According to new research published in the British Medical Journal, commonly used medications to treat pain and inflammation are linked to an increased risk of irregular heart rhythm, known as atrial fibrillation or flutter. The implicated agents involve non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors. While absolute risk increases are modest, there could be strong concerns regarding use of these agents by select patients.
These drugs have already been linked to an increased risk of heart attacks and strokes [see prior Pain-Topics UPDATES here and here], but no study has examined whether they also increase the risk of atrial fibrillation — a condition associated with increased long-term risk of stroke, heart failure, and death.
In a population based case-control study a team of researchers at Aarhus University Hospital in Denmark used the Danish National Registry of Patients to identify 32,602 case-patients with a first diagnosis of atrial fibrillation or flutter between 1999 and 2008 [Schmidt et al. 2011]. Each patient was compared with 10 age- and sex-matched control subjects randomly selected from the Danish population. Patients were classified as current or recent NSAID users; 2925 cases (9%) and 21 871 controls (7%) were current users of either non-selective NSAIDs or COX 2 inhibitors who were further classified as new users (first ever prescription within 60 days of diagnosis date) or long-term users.
The researchers found that use of NSAIDs or COX-2 inhibitors was significantly associated with an increased risk of atrial fibrillation or flutter. Compared with non-users, the association was strongest for new users, with around 40% increased risk of arrhythmia for non-selective NSAIDs and around 70% increased risk for COX-2 inhibitors. This is equivalent to approximately 4 extra cases of atrial fibrillation per year per 1000 new users of non-selective NSAIDs and 7 extra cases of atrial fibrillation per 1000 new users of COX-2 inhibitors. The risk appeared highest in older persons, and patients with chronic kidney disease or rheumatoid arthritis were at particular risk when starting treatment with COX-2 inhibitors.
Only non-aspirin NSAIDs, requiring prescription in Denmark, were tracked in the study. In terms of adjusted incidence risk ratios for arrhythmia, the various agents may be ranked in ascending order (from lowest to highest risk) as: ibuprofen, naproxen, etodolac, diclofenac, rofecoxib, and celecoxib. However, 95% confidence intervals for the risk ratios were overlapping, so there were no statistically significant differences between the NSAIDs and COX-2 inhibitors listed.
The authors conclude: "Our study thus adds evidence that atrial fibrillation or flutter need to be added to the cardiovascular risks under consideration when prescribing [non-aspirin] NSAIDs."
COMMENTARY: An accompanying editorial, by Jerry Gurwitz from the University of Massachusetts Medical School, observes that more than 2-million Americans and more than 4-million people in the European Union have paroxysmal (ie, sudden) or persistent atrial fibrillation. Its prevalence increases dramatically with advancing age, rising from 0.1% in adults younger than 55 years to 9.0% in those aged 80 or more [Gurwitz 2011].
In the study by Schmidt et al. the overall relative risks of atrial fibrillation associated with NSAIDs are robust and statistically significant but the absolute risks are relatively low. Still, Gurwitz emphasizes that the findings have "important clinical and public health implications because of the high prevalence of use of these agents, particularly among older adults, and the increasing prevalence of atrial fibrillation with advancing age."
Gurwitz further observes that, while the present study found the highest risk among new users, a prior study in the UK found the highest risk among long-term users. In both trials, there was a lack of consistent dose-response with the drugs, making the association somewhat tenuous. Furthermore, case-control studies are subject to unmeasured confounding variables, such as obesity. And, in their analysis, Schmidt and colleagues were unable to obtain data on several clinical measures, including body mass index.
What does the current evidence mean for clinical practice? "With uncertainty regarding a plausible biological mechanism, the susceptibility of case-control studies to unmeasured confounders, and inconsistent results in the two studies performed to date, a cautious approach seems warranted in applying the study's results to the care of patients," Gurwitz notes. Like any other drug, prescribing NSAIDs continues to be a question of balancing the benefits and risks, and extra caution may be appropriate in older patients with a history of hypertension or heart failure.
As with prior studies, common aspirin was excluded, so little is known about the potential cardiovascular harms of that agent. And, in the United States and some other countries, where many types of NSIADs are available over-the-counter without prescription, there might be special concerns about what patients are taking for pain; especially, on a continuing basis and by older persons who may have coexisting cardiovascular or other complicating conditions.
> Gurwitz JH. NSAIDs and atrial fibrillation. BMJ. 2011;343:d2495 [abstract here].
> Schmidt M, Christiansen CF, Mehnert F, et al. Non-steroidal anti-inflammatory drug use and risk of atrial fibrillation or flutter: population based case-control study. BMJ. 2011;343:d3450 [article available here].