Five-Year Paclitaxel DCB Data Attest to Long-term Safety, Efficacy

Freedom from reintervention is maintained out to 5 years in the large majority of patients with PAD treated with a paclitaxel-based drug-coated balloon (DCB), with no evidence of unexplained increases in deaths over time, extended follow-up from the IN.PACT Global Study suggests.

“These long-term results from this large, international, real-world study add to the growing body of  evidence that demonstrates the safety, effectiveness, consistency, and durability of the IN.PACT Admiral DCB for the treatment of femoropopliteal lesions,” write researchers led by Thomas Zeller, MD, PhD (Universitäts-Herzzentrum Freiburg-Bad Krozingen, Germany).

The rate of freedom from clinically driven TLR up to 5 years, the primary effectiveness endpoint, was 69.4% (95% CI 66.7%-72.0%), and the average time to first clinically driven TLR was 1,470.1 days, or just about 4 years from DCB intervention.

“I think this paper highlights that we can take care of these patients and provide them with great clinical outcomes,” commented Sahil Parikh, MD (NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY). “I know 70% freedom from TLR at 5 years doesn't sound like a lot to the coronary operator, but for a PAD patient population, that's pretty good.”

As Zeller previously reported, freedom from clinically driven TLR in this cohort was 73.4% at 4 years, down from 76.9% at 3 years.

Long-term data on endovascular therapies for PAD are scarce since most of the pivotal trials focused on safety and short-term patency outcomes. But they have become a topic of discussion in recent years due to a suspected mortality signal that first arose in late 2018 with publication of a meta-analysis of RCTs. Led by Konstantinos Katsanos, MD, PhD (Patras University Hospital, Rion, Greece), the meta-analysis showed a late mortality increase beginning 2 to 3 years after the procedure in patients treated with paclitaxel-based DES or DCB versus a plain balloon or plain stent. In the US, the Food and Drug Administration has issued three letters to healthcare providers and limited use of paclitaxel peripheral devices to those at highest risk for restenosis and repeat femoropopliteal interventions. The agency also has said there is a need for long-term mortality data out to 5 years or longer, along with reconciliation of data that were missing from the studies in the meta-analysis. The IN.PACT Global study is one of the first large paclitaxel DCB investigations to report its 5-year data.

Deaths in Context

The single-arm IN.PACT Global Study enrolled 1,535 patients (mean age 68.6; 67.8% male) from 64 international sites. The 5-year analysis, published online May 30, 2022, in EuroIntervention, includes 1,406 patients who were treated with the IN.PACT Admiral DCB (Medtronic), including many with complex lesions (18% of patients had in-stent restenosis) and known risk factors that contribute to disease progression, which would have kept them out of RCTs. Over the study, 253 patients died, 186 withdrew or exited the study, 21 were lost to follow-up, and 28 did not have completed follow-up.

The rate of major adverse events was 45.9%, which included a 31.9% incidence of clinically driven TLR and a 19.5% rate of all-cause death. Major target limb amputation occurred in < 2% and arterial thrombosis in 5.7%. In-stent restenosis, moderate-to-severe target lesion calcification, longer lesion length, and higher postprocedure residual diameter restenosis were all associated with greater risk of clinically driven TLR in multivariable analysis. The study also included a gender analysis, which showed no difference in the primary effectiveness outcome at 5 years between men and women (log-rank P = 0.602).

“If there's been any sort of message, it's that there needs to be longitudinal care of these patients, because they're extremely high risk from a cardiovascular standpoint and they need long-term management.” Sahil Parikh

Prior reports from the IN.PACT Global investigators have addressed the deaths that occurred up to year 3. Ninety-seven additional deaths were reported between 3 and 5 years. Of those, one was classified as device-related and was attributed to limb infection and sepsis. Based on vital status information for 96.4% of the participants, the 5-year rate of freedom from all-cause death was 78.9%.

According to Zeller and colleagues, the 5-year mortality rates need to be considered in the context of other reports from PAD studies. They can vary widely, at greater than 50% in PAD patients over age 75 with diabetes as well as in those with severe limb ischemia. On the other hand, some studies have put the lowest 5-year mortality rates at around 25% in claudicants undergoing endovascular interventions, which is higher than the 19.5% seen in IN.PACT Global.

Team Care Needed

To TCTMD, Parikh said while much of the focus since the publication of the meta-analysis has been on understanding or disproving the mortality signal, the importance of the long-term efficacy of the DCB treatment is what matters to most patients.

“When all of this first happened, our patients wanted to know what this meant for them. What it means is that 70% of the time you will not need another procedure for at least 5 years,” he noted. “COVID really changed the calculus in this respect because patients are really happy to not have to ever come back. In my conversations with patients, [the paclitaxel risk] is a complete nonissue.”

Just as importantly, he added, is the shift in perspective that has come from the paclitaxel debacle regarding what happens to patients after they have a peripheral intervention.

“If there's been any sort of message, it's that there needs to be longitudinal care of these patients, because they're extremely high risk from a cardiovascular standpoint and they need long-term management,” Parikh said. “More practically speaking, it takes a team [that should include] proceduralists and revascularization docs, plus primary care . . . and subspecialists who provide adjunctive care as needed.”