AT THE AHA SCIENTIFIC SESSIONS
NEW ORLEANS (FRONTLINE MEDICAL NEWS) – The cardiovascular safety profile of the nonsteroidal anti-inflammatory drug (NSAID) celecoxib, a selective inhibitor of COX-2, is no worse than those of the nonselective NSAIDs naproxen and ibuprofen, according to a trial reported at the American Heart Association scientific sessions.
The trial, known as PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen Or Naproxen) was undertaken after another selective COX-2 inhibitor, rofecoxib (Vioxx), was withdrawn from the market because of associated cardiovascular events. It compared the three drugs among more than 24,000 patients with painful arthritis and elevated cardiovascular risk.
Main results showed that 2%-3% of patients experienced a cardiovascular event (cardiovascular death, myocardial infarction, or stroke) during a follow-up approaching 3 years, regardless of which drug they were assigned to take, with the slight differences falling within predefined margins for noninferiority of celecoxib, investigators reported in a session and related press conference.
Additionally, celecoxib yielded a lower rate of gastrointestinal events when compared with each of the other drugs and a lower rate of renal events when compared with ibuprofen.
“After the withdrawal of rofecoxib, everybody thought they knew the answer, that COX-2 inhibitors had an unfavorable cardiovascular profile,” commented first author Steven E. Nissen, MD , chair of cardiovascular medicine at the Cleveland Clinic in Ohio. “We didn’t find that. And this is the type of study that once again teaches us that if we jump to conclusions about this based on mechanistic considerations, we often make very bad decisions.”
The trial did uncover some differences in the safety profiles of the three drugs that will require parsing. “Everyone is going to have to decide for themselves” among them, he said. “I am not going to tell you what drug people should take. I’m going to put out there what our findings are and let the chips fall where they may, including telling people that the trial is far from perfect, but it is the best we will ever be able to get.”
Efforts are under way to disseminate the PRECISION findings to rheumatologists and other groups who do much of the NSAID prescribing.
“Any time you have something that has findings like the findings we have, it takes some time to trickle down to the prescribers. It’s going to be our job to communicate both the value and the important limitations of the trial so that people can make informed decisions about which of these drugs to use and in whom,” Dr. Nissen said.
A cautionary view
“The investigators addressed an extremely important question, which is what is the cardiovascular safety of agents that we administer for a general medical condition over the long term,” commented invited discussant Elliott M. Antman, MD , a senior physician at Brigham and Women’s Hospital and associate dean for Clinical and Translational Research at Harvard Medical School in Boston. “We don’t see a lot of trials like that, but we do need this information.”
However, in his opinion, the trial fell short of its aim of squarely comparing the safety of these three NSAIDs in a population at high cardiovascular risk.
“This is not a comparison of drugs; this is a comparison of drug regimens because the investigators were able to increase the dose to control the subjects’ pain,” Dr. Antman elaborated. “And they were able to increase the dose of naproxen and ibuprofen comparatively more than they could for celecoxib,” which was capped at 200 mg per day at most study sites.
Furthermore, only about one-fifth of the patients studied had known heart disease. “We know that the more likely a person is to have atherosclerosis, the more likely they are to experience harm from COX-2 inhibition,” he said. “So given the profile of the patients in this trial, it’s unlikely that we would have been able to detect that signal of harm from COX-2 inhibition, particularly at this dose.”
Dr. Antman also had concerns about the impact on concomitant aspirin therapy (the benefit of which can be affected by nonselective NSAIDs) and about possible differences in the reasons for dropouts that may have biased findings toward celecoxib. “I believe we need more information in order to more completely interpret this trial,” he summarized.
For now, he advised physicians to follow guidance put forth by the American Heart Association: Avoid NSAIDs in patients with known heart disease, and if one must use them, try to use the lowest-risk drug in the lowest dose needed for the shortest period of time.
In the future, “we should actually break out of the mold of assigning everybody in the trial a common phenotype and reporting the average result, but instead take a precision medicine approach, where we look at the polymorphisms in the COX enzyme, look at the polymorphisms in the ability to metabolize these drugs, and actually see if we can be more precise,” Dr. Antman maintained. “Finally, there is an urgent clinical need for the development of novel analgesics and other therapeutics to avoid the cardiovascular risk from all NSAIDs.”
Trial details
Patients were eligible for PRECISION, a Pfizer-funded trial, if they had osteoarthritis or rheumatoid arthritis and were at increased cardiovascular risk.
