An update on specific COX-2 inhibitors: The COXIBs

An update on specific COX-2 inhibitors: The COXIBs

Gupta, Samardeep

Introduction

Specific COX-2 inhibitors (COXIBs) are nonsteroidal anti-inflammatory drugs (NSAIDs) specifically designed to inhibit cyclooxygenase-2 (COX-2) without inhibiting COX- I at maximal therapeutic doses (1,2). Currently, there are two COX[Bs available in the United States, celecoxib (Celebrex) and rofecoxib (Vioxx). The US Food and Drug Administration (FDA) has approved celecoxib for relief of the signs and symptoms of osteoarthritis (OA) and rheumatoid arthritis (RA) in adults, and for reduction in the number of adenomatous polyps in patients with familial adenomatous polyposis (FkP). The FDA has approved rofecoxib for relief of the signs and symptoms of OA, the management of acute pain in adults, and the treatment of primary dysmenorrhea.

The COXIBs have been available since early 1999, and their use in clinical practice is widespread. This update addresses the most recent clinical information regarding the efficacy, safety, and cost effectiveness of the COXIBs (Table 1).

Efficacy

Studies of patients with RA and OA have established that the COXIBs are at least as effective as other NSAIDs for the treatment of pain and stiffness (3-6). In published studies, differences between the efficacy of celecoxib and rofecoxib in the treatment of OA have not been convincingly demonstrated. Comparative studies using the dental pain model have suggested an increased benefit of a single dose of rofecoxib (50 mg) compared with a single dose of celecoxib (200 mg) (7).

GI Safety

Compared with the most commonly used NSAIDs, the COXIBs have a better safety profile with respect to endoscopic erosions, fecal red blood cell loss, symptomatic ulcers, and ulcer complications (8-12). Endoscopy data from studies of 1,427 patients with OA showed that ulcers were significantly less common in the rofecoxib group than in the ibuprofen group at 24 weeks (10). Another study of 1,149 patients with RA assessed the GI mucosal damage in groups treated with celecoxib, naproxen, or placebo (4). The incidences of endoscopically determined gastroduodenal ulcers in the celecoxib group, were not significantly different from the group receiving placebo. In contrast, the incidence in the naproxen group was significantly greater than either the placebo or celecoxib group.

Two large studies, the Celecoxib Long-term Arthritis Safety Study (CLASS) and the Vioxx GI Outcome Research (VIGOR) trial, have been performed to detect differences in clinically important GI events. The CLASS trial included 8,059 patients with OA or RA (approximately 80% had OA) (11). Patients were randomly assigned to receive celecoxib, 400 mg twice per day (twice the maximum RA dose); diclofenac, 75 mg twice per day; or ibuprofen, 800 mg three times per day. Low-dose aspirin was permitted in this study. Data were reported at 6 months; however, it should be noted that less than 60% of patients completed the study. The CLASS trial demonstrated a nonsignificant reduction in the incidence of adjudicated upper GI ulcer complications (perforation, gastric outlet obstruction, or bleeding) in the celecoxib-treated patients (0.76%) versus those treated with other NSAIDs (1.45%). These results translate into a relative risk of 0.5 for celecoxib as compared with other NSAIDs. The annualized incidence of upper GI ulcer complications plus symptomatic ulcers in the celecoxib group was 2.08% versus 3.54% for patients taking other NSAIDs (RR–0.6). Half of all ulcer complications occurred in the 20% of patients taking aspirin, and a statistically significant reduction of ulcer complications was found in the celecoxib patients not taking aspirin.

