Popular anti-inflammatory drugs raise risk of heart attack in patients with pre-existing cardiovascular risk

In patients with pre-existing heart problems, or those with cardiovascular risk factors, certain non-steroidal anti-inflammatory drugs (NSAIDs) like diclofenac (Voltaren, Cataflam) and indomethacin (Indocin) significantly increase the risk of serious cardiovascular events, such as heart attack and stroke. A systematic review of controlled observational studies performed at the Institute for Clinical Evaluative Sciences (ICES) in Toronto and Hull York Medical School in the United Kingdom has found that use of a popular anti-inflammatory drug can increase the risk of heart attack or stroke by a third or more.

“These drugs provide pain relief for millions of patients with chronic inflammatory disorders, and the cardiac risk is well known. Doctors and patients need to be able to make choices between the available drugs, and this requires a better understanding of which drugs provide the best balance between benefit and harm. For the first time we have enough data to make direct comparisons between drugs to determine which products are risky and which are relatively safe. We were able to study the effects of high and low doses of the different drugs and examine the effects in patients with a high or low ‘background’ risk of vascular disease,” says the study’s co-author, Dr. David Henry of ICES.

The review examined and combined data from 51 large-scale studies from Europe, the USA, Canada and Australia. Some of the review’s highlights were:

• Among drugs that are popular in Canada and the USA, the highest overall risks were seen with diclofenac, indomethacin and etodolac (brands include Lodine), while the lowest risks were seen with naproxen (brands include Aleve, Naprosyn).
• Among drugs used outside North America etoricoxib (Arcoxia) had the highest risk.
• Among the most widely used NSAIDs, naproxen and low-dose ibuprofen (brands include Motrin, Advil, Nuprin) are least likely to increase cardiovascular risk.
• The risk with ibuprofen rises when the dose is higher than 1200mg/day. In contrast, naproxen remains free of risk at higher doses and is safer overall.
• Celecoxib (Celebrex) had a similar risk profile to ibuprofen with an increased risk at higher doses (more than 200mg/day).
• Diclofenac elevates risk at low doses, which are available over-the-counter without a prescription in some countries.
• Indomethacin is an old, rather toxic drug and is still quite popular for treating gout. But the evidence on cardiovascular risk casts doubt on its continued clinical use.

“Many of these drugs are old and very familiar, and are produced by many different companies. This may be the reason that drug regulatory agencies around the world have been slow to take action against them, despite several having risk levels close to those seen with Vioxx (rofecoxib). That drug was withdrawn from sale in 2004 because of the increased risk of heart attacks,” says Henry.

The authors stress that doctors should prescribe selectively and discuss risk with their patients. This means assessing an individual’s background risk of a heart attack, or stroke, and estimating the additional risk posed by the drug. For instance, in a patient with previous heart problems, with an annual risk of heart attack over 5 per cent, use of diclofenac will increase that by 2 per cent. In other words, 1 in 50 such patients might suffer an avoidable heart attack. This is important information, particularly if there is a safer alternative.

The study “Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies,” is in the September 27, 2011, issue of PLoS Medicine.

ICES is an independent, non-profit organization that uses population-based health information to produce knowledge on a broad range of healthcare issues. Our unbiased evidence provides measures of health system performance, a clearer understanding of the shifting healthcare needs of Ontarians, and a stimulus for discussion of practical solutions to optimize scarce resources. ICES knowledge is highly regarded in Canada and abroad, and is widely used by government, hospitals, planners, and practitioners to make decisions about care delivery and to develop policy.

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