ABSTRACT

Background Icosapent ethyl (ICP), an ethyl ester of eicosapentaenoic acid (EPA), and omega-3 acid ethyl esters (DHA/EPA), comprised of ethyl esters of EPA and doxosahexaenoic acid (DHA), are approved as adjunctive therapy to statins for reducing adverse cardiovascular events (CV) in patients with CV risks. However, there are concerns regarding a potential association between ICP and atrial fibrillation (AF). This study evaluated the incidence of AF onset between ICP and DHA/EPA when used as adjuvant therapy with statins.

Methods and Results This retrospective study utilized administrative healthcare claims to analyze adult AF-naïve patients from one year preceding their first prescription for ICP or DHA/EPA. These patients were followed for two years, spanning from2013-2021. AF incidence was assessed during active treatment with either ICP or DHA/EPA as adjunct statin therapy. A propensity score (PS) matched cohort controlled for baseline characteristics and the effect of calendar year on the use of ICP or DHA/EPA. The cumulative incidence of AF was estimated using a product-limit estimator and compared between groups using a Cox proportional hazards regression model. The PS-matched cohort included 17,638 participants with a mean age 56 years, predominantly male (65.7% ICP vs. 64.5% DHA/EPA). Over two years, the cumulative incidence of AF from ICP and DHA/EPA was 5.32% and 3.99% respectively, resulting in a HR of 1.242 (95% CI: 1.061 to 1.455).

Conclusions In adult AF-naïve patients, ICP, when compared to DHA/EPA in conjunction with statin therapy, was associated with a significantly higher significant risk of developing AF.

What is New?

Does icopasent ethyl (ICP), an ethyl ester of eicosapentaenoic acid (EPA) and omega-3 acid ethyl esters comprised of ethyl esters of EPA and doxosahexaenoic acid (DHA) in atrial fibrillation (AF)-naïve patients taking statins increase the incidence of AF?

Over two years, the cumulative incidence of AF from ICP and DHA/EPA was 5.32% and 3.99% respectively, resulting in a HR of 1.242 (95% CI: 1.061 to 1.455).

In adult AF-naïve patients, ICP, when compared to DHA/EPA in conjunction with statin therapy was associated with a higher significant risk of developing AF.

What Question Should be Addressed Next?

What should be considered as clinical and demographic factors in identifying patients at risk of atrial fibrillation prior to being prescribed ICP or DHA/EPA agents.

Investigation into the underlying mechanism of the increase in atrial fibrillation with marine omega-3 ethyl esters should continue.

Understanding AF outcomes from ICP or DHA/EPA use including AF burden, need for AF medical or electrophysiological interventions, and health-care total costs.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

University of Utah Cardiovascular Clinical Pharmacology Fund

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The University of Illinois Chicago Institutional Review Board deemed the use of the database for this study exempt.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Availability

Data is available on request from the authors.

ABREVIATIONSACEiAngiotensin-converting enzyme inhibitorARBAngiotensin receptor blockerARNIAngiotensin Receptor-Neprilysin InhibitorAFAtrial FibrillationBBßeta-adrenergic blockerDHA/EPAEicosapentaenoic and doxosahexaenoic acidEPAEicosapentaenoic acidGLP-1raGlucoagon-like-peptide-1 receptor agonists.HRHazard RatioICPIcopasent EthylMACEMajor Adverse Cardiac EventPIEZOA mechanosensitive ion proteinPSPropensity ScoreSGLT2iSodium-glucose cotransporter-2 inhibitorsSPLSpironolactoneSMDStandard Mean Difference