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Things seem to be looking up for the field of endovascular revascularization for symptomatic peripheral artery disease (PAD), researchers suggested.

Paclitaxel-coated devices were safe for patients over several years, according to two studies presented at a late-breaking trial session at the virtual TCT Connect conference.

This may assuage safety concerns first raised by a 2018 meta-analysis showing drug-coated devices to be associated with a long-term mortality signal. Some had cautioned that the meta-analysis itself suffered from missing data in the PAD trials included and other issues, however.

Other studies at TCT Connect showed delivery by drug-coated balloons (DCB) and adventitial temsirolimus had promise in revascularization below the knee (BTK).

"We're seeing consistent benefit with administration of antiproliferative therapy to the infrapopliteal circulation," said Robert Lookstein, MD, of Mount Sinai Health System in New York City, during a press conference.

"Every single session today demonstrates that drug-based therapy is here to stay," he emphasized. "Drug delivery for PAD should be standard of care for symptomatic patients."

The major challenge in the infrapopliteal arteries has been restenosis, and three DCB trials (, , and the ) have failed to meet efficacy in this space.

VOYAGER PAD

A device's paclitaxel drug coating was associated with neither survival benefit nor harm in endovascular revascularization for PAD, according to a prespecified analysis of a trial.

All-cause mortality at 42 months reached 12.1% of people randomized to a drug-coated device, which was statistically no different than the 12.6% rate in peers who had no DCB (or similar device) placed during revascularization (HR 0.95, 95% CI 0.83-1.09), according to Connie Hess, MD, of University of Colorado Medicine in Aurora.

Notably, this analysis had the strengths of 99.6% ascertainment of mortality and independently adjudicated events -- an "incredible milestone" that raises the question of "whether it's time to shut the door on the paclitaxel controversy," according to Lookstein.

"Under randomized trial conditions, we see no effect on mortality by paclitaxel. This supports the idea of how we could have gotten the result that we got in the initial meta-analysis; that it could have been trial design all along," agreed fellow discussant Peter Schneider, MD, of the University of California San Francisco, during the press conference.

The main finding of VOYAGER PAD was that rivaroxaban (Xarelto) reduced acute limb ischemia, major amputation, myocardial infarction, ischemic stroke, or cardiovascular death at 3 years.

Hess reported that the benefit of rivaroxaban was consistent regardless of drug-coated device use (P=0.88 for interaction).

Hess and colleagues performed a prespecified analysis of the that randomized patients 1:1 to rivaroxaban 2.5 mg twice daily or placebo.

Enrolled were 6,564 people with symptomatic lower extremity PAD undergoing peripheral revascularization, 4,379 of whom had endovascular (or hybrid) procedures. Fewer than one in three received a drug-coated device, and those who did most commonly got DCBs.

About 90% of patients received treatment of a lesion above the knee (ATK). The remainder had infrapopliteal lesions.

ILLUMENATE Global

The safety of a low-dose paclitaxel DCB in ATK revascularization was upheld in postmarket registry data, the ILLUMENATE group announced.

Placed in the superficial femoral artery or popliteal arteries, the Stellarex DCB was associated with 77.9% freedom from device- and procedure-related mortality at 30 days and major target limb amputation, as well as clinically driven target lesion revascularization (TLR), at 48 months, according to Marianne Brodmann, MD, of Medical University of Graz in Austria.

Safety events were largely clinically driven TLR (21.8%) with few limb amputations (0.8%). The incidence of all-cause mortality at 4 years reached 8.1%.

The Kaplan-Meier estimate of freedom from clinically driven TLR through 4 years was 75.6%, with no interaction by sex, lesion length, or diabetes status, Brodmann reported.

Lookstein said that 75.6% figure is "just spectacular" in the real world. "There is consensus that DCB has become the go-to therapy for patients with lifestyle-limiting claudication," he said, calling the Stellarex DCB a "safe and effective technology."

Brodmann noted that the ILLUMENATE program as a whole (counting nine studies) has had over 2,300 patients treated ATK with the Stellarex DCB. No device- or procedure-related deaths have been reported to date.

is a registry of 371 Stellarex recipients (mean age 68.2; 73.0% men) who were largely classified as Rutherford 3 (57.7%) or Rutherford 2 (33.4%) at baseline.

Lesions were complex but not too long at 7.5 cm on average. Under a third were total occlusions, and 40.8% showed severe calcification.

Clinical and procedural characteristics in the registry mostly reflected those from the pivotal trials. However, provisional stenting was "rather high" at 31.3%, according to Brodmann.

Lookstein suggested that investigators perform additional subgroup analyses, including by calcification, for example. "If this device can be effective in super-calcified [lesions] it would just reinforce our collective comfort with this technology."

