Angiotensin Converting Enzyme (ACE) Inhibition and Peripheral Arterial Disease
Condition: Peripheral Arterial Disease
MeSH terms: Peripheral Arterial Disease; Peripheral Vascular Diseases
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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 name(s): Ramipril or matching placebo
Intervention type(s): Drug
Intervention description(s): 10 mg Ramipril or matching placebo once daily for 6 months
Other intervention name(s): Ramace
Intervention MeSH terms: Ramipril
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: peripheral arterial disease; angiotensin converting enzyme inhibitors; exercise