The controversy regarding the safety of treating peripheral artery disease (PAD) with paclitaxel-coated devices has only deepened in the new year, with two recent studies suggesting opposite safety findings.
As previously reported by theheart.org | Medscape Cardiology, a 2018 meta-analysis showing a late mortality signal associated with paclitaxel drug-coated balloons (DCBs) sent reverberations through the interventional cardiology community.
Now, in a new meta-analysis involving eight randomized controlled trials (RCTs) and more than 1400 patients with critical limb ischemia (CLI), the same researchers found significantly more early amputations and deaths in those treated with DCB below the knee, compared with conventional balloon angioplasty.
"The findings of our latest report add to previous evidence underpinning major safety concerns around use of paclitaxel in lower limb angioplasties — increased long-term patient mortality in cases of intermittent claudication," lead author Konstantinos Katsanos MD, MSc, PhD, Patras University Hospital, Greece, told theheart.org | Medscape Cardiology.
By contrast, a retrospective study of insurance claims in Germany showed no heightened mortality with paclitaxel-coated balloons and stents, compared with uncoated devices, in close to 38,000 patients with PAD.
On the contrary, use of paclitaxel-coated devices was associated with higher long-term survival, better amputation-free survival (AFS), and lower rates of major cardiovascular events in the treatment of chronic limb-threatening ischemia (CLTI).
These findings "emphasize the difference between population-based evidence and randomized trials," lead author Christian-Alexander Behrendt, MD, University Medical Center Hamburg-Eppendorf, Germany, told theheart.org | Medscape Cardiology.
In the new Katsanos meta-analysis, published January 15 in the Journal of Interventional Radiology, the 1420 patients were treated with five different DCBs and 97% had CLI.
In up to 1-year follow-up, the paclitaxel DCB group had fewer target lesion revascularizations (TLR) than the uncoated device group (11.8% vs 25.6%; risk ratio, 0.53; 95% CI, 0.35 - 0.81) but worse AFS (13.7% vs 9.4%; hazard ratio [HR], 1.52; 95% CI, 1.12 - 2.07).
The latter finding was driven by nonsignificant increased risks for all-cause death (odds ratio [OR], 1.39; 95% CI, 0.94 - 2.07) and major amputations (OR, 1.63; 95% CI, 0.92 - 2.90).
In dose-subgroup analyses, AFS was significantly worse in cases with high-dose (3.0–3.5 μg/mm2) devices, but not in the single trial with a low-dose DCB (2.0 μg/mm2).
"Considering the well-described downstream 'showers' of paclitaxel particles with current drug-coated balloons, we hypothesize that nontarget paclitaxel embolization is a plausible mechanism for distal foot and systemic toxicity," Katsanos commented.
Short Time Frame
To theheart.org | Medscape Cardiology, Eric Secemsky, MD, Harvard Medical School, and director of vascular intervention, Beth Israel Deaconess Medical Center, Boston, suggested that this theorized mechanism of harm in below-the-knee procedures could potentially shed light on a similar mechanism at play in above-the-knee procedures.
"We didn't understand why people could potentially be dying in above-the-knee [procedures], and the suggestion here is that these devices might perhaps be causing particular embolization or maybe delayed wound healing," Secemsky speculated.
However, "I don't know that this is true, so I am cautious to say this is true," he emphasized.
Secemsky said a strength of the Katsanos analysis is that the RCTs included more than 1000 patients, but noted that it is hard to vet the quality and rigor of the data, as some of the studies have not yet been published. He also noted that paclitaxel-coated devices are not FDA-approved in the United States for below-the-knee procedures.
Moreover, he continued, "two studies were driving the signal of harm: the IN.PACT DEEP, which included an iteration of their DCB that is no longer being tested; and the unpublished SINGA-PACLI trial. Both studies contributed most of the adverse events seen in this meta-analysis."
Additionally, the trials had different lengths of follow-up (6 months to 12 months), he said. "Thus, the five trials with data available to 12 months are driving the 1-year findings, whereas three RCTs, including the primary RCT showing safety (Lutonix-BTK trial), only contribute data to 6 months."
For this reason, "we are not too excited about this meta-analysis as of now, [because] all it tells us is that we need more data to support the safety of drug-coated devices in this population," Secemsky stated.