The VIGOR trial involved 8,076 patients with RA (12). Patients were randomly assigned to take rofecoxib, 50 mg once daily (twice the recommended dose for OA), or naproxen, 500 mg twice daily, for a median duration of 9 months. The primary endpoint of the VIGOR study was clinical upper GI events, including perforations, obstructions, bleeding, and symptomatic ulcers. The incidence of upper GI events was 54% lower in the group treated with rofecoxib than in the group treated with naproxen translating to a significantly reduced relative risk (RR=0.5). Rofecoxib was also associated with a lower risk than naproxen of ulcer complications (RR=O.4) and GI bleeding (from anywhere in the GI tract) (RR=0.5). Treatment with rofecoxib was associated with a similarly low relative risk in a number of subgroups, including those with prior GI events, concomitant glucocorticoid therapy, and patients with a positive serologic test for H. pylori.

The CLASS study had fewer withdrawals due to GI symptoms (8.7% vs. 10.7%) in the celecoxib treatment group than in the NSAID treatment group. Likewise, in the VIGOR study, fewer patients discontinued treatment as a result of GI symptoms in the rofecoxib than the naproxen treatment groups (3.5% vs. 4.9%).

Cost

Because more than 100,000 hospitalizations and 10,000 to 20,000 deaths each year in the United States can be attributed to NSAID-related complications, the reduced GI toxicity of the COXIBs makes them attractive treatment options. However, both rofecoxib and celecoxib are more expensive than the generic forms of NSAIDs (13). This greater cost may be offset by the money saved in not having to treat (with antisecretory agents, endoscopies, and hospitalizations) the GI complications related to traditional NSAIDs. Cost savings become less evident in settings where strategies for gastroprotection other than COXIBs are used.

The CLASS study demonstrates that aspirin is an independent risk factor for GI events. When aspirin treatment is indicated, therapy with misprostol or proton-pump inhibitors (PPIs) should be considered and may lead to increased cost. Some patients require treatment with PPIs for GI symptoms or reflux disease. The benefit of a COXIB over an NSAID in terms of absolute ulcer risk when factoring in the potential role for PPIs as protective agents is unknown.

Renal Effects

Prostaglandins play an integral role in renal physiology. Localization studies show that COX-2 is expressed in the adult rat renal cortex in a restricted subpopulation of cells in the cortical thick ascending limb cells in the region of macula densa and in the medullary interstitial cells (1). COX2 is also localized to the vasa recta of the medulla (14). The renal localization is consistent with a role for COX-2 in regulating glomerular function, blood pressure, and sodium excretion.

The COMs were shown to decrease renal prostacyclin production under physiological conditions in young volunteers (15,16). In the same population, COXMs caused a transient retention of sodium, but no depression of the glomerular filtration rate (GFR). In a different study of 75 elderly patients (aged 60 to 80 years) on a lowsodium diet low and high dosages of rofecoxib were compared with indomethacin and placebo, and decreases in the GFR were comparable in the rofecoxib- and indomethacin-treated groups (17). Another recent study of celecoxib found similar renal effects (18). Several studies have demonstrated that the effects of COXIBs on renal function are expected to be similar to those observed with nonselective NSAIDs.

In the CLASS trial, significantly lower incidence of hypertension was found in the group treated with celecoxib than in the group treated with other NSAIDs (11). A lower occurrence of clinically elevated creatinine was found in the celecoxib group. The rate of withdrawals for adverse events was similar for both treatment groups, however The VIGOR trial, which studied a daily 50 mg dosage of rofecoxib, reported a low incidence of adverse events related to renal function with the number of withdrawals being similar between the two treatment groups (12). Lower extremity edema and hypertension was reported in slightly more of the patients treated with rofecoxib versus the patients receiving naproxen.

