Influence of Omega-3 PUFA on Non-invasive factors determining the risk of arrhYthmias eXcess and sudden cardiac death in patients with HFpEF with ischemic etiology (ONYX)

Abstract

Aim Patients with heart failure with reduced left ventricular (LV) ejection fraction (HFrEF) who have had acute myocardial infarction have an unfavorable prognosis, largely due to ventricular arrhythmias (VA) and risk of sudden cardiac death (SCD). The optimal treatment (triple neurohormonal blockade plus implantable cardioverter defibrillator and cardiac resynchronization therapy) reduced the risk of SCD primarily due to reverse cardiac remodeling, but has not solved this problem completely. Efficacy of purified ω-3 polyunsaturated fatty acid esters (PUFA) in low doses (1 g/day) in reducing VA and risk of SCD in HFrEF patients was demonstrated in two large randomized clinical trials. The PUFA effects was suggested to be related also with increased heart rhythm variability (HRV) and chronotropic action, which might depend on the drug dose. The present open, prospective, randomized, comparative study in parallel groups evaluated the effect of Omacor in different doses on noninvasive markers of SCD risk in patients with ischemic HFrEF receiving the optimal drug therapy.Methods Patients (n=40) were randomized at a 1:1:2 ratio to the control group (n=10), the Omacor 1 g/day treatment group (n=10), and the Omacor 2 g/day treatment group (n=20) and were followed up for 12 months. Clinical evaluation included changes in the CHF functional class (FC) and Clinical Condition Scale (CCS) score; concentration of N-terminal pro-hormone brain natriuretic peptide (NT-proBNP); and peak oxygen consumption during exercise (peak VO2). The LV function was evaluated by LVEF. Holter ECG monitoring was used for evaluation of HRV (SDNN), average 24-h heart rate (HR), number of ventricular extrasystoles (VE) per hour and severity of VA, and presence of paired VE and VT runs.Results Improvement of CHF FC became significant only with the high-dose Omacor treatment (2 g/day). The CCS score showed a tendency towards decrease also with a lower dose (1 g/day) whereas the level of NT-proBNP significantly decreased with both Omacor doses. The increase in LV EF was significant only with the use of Omacor 2 g/day (+3 %, р=0.002). A negative chronotropic effect of ω-3 PUFA was observed. Average 24-h HR decreased by 8 bpm (р=0.05) and 11 bpm (р<0.001) with Omacor 1 g/day and 2 g/day, respectively. Either dose of ω-3 PUFA significantly improved VO2, which directly correlated with LV EF and inversely correlated with HR. The decrease in number of VE was associated not only with improved HRV (SDNN) but also with the decrease in 24-h HR, and thus Omacor 2 g/day significantly decreased the number of VE (by 16 per hour) and dangerous VA (paired VE and VT runs ceased to be detected in 40 % of patients).Conclusion Since HR, HRV, and VA are closely interrelated, the effect of ω-3 PUFA specifically on these noninvasive markers apparently determines its ability to decrease the risk of SCD in patients with ischemic HFrEF. The antiarrhythmic effect of Omacor was greater with higher doses of this drug.