Since Rofecoxib (Vioxx) was withdrawn from the worldwide market based on the safety findings of the Adenomatous Polyp Prevention on Vioxx (APPROVe) study, the uncertainty around the cardiovascular safety of NSAIDs and COX-2 inhibitors remains and leaves practitioners with difficult management decisions for the hundreds of millions of patients worldwide who continue to require pain-relieving therapy to maintain an acceptable quality of life.
Importantly, the Food and Drug Administration recently summarized a statement that in various controlled clinical trials the cardiovascular risks of COX-2 selective drugs have been indistinguishable from non-selective NSAIDs, thus also raising serious questions about the safety of the latter. As such, the FDA mandated a “boxed warning” for COX-2 selective inhibitors and traditional NSAIDs alike in view of the potential of these agents to increase adverse cardiovascular outcomes. Unfortunately, none of the reported randomised trials undertaken with NSAIDs and COX-2 selective inhibitors have thus far been specifically designed to examine cardiovascular outcomes. Thus, the current situation is one of classic ‘equipoise’. Adequately powered, independently run randomized clinical trials prospectively designed to capture cardiovascular outcomes are urgently needed.
In order to address at least some of the remaining clinically important questions concerning anti-inflammatory drugs, the PRECISION – Prospective Randomised Evaluation of Celecoxib Integrated Safety vs. Ibuprofen and Naproxen - trial in more than 20000 patients with osteoarthritis is now under way. Until trials like these are completed, careful risk benefit analysis needs to be undertaken for all anti-inflammatory agents regarding their potential gastrointestinal benefit, which in many cases remains yet to be definitely established, versus potential increase in cardiovascular risk, hypertension and its clinical sequels in particular.