Celecoxib noninferior to naproxen, ibuprofen in CV safety
Moderate doses of celecoxib are noninferior to naproxen or ibuprofen in terms of cardiovascular (CV) safety, according to results of the PRECISION* trial presented at the Scientific Sessions of the American Heart Association held recently in New Orleans, Louisiana, US.
In the intention-to-treat analyses, the incidence of CV death, nonfatal myocardial infarction, or nonfatal stroke was comparable in patients taking celecoxib, naproxen, and ibuprofen (2.3, 2.5, and 2.7 percent, respectively; hazard ratio [HR], 0.93, 95 percent confidence interval [CI], 0.76–1.13 for celecoxib vs naproxen; HR, 0.85, 95 percent CI, 0.70–1.04 for celecoxib vs ibuprofen; p<0.001 for noninferiority in both comparisons). [AHA 2016, LBCT 01; N Engl J Med 2016;doi:10.1056/NEJMoa1611593]
Findings were similar in the on-treatment analysis where the incidence of CV events was 1.7, 1.8, and 1.9 percent in the celecoxib, naproxen, and ibuprofen groups, respectively.
Incidence of serious gastrointestinal events was lower in the celecoxib group compared with the naproxen group (HR, 0.71; p=0.01) or the ibuprofen group (HR, 0.65; p=0.002). Serious renal events also occurred at a lower rate in the celecoxib group compared with the ibuprofen group (HR, 0.61; p=0.004) but not when compared with the naproxen group (HR, 0.79; p=0.19).
As a result of the withdrawal of the COX-2 inhibitor rofecoxib due to negative CV events, the US Food and Drug Administration mandated a postmarketing study to determine the CV safety of the sole remaining selective COX-2 inhibitor, celecoxib.
In this randomized, double-blind, multicentre, noninferiority trial, individuals (n=24,081, average age 63 years, 64 percent female) with osteoarthritis or rheumatoid arthritis requiring chronic daily doses of nonsteroidal anti-inflammatory drugs (NSAIDs) and with pre-existing or at high risk for CV disease were randomized to receive either celecoxib (100–200 mg twice daily), ibuprofen (600–800 mg three times daily), or naproxen (375–500 mg twice daily) for a mean 20.3 months and were followed-up for a mean 34.1 months. They were also allowed 75–100 mg of aspirin daily and were given esomeprazole (20–40 mg) for gastric protection. Over the course of the trial, 68.8 percent of participants discontinued the study drug, while 27.4 percent discontinued follow-up.
“[The PRECISION trial showed that] celecoxib was noninferior to either naproxen or ibuprofen. We now know that the risks that we’re seeing with rofecoxib do not appear to be shared by celecoxib,” said study author Dr Steven Nissen, chair of cardiovascular medicine at the Cleveland Clinic, Cleveland, Ohio, US.
“After the withdrawal of rofecoxib, there ensued a rush to judgment about the cardiovascular safety of COX-2 inhibitors. The PRECISION trial demonstrates the hazards inherent in prejudgment about the risks and benefits of therapies based upon expectations and indirect methods. These findings serve as an important warning to the medical community that we may arrive at erroneous conclusions when we fail to follow a systematic and unbiased approach to scientific and public health questions,”said Nissen.
The findings also challenge the “widely-held view” of the superior CV safety of naproxen. Nonetheless, Nissen cautioned that the results of the PRECISION trial are merely reflections of the relative safety of the three study drugs and not the other currently available NSAIDs. The results also pertain to moderate doses and not higher doses of celecoxib.
“These data [also] do not provide conclusive evidence regarding the safety of intermittent treatment or use of low-dose over-the-counter preparations. Between drug differences should be viewed as hypothesis generating, rather than conclusive,” said Nissen.
Discussant Dr Elliott Antman from the Brigham and Women’s Hospital in Boston, Massachusetts, US also noted that all trial participants were taking esomeprazole, the effects of which on celecoxib are not known. Furthermore, most participants were of low-to-intermediate CV risk. Thus, the effect of celecoxib on a high-risk population is yet to be established, he said.