Cardiovascular risk and inhibition of cyclooxygenase: traditional nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors

BACKGROUND The development of non-selective nonsteroidal anti-inflammatory drugs (tNSAIDs) and, more recently, of selective inhibitors of the cycloooxygenase-2 isoform (COXIBs), has contributed greatly towards the effective management of patients with arthritis and pain complaints. Although COXIBs have demonstrated an improved gastrointestinal tolerability compared with tNSAIDs, the cardiovascular effects of the two drugs types are much controversial. By blocking prostacyclin formation but leaving platelet-derived thromboxane A2 generation unopposed, the potential gastrointestinal benefit of COXIBs may come at cost of increased thrombotic risk. AIM OF THE STUDY This review aims at analysing the cardiovascular effects of the tNSAIDs and COXIBs. METHOD This review addresses the controversy of effects of COXIBs and tNSAIDs in 4 segments. It begins with a discussion about pathophysiological effects of cyclooxygenase inhibition on cardiovascular system. This is followed by a systematic review and meta-analysis of a control, randomized, double blind study and population-based matched case-control study to compare the risk of serious cardiovascular events with tNSAIDs and COXIBs. Then it answers to key questions with the aim to assist the clinicians for a systematic approach to evaluate the risk-benefit-ratio of NSAIDs in the clinical practice. Finally we analyse the open questions associated with the use of NSAIDs and the cardiovascular events. RESULTS The use of rofecoxib demonstrated an increase in adverse cardiovascular events. This toxic effect is not dose-related. The relationship between celecoxib and cardiovascular risk is less clear. The results of different clinical trials are conflicting: some didn’t demonstrate increase in cardiovascular toxicity but the APC study and recently a metanalysis reported a significant incidence of adverse cardiovascular events. Also valdecoxib and parecoxib appear to have increased risk for cardiovascular toxicity. Eterocoxib is still the object of three ongoing clinical trials. The TARGET study demonstrated for lumiracoxib a low increase in cardiovascular events compared with ibuprofen and naproxen. Also the use of ibuprofen (800 mg t.i.d.), diclofenac (75 mg b.i.d.) and indomethacin is reported to cause adverse cardiovascular events. The use of naprosen shows a better profile regarding cardiovascular toxicity. tNSAIDSs can worse clinical condition of patients affected by chronic cardiac failure and rofecoxib but not celecoxib can disclose clinical cardiac failure. A politherapy with both tNSAIDs and rofecoxib demonstrated an increase of blood arterial pressure and peripheral oedema. CONCLUSIONS This review confirms the findings from randomized trials, meta-analysis and observational studies regarding the risk of cardiovascular events with rofecoxib, valdecoxib e parecoxib, whereas the evidence for other COXIBs is not so clear. Also in the class of tNSAID some drugs (diclofenac and ibuprofen) can have an increased cardiovascular toxicity.