Moderate doses of celecoxib are noninferior to ibuprofen or naproxen in terms of cardiovascular safety

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Moderate doses of celecoxib are noninferior to ibuprofen or naproxen in terms of cardiovascular safety

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been used therapeutically around the world for over half decade now. In September 2004, confirmation of adverse cardiovascular outcomes lead to the withdrawal of selective COX-2 inhibitor rofecoxib. In April 2005, Valdecoxib was subsequently taken down from the market because of adverse cardiovascular effects and serious skin reactions. The Food and Drug Administration permitted celecoxib to remain in the market, but instructed a cardiovascular safety trial.

The PRECISION Safety Trial
A randomized, multicenter, double-blind, noninferiority trial including 24,081 patients with osteoarthritis (OA) or rheumatoid arthritis (RA), and with increased cardiovascular risk was conducted. Randomization was as per the patients’ primary diagnosis, aspirin use and geographic location. The objective of the trial was to estimate the non-inferiority of celecoxib in terms of cardiovascular death. Celecoxib (100 mg twice daily), ibuprofen (600 mg three times daily) or naproxen (375 mg twice daily) for treatment of patients for a mean duration of 20.3±16 months, with a mean follow-up of 34.1±13.4 months. Following the first visit, the investiagtors could increase the celecoxib dose to 200 mg twice daily, ibuprofen to 800 mg three times daily or naproxen to 500 mg twice daily. For gastric protection, all the participants were provided with esomeprazole 20–40 mg. Patients who were receiving low-dose aspirin (<325 mg), were allowed to use it further as well.

The primary composite result was the first occurrence of an adverse event that met Antiplatelet Trialists Collaboration (APTC) criteria (death due to cardiovascular causes, including hemorrhage, nonfatal myocardial infarction or nonfatal stroke). As per the secondary composite result, major adverse cardiovascular events, included components of the primary outcome plus coronary revascularization, hospitalization for unstable angina, or transient ischemic attack. These secondary outcomes also included the clinically significant gastrointestinal (GI) events. Tertiary results included iron deficiency anemia (GI origin), clinically significant renal events, and heart failure or hypertension hospitalization. A non-adjudicated secondary outcome was arthritis pain intensity, which was estimated via a Visual Analogue Scale (VAS) (scores range from 0 to 100 mm, higher scores equal worse pain). Noninferiority required a hazard ratio of 1.12 or lower, and an upper 97.5% confidence limit of 1.33 or lower in the intention-to-treat population and 1.40 or lower in the on-treatment population.

The duration of the trial was10 years, with 90% of the participants having OA, while 10% RA. During the trial, 69% of the patients ceased taking the study drug, and 27% of patients discontinued follow-up.

The primary poutcome was observed in 2.3% of celecoxib-treated patients (n=188), 2.5% of the naproxen-treated patients (n= 201), and 2.7% of the ibuprofen-treated patients (n=218). During the treatment population, the primary outcome (APTC) occurred in 1.7% of the celecoxib-treated patients (n=134), 1.8% of the naproxen-treated patients (n=144) and 1.9% of the ibuprofen-treated patients (n=155). Hazad ratios depicted 0.90 for celecoxib vs. naproxen; 0.81 for celecoxib vs. ibuprofen (P<0.001 for non-inferiority); and 1.12 for ibuprofen vs. Naproxen. On comparison of celecoxib with either ibuprofen or naproxen, all four of the prespecified noninferiority requirements were revealed.

The event rate for the mixed result of serious GI events was lower in the celecoxib group than in the naproxen-treated patients (0.71) or the ibuprofen-treated patients (0.65). Complicated renal events were lower in celecoxib-treated patients than in ibuprofen-treated patients (HR, 0.61), but the rate did not significantly differ from naproxen-treated patients (HR, 0.79). Hypertension hospitalization was lower in celecoxib-treated patients as compared to ibuprofen-treated patients, but not for naproxen-treated patients. For pain estimation, an important, but small, benefit was identified for naproxen vs. celecoxib or ibuprofen.

Concisely, as the higher doses of celecoxib were not studied, the data cannot be extrapolated to other, higher doses. Also, only two non-selective NSAIDs were compared, so the same holds true for data extrapolation. This data reveals that at moderate doses, celecoxib was found to be noninferior with respect to cardiovascular safety compared with ibuprofen or naproxen. Celecoxib use also led to fewer GI events than either NSAID, and fewer renal adverse events compared with ibuprofen.


The rheumatologist

Link to the source:

Original title of article:

Celecoxib & Cardiovascular Death: NSAID Safety Under Review


Michele B. Kaufman et al.

The rheumatologist
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