Clinical Pain Medicine
SEPTEMBER 14, 2017
Even Brief NSAID Use Increases Myocardial Infarction Risk
Oral prescription nonsteroidal anti-inflammatory drugs (NSAIDs) were found to increase the risk for acute myocardial infarction (MI), even with short-term use, according to a large international analysis (BMJ 2017 May 9. [Epub ahead of print]).
The analysis of eight studies in Canada, the United Kingdom and Finland, involving 446,763 patients, including 61,460 with acute MI, found that the real-world use of prescription NSAIDs, including naproxen, for one week or more was associated with a significantly increased risk for MI.
The researchers also found that the risk for MI with the use of celecoxib was similar to that with traditional NSAIDs, but was lower than rofecoxib, which has been withdrawn from the market.
“We documented that current use of all studied NSAIDs, including naproxen, was associated with an increased risk of acute myocardial infarction,” the researchers wrote in the study led by Michele Bally, BPharm, MSc, PhD, an epidemiologist and a researcher at the Montreal University Hospital Research Centre.
“Given that the onset of risk of acute myocardial infarction occurred in the first week and appeared greatest in the first month of treatment with higher doses, prescribers should consider weighing the risks and benefits of NSAIDs before instituting treatment, particularly for higher doses,” the researchers wrote.
“Pharmacologically, celecoxib is more like traditional NSAIDs with some blockade of COX-1 [cyclooxygenase-1] and increasing COX-2 blockade as the dose escalates,” said C. Michael White, PharmD, FCP, FCCP, professor and head, University of Connecticut School of Pharmacy, in Storrs, who was asked to comment on the report. “COX-1 blockade is known to provide the cardiovascular benefits of aspirin, due to an antiplatelet effect.
“As the dose of aspirin is increased, it becomes a better pain reliever due to greater COX-2 blockade, but a worse cardiovascular drug due to the loss of COX-1 specificity with greater blockade of prostacyclin via COX-2,” Dr. White said. “We also know pharmacologically that adding an NSAID to cardioprotective doses of aspirin negates the benefits of aspirin therapy.”
When the heart muscle experiences ischemia or near ischemia, it forms a neovasculature to partially bypass the area of coronary blockage, which enables the heart muscle to prepare for the sudden ischemic event, lessening the damage. “COX-2 blockade impedes both of these effects and makes adverse cardiac events more likely and more severe,” Dr. White explained, adding that he was not surprised that the risk for an event was greater in the first seven days and increased as more therapy was taken.
While the results reinforce the idea that both selective COX-2 inhibitors and nonselective NSAIDs are linked to an increased risk for MI, according to Zoltan Varga, MD, PhD, an internal medicine resident at Florida Hospital, in Orlando, it was surprising to see the high risk with naproxen in the report because previous studies found that naproxen had superior cardiovascular safety. “The results signal that naproxen, traditionally considered to be the safest NSAID for patients with preexisting cardiovascular conditions, might pose the same risk as other drugs from the group,” Dr. Varga said.
“That we were able to draw conclusions on the risk of myocardial infarction of NSAID dose levels and treatment durations corresponding to various scenarios of actual use is a novel contribution,” the authors wrote in their analysis.
The meta-analysis found that the probability of increased MI risk was 92% for celecoxib, 97% for ibuprofen and 99% for diclofenac, naproxen and rofecoxib, even when taken for one to seven days. The corresponding odds ratios (95% CI) were 1.24 (0.91-1.82) for celecoxib, 1.48 (1.00-2.26) for ibuprofen, 1.50 (1.06-2.04) for diclofenac, 1.53 (1.07-2.33) for naproxen and 1.58 (1.07-2.17) for rofecoxib. In addition, the analysis found that the higher the dose, the greater the risk, although the risk associated with shorter duration of use did not increase when NSAIDs were taken for longer than one month.
With use of more than 1,200 mg per day of ibuprofen or more than 759 mg per day of naproxen for one to four weeks, the results showed a possible 75% relative increase in risk for acute MI, the researchers found.
“It looks like the one outlier is the risk of event in people taking ibuprofen in doses less than 1,200 mg for eight to 30 days. They mention that the number of people in their study using this dose was very low, so we do not know if this suggests that lower-dose ibuprofen is safer than the others or if this is [a] statistical artifact. I tend to assume that ibuprofen is among the safest NSAIDs, especially at low doses,” Dr. White said.
“Finally, it should be clearly stated that this study is looking by and large at higher doses of these drugs and the results are not as applicable to those only using over-the-counter doses,” Dr. White noted. “In addition, they did not provide a good assessment of the number needed to harm, which is problematic. If your risk is doubled but it only happens in one in 10 million people at baseline, then is it really a pressing health issue regardless of what you take?”
Dr. Varga also found some limitations that are inherent to retrospective database studies. “Some of the most important limitations, clearly acknowledged by the authors, is that although the source databases contained information about NSAID prescription/dispensing, it’s impossible to prove the patients were actually using the prescribed medication. In our experience, compliance in the general public is alarmingly low, which could represent a possible bias.
He also said, “Taking into consideration the results of prior studies showing naproxen to be a relatively safe option, I don’t think we should change our approach to NSAID selection in patients with high [cardiovascular] risk on the basis of this study only.” He added that the results should serve as “a red flag, reemphasizing the need to avoid all NSAIDs whenever possible, or at least use the minimal dose for the shortest possible time.”
The researchers and Drs. White and Varga reported no relevant financial disclosures.