Key result
Celecoxib matches non-selective NSAIDs for major cardiovascular events in patients without established CVD.
Why the study?
Selective cyclooxygenase-2 inhibitors and conventional nsNSAIDs have been associated with adverse CV effects, prompting a comparison of the CV safety of switching to celecoxib versus continuing nsNSAID therapy.
Does switching to celecoxib reduce cardiovascular events compared to continuing non-selective NSAIDs in older patients with arthritis and no established cardiovascular disease?
RCT (n=7,297)
Open-label, Blinded Endpoint evaluation (PROBE)
Central randomization system, permuted blocks of 4, stratified by NSAID and arthritis status
Yes
Does switching to celecoxib reduce cardiovascular events compared to continuing non-selective NSAIDs in older patients with arthritis and no established cardiovascular disease?
Hazard Ratio: 1.04 (95% CI 0.81–1.33)
Absolute Event Rate: 1.14% vs 1.1%
p-value: p=0.75
In older arthritis patients without established cardiovascular disease, switching to celecoxib is non-inferior to continuing non-selective NSAIDs regarding cardiovascular safety, though it is associated with higher withdrawal rates.
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Overall, in subjects who do not have significant cardiovascular disease, taking nsNSAIDS or celecoxib does not appear to confer major risk of subsequent cardiovascular disease.”
“If you need to take these medicines for arthritis pains and you have no history of heart attack or stroke, then either type of medicine seems acceptably safe. These results offer significant reassurance to the many patients taking these medicines and can give increased confidence to the doctors prescribing these drugs.”
“Although the trial was set up to investigate whether there are striking differences in the risk of cardiovascular or gastrointestinal problems, the striking feature is how low the incidence of such problems was. This is consistent with other observations suggesting a decline in heart attacks and ulcer complications.”
Offers clinicians flexibility in NSAID selection for arthritis patients without CVD; extends randomized safety data to this lower-risk population.
BACKGROUND: Selective cyclooxygenase-2 inhibitors and conventional non-selective non-steroidal anti-inflammatory drugs (nsNSAIDs) have been associated with adverse cardiovascular (CV) effects. We compared the CV safety of switching to celecoxib vs. continuing nsNSAID therapy in a European setting. METHOD: Patients aged 60 years and over with osteoarthritis or rheumatoid arthritis, free from established CV disease and taking chronic prescribed nsNSAIDs, were randomized to switch to celecoxib or to continue their previous nsNSAID. The primary endpoint was hospitalization for non-fatal myocardial infarction or other biomarker positive acute coronary syndrome, non-fatal stroke or CV death analysed using a Cox model with a pre-specified non-inferiority limit of 1.4 for the hazard ratio (HR). RESULTS: In total, 7297 participants were randomized. During a median 3-year follow-up, fewer subjects than expected developed an on-treatment (OT) primary CV event and the rate was similar for celecoxib, 0.95 per 100 patient-years, and nsNSAIDs, 0.86 per 100 patient-years (HR = 1.12, 95% confidence interval, 0.81-1.55; P = 0.50). Comparable intention-to-treat (ITT) rates were 1.14 per 100 patient-years with celecoxib and 1.10 per 100 patient-years with nsNSAIDs (HR = 1.04; 95% confidence interval, 0.81-1.33; P = 0.75). Pre-specified non-inferiority was achieved in the ITT analysis. The upper bound of the 95% confidence limit for the absolute increase in OT risk associated with celecoxib treatment was two primary events per 1000 patient-years exposure. There were only 15 adjudicated secondary upper gastrointestinal complication endpoints (0.078/100 patient-years on celecoxib vs. 0.053 on nsNSAIDs OT, 0.078 vs. 0.053 ITT). More gastrointestinal serious adverse reactions and haematological adverse reactions were reported on nsNSAIDs than celecoxib, but more patients withdrew from celecoxib than nsNSAIDs (50.9% patients vs. 30.2%; P < 0.0001). INTERPRETATION: In subjects 60 years and over, free from CV disease and taking prescribed chronic nsNSAIDs, CV events were infrequent and similar on celecoxib and nsNSAIDs. There was no advantage of a strategy of switching prescribed nsNSAIDs to prescribed celecoxib. This study excluded an increased risk of the primary endpoint of more than two events per 1000 patient-years associated with switching to prescribed celecoxib. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/show/NCT00447759; Unique identifier: NCT00447759.
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MacDonald et al. (2016) conducted an RCT in Osteoarthritis or rheumatoid arthritis without established cardiovascular disease (n=7,297). Celecoxib vs. Continued non-selective NSAIDs (nsNSAIDs) was evaluated on Composite of hospitalization for non-fatal myocardial infarction or other biomarker positive acute coronary syndrome, non-fatal stroke or CV death (HR 1.04, 95% CI 0.81-1.33, p=0.75). Switching to celecoxib was non-inferior to continuing non-selective NSAIDs for the primary cardiovascular composite endpoint (HR 1.04, 95% CI 0.81-1.33, p=0.75) in patients without established cardiovascular disease.
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