Benefits and harms of celecoxib to treat people with osteoarthritis

Review question

We evaluated benefits and harms of celecoxib, a drug used to treat people with osteoarthritis, to improve pain, movement, quality of life and drug safety.

Background

Osteoarthritis is a joint disease (mostly knees and hips) caused when cartilage wears away leading to pain, joint stiffness and inflammation, which can cause limited mobility and reduces quality of life. Celecoxib is marketed as being as effective as traditional anti-inflammatory drugs (tNSAIDs such as naproxen and diclofenac) but with fewer gut and other problems.

Study characteristics

We searched up to April 2017 and included 36 trials that involved 17,206 adults who received 200 mg celecoxib daily (9402 participants), or either another drug (naproxen - 6 trials, or diclofenac - 3 trials, total of 1869 participants) or a fake treatment (placebo - 32 trials, 5935 participants).

On average, participants were aged 62 years and had osteoarthritis for 7.9 years. Participants had knee, hip, or both, osteoarthritis; most were women and white.

Study funding sources

Most studies (34/36) were funded by the studied drugs manufacturers, and (34/36) included authors who worked for drug companies.

Key results

Celecoxib, compared with placebo, slightly reduced pain, improved physical function, and probably did not increase numbers of people who withdrew from trials because of problems with the treatment. However, these results were unlikely to be clinically significant. Very low quality evidence meant that we are uncertain if celecoxib caused harms, such as gut or heart problems when compared with placebo. However, drug regulatory agencies have warned of increased risk of heart problems with celecoxib.

Celecoxib and tNSAIDs reduced pain by the same amount; celecoxib slightly improved physical function compared with tNSAIDs. Evidence comparing celecoxib and tNSAIDs was low to very low quality, so it is uncertain if harms (such as heart or gut problems) occurred from taking these drugs.

None of the high-quality studies assessed quality of life.

Quality of evidence

Evidence quality was poor and results should be interpreted cautiously. Because it is known that sponsorship by the manufacturing drug company may lead to more favorable results and conclusions than sponsorship from other sources, we are highly reserved about results due to significant drug industry involvement and few data.

We were unable to obtain data from three trials which included 15,539 participants (awaiting assessment); Pfizer declined to provide data for two reports that involved 14,042 participants.

We need access to all trials results to better understand the benefits and harms of celecoxib and other treatments. New trials researching benefits and harms of celecoxib versus tNSAIDs for people with osteoarthritis, that have longer follow-up periods, more direct comparisons with other tNSAIDs, and funded by non-commercial sources, are needed.

Authors' conclusions: 

We are highly reserved about results due to pharmaceutical industry involvement and limited data. We were unable to obtain data from three studies, which included 15,539 participants, and classified as awaiting assessment. Current evidence indicates that celecoxib is slightly better than placebo and some tNSAIDs in reducing pain and improving physical function. We are uncertain if harms differ among celecoxib and placebo or tNSAIDs due to risk of bias, low quality evidence for many outcomes, and that some study authors and Pfizer declined to provide data from completed studies with large numbers of participants. To fill the evidence gap, we need to access existing data and new, independent clinical trials to investigate benefits and harms of celecoxib versus tNSAIDs for people with osteoarthritis, with longer follow-up and more direct head-to-head comparisons with other tNSAIDs.

Read the full abstract...
Background: 

Osteoarthritis (OA) is the most common form of arthritis and is caused by degeneration of the joint cartilage and growth of new bone, cartilage and connective tissue. It is often associated with major disability and impaired quality of life. There is currently no consensus on the best treatment to improve OA symptoms. Celecoxib is a selective non-steroidal anti-inflammatory drug (NSAID).

Objectives: 

To assess the clinical benefits (pain, function, quality of life) and safety (withdrawals due to adverse effects, serious adverse effects, overall discontinuation rates) of celecoxib in osteoarthritis (OA).

Search strategy: 

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and clinical trials registers up to April 11, 2017, as well as reference and citation lists of included studies. Pharmaceutical companies and authors of published articles were contacted.

