Editor’s Perspective Lessons Learned from Recent Randomized Clinical Trials for Intermittent Claudication

It is well recognized that lower extremity peripheral arterial disease (PAD) is highly prevalent and results in significant cardiovascular mortality akin to cardiovascular disease.1 Among patients with PAD there is a broad range of clinical manifestations, with a third of patients having typical intermittent claudication (IC). The symptoms of lower extremity PAD, even in a stable nonlimb threatening form, result in measurable reductions in quality of life (QOL) and physical functioning, including mobility loss.2 The morbidity from PAD and relatively high rate of vascular procedures performed in symptomatic patients has resulted in health economic costs that are greater than ischemic heart disease and stroke.3 Moreover, the number of catheter-based interventions for PAD has increased in recent years, likely due to multiple factors, including disease recognition, development of endovascular devices, and a shift from open surgical procedures and performance of procedures by 3 disciples of medicine: interventional cardiology, interventional radiology, and vascular surgery.4,5 One of the major unresolved issues is how should outcomes be measured? Is it enough to improve QOL or do we need to demonstrate reductions in cardiovascular morbidity and mortality to justify the cost of invasive therapies? In 2007, over 2 million physician office visits were related to PAD; therefore, performing clinical trials to study the treatment of PAD should be relatively straightforward, but unfortunately this has not been the case. Randomized clinical trials in PAD are uncommon and notoriously slow to enroll. This may be due to restrictive enrollment criteria, or to an unfounded belief of lack of clinical equipoise between randomized treatments that bias physicians and patients.6,7 That the pace of research in the field is slow is reflected in the fact that from the PAD guidelines in 2005 to the update in 2011, which included clinical trials and new data believed to impact patient care through December 2010, not a single new study resulted in a change in the recommended treatment for IC.8,9 Since the publication of the updated PAD guidelines, however, 2 randomized clinical trials examining treatment strategies for IC in patients on optimal medical therapy have been reported. The focuses of the trials were exercise therapy and endovascular revascularization. The studies add to our understanding of the relative benefits of these therapies in IC and highlight the ongoing challenge in performing randomized clinical trials in this population. Although the trials were small, the lessons we learned from them are big. The first study, published in Circulation, is the 6-month outcomes from the Claudication: Exercise Versus Endoluminal Revascularization (CLEVER) study.10 This trial was designed to compare 3 therapies previously shown to be effective in the treatment of IC: optimal medical care (OMC), alone or in combination with supervised exercise or stent revascularization. Patients were randomized in a 1:2:2 fashion. The study initially had a fourth arm of stent therapy and supervised exercise, but unfortunately this was halted due to slow recruitment. The study was restricted to patients with aortoiliac disease, although concomitant treatment of femoral-popliteal disease was allowed. All arms included OMC, which consisted of guideline-driven management of PAD, including cilostazol.8 Patients in the OMC group alone also received instructions for self-directed exercise programs. The supervised exercise program consisted of 26 weeks of exercise 3 times a week for 1 hour, a regimen expected to improve walking ability based on prior studies.11 The stent arm had revascularization carried out for all hemodynamically significant aortoiliac stenosis. The mean lesion length was 3.9 cm, and 38% of patients had treatment of total occlusions. No patients received additional infrainguinal revascularization. In the 6-month analysis there were 20 patients in the OMC arm, 38 in the supervised exercise, and 41 in the stenting arm. Baseline characteristics were similar in the groups. Despite the small sample size, several differences in outcomes for the treatment arms emerged. As expected, the ankle brachial index (ABI) significantly improved in the stent arm by 0.29 from a baseline of 0.66. The ABI was unchanged in the OMC and supervised exercise arms. The primary end point was a change in peak walking time on a graded treadmill test. Patients in the supervised exercise and stent arms had greater gains compared with the OMC group, with patients in the supervised exercise arm achieving the greatest benefit. With respect to the secondary end points, including QOL, functional status, and free living step activity, supervised exercise and stent therapy were superior to OMC, but with stent therapy achieving a greater extent of improvement compared with supervised exercise. The trial suggests there is a role for both supervised exercise and stent therapy in patients with aortoiliac disease and IC, but did not examine whether combination therapy offered additional benefit. The opinions expressed in this article are not necessarily those of the American Heart Association. From the Division of Cardiology, Rhode Island Hospital, Brown University, Providence, RI. Correspondence to Dr J. Dawn Abbott, Division of Cardiology, Rhode Island Hospital, Assistant Professor Brown Medical School, 814 APC, 593 Eddy St, Providence, RI 02903, E-mail [email protected] (Circ Cardiovasc Interv. 2012;5:139-141.) © 2012 American Heart Association, Inc.