Cardiovascular effects of selective cyclooxygenase-2 inhibitors.
Selective cyclooxygenase-2 inhibitors represent a significant advance in the management of inflammatory disorders. They have similar efficacy to nonselective 'conventional' nonsteroidal anti-inflammatory drugs, but a superior gastrointestinal safety profile. However, a significant caveat is the perceived potential of cyclooxygenase-2 inhibitors to cause adverse cardiovascular effects, an issue first raised by the Vioxx Gastrointestinal Outcomes Research (VIGOR) study of rofecoxib (Vioxx, Merck & Co. Inc.). Mechanisms by which cyclooxygenase-2 inhibitors may increase cardiovascular risk are selective inhibition of prostaglandin I2 over thromboxane A2 within the eicosanoid pathway, which promotes thrombosis, and inhibition of prostaglandins E2 and I2 within the kidney, which leads to sodium and water retention and blood pressure elevation. In spite of this, the cardiovascular findings from VIGOR are not firmly supported by observations from large cohort studies and other clinical trials of selective cyclooxygenase-2 inhibitors, including the Celecoxib Long-term Arthritis Safety Study. The two main theories that explain the VIGOR findings are that the comparator used (naproxen; Naprosyn, Roche) is cardioprotective and that very high doses of rofecoxib were used, but at present neither is backed by firm evidence. Indeed, there is now early evidence that selective cyclooxygenase-2 inhibition with celecoxib may even protect against the progression of cardiovascular disease, on the basis that cyclooxygenase-2 mediates key processes in atherothrombosis. Currently, it is not clear what the net cardiovascular effects of cyclooxygenase-2 inhibitors are. The data are inconsistent and at best, speculative. It may be also that celecoxib and rofecoxib differ in their cardiovascular effects. Clarification of these issues is of vital importance given the vast number of patients presently taking both types of cyclooxygenase-2 inhibitors. Therefore, what is clear in this situation is the urgent need for randomized clinical trials designed specifically to examine the impact of selective cyclooxygenase-2 inhibitors on cardiovascular risk.
Krum
Henry
H
NHMRC Centre of Clinical Excellence in Therapeutics, Departments of Medicine, Epidemiology and Preventive Medicine, Monash University Central and Eastern Clinical School, Alfred Hospital, Melbourne, Victoria 3004, Australia. henry.krum@med.monash.edu.au
Liew
Danny
D
Aw
Juan
J
Haas
Steven
S
D002316:Cardiotonic Agents / Q000494:pharmacology; D002318:Cardiovascular Diseases / Q000517:prevention & control; D002319:Cardiovascular System / Q000187:drug effects*; D000068579:Celecoxib; D002986:Clinical Trials as Topic; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects* / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D018450:Disease Progression; D011464:Epoprostenol / Q000378:metabolism; D006801:Humans; D007783:Lactones / Q000009:adverse effects / Q000494:pharmacology; D011720:Pyrazoles; D013449:Sulfonamides / Q000009:adverse effects / Q000494:pharmacology; D013450:Sulfones
D002316:Cardiotonic Agents; D016861:Cyclooxygenase Inhibitors; D007783:Lactones; D011720:Pyrazoles; D013449:Sulfonamides; D013450:Sulfones; C116926:rofecoxib; D011464:Epoprostenol; D000068579:Celecoxib; D015232:Dinoprostone