Selection criteria: 

We included published studies (full reports in a peer reviewed journal) of prospective randomized controlled trials (RCTs) that compared oral celecoxib versus no intervention, placebo or another traditional NSAID (tNSAID) in participants with clinically- or radiologically-confirmed primary OA of the knee or hip, or both knee and hip.

Data collection and analysis: 

Two authors independently performed data extraction, quality assessment, and compared results. Main analyses for patient-reported outcomes of pain and physical function were conducted on studies with low risk of bias for sequence generation, allocation concealment and blinding of participants and personnel.

Main results: 

We included 36 trials that provided data for 17,206 adults: 9402 participants received celecoxib 200 mg/day, and 7804 were assigned to receive either tNSAIDs (N = 1869) or placebo (N = 5935). Celecoxib was compared with placebo (32 trials), naproxen (6 trials) and diclofenac (3 trials). Studies were published between 1999 and 2014. Studies included participants with knee, hip or both knee and hip OA; mean OA duration was 7.9 years. Most studies included predominantly white participants whose mean age was 62 (± 10) years; most participants were women. There were no concerns about risk of bias for performance and detection bias, but selection bias was poorly reported in most trials. Most trials had high attrition bias, and there was evidence of selective reporting in a third of the studies.

Celecoxib versus placebo

Compared with placebo celecoxib slightly reduced pain on a 500-point Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain scale, accounting for 3% absolute improvement (95% CI 2% to 5% improvement) or 12% relative improvement (95% CI 7% to 18% improvement) (4 studies, 1622 participants). This improvement may not be clinically significant (high quality evidence).

Compared with placebo celecoxib slightly improved physical function on a 1700-point WOMAC scale, accounting for 4% absolute improvement (95% CI 2% to 6% improvement), 12% relative improvement (95% CI 5% to 19% improvement) (4 studies, 1622 participants). This improvement may not be clinically significant (high quality evidence).

There was no evidence of an important difference for withdrawals due to adverse events (Peto OR 0.99, 95% CI 0.85 to 1.15) (moderate quality evidence due to study limitations).

Results were inconclusive for numbers of participants experiencing any serious AEs (SAEs) (Peto OR 0.95, 95% CI 0.66 to 1.36), gastro-intestinal events (Peto OR 1.91, 95% CI 0.24 to 14.90) and cardiovascular events (Peto OR 3.40, 95% CI 0.73 to 15.88) (very low quality evidence due to serious imprecision and study limitations). However, regulatory agencies have warned of increased cardiovascular events for celecoxib.

Celecoxib versus tNSAIDs

There were inconclusive results regarding the effect on pain between celecoxib and tNSAIDs on a 100-point visual analogue scale (VAS), showing 5% absolute improvement (95% CI 11% improvement to 2% worse), 11% relative improvement (95% CI 26% improvement to 4% worse) (2 studies, 1180 participants, moderate quality evidence due to publication bias).

Compared to a tNSAID celecoxib slightly improved physical function on a 100-point WOMAC scale, showing 6% absolute improvement (95% CI 6% to 11% improvement) and 16% relative improvement (95% CI 2% to 30% improvement). This improvement may not be clinically significant (low quality evidence due to missing data and few participants) (1 study, 264 participants).

Based on low or very low quality evidence (downgraded due to missing data, high risk of bias, few events and wide confidence intervals) results were inconclusive for withdrawals due to AEs (Peto OR 0.97, 95% CI 0.74 to 1.27), number of participants experiencing SAEs (Peto OR 0.92, 95% CI 0.66 to 1.28), gastro-intestinal events (Peto OR 0.61, 0.15 to 2.43) and cardiovascular events (Peto OR 0.47, 95% CI 0.17 to 1.25).

In comparisons of celecoxib and placebo there were no differences in pooled analyses between our main analysis with low risk of bias and all eligible studies. In comparisons of celecoxib and tNSAIDs, only one outcome showed a difference between studies at low risk of bias and all eligible studies: physical function (6% absolute improvement in low risk of bias, no difference in all eligible studies).

No studies included in the main comparisons measured quality of life. Of 36 studies, 34 reported funding by drug manufacturers and in 34 studies one or more study authors were employees of the sponsor.

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