"Now we have three DCBs that are FDA approved in the U.S. and likely soon four, or even five, in the next 12 to 18 months," he noted. The question is whether the field can generate more comparative effectiveness data in the femoropopliteal segment, and "we're just starting to see that," he said.

IN.PACT BTK

Despite the challenges of BTK revascularization, a paclitaxel-coated balloon was effective for angioplasty in the infrapopliteal arteries, according to a feasibility trial comparing the DCB with conventional plain balloon angioplasty (PTA).

Late lumen loss (LLL) at 9 months favored the DCB group on sub-segmental analysis dividing the entire lesion into 10 equal segments (0.59 vs 1.26 mm, P=0.017), but not significantly so with traditional LLL assessment at a single point in the lesion (0.89 vs 1.31, P=0.070).

There were "no safety concerns" with the IN.PACT 014 BTK DCB used in the study given similar safety composite outcome rates between groups (91.3% vs 87.5%), reported Antonio Micari, MD, of University of Messina in Italy.

Thus, it appears that a biologic therapy in the infrapopliteal arteries is "around the corner," Schneider said.

"I agree that we are probably going to have an effective DCB in the not-so-distant future. It's one step in the right direction," according to Lookstein.

However, he raised the question of what is a safe therapy for patients with active wounds. He also cautioned that the study was small and that it is unclear if subsegmental LLL analysis was appropriate for a Rutherford 5 cohort. Moreover, it will take further study of the clinical impact of the IN.PACT 014 BTK DCB to determine "whether we should be using this on a routine basis," he suggested.

The safety endpoint in the combined freedom from device- and procedure-related mortality at 30 days, major target limb amputation at 270 days, and clinically-driven TLR at 270 days.

At 9 months, DCB and PTA groups had similar all-cause mortality rates of 4.3% and 8.0%, respectively, and thrombosis at the target lesion site in 4.3% and 4.2% of cases.

Micari and colleagues conducted the feasibility study in Europe. Fifty critical limb ischemia patients with chronic total occlusions in the infrapopliteal arteries were randomized to DCB or PTA therapy after successful vessel dilation.

Baseline clinical and lesion characteristics were no different between groups.

Study participants made for a "complex population," Micari noted, as they were largely Rutherford 5 patients with TASC II C and D lesions BTK. Lesions were long (averaging over 215 mm), with a mean total occluded lesion length over 140 mm.

These are "real-world" lesions that "we take care of on a day-to-day basis," according to Schneider.

TANGO

Finally, adventitial drug delivery showed promise as a way to extend the durability of BTK procedures, the TANGO group reported.

Micro-infusion of temsirolimus (Torisel) after successful angioplasty in infrapopliteal segments was associated with 24% angiographic transverse view area loss (TVAL) at 6 months, which was significantly better than the 46% TVAL with saline control.

This is consistent with temsirolimus' reduction in stenosis and inflammation given that TVAL is a three-dimensional measure of neointimal hyperplasia, according to Ehrin Armstrong, MD, of VA Eastern Colorado Health System in Denver.

Freedom from clinically relevant target lesion failure at 12 months reached 70.2% of TANGO patients randomized to temsirolimus microinfusion and 31.0% of peers receiving saline instead.

"Many of us would agree in the BTK space that an endpoint powered for 6-12 months is clinically significant," Armstrong said, noting the treatment's potential for wound healing and prevention of major amputation. He added that his group anticipates more data at 24-36 months and a phase III study.

Notably, DCBs have not demonstrated benefit in BTK as opposed to the femoropopliteal space. The infrapopliteal arteries are characterized by heavy thrombus, plaque, and calcium burden, and balloon angioplasty remains the mainstay therapy, the presenter said.

Armstrong's group chose to administer temsirolimus, the active metabolized version of sirolimus (Rapamune), partially because the drug is cytostatic such that it may be expected to be safe compared with paclitaxel.

Temsirolimus was applied with the Bullfrog system to the site of inflammation after angioplasty. With this system, a syringe makes multiple injections across the length of the lesion without need for multiple balloons.

"You can paint the lesions" with injections every 40 mm, the researcher said. He noted that a newer version of the Bullfrog features a stiffer needle that can be directed away from bulky calcium.

was a phase II randomized dose-escalation trial in 61 patients with infrapopliteal disease who received successful angioplasty. Investigators tested temsirolimus dosing at 0.1 mg/mL and 0.4 mg/mL compared with saline control.

Lesion length averaged roughly 11 cm. More than half of lesions were TASC C and D, and approximately one-third had total occlusion at baseline.