Editor's Choice - Dynamic Risk of Death following Application of Paclitaxel Coated Devices in the Femoropopliteal Artery: A Contemporary Meta-analysis of Randomised Controlled Trials.

Abstract

There has been major controversy regarding the long term risk of death associated with the use of paclitaxel coated devices in the lower limbs. The authors performed a contemporary systematic review and meta-analysis. Data sources included published literature and repositories of regulatory agencies. All cause mortality was analysed on the intention to treat principle. Because of violation of proportional hazards, reconstructed patient level survival data (R² = 0.999) were fitted with piecewise Cox models and flexible generalised survival models with natural splines and shared frailty terms. Survival differences were summarised with the non-parametric statistical tests of the difference and the ratio of restricted mean survival time lost (RMTL). Thirty-four randomised studies with 7 486 subjects and 25 465 person years were included, more than twice the size of the latest industry sponsored meta-analysis for regulatory purposes. In the long term, there were 575 deaths amongst 4 231 patients in the paclitaxel arms (13.6% crude risk) vs. 367 deaths amongst 3 255 patients in the control arms (11.3% crude risk), with an average hazard ratio (HR) of 1.18 (95% confidence interval [CI] 1.03 - 1.35; p = .015). The RMTL ratio (non-parametric analogue of HR) was 1.21 times (95% CI 1.07 - 1.38; p = .003) at 5 years. The absolute RMTL difference was 0.08 years (95% CI 0.03 - 0.13; p = .004) at 5 years. The HR significantly varied over time, displaying a dynamic temporal pattern. Soon after treatment, HR progressively increased and became statistically significantly higher before the end of the first year and for most of the second year (HR 1.45, 95% CI 1.11 - 1.89; p = .007), before declining towards unity (neutral) again up to 5 years. There was modest between trial heterogeneity (θ = 0.083; p = .017) and level of certainty by Grading of Recommendations Assessment, Development and Evaluation was moderate. There is a significant, dynamic increase in all cause mortality following application of paclitaxel coated devices in the femoropopliteal artery.