Quality management of a large randomized double-blind multi-centre trial: the ACTION experience.

The ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine GITS) study was an independent, investigator-initiated, multi-national trial comparing nifedipine GITS to placebo in 7665 patients with stable angina pectoris. The trial was sponsored by the manufacturer of the medication concerned. 291 centers in 19 countries participated. Results have been published. We defined quality management (QM) as all activities directed at ensuring data integrity and consistency; and ensuring appropriate trial conduct, including pro-active prevention of deviations from protocol. We describe the QM framework that was adopted for the ACTION trial and the key tools that were used. In the protocol, particular attention was paid to explicit definition of tasks and responsibilities of all participants, and to unequivocal operational definitions of terms such as 'randomized', 'follow-up', etc. that could be applied by investigators, on-site monitors and during data processing at the coordinating centre. A comprehensive clinical trial and study management system based on simultaneous display of scanned documents and data base content had a central role. We describe in detail how compliance with good clinical practice was ensured, how the intention-to-treat principle was implemented, how compliance with study medication and completeness of follow-up was achieved, how double blinding was maintained throughout the study structure, and how patient safety was protected. The protocol ruled out participation in any other study at the same time by ACTION participants. Our experience showed that the reasons for this are not always understood by investigators. Unequivocal operational definitions of the procedural concepts that characterize randomized clinical trials should not only be the basis of QM, but also of reporting results.

Resource utilization implications of treatment were able to be assessed from appropriately reported clinical trial data.

BACKGROUND AND OBJECTIVE: Published clinical trial data rarely allow assessment of the health care resource utilization implications of treatment. We give an example of how these can be assessed given appropriate tabulation of data. METHODS: Data from a trial comparing long-acting nifedipine gastrointestinal therapeutic system to placebo in 7,665 patients with stable angina pectoris was analyzed. RESULTS: Relative to placebo, nifedipine significantly increased mean cardiovascular (CV) event-free survival by 41 days but had no effect on mean survival. Per 100 years of follow-up, 78.1 patient-years of double-blind nifedipine administration reduced use of another calcium antagonist, an angiotensin converting enzyme inhibitor, an angiotensin receptor blocker, a diuretic and a cardiac glycoside by 1.54, 3.73, 2.63, 2.23, and 0.64 years, respectively, whereas 0.21 less hospitalization for overt heart failure, 0.47 less hospitalization for any stroke or transient ischemic attack, 0.8 less coronary angiogram, 0.38 less coronary bypass procedure, and 0.13 additional orthopedic procedure was required. Combining resource utilization with cost data for one particular hospital showed that one additional year of CV event-free survival costs an average additional euro 3,036 in the setting considered. CONCLUSION: Appropriately tabulated clinical trial data allows clinicians to judge the resource utilization implications and economic effect of treatment decisions.

Diagnostic criteria and adjudication process both determine published event-rates: the ACTION trial experience.

OBJECTIVE: Few trials report event-adjudication procedures in detail. Using data from the ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine GITS) study, we compared the impact on event-rates of an adjudication strategy based on systematic screening of all reported serious adverse events (SAEs) with a strategy based on investigator diagnoses. The final diagnosis was always made by a critical events committee (CEC) using standard criteria. METHODS: ACTION randomized 7665 patients with stable angina to either nifedipine or placebo. Pre-specified events included acute or procedural myocardial infarction (MI), refractory angina, heart failure and debilitating stroke. Clinically related SAEs including in-hospital procedures were combined into episodes independent from the investigator diagnoses entered on SAE reports. All fatal episodes and those episodes suggestive of pre-specified events were adjudicated by the CEC. RESULTS: During follow-up, 17,081 episodes were reported in 5312 patients. The SAE descriptions ruled out the occurrence of a pre-specified event in 28%. The remaining 72% were adjudicated by the CEC and 616 cases of MI, 361 of refractory angina, 275 of heart failure and 190 of debilitating stroke were diagnosed (total=1442). Had adjudication by the CEC been limited to the 3924 episodes (2397 patients) that were fatal or for which the investigator had reported any of the diagnoses mentioned, 98 cases of MI, 35 of refractory angina, 81 of heart failure and 14 of debilitating stroke would have been missed (total=228). CONCLUSION: Both the diagnostic criteria used and the adjudication process determine event-rates and conclusions about treatment effects in clinical trials. Published trial reports should always state if event-adjudication was independent of the diagnoses of investigators, and if all events of interest were adjudicated or only the first one.