Celecoxib

Cardiovascular

The risk of cardiovascular events with celecoxib has been studied in a systematic review and meta-analysis of randomized double-blind trials of at least 6 weeks' duration with data on serious thromboembolic events [ ]. Four placebo-controlled trials in 4422 patients were analysed. The odds ratio for myocardial infarction with celecoxib was 2.26 (95% CI = 1.0, 5.1). There was no significant increase in risk with celecoxib for composite cardiovascular events, cardiovascular deaths, or stroke. A secondary meta-analysis of six studies with placebo, diclofenac, ibuprofen, and paracetamol as comparators in 12 780 patients showed similar findings: there was a significantly increased risk of myocardial infarction with celecoxib (OR = 1.88; 95% CI = 1.15, 3.08) but not other outcome measures.

Psychiatric

A 78-year-old woman had auditory hallucinations while taking celecoxib for osteoarthritis [ ]. Her symptoms occurred after she had taken celecoxib 200 mg bd for 48 hours and progressed over the next 8 days. Celecoxib was withdrawn and her hallucinations gradually disappeared over the next 4 days. Rechallenge with a lower dose (100 mg bd) caused recurrence.

There have been two reports of visual hallucinations in patients taking celecoxib.

• A 79-year-old woman presented to her optometrist with a 2-day history of seeing orange spots in both visual fields 2 months after starting to take celecoxib 100 mg/day [ ]. Physical examination and a CT scan were normal. Celecoxib was withdrawn and her symptoms resolved within 3 days.

• An 81-year-old woman took celecoxib 100 mg/day, and over the next 2 weeks developed delirium and auditory and visual hallucinations [ ]. Celecoxib was withdrawn and her symptoms resolved over several days. She took a few doses of rofecoxib 12.5 mg/day 6 months later without any problem. She began to take rofecoxib regularly again 2 months later, and after 1 month developed agitation, confusion, and hallucinations. Physical examination suggested no cause of the delirium other than rofecoxib. A CT scan was negative. The rofecoxib was withdrawn, and over the next 2 days her symptoms resolved.

Hematologic

Inhibition of COX-2 may be prothrombotic by suppression of endothelial prostacyclin synthesis while not affecting synthesis of COX-1-dependent platelet thromboxane A2. However, celecoxib reduces expression of endothelial tissue factor, a key initiator of the coagulation cascade and the overall effects are unclear [ ]. A report has raised the possibility that patients with a known prothrombotic state and raised platelet thromboxane A2 production may be at high risk of thrombosis when selective COX-2 inhibitors are used [ ].

Thrombosis occurred during celecoxib therapy (400 mg/day) in four women (aged 37–56 years) with connective tissue diseases and conditions that predisposed them to thrombosis, including Raynaud’s phenomenon, raised anticardiolipin antibody titers, and a previous history of thrombosis. Peripheral artery thrombosis (three patients) and pulmonary embolism (one patient) were documented after starting celecoxib. Symptoms of thrombosis began to appear within 1 week of starting celecoxib in three patients and 2 months after starting celecoxib in the fourth patient.

A causal relation between celecoxib and these thrombotic events cannot be established with certainty on the basis of the available evidence. However, the temporal relation between the start of treatment and the thrombotic event was impressive, at least in three patients, and the findings were consistent with the hypothesis that thrombosis is an adverse consequence of reduced production of systemic prostaglandin I2 brought about by COX-2 inhibition. Reduced synthesis of prostaglandin I2 may act in concert with other thrombotic risk factors (such as those occurring in this series of patients) to precipitate acute vascular occlusion.

Gastrointestinal

With extensive use of COX-2 inhibitors, gastrointestinal adverse reactions similar to those observed with non-selective NSAID are being increasingly observed.

• An 87-year-old man developed severe esophagitis with a chronic peptic esophageal stricture and had dysphagia and odynophagia. He had taken celecoxib for 5 months (200–400 mg/day) and endoscopy showed severe desquamative esophagitis. Celecoxib was withdrawn and he was given esomeprazole. His symptoms improved and 3 months later the esophageal mucosa had completely healing [ ].

Inhibition of COX-2 in the large bowel can worsen inflammatory bowel disease and collagenous colitis has been reported.

• An 80-year-old woman who had taken celecoxib 100 mg bd for 18 months developed a collagenous colitis, with watery diarrhea, with multiple non-bloody stools each day, and crampy lower abdominal pain [ ]. Colonoscopy showed diffuse erythema, hyperemia, and multiple linear ulcers. Ulcer biopsies were consistent with collagenous colitis. Celecoxib was withdrawn, she was given mesalazine, and the diarrhea resolved.

Celecoxib reportedly exacerbated inflammatory bowel disease in two patients [ ].

• An 80-year-old woman with ulcerative colitis started taking celecoxib for arthritic pain, and 3 days later developed abdominal pain and diarrhea. Celecoxib was withdrawn and her symptoms improved.

• A 35-year-old woman with ileal and perianal Crohn’s disease took four doses of celecoxib for an orthopedic injury, and had rectal bleeding, severe abdominal pain, and worse diarrhea. Celecoxib was withdrawn and her symptoms returned to baseline within 5 days.

The possible association of NSAIDs with inflammatory bowel disease is a matter of controversy [ , ], and there is little clinical experience with the selective COX-2 inhibitors. Coxibs should not be prescribed for patients with chronic inflammatory bowel disease until more experience has accumulated.