IN.PACT BTK Provides Renewed Hope for Attacking CLI With DCBs

Endovascular sessions took over the “Main Arena” channel on the final day of TCT Connect 2020, with promising short-term data from a dedicated below-the-knee drug-coated balloon (DCB), and longer-term looks at mortality in patients treated with paclitaxel-based devices in the VOYAGER PAD trial and the ILLUMENATE global study.

Outcome data on treating below-the-knee lesions with DCBs are scarce, with the largest and longest dataset being from IN.PACT DEEP, in which patients were randomized to the paclitaxel-coated IN.PACT Amphirion DCB (Medtronic) or percutaneous transluminal angioplasty (PTA). The device was withdrawn from the market after it failed to show superiority in IN.PACT Deep. The IN.PACT BTK study, reported here by lead investigator Antonio Micari, MD (Maria Eleonora Hospital, Messina, Italy), looked at safety and efficacy of a different DCB, the IN.PACT 014 containing a paclitaxel dose density of 3.5 μg/mm2, in 50 critical limb ischemia (CLI) patients.

Reporting 9-month data from IN.PACT BTK, Micari showed that compared with PTA, the DCB was associated with similar rates of all-cause death, and a numerically lower rate of late lumen loss, the primary effectiveness endpoint, in the DCB arm (0.89 ± 0.77 mm vs 1.31 ± 0.72 mm; P = 0.070). There were no major target limb amputations in either group.

Calling the results “a step in the right direction,” Micari also showed that the safety composite endpoint (freedom from device- and procedure-related mortality within 30 days, freedom from major target limb amputation, and freedom from clinically-driven target lesion revascularization within 9 months post-index procedure) was met in 91.3% of the DCB arm and 87.5% of the PTA arm (P = 1.00). Rates of all-cause death were not significantly different, occurring in 4.3% of the DCB group and 8.0% of the PTA group (P = 1.00). Similarly, thrombosis at the target lesion site was seen in 4.3% of the DCB group and 4.2% of the PTA group (P = 1.00).

Hopes Run High for BTK

The study also included sub-segmental angiographic measurements. Essentially, segmental measurements were obtained along the entire lesion length, rather than at a single point in the lesion. Again, there was less late lumen loss with the DCB arm compared with PTA (0.592 ± 0.944 mm vs 1.260 ± 0.810 mm; P = 0.017).

Extrapolating what the implication of the difference in late lumen loss actually means in terms of the therapy making a difference for patients is difficult, however.

“We showed that with this very small population that something is different between PTA and DCB, but we need more,” Micari told TCTMD. “We will see hopefully in larger trials if this has an indication [for use] in clinical therapy.”

We've been working on it for so long, but it feels imminent to me, and this looks very promising. Peter Schneider

“Ultimately, no one is going to use a device because of the presence or absence of a better late lumen loss,” observed Peter Schneider, MD (University of California, San Francisco), in a press conference prior to Micari’s presentation. “To me, both of these numbers, the classic late lumen loss and the subsegmental lumen loss are saying that there was an effect of medication, at least that's my interpretation.”

Schneider also pointed out several important facets of the study. “One is that every patient had a CTO. Another is that the mean lesion length was over 20 centimeters. So, this is real world stuff,” he said.

Additionally, Schneider noted that the subsegmental lumen loss analysis is a way of gaining more clarity in longer lesions lengths, and further pointed out that the investigators used functional duplex ultrasound assessment on the table at the conclusion of each procedure to ensure that the PTA group “was not given short shrift,” and thus had optimization of balloon angioplasty.  

“[T]his is really another indication that, in fact, the potential for biologic therapy in the BTK arteries is something that feels like it's right around the corner. We've been working on it for so long, but it feels imminent to me, and this looks very promising,” Schneider said.

Similarly, Robert Lookstein, MD (Icahn School of Medicine at Mount Sinai, New York, NY), called the IN.PACT BTK data a “valuable contribution to the literature” and “a step in the right direction” following three prospective randomized trials of DCBs in the below-knee circulation that failed to meet their primary efficacy endpoints.

However, Lookstein expressed concern that subsegment late lumen loss may not be an appropriate endpoint for a Rutherford 5 cohort, saying “we really, really do need to dive into the actual clinical impact on the patient in order to determine whether or not we should be using [a BTK DCB] on a routine basis.” He added that questions surrounding safety and efficacy remain to be answered, especially in the context of very ill CLI patients with active wounds.

VOYAGER PAD

Connie Hess, MD (University of Colorado School of Medicine, Aurora), presented 3-year mortality data from VOYAGER PAD, which randomized 6,564 PAD patients to rivaroxaban 2.5 mg twice daily or placebo. All were symptomatic and had undergone a limb revascularization in the previous 10 days. The new analysis focused on the 4,379 patients who had endovascular lower extremity revascularization. Of those 1,342 were treated with a drug-coated device and 2,974 with a non-drug-coated device.

“We found no mortality risk or benefit associated with drug-coated device use,” Hess said in her presentation. “And we also demonstrated that the effect of rivaroxaban on reducing ischemic limb and cardiovascular outcomes is consistent regardless of drug-coated device use.”

Hess said the VOYAGER PAD analysis addresses some limitations of currently available data on mortality related to treatment with paclitaxel-based devices in PAD. The mortality issue has been an ongoing concern since it was first raised in a 2018 meta-analysis.

As Hess showed, in an unweighted analysis, patients who received a drug-coated device had lower mortality at 3.5 years compared with those receiving a non-drug-coated device (2.9 vs 3.9 per 100 patient-years), but after weighting there was no longer any association between drug-coated device use and death (HR 0.95; 95% CI 0.83-1.09).

I think it really starts to raise the question of whether it's time to shut the door on the paclitaxel controversy. Robert Lookstein

Commenting on the findings, Lookstein said that fact that the study has 99.6% mortality ascertainment at 3.5 years is an important milestone.

“I think it really starts to raise the question of whether it's time to shut the door on the paclitaxel controversy,” he added.

Hess did not provide data on mortality breakdown by device or paclitaxel dosage, but said the VOYAGER PAD investigators have the ability to look into the issue further, although she noted paclitaxel dose analyses are “tricky” and must incorporate certain assumptions, which may not be accurate, about the steady state of drug in tissue.

ILLUMENATE Global Study

Finally, new data from the ILLUMENATE Global study, presented at TCT Connect 2020 by Andrew Holden, MBChB (Auckland City Hospital, New Zealand), showed that the primary endpoint of freedom from clinically driven TLR was 75.6%, with only three instances of major target limb amputation among the 371 patients evaluated through 48 months, with no differences between a variety of subgroups. All-cause mortality was 8.1%.

ILLUMENATE Global is a single-arm, multi-center study being conducting at 37 European centers to examine outcomes with the Stellarex low dose paclitaxel-coated DCB (Philips) in PAD patients with Rutherford class 2-5. Patients in the study are being followed to 5 years.

Commenting on the results, Schneider said the 8.1% mortality rate was “strikingly low” considering the number of patients with high Rutherford scores, adding he would have expected to see 10% to 20% mortality at 4 years.

Marianne Brodmann, MD (Medical University of Graz, Austria), who presented the data during a press conference yesterday, did not present 4-year primary patency data for the cohort, telling TCTMD that follow-up to date has only been by phone.