Review Confirms CVD Risk With NSAIDS Rofecoxib, Diclofenac

September 27, 2011

September 27, 2011 (Hull, United Kingdom and Toronto, Ontario) — A large systematic review of available evidence on nonsteroidal anti-inflammatory drugs (NSAIDs) confirms that rofecoxib (Vioxx, Merck) is associated with a significantly increased risk of cardiovascular events, while also suggesting that diclofenac, a widely used, over-the-counter NSAID, also poses an equivalent risk to patients [1]. Of the medications studied, ibuprofen and naproxen are the least likely to increase the risk of MI and coronary heart disease death.

"What this allows us to do is start to discriminate a little better between the individual drugs than was possible in the past," Dr David Henry (University of Toronto, ON), the senior investigator of the review, told heartwire . "The paper is not to guide drug regulation but really to guide clinical practice in what drugs doctors might choose in people at high risk for having a heart attack or stroke. There are no huge surprises, but it does give us more confidence in the data."

The study, with first author Dr Patricia McGettigan (Hull York Medical School, UK), provides estimates of the risks of individual NSAIDs at standard doses in community settings and is published September 27, 2011 in the open-access journal PLoS Medicine. The updated review includes data from 31 case-control studies with 184 946 cardiovascular events and 21 cohort studies that include outcomes in more than 2.7 million individuals exposed to the drugs.

To heartwire , Henry noted that when the selective COX-2 inhibitor rofecoxib was taken off the market in 2004, there were questions about the risk of other NSAIDs, and this led to an outpouring of published data. In 2006, McGettigan and Henry published a systematic review of observational studies that focused on the cardiovascular risk of selective COX-2 inhibitors and nonselective NSAIDs. That study, reported by heartwire , showed that cardiovascular risk was increased with diclofenac, indomethacin, and meloxicam as well as with rofecoxib. Naproxen was not cardioprotective, as had been previously suggested, but appeared to have a neutral risk, and results with ibuprofen were inconclusive.

The new review confirms the increased risk of cardiovascular events with rofecoxib, as well as an increased risk with diclofenac. Although rofecoxib is no longer on the market, Henry said that diclofenac is still available, even though the risk between the two drugs is nearly identical. Regulatory agents seem reluctant to remove the drug from the market, he said, adding that clinicians should take regulatory action on their own and not use diclofenac in certain patients.

"We think this is a significant issue and that people should know about this," said Henry. "It probably doesn't matter in people at very low risk of a heart attack. But if you have had a heart attack or have a lot of cardiovascular risk factors, you probably want to avoid diclofenac because it increases the risk by about 40%. For somebody that has a 5% to 10% risk of having a heart attack, that's a significant increase in absolute risk, particularly if there are other drugs that don't seem to have that risk. For people at very low risk, it probably doesn't matter what drugs you use."

Drugs and Pooled Relative Risks of Cardiovascular Events

Drug Pooled relative risks (95% CI)
Naproxen 1.09 (1.02–1.16)
Ibuprofen 1.18 (1.11–1.25)
Celecoxib 1.17 (1.08–1.27)
Rofecoxib 1.45 (1.33–1.59)
Diclofenac 1.40 (1.27–1.55)
Indomethacin 1.30 (1.19–1.41)
Piroxicam 1.08 (0.91–1.30)
Meloxicam 1.20 (1.07–1.33)
Etodolac 1.55 (1.28–1.87)
Etoricoxib 2.05 (1.45–2.88)
Valdecoxib 1.05 (0.81–1.36)

Naproxen was consistently shown to be safe, even at high doses, suggesting it should be the NSAID of choice in patients with increased cardiovascular risk. Naproxen was shown to be safer than ibuprofen, with the risk of cardiovascular events increasing with ibuprofen at daily doses ranging from 1200 mg to 1600 mg. If ibuprofen is used in high-risk patients, Henry said the dose should be kept low, but if a higher dose is needed, clinicians should switch to naproxen. Of the three NSAIDs available over the counter, ibuprofen and naproxen were safe at low doses, while diclofenac was associated with a 22% increase in risk at low doses.

The researchers also observed a significantly increased risk of cardiovascular events in patients treated with indomethacin, an older NSAID historically used to treat gout. While the drug is known to cause gastrointestinal problems as well as confusion in the elderly, the increased risk of cardiovascular events suggests it shouldn't be used at all, said Henry. Celecoxib (Celebrex, Pfizer), on the whole, had an increased risk of cardiovascular events at low and high doses, although there were few studies testing doses >200 mg/day. Henry said celecoxib, especially at doses >400 mg/day, should not be used in patients at high risk of cardiovascular disease.

To heartwire , Henry commented that 10 years ago there were many NSAIDs in widespread use, but the number of drugs considered safe to use has declined substantially, down to just two. "The number we're settling on, the number of preferred drugs, is actually quite small now," he said.