“Painkillers used by millions of Britons have been linked to higher risk of an irregular heartbeat that could trigger a stroke,” the Mail Online reports.
This headline follows the publication of a long-term study that aimed to find out whether older adults developed atrial fibrillation. The researchers looked at whether adults who had developed the condition had used non-steroidal anti-inflammatory drugs (NSAIDs) recently, previously or not at all.
NSAIDs are a type of painkiller and have been associated with a higher risk of atrial fibrillation – a condition that causes an irregular and often abnormally fast heart rate. Complications of atrial fibrillation include stroke and heart failure.
Out of the 8,423 participants, 857 people developed atrial fibrillation. Those who had used NSAIDs during the past 15-30 days had a 76% increased risk of atrial fibrillation, compared to those who had never used NSAIDS. Those who had used them within the previous 30 days also had an 84% increased risk of atrial fibrillation, compared to those who had never used them. However, these results were based on just 64 people.
Current use of NSAIDs for less than 14 days or more than 30 days, or past use more than 30 days ago, was not linked to an increased risk of atrial fibrillation.
Although this study was conducted over a long period of time, assessing a person’s current or recent use of NSAIDs at the time they were diagnosed cannot prove that NSAIDs caused atrial fibrillation.
Other factors may also have influenced the results, including whether the patients were prescribed the NSAIDs for pain following surgery.
You should not stop taking prescribed medication, but if you have any concerns, talk to your pharmacist or GP.
Where did the story come from?
The study was carried out by researchers from Erasmus Medical Center (Rotterdam), the Netherlands Consortium for Healthy Ageing and the Inspectorate of Health Care (Hague). It was funded by a variety of Dutch government and charitable sources, in addition to money from the European Commission. Nestle Nutrition (Nestec Ltd), Metagenics Inc and AXA also funded the research, but they were not involved in designing, analysing or writing the study.
The media generally reported the study accurately, but none explained its limitations and the very small numbers that the significant results were based on.
What kind of research was this?
This was a prospective cohort study of the general older population in Rotterdam, in the Netherlands.
The researchers aimed to see if there was a link between the use of non-steroidal anti-inflammatory drugs (NSAIDs) and developing atrial fibrillation.
Previous research has shown a link between NSAIDs usage and increased risk of atrial fibrillation, but they have been retrospective case-control studies with limited ability to account for confounding factors.
Although this was a prospective cohort study that followed people over a period of time, the assessments within it were predominantly cross sectional. This means that it assessed people at several follow-up points during the study and looked at whether the person had a current or past prescription of NSAIDs at the time atrial fibrillation was diagnosed.
Despite the researchers adjusting their analyses for other medical and lifestyle factors that may be influencing results (confounders) it cannot prove that their current or recent use of NSAIDs caused atrial fibrillation.
A randomised control trial would be ideal, though it may be both unethical and unfeasible. Such a trial would require a very large number of people to be given regular NSAIDs and following them up for a prolonged period of time purely to see if they developed atrial fibrillation.
A better method may have been to assess the use of NSAIDs in a group of people without the condition, then following them up over time to see if they developed atrial fibrillation, to better separate exposure and outcome.
What did the research involve?
Researchers followed a group of older adults who did not have atrial fibrillation at the study’s start, and recorded during the follow up whether they developed atrial fibrillation and if they were taking NSAIDs around that time. The results took into account factors such as age, sex and BMI, and looked for links between atrial fibrillation and NSAIDs usage.
The study included 8,423 older adults (average age 68.5 years) from Rotterdam, who did not have atrial fibrillation. The majority of participants were recruited between 1990 and 1993, and were followed up on three occasions (1993-1995, 1997-1999 and 2002-2004). A second, smaller group of people had been recruited over the 2000-2001 period and were followed up once, over 2004-2005. They followed up the people until they had a diagnosis of atrial fibrillation, died, were lost to follow-up or to the end of the study period in January 2009.
At the beginning of the study, and at each follow-up point, the presence of atrial fibrillation was examined by taking a heart tracing (electrocardiogram, known as an ECG), which was examined by a doctor, as well as looking at medical records from GPs and hospital specialists.
