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COX-2 inhibitors and gastroduodenal toxicity: Major clinical trials

COX-2 inhibitors and gastroduodenal toxicity: Major clinical trials
Literature review current through: Jan 2024.
This topic last updated: Feb 28, 2023.

INTRODUCTION — The primary effect of nonsteroidal anti-inflammatory drugs (NSAIDs) is to inhibit cyclo-oxygenase (prostaglandin H synthase, or PGHS), thereby impairing the ultimate transformation of arachidonic acid to prostaglandins, prostacyclin, and thromboxanes. Two related isoforms of the cyclo-oxygenase (COX) enzyme have been described: COX-1 (PGHS-1) and COX-2 (PGHS-2). COX-1 is involved in gastric cytoprotection. It had been proposed that the ideal NSAID would inhibit the inducible COX-2 isoform (thereby decreasing inflammation) without having any effect on the constitutive COX-l isoform (thereby minimizing gastric toxicity) [1]. (See "NSAIDs (including aspirin): Pharmacology and mechanism of action".)

One NSAID that selectively inhibits COX-2, celecoxib, is approved by the US Food and Drug Administration (FDA). Rofecoxib is a COX-2 inhibitor that was removed due to an increased risk of stroke and myocardial infarction with long-term use. Valdecoxib was removed because of concerns of cardiovascular risk and reports of Stevens-Johnson syndrome. An increased risk of cardiovascular events has also been observed with celecoxib, especially in higher doses. These observations led the FDA to issue warnings regarding the use of these drugs. (See "NSAIDs: Adverse cardiovascular effects".)

Other COX-2 inhibitors (parecoxib, etoricoxib, and lumiracoxib) are available in some countries. Parecoxib is a prodrug that is converted to valdecoxib. These drugs have at least a 200- to 300-fold selectivity for inhibition of COX-2 over COX-1. (See "Overview of COX-2 selective NSAIDs".)

This topic review will summarize the major clinical trials that have focused on the gastroduodenal protective effects of the COX-2 inhibitors as compared to nonselective NSAIDs. An approach to patients at risk for gastroduodenal toxicity is presented separately. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity".) An overview of COX-2 inhibitors is also available. (See "Overview of COX-2 selective NSAIDs".)

CELECOXIB — Celecoxib was approved by the FDA based upon the results of clinical trials involving more than 5200 patients with osteoarthritis (OA) or rheumatoid arthritis (RA) in which its efficacy and toxicity were compared with that of nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) and placebo. These data demonstrated that celecoxib produced comparable analgesic and anti-inflammatory effects to nonselective NSAIDs.

Two trials in patients with RA that used a primary endpoint of endoscopically detected ulcers found a lower ulcer incidence in patients on celecoxib compared with nonselective NSAIDs [2,3]:

One of the published studies included 688 patients with RA who completed a controlled trial comparing various doses of celecoxib to naproxen or placebo for 12 weeks [2]. All doses of celecoxib and naproxen improved symptoms and signs of RA compared with placebo. The incidence of endoscopically determined gastroduodenal ulcers among patients taking celecoxib was similar to placebo (approximately 4 percent) and was much lower than observed with naproxen (26 percent).

Similar results were found in a second study of 655 patients with RA, which compared the efficacy and gastrointestinal toxicity of celecoxib versus diclofenac [3].

Subsequent trials that focused on more clinically relevant endpoints of symptomatic ulcers and ulcer complications have been conflicting:

The CLASS study, involving 8059 patients with OA or RA, found that celecoxib was associated with significantly fewer symptomatic ulcers and ulcer complications than ibuprofen or diclofenac during the first six months of therapy [4]. However, during the second six months of treatment (a time period that was not included in the published report) the incidence of ulcer complications was higher in the celecoxib than in the ibuprofen or diclofenac treated groups. As a result, at the end of a year of observation, there were no significant differences in incidence of ulcer complications among the three groups [5]. Possible reasons for the apparent failure of celecoxib to reduce the risk of ulcer complications in this study include the use of low-dose aspirin in approximately 20 percent of patients, the use of a high (less COX-2 selective) dose of celecoxib (800 mg per day), and the use of comparator NSAIDs with relatively low potential for causing such adverse GI effects. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity".)