In all, 24,081 patients from 926 centers globally were randomly assigned to double-blind treatment with celecoxib, naproxen, or ibuprofen, all of which are now available as generics in the United States.
“Patients were randomized to the FDA-approved doses of these drugs, and they could have their dose increased if they had unrelieved pain up to the maximum allowed by regulatory authorities in the local jurisdictions where the study was done,” Dr. Nissen noted, pointing out that studies initially generating some concern about celecoxib used a supratherapeutic dose of 800 mg daily.
As COX-2 inhibitors are less likely than nonselective NSAIDs to cause ulcers, which might affect compliance and outcomes, all patients additionally received esomeprazole for gastroprotection “to try to level the playing field,” he explained.
The mean treatment duration was 20.3 months, and the mean follow-up duration was 34.1 months, according to data reported at the meeting and simultaneously published (N Engl J Med. 2016 Nov 13. doi: 10.1056/NEJMoa1611593 ). On average, the daily dose of drug received was 209 mg for celecoxib, 852 mg for naproxen, and 2,045 mg for ibuprofen.
In intention-to-treat analyses, the rate of the primary composite outcome of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke was 2.3% in the celecoxib group, 2.5% in the naproxen group, and 2.7% in the ibuprofen group. The hazard ratio was 0.93 for celecoxib versus naproxen (P less than .001 for noninferiority) and 0.85 for celecoxib versus ibuprofen (P less than .001 for noninferiority).
Differences were more marked in the on-treatment population. Here, the rate of the primary outcome was 1.7% in the celecoxib group, 1.8% in the naproxen group, and 1.9% in the ibuprofen group. The HR was 0.90 for celecoxib versus naproxen (P less than .001 for noninferiority) and 0.81 for celecoxib versus ibuprofen (P less than .001 for noninferiority).
Secondary outcomes, which tested for superiority, showed that the rate of major adverse cardiovascular events was 15% higher in the ibuprofen group as compared with the celecoxib group in the intent-to-treat population. The difference translated to a near-significant reduction in risk with the latter (HR, 0.87; P = .06) that appeared greater in the on-treatment population.
However, Dr. Nissen cautioned that he could not state that celecoxib was superior. “Secondary and tertiary endpoints in a clinical trial are hypothesis generating, and they are not considered definitive evidence,” he commented. At the same time, “the FDA is going to have to deal with that because what do they do with labeling? What do they do with over-the-counter access to these various drugs?”
The rate of all-cause mortality was 25% higher with naproxen than with celecoxib (HR, 0.80; P = .052).
The rate of gastrointestinal events was 54% higher with ibuprofen (HR, 0.65; P = .002) and 41% higher with naproxen (HR, 0.71; P = .01) as compared with celecoxib. And the rate of renal events was 64% higher with ibuprofen than with celecoxib (HR, 0.61; P = .004).
In a post hoc analysis of global safety, the rate of serious cardiovascular, gastrointestinal, and renal events was 28% higher with ibuprofen (HR, 0.78; P less than .001) and 15% higher with naproxen (HR, 0.87; P = .03) than with celecoxib.
Of note, the findings for the primary endpoint were similar regardless of whether patients were taking low-dose aspirin or not. “There was no interaction with aspirin use,” Dr. Nissen stated. “This was not about the interference of ibuprofen or naproxen with aspirin use.”
Analyses of pain relief using a visual analogue scale showed no clinically meaningful differences, suggesting that the drug doses used were equally analgesic, he said. Stopping of study drug because of lack of efficacy was slightly more common in the celecoxib group.
“We didn’t study the low-dose, intermittent use of these drugs that most of the public engages in, and it’s really important that we crisply communicate that to the public because somebody who takes occasionally ibuprofen or naproxen for a headache should not look at these comparative data in a way that should necessarily influence their behavior. We just don’t know the answer,” cautioned Dr. Nissen, who disclosed that he received grant support from Pfizer during the conduct of the trial.
But the findings are relevant for individuals who take over-the-counter NSAIDs at doses exceeding the label, a phenomenon known as dose creep. “We need to reemphasize to the public that the labeled over-the-counter dose is what you should take. You shouldn’t double up or triple up on the drugs because the issue of high-dose therapy, which is what we studied, suggests that there are really potentially important gastrointestinal, renal, and cardiovascular risks,” he said.
