Improved amputation-free survival in unreconstructable critical limb ischemia and its implications for clinical trial design and quality measurement

Abstract

Amputation-free survival (AFS), a composite endpoint of mortality and amputation, is the preferred outcome measure in critical limb ischemia (CLI). Given the improvements in systemic management of atherosclerosis and interventional management of limb ischemia over the past 2 decades, we examined whether these outcomes have changed in patients with CLI without revascularization options (no option-critical limb ischemia [NO-CLI]). We reviewed the literature for published 1-year AFS, mortality, and amputation rates from control groups in NO-CLI trials. Summary proportions of events were estimated by conducting a random effects meta-analysis of proportions. To determine whether there had been any change in event rates over time, we performed a random effects meta-regression and a mixed effects logistic regression, both regressed against the variable "final year of recruitment." Eleven trials consisting of 886 patients satisfied search criteria, 7 of which presented AFS data. Summary proportion of events (95% confidence interval) were 0.551 (0.399 to 0.693) for AFS; 0.198 (0.116 to 0.317) for death; and 0.341 (0.209 to 0.487) for amputation. Regression analyses demonstrated that AFS has risen over time as mortality rates have fallen, and these improvements are statistically significant. The decrease in amputation rates failed to reach statistical significance. The lack of published data precluded a quantitative evaluation of any change in the clinical severity or comorbidities in the NO-CLI population. AFS and mortality rates in NO-CLI have improved over the past 2 decades. Due to declining event rates, clinical trials may underestimate treatment effects and thus fail to reach statistical significance unless sample sizes are increased or unless a subgroup with a higher event rate can be identified. Alternatively, comparing outcomes to historical values for quality measurement may overestimate treatment effects. Benchmark values of AFS and morality require periodic review and updating.