Risk of Death Following Application of Paclitaxel-Coated Balloons and Stents in the Femoropopliteal Artery of the Leg: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Abstract

Background Several randomized controlled trials ( RCT s) have already shown that paclitaxel-coated balloons and stents significantly reduce the rates of vessel restenosis and target lesion revascularization after lower extremity interventions. Methods and Results A systematic review and meta-analysis of RCT s investigating paclitaxel-coated devices in the femoral and/or popliteal arteries was performed. The primary safety measure was all-cause patient death. Risk ratios and risk differences were pooled with a random effects model. In all, 28 RCT s with 4663 patients (89% intermittent claudication) were analyzed. All-cause patient death at 1 year (28 RCT s 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). All-cause death at 2 years (12 RCT s 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]). All-cause death up to 5 years (3 RCT s 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 absolute risk of death (0.4±0.1% excess risk of death per paclitaxel mg-year; P<0.001). Trial sequential analysis excluded false-positive findings with 99% certainty (2-sided α, 1.0%). Conclusions There is 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. Clinical Trial Registration URL : www.crd.york.ac.uk/PROSPERO . Unique identifier: CRD 42018099447.

Keywords: balloon angioplasty; paclitaxel; paclitaxel‐coated balloon; paclitaxel‐eluting stent.

Figure 1

Random effects forest plot of all‐cause patient death at 1 year. Pooled point estimate was expressed as risk ratio (RR).

Figure 2

Random effects forest plot of all‐cause death at 2 years. Pooled point estimate was expressed as risk ratio (RR).

Figure 3

Random effects forest plot of all‐cause death at 4 to 5 years. Pooled point estimate was expressed as risk ratio (RR).

Figure 4

Trial sequential analysis of all‐cause death. External red lines denote the O'Brien‐Fleming alpha spending trial sequential monitoring boundaries. Internal red wedge lines denote the futility O'Brien‐Fleming beta spending lines. Cumulative Z curve (blue line) crossed the alpha monitoring boundaries and the required information size (patient sample) has been reached in both illustrative scenarios; (A) α=5%, β=10%; and (B) α=1%, β=10%). Vertical red line denotes the calculated required sample size, whereas the Z value is the test statistic (|Z|=1.96 corresponds to a P value of 0.05; the higher the Z value, the lower the P value).

Figure 5

Meta‐regression (mixed effects model) of all‐cause death against paclitaxel exposure (dose‐time product calculated in milligram‐years). The size of the blue symbols is inversely proportional to the variance of the estimated treatment effect for each study. Solid and dotted red lines indicate the regression line with its corresponding 95% confidence bands. Intercept is −0.8±0.9% and coefficient of the regression line is 0.4±0.1% (95% confidence interval, 0.1–0.6%; P<0.001). The equation of the regression line is Y=(−0.008)+0.004X. The “metareg” function of the “meta” library was employed in R language.