What is the ideal study design for evaluation of treatment for heart failure?: Insights from trials assessing the effect of ACE inhibitors on exercise capacity

There is a wealth of evidence that angiotensin converting enzyme (ACE) inhibitors improve symptoms, morbidity and mortality in patients with heart failure. In this context the use of ACE inhibitors could be considered a tool with which to assess the effect of trial design and methodology on the ability to detect improvement in symptoms and exercise performance. Thirty-five published, double-blind, randomized placebo-controlled trials, involving a total of 3411 patients, which compared the effect of ACE inhibitors and placebo on exercise capacity in patients with symptomatic chronic heart failure were identified. Studies were examined in relation to whether they used cross-over or parallel group study design, study size, use of treadmill vs bicycle exercise test, year of publication, patient entry criteria, duration of follow-up and the particular ACE inhibitor used. Exercise duration improved in 23 of the studies, while symptoms improved in 25 of the 33 studies which evaluated this. In the majority of the trials (27 of 33) there was concordance between the effect on symptoms and on exercise capacity. There were six trials which showed discrepant results. Study size, duration of follow-up and method of exercise testing used were found to be major factors affecting the outcome. Trials using treadmill exercise tests were more likely to be positive than those using bicycle ergometry. All nine trials with study size more than 50, follow-up of 3-6 months and using treadmill exercise tests showed improved exercise capacity as well as symptoms. These findings may be useful in designing future trials for evaluating treatment for heart failure.