Medications for Improving Walking Performance in Peripheral Artery Disease

Abstract

LOWER EXTREMITY PERIPHERAL ARTERY DISEASE (PAD) is a global health problem that will become increasingly prevalent as the world population lives longer with chronic disease. One report estimated that 1 in 16 Americans 40 years or older has PAD. Improving functional performance is a major treatment goal for patients with PAD. Men and women with PAD have greater functional impairment and more rapid functional decline than those without PAD. Among participants in the Walking and Leg Circulation Study (WALCS), a longitudinal observational study of 676 men and women (overall mean age, 71.0 years) with and without PAD, those with severe PAD, defined as an ankle brachial index less than 0.50, were 12 times more likely to become unable to walk continuously for 6 minutes at 2-year follow-up, compared with those with a normal ankle brachial index at baseline. At 5-year follow-up in the WALCS cohort, participants with severe PAD had a 4-fold increased risk of mobility loss, compared with participants without PAD at baseline. Participants with moderate and mild PAD, respectively, had a 3.82-fold and 3.22-fold increased risk of mobility loss at 5-year followup, compared with participants without PAD at baseline. The functional limitations experienced by patients with PAD are associated with poorer quality of life, increased hospitalization rates, higher mortality, and higher medical care costs. Given the increasing burden of PAD and its associated functional impairment, identifying interventions to improve functional performance in patients with PAD is an important public health challenge. In patients with PAD, supervised treadmill exercise improves maximal treadmill walking time by 50% to more than 200%. However, medical insurance typically does not pay for supervised treadmill exercise for patients with PAD, and most such patients do not participate in supervised treadmill exercise programs. Only 2 medications (pentoxifylline and cilostazol) are currently approved by the US Food and Drug Administration (FDA) for treating PAD-associated walking impairment. However, a recent systematic review concluded that pentoxifylline and cilostazol are associated with improvement in maximal treadmill walking distance of only 15% and 25%, respectively. New medical therapies are needed to improve functional performance in patients with PAD. In this issue of JAMA, Ahimastos and colleagues report results of a randomized, placebo-controlled clinical trial of rampiril vs placebo for improving walking performance in patients with PAD. In this trial, 212 patients with PAD and intermittent claudication were randomized to receive 10 mg of ramipril or matching placebo. At 24-week follow-up, participants with PAD randomized to receive ramipril achieved significantly greater increases in pain-free and maximum treadmill walking time, the 2 primary outcomes. Improvements in pain-free and maximum walking time were 75 seconds and 255 seconds greater, respectively, in the ramipril group relative to the placebo group. The magnitude of the increase in pain-free and maximum walking distance was substantial, corresponding to 77% and 123% increases, substantially greater than that observed with FDA-approved medications for claudication. Participants with PAD randomized to receive ramipril also achieved significantly greater gains in the Walking Impairment Questionnaire distance, walking speed, and stair climbing scores compared with the placebo group. Prior trials of ramipril therapy to improve walking performance in patients with intermittent claudication have yielded mixed results. A previous randomized controlled trial of ramipril vs placebo by Ahimastos et al involving 40 patients with symptomatic infrainguinal PAD and no history of diabetes or hypertension demonstrated gains in painfree and maximum walking distance of 227 and 451 seconds, respectively, compared with placebo. However, a recent meta-analysis by Shahin et al of 4 randomized trials involving 137 patients with PAD, including the 40 participants in the prior trial by Ahimastos et al, demonstrated no association between use of angiotensin-converting enzyme (ACE) inhibitors and improved walking performance. The trials included in this meta-analysis were heterogeneous and evaluated several different ACE inhibitors. Three of the trials were completed in the early 1990s, raising ques-