Atrial fibrillation risk increased by non-steroidal antiinflammatory drugs

Atrial fibrillation, the most common heart rhythm disorder, is a troublesome, uncomfortable condition that significantly increases the risk for heart attack and stroke. While it is becoming better recognized that none of the non-steroidal anti-inflammatory drugs (NSAIDs) other than aspirin are safe in cardiovascular terms, it is often overlooked that NSAIDs increased the risk for atrial fibrillation specifically. Consider a study published in BMJ (British Medical Journal) in which the authors state...

"Any confirmed association between use of NSAIDs and atrial fibrillation would have major clinical and public health implications. Older people are of special concern because the prevalence of use of NSAIDs and the incidence of atrial fibrillation increase with age. To address the limitations of the existing literature, we conducted a large population based case-control study examining whether and to what extent use of NSAIDs increases the risk of atrial fibrillation or flutter."

They examined data on 32,602 patients with atrial fibrillation compared to 325,918 age matched and sex matched controls for exposure to NSAID use before or at the time of admission for their arrhythmia. They also distinguished between recent and long term use and found significantly increased risk:

"2925 cases (9%) and 21 871 controls (7%) were current users of either non-selective NSAIDs or COX 2 inhibitors. Compared with no use, the incidence rate ratio associating current drug use with atrial fibrillation or flutter was 1.33 for non-selective NSAIDs and 1.50 for COX 2 inhibitors. Adjustments for age, sex, and risk factors for atrial fibrillation or flutter reduced the incidence rate ratio to 1.17 for non-selective NSAIDs and 1.27 for COX 2 inhibitors. Among new users, the adjusted incidence rate ratio was 1.46 for non-selective NSAIDs and 1.71 for COX 2 inhibitors. Results for individual NSAIDs were similar."

That's a 46% and 71% increase for non-selective NSAIDs and COX 2 inhibitors respectively in new users, and it didn't appear to matter which NSAID was used. The authors conclude:

"Use of non-aspirin NSAIDs was associated with an increased risk of atrial fibrillation or flutter. Compared with non-users, the association was strongest for new users, with a 40-70% increase in relative risk (lowest for non-selective NSAIDs and highest for COX 2 inhibitors). Our study thus adds evidence that atrial fibrillation or flutter needs to be added to the cardiovascular risks to be considered when prescribing NSAIDs."

 Evidence that  antiinflammatory medications increase the risk for atrial fibrillation was also presented in a paper published in JAMA Internal Medicine. Having noted the previously described association between the use of corticosteroids (steroidal anti-inflammatory drugs [SAIDs]) and the risk of atrial fibrillation (AF) they examined data for 1035 patients with incident chronic AF and 525 with paroxysmal AF and found:

"We confirmed the previously reported association between current use of SAIDs and chronic AF (rate ratio [RR], 2.49. However, we also found that the current use of NSAIDs was associated with an increased risk of chronic AF. Such risk was further increased among long-term users with a treatment duration of longer than 1 year. The increased risk of chronic AF was not explained by the occurrence of heart failure. The use of NSAIDs was not associated with paroxysmal AF."

They posit that inflammation may be a common cause for atrial fibrillation and the use of NSAIDs:

"Underlying inflammatory conditions could favor the onset or maintenance of AF. Atrial fibrosis is the most frequent pathoanatomical change found in AF. Patchy fibrosis in close proximity with normal atrial fibers may account for conduction inhomogeneities, and it has been argued that fibrosis precedes the onset of AF. Atrial fibrosis is currently the main structural target for the proposed use of drugs inhibiting the renin-angiotensin system in AF and may be caused by inflammation, as seen in cardiac sarcoidosis and autoimmune disorders. Inflammation, possibly also through the production of thromboxane A2 and prostaglandin F2α, has recently been shown to cause inflammatory tachycardia. It is possible, and we would like to propose, that conditions presenting systemic inflammation, such as autoimmune and rheumatic disorders, represent an independent risk factor for atrial fibrosis and subsequently for an increased risk of onset or persistence of AF. Consequently, the use of anti-inflammatory drugs may be a proxy for an underlying inflammatory substrate favoring AF."

