Key points from the evidence | Symptoms of peripheral arterial disease: ramipril | Advice

Summary

The evidence for the efficacy of ramipril in relieving the symptoms of peripheral arterial disease is very limited.

Two small RCTs (Ahimastos et al. 2006, n=40 and Shahin et al. 2013a, n=33) found that, compared with placebo, over 24 weeks, ramipril 10 mg daily improved maximum and pain‑free walking times and distances in people with stable intermittent claudication, a symptom of peripheral arterial disease. However, while these differences were statistically significant, the clinical importance of the results is unclear. No adverse effects were reported in 1 study. In the other study, the adverse effect most often reported with ramipril was cough, which led to discontinuation in some cases.

The studies have many limitations and ramipril has not been compared directly with other treatments for intermittent claudication. Higher quality evidence on the efficacy and safety of ramipril is needed in order to determine its place in therapy.

A third study (n=212) was originally included in this evidence summary but has now been removed. This follows a statement published in the Journal of the American Medical Association (JAMA), which advises that the study has been retracted after the lead author admitted to fabricating the results of this and a related study. This author was also the lead author for another study included in this evidence summary (Ahimastos et al. 2006) and it is unclear whether the integrity of that study is also affected. However, because of the paucity of evidence, the decision has been taken to present the results, with the proviso that the data may not be robust.

Regulatory status: Ramipril is licensed for reducing cardiovascular risk in people with peripheral arterial disease, but its use to treat symptoms of peripheral arterial disease is off‑label.

Effectiveness

Compared with placebo over 24 weeks, ramipril 10 mg daily statistically significantly improved:

mean maximum walking time and mean pain‑free walking time (Ahimastos et al. 2006, n=40; both p<0.001; clinical importance unclear)
mean maximum walking distance and mean pain‑free walking distance (Shahin et al. 2013a, n=33; both p=0.001; clinical importance unclear).

Safety

According to the summary of product characteristics for Tritace, common adverse effects of ramipril (seen in between 1 in 10 and 1 in 100 people) include headache, dizziness, cough, sinusitis, dyspnoea, gastrointestinal disturbances, rash, muscle spasms, myalgia, hyperkalaemia, hypotension, syncope, chest pain and fatigue.
No adverse effects were reported the study by Ahimastos et al. (2006). In Shahin et al. (2013a), the adverse effect most often reported with ramipril was cough, which led to discontinuation in some cases.

Patient factors

Renal function should be assessed before and during ramipril treatment, particularly in people with renal impairment.
The results of the studies may not be generalisable to people with certain comorbid conditions (for example, disease limiting mobility or renal impairment).
Most of the participants in the studies were white and it is known that ACE inhibitors are less effective for treating hypertension in people of African or Caribbean family origin; therefore, the studies may not apply to this population.
It is not known how ramipril compares with other treatments for intermittent claudication.

Resource implications

The cost of 28 days' treatment with ramipril 10 mg is £1.28 for capsules, £1.32 for tablets and £358.40 for 2.5 mg/5 ml oral solution (Drug Tariff, October 2015).

Introduction and current guidance

Peripheral arterial disease, also known as peripheral vascular disease, is a condition in which arteries that carry blood to the legs (or less commonly the arms) are narrowed or blocked. Peripheral arterial disease is generally caused by atherosclerosis and it is associated with an increased risk of cardiovascular events even when it is asymptomatic. The most common initial symptom of peripheral arterial disease is pain in the legs while walking, which is relieved by rest, known as intermittent claudication.

Treatment options for intermittent claudication include management of cardiovascular risk factors (for example, smoking, obesity, diabetes, hypertension, using antiplatelet drugs and statins), supervised exercise and vasoactive drug treatment (naftidrofuryl oxalate). See the NICE guideline on lower limb peripheral arterial disease: diagnosis and management for more information.

Full text of introduction and current guidance.

Product overview

Ramipril is an angiotensin‑converting enzyme inhibitor (ACE inhibitor) that is licensed for treating hypertension, renal disease and symptomatic heart failure. It is also licensed for the secondary prevention of acute myocardial infarction, and the reduction of cardiovascular morbidity and mortality in people with manifest atherothrombotic cardiovascular disease (including peripheral arterial disease) or diabetes with at least one cardiovascular risk factor. See the summary of product characteristics for Tritace for more information.

