Effect of ramipril on walking times and quality of life among patients with peripheral artery disease and intermittent claudication: A randomized controlled trial. Journal of the American Medical Association 2013;309: 453–460

Abstract

Study objective:

The objective of the trial was to examine whether ramipril, an angiotensin-converting enzyme (ACE), improves walking distance and health-related quality of life in patients with peripheral artery disease (PAD) associated with claudication.

Study population:

The study enrolled 212 patients with risk factors and symptoms of PAD treated by conventional therapies at three centers in Australia. All patients had an ankle–brachial index (ABI) of less than 0.90 at rest and intermittent claudication in at least one leg, which were stable for at least 6 preceding months along with the medication regimen. The patients were excluded if blood pressure was not controlled (brachial blood pressure of 160/100 mmHg or greater); if there was current or recent use of either ACE inhibitors or angiotensin II receptor blockers, potassium-sparing diuretics, or potassium supplements; renal failure (serum creatinine level 2.3 mg/dL or greater [200 µmol/L]); renal artery stenosis; previous coronary or peripheral artery revascularizations, recent myocardial infarction and other health conditions other than PAD that could adversely influence walking ability at the time of screening and for 1 year thereafter.

Design and methods:

This was a randomized, placebo-controlled, triple blinded study of ramipril at the high daily dose (10 mg) for 6 months. Primary outcomes were pain-free and maximum walking times assessed by a standard treadmill exercise test. Secondary outcomes were ABI changes; symptoms and functional status assessed by the Walking Impairment Questionnaire (WIQ)¹; health-related quality of life assessed by the Short-Form 36 Health Survey (SF-36)²; and stenosis severity assessed by duplex ultrasound of the lower limb arteries. At baseline and at follow-up, pain-free and maximum walking distances were assessed by the standard constant load treadmill exercise test performed at a speed of 3.2 km/h and a grade of 12%.³ ABI was calculated in both legs. Duplex ultrasonography was used to determine stenosis in lower-limb vessel segments. Functional changes per WIQ, and perceived disability assessed on the Physical Component Summary and the Mental Component Summary of the SF-36 were self-reported. Sample size was calculated as 100 patients per each group needed to provide a power of 80% at an α of 0.05 to detect a 120-second change in walking time and a 65-second change in pain-free walking time. A two-sided p-value of less than 0.05 was considered significant. Baseline variables were compared using the χ² test and one-way analysis of variance. The analysis of covariance model with baseline and post-treatment values after 6 months used Kruskal–Wallis analysis of variance. Imputations for missing 6-month data were performed. Data were analyzed on the intention-to-treat basis.

Results:

Of 921 potential participants screened, 212 eligible participants were randomized into equal-sized ramipril and placebo groups where baseline parameters were not different. Compliance was monitored by pill count and adverse effects were monitored through interval clinical assessments, laboratory tests, and telephone calls. There was a 100% adherence rate to the study medications among 200 patients who completed the study. Ramipril was associated with a 75-second increase in mean pain-free and a 255-second increase in maximum walking time. There was a modest (less than 5 mmHg) blood pressure reduction and a small (0.1) ABI increase at rest and after exercise compared to placebo. The maximum walking time increase after ramipril therapy compared to placebo was greater in the subgroup of patients with femoropopliteal disease (286 seconds) than in those with aortoiliac disease (127 seconds). Patients treated with ramipril showed improvement of the median distance, speed and stair climbing scores on the WIQ, as well as of the Physical, but not the Mental, Component Summary score on the SF-36. The most frequent side effect was dizziness, more common in the ramipril (8.5%) than in the placebo (2.8%) group. Persistent cough occurred in 6.6% of patients on ramipril, causing their withdrawal from the study.

