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SAN FRANCISCO -- Pooling individual patient-level data may help ease the fear surrounding paclitaxel-coated balloon angioplasty for femoropopliteal peripheral artery disease (PAD), but clinicians warned that the signal of excess late mortality cannot be excluded just yet.

Across several LEVANT studies, people randomized to the Lutonix 035 drug-coated balloon (DCB) shared similar chances of mortality at 5 years as those getting uncoated percutaneous transluminal angioplasty (PTA): survival was 84.5% and 86.1%, respectively (HR 1.01, 95% CI 0.68-1.52), according to Kenneth Ouriel, MD, of Syntactx, a clinical research organization in New York City, in a presentation at the Transcatheter Cardiovascular Therapeutics (TCT) annual meeting. The study was simultaneously published online in .

"Analyses of patient-level data identified no mortality differences between DCB and PTA. Furthermore, the lack of dose-response relationships or clustering of causes of death argues against a causal relationship between paclitaxel and mortality," Ouriel said.

Studies included in the analysis were the LEVANT 1 (n=101), LEVANT 2 (n=476), and LEVANT Japan trials (n=109), along with the observational LEVANT 2 Continued Access arm (n=657). Available follow-up data spanned nearly 5 years across studies.

In LEVANT 2 specifically -- the largest Lutonix trial with the longest-available follow-up -- there was a numerical but non-statistically significant signal of excess deaths with DCB therapy at 2 years (HR 1.40, 95% CI 0.62-3.14) that continued out to 5 years (HR 1.60, 95% CI 0.94-2.72).

Conducted in response to the December 2018 meta-analysis showing a near doubling in deaths among people getting pacitaxel devices for PAD, the present study on patient-level data from the Lutonix program is one of a "flurry" of studies that seem to contradict that smoking gun, the investigator said.

"It is important to note that none of the studies included in the were...designed to assess nor powered to detect a mortality signal, especially in the later years of follow-up. As such, the observations should be treated as hypothesis-generating only," he cautioned.

The new patient-level analyses are "certainly" the right way to go about the issue, but it's "hard to judge whether the meta-analysis was wrong or right at this point," said Dharam Kumbhani, MD, of UT Southwestern Medical Center in Dallas.

"It's reassuring that perhaps what they saw was maybe a fluke, but personally for me, the jury's still out," Kumbhani commented during a TCT press conference. "We need data from all the other trials to know what the answer is."

The FDA's ongoing probe has so far backed the presence of a paclitaxel mortality signal in PAD with the caveats of small sample size and missing data in available datasets, and the lack of apparent dose-related effect and a plausible mechanism.

In the current study, Ouriel's group took pains to put patient deaths in LEVANT 1 and 2 through a re-adjudication process by blinded, independent vascular surgeons, interventional radiologists, and oncologists with systemic paclitaxel chemotherapy knowledge. Researchers continued to observe no clustering of deaths in any category.

Across the LEVANT studies, patients in the DCB (n=1,093) and PTA (n=250) groups shared comparable baseline characteristics.

The predictors of mortality following PAD intervention were age, prior treatment of target lesion, arrhythmia, diabetes.

Ouriel acknowledged that the LEVANT program comprised relatively small trials with relatively few PTA recipients, a group that was whittled down to 70 people who actually reached 5-year follow-up.

Additionally, the Continued Access dataset has yet to undergo peer review and publication, according to an accompanying editorial by Krishna Rocha-Singh, MD, of Prairie Heart Institute at St. John's Hospital in Springfield, Illinois, and Sue Duval, PhD, of University of Minnesota in Minneapolis.

Other limitations, the duo suggested, include the questions of "whether the interventional metrics and outcomes reported from this large registry were site reported and the degree to which independent data monitoring was performed."

Earlier at TCT, Rocha-Singh presented another meta-analysis showing "a modest and consistent mortality signal" with paclitaxel devices.

"We have to be open and honest about the fact that peripheral vascular disease [trials] have not been so careful about follow-up," so "now we have to backtrack to figure out what the signal actually means," said TCT press conference moderator Roxana Mehran, MD, of Mount Sinai School of Medicine in New York City.

"If there's one thing we learned in our trials in peripheral vascular disease, it's that we need to parallel what we've seen [from trials] in the heart," Ouriel agreed.

"Our medical community, given the conundrum of discerning conclusions drawn from relatively small-to-moderate sized [randomized controlled trials] combined with non-randomized observational studies, is faced with the important question of how to proceed down the long road ahead," wrote Rocha-Singh and Duval.

The bad news is that current research efforts "will take considerable time, funding and collaboration, both across industry members, professional societies and regulators, for all the proposals to accrue a sufficient cohort size to detect a safety signal of PTXD [paclitaxel drug-coated devices] for the treatment of PAD," they continued. "In the interim, we are left to our personal conversations with our patients and the review of a new, yet to be released Instructions for Use (IFU) document to assist informed decision-making in conveying our current understanding of the potential mortality risks of PTXD use, if any."