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Cardiovascular Risks of Coxibs: The Orthopaedic Perspective
Timothy Bhattacharyya, MD1; R. Malcolm Smith, MD2
1 Massachusetts General HospitalBrigham and Women's HospitalBoston, Massachusetts
2 Massachusetts General HospitalBoston, Massachusetts
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The authors did not receive grants or outside funding in support of their research or preparation of this manuscript. They did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

The Journal of Bone and Joint Surgery, Incorporated
J Bone Joint Surg Am, 2005 Feb 01;87(2):245-246. doi: 10.2106/JBJS.D.02855
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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 $2.5 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.
FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med.2001;345: 433-42.345433  2001  [PubMed][CrossRef]
 
Ekman EF, Koman LA. Acute pain following musculoskeletal injuries and orthopaedic surgery. Mechanisms and management. J Bone Joint Surg Am.2004;86: 1316-27.861316  2004 
 
FitzGerald GA. Coxibs and cardiovascular disease. N Engl J Med.2004;351: 1709-11.3511709  2004  [PubMed][CrossRef]
 
Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, Makuch R, Eisen G, Agrawal NM, Stenson WF, Burr AM, Zhao WW, Kent JD, Lefkowith JB, Verburg KM, Geis GS. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA.2000;284: 1247-55.2841247  2000  [PubMed][CrossRef]
 
Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ; VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med.2000;343: 1520-30.3431520  2000  [PubMed][CrossRef]
 
Gerstenfeld LC, Thiede M, Seibert K, Mielke C, Phippard D, Svagr B, Cullinane D, Einhorn TA. Differential inhibition of fracture healing by non-selective and cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs. J Orthop Res.2003;21: 670-5.21670  2003  [PubMed][CrossRef]
 
Dahners LE, Mullis BH. Effects of nonsteroidal anti-inflammatory drugs on bone formation and soft-tissue healing. J Am Acad Orthop Surg.2004;12: 139-43.12139  2004  [PubMed]
 
White WB, Faich G, Borer JS, Makuch RW. Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib. Am J Cardiol.2003;92: 411-8.92411  2003  [PubMed][CrossRef]
 
Ray WA, Stein CM, Daugherty JR, Hall K, Arbogast PG, Griffin MR. COX-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease. Lancet.2002;360: 1071-3.3601071  2002  [PubMed][CrossRef]
 
Solomon DH, Schneeweiss S, Glynn RJ, Kiyota Y, Levin R, Mogun H, Avorn J. Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation.2004;109: 2068-73.1092068  2004  [PubMed][CrossRef]
 
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: 244-50.11244  2004  [PubMed][CrossRef]
 
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: 1481-92.1251481  2003  [PubMed][CrossRef]
 
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.  2004 
 
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  2004 
 

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References

FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med.2001;345: 433-42.345433  2001  [PubMed][CrossRef]
 
Ekman EF, Koman LA. Acute pain following musculoskeletal injuries and orthopaedic surgery. Mechanisms and management. J Bone Joint Surg Am.2004;86: 1316-27.861316  2004 
 
FitzGerald GA. Coxibs and cardiovascular disease. N Engl J Med.2004;351: 1709-11.3511709  2004  [PubMed][CrossRef]
 
Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, Makuch R, Eisen G, Agrawal NM, Stenson WF, Burr AM, Zhao WW, Kent JD, Lefkowith JB, Verburg KM, Geis GS. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA.2000;284: 1247-55.2841247  2000  [PubMed][CrossRef]
 
Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ; VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med.2000;343: 1520-30.3431520  2000  [PubMed][CrossRef]
 
Gerstenfeld LC, Thiede M, Seibert K, Mielke C, Phippard D, Svagr B, Cullinane D, Einhorn TA. Differential inhibition of fracture healing by non-selective and cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs. J Orthop Res.2003;21: 670-5.21670  2003  [PubMed][CrossRef]
 
Dahners LE, Mullis BH. Effects of nonsteroidal anti-inflammatory drugs on bone formation and soft-tissue healing. J Am Acad Orthop Surg.2004;12: 139-43.12139  2004  [PubMed]
 
White WB, Faich G, Borer JS, Makuch RW. Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib. Am J Cardiol.2003;92: 411-8.92411  2003  [PubMed][CrossRef]
 
Ray WA, Stein CM, Daugherty JR, Hall K, Arbogast PG, Griffin MR. COX-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease. Lancet.2002;360: 1071-3.3601071  2002  [PubMed][CrossRef]
 
Solomon DH, Schneeweiss S, Glynn RJ, Kiyota Y, Levin R, Mogun H, Avorn J. Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation.2004;109: 2068-73.1092068  2004  [PubMed][CrossRef]
 
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: 244-50.11244  2004  [PubMed][CrossRef]
 
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: 1481-92.1251481  2003  [PubMed][CrossRef]
 
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.  2004 
 
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  2004 
 
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These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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Subspecialty CME | May 15, 2005
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