Ramipril improves walking performance in PAD study

Patients with peripheral artery disease (PAD) who received 24-week treatment of ramipril showed significant improvement in pain-free and maximum walking times in a randomized clinical trial. While the results are “particularly notable,” the author of an accompanying editorial cautioned that they may apply to a limited patient population.

The results were published in the Feb. 6 issue of the Journal of the American Medical Association.

In 2006, Anna A. Ahimastos, PhD, of the Baker IDI Heart and Diabetes Institute in Melbourne, Australia, and colleagues reported the results of a randomized pilot study that compared the angiotensin-converting enzyme (ACE) inhibitor ramipril (Ramace, Sanofi-Aventis) with placebo in 40 adults with symptomatic PAD (Ann Intern Med 2006;144[9]:660-664). They found that the mean pain-free walking time was 227 seconds longer in the ramipril group and maximum walking time improved by 451 seconds. But the patients selected for the study had no history of diabetes or hypertension, which limited the applicability of the findings.

Ahimastos and colleagues designed the current study to overcome some of those limitations. They enrolled 212 patients (mean age 65.5 years) in Australia who had PAD between May 2008 and August 2011. Patients with an ankle brachial index of less than 0.90 at rest in at least one leg, a history of intermittent claudication and a stable medication regimen for at least six months met the inclusion criteria. They excluded patients with poorly controlled hypertension, other major comorbid conditions as well as any other condition that limited walking.

The primary outcome was pain-free walking time and maximum walking time on a treadmill at baseline and six months. Patients were randomized to receive either 10 mg a day of ramipril or a placebo for 24 weeks. Baseline characteristics were similar in both groups.

The researchers reported that at six-months ramipril was associated with a 77 percent and 123 percent increase in pain-free and maximum walking times, respectively. The ramipril group had a 75-second increase in mean pain-free walking time and a 255-second increase in maximum walking time compared with the placebo group.

Ahimastos et al noted that the magnitude of improvement had been larger in their pilot study and attributed that to the exclusion of patients with diabetes and aortoiliac disease. In the present study, they found that the maximum walking time was greater in patients with femoropopliteal disease compared with patients with aortoiliac disease, at 286 seconds and 127 seconds, respectively. “The broader inclusion criteria and larger study population make the current findings applicable to a more representative PAD population with claudication,” they wrote.

They speculated about the mechanisms that might explain the improvement, including the possible effect of ACE inhibitors on skeletal muscle and glucose metabolism. But they noted that any such benefits are controversial.

Although the patient population was more diverse than in the pilot study, results still may not be generalizable to the broader patient population, they acknowledged. Editorial writer Mary McGrae McDermott, MD, of Northwestern University Feinberg School of Medicine in Chicago, agreed that the exclusion criteria limited the study’s applicability. She pointed out that the study population was restricted to Australians but she also emphasized that the sample size exceeded that of prior trials.

“Given the paucity of effective therapies for treating functional limitation in PAD and recent randomized controlled clinical trials that have failed to demonstrate improved walking performance in response to novel medical therapies in PAD, the magnitude of improvement associated with ramipril in the study by Ahimastos et al is particularly notable,” she wrote. She recommended further studies to confirm the results and to assess ramipril’s benefits in more ethnically diverse populations.