Correspondence
The Coxibs, Selective Inhibitors of Cyclooxygenase-2
N Engl J Med 2001; 345:1708-1709December 6, 2001
- Article
To the Editor:
The review article by FitzGerald and Patrono (Aug. 9 issue)1 on the coxibs, selective inhibitors of cyclooxygenase-2 (COX-2), included a table listing pharmacokinetic and metabolic features as well as drug interactions. According to the table, in patients taking warfarin, rofecoxib causes a 10 percent increase in the international normalized ratio (INR), but there is no interaction between celecoxib and warfarin.
Since the introduction of celecoxib in Australia in October 1999, the Adverse Drug Reactions Advisory Committee has received 2218 reports of suspected adverse drug reactions. Of these, 21 involved an increase in INR values in patients treated with celecoxib and warfarin, some of whom had large hemorrhages.2 In addition to these cases, there were 11 cases of bleeding in patients who took both drugs but for whom INR values are not given. In these patients, the bleeding may have been the result of a drug interaction, an additive effect of the two drugs, or an effect of celecoxib alone, or it may have been unrelated to the celecoxib therapy.
Since warfarin is metabolized mainly by cytochrome CYP2C9 and since this enzyme can be inhibited by celecoxib, some patients may have substantial inhibition of CYP2C9, resulting in higher plasma concentrations of warfarin. Two recent reports described this interaction,3,4 but no comprehensive evaluation of either celecoxib or rofecoxib has been performed. The reports of adverse reactions should prompt precisely that type of study.
4 ReferencesJohn Paul Killen, M.B., B.S.
Royal Darwin Hospital, Casuarina, NT 0811, Australia
ojpo@hotmail.com 1
FitzGerald GA ,Patrono C . The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001;345:433-442
Full Text | Web of Science | Medline2
Adverse Drug Reactions Advisory Committee. Interaction of celecoxib and warfarin. Australian Adverse Drug Reactions Bulletin. February 2001.
3
Mersfelder TL ,Stewart LR . Warfarin and celecoxib interaction. Ann Pharmacother 2000;34:325-327
CrossRef | Web of Science | Medline4
Haase KK ,Rojas-Fernandez CH ,Lane L ,Frank DA . Potential interaction between celecoxib and warfarin. Ann Pharmacother 2000;34:666-667
CrossRef | Web of Science | Medline
To the Editor:
FitzGerald and Patrono failed to address the renal toxicity of the COX-2–inhibitor drugs. Although preliminary data suggested that these drugs might have less nephrotoxicity than the nonselective nonsteroidal antiinflammatory drugs,1 emerging data suggest that the COX-2 inhibitors have substantial nephrotoxicity. The risk of nephrotoxic effects appears to be particularly high in patients with decreased renal perfusion (for example, those with volume depletion or congestive heart failure), in whom prostaglandins play a critical part in maintaining renal blood flow.
Perazella and Eras recently described three cases of reversible acute renal failure in patients taking a selective COX-2 inhibitor.2 In these patients, acute renal failure was reversed by the cessation of COX-2–inhibitor therapy, although one patient required hemodialysis. In another report, the occurrence of acute tubulointerstitial nephritis and acute renal failure due to rofecoxib was described.3 This is hardly surprising, considering that COX-2 is constitutively expressed in glomeruli, the renal interstitium, and the renal vasculature. Because of this emerging risk profile, it seems prudent to avoid the use of these drugs in patients with compromised renal blood flow.4
4 ReferencesChike Magnus Nzerue, M.D.
Morehouse School of Medicine, Atlanta, GA 303011
Whelton A ,Maurath CJ ,Verburg KM ,Geis GS . Renal safety and tolerability of celecoxib, a novel cyclooxygenase-2 inhibitor. Am J Ther 2000;7:159-175[Erratum, Am J Ther 2000;7:341.]
