Renewed Questions About Safety of Paclitaxel Devices in PAD: SWEDEPAD

Drug-coated balloons (DCB) and stents may not reduce the risk of needing a major amputation compared with uncoated devices in patients with chronic limb-threatening ischemia (CLTI) nor improve quality of life (QoL) or survival in those with intermittent claudication, suggest the SWEDEPAD 1 and 2 national registry trials.

The number of major amputations for CLTI patients treated with any drug-coated device was nearly identical at both 1 year and 5 years compared with those who received uncoated devices in SWEDEPAD 1. While the drug-coated device group had a lower incidence of target vessel revascularization in the first year than the uncoated group (HR 0.81; 95% CI 0.66-0.98), the difference dissipated with longer follow-up.

In SWEDEPAD 2, which involved the intermittent claudication population, there was no difference at 1 year in the primary endpoint of disease-specific QoL as measured with the VascuQoL-6 questionnaire. Unlike in the CLTI population, there was no difference in rates of TVR between those treated with or without a drug-coated device at any other time point and no difference in all-cause mortality at 10 years of follow-up.

“Interestingly, and a bit surprisingly, all-cause mortality did not differ throughout the entire follow-up period, [but] the prespecified 5-year mortality incidence was higher in patients randomized to drug-coated devices, with a hazard ratio of 1.47,” noted co-principal investigator Mårten Falkenberg, MD, PhD (University of Gothenburg, Sweden), in a press conference this week at the European Society of Cardiology Congress 2025.

SWEDEPAD 1 and 2, which were simultaneously published in the Lancet, were among several peripheral vascular disease trials that halted enrollment in 2018 following the publication of a summary-level meta-analysis that suggested a late mortality signal in patients with PAD who were treated with a paclitaxel-based DES or DCB compared with an uncoated device.

But by the end of 2020, the SWEDEPAD investigators conducted an interim analysis and found no significant difference in all-cause death in paclitaxel-treated versus uncoated device-treated patients in either SWEDEPAD 1 or SWEDEPAD 2 at a mean follow-up of 2.5 years. They then resumed enrollment in both arms even as the peripheral vascular community and regulators struggled to make sense of the mortality signal in the original meta-analysis.

Since that time, there’s a been cannon of data published, including a patient-level, pooled meta-analysis and a 5-year follow-up study of more than 32,000 patients, which led the US Food and Drug Administration to reverse all restrictions on the use of paclitaxel-based devices for PAD by 2023.

So, what does SWEDEPAD add to the paclitaxel story? According to Falkenberg, 99% of the devices used in the trial—all at the discretion of the participating operators—were paclitaxel-based. At 5 years, 104 patients with intermittent claudication had died after treatment with a DES or DCB and 77 had died after treatment with an uncoated device (P = 0.010).

“If you do the math, the all-cause incidence was 4.57 deaths per 100 person-years in the drug-coated group, whereas it was 3.28 per 100 person-years in the uncoated group,” the study’s other co-principal investigator, Joakim Nordanstig, MD, PhD (University of Gothenburg), said in the press conference. That math yields the HR of 1.47. But looking at that same math at 10 years, the event rates for all-cause death were 5.01 versus 4.61 per 100 person-years (HR 1.18; 05% CI 0·94-1.48).

Are patients getting reinterventions also getting more follow-up visits, more office visits, [and] perhaps more aggressive care? Marianne Brodmann

Discussant Marianne Brodmann (Medical University of Graz, Austria), challenged the findings, noting there are several limitations given the nature of registry studies. For example, the trial allowed any CE Mark-approved DCB or DES, but there is no way of knowing if best-in-class paclitaxel-based devices were used given that the studies do not contain a detailed list of specific products.

Additionally, she stressed the importance of ascertaining completeness of the follow-up, noting that in the aftermath of the meta-analysis that suggested a mortality signal, follow-up data from some of the included RCTs were found to be missing or “inadvertently omitted.” As data reconciliation occurred, the original mortality signal slowly deflated.

Regarding the lack of difference in amputation-free survival with coated and uncoated devices, Brodmann said this outcome “can be influenced [by] so many things,” and even the FDA has questioned whether it is an adequate endpoint in CLTI.

Additionally, more information is needed about the TVRs, specifically how patients were treated and whether the same or different devices were used for additional procedures.

“Are patients getting reinterventions also getting more follow-up visits, more office visits, [and] perhaps more aggressive care?” she said, noting that the mortality signal “has been present in smaller [studies] where there was less follow-up.”

Lastly, Brodmann questioned the absence of the mortality signal in the larger SWEDEPAD 1 trial, which included an older and sicker population than did SWEDEPAD 2.

Still an Ongoing Discussion

SWEDEPAD 1 enrolled 2,400 patients with Rutherford stage 4 to 6 CLTI (median age 77 years; 44% female). Of those, 1,206 were randomized to treatment with a DES or DCB and 1,194 to an uncoated device. In addition to the lack of difference in QoL between the treatment groups, there also was no difference in the percentage of those who had an improvement in Rutherford category at follow-up.

SWEDEPAD 2 enrolled 1,155 patients with intermittent claudication (median age 73 years; 46.1% female). Of those, 577 were randomly assigned to a DES or DCB and 578 to an uncoated device. In addition to the lack of difference in TVR, there was no difference in the total number of ipsilateral reinterventions during the follow-up period. A per-protocol analysis confirmed the higher rate of all-cause mortality at 5 years in the paclitaxel-treated group.

In the press conference, Nordanstig said the paclitaxel mortality signal is “still an ongoing discussion,” and something that is “hard to ignore.”

In an editorial accompanying the studies in Lancet, Konstantinos Katsanos, MD, PhD (Patras University Hospital, Rion, Greece), who authored the meta-analysis that first raised the mortality signal, says these results might be a catalyst to reevaluate current clinical practices in PAD.

“The SWEDEPAD findings not only challenge the presumed benefits of paclitaxel-coated devices but also reestablish the mortality signal in low-risk claudicant patients—a scenario in which potential harm clearly outweighs any conceivable benefit, rendering their routine use difficult to defend,” he writes. “It is unknown whether this signal represents a class effect incriminating all paclitaxel-coated devices.”

At this point, it’s not clear to me that these data are consistent with a mortality signal. Sahil Parikh

Sahil Parikh, MD (NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY), who led the patient-level meta-analysis that helped convince the FDA to reverse the paclitaxel restrictions, told TCTMD that the deaths of the SWEDEPAD patients could hold important answers and suggested that a patient-level analysis should be done.

“There’s no plausible mechanism, and we don’t even know the cause of death of the patients,” he said. “The studies were ongoing during the COVID-19 pandemic, so that is a potential confounder. We also would want to know what percentage of these deaths were cardiovascular. How many were due to cancer in this older population? How old were they? What were the lesion lengths? We also don’t know anything about laterality of treatment or crossovers.

“At this point, it’s not clear to me that these data are consistent with a mortality signal,” Parikh commented.

Falkenberg and colleagues say they are planning to explore whether causes of death differ between patients with claudication and those with CLTI. They also say they cannot rule out whether the use of a variety of excipients and doses could have impacted the outcomes differently than if only certain devices had been permitted.

“Another potential confounder is the duration of balloon inflation, which was specified in the instructions for use for drug-coated balloons but not for uncoated balloons, which could have led to differences in procedural technique between groups,” they write.