Why can icosapent ethyl (IPE) (generic name: eicosapentaenoic acid ethyl ester) cause atrial fibrillation?

From the Guidelines

Icosapent ethyl can cause atrial fibrillation, as evidenced by a significant increase in atrial fibrillation risk in clinical trials, with a hazard ratio of 1.69 (95% CI: 1.29-2.21) in the STRENGTH trial 1. The exact mechanisms are not fully understood but may involve direct effects on cardiac electrophysiology, including alterations in ion channel function, and structural changes in atrial tissue through anti-inflammatory effects. Key points to consider include:

• Icosapent ethyl is typically prescribed at doses of 4 grams daily for hypertriglyceridemia or cardiovascular risk reduction.
• Clinical trials have shown an increase in atrial fibrillation risk by approximately 1-1.5% compared to placebo.
• The mechanisms likely involve direct effects on cardiac electrophysiology and structural changes in atrial tissue.
• Patients with existing risk factors for atrial fibrillation, such as advanced age, hypertension, structural heart disease, or previous arrhythmias, may be more susceptible to this side effect.
• Healthcare providers should monitor patients on icosapent ethyl for symptoms like palpitations, irregular heartbeat, shortness of breath, or dizziness that might indicate development of atrial fibrillation, as supported by the findings of the REDUCE-IT trial 1 and the 2021 ACC expert consensus decision pathway 1.

From the FDA Drug Label

Icosapent ethyl is associated with an increased risk of atrial fibrillation or atrial flutter requiring hospitalization In a double-blind, placebo-controlled trial of 8,179 subjects, adjudicated atrial fibrillation or atrial flutter requiring hospitalization for 24 or more hours occurred in 127 (3%) patients treated with icosapent ethyl compared to 84 (2%) patients receiving placebo [HR= 1.5 (95% CI 1.14,1. 98)]. The incidence of atrial fibrillation was greater in patients with a previous history of atrial fibrillation or atrial flutter.

Icosapent ethyl can cause atrial fibrillation due to its association with an increased risk of this condition, as demonstrated in a double-blind, placebo-controlled trial 2. The exact mechanism is not specified in the drug label, but it is noted that the incidence of atrial fibrillation is greater in patients with a previous history of atrial fibrillation or atrial flutter. Key points include:

• Increased risk of atrial fibrillation or atrial flutter requiring hospitalization
• Greater incidence in patients with a previous history of atrial fibrillation or atrial flutter
• Observed in a double-blind, placebo-controlled trial of 8,179 subjects 2

From the Research

Icosapent Ethyl and Atrial Fibrillation

• Icosapent ethyl (IPE) has been associated with an increased risk of atrial fibrillation, as seen in the REDUCE-IT study 3.
• The study found that IPE resulted in a statistically significant increased risk of atrial fibrillation, although the risk of stroke was reduced and there were no cases of fatal bleeding 3.
• Another study found that treatment with eicosapentaenoic acid (EPA), a component of IPE, did not reduce the burden of atrial fibrillation in patients with paroxysmal atrial fibrillation 4.
• However, a rabbit model study found that EPA prevented atrial fibrillation associated with heart failure by attenuating atrial fibrosis and modulating adipokine production 5.
• A post hoc analysis of the REDUCE-IT study found that IPE reduced the risk of cardiovascular events, including myocardial infarction, stroke, and coronary revascularization, but was associated with a slight increase in atrial fibrillation 6.

Mechanisms and Risk Factors

• The exact mechanism by which IPE increases the risk of atrial fibrillation is not fully understood, but it may be related to its effects on serum triglyceride levels and cardiovascular risk factors 3, 7.
• Patients with elevated triglyceride levels and cardiovascular disease or type 2 diabetes may be at increased risk of atrial fibrillation when treated with IPE 3, 7.
• The use of IPE in combination with other medications, such as statins and antiarrhythmic drugs, may also affect the risk of atrial fibrillation 4, 6.

Clinical Implications

• The increased risk of atrial fibrillation associated with IPE should be carefully considered when prescribing this medication to patients with elevated triglyceride levels and cardiovascular disease or type 2 diabetes 3, 7.
• Patients treated with IPE should be monitored for signs and symptoms of atrial fibrillation, and alternative treatments should be considered if necessary 3, 6.