The ACE inhibitor ramipril substantially improves pain-free walking time and maximum walking time in patients who have peripheral artery disease with intermittent claudication, according to a report in the Feb. 6 issue of JAMA.
In what the investigators described as the first adequately powered randomized controlled trial to demonstrate ramipril’s benefit in this patient population, the magnitude of improvement in walking performance exceeded that reported for all other drug therapies.
Dr. Anna Ahimastos
The study subjects reported concomitant improvements in their ability to perform daily activities and their health-related quality of life, said Anna A. Ahimastos, Ph.D., of Baker IDI Heart and Diabetes Institute, Melbourne, and her associates.
The only two drugs currently approved in the United States for this indication, pentoxifylline and cilostazol, are reported to increase walking distance by 15% and 25%, respectively. In this trial, ramipril increased pain-free and maximum walking times by 77% and 123%.
Dr. Ahimastos and colleagues enrolled 212 patients with PAD and intermittent claudication in the double-blind trial, randomly assigning 106 to 6 months of ramipril (10 mg/d) and 106 to matching placebo. The mean age of the subjects was 65.5 years, and all were followed at three medical centers in Australia.
All the study subjects were receiving usual care according to their symptoms and risk profiles, which included antiplatelet and lipid-lowering agents. Roughly one-fourth of each group had diabetes, and the cohort included patients with aortoiliac as well as infrainguinal disease.
At 6-month follow-up, ramipril extended the pain-free walking time by a mean of 75 seconds and the maximum walking time by a mean of 255 seconds, compared with placebo. This corresponds to "a clinically significant increase in uphill walking distance of 184 meters," the investigators said (JAMA 2013;309:453-60).
The drug was particularly effective in patients who had femoropopliteal disease, increasing maximal walking time to 286 seconds, compared with patients who had aortoiliac disease, whose maximal walking time improved by 127 seconds.
These increases were independent of the small changes in blood pressure and ankle-brachial index associated with the drug. They exceed the improvements reported in the literature for other conventional PAD drug therapies including pentoxifylline, cilostazol, dipyridamole, ticlopidine, beraprost, iloprost, naftidrofuryl, and statins, Dr. Ahimastos and her associates said.
Patients in the ramipril group also showed improvements on the Walking Impairment Questionnaire in median walking distance, walking speed, and stair-climbing ability, compared with those in the placebo group. Similarly, the ramipril group showed improvement in the physical component of the Short Form–36, a measure of health-related quality of life, relative to the placebo group.
Ramipril did not significantly change any of the laboratory factors measured in the safety monitoring portion of the study. The only adverse events were transient dizziness, which affected 8.5% of the ramipril group and 2.8% of the placebo group, and persistent cough, which prompted seven patients in the ramipril group to withdraw from the study.
It is not yet known how ramipril improves functional capacity in PAD patients with intermittent claudication. Laboratory and animal studies suggest that the drug may increase peripheral blood flow and promote structural and functional changes in skeletal muscle, the researchers said.
This study was limited in that most of the subjects were whites of European descent, and the investigators had to select a population of patients with stable PAD "in whom we could ethically administer either a placebo or an ACE inhibitor" for 6 months. The cohort was thus "restricted to the lower end of the blood pressure spectrum and excluded patients with other major comorbid conditions," so the findings may not be generalizable to patients with higher blood pressure or to ethnically diverse populations, they added.