This evidence summary considers the evidence for using ramipril to treat the symptoms of peripheral arterial disease (intermittent claudication), rather than for reducing cardiovascular risk in people with peripheral arterial disease. The use of ramipril to treat symptoms of peripheral arterial disease is off‑label.

Full text of product overview.

Evidence review

This evidence summary discusses 2 randomised controlled trials (RCTs: Ahimastos et al. 2006 and Shahin et al. 2013a [n=40 and n=33 respectively]) that evaluated ramipril for treating people with stable intermittent claudication and concurrent medical treatment, and no comorbid conditions limiting walking ability or renal impairment. Participants were randomised to receive ramipril 10 mg daily or placebo for 24 weeks (including a 2‑week dose titration period using ramipril 5 mg daily in Shahin et al. 2013a).
Ahimastos et al. (2006) found that ramipril 10 mg daily statistically significantly increased mean maximum walking time (451 seconds, p<0.001) and mean pain‑free walking time (227 seconds, p<0.001) compared with placebo over 24 weeks. Shahin et al. (2013a) reported walking distance rather than time and found that, compared with placebo, ramipril 10 mg daily statistically significantly improved mean maximum walking distance (131 m, p=0.001) and mean pain‑free walking distance (122 m, p=0.001) over 24 weeks. Although unclear from the data reported, improvements from baseline in the studies may be clinically important (see the evidence review section of this evidence summary for more details).
Ahimastos et al. (2006) found that ramipril 10 mg daily improved Walking Impairment Questionnaire distance, speed and stair‑climbing scores at 24 weeks compared with baseline (all p<0.001) but no comparisons with placebo are reported.
Shahin et al. (2013a) found no statistically significant differences between the groups in the 3 quality of life measures used in the study (scores (EQ-5D, Short-Form 36 Health Survey [SF-36] and King's College Hospital's vascular quality of life questionnaire [VascuQoL]).
According to the summary of product characteristics for Tritace, common adverse effects of ramipril (seen in between 1 in 10 and 1 in 100 people) include headache, dizziness, cough, sinusitis, dyspnoea, gastrointestinal disturbances, rash, muscle spasms, myalgia, hyperkalaemia, hypotension, syncope, chest pain and fatigue. Renal function should be assessed before and during ramipril treatment, particularly in people with renal impairment.
No adverse effects were reported the study by Ahimastos et al. (2006). In Shahin et al. (2013a), the adverse effect most often reported with ramipril was cough, which led to discontinuation in some cases.
The 2 studies were small (n=33 and n=40), affecting their statistical power to detect differences between the groups. Participants had stable intermittent claudication that limited their mobility and exercise tolerance, and stable concurrent medical therapies. The results may not be generalisable to people with less severe intermittent claudication or comorbid conditions (for example, concomitant disease limiting walking, including coronary artery disease, or renal impairment). Most of the participants in the studies were white and it is known that ACE inhibitors are less effective for treating hypertension in people of African or Caribbean family origin; therefore, the studies of intermittent claudication may not apply to this population. The treatment period was 24 weeks and it is not known whether benefits will be maintained in the longer term. It is also not known how ramipril compares with other treatments for intermittent claudication because the studies were placebo controlled.

Full text of evidence review.

Context and estimated impact for the NHS

The cost of 28 days' treatment with ramipril 10 mg is £1.28 for capsules, £1.32 for tablets and £358.40 for 2.5 mg/5 ml oral solution (Drug Tariff, October 2015).

Full text of context and estimated impact for the NHS.

Information for the public

A plain English summary is available on the NICE website. This sets out the main points from the evidence summary in non‑technical language and may be especially helpful for people with peripheral arterial disease who are thinking about trying ramipril.

About this evidence summary

'Evidence summaries: unlicensed or off‑label medicines' summarise the published evidence for selected unlicensed or off‑label medicines that are considered to be of significance to the NHS, where there are no clinically appropriate licensed alternatives. The summaries provide information for clinicians and patients to inform their decision‑making and support the construction and updating of local formularies.

The summaries support decision‑making on the use of an unlicensed or off-label medicine for an individual patient, where there are good clinical reasons for its use, usually when there is no licensed medicine for the condition requiring treatment, or the licensed medicine is not appropriate for that individual.

The strengths and weaknesses of the relevant evidence are critically reviewed within this summary, but this summary is not NICE guidance.