Imprecision
Authors: Garret A. FitzGerald
Journal: Circulation (2016)

andomized 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 E 2 and I 2 (prostacyclin), whereas their gastrointestinal adverse effects result from the inhibition of cyclooxygenase 1 (COX-1)derived gastroduodenal prostaglandins E 2 and I 2 and COX-1-derived thromboxane A 2 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. 2 The 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 I 2 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 trials 3 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 NSAIDs was fragmentary or nonexistent.Coincident with the emergence of evidence that valdecoxib conferred a cardiovascular hazard (a finding delayed for months as the rofecoxib story unfolded), Pfizer announced in October 2004 plans to sponsor a placebo-controlled study of celecoxib in 4000 patients at high cardiovascular risk.Almost a year later, Pfizer announced that they would spend "at least $100 million" to conduct what became PRECISION, a comparison of celecoxib, ibuprofen, and naproxen in high-risk cardiovascular patients.The principal investigator predicted completion within 4 years. 4t the outset, the ethics and the interpretability of the trial prompted controversy.European Union countries declined to participate because of concerns about the safety of celecoxib.It was suggested that such concerns, together with the eventdriven nature of the trial, would delay completion, perhaps until expiration of the patent on celecoxib. 4Furthermore, such high-risk patients would likely be taking lowdose aspirin, which targets platelet COX-1-derived thromboxane A 2 .Both ibuprofen and naproxen interact to undermine sustained cardioprotection by aspirin; however, COX-2 is not extant in platelets, risking an intrinsic bias in favor of celecoxib. 2