In CAD, No Long-term Safety Signal for Paclitaxel DCBs: Meta-analysis

Despite recent concerns over a signal of late deaths seen with paclitaxel-based devices in patients treated for PAD, a large meta-analysis of long-term outcomes with paclitaxel-coated balloons in patients with either coronary in-stent restenosis or de novo lesions shows no increase in mortality.

At 3-year follow-up, risk of both all-cause and cardiac mortality was significantly lower in those treated with the drug-coated balloons (DCBs) compared with controls. Although DCBs are not currently approved in the United States for use in the coronary vasculature, multiple RCTs in Europe have investigated their use and 26 of those studies formed the basis of the meta-analysis. The recent concerns about paclitaxel stem from a meta-analysis published in 2018 that identified an increased risk of death with paclitaxel-based balloons and stents in PAD patients beyond 2 years.

“It's good to have some reassuring data to show that in the coronary arteries, at least in this population of mainly in-stent restenosis or small-vessel disease, that there is no signal of excess mortality with these drug-coated balloons,” said Bimmer E. Claessen, MD, PhD (Icahn School of Medicine at Mount Sinai, New York, NY), who was not involved in the meta-analysis. Claessen was an investigator on the DARE trial, one of the studies included in the meta-analysis published last week in the Journal of the American College of Cardiology.

Led by Bruno Scheller, MD (Saarland University, Homburg/Saar, Germany), the meta-analysis included RCTs that were published between 2006 and 2019. Of these, 14 involved treatment of in-stent restenosis, while the other 12 involved treatment of de novo lesions. The most frequently used paclitaxel DCB was the iopromide-coated SeQuent Please, or its successor SeQuent Please Neo (B. Braun, Berlin, Germany). Comparators ranged from conventional uncoated plain old balloon angioplasty and scoring balloons to BMS or DES. When stents were used, the most common among them were everolimus-eluting, followed by paclitaxel-, sirolimus-, and zotarolimus-eluting stents.

Among the 4,590 total patients, mortality rates were similar at 6- to 12-month follow-up between the DCB and non-DCB groups (P = 0.116), as well as at 2 years (P = 0.478). However, at 3 years of follow-up the risk of all-cause mortality was lower in the DCB group compared with controls (RR 0.73; 95% CI 0.53-1.00), with a number-needed-to-treat of 36 to prevent one death.

“One may speculate that this is related to a significant reduction in the number and length of permanent implants, which should lead to a reduction in stent-associated short- and long-term events,” Scheller and colleagues write.

Similarly, the risk of cardiac death was lower as well (RR 0.53; 95% CI 0.33-0.85), with the late mortality benefits driven primarily by the de novo trials. Across all time points, rates of TLR were similar between DCB and non-DCB patients. The risk of MI, however, was lower in the DCB at 1 year, but not at years 2 or 3. In a subgroup analysis that compared only paclitaxel DCBs and non-DCBs, cardiac mortality remained significantly lower at 3 years for DCB treatment.

Limitations and Opportunity for Innovation

In an accompanying editorial, Fernando Alfonso, MD, PhD (Universitario de La Princesa, Madrid, Spain), Fernando Rivero, MD (Universitario de La Princesa), and Juan F. Granada, MD (Cardiovascular Research Foundation and Columbia University Irving Medical Center, New York, NY), write that these results “complement the available clinical evidence, stemming from multiple RCTs including surrogate angiographic endpoints, demonstrating the antirestenosis efficacy of PCBs in patients with coronary [in-stent restenosis] and de novo lesions.”

However, both Alfonso et al and Claessen point out methodological issues that prevent broad interpretation.

“One of the limitations of the current study that it’s a very selected population of mostly patients with in-stent restenosis,” Claessen noted. “At 3-year follow up only about one-third of patients remain, which again makes it more of a selected group.”

Likewise, the editorialists point out that a patient-level meta-analysis, which became a crucial part of investigating the mysterious mortality signal in PAD patients, “could have provided additional granularity and perhaps novel insights on factors affecting both the safety and efficacy of [paclitaxel-coated balloons].” They also note that the new report excluded RCTs in which DCBs were used in hybrid strategies in combination with DES or BMS.

Another issue, said Claessen, is the mixed bag of comparator devices, which complicates the interpretation of DCB’s impact. Nonetheless, he said, the paclitaxel controversy in PAD has implications for coronary DCB therapy in the sense that it may be the catalyst needed to spur innovation.

“We've been using paclitaxel because that's the drug that seems the most suitable for this indication,” he observed. “Recently, though, there has been interest in a sirolimus-eluting balloon . . . and if more research and effort is put into that, hopefully one will become commercially available sooner.”

The paclitaxel uproar has also prompted investigators of coronary paclitaxel device trials like the ones in the current meta-analysis to obtain longer follow-up than they had planned in order to look closely at mortality, Claessen added.

“For DARE, we originally planned on 1-year data, but we are collecting data to 5 years now,” he said. “It’s a good thing that has come out of all this and will bring more answers to hopefully address some of the questions that have been raised about paclitaxel.”

Note: Juan F. Granada, MD, a co-author of the editorial, is CEO of the Cardiovascular Research Foundation, the publisher of TCTMD.