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The PRECISION study will be presented on Tuesday, November 15, 2016 by Dr. Elaine Husni from the Cleveland Clinic. This report brings to a climax the controversy ignited by the February 2005 3 day FDA Arthritis Advisory Committee review of the safety of the blockbuster COX-2 inhibitors, celecoxib, rofecoxib, and valdecoxib.
Despite the committee’s unanimous vote to keep these agents on the market, the FDA: 1) affirmed the removal of rofecoxib (Vioxx) from the market; 2) removed valdecoxib (Bextra), citing safety concerns; 3) kept celecoxib on the market (calling for future safety studies); and 4) called for a large “ALL-HAT” design prospective trial that would study the comparative safety of nonselective NSAIDs and celecoxib, a selective COX-2 inhibitor.
Instead of a government funded study, a Pfizer sponsored trial called PRECISON (Prospective Randomized Evaluation of Celecoxib Integrated Safety Vs Ibuprofen or Naproxen) was initiated in June 2006 and completed in July 2016.
PRECISION is a randomized, double-blind, three-arm, non-inferiority study to compare the cardiovascular safety of celecoxib, ibuprofen and naproxen in OA and RA in patients at high risk for cardiovascular disease. This was a phase IV, noninferiority trial wherein celecoxib would be non-inferior to naproxen. The doses used included: Celecoxib 100-200 mg bid; Ibuprofen 600-800 mg tid; and Naproxen 375-500 mg bid.
The trial size and duration are event-driven but all patients must have 18 months’ follow-up or longer Original planned sample size ~20,000 total patients and 762 APTC cardiovascular events.
Over 24,000 patients with either osteoarthritis (OA) or rheumatoid arthritis (RA) were randomized to receive either naproxen or celecoxib. The trial was very slow to enroll, taking over 10 years and 1027 enrolling sites to complete the trial.
The study population focused on OA and RA patients with or at risk for cardiovascular (CV) disease outcomes. Thus, the primary outcome was the first occurrence of cardiovascular death (including hemorrhagic death), non-fatal myocardial infarction, or non-fatal stroke (APTC composite endpoint). Overall safety outcomes also included gastrointestinal and renal safety and symptomatic benefit in each treatment group were assessed.
The results of the PRECISION trial will be presented on Tuesday November 15th, but the preliminary abstract data finds that 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 authors intend to present primary ATPC endpoints as well as GI and renal outcomes – all of which were adjudicated.
Why is the PRECISION trial important? Several reasons standout. Primary is the debate about the cardiovascular safety of nsNSAIDs and COX-2 inhibitors. While all will agree, there are renal, hypertensive and cardiovascular risks, rheumatologists are of the opinion that there use in patients without risk factors may be advantageous. By contrast, the American College of Cardiology has indicted the use of NSAIDs, taking the stance that they should only be short-term therapy and may be viewed as “life-style” therapies. Regardless of one’s views, large scale data from at-risk individuals will likely settle many of these debates.
PRECISION is also important to the FDA, EMA and other regulatory agencies charged with protecting the public from unsafe therapies. In February 2014 FDA convened another review of the Cardiovascular Safety of NSAIDs. The Arthritis Advisory Committee Drug Safety and Risk Management Advisory Committee met to review available data and to receive updated information from NSAID manufacturers on drug safety.
- As a result of this advisory meeting, in July 2015 the FDA issued a Drug Safety Communication on the safety of NSAIDs. The net result was that prescription NSAID labels were to be revised to reflect the following information:
- The risk of heart attack or stroke can occur as early as the first weeks of using an NSAID. The risk may increase with longer use of the NSAID.
- The risk appears greater at higher doses.
- Newer data is still not sufficient to determine that the risk of any particular NSAID is definitely higher or lower than that of any other particular NSAID.
- NSAIDs can increase the risk of heart attack or stroke in patients with or without heart disease or risk factors for heart disease.
- Patients with heart disease or risk factors for CV disease have a greater likelihood of heart attack or stroke following NSAID use than patients without these risk factors.
- Patients treated with NSAIDs following a first heart attack were more likely to die in the first year after the heart attack compared to patients who were not treated with NSAIDs after their first heart attack.
- There is an increased risk of heart failure with NSAID use.
These recommendations were carried over in the Drug Facts labels of OTC non-aspirin NSAIDs.
While many await the results of the PRECISION trial, others have been openly critical of the design, pointing out that as a noninferiority trial, it only 80% has power to detect a meaningful difference. Moreover, the study is not powered to accurately comment on the influence of background aspirin therapy. This is important since the effects of low dose aspiring on platelet inhibition may be negatively influenced by ibuprofen and naproxen, but not by celecoxib (Science. 2005 Dec 23;310(5756):1890-1). Lastly, there may well be issues of adherence in OA and RA patients asked to stay on a stable dose of one NSAID for greater than 18 months.