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Celecoxib update review 2005

 

Clinical bottom line

Celecoxib adverse events in 40,000 patients were better than those for NSAIDs. There was no increased risk of myocardial infarction.


Reference

RA Moore, S Derry, GT Makinson, HJ McQuay. Tolerability and adverse events in clinical trials of celecoxib in osteoarthritis and rheumatoid arthritis: systematic review and meta-analysis of information from clinical trial reports. Arthritis Research & Treatment 2005 7:R644-R665 (http://arthritis-research.com/content/7/3/R644)

Systematic review

This was a review of clinical trials of celecoxib using clinical trial reports provided by Pfizer. Thirty-one trials with 39,600 patients formed the basis of the review, 21 trials in OA, 4 in RA, and 6 in mixed OA and RA. Clinical trial reports are comprehensive documents, and there were over 200,000 pages available.

Information was analysed according to comparator - placebo, paracetamol, rofecoxib, or NSAID at maximum licensed dose. Against NSAID the comparison was both all doses of celecoxib use, and licensed doses of 200-400 mg per day.

Results

This was a large and detailed analysis. Only a brief summary can be given here, with a summary sheet in Figure 1.

Figure 1: Overall summary of results of review

Discontinuations

Gastrointestinal discontinuations were lower with celecoxib than with NSAIDs (Figure 2), as were adverse event discontinuations generally. Lack of efficacy discontinuations were higher with licensed doses of celecoxib than top doses of NSAIDs overall, though this was principally in shorter duration studies. In longer durations studies of 12 weeks or more, lack of efficacy discontinuations were usually lower with celecoxib than NSAIDs.

Figure 2: Gastrointestinal AE discontinuations (red symbol is 52-week trial)

Gastrointestinal adverse events

Celecoxib had lower rates of adverse events like GI tolerability (described in the paper as the proportion of any patient having moderate or severe nausea, dyspepsia or abdominal pain), vomiting, abdominal pain, dyspepsia, diarrhoea, and clinical ulcers and bleeds than with NSAIDs.

Cardio-renal adverse events

No cardio-renal adverse event (cardiac failure, raised creatinine, hypertension, oedema) occurred more frequently than with NSAIDs.

Myocardial infarction

No analysis demonstrated a statistical difference between celecoxib and any comparator. For the comparison of licensed doses of celecoxib against NSAID the number of events was 20/13,509 (0.15%) for celecoxib 200-400 mg daily, and 3/8,309 (0.04%) for NSAID. Forty-four cases of myocardial infarction occurred in the two largest trials (096, 102) with 21,162 patients. Their planned duration was 12 and 52 weeks, and they had a combined actual duration of about 4.5 months. Here 29/12787 (0.23%) of patients taking celecoxib (200-800 mg) suffered a myocardial infarction, compared with 15/8375 (0.18%) on NSAID. The relative risk was 1.7 (0.88 to 3.2).

Anaemia

Falls in haematocrit of 5% or more, or of haemoglobin of 20 g/L or more occurred less frequently with celecoxib than with NSAIDs.

Endoscopic ulcers

Information on endoscopic ulcers, with and without aspirin, is shown in Figure 3, which also includes all information available for all coxib endoscopy studies, with or without aspirin. Coxib plus aspirin rates of endoscopic ulcer were much less than those with NSAID plus aspirin.

Figure 3: Endoscopic ulcers from all data for coxibs

Comment

The study has the importance of fulfilling requirements of quality (all studies scored maximum for indicators of lack of bias), size (nearly 40,000 patients), and mostly for validity (maximum on validity scoring). Some studies were relatively short, though.

The results demonstrate a generally benign picture for celecoxib compared with any comparator. There was no evidence of increased rate of myocardial infarction, without taking into account the propensity for duration of exposure to be less for NSAIDs (more discontinuations) than celecoxib, which would tend not to favour celecoxib.