is a hierarchical classification of evidence useful or a hindrance?
PURPOSE: Only randomized clinical trials (RCTs) are deemed suitable to determine causality, as epidemiological studies are considered not ‘robust’. The objective of this study was to evaluate whether causality should remain the only consideration with drug toxicity signals. Cyclooxygenase-2 (Cox-2) inhibitors provided an example. METHODS: Our study population included patients aged 40+ years prescribed Cox-2 inhibitors in the General Practice Research Database (GPRD) (N = 150 000). We estimated the risks of upper gastrointestinal (GI) events and myocardial infarction (MI). Attributable risks were estimated using simulation methodology based on various hypothetical scenarios. RESULTS: The risk-benefit profile was strongly related to the rate of GI events. With a RCT incidence, the GI benefits would exceed MI risks. With a ‘real-life’ GI incidence, the benefits did not exceed the risks substantially. The onset and offset of drug effects also predicted the magnitude of both risks and bene
