Ramipril Improves Walking Ability in Selected Patients with Stable PAD and Intermittent Claudication
EBM Focus - Volume 8, Issue 7
About a third of patients with peripheral arterial disease (PAD) suffer from intermittent claudication that is relieved with rest. Cilostazol has been recommended by the American College of Cardiology/American Heart Association (J Am Coll Cardiol 2006 Mar 21;47(6):1239) for patients with PAD and claudication, but cilostazol and pentoxifylline, the only FDA-approved drugs for claudication, are each associated with relatively small improvements in walking performance (Cochrane Database Syst Rev 2008 Jan 23;(1):CD003748, Cochrane Database Syst Rev 2012 Jan 18;(1):CD005262, Br J Surg 2012 Dec;99(12):1630). A recent systematic review of small randomized trials assessing ACE inhibitors as a class found no overall improvements in walking (Int J Surg 2011;9(3):209). However, one of the included trials with 40 patients did show a benefit with the ACE inhibitor ramipril. Now, a larger trial of ramipril provides strong evidence for its efficacy for claudication.
A total of 212 patients (mean age 66 years, 83% men) with stable PAD and intermittent claudication were randomized to ramipril 10 mg/day orally vs. placebo for 24 weeks. All patients were on a stable drug regimen for at least 6 months prior to randomization (55% taking antiplatelet agents, 55% taking statins, 9.4% taking cilostazol). The list of exclusion criteria was long, and included blood pressure ≥ 160/100 mmHg, use of ACE inhibitors or ARBs within 6 months, and any condition other than PAD that limited walking. Quality of life was assessed using the SF-36. Walking performance was assessed at baseline and at 6-months by a treadmill test (3.2 km/hour [2 miles/hour] and 12% grade). At baseline, the mean pain-free walking times were 140 seconds for the ramipril group and 144 seconds for the placebo group. The mean maximum walking times were 234 seconds (ramipril) and 238 seconds (placebo).
At 6 months, the pain-free walking time was increased by mean 88 seconds with ramipril vs. mean 14 seconds with placebo (p < 0.001), corresponding to an increased walking distance of 184 meters with ramipril (level 1 [likely reliable] evidence). Maximum walking times were increased by mean 277 seconds vs. 23 seconds (p < 0.001). Ramipril was also associated with improvements in patient-reported walking distance, walking speed, and stair climbing (p < 0.001 for each), and in quality of life on the physical component of the SF-36 (p = 0.02) (JAMA 2013 Feb 6;309(5):453). Whether these findings can be generalized to a larger PAD population, including patients with a greater degree of hypertension, or with comorbidities that also limit walking are questions for further study.
For more information, see the Peripheral arterial disease (PAD) of lower extremities topic in DynaMed.