Use of alternative methodologies for evaluation of composite end points in trials of therapies for critical limb ischemia

Critical limb ischemia (CLI) represents advanced atherosclerosis of the lower extremities; results in severe hemodynamic compromise at rest; and manifests with lower extremity ischemic rest pain, ulceration, or gangrene. Patients with CLI have strikingly high morbidity and mortality rates, with 1-year mortality rates ranging from roughly 10% to 25% and 1-year amputation rates ranging from 10% to 20%. 1–4 Given the high morbidity and mortality associated with this CLI, goals of therapy include (1) reduction in overall mortality, (2) limb preservation with wound healing (in patients with wounds), and (3) improvement in quality of life with greater mobility and less pain. Attempts at medical therapies for CLI have included use of intravenous prostanoids, strict control of diabetes, smoking cessation, and wound care. Increasingly, the use of biologic therapies to induce angiogenesis (i.e., protein therapy, gene therapy, and cell therapy) is being investigated for treatment of advanced peripheral artery disease. 2, 5–9 Furthermore, advances in technologies (i.e., drug-coated balloons, atherectomy devices, and improvements in stent technology) for revascularization are increasingly being examined to improve outcomes in CLI. 10–12 As these therapies evolve, a reappraisal of study designs and end points to evaluate newer biologics and device therapies will be needed. Ideally, study designs with end points that capture the major clinical goals of CLI therapy with sufficient sensitivity to detect meaningful differences should be sought. Many trials use a time-to-event analysis to compare therapies with respect to their impact on composite end points (including fatal and non-fatal components). Trial designs have also incorporated both safety and efficacy end points into the composite end point in hopes to provide clinicians a more comprehensive understanding of the effect of the investigational therapy. In addition, single-arm trials using Objective Performance Goals (OPGs) as therapeutic benchmarks are now accepted for select therapies (usually device therapies) in the absence of randomized, controlled trials of new therapies in CLI.13,14 However, clinicians should be aware of several major limitations and challenges in using the time- to-event analysis and OPGs. This article addresses limitations inherent in the interpretation of trial results using these methodologies. Meanwhile, an ideal evaluation of an investigational therapy should allow comparison of clinically important end points, capture clinically meaningful recurrent events (events that occur after the first event) and assign relative values to the end points of interest such that end points of more clinical significance contribute to a greater extent to the final statistical comparison between therapies than less meaningful events. Consequently, we introduce alternative methodologies that achieve these three goals allowing for a more comprehensive evaluation of the effect of a therapy. We focus our discussion on one of these methodologies referred to as Global Rank Method for end point analysis and provide an outline on how to perform such analysis using a hypothetical example. No extramural funding was used to support this work, and the authors are solely responsible for the design, drafting, and editing of this manuscript and its final contents.