Informative noncompliance in endpoint trials

Noncompliance with study medications is an important issue in the design of endpoint clinical trials. Including noncompliant patient data in an intention-to-treat analysis could seriously decrease study power. Standard methods for calculating sample size account for noncompliance, but all assume that noncompliance is noninformative, i.e., that the risk of discontinuation is independent of the risk of experiencing a study endpoint. Using data from several published clinical trials (OPTIMAAL, LIFE, RENAAL, SOLVD-Prevention and SOLVD-Treatment), we demonstrate that this assumption is often untrue, and we discuss the effect of informative noncompliance on power and sample size

ACE Inhibition and Endothelial Function: Main Findings of PERFECT, a Sub-Study of the EUROPA Trial

Background: ACE inhibition results in secondary prevention of coronary artery disease (CAD) through different mechanisms including improvement of endothelial dysfunction. The Perindopril-Function of the Endothelium in Coronary artery disease Trial (PERFECT) evaluated whether long-term administration of perindopril improves endothelial dysfunction. Methods: PERFECT is a 3-year double blind randomised placebo controlled trial to determine the effect of perindopril 8 mg once daily on brachial artery endothelial function in patients with stable CAD without clinical heart failure. Endothelial function in response to ischaemia was assessed using ultrasound. Primary endpoint was difference in flow-mediated vasodilatation (FMD) assessed at 36 months. Results: In 20 centers, 333 patients randomly received perindopril or matching placebo. Ischemia-induced FMD was 2.7% (SD 2.6). In the perindopril group FMD went from 2.6% at baseline to 3.3% at 36 months and in the placebo group from 2.8 to 3.0%. Change in FMD after 36 month treatment was 0.55% (95% confidence interval −0.36, 1.47; p = 0.23) higher in perindopril than in placebo group. The rate of change in FMD per 6 months was 0.14% (SE 0.05, p = 0.02) in perindopril and 0.02% (SE 0.05, p = 0.74) in placebo group (0.12% difference in rate of change p = 0.07). Conclusion: Perindopril resulted in a modest, albeit not statistically significant, improvement in FMD

The use of ACE-inhibitors after myocardial infarction

Background: There is good evidence that angiotensin-converting enzyme (ACE) inhibitors are beneficial after myocardial infarction (MI). However, it is not known how widely this evidence is used in practice and whether all eligible patients receive this therapy. Aim: To assess the usage of ACE inhibitors in patients after MI in a large teaching hospital. Method: A one month prospective analysis, combined with a three month retrospective analysis, was conducted at the Royal Brisbane Hospital (RBH) in February-March 2000. Patients admitted with an MI or who had been diagnosed with an MI during admission from November 1999 to March 2000 were identified from the coronary care unit (CCU) records. Inpatient medication charts and outpatient records were then reviewed. Information collected included: ACE inhibitor use, doses, reasons for prescribing/not prescribing ACE inhibitors, and ACE inhibitor prescribers (cardiologists or general physicians). Results: Forty four patients with an MI were included in the study, 28 of whom were prescribed ACE-inhibitors (64%). Twenty four of the 28 patients on ACE inhibitors were prescribed perindopril. The major reason given for prescribing ACE inhibitors was signs of congestive cardiac failure. All ACE inhibitors initiated in patients after MI at RBH were ordered by cardiologists. Conclusion: ACE inhibitors were prescribed appropriately in 88% of patients who met criteria for their use. This high percentage of appropriate prescribing was encouraging. Reevaluation as part of an ongoing quality assurance activity could be used to ensure this is maintained