually.

Serious adverse events occurred in 58.1% of each of the randomized groups. The numerically lower rate of all-cause death in the experimental arm (11.8% vs 12.8%; P = .67) did not approach significance.

All-Comer Design Supports Generalizability

The all-comer design of the trial suggests that these results are relevant outside of the confines of this study, according to Ehrin J. Armstrong, MD, director of interventional cardiology at the VA Eastern Colorado Healthcare System in Denver.

“[This study] was considerably different from other trials of new endovascular devices because it was a strategy-based trial and enrolled a substantial percentage of patients with critical limb ischemia, who are typically excluded from device trials,” he wrote in an accompanying editorial.

“Typically, femoropopliteal and infrapopliteal lesions are studied separately because of the higher risk of restenosis associated with infrapopliteal disease,” he wrote. “These trial features contribute to the generalizability of the results because they reflect real-world practice.”

Calling the results and conduct of the study “truly remarkable,” the ACC-invited discussant, Douglas E. Drachman, MD, director of the Interventional Cardiology Fellowship Program at Massachusetts General Hospital in Boston, suggested these data represent an important step toward “encompassing this idea of leaving nothing behind.”

He considers a strategy of avoiding stents particularly important in the infrapopliteal segment, which is “truly tortured by extrinsic compression and torsion.”

The SirPAD study showed benefits not previously achieved with paclitaxel-coated balloons in PAD, which were briefly linked to increased mortality in a meta-analysis — a finding that was subsequently refuted in a registry-based clinical trial.

Nevertheless, in the absence of a direct comparison between the sirolimus-coated balloon and devices employing paclitaxel coating, relative efficacy cannot be assumed, Barco said. Even if previous trials with paclitaxel-coated devices did not demonstrate comparable event risk reductions, Barco indicated a direct comparison is needed.

If a direct comparison is needed for an evidence-based conclusion, Barco pointed out that SirPAD “is the first that applied the best medical treatment for our patients.”

Referring, for example, to tight control of modifiable risk factors, such as hypertension and hyperlipidemia, “none of the paclitaxel trials done 10 years ago actually benefited from advances that have since become available.”

Barco reported having financial relationships with Bayer, Boston Scientific, Daiichi Sankyo, INARI, Medtronic, Novartis, Penumbra, Sanofi, Viatris, and Concept Medical, which provided funding for this study. Drachman reported having financial relationships with Abbott Laboratories, Abiomed, and Shockwave.