SAFE-PAD Throws More Doubt on the Paclitaxel Mortality Signal

A study conducted in conjunction with the US Food and Drug Administration to provide ongoing evaluation of paclitaxel-based devices for the treatment of PAD is the latest to find no increased risk of death compared with non-drug-coated devices.

“We're really demonstrating again that the original safety signal seems to be more of a signal than a real causal relationship,” Eric Secemsky, MD (Beth Israel Deaconess Medical Center, Boston, MA), told TCTMD. Mortality at a median of 2.7 years of follow-up, the primary endpoint, was 53.8% for PAD patients treated with drug-coated devices and 55.1% for those treated with non-drug-coated devices (noninferiority P < 0.001).

Secemsky presented the SAFE-PAD results today during the virtual American College of Cardiology (ACC) 2021 Scientific Session, and they were simultaneously published online in JAMA Internal Medicine.

The concern about a possible mortality signal first arose in late 2018 with publication of a meta-analysis of RCTs led by Konstantinos Katsanos, MD, PhD (Patras University Hospital, Rion, Greece). It found a late mortality increase beginning at 2 to 3 years postprocedure in patients treated with paclitaxel-based DES or drug-coated balloon (DCB) compared with a plain balloon or plain stent. In the US, the FDA has issued three letters to healthcare providers, held a 2-day Circulatory System Devices panel meeting on the topic, and limited use of paclitaxel peripheral devices to those at highest risk for restenosis and repeat femoropopliteal interventions.

SAFE-PAD was designed with input from the FDA after their own subsequent internal analyses of data from the original meta-analysis could not refute the mortality signal. It included 168,553 Medicare fee-for-service patients treated at 2,978 inpatient and outpatient facilities in the US from 2015 through 2018 and involved multiple prespecified subgroups and sensitivity analyses.

“At end of the day, every which way we looked at the data, we continued to find that there is no difference in survival between drug-coated devices and non-drug-coated devices used during peripheral vascular interventions,” Secemsky said.

New Thoughts on PAD Mortality

The SAFE-PAD researchers performed Cox regression and instrumental variable analyses, which also were consistent with the primary findings. Similarly, the subgroup analyses found no increased harm compared with non-drug-coated device. In fact, those analyses favored the drug-coated devices in eight subgroups including patients treated with drug-coated stents (HR 0.97; 95% CI 0.95-1.00) or balloons (HR 0.94; 95% CI 0.92-0.96), those with critical limb ischemia (CLI; HR 0.95; 95% CI 0.93-0.97), those without CLI (HR 0.97; 95% CI 0.95-0.99), and those within the lowest quartile of total comorbidities (HR 0.95; 95% CI 0.92-0.99).

Secemsky and colleagues say the findings of SAFE-PAD align with those of SWEDEPAD, which found no significant difference in all-cause death in paclitaxel-treated versus uncoated device-treated patients at a mean follow-up of 2.5 years in patients with CLI (HR 1.04; 95% CI 0.90-1.21) or intermittent claudication (HR 1.18; 95% CI 0.72-1.93).

In an editorial accompanying the study, Rita F. Redberg, MD (University of California, San Francisco), and Mary M. McDermott, MD (Northwestern University Feinberg School of Medicine, Chicago), caution that beyond the discussion of mortality as it relates to paclitaxel, the study “raises a new and important question” about the greater than 50% mortality rates at long-term follow-up, whether endovascular revascularization involved a drug or not.

At end of the day, every which way we looked at the data, we continued to find that there is no difference in survival between drug-coated devices and non-drug-coated devices. Eric Secemsky

Noting that PAD patients are at greater risk of death from CV events, cancer, and infection than those without PAD, Redberg and McDermott say peripheral interventions do not address any of these causes of death. “Physicians should continue to focus on conservative treatment, including smoking cessation and exercise therapy for improving quality of life, in patients with PAD,” they write.

“This is a real-world population, so they are not always the patients that make it into clinical trials, but these are the patients we treat,” Secemsky countered. “Just because prognosis is poor doesn't mean that these procedures don't add other benefits, including improvements in quality of life, whether that's reducing the amount of time spent in hospitals, reducing minor amputations that might be disabling, or improving walking distance.”

A Hope of Loosened Restrictions

After SWEDEPAD was published late last year, FDA scientists made a rare public comment in a perspective, published in the New England Journal of Medicine, noting the study’s importance and calling its data “comforting.” Yet the piece also points out that fewer than 300 of the SWEDEPAD patients have been followed to 4 years.

Asked what his expectation is from the FDA given the SWEDEPAD and now the SAFE-PAD results both show no hint of the mortality signal, Secemsky noted that this is only the first report to emerge from SAFE-PAD, with at least seven more to go as the patients move through 5 years of follow-up.

“That doesn't mean that the FDA can't revisit their stance on these devices before the final result of the analysis,” he said. “I don't know if they will go to the degree of saying that these devices are 100% safe, but our hope is that they can remove some of the restrictions, particularly the restrictions that say to refrain from using this unless patients are a particular high risk for restenosis. I think we'd all like to see that wording removed, and also [see] a little bit more liberalization of use so that providers don't feel medically liable if they use these devices for their patients, because that's really been what's kept them from being used at the level of the pre-Katsanos era.”