A second trial (the SUCCESS-I study) included over 13,000 patients with OA from 39 countries, 8,800 of whom were randomly assigned to celecoxib (100 or 200 mg twice daily for 12 weeks) and 4394 of whom were assigned to a nonselective NSAID (diclofenac 50 mg or naproxen 500 mg twice daily for 12 weeks) [6]. The drugs were similarly effective in reducing OA symptoms. The number of clinically significant ulcers was higher in the NSAID group, but there were only nine ulcer complications in this study (seven and two, respectively, OR 7.0; 95% CI 1.5-33.8).

The CONDOR study compared celecoxib with diclofenac plus omeprazole. The primary endpoint was a composite of clinically significant upper or lower gastrointestinal events. In this study, the diclofenac and omeprazole group was associated with an increased risk of gastrointestinal events compared with the celecoxib group (hazard ratio 4.3, 95% CI 2.6-7.0) [7].

PARECOXIB — The safety of short-term parenteral administration of parecoxib, which is converted to valdecoxib, was assessed in an endoscopic study of 92 healthy elderly people ages 65 to 75 who were randomly assigned to receive one of three interventions for seven days: intravenous parecoxib sodium (40 mg twice daily), intravenous ketorolac (15 mg four times daily), or placebo [8]. Endoscopic evaluation revealed no gastric or duodenal ulceration among those who received placebo or parecoxib compared with ulcers in 23 percent of subjects in the ketorolac group.

Parecoxib is available in much of Europe.

ETORICOXIB — Controlled trials have compared etoricoxib to nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) [9]. A combined analysis evaluated ten phase II/III randomized trials of etoricoxib in the treatment of osteoarthritis, rheumatoid arthritis, and chronic low back pain [10]. In this analysis, the number of confirmed gastroduodenal events (defined as a clinical, not just an endoscopic, diagnosis of peptic ulcer disease) was significantly lower in patients who received etoricoxib compared with those treated with nonselective NSAIDs (0.95 versus 2.24 percent, RR for etoricoxib 0.42; 95% CI 0.26-0.67). The risk of gastroduodenal toxicity with etoricoxib may be higher than other COX-2 inhibitors [11].

Etoricoxib is approved in many countries but not in the United States.

LUMIRACOXIB — Lumiracoxib, a highly selective COX-2 inhibitor, is a phenylacetic acid analog of diclofenac and not a tricyclic compound like the other coxibs. A combined report of two studies with identical design (the "TARGET" trial) included 18,325 patients with osteoarthritis who were randomly assigned to lumiracoxib (400 mg once daily), naproxen (500 mg twice daily), or ibuprofen (800 mg three times daily) for 52 weeks [12]. In patients who were not taking aspirin, the cumulative incidence of ulcer complications (ie, bleeding, perforation, or obstruction) was significantly lower with lumiracoxib than with naproxen or ibuprofen (hazard ratio 0.21, 95% CI 0.12-0.37). However, there was no reduction in ulcer complications in patients concurrently taking aspirin.

In the "TARGET" trial, there were more myocardial infarctions in the lumiracoxib group compared with naproxen (0.38 versus 0.21 percent), but the differences were not statistically significant. However, the study excluded most patients with known, symptomatic coronary artery disease, a group at increased risk for adverse cardiovascular events. Furthermore, the study may have been underpowered to detect a difference in the rates of myocardial infarction [13].

In another study that did not address cardiovascular risks [14], the risk of gastroduodenal ulceration with lumiracoxib was similar to celecoxib and significantly less than ibuprofen [14].

Lumiracoxib has been associated with hepatotoxicity and is therefore not widely available.

ROFECOXIB — Rofecoxib was found to have a 50 percent relative risk reduction in adverse gastrointestinal events compared with naproxen in rheumatoid arthritis patients in the VIGOR trial [15]. However, in a three-year placebo-controlled trial for colorectal adenoma chemoprevention, rofecoxib was associated with an increased incidence in clinically relevant upper gastrointestinal bleeding compared with placebo (RR 4.9, 95% CI 1.98-14.54) [16]. These findings underscore that the COX-2 inhibitors may be safer than conventional nonsteroidal anti-inflammatory drugs (NSAIDs) for reduction in the risk of gastrointestinal bleeding, but are still associated with an increased risk.