Our recommendation is to observe precautions when using COXIBs similar to those for traditional NSAIDs in patients with congestive heart failure, cirrhosis and ascites, hypovolemia, glomerulonephritis, and chronic renal insufficiency. Blood pressure should be monitored in hypertensive patients to assure that adequate control is maintained after treatment with COXIBs (or other NSAIDs) is initiated. Vascular Effects

Whether treatment with COXIBs has an effect on thrombosis is unknown. Theoretically, however, specific inhibition of COX-2 has the potential to affect vascular tone and coagulation. Prostaglandins and thromboxane (TX) are regulators of platelet and endothelial cell function. Activated platelets synthesize TXA2, which promotes platelet aggregation and vasoconstriction, via COX- 1-dependent pathway. Prostacyclin (PGI2), which is synthesized by endothelial cells primarily via a COX-2-dependent pathway, inhibits platelet activation by elevating platelet cyclic AMP and induces vasodilation.

The antiplatelet effects of aspirin are mediated through irreversible inhibition of platelet COX- 1 (19). In contrast, COMs have no effect on platelet TXA, and thus do not inhibit platelet function (20,21). Because COXIBs block production of systemic PGI2, questions about whether these agents may alter vascular physiology have been raised (15,16,22). There are case reports of thrombosis occurring shortly after the institution of celecoxib in patients with multiple risk factors for thrombotic events (22), but no increase in the incidence of cardiovascular events has been noted in any controlled trials of celecoxib.

In the VIGOR trial of RA patients, the incidence of myocardial infarction was 0.4% for patients treated with rofecoxib and 0.1% for naproxen-treated patients, a statistically significant difference (12). However, naproxen does lead to a longlasting high-level inhibition of platelet TXA2 and may lead to some cardio protection. The incidence rates of cerebrovascular events (0.2% vs. 0.2%), deaths due to cardiovascular events (0.2% vs. 0.2%), and all deaths (0.5% vs. 0.4%) were not statistically different in the rofecoxib versus the naproxen groups. In the posthoc analysis of the data, 4% of enrolled patients had pre-existing risk factors for cardiovascular disease for which lowdose aspirin would be indicated for prophylaxis (none of the patients in VIGOR trial were allowed aspirin co-therapy). The incidence of myocardial infarctions in the remaining 96% of study patients (for whom aspirin was not indicated for prophylaxis) was 0.2% for the patients treated with rofecoxib and 0.1% for those treated with naproxen.

In the CLASS trial, in which the use of aspirin was permitted, no increase in the incidence of thromboembolic cadiovascular events (ie, myocardial infarctions and cerebrovascular disorders) was shown for the celecoxib group relative to comparator NSAID groups, either for non-aspirin users or for the entire study population (11). It should be noted that the CLASS trial was comprised mostly of OA patients, whereas the VIGOR trial included only patients with RA. Patients with RA are more likely to develop coronary artery disease compared with an age-matched population (23). Whether there is a specifically increased thromboembolic risk associated with COXIBs in RA or other patient populations is currently unknown.

Conclusion

COXIBs were developed rapidly following the discovery and characterization of COX-2 as the inducible isoform of the COX enzyme responsible for the production of the prostaglandins involved in inflammation. The therapeutic efficacy of COX[Bs matches that of traditional NSAIDs in all studies completed to date. Because of improved GI safety with regard to symptomatic ulcers and ulcer complications in all patient groups, COXIBs can be considered whenever long-term treatment of arthritis is initiated. Their use may not justify their cost for patients for whom the risk of GI complications is low, but this has not been carefully studied yet. For patients with an increased risk of clinically important GI toxicity, COXIBs are preferred over traditional NSAIDs (24). However, the role for COXIBs in situations where other gastroprotective agents (eg, PPIs) are indicated, including patients treated with low-dose aspirin, has not yet been established. As with other NSAIDs, renal precautions should be observed and blood pressure monitored when treating with COX[Bs. More data is required to determine the risk, if any, of thrombotic events associated with COXIBs.

References

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By Sam– Gupta, MD, and Leslie J. Crofford, MD

Division of Rheumatology

University of Michigan Medical Center Ann Arbor, MI

Dr. Crofford has acted as a consultant and speaker and has received unrestricted educational gifts from Merck & Co., Searle/Pharmacia, Pfizer, and Boehringer Ingelheim

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