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PRECISION Trial Shows Celecoxib Less Hazardous Than Ibuprofen and Naproxen

November 15, 2016
In the wake of the 2004 withdrawal of the selective COX-2 inhibitor rofecoxib (Vioxx) from the market over cardiovascular safety concerns, a large randomized controlled trial investigates the safety of celecoxib, the sole remaining COX-2 inhibitor approved in the United States. Its results are controversial.

Commentary by Elaine Husni, MD, MPH; Steven E. Nissen, MD, MACC; and Elliott Antman, MD

Celecoxib does not have a higher cardiovascular safety risk compared to ibuprofen (Advil, Motrin, generic) or naproxen (Aleve, generic), reported investigators at the late-breaking session at the American Heart Association’s Scientific Sessions in New Orleans.1

Investigators presented results from the PRECISION trial, whose primary objective was to conduct a noninferiority assessment of the cardiovascular risk of celecoxib (Celebrex, other) versus 2 widely used nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), ibuprofen and naproxen, in patients with osteoarthritis or rheumatoid arthritis. In 2015, the Food and Drug Administrated updated the warning for NSAIDs and cardiovascular risk. The PRECISION trial also compared all-cause mortality and gastrointestinal and renal adverse events among the 3 treatment groups.2 A generic version of celecoxib was approved in 2015.

“There has been ongoing debate on the safety of existing NSAIDs since rofecoxib was taken off the market and new FDA labeling on traditional NSAIDs took place,” said Elaine Husni, MD, MPH, one of the study authors. “The PRECISION study found celecoxib was less hazardous than ibuprofen or naproxen on cardiovascular outcomes as well as other outcomes. The results of the PRECISION trial offer clinicians increased detail on how to monitor patients who take chronic NSAIDs with a more individualistic approach.”

The study authors noted that adherence and retention were lower than in other cardiovascular outcome trials although similar to that in other pain studies. Nearly 70% of all patients, regardless of treatment group, discontinued treatment, and more than a quarter of patients discontinued the study during follow-up.

“These patients with chronic pain were very difficult to keep on their randomized treatment, and a significant number—much larger than we would like to see—left the trial, often because of their dissatisfaction with their level of pain relief,” said PRECISION presenter and lead author Steven E. Nissen, MD, MACC at a media briefing.

The investigators also noted that the celecoxib dose was moderate (100 mg twice a day) while earlier trials suggested that cardiovascular harm may occur at much higher doses of celecoxib (up to 800 mg twice a day). The investigators were also not able to draw conclusions on the safety of intermittent treatment or the use of low-dose, over-the-counter drugs.

“The hope was that the PRECISION trial would tell doctors and patients which NSAIDs were safe for patients with heart disease,” stated Elliott Altman, MD, a session discussant.“What we learned is that the cardiovascular safety of the 3 drug regimens tested for controlling arthritic pain were about the same in a low-risk population. The question of what to do in patients with known heart disease still remains. Based on the totality of the data, physicians prescribing NSAIDs should use them in the lowest risk patient, prescribe the safest drug, in the lowest dose required, and for the shortest period of time need to control symptoms,” he said.

During the media briefing, PRECISION presenter Dr. Nissen offered, “After the withdrawal of rofecoxib, everybody thought they knew the answer, that COX-2 inhibitors had an unfavorable cardiovascular [safety] profile. We didn’t find that [in the PRECISION trial]…. This trial we recognize, like all trials, is not perfect, but it certainly does not show an excess of cardiovascular events with celecoxib.”

Patients with chronic pain may need higher doses of NSAIDs than studied in the trail.

Study Details

Cardiovascular risk was defined as the risk of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke. Celecoxib’s cardiovascular risk was not significantly higher than that of either ibuprofen (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.70–1.04; P<0.001) or naproxen (HR, 0.93; 95% CI, 0.76–1.12; P<0.001) in the intention-to-treat (ITT) population.

In secondary analyses, which the authors considered hypothesis-generating and not conclusive, compared to celecoxib,

  • Ibuprofen had a 15% higher risk (borderline significant) of a major cardiovascular event (HR for celecoxib, 0.87; 95% CI, 0.75–1.01, P=0.06)
  • Ibuprofen had a 54% higher risk and naproxen a 41% higher risk of a major gastrointestinal event (ibuprofen: HR for celecoxib, 0.65; 95% CI, 0.50–0.85, P=0.002; naproxen: HR for celecoxib, 0.71; 95% CI, 0.54–0.93, P=0.01)
  • Ibuprofen had a 64% higher risk of a major renal event (HR for celecoxib, 0.61; 95% CI, 0.44–0.85, P=0.004)
  • Naproxen had a 25% higher risk (borderline significant) of all-cause mortality (HR for celecoxib, 0.80; 95% CI, 0.63–1.00, P=0.052)

There was no significant difference among the 3 treatment groups in time to death from cardiovascular causes.

In a post hoc analysis of global safety, both ibuprofen and naproxen were more likely to result in a major adverse event (cardiovascular, gastrointestinal, or renal) than celecoxib. Ibuprofen had a 28% higher risk (HR for celecoxib, 0.78; 95% CI, 0.69–0.87, P<0.001), and naproxen had a 15% higher risk (HR for celecoxib, 0.87; 95% CI, 0.77–0.99, P=0.03).

PRECISION Trial: 24,081 Patients with Osteoarthritis or Rheumatoid Arthritis

The PRECISION trial began in 2006 and included 24,081 patients at 926 centers in 13 countries. Approximately 90% of patients had osteoarthritis and 10% of patients had rheumatoid arthritis. All patients had required NSAIDs for symptom relief for at least 6 months. Patients also had established cardiovascular disease or were at increased risk of cardiovascular disease.

Patients were randomized to 1 of 3 treatment arms: celecoxib (100 mg twice a day), ibuprofen (600 mg twice a day), or naproxen (375 twice a day), the FDA-approved dosages. Dosage was allowed to increase to the maximum approved dose for unrelieved symptoms, and patients were also allowed to take aspirin (75–100 mg, according local guidelines). Participants also took daily esomeprazole for gastrointestinal protection. Mean drug exposure was 20.3 months, and mean follow-up time was 34.1 months.

The PRECISION trial was funded by Pfizer. Any honoraria and speaking and consulting fees were paid directly to charity.

 

Last updated on: November 15, 2016
Continue Reading:
Is There a Role for NSAIDs in Patients With Cardiovascular Disease?
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