High doses of naproxen are not associated with the excess cardiovascular risk of other non-steroidal antiflammatory drugs (NSAIDs) and GPs should consider using the painkiller in patients at high risk, concludes the latest analysis of data.
The UK meta-analysis of over 600 trials in arthritis patients found that high doses of ibuprofen and diclofenac caused an average of three extra major vascular events each year for every 1,000 patients treated.
In contrast, use of high doses of naproxen was not associated with any increased vascular risk.
The study’s authors recommended that the choice of NSAID should be made on the patient’s individual baseline cardiovascular or gastrointestinal risk, as the risk of complications appears to rise as this risk increases.
However, they cautioned that naproxen was still associated with a relatively high risk of gastrointestinal bleeding and its effects at lower doses and in patients taking aspirin remained unclear.
GPs have been aware for some time about the potential cardiovascular risk with the traditional NSAIDs diclofenac and ibuprofen. The high risk with diclofenac in particular prompted calls for the drug to be banned, after a study found it to be as risky as rofecoxib, which was withdrawn from the market back in 2004 because of concerns over CV safety.
The meta-analysis, published in The Lancet, included a total of 639 randomised trials involving over 300,000 mainly arthritis patients taking high-dose NSAIDs.
Overall, diclofenac was associated with a 37% increased risk of major vascular events and ibuprofen with a 2.2-fold increased risk of coronary events, compared with placebo. Similarly increased risks were seen with selective COX-2 inhibitors (coxibs).
Diclofenac and coxibs were also associated with significant 60% to 70% increased risk of vascular death.
Naproxen had no effect on vascular events or death, but was associated with a four-fold increased risk of gastrointestinal bleeding compared with placebo, as was ibuprofen, while diclofenac and coxibs doubled the risk of gastrointestinal complications.
The authors found NSAIDs had proportional effects on each of the outcomes at low, intermediate and high risks of vascular events and across varying risks of upper gastrointestinal events.
They explained this would mean, for example, that among high-risk patients, high-dose diclofenac would result in around seven or eight additional major vascular events per 1,000 patients treated each year, of which two would be fatal. High-dose ibuprofen would result in a similarly increased risk in this group, but also result in a greater excess of gastrointestinal complications.
The researchers concluded: ‘Our meta-analysis, which is unaffected by selection and other biases inherent in observational studies, showed clearly that the vascular risks of diclofenac, and possibly ibuprofen, are similar to coxibs, but that naproxen is not associated with an increased risk of major vascular events.
‘However, it also showed that the excess risk of both vascular and gastrointestinal events can be predicted once the baseline risks of such hazards are known, which could help clinical decision making.’
Lead researcher Professor Colin Baigent, professor of epidemiology at the University of Oxford, said although the risk increases seem small, it was important that patients were given this information to make an informed judgement.
He said: ‘The judgement has to be made by patients – if you’re a patient sitting down in front of your doctor and discussing it, you are the one who should be making the judgement about whether [the risk] is worth it, to allow you potentially to go about your daily life.
‘Not everybody is at average risk - the higher your risk of heart disease, the higher your risk of a cardiovascular complication with [diclofenac or ibuprofen].
‘Roughly speaking, if you’ve got double the risk of heart disease, then the risk of having a heart attack [from the NSAID] is roughly doubled.’
Professor Simon Maxwell, member of the British Pharmacological Society and professor of clinical pharmacology at the University of Edinburgh, said: ‘This study adds further information by confirming that commonly used standard NSAIDs such as diclofenac and ibuprofen appear to carry the same excess risk as the newer and more selective coxibs.
‘The interesting finding is that a rather less commonly used NSAID, naproxen, appears to carry no excess risk of heart attack or stroke compared to placebo. This might lead to a review of prescribing advice by some NHS organisations who currently advocate the use of diclofenac and ibuprofen.’
Dr Louise Warburton, a GP in Shrewsbury and president of the Primary Care Rheumatology Society, told Pulse: ‘We have already started switching people from diclofenac to naproxen in primary care.
‘Importantly, coxibs have the same risks as diclofenac [and] ibuprofen. Originally we were led to believe that coxibs were worse than NSAIDs [for] CV risk.’
Lancet 2013; available online 30 May