Katsanos explained that, "to address the differences in follow-up period and number of cases lost to follow-up, the primary end point was calculated on the log-hazard scale and expressed as a hazard ratio, as recommended for time-to-event outcomes."
He highlighted that a short-term time frame of 6 months to 1 year was chosen "because it is clinically relevant to limb-threatening-CLI."
Sensitivity tests also "showed consistent direction and magnitude of the summary treatment effects in case of both AFS and freedom from TLR," Katsanos emphasized.
Lower Mortality, Fewer Amputations
The second study, published January 8 in the European Journal of Vascular and Endovascular Surgery, drew on health-insurance claims in the German BARMER database to analyze 37,914 patients (mean age, 73.3 years, 48.8% female) and 21,546 propensity-score-matched patients with symptomatic CLTI or intermittent claudication (IC) with an index revascularization between January 2010 and December 2018.
Patients were first stratified by CLTI or IC, and then by balloon vs stent use. Paclitaxel-coated devices were then compared with uncoated devices within each stratum. The primary outcome was all-cause mortality at the end of follow-up.
From 2010 to 2018, the annual use of paclitaxel-coated devices increased dramatically from 3% to 39% in the CLTI group and from 4% to 48% in the IC group (P < .001 for both).
A total of 2454 deaths occurred within 5 years of follow-up (median, 2.7 years; longest, 8 years).
A Cox proportional hazards model (based on propensity-score-matched cohorts at 5 years) showed that, compared with uncoated devices, use of paclitaxel-coated devices in the CLTI group was associated with several improvements:
Overall survival: HR, 0.83; 95% CI, 0.77 - 0.90
Amputation-free survival: HR, 0.85; 95% CI, 0.78 - 0.91
Major cardiovascular events: HR, 0.82; 95% CI, 0.77 - 0.88
In the IC group, mortality was significantly better with DCB (HR, 0.87; 95% CI, 0.76 - 0.99) or a combination of DCB and drug-eluting stents (HR, 0.88; 95% CI, 0.80 - 0.98) than with uncoated devices, but similar for DES alone (HR, 0.91; 95% CI, 0.77 - 1.08).
No benefit was found for paclitaxel-coated devices in the IC group for AFS (HR, 0.91; 95% CI, 0.82 - 1.00) or major cardiovascular events (HR, 0.93; 95% CI, 0.87 - 1.00).
The authors acknowledge that "unmeasured confounding" may partly explain the results. It may be that patients revascularized with DCB or DES "are more likely to be treated in highly specialized trial centers with clear follow-up protocol."
Moreover, these patients may have received "the best treatment," including statin therapy, added Behrendt.
More Evidence Needed
Secemsky, who was not involved with either study, said the German investigators "did a wonderful job with this analysis in a large population of several thousand patients, showing nicely that after accounting for differences in comorbidities, the patients had no evidence of harm with [paclitaxel-coated] devices through 5 years."
However, he cautioned, median follow-up time was just over 2 years. "Although the investigators had data all the way out to 5 years, over time, the number of patients contributing data became smaller, which results in more uncertainty with these longer-term findings," he said. "As such, we still need to look at additional long-term data in this patient population to confirm the safety of these devices."
At present, the "major consideration we want to address is whether it's safe to use these devices, and we're undertaking these analyses to examine safety, not to see if they improve mortality," although the present study "has a suggestion of mortality benefit," Secemsky stated.
Katsanos added that paclitaxel-coated balloons "remain under investigation for below-knee arteries and critical limb ischemia," with "a few randomized controlled trials on the way."
"We need definitive evidence from high-quality multicenter controlled trials that these devices may improve wound healing and limb salvage without any systemic mortality risk," he said.
Katsanos receives personal fees from Boston Scientific and Philips Healthcare. The study by Behrendt was part of the IDOMENEO project funded by the German Joint Federal Committee. Behrendt reports no relevant financial relationships. Secemsky reports institutional grants from Cook Medical, BD Bard, Medtronic, Beth Israel Deaconess Medical Center, and Boston Scientific, and reports consultancy for Cook Medical, BD Bard, and Medtronic.
J Vasc Interv Radiol. Published online January 15, 2020. Abstract
Eur J Vasc Endovasc Surg. Published online January 8, 2020. Full text
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Cite this: More Conflicting Evidence on Paclitaxel Devices in PAD - Medscape - Feb 07, 2020.