Sense of Security May Be False with Tried and True Anti-inflammatories

Ibuprofen, Naproxen, Acetaminophen Can Raise Cardiovascular Risk

One of the biggest drug-safety stories in recent years has centered on the increased risk of serious cardiovascular side effects from the newer selective nonsteroidal anti-inflammatory drugs (NSAIDs). Rofecoxib (Vioxx) and valdecoxib (Bextra) have been pulled from the U.S. market. Celecoxib (Celebrex) now carries a black-box warning.

Surprisingly, switching back to the most widely used older drugs may not be much better for the heart. Amid the rhetoric, finger-pointing, and lawsuits directed at makers of the newer agents, a quieter and perhaps more profound reassessment of the risks and benefits of the entire class of drugs is under way, including traditional NSAIDs, such as ibuprofen (Advil, Motrin, Nuprin) and naproxen (Aleve, Naprosyn).

Lending more credence to the concerns, a large new study has found a significantly increased risk of heart attacks and strokes in women who took NSAIDs almost daily or at higher doses. The potential problem was worse for smokers. The study turned up a similar risk for acetaminophen (Tylenol), but not for aspirin. Reassuringly, the researchers found no increased risk at lower doses and with less frequent use.

Compelling evidence suggests that NSAIDS can prevent colon cancer, but they also increase the risk of heart attacks, strokes, and other cardiovascular problems, according to Andrew Chan (left), Charles Fuchs, and their co-authors.

“A lot of people have long assumed, perhaps wrongly, that because these drugs are already in widespread use and are available over the counter they are safe to use at any frequency and dose, for as long as you need to take them,” said gastroenterologist Andrew Chan, HMS instructor in medicine at Massachusetts General Hospital and first author of the study. “On a practical level, physicians and patients need to think about using these agents at the lowest possible dose for the shortest period of time.”

The older NSAIDs have not been subjected to the same kind of long-term, placebo-controlled testing as the newer selective medications, said Jerome Avorn, HMS professor of medicine and chief of the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital. Independent teams, such as Chan and his co-authors, are working to fill in the missing information.

“I don’t think people should give up on taking these drugs,” said Avorn, whose team has shown that ibuprofen raises blood pressure, a risk factor for cardiovascular disease. “Being in pain all the time is not good either.”

Upside, Downside
The older NSAIDs block two isoforms of cyclooxygenase (COX). The newer selective agents spare COX1, which helps protect the mucosal lining of the stomach and intestines, and target COX2, which retains their power against pain, fever, and inflammation. The attraction of COX2 inhibitors was their promise of fewer stomach ulcers and fewer potentially fatal upper gastrointestinal effects, which remains mostly unproven, except for rofecoxib. But they were prescribed far beyond the population at risk and quickly became the most popular choice for first-line NSAID use.

The most worrisome side effects of the selective inhibitors surfaced in large, long trials to prevent colon cancer, five years after the Food and Drug Administration approved COX2 inhibitors as safe and effective. A twofold increase in cardiovascular events during the Adenomatous Polyp Prevention on Vioxx (APPROVe) trial precipitated Merck’s withdrawal of rofecoxib from the market in September 2004. This randomized placebo-controlled study confirmed hints from observational studies and biological logic about the vascular side effects of the selective NSAIDs.

“On a practical level, physicians and patients need to think about using these agents at the lowest possible dose for the shortest period of time.”

Two similar studies were halted in December 2004 after three years when an independent review found a threefold increase in cardiovascular risk from high doses of celecoxib. Scott Solomon, HMS associate professor of medicine and director of noninvasive cardiology at BWH, led the review and published the results last year in the New England Journal of Medicine just before the FDA hearings on the COX2 inhibitors.

“At the time, a lot of people asked, how do we know traditional NSAIDs are not associated with the same kind of risk?” Solomon explained. “The question asked was, Does it make sense to take people off drugs like Celebrex and put them on another NSAID?”

The most authoritative answer to date—a qualified “maybe not”—comes from the prospective observational study by Chan and his colleagues in the March 28 Circulation. Among nearly 71,000 women in the Nurses’ Health Study, taking NSAIDs more than 22 days a month increased the risk of cardiovascular events by nearly half, compared to nonusers, and those who took more than 15 tablets a week had nearly double the risk. The researchers adjusted for other analgesic use as well as other cardiovascular risk factors. They also ran the numbers in the years before the COX2 inhibitors came on the market in 1999 and found consistent relationships with the older NSAIDs and thrombotic events.

For all of the study’s strengths, the nature of observational studies like this does not permit scientists to blame NSAIDs as the unequivocal cause of the extra heart attacks and strokes. After all, more frequent use of NSAIDs also corresponded with less exercise, more hypertension, and other cardiovascular risk factors, for which the researchers adjusted as best they could.

Refining Drug Use
Despite the risks of NSAIDs, the potential benefits are too tantalizing to ignore. Unfortunately, some benefits, like the risks, increase with higher doses. “There is compelling evidence that these drugs can prevent colorectal cancer,” said Charles Fuchs, senior author of the Circulation paper. “The problem is that, outside of aspirin, they all seem to increase the risk of heart disease, at least at high doses. And when it comes to preventing colon cancer, more is better,” said Fuchs, HMS associate professor of medicine and director of the gastroenterology malignancy program at the Dana–Farber/Harvard Cancer Center.

In July, Chan, Fuchs, and their colleagues showed in the same cohort that NSAIDs are associated with a lower risk of colon cancer. And a more selective NSAID, celecoxib, reduced the three-year rate of detecting all adenomas by nearly half and by two thirds for high-risk adenomas, reported Monica Bertagnolli, HMS associate professor of surgery at Brigham and Women’s Hospital, on April 4 at the meeting of the American Association for Cancer Research.

Researchers are trying to generate better risk estimates and identify the best candidates for the drugs, such as people at high risk of colon cancer and low risk of cardiovascular disease. Chan and his colleagues are following up by studying how genetic variations in enzymes responsible for metabolizing the different drugs influence disease risk and drug effectiveness.

All of this clinical information will feed back into a better understanding of the basic mechanisms of drug action, Chan predicts, which in turn may lead to better therapies. In the meantime, Avorn and his collea gues offer a noncommercial, evidence-based assessment of NSAIDs, including COX2 inhibitors, online at the Independent Drug Information Service.

(Originally published in Focus, the twice monthly newsletter for the Harvard medical community)
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