 The authors of the JAMA paper concentrate on inflammation as a shared cause for atrial fibrillation and the prescription of NSAIDs, but it's important to reflect on the fact that NSAIDs increase intestinal barrier permeability which contributes to the loss of immune tolerance and autoimmunity. The resultant autoimmune inflammation can target the conductive system of the heart and produce arrhythmias as described in a paper published in the journal Heart Rhythm:

"...accumulating evidence suggests that a number of vascular and cardiac conditions are autoimmune mediated. Recent studies indicate that autoantibodies play an important role in the development of cardiac arrhythmias, including atrial fibrillation, modulation of autonomic influences on heart rate and rhythm, conduction system abnormalities, and ventricular arrhythmias. This article will review the current evidence for the role of autoantibodies in the development of cardiac arrhythmias."

 And a recent paper in the same journal identified autoantibodies to β-adrenergic receptors (β2ARs) as culprits for inducing atrial arrhythmias:

"Taking into account only the sustained arrhythmias, there were 6 episodes in 20 events in the postimmune studies compared with 0 episodes in 20 events in the preimmune studies. Immunized rabbits demonstrated immunoglobulin G deposition in the atria, and their sera induced significant activation of β2AR in transfected cells in vitro compared to the preimmune sera...Enhanced autoantibody activation of β2AR in the rabbit atrium leads to atrial arrhythmias mainly in the form of sustained atrial tachycardia."

 Clinicians should bear in mind that athletes are especially vulnerable because exercise induces small intestinal micro-injury. The authors of a study published in the journal Medicine & Science in Sports & Exercise state:

"Nonsteroidal anti-inflammatory drugs are commonly used by athletes to prevent anticipated exercise-induced pain, thereby putatively improving physical performance. However, these drugs may have potentially hazardous effects on the gastrointestinal (GI) mucosa during strenuous physical exercise. The aim of the current study was to determine the effect of oral ibuprofen administration before exercise on GI integrity and barrier function in healthy individuals."

They examined the effects of 400 mg of ibuprofen taken twice before cycling, cycling without ibuprofen, 400 mg of ibuprofen taken twice while at rest, and 4) rest without any ibuprofen. They used plasma intestinal fatty acid binding protein (I-FABP) levels and urinary excretion of orally ingested multisugar test probes to assess small intestinal injury and GI permeability respectively:

"Both ibuprofen consumption and cycling resulted in increased I-FABP levels, reflecting small intestinal injury. Levels were higher after cycling with ibuprofen than after cycling without ibuprofen, rest with ibuprofen, or rest without ibuprofen. In line, small intestinal permeability increased, especially after cycling with ibuprofen, reflecting loss of gut barrier integrity. Interestingly, the extent of intestinal injury and barrier dysfunction correlated significantly."

This study reveals a link between ibuprofen taken during exercise and atrial fibrillation due to autoimmune inflammation promoted by damage to the intestinal barrier. The authors conclude:

"This is the first study to reveal that ibuprofen aggravates exercise-induced small intestinal injury and induces gut barrier dysfunction in healthy individuals. We conclude that nonsteroidal anti-inflammatory drugs consumption by athletes is not harmless and should be discouraged."

 Sadly, the wonder drug aspirin does not get a free pass in this context. The authors of a study published in the International Journal of Sports Medicine provide evidence that aspirin also increases gut permeability:

"The primary purpose of this study was to determine the aspirin dose that increases gastrointestinal (GI) permeability. A pilot study was also conducted to determine whether the menstrual cycle affects GI permeability. Both portions of the study involved 4 experimental conditions. For the aspirin portion, 8 subjects ingested 0 mg, 325 mg, 650 mg, or 975 mg of aspirin the night before and the morning of an experiment. For the menstrual cycle pilot study, 5 female subjects with regular menstrual cycles were tested for GI permeability on the same day each week for 4 weeks. GI permeability was assessed by the urinary excretion of ingested probes. Sucrose (5 g) was used to determine gastroduodenal permeability. Lactulose (5 g) and rhamnose (2 g) were used to assess small intestinal permeability via the lactulose-to-rhamnose urinary excretion ratio (L/R)."

Interestingly, menstruation did not increase gut permeability in their study subjects, but aspirin certainly did:

"The data indicated that the menstrual cycle had no effect on GI permeability. In contrast, gastroduodenal permeability was significantly increased following a dose of 650 mg aspirin and small intestinal permeability (L/R) was significantly increased following a dose of 975 mg aspirin. These results suggest healthy individuals should be cautious even with acute aspirin use as it may result in GI barrier dysfunction."

 Clinical note: practitioners must bear in mind the potential for all non-steroidal anti-inflammatory drugs to cause atrial fibrillation by aggravating or triggering latent autoimmune inflammation due to gut barrier compromise.