Lacosamide-Related Arrhythmias: A Systematic Analysis and Review of the Literature

Lacosamide (LCM) is a new antiepileptic drug used as an adjunctive treatment for partial seizures with and without secondary generalization. One of the modes of action is the enhancement of slow inactivation of voltage-gated sodium channels. Experimental studies and clinical trials suggest that LCM acts upon both neurons and the heart and may increase the risk of cardiac arrhythmias. A systematic review was conducted to investigate characteristics of arrhythmias related to the use of LCM for the treatment of seizures. The search terms “lacosamide”, “arrhythmias”, “AV block”, “atrial fibrillations/flutter”, “cardiac conductions defects”, “ventricular tachycardia”, “ventricular fibrillation were used. Case reports and retrospective studies were gathered by searching Medline/PubMed, Google Scholar, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Cochrane CENTRAL (Cochrane Central Register of Controlled Trials), and Web of Science databases. Seventeen articles were selected for review. Ventricular tachycardia was the most reported LCM related arrhythmia (29.4%), followed by new-onset atrial fibrillation (17.6%), complete heart block (17.6%), Mobitz type 1 Atrio-ventricular block (11.8%), sinus pauses (11.8%), pulseless electrical activity (5.9%) and widening QRS complex (5.9%). Further research and clinical trials are needed to explore the etiopathogenesis and causative relationship between the use of LCM and arrhythmias.


Introduction And Background
Lacosamide (LCM) is a new antiepileptic drug approved by the United States Food and Drug Administration (FDA) in October 2008 as an adjunctive treatment for partial seizures with and without secondary generalization [1]. It is composed of (R)-2-acetamido-N-benzyl-3-methoxyproionamide, causing slow inactivation of voltage-gated sodium channels in neurons [2]. Based on the above mechanism of action several reports of dose-dependent cardiac arrhythmias have been reported in the literature [3][4][5][6]. LCM inhibits cardiac sodium channel SCN5A that could be an underlying possible mechanism for cardiac arrhythmias, including ventricular tachycardia, sinus pauses, atrial fibrillation, and sudden death [7,8]. Limited data is available on the relationship between the use of antiepileptic drugs/LCM and cardiac arrhythmias. Multiple isolated cases of arrhythmias have been associated with LCM use [5,6,9]. Here we present a systematic review of such cases of LCM-related arrhythmias to evaluate the need for assessment of risk factors and potentially warn physicians of the dose-related cardiac effects of LCM.

Review Method
A comprehensive literature search was conducted by two authors, using Medline/Pubmed, Google Scholar, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Cochrane CENTRAL (Cochrane Central Register of Controlled Trials), and Web of Science databases, for relevant studies since 2008. The terms "lacosamide, arrhythmias, AV block, atrial fibrillations/flutter, cardiac conductions defects, ventricular tachycardia, ventricular fibrillation, cardiac conductions defects" were used to identify cases of myocardial arrhythmias associated with LCM use. A total of 108 articles were found related to LCM and arrhythmias. Only articles that reported LCM use and the presence of cardiac arrhythmias were included. Seventeen studies that included the case reports were then deemed eligible for inclusion in this review as shown in Table 1. Studies were excluded if: 1) Articles were not case reports, case series or observational studies, or 2) Articles were reviews or editorials. The reference list of each report was reviewed for potential additional cases. All cases were reviewed in detail. The present analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A PRISMA flow diagram detailing the process of identification, selection, and inclusion of studies is shown in Figure 1.    Data was collected by four authors that included demographic data, cardiovascular (CV) risk factors, indication for LCM use, electrocardiography (EKG) findings, transthoracic echocardiography (TTE) findings, type of arrhythmias, cardiac arrest, and management when available as shown in Table 1.

Discussion
LCM is a novel antiepileptic agent used for add-on therapy in patients with partial and secondarily generalized seizures [2]. Intravenous LCM has been used for the treatment of status epilepticus [2]. Its main mechanism of action is the enhancement of the slow inactivation of voltage-gated sodium channels thus reducing the ability of neurons to sustain prolonged firing bursts [3]. Experimental studies and clinical trials suggest that LCM acts upon both neurons and the heart and may increase the risk of cardiac arrythmias [4]. The action potentials of most of the cardiac tissues, including the His-Purkinje system, are generated through voltage-gated sodium channels however that of AV node is through voltage-gated calcium channels [4,7]. As seen with other anticonvulsant agents, dose-dependent inhibition of sodium channels produces infra-Hisian delays and conduction defects that could be one of the postulated mechanisms of cardiac arrhythmias with the use of LCM [2,4]. It follows linear pharmacokinetics with a maximum concentration reached within 1-4 hours and a half-life of 13 hours [2]. Clinical trials [4,23] have shown the association of LCM, dose-ranging from 200-600 mg/day, with cardiac conduction defects including atrial fibrillation and flutter. Few case reports suggesting first-degree AV block and third-degree AV blocks with LCM use have been retrieved from the literature [10] [24]. Traditional sodium channel blocking agents such as carbamazepine and phenytoin cause the fast inactivation of voltage-dependent sodium channels and may have potential synergistic action with LCM [12].
However, clinical trials [25] did not show any additional adverse effects with concomitant use of other sodium channel blockers. Several studies, including our systematic review, have documented cardiac arrhythmias with the use of LCM hence recommendations before the initiation may include baseline EKG, evaluation of cardiac risk factors, electrolytes levels, and adjusting the dose of LCM based on renal and hepatic functions.

Conclusions
Arrhythmias associated with the use of LCM in seizures have been documented in several case reports and studies. LCM inhibits the cardiac sodium channel by enhancing slow inactivation in a concentrationdependent manner. The timing of several cardiac arrhythmias after initiation of LCM and their resolution after discontinuation suggests a possible pro-arrhythmic role of LCM as described in Table 1. Identification of any pre-existing cardiac/arrhythmogenic risk factors may prove to be beneficial before commencing treatment with LCM. One must also consider reviewing the home medications and their dosage to prevent any drug-drug interactions with the use of LCM. In our systematic review study, ventricular tachycardia was the most reported of LCM-related arrhythmia, and wide QRS complex was the least common one. Discontinuation of LCM was one of the common factors that helped to restore the sinus rhythm in most of the studied case reports. Comparative studies may be warranted for defining the role of a higher dosage of LCM~600 mg/day as compared to ~400mg/day in causing arrhythmias. Further research and clinical trials are needed to explore the etiopathogenesis and causative relationship between the use of LCM and arrhythmias.
In addition, further investigations are needed to study the cardiac effects of LCM and its interactions with other antiepileptic drugs involving the inhibition of cardiac sodium channels. Electrocardiographic (ECG) testing before and during LCM therapy along with close monitoring may help to avoid cardiac arrhythmias

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.