EDITORIAL

Selective cyclooxygenase-2 inhibitors: hope and facts

Francis Berenbaum*Department of rheumatology and UPRES-A 7079, Pierre et Marie Curie University, Paris VI, Hôpital Saint-Antoine, 184,rue du faubourg-Saint-Antoine, 75012 Paris, France

Selective cyclooxygenase-2 (COX-2) inhibitors, a newclass of nonsteroidal anti-inflammatory drugs(NSAIDs), are at the center of a heated debate, as isoften the case when novel drugs become available. Thisdebate is driven in part by the huge size of the potentialmarket for selective COX-2 inhibitors: all patients whoare seeking relief from pain or inflammation are poten-tial candidates for COX-2 inhibitor therapy, and thereis evidence that COX-2 inhibitors may prove useful inthe treatment of selected malignancies.

COX-2 inhibitors were not discovered empirically:rather, they were designed based on a hypothesis derivedfrom the results of basic research. In the early 1990s,studies showed that the enzyme cyclooxygenase exists astwo isoforms, which were called COX-1 and COX-2.Extensive investigations demonstrated that COX-2 wasusually absent under normal conditions but presentduring inflammation. COX-1 is found in small amountsin all tissues, particularly the stomach, and catalyzes theproduction of cytoprotective prostaglandins. Thesefindings led to the hypothesis that the therapeutic effectsof NSAIDs may be related to inhibition of COX-2 andtheir adverse effects to inhibition of COX-1, openingup the possibility that drugs capable of inhibitingCOX-2 but not COX-1 may be both effective and saferthan conventional NSAIDs. This simple hypothesisprovided the impetus for the development of Celebrext

(celecoxib) and Vioxxt (rofecoxib).

Celebrext was approved in the United States in late1998 and Vioxxt in early 1999. Both drugs are nowextraordinarily popular in virtually all the countrieswhere they are available. Is this a honeymoon phenom-enon, or will conventional NSAIDs fall into disuse inthe near or medium term?

Many facts suggest that gastric ulcers are less com-mon with COX-2 inhibitors than with conventionalNSAIDs. Endoscopic studies and recent clinical studiesin osteoarthritis or rheumatoid arthritis have demon-strated a significant decrease in the rate of adversegastrointestinal events (perforation, clinical ulcer, orbleeding). The Food and Drug Administration askedeach of the pharmaceutical companies that developedCelebrext and Vioxxt to conduct a randomized studycomparing the COX-2 inhibitor in twice the recom-mended dosage to a conventional NSAID and using therate of adverse gastrointestinal events as the primaryoutcome of interest. These two studies have been pre-sented recently, under the names VIGOR (Vioxx Gas-trointestinal Outcomes Research) and CLASS(Celecoxib Long-Term Arthritis Safety Study).

THE VIGOR STUDY

VIGOR compared Vioxxt (50 mg once a day, 4,047patients) to naproxen (1,000 mg/day in two divideddoses, 4,029 patients) in patients with rheumatoidarthritis. The rate of adverse gastrointestinal events(perforation, ulcer, or bleeding) was the primary out-come and was evaluated after nine months of treatmenton average. The rate of adverse gastrointestinal eventswas lower by 54% in the rofecoxib group than in thenaproxen group (2.1% per year vs 4.5% per year,P < 0.001). The difference remained significant when

* Correspondence and reprints.E-mail address: francis.berenbaum@sat.ap-hop-paris.fr (F. Berenbaum).

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only perforation and bleeding were taken into account(57% decrease, P = 0.005). However, the risk of myo-cardial infarction was five times higher in the rofecoxibgroup than in the naproxen group (0.5% vs 0.1%,P < 0.05). Use of aspirin in any dosage was an exclusioncriterion for this study. Among the study patients, 4%were candidates for low-dose aspirin therapy to preventcardiovascular events; the myocardial infarctionsrecorded during the study mainly occurred in thissubset of patients.

THE CLASS STUDY

CLASS compared celecoxib (800 mg/day in twodivided doses) to diclofenac (150 mg/day in two divideddoses) or ibuprofen (1200 mg/day in three divideddoses) in 8,000 patients with rheumatoid arthritis orosteoarthritis [1]. Treatment duration was six to 13months. Twenty-two percent of the study patientsreceived low-dose aspirin throughout the study. Theprimary outcome was the rate of gastrointestinal perfo-ration or bleeding; uncomplicated ulcers were not stud-ied. The difference was not statistically significant:perforation or bleeding occurred in 0.8% of patients oncelecoxib and in 1.5% of patients on conventionalNSAID therapy (P = 0.09). A significant difference wasfound when the patients on aspirin were excluded fromthe analysis (0.4% vs 1.3%, P = 0.04) or when uncom-plicated ulcers were taken into account (2% vs 3.5%,P = 0.02). The rate of myocardial infarction was similarin the celecoxib and conventional NSAID group.

