ILLUMENATE EU: No Higher Paclitaxel-Related Deaths as Talk Turns to Patency

ILLUMENATE EU is the latest RCT to provide long-term data that confirm no excess deaths among PAD patients treated with paclitaxel drug-coated balloons (DCBs) versus percutaneous transluminal angioplasty (PTA). 

“All-cause mortality, an important highlighted issue these days, was not found to be different between the two groups at 4 years, nor was cardiovascular mortality,” said William A. Gray, MD (Main Line Health/Lankenau Heart Institute, Wynnewood, PA). Gray presented the results in a late-breaking trial livestream hosted last week by VIVA Physicians.

The findings are the latest in a large-scale effort by trialists, industry, and regulatory authorities to investigate reports of a mortality signal associated with paclitaxel therapy for PAD that was first suggested in a meta-analysis published in late 2018.

“One of the things that it shows us is that we're not seeing a consistent mortality signal across all the different studies,” noted Gary M. Ansel, MD (OhioHealth, Columbus), a panelist for the livestream.

For the ILLUMENATE EU trial, 294 patients at 18 European sites were enrolled between 2012 and 2015. Patients with symptomatic femoropopliteal disease were randomized to the DCB (Stellarex; Philips) or uncoated PTA. At 4 years, there were 151 patients available for follow-up in the DCB group and 51 in the PTA group. More than one-third of patients in each arm were diabetic and 20% in each arm had chronic total occlusions.

For the composite safety endpoint of freedom from device and procedure-related death through 30 days and freedom from target limb major amputation and clinically driven TLR through 48 months, there was no statistically significant difference between the DCB and PTA arms (66.3% vs 62.5%; P = 0.609).

Similarly, there were no differences in the individual endpoints of safety and efficacy.

Key Endpoints at 4-Year Follow-up

As Gray showed, the follow-up included confirmed vital status for approximately 94% of all trial participants at 4 years. Cumulative mortality rates parsed by 12 months, 24 months, 36 months, and 48 months show no difference between treatment groups. As of March 2020, the cumulative mortality rates were 17.7% in the DCB arm and 14.1% in the PTA arm (P = 0.494). Those results are in line with the 4-year mortality data from the US sister trial, ILLUMENATE Pivotal, which were presented earlier this year at LINC 2020. In that trial, mortality at 4 years was 15.6% in the DCB arm and 15.2% in the PTA arm (P = 0.929). Combined, the trials included nearly 600 patients.

Patency Signals

Noting that the 3-year data from ILLUMENATE EU indicated that more DCB patients than PTA patients had maintained patency, Ansel asked if similar data are available for the 4-year follow-up. While Gray said he did not have the exact numbers, he confirmed that there is a delay in repeat revascularization in the DCB group at the later time point.

Sean P. Lyden, MD (Cleveland Clinic, OH), who moderated the livestream, questioned how the FDA will integrate the updated RCT data from ILLUMENATE EU and other recently recovered patient-level paclitaxel information into their ongoing evaluation of the mortality signal.

The agency’s Misti Malone, PhD (US Food and Drug Administration, Silver Spring, MD), said, “When we reevaluate this data, one thing we’re interested in is weighing mortality with benefit . . . as more data becomes available. We don’t want to reevaluate the signal over and over and over.”

Malone also stated that the agency would be interested in exploring the value of a time-to-event analysis that could potentially support the concept that paclitaxel DCB therapy is associated with a delay in repeat revascularization in some of the studies that have recovered lost data sufficiently enough to have robust patient-level long-term follow-up.

Longer-Term Advantages?

Another interesting sign that there could be a long-term advantage to paclitaxel comes from a recent paper published online last week in JACC: Cardiovascular Interventions. Researchers led by Tanja Böhme, MD (Universitäts-Herzzentrum Freiburg-Bad Krozingen, Germany), evaluated all-cause mortality in 1,579 patients treated with a paclitaxel-based DCB or PTA for a mean of 52 months. They found a mortality rate of 16.9% in the paclitaxel group and 27.8% in the control group (P < 0.001). When patients older than 80 years were excluded, the difference in mortality was even more striking: 23.6% for PTA versus 12.3% for paclitaxel (P  < 0.001). Additionally, multivariable analysis after propensity score matching showed that treatment with PTA, but not paclitaxel, was among the independent predictors of mortality.

Böhme and colleagues say all-comers RCTs will be needed to confirm the long-term survival benefit they demonstrate with paclitaxel and to pinpoint what, if anything, could be responsible for it. They suggest one potential explanation could be “a mobility benefit resulting in a positive risk profile modification as a result of a patent vessel.”

But in an editorial, Krishna J. Rocha-Singh, MD (Prairie Heart Institute at St. John’s Hospital, Springfield, IL), says the authors show no proof to support that theory, and cautions others to be wary about drawing strong conclusions based on the single-center study.

In addition to outlining multiple critiques of the methodology, Rocha-Singh notes that “the inability of the investigators to define the cause of death in nearly half of the cases detracts from any inference of a potential mortality benefit of DCB use.”