In FDA-designed cohort study, mortality risk not related to paclitaxel-coated devices
In the SAFE-PAD cohort study of patients with peripheral artery disease designed in part by the FDA, there was no difference in mortality between those treated with paclitaxel-coated devices and those treated with uncoated devices.
The results of SAFE-PAD, a retrospective cohort study designed after feedback from the FDA, were presented by Eric A. Secemsky, MD, MSc, RPVI, FACC, FSCAI, FSVM, director of vascular intervention at Beth Israel Deaconess Medical Center, director of vascular research at the Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology and assistant professor of medicine at Harvard Medical School, at the American College of Cardiology Scientific Session and simultaneously published in JAMA Internal Medicine.
As Healio previously reported, concern about long-term mortality risk posed by paclitaxel-coated devices used in patients with PAD began after a summary-level meta-analysis of randomized controlled trials was published in December 2018. The FDA held a panel meeting on the issue and decided to allow the devices to remain on the market if manufacturers revised their labeling, but recommended they only be used in patients at very high risk for restenosis.
Secemsky said during a presentation that the analyses showing mortality signals associated with paclitaxel-coated devices produced “no clear cause” for elevated mortality in the paclitaxel group, and long-term data were missing for a lot of patients.
“The question came up of conducting a randomized controlled trial on the safety of paclitaxel-coated devices, but from the FDA’s own analyses, this would be nearly prohibitive, as it would require more than 40,000 patients in a 3-year study powered for mortality, and more than 20,000 patients for 5 years of follow-up,” he said. “So, we were engaged with the FDA to design a real-world study to make a regulatory decision about paclitaxel-coated device safety using a Medicare data set.”
The analysis included 168,553 patients (mean age, 77 years; 45% women; 45.7% with critical limb ischemia; 7.9% with prior amputation) who underwent femoropopliteal endovascular treatment from 2015 to 2018, of whom 41.9% were treated with a drug-coated device and the rest were treated with an uncoated device. Median follow-up was 2.72 years. The primary analysis was performed with inverse probability of treatment weighting.
During the study period, 53.8% of patients in the drug-coated group died compared with 55.1% of those in the uncoated group (HR = 0.95; 95% CI, 0.94-0.97; P for noninferiority < .001), according to the researchers. Cox regression and instrumental variable analyses did not change the results.
There was no elevated mortality risk from paclitaxel-coated devices in patients treated with stents (HR = 0.97; 95% CI, 0.95-1), patients treated with balloons (HR = 0.94; 95% CI, 0.92-0.96), patients with CLI (HR = 0.95; 95% CI, 0.93-0.97), patients without CLI (HR = 0.97; 95% CI, 0.95-0.99) and patients in the lowest quartile of total comorbidities (HR = 0.95; 95% CI, 0.92-0.99), the researchers found.
“Looking at the general landscape of data available, we know that meta-analyses of prior pivotal randomized trial data have shown similar risk estimates, but none of this has been replicated in independent randomized trial data or observational data,” Secemsky said during the presentation. “It’s time for us to revisit this question [of mortality risk]. These are critically important devices that have reduced the need for repeat procedures in patients who have a lot of comorbid diseases. We are awaiting further guidance from the FDA.”
In a related editorial in JAMA Internal Medicine, Cardiology Today Editorial Board Member Rita F. Redberg, MD, MSc, professor of medicine at the University of California, San Francisco, and editor of JAMA Internal Medicine, and Mary M. McDermott, MD, Jeremiah Stamler professor, professor of general internal medicine and geriatrics, professor of preventive medicine at Northwestern University Feinberg School of Medicine and deputy editor of JAMA, wrote that it is concerning that more than half the patients died during the study period.
Although it is known that PAD is associated with elevated risk for death from CV causes, cancer and infection, “[p]eripheral revascularization does not address any of these causes of death,” Redberg and McDermott wrote. “Thus, while this well-done observational study provides new information on the association of paclitaxel stents with mortality, a major conclusion should be that mortality is high among Medicare beneficiaries undergoing revascularization with any devices. Physicians should continue to focus on conservative treatment, including smoking cessation and exercise therapy, for improving quality of life in patients with PAD.”
References:
- Redberg RF, et al. JAMA Intern Med. 2021;doi:10.1001/jamainternmed.2021.2782.
- Secemsky EA, et al. JAMA Intern Med. 2021;doi:10.1001/jamainternmed.2021.2738.
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Secemsky EA, et al. Featured Clinical Research II. Presented at: American College of Cardiology Scientific Session; May 15-17, 2021 (virtual meeting).
