The use of paclitaxel-coated balloons and stents in the femoropopliteal arteries of patients with peripheral artery disease (PAD) was associated with a significantly increased risk of death at two and five years of follow-up, according to a meta-analysis published Dec. 6 in the Journal of the American Heart Association.
Researchers led by Konstantinos Katsanos, MD, PhD, said these findings mean additional investigations into these commercially approved devices are “urgently warranted.”
Paclitaxel drug-eluting stents (DES) for coronary arteries have been linked to higher rates of mortality and myocardial infarction past one-year of follow-up when implanted, leading to a decline in their use. However, paclitaxel-coated balloons and stents have remained a staple therapy for femoropopliteal disease, with researchers writing off findings of increased late mortality associated with the devices as “statistical artifacts or anomalies,” according to Katsanos et al.
To investigate this potential link further, the researchers pooled results from 28 randomized controlled trials (RCTs)—four of which investigated paclitaxel DES and 24 of which evaluated paclitaxel drug-coated balloons (DCBs), usually in comparison to percutaneous transluminal angioplasty. A total of 4,663 patients were included, 89 percent of whom were treated for short-distance intermitted claudication and 11 percent for critical limb ischemia.
While mortality rates were similar between the paclitaxel-coated devices and the control groups at one-year post-implantation, a disturbing trend emerged after that. All-cause death at two years was 7.2 percent for the drug-coated devices and 3.8 percent in the control arm, a relative increase of 68 percent. Katsanos and colleagues calculated a number needed to harm of 29 for this timepoint.
At five years, crude death rates were 14.7 percent for paclitaxel-coated DES and DCBs versus 8.1 percent for the control group. This translated to a relative risk increase of 93 percent and a number needed to harm of 14 patients.
“The authors consider the herein reported findings of particular concern because most of the interrogated devices have already received clearance by regulatory authorities and are currently under routine clinical use,” wrote Katsanos, with the department of interventional radiology at Patras University Hospital in Greece, and coauthors. “The potential causes of this alarming late increased incidence of death remain unknown.”
Without being able to tease out the contributing factors to mortality, an ability further limited by most studies in the analysis not reporting specific causes of death, the authors said late toxicity of paclitaxel could be one explanation.
“Contrary to solvent‐based (eg, cremophor) intravenous paclitaxel used in cancer chemotherapy that has a half‐life of around 6 hours, paclitaxel crystals loaded on DCB or DES for the peripheral arteries have a half‐life of weeks to months, depending on the exact chemical properties of the applied paclitaxel formulation,” they wrote. “Increased paclitaxel crystallinity helps achieve higher tissue uptake and retention and improved biologic effect, however, at the expense of microparticle formation that may embolize in the downstream systemic circulation.”
The researchers expressed confidence in their finding of increased late mortality associated with paclitaxel-coated devices, noting the association held up upon various sensitivity tests and that the included studies were relatively homogenous.
“Collection and reporting of longer‐term follow‐up (beyond 1 year) in case of all commercial clinical studies is recommended to confirm or refute the present findings,” Katsanos et al. wrote. “Pharmacological studies may also help understand the potential biological mechanisms behind the association of paclitaxel in the lower limbs and patient mortality.”