Heart and lungs

High-dose painkiller heart risk: small but significant

"Study links painkillers to increased risk of heart attack," The Independent reports. This major study found that high doses of the non-steroidal anti-inflammatory drugs (NSAIDs) type of painkiller increased the risk of serious conditions such as heart attacks.

NSAIDs, such as ibuprofen, diclofenac, naproxen and coxibs, are widely used to relieve pain and inflammation.

Many people with painful long-term conditions, such as rheumatoid arthritis, are prescribed high doses of NSAIDs on a long-term basis. It is thought that these people have an increased risk of serious heart conditions compared with those who just take an occasional low-dose ibuprofen pill for a headache.

This new review of hundreds of studies found that coxibs and diclofenac increased the risk of major vascular events – mainly heart attacks – by a third, while ibuprofen was also associated with a greater risk of heart attack. High-dose naproxen did not affect the risk of heart attack.

The actual risk to individuals is small. For example, this study found that for every 1,000 patients taking a high dose of coxib or diclofenac for a year, three more had a major vascular event, one of which was fatal, compared with placebo.

Every treatment comes with both benefits and risks. Your doctor can provide you with information to allow you to make an informed choice and can help you to weigh the benefits of these painkillers against this small risk of a serious side effect.

Where did the story come from?

The study was carried out by researchers from the University of Oxford and was funded by the UK Medical Research Council and the British Heart Foundation. It was published in the peer-reviewed medical journal The Lancet.

It was widely reported in the UK media, and the quality of the reporting was generally of a high standard. Unlike in previous ‘drug-scare’ stories most media sources put the individual risk in its proper context, explaining that it is very small. They also reported the comments made by the researchers that people taking the occasional low dose of an NSAID are unlikely to be at risk.

What kind of research was this?

This research involved meta-analyses of randomised controlled trials (RCTs), including nearly 354,000 participants. The study looked at the risks of NSAIDs compared with placebo treatment and the comparable risks of different NSAIDs. Popular NSAIDs include the older types – ibuprofen, diclofenac, naproxen – and newer cox-II inhibitors (coxibs). Coxibs include celecoxib, etoricoxib and rofecoxib (rofecoxib was withdrawn from the market in 2004 because of concerns over an increased risk of heart attack and stroke).

The researchers were particularly interested in the risk of major cardiovascular events and gastrointestinal complications. They point out that previous research has found that both older and newer types of NSAIDs have a risk of vascular events, while the newer coxib-type NSAIDs are thought to have fewer gastrointestinal effects than older NSAIDs.

This review aimed to provide more accurate estimates of the size, timing and severity of the risk, among different types of patients.

What did the research involve?

The researchers carried out searches of randomised controlled trials that either compared the risks of NSAIDs with placebo treatment or compared the risk of one NSAID with another. The main risks they looked at were of major vascular and coronary events (heart attack, coronary death, stroke, death from any of these and heart failure) and of gastrointestinal complications (perforation of the stomach lining, obstruction or bleeding).

They searched various electronic databases, clinical trial registers, reference lists of relevant papers and also made contact with pharmaceutical companies. Trials (up to 2011) were eligible if they were properly randomised, lasted at least four weeks and compared an NSAID with either a placebo (or open control) or another NSAID.

All trials were reviewed for their eligibility by two researchers, who recorded the key characteristics of the trials that might affect the risk of bias (such as method of randomisation). Where possible, the researchers used data on individual participants or aggregate data (a standard format of results provided by the original researchers). They used standard meta-analytical techniques to give estimates of the risks.

What were the basic results?

The researchers included 639 trials in their analysis. Almost all trials involved a coxib or a high-dose NSAID (diclofenac 150mg daily, ibuprofen 2,400mg daily, naproxen 1,000mg daily).

  • Coxibs and diclofenac increased the risk of a major vascular event by about a third (coxibs rate ratio (RR) 1.37, 95% confidence interval (CI) 1.14–1.66; diclofenac RR 1.41, CI 1.12–1.78). Most of this increased risk was due to an increase in major coronary events such as heart attack.
  • Ibuprofen also significantly increased major coronary events (RR 2.22, CI 1.10–4.48), but not major vascular events, such as stroke.
  • Of 1,000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events (one of which was fatal) compared with placebo.
  • Naproxen did not significantly increase major vascular events (RR 0.93, CI 0.69–1.27).
  • The risk of death from a vascular event was increased significantly by coxibs (RR 1.58, 99% CI 1.00–2.49) and diclofenac (RR 1.65, CI 0.95–2.85), but the increase seen with ibuprofen (RR 1.90, CI 0.56–6.41) and naproxen (RR 1.08, 0.48–2.47, p=0.80) was not significant.
  • Heart failure risk was roughly doubled by all NSAIDs.

All NSAIDs increased upper gastrointestinal complications:

  • naproxen RR 4.22, CI 2.71–6.56
  • ibuprofen RR 3.97, CI 2.22–7.10
  • diclofenac RR 1.89, CI 1.16–3.09
  • coxibs RR 1.81, CI 1.17–2.81

A further hypothetical analysis by the researchers indicated that the increased risk of heart attacks is highest in those with a previous history of heart disease or risk factors such as high cholesterol.

How did the researchers interpret the results?

The researchers say that the vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs.

Although NSAIDs increase vascular and gastrointestinal risks, they say that the size of these risks can be predicted, which could help guide doctors making decisions on medications for their patients.


This large review adds to, and expands on, the current evidence on the risks of vascular disease and gastrointestinal complications for different NSAIDs. It largely concentrates on trials of high doses of NSAIDs that can only be prescribed by a doctor. It is unclear from this study whether there is any risk from taking lower doses available over the counter. While most experts advise that low-dose NSAIDs, taken occasionally, are safe for most people, an accompanying editorial points out that there are still “large gaps” in evidence on the risks with lower doses of NSAIDs.

While the risk to individuals is small, it is important to remember that high doses of NSAIDs are used by millions of people worldwide to manage chronic pain, for example from arthritis.  Even a one in 1,000 risk of NSAID-associated death would amount to 1,000 deaths in a population of 1 million. Such risks are worth bearing in mind when deciding on treatment with your doctor.

This means that any evidence that improves the safety of prescribing of this kind of medication is vital. The evidence presented in this study is likely to be of particular interest to organisations that advise doctors on which drugs to prescribe, such as NICE (the National Institute for Health and Care Excellence).

As an accompanying editorial argues, “identification of safe and effective strategies for chronic pain is sorely needed. In the meantime, long-term use of high dose NSAIDs should be reserved for those who receive considerable symptomatic benefit from the treatment and understand the risks”.

Anyone concerned about using NSAIDs on a long-term basis should seek the advice of their GP or the doctor in charge of their care.

NHS Attribution