Commentary

While PAD affects millions of people in the US and worldwide, ⁴ the number of pharmacological agents available for the treatment of symptomatic PAD is limited, with only pentoxifylline and cilostazol approved by the US Food and Drug Administration. The use of these agents is often limited by their side-effect profiles, while their effectiveness is modest – with walking distance improved in studies by dozens of meters at best.^5,6 Prior studies of ACE inhibitors in PAD yielded inconsistent results.^7,8 Patients with PAD share multiple cardiovascular risk factors, frequently not adequately addressed, prompting the need to evaluate the effects on PAD of existing pharmacological agents and other interventions geared towards common risk factors. ⁹ ACE inhibitors represent one such class of potential agents with emerging evidence from populational and smaller observational and experimental studies suggesting benefits of improved symptom control, lower all-cause mortality, but also, possibly, an increased long-term risk of recurrent vascular interventions.^10,11

This study was an investigator-initiated, randomized, placebo-controlled trial of ACE inhibitor therapy in PAD. It also included patients with multilevel disease and diabetes previously excluded from some studies, thus making the patient profile more realistic. ⁷ However, the study was conducted at three geographically proximal sites in Australia, potentially limiting its generalizability. Approximately two-thirds of potential participants were excluded. The participants had blood pressures that were only modestly elevated to allow for the use of placebo and some of the common, but significant, comorbidities of PAD were excluded, making the studied group less reflective of the real-life PAD population. There was only one baseline exercise test and the less than expected placebo response may have exaggerated the response to ramipril.

While the absolute numbers of the increase of pain-free and maximum walking times in this study may seem modest (slightly over 1 and 4 minutes on average, respectively), these changes are clinically significant as they may empower some patients enough to maintain more independent living. In fact, there was a clinically significant improvement in uphill walking of 184 meters. This translates to greater than two city blocks of walking, a distance sufficient for some patients to be reclassified from Fontaine IIb to IIa stage, although this assessment is not offered in the article directly. Further, symptomatic improvements demonstrated in the ramipril arm of the study are at least on par with, and potentially greater than, the effects produced by walking exercises and the approved pharmacological agents pentoxifylline and cilostazol, thus opening the possibility of combination therapy.^5,12 Besides, ACE inhibitors are the mainstay of therapy in patients with heart failure, which often accompanies PAD, where cilostazol is contraindicated. If a class effect exists, ACE inhibitors may become a particularly attractive element of therapy for many PAD patients. This study reinforces the positive effects of ramipril in the PAD population observed in the HOPE trial and the need to titrate the dose to maximum therapy.^13,14

Aside from the intervention, the patients in this study were on a stable medication regimen for 6 months prior to and after randomization. There is a mention of lifestyle advice being given to participants before commencing the trial, but it is unclear whether active lifestyle modification was attempted. Walking exercise programs have been effective in relieving claudication. ¹² In the recent CLEVER study, despite better walking performance, the reported quality of life by the patients in supervised exercise programs was inferior to that reported by the patients who underwent stent revascularization. ¹⁵ This highlights the fact that although apparently effective, structured walking exercise programs may be too challenging and not always feasible for some patients with possible individual preferences for more ‘passive’ treatments, driving the demand for effective pharmacological agents. Similarly, in this study, improved stair climbing scores on the WIQ and of the Physical Component on the SF-36 were not associated with improvement of the Mental Component Summary score. This may again reflect the fact that individual therapies producing appreciable but modest positive effects may not be sufficient to confer enough satisfaction to the patients with the disease to be profoundly lifestyle altering.

While the findings of this study are encouraging, the mechanisms remain putative and may range from increased blood flow through vascular collaterals and angiogenesis, to enhanced energy production with improved endothelial function and glucose metabolism, to antifibrotic effects. More research of class effects of ACE inhibitors, their comparison with other treatments and of combination therapies is necessary.

Vascular viewpoint rating

• Study design: Randomized clinical trial

• Was the study valid: Yes, the study demonstrated internal validity, but needs to be replicated, given the large effect size

• Are the results believable: Yes, although their generalizability is uncertain as exclusions, geographical and other epidemiologic factors may have played a role.