On September 30, 2004, Merck & Co. (Whitehouse Station, New Jersey) withdrew its blockbuster drug rofecoxib from the worldwide market. After just five years on the market, the annual sales of rofecoxib (Vioxx) had grown to $1.5 billion. Rofecoxib and celecoxib (Celebrex; Pfizer, New York, NY) belong to a relatively new class of nonsteroidal anti-inflammatory drugs that were designed to selectively inhibit the COX-2 (cyclooxygenase-2) enzyme and thus reduce gastrointestinal side effects. While the coxibs have been proven to be effective for reducing arthritis symptoms, their safety has been controversial. This review updates orthopaedic surgeons on the present status of the coxib controversy.
The COX-1 enzyme metabolizes arachidonic acid to prostaglandins. The COX-1 enzyme is constitutively expressed in most tissues, including the gastric mucosa, whereas expression of COX-2 is thought to be induced in response to inflammation. Thus, COX-2-selective inhibitors were designed to produce the analgesic effects of nonsteroidal anti-inflammatory drugs while minimizing gastrointestinal side effects1.
Nonselective nonsteroidal anti-inflammatory drugs reduce thromboxane-A2 production in platelets and may decrease platelet aggregation, leading to bleeding. Selective coxibs are particularly attractive in the perioperative period because they do not inhibit thromboxane-A2 production and thus do not promote bleeding2.
FitzGerald3 proposed that COX-2-selective inhibitors have a curious side effect: they reduce production of prostaglandin I2 (prostacyclin). Prostaglandin I2 is produced by COX-2 in the vascular endothelium, and it causes vasodilatation and inhibits platelet aggregation. Selective inhibition of COX-2 thus may reduce prostacyclin production, resulting in vasoconstriction (which may cause hypertension) and platelet clumping (which could accelerate formation of atherosclerotic plaques)3.
The coxibs were approved by the United States Food and Drug Administration (FDA) on the basis of two large prospective, randomized clinical studies. The CLASS (Celecoxib Long-Term Arthritis Safety) study of 8059 patients documented a significant reduction in the prevalence of gastrointestinal ulcers in those taking celecoxib compared with the prevalences in those taking ibuprofen or diclofenac (p < 0.02)4. The VIGOR study, involving 8076 patients, showed a similar reduction in gastrointestinal side effects when rofecoxib was compared with naproxen5.
The orthopaedic community embraced the coxibs as a result of their effectiveness and favorable side-effect profile. Coxibs have proved valuable in the treatment of postoperative pain as well as pain associated with knee and hip osteoarthritis2. Studies of animals, however, have raised concern that coxibs may delay fracture-healing and tendon-healing6,7.
The early clinical studies of the coxibs raised concern about their cardiovascular safety. Although the VIGOR study was not designed to address the issue of cardiovascular side effects, it did show an increased risk of myocardial infarction in patients treated with rofecoxib (p < 0.01). A meta-analysis of large clinical trials of celecoxib (including the CLASS study4) did not show any increased risk of cardiovascular events8. Two pharmacoepidemiologic analyses demonstrated that rofecoxib was associated with an increase in the risk of myocardial infarction9,10.
Merck's decision to withdraw rofecoxib was based on interim results from the APPROVe study (www.rheumatology.org/annual/press/APPROVesession_annouce.asp), a randomized, prospective, placebo-controlled multicenter study designed to investigate the role of rofecoxib in the progression of colorectal adenomas. APPROVe was the first study performed to investigate the long-term use of coxibs. There were 0.75 cardiovascular thrombotic events per patient-year in the placebo group of that study and 1.5 events per patient-year in the rofecoxib group. Thus, 25 mg of rofecoxib per day was associated with a twofold increase in cardiovascular thrombotic events (95% confidence interval, 1.20 to 3.19; p < 0.007). The cardiovascular risk was not observed until after eighteen months of treatment.
With rofecoxib removed from the market, orthopaedists are left with two FDA-approved coxibs for the treatment of musculoskeletal pain: celecoxib (Celebrex) and valdecoxib (Bextra; Pfizer). But is the increased cardiac risk unique to rofe-coxib or is it a class effect of all coxibs? Valdecoxib (Bextra) itself has not been shown in prospective studies to have cardiac side effects11. However, a study of the intravenous use of parecoxib, a pro-drug that turns into valdecoxib in vivo, showed a significant increase in cardiac events and wound infections (p < 0.015)12. It would be reasonable to predict that valdecoxib has the same cardiac effects in vivo as does its pro-drug, parecoxib. FitzGerald recently presented meta-analysis data showing a slightly increased risk of thrombotic events in patients taking valdecoxib13. The FDA recently added a warning label to Bextra (valdecoxib) noting an increased risk of Stevens-Johnson syndrome and an elevated thrombotic risk in patients who had undergone a cardiac artery bypass grafting procedure (www.fda.gov/bbs/topics/ANSWERS/2004/ANS01331.html).
The available published data seem to indicate that cele-coxib does not increase the risk of cardiac problems6,8,14. However, on December 17, 2004, Pfizer informed the FDA that the Adenoma Prevention with Celecoxib (APC) trial had been halted. The APC trial was a thirty-three month trial of a 400 or 800-mg daily dose of celecoxib for prevention of colonic polyps. Analyses showed that patients taking these supratherapeutic doses were 2.5 times more likely to have a cardiovascular event. At the same time, results from a similar trial of a 400-mg daily dose of celecoxib to prevent colorectal adenomas did not show an increased cardiovascular risk over a placebo (www.celebrex.com/cardiovascular_safety_of_celebrex_tp.asp). Thus, the possibility of a class effect has not been eliminated. Pfizer has proposed a full-scale trial specifically designed to address the cardiac safety of celecoxib.
In the face of rapidly changing data on the coxibs, what course should the prudent orthopaedic surgeon take? Acetaminophen and nonselective nonsteroidal anti-inflammatory drugs should be the first-line treatments for musculoskeletal pain, particularly when chronic therapy is anticipated. Patients who are more than sixty-five years old, have a history of gastric ulcers, or have a history of gastrointestinal bleeding could benefit from a coxib. The surgeon should probe for a history of hypertension or cardiovascular risk. Until definitive data on cardiovascular safety are available, surgeons should avoid prescribing coxibs for patients with or at high risk for coronary artery disease.
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11. White WB, Strand V, Roberts R, Whelton A. Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal antiinflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis. Am J Ther. 2004;11: 244-50.
12. Ott E, Nussmeier NA, Duke PC, Feneck RO, Alston RP, Snabes MC, Hubbard RC, Hsu PH, Saidman LJ, Mangano DT; Multicenter Study of Perioperative Ischemia (McSPI) Research Group; Ischemia Research and Education Foundation (IREF) Investigators. Efficacy and safety of the cyclooxygenase 2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery. J Thorac Cardiovasc Surg. 2003;125: 1481-92.
13. FitzGerald GA. Russel Ross Memorial Lecture on vascular biology. Read at the Annual Meeting of the American Heart Association; 2004 Nov 7-10; New Orleans, LA.
14. Graham DJ, Campen D, Cheetham C, Hui R, Spence M, Ray WA. Risk of acute cardiac events among patients treated with cyclooxygenase-2 selective and nonselective nonsteroidal antiinflammatory drugs. Read at the Annual International Conference on Pharmacoepidemiology (ICPE); 2004 Aug 22-25; Bordeaux, France