The VIGOR and CLASS studies leave three impor-tant issues unanswered.– Is COX-2 inhibitor therapy associated with a higherrisk of cardiovascular events than conventional NSAIDtherapy?

In the VIGOR study, the rate of myocardial infarc-tion was significantly higher in the rofecoxib than in thenaproxen group. Vascular events have been reportedrecently at initiation of celecoxib therapy in four patientswith lupus and circulating anticoagulants [2]. Twopossible explanations can be put forward. First, none ofthe VIGOR patients took low-dose aspirin, whichinhibits platelet aggregation by inhibiting COX-1,although an indication for low-dose aspirin was presentin 4% of the patients. Naproxen inhibits COX-1 butrofecoxib does not. However, there is no evidence todate that naproxen can be used to prevent cardiovascu-lar events, whereas aspirin and sulindac have beenproven effective in this indication. The second hypoth-

esis rests on experimental data. Selective COX-2 inhi-bition produces an imbalance in the synthesis of lipidmediators, with a shift toward greater productionof vasoconstricting prostaglandins([thromboxane] > > [prostaglandins]). Under conven-tional NSAID therapy, both cyclooxygenases are inhib-ited, and the balance between vasoconstricting andvasodilating prostaglandins remains unchanged (figure1).

These hypotheses and the results of the VIGOR andCLASS studies indicate that low-dose aspirin used as aplatelet inhibitor should be continued in patients whoare put on a COX-2 inhibitor.– The CLASS study casts some doubt on whethercelecoxib has a better gastrointestinal safety profile thanconventional NSAIDs in patients who require long-term aspirin therapy. In this population, the rate ofadverse gastrointestinal events was not significantlylower with celecoxib. However, this finding is at vari-ance with the results of earlier studies of celecoxib,indicating a need for further investigation of this issue.– The third issue is whether COX-2 inhibitors arebetter than conventional NSAIDs in terms of publichealth objectives and healthcare cost containment. Moststudies conducted to date focused on gastrointestinalperforation, ulcers, and bleeding. However, it can beargued that only perforation and bleeding may be rel-evant, since these are the events with the highest humanand economic costs. The CLASS study illustrates theimportance of this issue: a significant difference wasfound when all three types of gastrointestinal eventwere analyzed but not when uncomplicated ulcers wereexcluded.

In conclusion, despite the strong demand for COX-2inhibitors from patients exposed to well-organizedadvertising campaigns, NSAIDs may still have a brightfuture. All studies conducted to date found that efficacywas similar with COX-2 inhibitors and conventionalNSAIDs: the term “super aspirin” used in the media todescribe COX-2 inhibitors is misleading. On the otherhand, there is incontrovertible evidence that COX-2inhibitors are less likely to cause uncomplicated ulcersand probably perforation and bleeding than conven-tional NSAIDs. COX-2 inhibitors will become success-ful medically (as opposed to commercially) if concernsabout their possible adverse cardiovascular effects arelaid to rest and if they are proved cost-effective. InFrance, one box of 28 Vioxxt or Celebrext tablets (theamount needed for one month) costs at least 300 FF(46 euros). COX-2 inhibitors may be medically and

500 F. Berenbaum

economically effective only in patients at high risk forNSAID-induced ulcers.

REFERENCES

1 Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T,Whelton A, et al. Gastrointestinal toxicity with celecoxib vs

nonsteroidal anti-inflammatory drugs for osteoarthritis andrheumatoid arthritis: the CLASS study: a randomized con-trolled trial. Celecoxib long-term arthritis safety study. JAMA2000 ; 284 : 1247-55.

2 Crofford LJ, Oates JC, McCune WJ, Gupta S, Kaplan MJ,Catella-Lawson F, et al. Thrombosis in patients with connectivetissue diseases treated with specific cyclooxygenase 2 inhibitors.A report of four cases. Arthritis Rheum 2000 ; 43 : 1891-6.

Figure 1. Hypothetical explanation of the increased cardiovascular event rate in patients not treated by prophylactic aspirin despite cardiovas-cular risk factors. The levels of synthesis of compounds produced in endothelial cells during reactions catalyzed by cyclooxygenases in thepresence and absence of a conventional NSAID or a COX-2 inhibitor are illustrated. COX-1: production of thromboxane, which promotes plateletaggregation and vasoconstriction; COX-2: production of prostaglandin I2, which inhibits platelet aggregation and promotes vasodilation.

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