Arthritis, Painkillers and Heart Health

2016 Highlight from the American College of Rheumatology (ACR)/Association of Rheumatology Health Professonals (ARHP) Annual Meeting in Washington, DC

Written by Kathleen Doheny

Ten-year trial with osteoarthritis (OA) and rheumatoid arthritis (RA) patients had surprising findings about celecoxib, naproxen and ibuprofen. Painkillers are a mainstay of daily treatment for legions of patients with OA and RA, despite ongoing debate and some fears about the cardiovascular (CV) risk linked with the drugs.
Results of the 10-year PRECISION study aimed to put to rest the debate. Researchers comparing celecoxib (Celebrex), naproxen (Aleve, Anaprox) and ibuprofen (Advil, Motrin) found some safer than believed, others not, and that all three drugs seem to offer similar pain relief.1,2

Bottom line for OA and RA patients in pain and their doctors? "I think the take home is, if you really need the celecoxib you can take it with less worry about the increased risk in heart disease," said Suzanne Steinbaum, DO, director of women's heart health at Northwell Lenox Hill Hospital. She was not involved in the study but reviewed the findings. Still, her ''less is more'' advice would stand for her patients with arthritic pain, she said, and that means relying on over-the-counter medicines if they suffice.

PRECISION Trial: Subgroup Analysis
Researchers involved in the PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen) reported a subgroup analysis of OA and RA patients at the ACR/ARHP meeting in Washington, DC, while others presented results of the parent trial at the American Heart Association scientific sessions. The study, sponsored by Pfizer, was published simultaneously in the New England Journal of Medicine.2

PRECISION included information on 24,081 patients from 13 countries with either OA or RA and at cardiovascular risk. It was evidence of adverse cardiovascular outcome in a placebo-controlled trial that led to the withdrawal in 2001 of the selective COX-2 inhibitor (cyclooxygenase-2) rofecoxib (Vioxx). After that, the FDA allowed continued marketing of celecoxib, the only remaining COX-2 inhibitor, but mandated a cardiovascular safety trial.

The trial's aim was to compare the three medications and evaluate cardiovascular, gastrointestinal, renal and other outcomes, including pain relief.

Safety, Pain Outcomes
"At usual dosages of celecoxib, naproxen and ibuprofen, celecoxib is at least as safe as these other commonly used NSAIDs,'' said co-first author Daniel Solomon, MD, MPH, chief of clinical sciences, division of rheumatology and pharmacoepidemiology at Brigham and Women's Hospital and professor of medicine, Harvard Medical School. "It appears safer in several categories, but the trial was designed to determine equivalency not superiority."

Secondary endpoints were pain and function, Dr. Solomon said. "In the vast majority of patients in the trial who had OA, improvements in pain and function were very similar across the three treatment groups. In the RA subgroup, there was less improvement for celecoxib and naproxen users than ibuprofen."

For patients with osteoarthritis, the overall change in means of Visual Analog Score (VAS) was:

For patients with rheumatoid arthritis, the overall change in means of VAS scores was:

For the composite outcome of MACE (major adverse cardiovascular events), the hazard ratio (HR) for celecoxib versus naproxen was 0.97 (95% confidence interval [CI], 0.83 to 1.12; P=0.64). The HR for celecoxib versus ibuprofen was 0.87 (95% CI, 0.75 to 1.01; P=0.06). The authors write: "In pairwise comparisons for the components of the primary outcome, the differences between celecoxib and naproxen and between celecoxib and ibuprofen were not significant. The hazard ratio for death from any cause was 0.80 for celecoxib versus naproxen (95% CI, 0.63 to 1.00; P=0.052). The rate of nonfatal myocardial infarction was higher in the ibuprofen group than in the naproxen group (hazard ratio, 1.39; 95% CI, 1.01 to 1.91; P=0.04).''

One surprising finding: RA patients had a doubling of all-cause mortality risk with naproxen versus celecoxib. In those with RA, 15 deaths occurred in the celecoxib group and 30 in the naproxen arm (HR 0.47, 95% CI 0.25-0.88, P-0.02). However, study co-first author M. Elaine Husni, MD, MPH, vice chair of rheumatic and immunologic diseases, Cleveland Clinic, cautioned that the RA subgroup had many fewer patients—only about 2400. With the OA patients, all-cause mortality was similar in all three drug arms.

Take-Home Points
Although the study found similar pain relief from all three drugs for OA patients, Dr. Steinbaum said, ''What I always tell patients is, if you have pain, you have to take something, but less is more. If you can get away with the over-the-counter dose of naproxen or ibuprofen, I would recommend that."

The value of the new sub group analysis, according to Dr. Husni, is that ''we can make more individualized treatment options for people who need long-term NSAIDs."

Overall, Dr. Husni said, she views the results as ''reassuring for patients who need this [pain relief] long term."

Limitations include lower adherence and retention than in most CV outcome trials but not analgesic trials, as switching medicines is common among pain patients, the researchers said. The dose of celecoxib was moderate, at 100 mg b.i.d., and trials that showed cardiovascular harm used 400 to 800 mg daily, the researchers said.

Disclosures: Dr. Steinbaum has no pharmaceutical disclosures. Dr. Solomon reports research grants from Pfizer on non-NSAID-related topics. He receives royalties from UpToDate on chapters related to NSAIDs and selective Cox-2 inhibitors. Dr. Husni has research grants from Genzyme/Sanofi on a knee OA trail related to hyaluronic acid injections.

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