At the beginning of the study, the following cardiovascular risk factors were also recorded:
- body mass index (BMI)
- blood pressure
- blood pressure lowering drugs
- total cholesterol
- high-density lipoprotein (HDL “good”)
- history of having a heart attack (myocardial infarction)
- any heart failure
- diabetes status
- smoking status
During follow-up, they recorded the date that people first had any symptoms of atrial fibrillation that was later confirmed by ECG.
NSAID usage was calculated from filled automated prescription records from participating pharmacies. They assumed that the medication was taken in the dosage and quantity prescribed. They put them into three categories:
- current user: last used 14 or fewer days ago; 15-30 days ago; 30 or more days ago
- past user: stopped 30 or fewer days ago; 31-180 days ago; more than 180 days ago
- never used
They matched the date of atrial fibrillation, starting with the person’s NSAIDs category at this time, and compared this with the NSAID usage of all other participants who did not have atrial fibrillation. They analysed the results, just taking into account age and sex. They then analysed the results, taking into account all of the cardiovascular risk factors listed above.
What were the basic results?
After a mean follow-up time of 12.9 years, 857 people developed atrial fibrillation. At the time of their atrial fibrillation diagnosis:
- 261 had never used NSAIDs
- 554 had used NSAIDs in the past
- 42 were currently using NSAIDs
Taking age, sex and cardiovascular risk factors into account, the researchers calculated that current use for 15-30 days was associated with a 76% increased risk of atrial fibrillation, compared with those that had never used them (hazard ratio (HR) 1.76, 95% Confidence Interval (CI) 1.07 to 2.88).
Recent past usage, within the previous 30 days, was also associated with an 84% increased risk of atrial fibrillation compared to those that had never used (HR 1.84, 95% CI 1.34 to 2.51).
These were the only statistically significant associations found. Current usage for less than 14 days or more than 30 days was not associated with atrial fibrillation, nor was past usage more than 30 days previously. Neither was NSAID dosage (high or low) significantly associated with increased risk of atrial fibrillation, compared with those that had never used them.
How did the researchers interpret the results?
The researchers concluded that the “use of NSAIDs is associated with an increased risk of atrial fibrillation. Current use and recent past use were especially associated with a higher risk of atrial fibrillation, adjusted for age, sex and cardiovascular risk factors. The underlying mechanism behind this association deserves further attention”.
This prospective cohort study claims an association between NSAIDs usage and developing atrial fibrillation. However, there are many limitations to this research.
Despite this being a large prospective cohort study that followed people over a period of time, the assessments within it were predominantly cross-sectional. That means it assessed the person’s current or recent prescription of NSAIDs at the time they were diagnosed, but this cannot prove that using NSAIDs caused atrial fibrillation.
A better method may have been to assess the use of NSAIDs in people without atrial fibrillation at the start of the study, then follow them up over time to see if they developed atrial fibrillation, which would have better separated exposure and outcome.
There is the potential for causes other than the cardiovascular risk factors measured to have influenced the results. For example, the reason for taking NSAIDs was not known, but there could have been other risk factors for developing atrial fibrillation, such as:
- recent surgery, which would often lead to short-term NSAIDs usage
- the need to take high-dose steroids – this includes people with inflammatory conditions like rheumatoid arthritis, who would also be more likely to take NSAIDs
Participants’ NSAID usage was also not accurately recorded. It was determined purely by prescription usage and then assumed that the medication was taken as prescribed. It is well known that people often deviate from this, and this is even more likely for painkillers due to the repeated daily dosing that is needed and the often fluctuating nature of pain. It also did not include any over-the-counter NSAIDs, like ibuprofen.
The study only found significant associations between assumed current use of NSAIDs (between 15 and 30 days) or those that had discontinued within the past 30 days. However, these risk calculations are based only on 17 people with atrial fibrillation who had used NSAIDs in the past 15 to 30 days, and 47 people with the condition who had used them within the past 30 days. These sample sizes are very small, which decreases the reliability of these risk estimates.
If the use of NSAIDs increases the risk of atrial fibrillation, you may expect that prolonged usage for greater than 30 days would also increase the risk, but this was not seen. However, only eight people who developed atrial fibrillation had ongoing current use of NSAIDs for more than 30 days. Again, the risk calculation involving such a small number of cases may be unreliable.
Overall, this study does not conclusively prove that NSAIDs increase the risk of atrial fibrillation.