Imprecision

Randomized controlled trials are viewed as providing gold standard evidence, and the declaratively named PRECISION trial (Prospective Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen)1 implies the final word on the comparative cardiovascular safety of nonsteroidal anti-inflammatory drugs (NSAIDs).The analgesic efficacy of NSAIDs derives largely from suppressing cyclooxygenase 2 (COX-2)–derived prostaglandins E2 and I2 (prostacyclin), whereas their gastrointestinal adverse effects result from the inhibition of cyclooxygenase 1 (COX-1)–derived gastroduodenal prostaglandins E2 and I2 and COX-1–derived thromboxane A2 in platelets. This prompted the development of NSAIDs engineered to inhibit COX-2 specifically, such as rofecoxib, celecoxib, and valdecoxib. Randomized comparisons, such as VIGOR (Vioxx Gastrointestinal Outcomes Research), comparing rofecoxib and naproxen, showed fewer complicated gastrointestinal events with the COX-2 inhibitors.2The value of randomized trials was also evident when evidence, first from clinical pharmacology and then from experiments in model systems, predicted that cardiovascular events would complicate COX-2 inhibition of prostaglandin I2 in the vasculature. Evidence consistent with this hypothesis emerged from VIGOR with more serious thromboembolic events with rofecoxib. Definitive evidence of cardiovascular hazard subsequently emerged from 10 placebo-controlled trials of structurally distinct COX-2 inhibitors.2 Last, overview analysis of individual data derived from ≈750 randomized trials3 provided a risk estimate of the magnitude of this hazard from COX-2 inhibitors with a rate ratio (RR) for serious vascular events of 1.37 (95% confidence interval, 1.14–1.66). As mechanistically predicted,2 the RRs for celecoxib (average daily dose, 400 mg) and rofecoxib (average daily dose, 25 mg) were superimposable. By contrast, information on older …