Rofecoxib was removed from the market because of an increased risk of myocardial infarctions and stroke associated with long-term use.

CONCURRENT ASPIRIN — The potential gastroduodenal sparing effect of selective COX-2 inhibitors may be reduced by concurrent low-dose aspirin therapy for primary or secondary prevention of cardiovascular or cerebrovascular disease [4,6,17]. (See "Aspirin in the primary prevention of cardiovascular disease and cancer" and "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)

Loss of the gastroduodenal sparing effect of selective COX-2 inhibitors with concurrent aspirin use is most likely related directly to blockade of COX-1 in the upper gastrointestinal tract [18].

In the CLASS study, similar rates of ulcers and ulcer complications were noted among those receiving celecoxib plus low-dose aspirin as among patients receiving a nonselective nonsteroidal anti-inflammatory drug (NSAID) plus low-dose aspirin (2.02 and 2.12 percent, respectively) [4]. Thus, patients receiving both aspirin and a selective COX-2 inhibitor may require prophylactic antiulcer therapy if they are at increased risk for gastroduodenal toxicity. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity".)

Another study included 1615 patients with osteoarthritis who were randomly assigned to placebo, enteric-coated aspirin (81 mg daily), enteric-coated aspirin (81 mg daily) plus rofecoxib (25 mg daily), or ibuprofen (800 mg three times daily) [19]. The 12-week cumulative incidence of endoscopically detected ulcers was significantly higher in the rofecoxib plus aspirin group than in the aspirin alone group (16.1 percent versus 7.3 percent). The endoscopic ulcer rate of 16.1 percent with rofecoxib plus aspirin was similar to the rate in the ibuprofen group (17.1 percent). The rate of endoscopic ulcers with low-dose aspirin alone (7.3 percent) was numerically higher than the incidence with placebo (5.8 percent), but the difference was not statistically significant. The authors concluded that the addition of rofecoxib to low-dose aspirin increased the incidence of endoscopic ulcers to a rate comparable to nonselective NSAIDs.

Conversely, other studies suggest that gastrointestinal (GI) toxicity of COX-2 inhibitors may be less than that of nonselective NSAIDs even with concurrent use of aspirin, as illustrated by the following examples:

A randomized controlled trial addressing (as the primary endpoint) cardiovascular toxicity of the COX-2 inhibitor etoricoxib versus the nonselective NSAID diclofenac showed less GI toxicity in the etoricoxib arm regardless of proton pump inhibitor (PPI) or ASA co-administration [20]. However, this benefit only held true for uncomplicated GI events; there was no difference between the two groups for complicated GI events.

Two randomized controlled endoscopic studies assessed the occurrence of gastroduodenal ulcers in healthy volunteers given aspirin together with either celecoxib, naproxen, or placebo [21,22]. Although the incidence of ulcers was increased with celecoxib compared with placebo, significantly fewer ulcers were found with celecoxib than with naproxen.

A Cochrane review concluded that COX-2 inhibitors appear to offer greater upper GI safety than nonselective NSAIDs, but that the coadministration of aspirin might reduce this safety advantage [23].

COMBINED USE OF COX-2 INHIBITORS AND PPIs — In patients considered to be at exceptionally high risk for peptic ulcer disease, combining a selective COX-2 inhibitor with a proton pump inhibitor (PPI) may confer added protection against gastrointestinal (GI) toxicity. A randomized controlled trial of Helicobacter pylori-negative patients who had been hospitalized for upper GI bleeding associated with nonselective nonsteroidal anti-inflammatory drugs (NSAID) use found that after 13 months none of the patients placed on celecoxib in combination with a PPI had recurrent ulcer bleeding compared with 9 percent of patients placed on celecoxib and placebo [24].

