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Risk of irregular heart rhythm from ibuprofen ‘small’

“Commonly used painkillers including ibuprofen increase the risk of developing an irregular heart rhythm by up to 40 per cent”, reported The Daily Telegraph. It said that a new study has found a link between the anti-inflammatories and atrial fibrillation and atrial flutter.

This study looked at a large sample of people who had a first diagnosis of either of these heart rhythm abnormalities. The patients’ past use of NSAIDs was compared with that in people who did not have these abnormalities, and who were matched for age and sex.

The use of NSAIDs was found to be slightly more common among patients than controls (9% vs. 7%). The researchers estimated there would be four extra cases a year of atrial fibrillation per 1,000 new users (first prescription in past 60 days) of non-selective NSAIDs (e.g. ibuprofen). For COX-2 inhibitors (a subgroup of NSAIDs, e.g. celecoxib) there would be seven extra cases per year of atrial fibrillation per 1,000 new users.

Although the authors found an increased risk of AF, the overall increase was small and not enough to recommend that people taking these medicines for painful conditions stop taking them. Doctors are already well aware of the risks and benefits of these medicines and when and how they should be used. Patients taking NSAIDs or COX-2 inhibitors prescribed by their doctors are advised to continue to do so, and discuss any concerns at their next regular or scheduled appointment. Occasional one-off doses or short courses (e.g. two or three days) of over-the-counter-strength ibuprofen are still considered safe.

Where did the story come from?

The study was carried out by researchers from the Aarhus University Hospital Denmark. Funding was provided by the Danish Medical Research Council, the Clinical Epidemiological Research Foundation and the Danish Heart Association.

The study was published in the (peer-reviewed) British Medical Journal.

Generally, this research was accurately covered by the newspapers, but many did not make clear what the risk associated with taking the drugs was being compared to (i.e. they were comparing current users with people who had not taken NSAIDs in the year prior to the index date).

However, a problem faced by the researchers was that they assessed NSAID use through a proxy measure (prescription data). As such, it is not clear whether users took NSAIDs once a day as the Daily Mail suggests.

Additionally, the Daily Express said, “of the nine million people in Britain who take ibuprofen each day – and at least 1.5 million who use a new class of pain reliever – more than 700,000 suffer with the condition.” However, it is not clear where these figures come from.

What kind of research was this?

The aim was to investigate whether the risk of two types of abnormal heart rhythm (atrial fibrillation or atrial flutter) was associated with the use of ‘non-selective non-steroidal anti-inflammatory drugs’ (NSAIDs). The researchers looked at two subgroups of NSAID – ‘non-selective’ NSAIDs, such as ibuprofen or aspirin, and selective cyclo-oxygenase (COX) 2 inhibitors (including celecoxib, etoricoxib and parecoxib – the only three COX-2 inhibitors currently licensed in the UK).

This was a population-based case control study, carried out in northern Denmark. The researchers compared people who had a first diagnosis of these abnormal heart rhythms to people who did not have heart problems and matched them in age and sex. The researchers were particularly interested in older people as NSAID use is prevalent in this population. The incidence of atrial fibrillation is also greater in older people.

These types of drugs are already known to be associated with cardiovascular risk. They are used cautiously, or not at all, in people with known disease (all NSAIDs are contraindicated in severe heart failure, while COX-2 inhibitors are contraindicated in people with coronary heart disease or who have had a stroke). However, it has not been determined whether NSAIDs, and COX-2 inhibitors in particular, have any effect on the risk of atrial fibrillation.

What did the research involve?

The study was carried out in Denmark. The researchers obtained the data for their study from a registry that had covered all non-psychiatric hospital visits since 1977 and emergency room and outpatient visits since 1995. The registry was used to identify all patients who had a first-time inpatient or outpatient diagnosis of atrial fibrillation or flutter between January 1, 1999 to December 31, 2008. The researchers aimed to assess the patients’ use of NSAIDS leading up to the date of their first diagnosis of atrial fibrillation or flutter (known as the ‘index date’).

Controls were selected from the Danish Civil Registration System, and matched each case for age and sex. The registration system records vital statistics of the Danish population. For each person who had atrial fibrillation or flutter, 10 controls were selected. These controls were then assigned an “index date”, which matched their paired case’s first instance of atrial fibrillation or flutter, so that their NSAID use could be assessed at the same point in time as their paired case.

Information on prescriptions of NSAIDs was provided by a regional prescription database. In Denmark (with the exception of aspirin and ibuprofen in the 200mg tablet dose) all NSAIDS are available by prescription only. However, the researchers say that regular users of ibuprofen are typically registered in the database because the cost is automatically part-funded when prescribed by a doctor. The researchers assessed prescriptions of NSAIDS prior to the index date in cases and controls.

