Brief Communication: Ramipril Markedly Improves Walking Ability in Patients with Peripheral Arterial Disease

Context Few therapies substantially reduce symptoms and improve exercise performance in patients with peripheral arterial disease (PAD). Contribution In this double-blind trial, investigators randomly assigned 40 older adults without diabetes and with symptomatic PAD to receive either ramipril or placebo, 10 mg once daily for 24 weeks. Compared with placebo, ramipril increased maximum and pain-free walking time and walking speed and distance. Cautions The trial was small and involved selected patients with limited mobility and exercise tolerance. Implications Ramipril may improve symptoms in some patients with PAD. The Editors This article has been retracted. See Notice of Retraction. Peripheral arterial disease (PAD) is a common disorder, with 12% of adults older than 50 years of age having an anklebrachial index (ABI) that is diagnostic of PAD (<0.9) (1). Approximately one third of these patients experience intermittent claudication during walking, limiting normal activities. Medical treatments to improve walking distance are limited. The angiotensin-converting enzyme (ACE) inhibitor ramipril reduced cardiovascular morbidity and mortality compared with placebo in patients with established atherosclerotic disease, including PAD, in the Heart Outcomes Prevention Evaluation (HOPE) study (2). This effect seemed to be independent of blood pressure reduction (3) and may relate to the known benefits of ACE inhibitors on both coronary and brachial endothelial function (4). No previous controlled studies have investigated the effect of ACE inhibitors on symptoms of intermittent claudication. Given the positive effects of ramipril in the HOPE trial and its convenient once-daily dosing formulation, we hypothesized that therapy with ramipril would improve intermittent claudication symptoms. We aimed to examine the effect of 6-month ramipril therapy on walking distance and claudication pain in a defined group of patients with claudication due to infrainguinal PAD by using a double-blind, randomized, placebo-controlled design. Methods This article has been retracted. See Notice of Retraction. We screened 152 patients with PAD from general practice clinics in the Melbourne, Australia, metropolitan area (Figure 1). Of them, 40 patients (mean age, 66 years [SD, 4]) were recruited and completed the trial. All patients gave written informed consent to participate in the study. The Ethics Committee of the Alfred Hospital, Melbourne, Australia, approved the study, and we performed the study in accordance with the Declaration of Helsinki 2000. All participants had an ABI less than 0.9 at rest in at least 1 leg; had a history of intermittent claudication (unilateral or bilateral), which was stable for 6 months; had evidence of superficial femoral artery stenosis or occlusion on duplex ultrasonography; had blood pressure of 160/90 mm Hg or less; had a stable medication regimen for at least 6 months; and had not previously been treated with ACE inhibitors. We excluded patients with limiting coronary artery disease, renal failure, history of hypertension, or type 2 diabetes mellitus. Figure 1. Flow of patients through the study. Computer-generated numbers specified the allocation sequence. A tamper-proof randomization process generated by the hospital research center randomly assigned participants into blocks of 10 to receive either ramipril (Tritace, Aventis Pharma Pty. Ltd., Macquarie Park, Australia, 10 mg once daily for 24 weeks) or placebo (10 mg once daily for 24 weeks) in a parallel-group, double-blind design. Both investigators and patients were blinded to drug assignment. Furthermore, investigators did not have access to baseline data when they performed follow-up measurements and patients were not asked which treatment they thought they were receiving. No patient assigned to placebo crossed over to ramipril during the trial or vice versa. We advised participants to maintain all aspects of their lifestyle throughout the trial and requested them to refrain from exercise, smoking, and caffeine for 24 hours before all testing. On the morning of testing, patients rested in a supine position for 15 minutes in a quiet room before the measurements. We assessed blood pressure, ABI, walking distance, duplex ultrasounds of leg arteries, and the Walking Impairment Questionnaire (WIQ) scores before and after both interventions. We advised patients about potential side effects and requested that they report any adverse event to the study coordinator. All patients performed a treadmill exercise test at a speed of 3.2 km/h and a grade of 12% (5), and we recorded pain-free walking time (time to onset of claudication pain) and maximum walking time. In our study, all patients reached a maximal level of claudication pain that limited exercise during the graded treadmill test. The WIQ was developed and validated against treadmill walking and is used to evaluate limitations in community-based