Long-Term Risk of Death Shows Dramatic Increase Following Femoropopliteal Application of Paclitaxel-Coated Balloons and Stents A Systematic Review and Meta-Analysis of Randomized Controlled Trials

The results of a systematic review and meta-analysis of randomized controlled trials conducted by Konstantinos Katsanos and his colleagues have showcased an increased risk of death following application of paclitaxel-coated balloons and stents in the femoropopliteal artery of the lower limbs. Further investigations are urgently warranted, the authors state in their publication in Circulation.

Paclitaxel-coated balloon and stents have emerged as the most promising strategy for the inhibition of neointimal hyperplasia following angioplasty of the femoropopliteal artery of the leg. The femoropopliteal artery is the most common site of involvement in atherosclerosis of the lower limb and is typically characterized by multilevel steno-occlusive disease, often complex calcified morphology, and aggressive postangioplasty neointimal hyperplasia associated with high rates of early vessel restenosis and failure. Drug-eluting stents (DESs) and drug-coated balloons (DCBs) have been extensively investigated as a potential solution to inhibit vessel restenosis and improve clinical outcomes after endovascular revascularization of the femoropopliteal artery. In the past, several randomized controlled trials (RCTs) had already shown that paclitaxel-coated balloons and stents significantly reduced the rates of vessel restenosis and target lesion revascularization after lower extremity interventions. In the light of this, Katsanos et al. conducted a systematic review and meta-analysis of RCTs investigating paclitaxel-coated devices in the femoral and/or popliteal arteries. Here. the primary safety measure was all-cause patient death. Risk ratios and risk differences were pooled with a random effects model. In all, 28 RCTs with 4663 patients (89% intermittent claudication) were analyzed.

The investigators reported that all-cause patient death at 1 year (28 RCTs with 4432 cases) was similar between paclitaxel-coated devices and control arms (2.3% versus 2.3% crude risk of death; risk ratio, 1.08; 95% CI, 0.72–1.61). However, all-cause death at 2 years (12 RCTs with 2316 cases) was significantly increased in the case of paclitaxel versus control (7.2% versus 3.8% crude risk of death; risk ratio, 1.68; 95% CI, 1.15–2.47; —number-needed-to-harm, 29 patients [95% CI, 19–59]). Moreover, all-cause death up to 5 years (3 RCTs with 863 cases) increased further in the case of paclitaxel (14.7% versus 8.1% crude risk of death; risk ratio, 1.93; 95% CI, 1.27–2.93; —number-needed-to harm, 14 patients [95% CI, 9–32]). Meta-regression showed a significant relationship between exposure to paclitaxel (dose-time product) and the absolute risk of death (0.4_0.1% excess risk of death per paclitaxel mg-year; P<0.001). The trial sequential analysis excluded false-positive findings with 99% certainty (2-sided a, 1.0%).

The investigators concluded that there is strong evidence from the statistical inference that the risk of death is significantly increased beyond the first year following application of paclitaxel-coated balloons and stents in the femoropopliteal artery of the leg in patients with intermittent claudication. However, the actual causes remain unknown and further clinical investigations are urgently warranted. Speaking of its clinical Implications, the investigators profess that 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. Additionally, pharmacological studies may also help understand the potential biological mechanisms behind the association of paclitaxel in the lower limbs and patient mortality.