There is limited information about the relative safety of selective cyclooxygenase-2 inhibitors. In particular, concerns exist regarding the adverse cardiovascular effects associated with celecoxib. In the aftermath of the withdrawal of rofecoxib from a placebo-controlled trial because of evidence of adverse cardiovascular outcomes associated with the cyclooxygenase-2 inhibitor, Steven E. Nissen, MD, Cardiologist, Cleveland Clinic, OH, and colleagues designed the 10-year PRECISION trial to compare the cardiovascular, gastrointestinal, and renal outcomes of celecoxib with those of naproxen or ibuprofen (Nissen SE, et al. N Engl J Med. 2016; 375:2519-2529).
The double-blind, multicenter, noninferiority trial randomized 24,081 patients with osteoarthritis or rheumatoid arthritis who were at increased cardiovascular risk to receive celecoxib 100 mg twice daily (n = 8072), ibuprofen 600 mg 3 times daily (n = 8040), or naproxen 375 mg twice daily (n = 7969) with matching placebo in a 1:1:1 ratio. Patients were aged ≥18 years, required daily treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) for arthritis pain, and were given esomeprazole 20 mg to 40 mg for gastric protection.
During their subsequent visits, patients with rheumatoid arthritis could have their doses of celecoxib, ibuprofen, and naproxen increased to 200 mg twice daily, 800 mg 3 times daily, and 500 mg twice daily, respectively. Although patients with osteoarthritis could also be given increased doses, regulatory dosing restrictions were set for celecoxib.
Dr Nissen and his colleagues selected naproxen as the primary comparator for the assessment of celecoxib noninferiority, and conducted noninferiority comparisons of celecoxib versus ibuprofen and of ibuprofen versus naproxen. Noninferiority was defined as a hazard ratio (HR) ≤1.12.
Separate analyses were performed for the intention-to-treat phase, and for when patients were taking the study drug (including 30 days postdiscontinuation). During the intention-to-treat phase, noninferiority required an upper 97.5% confidence limit of ≤1.33, and when patients were receiving treatment, an HR of ≤1.40 was requisite. To calculate the HRs and confidence intervals (CIs), the investigators used a Cox proportional hazards model that was adjusted for stratification factors.
The primary end point was the first adverse event incident that met Antiplatelet Trialists, Collaboration criteria, including cardiovascular-associated death, nonfatal stroke, or nonfatal myocardial infarction.
Major adverse cardiovascular events were the secondary end point, and included coronary revascularization, hospitalization for unstable angina or transient ischemic attack, and significant gastrointestinal events, in addition to the primary end point components.
Throughout the trial, 27.4% of the patients stopped participating in follow-ups, and 68.8% of the patients discontinued use of their respective study drug. During the intention-to-treat phase, 188 (2.3%) patients met the primary end point in the celecoxib group, as did 201 (2.5%) in the naproxen group, and 218 (2.7%) in the ibuprofen group (celecoxib vs naproxen: HR, 0.93; 95% CI, 0.76-1.13; celecoxib vs ibuprofen: HR, 0.85; 95% CI, 0.70-1.04; in both comparisons, P <.001 for noninferiority).
Results of the analysis during and after the treatment period showed that the primary end point was reached by 134 (1.7%), 144 (1.8%), and 155 (1.9%) patients in the celecoxib, naproxen, and ibuprofen groups, respectively (celecoxib vs naproxen: HR, 0.90; 95% CI, 0.71-1.15; celecoxib vs ibuprofen: HR, 0.81; 95% CI, 0.65- 1.02; in both comparisons, P <.001 for noninferiority).
Among patients receiving celecoxib, the risk for gastrointestinal events was significantly lower than that of those taking naproxen or ibuprofen. Celecoxib was also associated with significantly lower risk for renal events than ibuprofen; however, the risk for renal events was not significantly lower for celecoxib compared with naproxen.
According to the investigators, these results do not support the popular belief that therapy with naproxen has better cardiovascular outcomes than treatment with other NSAIDs. Instead, they assert that, per the results of their analyses, celecoxib administered in moderate doses is noninferior to ibuprofen or naproxen in cardiovascular safety.
“The PRECISION trial provides statistically strong evidence that the cardiovascular risk associated with moderate doses of celecoxib is not greater than that associated with nonselective NSAIDs. As compared with two widely used nonselective NSAIDs—naproxen and ibuprofen—celecoxib was associated with numerically fewer cardiovascular events,” Dr Nissen and colleagues reported.
They also stressed that the results of the current trial only reflect the relative safety of the drugs involved—celecoxib, naproxen, and ibuprofen.
“The current results...cannot provide insight into the effects of the more than two dozen other marketed NSAIDs, particularly because each of these drugs may have a unique safety profile,” Dr Nissen and colleagues concluded.