Celecoxib Shines and Naproxen Tanks in the PRECISION Study Save
The PRECISION trial was published this week in the NEJM, presented at the Cardiology meetings in New Orleans, and presented today by Dr. Daniel Solomon at the 2016 ACR annual meeting in Washington, D.C. (citation source http://buff.ly/2fUmoqO)
The trial that in 2005 set out to establish the comparative safety of celecoxib, ibuprofen and naproxen has been delivered with a bang.
PRECISION was a randomized, double-blind, three-arm, non-inferiority study to primarily study the cardiovascular safety of celecoxib 100-200 mg bid; ibuprofen 600-800 mg bid; and naproxen 375-500 mg bid n OA and RA in patients at high risk for cardiovascular disease.
24,081 subjects were enrolled (90% OA; 10% RA). The mean age of subjects was over 60 yrs and 63% to 73% were female. The trial size and duration were event-driven until they accumulated at least 762 APTC cardiovascular events.
In addition to primary ATPC endpoints, secondary endpoints included GI and renal outcomes – all of which were adjudicated.
The trial was very slow to enroll, taking over 10 years and 1027 enrolling sites in 13 countries to complete the trial.
The topline results of the PRECISION trial include:
- High dropouts: While the study required patients to stay on the NSAID for at least 18 months, 68.8% of the patients stopped taking the study drug, and 27.4% of the patients discontinued follow-up.
- Celecoxib was shown to NOT be more hazardous than comparator NSAIDs. There were less ATPC cardiac events in celecoxib treated patients. Adjudicated cardiac events occurred in 188 patients in the celecoxib group (2.3%), 201 patients in the naproxen group (2.5%), and 218 patients in the ibuprofen group (2.7%) (hazard ratio for celecoxib vs. naproxen, 0.93; 95% confidence interval [CI], 0.76 to 1.13; hazard ratio for celecoxib vs. ibuprofen, 0.85; 95% CI, 0.70 to 1.04; P
- Overall, celecoxib demonstrated an 18% reduction in major CV events and a 32% reduction in all cause mortaility compared to ibuprofen.
- Not surprisingly, gastrointestinal events were significantly lower (~55%) with celecoxib than with naproxen (P=0.01) or ibuprofen (P=0.002).
- Renal events were also significantly lower (~45%) with celecoxib than with ibuprofen (P=0.004) but was not significantly lower with celecoxib than with naproxen (P=0.19).
- All patients showed clinical improvement by HAQ and Pain scales, but there was no difference between drugs in OA but in RA patients, Ibuprofen out performed celecoxib and naproxen.
- In the end celecoxib (now generic) looked good, and the big surprise was that naproxen was not as cardioprotective as has been show in many past NSAID trials.
Some caveats to this study:
- Roughly 45% of patients received background low dose daily aspirin. However, Dr. Solomon indicated that analyses failed to show any influence of ASA on these outcomes.
- Remember these patients were enrolled if they had RA or OA but also had to have an increased risk of CV events - meaning they either had established cardiovascular disease or were at an increased risk to develop cardiovascular disease (e.g., DM, HTN, dyslipidemia, CAD, etc.).
- There was no placebo in this trial (unethical) and acetaminophen was rejected as a comparator because previous studies had shown this drug to be ineffective for the treatment of patients with NSAID-dependent arthritis.