Celecoxib for osteoarthritis

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 methods: 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 placeboCompared 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 tNSAIDsThere 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.

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.

Conflict of interest statement

Livia Puljak: None known. Ana Marin: None known. Davorka Vrdoljak: None known. Filipa Markotic: None known. Ana Utrobicic: None known. Peter Tugwell: None known.

Figures

1

Study flow diagram

2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study

4

Funnel plot of comparison: 1 Celecoxib versus placebo, outcome: 1.3 Number withdrawn due to adverse events.

5

Funnel plot of comparison: 1 Celecoxib versus placebo, outcome: 1.4 Number experiencing any serious adverse events.

1.1. Analysis

Comparison 1 Celecoxib versus placebo, Outcome 1 Pain.

1.2. Analysis

Comparison 1 Celecoxib versus placebo, Outcome 2 Physical function.

1.3. Analysis

Comparison 1 Celecoxib versus placebo, Outcome 3 Number withdrawn due to adverse events.

1.4. Analysis

Comparison 1 Celecoxib versus placebo, Outcome 4 Number experiencing any serious adverse events.

1.5. Analysis

Comparison 1 Celecoxib versus placebo, Outcome 5 Number experiencing gastro‐intestinal events (perforation, ulcer, bleeds).

1.6. Analysis

Comparison 1 Celecoxib versus placebo, Outcome 6 Number experiencing cardiovascular events (myocardial infarction, stroke).

2.1. Analysis

Comparison 2 Celecoxib versus tNSAIDs, Outcome 1 Pain.

2.2. Analysis

Comparison 2 Celecoxib versus tNSAIDs, Outcome 2 Physical function.

2.3. Analysis

Comparison 2 Celecoxib versus tNSAIDs, Outcome 3 Number withdrawn due to adverse events.

2.4. Analysis

Comparison 2 Celecoxib versus tNSAIDs, Outcome 4 Number experiencing any serious adverse events.

2.5. Analysis

Comparison 2 Celecoxib versus tNSAIDs, Outcome 5 Number experiencing gastro‐intestinal events (perforation, ulcer, bleeds).

2.6. Analysis

Comparison 2 Celecoxib versus tNSAIDs, Outcome 6 Number experiencing cardiovascular events (myocardial infarction, stroke).

3.1. Analysis

Comparison 3 Celecoxib versus placebo (all eligible studies), Outcome 1 All pain

3.2. Analysis

Comparison 3 Celecoxib versus placebo (all eligible studies), Outcome 2 Pain VAS at 6 weeks.

3.3. Analysis

Comparison 3 Celecoxib versus placebo (all eligible studies), Outcome 3 Pain VAS at 12 weeks.

3.4. Analysis

Comparison 3 Celecoxib versus placebo (all eligible studies), Outcome 4 Pain VAS at 13 weeks.

3.5. Analysis

Comparison 3 Celecoxib versus placebo (all eligible studies), Outcome 5 Pain on walking VAS at 6 weeks.

3.6. Analysis

Comparison 3 Celecoxib versus placebo (all eligible studies), Outcome 6 Pain on walking WOMAC at 12 weeks.

3.7. Analysis

Comparison 3 Celecoxib versus placebo (all eligible studies), Outcome 7 Pain WOMAC at 6 weeks.

3.8. Analysis

Comparison 3 Celecoxib versus placebo (all eligible studies), Outcome 8 Pain WOMAC at 12 weeks.

3.9. Analysis

Comparison 3 Celecoxib versus placebo (all eligible studies), Outcome 9 Pain WOMAC at 13 weeks.

3.10. Analysis

Comparison 3 Celecoxib versus placebo (all eligible studies), Outcome 10 Pain WOMAC at 24 weeks.

3.11. Analysis

Comparison 3 Celecoxib versus placebo (all eligible studies), Outcome 11 All physical function

3.12. Analysis

Comparison 3 Celecoxib versus placebo (all eligible studies), Outcome 12 Physical function WOMAC at 6 weeks.

3.13. Analysis

Comparison 3 Celecoxib versus placebo (all eligible studies), Outcome 13 Physical function WOMAC at 12 weeks.

3.14. Analysis

Comparison 3 Celecoxib versus placebo (all eligible studies), Outcome 14 Physical function WOMAC at 13 weeks.

3.15. Analysis

Comparison 3 Celecoxib versus placebo (all eligible studies), Outcome 15 Physical function WOMAC at 24 weeks.

3.16. Analysis

Comparison 3 Celecoxib versus placebo (all eligible studies), Outcome 16 Quality of life: SF‐36 physical component scores.

3.17. Analysis

Comparison 3 Celecoxib versus placebo (all eligible studies), Outcome 17 Quality of life: SF‐36 mental component scores.

3.18. Analysis

Comparison 3 Celecoxib versus placebo (all eligible studies), Outcome 18 Number of responders with at least 50% improvement in WOMAC pain.

3.19. Analysis

Comparison 3 Celecoxib versus placebo (all eligible studies), Outcome 19 Number withdrawn due to adverse events.

3.20. Analysis

Comparison 3 Celecoxib versus placebo (all eligible studies), Outcome 20 Number experiencing any serious adverse events.