CrossRef | Medline2
Perazella MA ,Eras J . Are selective COX-2 inhibitors nephrotoxic? Am J Kidney Dis 2000;35:937-940
CrossRef | Web of Science | Medline3
Rocha JL ,Fernandez-Alonso J . Acute tubulointerstitial nephritis associated with the selective COX-2 enzyme inhibitor, rofecoxib. Lancet 2001;357:1946-1947
CrossRef | Web of Science | Medline4
Eras J ,Perazella MA . NSAIDs and the kidney revisited: are selective cyclooxygenase-2 inhibitors safe? Am J Med Sci 2001;321:181-190
CrossRef | Web of Science | Medline
To the Editor:
I disagree with the recommendation of FitzGerald and Patrono that low-dose aspirin be given to mitigate the potential prothrombotic effects of COX-2 inhibitors. The theoretical basis for a prothrombotic effect of these drugs is their ability to alter the metabolism of arachidonic acid to favor thromboxane formation over prostaglandin formation.1 This effect is opposite to that of aspirin. The use of a nonselective, and irreversible, cyclooxygenase inhibitor such as aspirin is likely to negate any potential gastrointestinal benefit of a COX-2 inhibitor. This conclusion is supported by the results of the Vioxx Gastrointestinal Outcomes Research (VIGOR) study, in which rofecoxib was not associated with fewer gastrointestinal side effects than naproxen in patients taking aspirin.2 The only way to avoid the potential adverse cardiovascular effects of COX-2 inhibitors is to avoid their use in patients with risk factors for cardiovascular disease.
2 ReferencesSteven A. Rich, M.D.
Lifetime Health, Rochester, NY 14621
steven.rich@excellus. com 1
Crofford LJ ,Oates JC ,McCune WJ , et al. Thrombosis in patients with connective tissue diseases treated with specific cyclooxygenase 2 inhibitors: a report of four cases. Arthritis Rheum 2000;43:1891-1896
CrossRef | Web of Science | Medline2
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 Med 2000;343:1520-1528
Full Text | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Drug interactions emerge initially as case reports, such as those alluded to by the correspondents, and such anecdotal observations may prompt rational study. Thus, despite initial evidence suggesting the absence of an interaction between warfarin and celecoxib, we agree with Dr. Killen that further evaluation of this possibility is now appropriate. Similarly, we agree with Dr. Nzerue's advocacy of further evaluation of the renal effects of coxibs.
In response to Dr. Rich: the effect of low-dose aspirin on the risk–benefit ratio of coxibs can be assessed only in controlled clinical trials. As discussed in our review, it remains unknown whether coxibs represent a cardiovascular hazard and, if so, in which patients. Although we have raised the possibility of such a hazard,1,2 the results of the VIGOR study with respect to cardiovascular effects may be explicable in terms of chance or the effects of naproxen, as mentioned in our review.
A report that followed the publication of our review3 claimed that both celecoxib and rofecoxib increase the risk of cardiovascular events, a claim that attracted considerable media attention. Although one might expect a prostacyclin-based mechanism to be a class effect, we question the statistical approach used in that study and thus the validity of the conclusions. For now, studies that further explore the cardiovascular pharmacology of the coxibs are necessary to determine which, if any, patients are at risk for cardiovascular events from these drugs.
3 ReferencesGarret A. FitzGerald, M.D.
University of Pennsylvania Medical Center, Philadelphia, PA 19104-6084
garret@spirit.gcrc. upenn. edu Carlo Patrono, M.D.
University of Chieti, 66013 Chieti, Italy1
McAdam BF ,Catella-Lawson F ,Mardini IA ,Kapoor S ,Lawson JA ,FitzGerald GA . Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci U S A 1999;96:272-277[Erratum, Proc Natl Acad Sci U S A 1999;96:5890.]
CrossRef | Web of Science | Medline2
Catella-Lawson F ,McAdam B ,Morrison BW , et al. Effects of specific inhibition of cyclooxygenase-2 on sodium balance, hemodynamics, and vasoactive eicosanoids. J Pharmacol Exp Ther 1999;289:735-741
Web of Science | Medline3
Mukherjee D ,Nissen SE ,Topol EJ . Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001;286:954-959
CrossRef | Web of Science | Medline
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Tanya Wilton. (2004) Cyclooxygenase-2 inhibitors: Do they have a role in emergency department prescribing?. Emergency Medicine Australasia 16:1, 65-73
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