COMPARE: Similar Efficacy and Safety for Paclitaxel Balloons Regardless of Dose

LEIPZIG, GERMANY—A comparison of low-dose and high-dose paclitaxel drug-coated balloons (DCBs) suggests that both are safe and effective in treating patients with femoropopliteal artery disease who have a range of complex lesion types.

“This is the first head-to-head comparison of two different DCBs with different coating strategies and different paclitaxel dosages,” said Sabine Steiner, MD (University Hospital Leipzig, Germany), in her presentation here at LINC 2020. The data from the trial were simultaneously published online ahead of print in the European Heart Journal.

When controversy erupted in late 2018 around a meta-analysis suggesting increased long-term mortality in patients treated with paclitaxel DCBs and stents compared with plain old balloon angioplasty (POBA), significant discussion centered on whether or not the dose on the balloon might be responsible for toxicity and deaths in the paclitaxel-treated patients. A major impediment in exploring the issue further was that although there were multiple paclitaxel devices on the market with different excipients and doses that had demonstrated safety and efficacy when pitted against POBA, none of them had been directly compared.

Steiner and colleagues enrolled patients with moderate-to-severe intermittent claudication or ischemic rest pain who were being treated at 15 centers in Germany. Lesions were stratified according to whether they were short (≤ 10 cm), moderate (>10 cm and ≤ 20 cm), or long (> 20 cm and ≤ 30 cm). In her presentation, Steiner emphasized that patient characteristics in both groups were similar to patients included in the pivotal RCTs of paclitaxel-based devices.

Patients in COMPARE were randomized to endovascular treatment with either a high-dose paclitaxel DCB (In.Pact Admiral or In.Pact Pacific; Medtronic) or a low-dose paclitaxel DCB (Ranger; Boston Scientific). Although the latter device is approved in Europe, it remains investigational in the United States.

At 12 months, the rate of primary patency was 81.5% in the high-dose group and 83.0% in the low-dose group, meeting the criteria for noninferiority (P < 0.01). Patency results were similar when patients were analyzed by lesion length. The rate of bail-out stenting was high in both groups (30% in the low-dose group and 25% in the high-dose group) owing to lesion complexity, with lower patency rates at 12 months in patients who received a bailout, regardless of dosing group.

The primary safety endpoint (composite of freedom from device and procedure-related death through 30 days and freedom from major target limb amputation and clinically driven TLR through 12 months), was reached in 92.6% of patients in the high-dose group and in 91.0% in the low-dose group, again meeting criteria for noninferiority (P for noninferiority < 0.01). Among the secondary outcomes, Steiner highlighted all-cause mortality at 12 months, which was 2.5% in the low-dose group and 1.6% in the high dose group (P = 0.73). “None of these deaths was considered device- or procedure-related by the clinical events committee,” she added.

Kaplan-Meier analysis confirmed no significant difference in freedom from clinically driven TLR between the low- and high-dose groups. Steiner reported that there were no major target limb amputations during the study period and that 80% of patients in both groups presented in Rutherford category 0 or 1 at 12 months.

Commenting on the study for TCTMD, Sahil A. Parikh, MD (NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY), said that COMPARE, which was begun before “paclitaxelgate” erupted, was a well done study with good comparators.

“It’s valuable and it sort of debunks the dose-efficacy calculus,” he observed. “The dose on the balloon neither predicts efficacy nor toxicity.”

However, Parikh said the 1-year data don’t provide too much reassurance with regard to safety. “It’s not a long enough time point, and the situation is much more complex with regard to the overall controversy and the mortality signal,” he explained.

Potential New Paths Forward

Following Steiner’s presentation, Dierk Scheinert, MD (University Hospital Leipzig), session moderator and senior author of COMPARE, polled the audience about paclitaxel safety. While a small number reported still being “severely concerned” and not currently using paclitaxel devices, 85.2% said they are using the devices because they believe there is an acceptable risk-benefit ratio. Scheinert said he couldn’t be certain what the exact numbers were last year when the same poll was taken at LINC, but acknowledged a significant decrease in the percentage who were concerned and not using the devices. Though not the final word, Scheinert said, “I think we’ve made progress.”

Speaking in the same session, William A. Gray, MD (Main Line Health/Lankenau Heart Institute, Wynnewood, PA), said he believes that while paclitaxel is making a comeback, effective and safe nonpaclitaxel options are needed going forward.

“Trust me, [every manufacturer] who has a paclitaxel device is looking at sirolimus as an alternative in case this market doesn't come back,” Gray noted. Compared with paclitaxel, sirolimus offers some potential benefits that include anti-inflammatory properties and a wide therapeutic range, he said. However, it has relatively slow tissue absorption in its natural state and short tissue retention times, both of which pose potential drawbacks.

But Gray said early data for the sirolimus-based Selution DCB (MedAlliance), which has a microreservoir to slow the elution of sirolimus over time and promote adherence in the tissue, appears promising. “Tissue transfer with this technology is actually as good or better—significantly better—than some of the paclitaxel devices that came before it,” he added. Bioresorbable scaffolds mounted on a single delivery system are another option in early stages of development, as is targeted drug delivery with the so-called “bullfrog” approach, as was used in the DANCE trial.

To TCTMD, Parikh said if sirolimus ultimately ends up supplanting paclitaxel as the drug of choice in PAD interventions, it may not be that surprising and certainly won’t be unprecedented.

“If one looks to the coronary field as an analogy, paclitaxel-eluting devices were driven out of the market because of superior efficacy of the limus devices,” he noted. “I think the next 5 to 7 years are going to be important and interesting in this regard.”