REVIEW - COX-2 selective NSAIDs for OA and RA

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Health Technol Assess. 2008 Apr;12(11):1-278, iii.

Cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs

(etodolac, meloxicam, celecoxib, rofecoxib, etoricoxib, valdecoxib and

lumiracoxib) for osteoarthritis and rheumatoid arthritis: a systematic

review and economic evaluation.

Chen YF, Jobanputra P, Barton P, S, Fry- A, G, RS.

Department of Public Health and Epidemiology, University of Birmingham, UK.

OBJECTIVES: To review the clinical effectiveness and

cost-effectiveness of cyclooxygenase-2 (COX-2) selective non-steroidal

anti-inflammatory drugs (NSAIDs) (etodolac, meloxicam, celecoxib,

rofecoxib, etoricoxib, valdecoxib and lumiracoxib) for osteoarthritis

(OA) and rheumatoid arthritis (RA).

DATA SOURCES: Electronic databases were searched up to November 2003.

Industry submissions to the National Institute for Health and Clinical

Excellence (NICE) in 2003 were also reviewed.

REVIEW METHODS: Systematic reviews of randomised controlled trials

(RCTs) and a model-based economic evaluation were undertaken.

Meta-analyses were undertaken for each COX-2 selective NSAID compared

with placebo and non-selective NSAIDs. The model was designed to run

in two forms: the 'full Assessment Group Model (AGM)', which includes

an initial drug switching cycle, and the 'simpler AGM', where there is

no initial cycle and no opportunity for the patient to switch NSAID.

RESULTS: Compared with non-selective NSAIDs, the COX-2 selective

NSAIDs were found to be equally as efficacious as the non-selective

NSAIDs (although meloxicam was found to be of inferior or equivalent

efficacy) and also to be associated with significantly fewer clinical

upper gastrointestinal (UGI) events (although relatively small numbers

of clinical gastrointestinal (GI) and myocardial infarction (MI)

events were reported across trials). Subgroup analyses of clinical and

complicated UGI events and MI events in relation to aspirin use,

steroid use, prior GI history and Helicobacter pylori status were

based on relatively small numbers and were inconclusive. In the RCTs

that included direct COX-2 comparisons, the drugs were equally

tolerated and of equal efficacy. Trials were of insufficient size and

duration to allow comparison of risk of clinical UGI events,

complicated UGI events and MIs. One RCT compared COX-2 (celecoxib)

with a non-selective NSAID combined with a gastroprotective agent

(diclofenac combined with omeprazole); this included arthritis

patients who had recently suffered a GI haemorrhage. Although no

significant difference in clinical GI events was reported, the number

of events was small and more such studies, where patients genuinely

need NSAIDs, are required to confirm these data. A second trial showed

that rofecoxib was associated with fewer diarrhoea events than a

combination of diclofenac and misoprostol (Arthrotec). Previously

published cost-effectiveness analyses indicated a wide of range of

possible incremental cost per quality-adjusted life-year (QALY) gained

estimates. Using the simpler AGM, with ibuprofen or diclofenac alone

as the comparator, all of the COX-2 products are associated with

higher costs (i.e. positive incremental costs) and small increases in

effectiveness (i.e. positive incremental effectiveness), measured in

terms of QALYs. The magnitude of the incremental costs and the

incremental effects, and therefore the incremental cost-effectiveness

ratios, vary considerably across all COX-2 selective NSAIDs. The

base-case incremental cost per QALY results for COX-2 selective NSAIDs

compared with diclofenac for the simpler model are: celecoxib (low

dose) 68,400 pounds; celecoxib (high dose) 151,000 pounds; etodolac

(branded) 42,400 pounds; etodolac (generic) 17,700 pounds; etoricoxib

31,300 pounds; lumiracoxib 70,400 pounds; meloxicam (low dose) 10,300

pounds; meloxicam (high dose) 17,800 pounds; rofecoxib 97,400 pounds;

and valdecoxib 35,500 pounds. When the simpler AGM was run using

ibuprofen or diclofenac combined with proton pump inhibitor (PPI) as

the comparator, the results change substantially, with the COX-2

selective NSAIDs looking generally unattractive from a

cost-effectiveness point of view (COX-2 selective NSAIDs were

dominated by ibuprofen or diclofenac combined with PPI in most cases).

This applies both to 'standard' and 'high-risk' arthritis patients

defined in terms of previous GI ulcers. The full AGM produced results

broadly in line with the simpler model.

CONCLUSIONS: The COX-2 selective NSAIDs examined were found to be

similar to non-selective NSAIDs for the symptomatic relief of RA and

OA and to provide superior GI tolerability (the majority of evidence

is in patients with OA). Although COX-2 selective NSAIDs offer

protection against serious GI events, the amount of evidence for this

protective effect varied considerably across individual drugs. The

volume of trial evidence with regard to cardiovascular safety also

varied substantially between COX-2 selective NSAIDs. Increased risk of

MI compared to non-selective NSAIDs was observed among those drugs

with greater volume of evidence in terms of exposure in patient-years.

Economic modelling shows a wide range of possible costs per QALY

gained in patients with OA and RA. Costs per QALY also varied if

individual drugs were used in 'standard' or 'high'-risk patients, the

choice of non-selective NSAID comparator and whether that NSAID was

combined with a PPI. With reduced costs of PPIs, future primary

research needs to compare the effectiveness and cost-effectiveness of

COX-2 selective NSAIDs relative to non-selective NSAIDs with a PPI.

Direct comparisons of different COX-2 selective NSAIDs, using

equivalent doses, that compare GI and MI risk are needed. Pragmatic

studies that include a wider range of people, including the older age

groups with a greater burden of arthritis, are also necessary to

inform clinical practice.

PMID: 18405470

http://www.ncbi.nlm.nih.gov/pubmed/18405470

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