Official Title: “ACE Inhibition; A Potential New Therapy for Peripheral Arterial Disease”

Leg pain caused by peripheral arterial disease (PAD) can severely impede walking ability. Our preliminary findings indicate that the drug ramipril is much more effective in improving walking ability than current therapies. To be accepted as a new treatment for PAD these findings require validation in a much larger clinical trial.We propose to examine the effects of ramipril therapy for 6 months in a randomized, controlled trial of patients with PAD. If positive, this study will identify ramipril as a potential new therapy for PAD.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Efficacy Study

Study Primary Completion Date: December 2010

This proposal extends our novel finding that the angiotensin-converting enzyme (ACE) inhibitor, ramipril markedly improves walking ability in patients with peripheral arterial disease (PAD), by conducting a larger clinical trial including a broader cross-section of PAD patients.

Hypothesis:

That ramipril therapy for 24 weeks will result in clinically significant increases in both pain-free and maximum walking time and improve quality of life in patients with PAD.

Background Synopsis:

Peripheral arterial disease is a common disorder, with 12% of adults over 50 having an ankle-brachial index (ABI) diagnostic of PAD (<0.9). Approximately one third of these patients experience intermittent claudication during walking, limiting the ability of these older individuals to participate in normal activities. The aim of PAD treatment is to improve walking distance and quality of life in those with intermittent claudication, and to decrease long term cardiovascular morbidity and mortality. However, the range of medical treatments to improve walking distance in these patients is limited. Our pilot study demonstrates that treatment of PAD patients, with infra-inguinal disease and without diabetes with ramipril for 24 weeks, markedly improves waking ability. Relative to placebo, ramipril increased mean treadmill-assessed pain-free waking time by 227s (160%, p<0.001) and mean maximum walking time by 451s (240%, p<0.001). Assuming a constant speed of 0.89 m/s (3.2 km/hr), this corresponds to a clinically significant increase in walking distance of 401m (95% CI 330m to 480m) which would impact appreciably on daily functional capacity. The magnitude of this effect is significantly greater than that reported for conventional medical therapies and provides worthwhile clinical benefit.

Research Plan Synopsis:

The dramatic findings of our pilot study clearly warrant verification in a larger clinical trial including diabetic patients and those with aorto-iliac disease as well as infra-inguinal disease. The current proposal is to expand our pilot study into a large trial with broad inclusion criteria. We propose to include patients with diabetes mellitus not currently medicated with ACE inhibitors. 264 PAD patients will be randomised to either ramipril (10mg once daily) or matching placebo for 24 weeks in a randomised, double-blind placebo controlled trial. All patients will undergo a treadmill exercise test to determine pain free and maximum walking times, ABI measurements and Duplex scanning to determine stenosis severity, both at baseline and following 6 months of ramipril therapy. Functional capacity in a daily life setting, will be assessed using standardised questionnaires (Walking Impairment Questionnaire and Quality of Life Questionnaire).

Outcomes and Significance:

If positive this trial will validate our pilot findings that the ACE inhibitor ramipril is an efficacious new therapy for the treatment of patients with claudication resulting from PAD.

Given the escalating prevalence of PAD, this work has the potential for widespread impact.

Intervention(s) in this Clinical Trial

• Drug: Ramipril or matching placebo
  • 10 mg Ramipril or matching placebo once daily for 6 months

Primary Measures

• walking time
  • Time Frame: baseline and 6 months
    Safety Issue?: No

Secondary Measures

• walking impairment questionnaire
  • Time Frame: baseline and 6 months
    Safety Issue?: No

Inclusion Criteria:

• Ankle brachial index of <0.9 in at least one leg
• History of intermittent claudication (unilateral or bilateral)
• A stable medication regimen for at least 6 months

Exclusion Criteria:

• Limiting coronary artery disease
• Renal failure (serum creatinine > 0.20 mmol/L)
• Current treatment or treatment within the previous 6 months with ACE inhibitors or angiotensin II receptor antagonists

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 40 Years

Maximum Age for this Clinical Trial: 85 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Bayside Health

Overall Clinical Trial Officials and Contacts

Bronwyn A Kingwell, PhD Principal Investigator Baker Heart Research Institute  

Overall Contact: Anna A Ahimastos, PhD +61 3 9076 2356 A.Ahimastos@alfred.org.au

Information obtained from ClinicalTrials.gov on October 10, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00681226

Study ID Number: 273/06

ClinicalTrials.gov Identifier: NCT00681226

Health Authority: Australia: National Health and Medical Research Council