The NSAID prescriptions assessed were ibuprofen, naproxen, ketoprofen, dexibuprofen, piroxicam and tolfenamic acid. COX-2 inhibitors were also assessed. The study listed ‘newer’ COX-2 inhibitors as celecoxib, rofecoxib, valdecoxib, parecoxib and etoricoxib. ‘Older’ COX-2 inhibitors were diclofenac, etodolac, nabumeton and meloxicam. Currently in the UK, the only licensed COX-2 inhibitors are celecoxib, etoricoxib and parecoxib. In the UK, diclofenac, etodolac, nabumeton and meloxicam are listed in the BNF as non-selective NSAIDs, i.e. drugs in the same category as ibuprofen.

Current users of NSAIDS were defined as people who redeemed their most recent prescription within 60 days before their index date. Current users were then divided into two groups:

  • new users, whose first ever prescription was in the 60 days prior to the index date
  • long-term users, who had redeemed their first prescription more than 60 days prior to the index date

Non-users were defined as people who had not redeemed a prescription for NSAIDs in the year prior to the index date. They were used as a reference group.

The researchers assessed diagnoses of other conditions the participants had which may have affected the risk of atrial fibrillation (e.g. thyroid conditions, rheumatoid arthritis, diabetes, liver conditions). They also looked at other medications the participants were taking that may have affected the risk.

The researchers used a statistical technique called logistic regression to calculate the odds of developing atrial fibrillation or flutter among current, new, long-term and recent users of non-selective NSAIDs or COX-2 inhibitors.

What were the basic results?

In total, there were 32,602 cases and 325,918 population controls. The average age was 75 years, and 54% were male; 85.5% had been diagnosed with heat rhythm abnormalities while staying in hospital, 12.9% at an outpatient clinic and 1.2% in a casualty department. Among the cases, 80.1% had been previously diagnosed with cardiovascular disease while only 58.7% of the controls had a similar diagnosis. A variety of other diseases were found to be more common among the cases, including cancer, chronic obstructive pulmonary disease or asthma, diabetes and arthritis.

Of the cases, 9% were current users of either non-selective NSAIDs or COX-2 inhibitors, compared to 7% of the controls.

The researchers compared the rates of incident atrial fibrillation or flutter in current users compared to non-users. The results were adjusted for age, sex and risk factors for atrial fibrillation or flutter. The incidence rate was 17% greater in current users of non-selective NSAIDs compared to non-users (incidence rate ratio 1.17, 95% confidence interval [CI] 1.10 to 1.24) and 27% greater in current users of COX-2 inhibitors compared to non-users (incidence rate ratio 1.27, 95% CI 1.20 to 1.34).

New users of NSAIDs had a 46% increased incidence rate compared to non-users (adjusted incidence rate ratio 1.46 95% CI 1.33 to 1.62). New users of COX-2 inhibitors had a 71% increased incidence rate compared to non-users (adjusted incidence rate ratio 1.71, 95% CI 1.56 to 1.88).

The results for individual NSAID drugs were similar.

How did the researchers interpret the results?

The researchers said, “patients starting treatment with non-aspirin NSAIDs were at increased risk of atrial fibrillation or flutter compared with those not using NSAIDs. The relative risk increase was 40 to 70%, equivalent to approximately four extra cases per year of atrial fibrillation per 1,000 new users of non-selective NSAIDs and seven extra cases per year of atrial fibrillation per 1,000 new users of COX-2 inhibitors”.

The researchers suggest that the short-term effects of NSAIDs on kidney function could potentially trigger atrial fibrillation.

Conclusion

This study assessed whether using NSAIDs or COX-2 inhibitors was associated with subsequent development of atrial fibrillation. The study found that, compared to non-users, recent users were more likely to have incident atrial fibrillation. Consequently, the study estimated that for every 1,000 people who started taking NSAIDs there would be four to seven extra cases of atrial fibrillation.

This study had various strengths, including the population-based design and the use of comprehensive hospital and prescription records available in Denmark. However, there was certain information that the researchers could not obtain from these registries, including:

  • Prescription data was used as a proxy for actual use of NSAIDs, so they could not determine the amount of NSAIDs the participants actually took.
  • Although the researchers adjusted for some potential confounders, there may have been other unmeasured variables that could have confounded the results; in particular, inflammatory conditions could lead to both use of NSAIDs, and also independently increase the risk of atrial fibrillation.
  • There was no available data on lifestyle factors, including smoking and body size. Neither smoking nor overweight/obesity are established risk factors for atrial fibrillation, but they are known to increase the risk of other cardiovascular conditions that are known to increase the risk of atrial fibrillation (e.g. high blood pressure and coronary heart disease).

In conclusion, although the authors found an increased risk of AF, the overall increase was small and not enough to recommend that people taking these medicines for painful conditions stop them. Doctors are already well aware of the risks and benefits of these medicines, and when and how they should be used.

Patients taking NSAIDs or COX-2 inhibitors prescribed by their doctors should continue to do so and discuss any concerns at their next regular or scheduled appointments. Occasional one-off doses or short courses (e.g. two or three days) of over-the-counter-strength ibuprofen are still considered safe.

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