Rheumatology Drug Updates: Celecoxib and Cardiovascular Safety Trial Results Reviewed

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Nonsteroidal anti-inflammatory drugs (NSAIDs) have been used therapeutically since the 1960s.¹ Evidence of adverse cardiovascular outcomes led to the withdrawal of the selective COX-2 inhibitor rofecoxib in September 2004, when the question of cardiovascular safety of NSAIDs first came into the limelight.² Valdecoxib (Bextra) was subsequently withdrawn from the market in April 2005 due to adverse cardiovascular effects and serious skin reactions.³ The Food and Drug Administration (FDA) allowed celecoxib to remain on the market, but mandated a cardiovascular safety trial.^4,5 The results of this trial, Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen (PRECISION), were recently published.⁶

PRECISION Safety Trial

This was a randomized, multicenter, double-blind, non-inferiority trial in 24,081 patients with osteoarthritis or rheumatoid arthritis, and with increased cardiovascular risk. Randomization was stratified by the patients’ primary diagnosis, aspirin use and geographic location. The trial goal was to assess the non-inferiority of celecoxib with regard to the primary composite outcome of cardiovascular death.

Patients were treated with celecoxib (100 mg twice daily), ibuprofen (600 mg three times daily) or naproxen (375 mg twice daily) for a mean duration of 20.3±16 months, with a mean follow-up of 34.1±13.4 months. Investigators could increase the celecoxib dose to 200 mg twice daily, ibuprofen to 800 mg three times daily or naproxen to 500 mg twice daily, following the first visit. All participants were provided with esomeprazole 20–40 mg for gastric protection. Patients who were receiving low-dose aspirin (The primary composite outcome was the first occurrence of an adverse event that met Antiplatelet Trialists’ Collaboration (APTC) criteria. These criteria included death due to cardiovascular causes (including hemorrhage), nonfatal myocardial infarction or nonfatal stroke. A secondary composite outcome, major adverse cardiovascular events, included components of the primary outcome plus coronary revascularization, hospitalization for unstable angina, or transient ischemic attack. Clinically significant gastrointestinal (GI) events were also secondary outcomes. Tertiary outcomes 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 assessed using a Visual Analogue Scale (VAS) (scores range from 0 to 100 mm, higher scores equal worse pain). Non-inferiority required a hazard ratio of 1.12 or lower, as well as 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 trial duration was 10 years, and 90% of the participants had osteoarthritis, while 10% had rheumatoid arthritis. During the trial, 69% of the patients stopped taking the study drug, and 27% of patients discontinued follow-up.

Results

The primary outcome (APTC) occurred 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). In the on-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). Hazard ratios were: 0.90 for celecoxib vs. naproxen; 0.81 for celecoxib vs. ibuprofen (P

For pain assessment, a significant, but small, advantage was identified for naproxen vs. celecoxib or ibuprofen.

The event rate for the composite outcome 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). Serious renal events occurred at a lower rate 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 for celecoxib-treated patients than for ibuprofen-treated patients, but not for naproxen-treated patients. For pain assessment, a significant, but small, advantage was identified for naproxen vs. celecoxib or ibuprofen.