Recently, cyclooxygenase-2 (COX-2) inhibitors (coxibs), a class of drugs intended to be painkillers, have created unprecedented controversy because of their cardiovascular risk profile. The controversy has affected the patients, health-care providers, the Food and Drug Administration, and the manufacturers of these agents alike. We summarize the mechanisms of actions of this class of agents, their cardiovascular risk as evident in multiple trials, the basis of their adverse risk profile, and our views on this issue.
Bresalier RS , Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med352:1092-1102, 2005
2.
Bombardier C , Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med343:1520-1528, 2000
3.
Mukherjee D . Selective cyclooxygenase-2 (COX-2) inhibitors and potential risk of cardiovascular events. Biochem Pharmacol63:817-821, 2002
4.
FitzGerald GA . COX-2 and beyond: Approaches to prostaglandin inhibition in human disease. Nature Drug Disc2:879-890, 2003
5.
Silverstein FE , Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal antiinflammatory drugs for osteoarthritis and rheumatoid arthritis: The CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA284:1247-1255, 2000
6.
Jüni P , Rutjes AWS, Dieppe PA. Are selective COX-2 inhibitors superior to traditional non-steroidal anti-inflammatory drugs?Br Med J324:1287-1288, 2002
7.
FitzGerald GA . Coxibs and cardiovascular disease. N Engl J Med351:1709-1711, 2004
8.
FDA CLASS Advisory Committee . CLASS Advisory Committee briefing document. Available at http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b1_01_searle.pdf. Accessed March 26, 2005
9.
Solomon SWD , McMurray JJV, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med352:1071-1078, 2005
10.
Farkouh ME , Korshner H, Harrington RA, et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event trial (TARGET), cardiovascular outcomes: Randomised controlled trial. Lancet364:675-684, 2004
11.
Schnitzer TJ , Burmester GR, Mysler E, et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event trial (TARGET), cardiovascular outcomes: Randomised controlled trial. Lancet364:665-674, 2004
12.
Topol EJ , Falk GW. A coxib a day won’t keep the doctor away. Lancet364:639-640, 2004
13.
Nussmeier NA , Whelton AA, Brown MT, et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med352:1081-1091, 2005
14.
Alsalameh S , Burian M, Mahr G, et al. The pharmacological properties and clinical use of valdecoxib, a new cyclooxygenase-2-selective inhibitor. Aliment Pharmacol Ther17:489-501, 2003
15.
McAdam BF , Catella-Lawson F, Mardini IA, et al. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: The human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci USA96:272-277, 1999
16.
Zimmermann KC , Sarbia M, Schrör K, et al. Constitutive cyclooxygenase-2-expression in healthy human and rabbit gastric mucosa. Mol Pharmacol54:536-540, 1998
17.
Rabausch K , Bretschneider E, Sarbia M, et al. Regulation of thrombomodulin expression in human vascular smooth muscle cells by COX-2-derived prostaglandins. Circ Res96:E1-e6, 2005
18.
FitzGerald GA , Smith B, Pedersen AK, et al. Prostacyclin biosynthesis is increased in patients with severe atherosclerosis and platelet activation. N Engl J Med310:1065-1068, 1984
19.
Mehta JL , Lawson DL, Mehta P, et al. Increased prostacyclin and thromboxane A2 biosynthesis in atherosclerosis. Proc Natl Acad Sci USA85:4511-4515, 1988
20.
Belton O , Byrne D, Kearney D, et al. Cyclooxygenase-1 and -2-dependent prostacyclin formation in patients with atherosclerosis. Circulation102:840-845, 2000
21.
Mehta JL , Nichols WW. What is the potential role of thromboxane inhibitors in preventing myocardial ischaemic injury?DRUGS40:657-665, 1990
22.
Coussens LM . Inflammation and cancer. Nature420:860-867, 2002
23.
Augenlicht LH , Velcich A, Klampfer L, et al. Application of gene expression profiling to colon cell maturation, transformation and chemoprevention. J Nutr133 (7 Suppl):2410S-2416S, 2003
24.
Kokawa A , Kondo H, Gotoda T, et al. Increased expression of cyclooxygenase-2 in human pancreatic neoplasms and potential for chemoprevention by cyclooxygenase inhibitors. Cancer91:333-338, 2001
25.
Maitra A , Ashfaq R, Gunn CR, et al. Cyclooxygenase 2 expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasia: An immunohistochemical analysis with automated cellular imaging. Am J Clin Pathol118:194-201, 2002
26.
Sung YK , Hwang SY, Kim JO, et al. The correlation between cyclooxygenase-2 expression and hepatocellular carcinogenesis. Mol Cells17:35-38, 2004
27.
Waddell WR , Loughry RW. Sulindac for polyposis of the colon. J Surg Oncol24:83-87, 1983
28.
Waddell WR , Ganser GF, Cerise EJ, et al. Sulindac for polyposis of the colon. Am J Surg157:175-179, 1989
29.
Bresalier RS . Chemoprevention comes to clinical practice: COX-2 inhibition in familial adenomatous polyposis. Gastroenterology119:1797-1798, 2000
30.
Moran EM . Epidemiological and clinical aspects of nonsteroidal anti-inflammatory drugs and cancer risks. J Environ Pathol Toxicol Oncol21:193-201, 2002
31.
Ding H , Han C, Zhu J, et al. Celecoxib derivatives induce apoptosis via the disruption of mitochondrial membrane potential and activation of caspase 9. Int J Cancer113:803-810, 2005