The PRECISION trial addressed (as the primary endpoint) cardiovascular toxicity of celecoxib versus the nonselective NSAIDs naproxen and ibuprofen in patients who were at increased risk for cardiovascular disease (nearly half taking low dose aspirin) and whose arthritis pain was resistant to acetaminophen [25]. Patients with GI ulceration within 60 days of randomization or perforation, obstruction, or ulcer bleeding within six months of randomization were excluded from the trial. This randomized trial compared the safety of celecoxib (100 to 200 mg twice daily) with naproxen (375 to 500 mg twice daily) and ibuprofen (600 to 800 mg three times daily) in 24,081 patients with arthritis. All patients were provided esomeprazole (20 or 40 mg per day). During a median follow up period of 34 months, clinically significant GI events were uncommon and occurred in 0.3 percent, 0.7 percent, and 0.7 percent of patients, respectively. It is unclear what proportion of patients were at high-risk of GI bleeding as the proportion of patients with a remote peptic ulcer or ulcer bleeding were not reported. (See "NSAIDs: Adverse cardiovascular effects".)

In another trial, 514 patients with a history of upper GI bleeding who were on nonselective NSAIDs and required low dose aspirin, were randomly assigned to continuous low dose aspirin (80 mg daily), esomeprazole (20 mg daily), and either celecoxib (100 mg twice daily) or naproxen (500 mg twice daily) [26]. The cumulative incidence of recurrent upper gastrointestinal bleeding from gastroduodenal ulcers or bleeding erosions at the 18-month follow-up was significantly lower in the celecoxib group as compared with the naproxen group (5·6 percent, 95% CI 3·3-9·2 versus 12·3 percent, 95% CI 8·8-17·1). There was no significant difference in the number of serious cardiovascular events between the two groups but the study was not powered to detect such a difference.

SUMMARY

The primary effect of nonsteroidal anti-inflammatory drugs (NSAIDs) is to inhibit cyclo-oxygenase, thereby impairing the ultimate transformation of arachidonic acid to prostaglandins, prostacyclin, and thromboxanes. There are two isoforms of the cyclo-oxygenase enzyme. The COX-1 isoform is involved in gastric cytoprotection, and the COX-2 isoform is increased during states of inflammation. (See 'Introduction' above.)

COX-2 inhibitors appear to be safer than conventional NSAIDs for reduction in the risk of gastrointestinal (GI) bleeding, but are still associated with an increased risk of bleeding compared with placebo. The potential gastroduodenal sparing effect of selective COX-2 inhibitors is probably reduced by concurrent low-dose aspirin therapy. (See 'Concurrent aspirin' above.)

In patients considered to be at exceptionally high risk for peptic ulcer disease, combining a selective COX-2 inhibitor (eg, celecoxib) with a proton pump inhibitor (PPI) (eg, esomeprazole) confers added protection against GI toxicity. (See 'Combined use of COX-2 inhibitors and PPIs' above.)

Celecoxib produces comparable analgesia and anti-inflammatory effects to nonselective NSAIDs. Compared with nonselective NSAIDs, celecoxib has been associated with fewer endoscopically detectable, but not necessarily fewer clinically significant gastric and duodenal ulcers. (See 'Celecoxib' above.)

Short-term parenteral administration of parecoxib has been associated with a lower risk of gastric or duodenal ulceration compared with ketorolac.

Etoricoxib has been associated with an approximately 50 percent lower incidence of investigator-reported and confirmed adverse upper GI events compared with treatment with nonselective NSAIDs in phase II/III clinical studies. (See 'Etoricoxib' above.)

Lumiracoxib is a highly selective COX-2 inhibitor. In one study, the cumulative incidence of ulcer complications (ie, bleeding, perforation, or obstruction) was significantly lower with lumiracoxib than with naproxen or ibuprofen, in patients who were not taking aspirin. Reductions in ulcer complications were not apparent in patients concurrently taking aspirin.

Rofecoxib was found to have a 50 percent relative risk reduction in GI events compared with naproxen in rheumatoid arthritis patients in the VIGOR trial. However, in a three-year, placebo-controlled trial for colorectal adenoma chemoprevention, rofecoxib was associated with an increased incidence in clinically relevant upper GI bleeding compared with placebo. Rofecoxib was removed from the market because of an increased risk of MIs and stroke associated with long-term use. (See 'Rofecoxib' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff thank Dr. Das Shounak, MD, for his contributions as author to prior versions of this topic review.

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