No Increased Mortality With Paclitaxel Balloon Angioplasty in PAD

Roxanne Nelson RN, BSN

October 02, 2019

SAN FRANCISCO — A new analysis of data from the LEVANT trials shows no mortality difference between patients treated with paclitaxel-coated balloon angioplasty (DCB) for femoropopliteal peripheral artery disease (PAD) and those treated with uncoated balloon angioplasty (PTA).

In an aggregate dataset from the LEVANT 1 (n = 101), LEVANT 2 (n = 476), and LEVANT Japan (n = 109) trials, along with the observational LEVANT 2 Continued Access cohort (n = 657), the hazard rate (HR) for mortality was 1.01 (95% CI, 0.68 - 1.52) at 5 years.

There was no clustering of causes of death within any category of cause of death and no dose–response relationships were observed, the researchers note.

The 5-year survival of patients randomized to the Lutonix 035 (Bard/BD) DCB was 84.5%, compared with 86.1% for those randomized to PTA.

These findings argue against a causative link between the use of paclitaxel-coated balloons in femoropopliteal disease and mortality, said study author Kenneth Ouriel, MD, MBA, president and CEO of Syntactx in New York City.

"There is no significant increase in the hazard ratio for mortality in any analysis of Lutonix 035," he said.

Ouriel presented the results at Transcatheter Cardiovascular Therapeutics (TCT) 2019, which were simultaneously published online September 28 in JACC: Cardiovascular Interventions.

Jury Still Out

The LEVANT study was conducted in response to the findings of a systematic review and meta-analysis published late last year, which showed an increased long-term risk for death beyond the first year after treatment with paclitaxel-coated balloons and stents for PAD.

After analyzing 28 randomized controlled trials, Konstantinos Katsanos, MD, PhD, Patras University Hospital, Rion, Greece, and colleagues reported that paclitaxel-based devices were associated with a 68% relative risk increase in all-cause death at 2 years and a 93% relative risk increase at 5 years compared with noncoated devices.

The meta-analysis prompted a federal investigation and a flurry of new research from the major device makers, including a new patient-level meta-analysis that showed no correlation between mortality and paclitaxel exposure in patients treated with the IN.PACT Admiral (Medtronic) DCB in two single-group and two randomized controlled trials.

The new patient-level analyses are "certainly" the right way to go about the issue, "but I think it's a little hard to judge whether the meta-analysis was wrong or right at this point," said Dharam Kumbhani, MD, UT Southwestern Medical Center, Dallas, speaking as a panelist during a press briefing. "I do think it was ethically hypothesis-generating, but these other studies, including the one that was just presented, are reassuring and what they saw was maybe a fluke."

"I think the jury's still out and these studies help, but we need data from all of the other trials to know what the answer is," he added.

No Survival Differences

In the current study, Ouriel and colleagues assessed mortality after DCB treatment of femoropopliteal disease, using independent patient level data from the three LEVANT trials. The cohort included 1093 DCB patients and 250 treated with PTA.

"This is the first time that these studies have been put together to look at end points that weren't previously available because they were underpowered for mortality," he explained.

At 5 years, the HR for all-cause mortality in LEVANT 2 was 1.60 (95% CI, 0.94 - 2.72). Overall survival in LEVANT 2 at 5 years was 87.7% in the PTA group and 80.8% in the DCB group, but the difference did not reach statistical significance (= .084). But when the data from all three trials was aggregated, the HR decreased to 1.01 (95% CI, 0.68 - 1.52).

"If we just pool the data from the three trials, which has been done by other groups and with other devices, the result is a hazard ratio for mortality that is essentially 1.0," said Ouriel. "When adjusted by propensity scoring, the hazard ratio increases a little bit, but not much, to 1.16."

A total of 173 deaths occurred in LEVANT 1 and LEVANT 2, including the Continued Access patients. Of those, 151 were in the DCB group (14.0%) and 22 in the PTA group (10.4%). However, none were related to the use of paclitaxel.

"Regardless of how you look at it, if there was an increased mortality, the signal should increase," he said. "It should get worse as more data are combined. In fact, it's the opposite — with more data, the mortality signal vanished."

When looking at serious adverse events (SAEs) and nonserious causes of death, no clustering was observed and the proportion of events was balanced between the two groups. There were a total of 530 SAEs in the 316 DCB patients (1.7/patient) and 284 in the 160 PTA patients, and SAEs of any type occurred in 30.4% of DCB patients and 27.5% of PTA patients (P = .525).

Ouriel noted that they also looked at dose–response to assess whether there was any causation, "and most of the variables predictive of death are what you'd expect, most notably age."

Speaking in the press conference, Roxana Mehran, MD, a professor of medicine at the Icahn School of Medicine at Mount Sinai, New York City, commented that "we have to be open and honest" about the fact that clinical trials in peripheral vascular disease have not been as careful as they could be about follow-up, "and now we have to backtrack to figure out what the signal actually means. That's an important lesson that we learned."

She added that "as I understood it," the conclusion of the FDA panel in June was that it's still inconclusive about the relation with paclitaxel and they are not yet convinced that there's not an issue there.

Ouriel agreed that the jury is still out. "I think the FDA is kind of at an impasse. No one has come up with a mechanism, so what can you say?" he said. "The FDA's third letter is better than number 1 and number 2, but we're not there yet."

The study was sponsored by BD Peripheral Interventions. Ouriel is an employee of and holds equity in Syntactx, which receive fees from Bard. Several of the coauthors have disclosed relationships with industry, as noted in the paper.

JACC Cardiovasc Interv. Published online September 28, 2019. Full text

Transcatheter Cardiovascular Therapeutics (TCT) 2019: LBA Levant. Presented September 28, 2019.

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