walking ability (6). The WIQ assessed walking distance, speed, and stair-climbing ability, using a weighted standardized formula and returning a summary score between 0% and 100% (6, 7). Statistical Analyses All analysts were blinded to treatment assignment, and an independent investigator double-checked all measurement calculations and database entries. The study was powered to detect a 180-second change in maximum walking time with ramipril, assuming a standard deviation of 250 seconds ( = 0.05 [2-sided]; power, 86%). We compared 24-week changes from baseline in pain-free walking time, maximum walking time, and WIQ scores between treatments by using an analysis of covariance model with terms for treatment and baseline value as the analysis end points. We log-transformed the WIQ data to achieve a normal distribution before analysis. We conducted all statistical analyses by using Stata software, version 8.2 (Stata Corp., College Station, Texas). We expressed normally distributed data as means (SDs) or 95% CIs and non-normally distributed data as medians (ranges). A P value less 0.05 was deemed to be significant. No data were missing for any clinical variable measured in our study. Role of the Funding Sources This work was funded by the National Health and Medical Research Council of Australia. Aventis Pharma Pty. Ltd. provided ramipril (Tritace) and matching placebo capsules but provided no other funding for the study or to the investigators. The funding sources had no role in the design, conduct, or reporting of the study or in the decision to submit the manuscript for publication. Results This article has been retracted. See Notice of Retraction. The ramipril and placebo groups were similar in age, other cardiovascular risk factors, medication use, and PAD severity, as evidenced by clinical symptoms (walking times), WIQ scores, and resting ABI (Table). No patient was taking cilostazol or pentoxifylline. On duplex ultrasonography, 6 of 40 patients had a superficial femoral artery occlusion (2 placebo patients and 4 ramipril patients), and the remaining patients had stenotic disease in the superficial femoral artery. Only 25% of patients were taking antiplatelet or lipid-lowering therapy. No adverse events were reported. Table. Baseline Characteristics AnkleBrachial Index Ramipril significantly increased ABI both at rest (change with placebo, 0.05 mm Hg [SD, 0.04]; change with ramipril, 0.07 mm Hg [SD, 0.08]; P< 0.001) and after exercise (change with placebo, 0.04 mm Hg [SD, 0.05]; change with ramipril, 0.08 mm Hg [SD, 0.14]; P< 0.001). At rest, this increase was due to reduction in brachial systolic blood pressure with ramipril treatment (0.85 mm Hg [SD, 1.57] vs. 5.05 mm Hg [SD, 2.33]; P< 0.001) rather than an increase in limiting leg pressure (0.75 mm Hg [SD, 1.71] vs. 0.15 mm Hg [SD, 1.27]; P= 0.26). After exercise, both a reduction in brachial pressure (change with placebo, 0.30 mm Hg [SD, 2.45]; change with ramipril, 6.80 mm Hg [SD, 6.07]; P< 0.001) and an increase in limiting leg pressure (change with placebo, 5.40 mm Hg [SD, 7.56]; change with ramipril, 7.10 mm Hg [SD, 4.59]; P< 0.001) contributed to the increase in ABI. Treadmill Test After adjustment for the baseline pain-free walking time, mean pain-free walking time after ramipril treatment was 227 seconds (95% CI, 175 seconds to 278 seconds; P< 0.001) longer than after placebo treatment (Figure 2). Similarly, maximum walking time significantly improved over the 24-week treatment period by 451 seconds (CI, 367 seconds to 536 seconds; P< 0.001) in the ramipril group after adjustment for baseline values (Figure 2). The lack of change observed over the 24-week treatment period in the placebo group (change in mean walking time, 10 seconds [SD, 9] [CI, 14 seconds to 6 seconds]; P< 0.001) may reflect both the advanced age of participants and the fact that they all had limiting infrainguinal disease, which would probably give more reproducible treadmill data than aortoiliac disease. In addition, we asked patients to maintain all aspects of their lifestyle throughout the trial. Figure 2. Effect of ramipril on maximum treadmill walking times. Walking Impairment Questionnaire Ramipril improved WIQ median distance score from 5% (range, 1% to 39%) to 21% (range, 12% to 58%) (P< 0.001), speed score from 3% (range, 3% to 39%) to 18% (range, 8% to 50%) (P< 0.001), and stair-climbing score from 17% (range, 4% to 80%) to 67% (range, 38% to 88%) (P< 0.001). Duplex Ultrasonography Volume flow was unaltered in the limiting leg at the stenotic site. However, ramipril significantly increased volume flow in the common femoral artery proximal to the site of stenosis in both the limiting leg (change with placebo, 0.014 L/min [SD, 0.022]; change with ramipril, 0.017 L/min [SD, 0.034]; P= 0.008) and the nonlimiting leg (change with placebo, 0.006 L/min [SD, 0.041]; change with ramipril, 0.019 L/min [SD, 0.019]; P= 0.035). Discussion This article has been retracted. See Notice of Retraction. Our study shows that treatment