3.21. Analysis

Comparison 3 Celecoxib versus placebo (all eligible studies), Outcome 21 Number experiencing gastro‐intestinal events (perforation, ulcer, bleeds).

3.22. Analysis

Comparison 3 Celecoxib versus placebo (all eligible studies), Outcome 22 Number experiencing cardiovascular events (myocardial infarction, stroke).

4.1. Analysis

Comparison 4 Celecoxib versus tNSAIDs (all eligible studies), Outcome 1 All pain under 24 weeks.

4.2. Analysis

Comparison 4 Celecoxib versus tNSAIDs (all eligible studies), Outcome 2 All pain over 24 weeks.

4.3. Analysis

Comparison 4 Celecoxib versus tNSAIDs (all eligible studies), Outcome 3 All physical function under 24 weeks.

4.4. Analysis

Comparison 4 Celecoxib versus tNSAIDs (all eligible studies), Outcome 4 Number withdrawn due to adverse events.

4.5. Analysis

Comparison 4 Celecoxib versus tNSAIDs (all eligible studies), Outcome 5 Number experiencing any serious adverse events.

4.6. Analysis

Comparison 4 Celecoxib versus tNSAIDs (all eligible studies), Outcome 6 Number experiencing gastro‐intestinal events (perforation, ulcer, bleeds).

4.7. Analysis

Comparison 4 Celecoxib versus tNSAIDs (all eligible studies), Outcome 7 Number experiencing cardiovascular events (myocardial infarction, stroke).

5.1. Analysis

Comparison 5 Celecoxib versus naproxen 1000 mg, Outcome 1 All pain ≤ 24 weeks.

5.2. Analysis

Comparison 5 Celecoxib versus naproxen 1000 mg, Outcome 2 Pain VAS at 6 weeks.

5.3. Analysis

Comparison 5 Celecoxib versus naproxen 1000 mg, Outcome 3 Pain VAS at 12 weeks.

5.4. Analysis

Comparison 5 Celecoxib versus naproxen 1000 mg, Outcome 4 Pain WOMAC at 6 weeks.

5.5. Analysis

Comparison 5 Celecoxib versus naproxen 1000 mg, Outcome 5 Pain WOMAC at 12 weeks.

5.6. Analysis

Comparison 5 Celecoxib versus naproxen 1000 mg, Outcome 6 Pain WOMAC at 6 months.

5.7. Analysis

Comparison 5 Celecoxib versus naproxen 1000 mg, Outcome 7 All physical function ≤ 24 weeks.

5.8. Analysis

Comparison 5 Celecoxib versus naproxen 1000 mg, Outcome 8 Physical function WOMAC at 6 weeks.

5.9. Analysis

Comparison 5 Celecoxib versus naproxen 1000 mg, Outcome 9 Physical function WOMAC at 12 weeks.

5.10. Analysis

Comparison 5 Celecoxib versus naproxen 1000 mg, Outcome 10 Physical function WOMAC at 6 months.

5.11. Analysis

Comparison 5 Celecoxib versus naproxen 1000 mg, Outcome 11 Number withdrawn due to adverse events.

5.12. Analysis

Comparison 5 Celecoxib versus naproxen 1000 mg, Outcome 12 Number experiencing any serious adverse events.

5.13. Analysis

Comparison 5 Celecoxib versus naproxen 1000 mg, Outcome 13 Number experiencing gastro‐intestinal events (perforation, ulcer, bleeds).

6.1. Analysis

Comparison 6 Celecoxib versus diclofenac 100 mg, Outcome 1 Pain VAS at 1 year.

6.2. Analysis

Comparison 6 Celecoxib versus diclofenac 100 mg, Outcome 2 Number withdrawn due to adverse events.

6.3. Analysis

Comparison 6 Celecoxib versus diclofenac 100 mg, Outcome 3 Number experiencing any serious adverse events.

6.4. Analysis

Comparison 6 Celecoxib versus diclofenac 100 mg, Outcome 4 Number experiencing gastro‐intestinal events (perforation, ulcer, bleeds).

6.5. Analysis

Comparison 6 Celecoxib versus diclofenac 100 mg, Outcome 5 Number experiencing cardiovascular events (myocardial infarction, stroke).

7.1. Analysis

Comparison 7 Celecoxib versus diclofenac 150 mg, Outcome 1 Pain VAS at 6 weeks.

7.2. Analysis

Comparison 7 Celecoxib versus diclofenac 150 mg, Outcome 2 Pain WOMAC at 6 weeks.

7.3. Analysis

Comparison 7 Celecoxib versus diclofenac 150 mg, Outcome 3 Pain on walking at 12 weeks.

7.4. Analysis

Comparison 7 Celecoxib versus diclofenac 150 mg, Outcome 4 Physical function WOMAC at 6 weeks.

7.5. Analysis

Comparison 7 Celecoxib versus diclofenac 150 mg, Outcome 5 Number withdrawn due to adverse events.

7.6. Analysis

Comparison 7 Celecoxib versus diclofenac 150 mg, Outcome 6 Number experiencing any serious adverse events.

7.7. Analysis

Comparison 7 Celecoxib versus diclofenac 150 mg, Outcome 7 Number experiencing gastro‐intestinal events (perforation, ulcer, bleeds).