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Can Sacubitril/Valsartan Have a Proarrhythmic Effect in Some High-Risk Patients?

Dear Editor, We read with great interest the article by Weir [1] regarding the potential proarrhythmic effect of the combination sacubitril/valsartan (SV)/mexiletine based on two cases with ventricular arrhythmias shortly after the initiation of SV. Although the hypothesis about the pharmacokinetic mechanism of the combination of both drugs as a trigger for ventricular arrhythmias is interesting, we would like to consider the possibility that ventricular arrhythmias were directly related with SV initiation. Compared with enalapril, SV reduces mortality, heart failure hospitalizations, and sudden death [2]. It has been hypothesized that this drug could have an antiarrhythmic effect [3], and a decrease in ventricular arrhythmias after starting SV has been described [4]. However, we have recently reported a number of cases that presented sustained ventricular arrhythmias after initiating SV [5, 6]. All were male and had a high risk for ventricular arrhythmias; however, they had been electrically stable in the previous 6 months. Of note, 85% were carriers of an implanted cardioverter defibrillator, an interesting fact as real-life data have shown that the prevalence of implanted cardioverter defibrillator carriers among SV users is much higher than the one reported in the Prospective Comparison of ARNi With ACE-I to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial [7]. Our series does not suggest a role for drug interactions, as the initiation of SV was the only therapeutic change made prior to the ventricular arrhythmic storm, and none of our patients were receiving mexiletine. All were hemodynamically stable without heart failure decompensation, and no electrolyte disturbances were observed. SV was discontinued in all but 2 patients. Arrhythmia control was achieved in all but 1 patient of those who ceased the drug. Therefore, discontinuation of SV may be an appealing option for controlling arrhythmias in some cases, as Weir describes in the second case report. To date, a total of 16 cases of ventricular arrhythmias after initiating SV have been reported, 13 from our center, the two reported by Weir and the one reported by Okutucu and Oto [8]. It is remarkable that 15 (94%) were male. We can presume that males have a higher risk to have this adverse event, as it has been described in other settings [9]. The structural changes that take place with SV treatment modify the electrical characteristics of the myocardial tissue. Although reverse remodeling has an unquestionable beneficial impact on most patients, these structural modifications could trigger the onset of arrhythmias in specific high-risk patients, especially in the case of males. We should be aware that some patients may require a closer follow-up after SV initiation to detect the occurrence of ventricular arrhythmias early. SV withdrawal might be an option in some of these cases.