Researchers from the Hull York Medical School (HYMS) and the Institute for Clinical Evaluative Sciences in Canada carried out a systematic review of controlled observational studies. They found that in patients with heart problems, or those with cardiovascular risk factors, use of non-steroidal anti-inflammatory drugs (NSAIDs) including diclofenac and indomethacin was significantly associated with an increase in the risk of serious cardiovascular events such as heart attack and stroke.
Other common NSAIDs, including naproxen and low doses of ibuprofen do not appear to be associated with an increase in risk.
The results of the study, which involved examining and combining data from 51 large scale studies conducted in Europe, USA, Canada and Australia, are published in PLoS Medicine this week.
Lead researcher Dr Patricia McGettigan, is from the Hull York Medical School (HYMS), a joint venture between the Universities of Hull and York and the NHS.
She said: “NSAIDs provide pain relief for millions of patients with chronic inflammatory disorders. The cardiovascular risk is well described but often overlooked. In choosing which one of the many available NSAIDs to use, patients and doctors would benefit from knowledge of the balance between benefit and harm for individual NSAIDs.
“For example, diclofenac, the NSAID most commonly prescribed in England in 2010, was associated with an increase in cardiovascular risk of 40 per cent (compared with non-use). At high doses, the increase in risk was almost doubled. An alternative, naproxen, prescribed only half as often, was not associated with increased risk at any dose. For the first time, we have enough data to make direct comparisons between NSAIDs to determine which are most risky and which are relatively safe.”
NSAIDs are widely used for their pain relief and anti-inflammatory effects in conditions including arthritis, back pain, gout, headache, and the aches and fever associated with flu. They are effective and many are prescribed by doctors. In 2010 in England, almost 17 million prescriptions were written by GPs for NSAIDs; almost 6 million, more than one in three, were for diclofenac; 5 million were for ibuprofen; 3 million for naproxen. Diclofenac, ibuprofen and naproxen can also be bought from pharmacies without prescription. Ibuprofen is available from supermarkets nationally.
Some of the review’s findings were:
Most commonly used NSAIDs
- Among NSAIDs that are widely prescribed in the UK, the highest risks were seen with diclofenac. Overall, it was associated with an increase in risk of 40 per cent for a cardiovascular event like a heart attack (compared with not using the drug).
- The lowest risks were seen with naproxen and low doses of ibuprofen; these were not associated with increased cardiovascular risks. However, at doses above 1200mg/day, ibuprofen was associated with an increase in risk of 80 per cent.
- Diclofenac was associated with an increase in cardiovascular risk at both low and high doses; the increase in risk was almost doubled at high doses.
- Neither low nor high doses of naproxen were associated with an increase in risk. Naproxen was judged the safest drug from a cardiovascular perspective.
New NSAIDs Newer ‘Cox-2 selective’ NSAIDs, available only on prescription, were also associated with cardiovascular risks.
- Rofecoxib, one of the first Cox-2 selective NSAIDs, was withdrawn from the world market in September 2004 owing to its cardiovascular risks. It was associated with an increase in risk of 45 per cent.
- Among Cox-2 selective NSAIDs on the UK market, celecoxib was associated with an increase in risk at both low and high doses. Etoricoxib was associated with a higher risk than celecoxib.
- Indomethacin is an old NSAID that is still quite popular for treating gout. It was associated with an increase in cardiovascular risk of 30 per cent, and added to its other side effects, its continued clinical use should be questioned.
The researchers stress that doctors should discuss a patient’s background risk of a heart attack or stroke, and calculate the additional risk posed by a NSAID.
Dr McGettigan said: “For example, a patient with previous heart problems, high blood pressure and diabetes has an annual background risk of heart attack over five per cent, use of diclofenac will increase that by 40 per cent, giving an annual risk of over seven per cent. In other words, one in 50 such patients might suffer an avoidable heart attack. This is important information in making choices, particularly if there is a safer alternative.
“In contrast, a healthy young woman has an annual risk of heart attack of less than 0.1 per cent – she will experience a negligible increase in cardiovascular risk with any of the commonly used NSAIDs.”
A separate well-known downside of NSAIDs is that they increase the risk of gastrointestinal ulcers. This risk can be greatly reduced by taking anti-ulcer drugs like omeprazole. There is no equivalent way to reduce the cardiovascular risks of NSAIDs.
“This is another reason why information on the comparative cardiovascular risks of NSAIDs is valuable,” said Dr McGettigan. “New NSAIDs like celecoxib were developed to have a much lower risk of gastrointestinal ulcers compared with older drugs like ibuprofen, diclofenac and naproxen. They achieved this, but as the review finds, they do not have lower cardiovascular risks.”
Notes to editors:
- The study “Cardiovascular risk with non-steroidal anti-inflammatory drugs: Systematic review of population-based controlled observational studies” is published in PLoS Medicine. www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001098
- For further information on the Hull York Medical School visit www.hyms.ac.uk
- ICES is an independent, non-profit organization that uses population-based health information to produce knowledge on a broad range of health care issues in Ontario, Canada. For further information visit www.ices.on.ca.