-
Neurology. Clinical Practice Oct 2021Myotonic dystrophy types 1 and 2 are progressive multisystem genetic disorders whose core clinical feature is myotonia. Mexiletine, an antagonist of voltage-gated sodium...
BACKGROUND AND OBJECTIVE
Myotonic dystrophy types 1 and 2 are progressive multisystem genetic disorders whose core clinical feature is myotonia. Mexiletine, an antagonist of voltage-gated sodium channels, is a recommended antimyotonic agent in the nondystrophic myotonias, but its use in myotonic dystrophy is limited because of lack of data regarding its long-term efficacy and safety profile.
METHODS
To address this issue, this study retrospectively evaluated patients with myotonic dystrophy receiving mexiletine over a mean time period of 32.9 months (range 0.1-216 months).
RESULTS
This study demonstrated that 96% of patients reported some improvement in myotonia symptoms with mexiletine treatment. No clinically relevant cardiac adverse events were associated with the long-term use of mexiletine.
CONCLUSIONS
These findings support that mexiletine is both safe and effective when used long-term in myotonic dystrophy.
CLASSIFICATION OF EVIDENCE
This study provides Class IV evidence that mexiletine is a well-tolerated and effective treatment for myotonic dystrophy types 1 and 2.
PubMed: 34840883
DOI: 10.1212/CPJ.0000000000001073 -
Frontiers in Pharmacology 2023This study aimed to identify the different associations between antiarrhythmic drugs (AADs) and arrhythmias, and to determine whether pharmacokinetic drug interactions...
This study aimed to identify the different associations between antiarrhythmic drugs (AADs) and arrhythmias, and to determine whether pharmacokinetic drug interactions involving AADs increase the risk of AAD-related arrhythmias compared to using AADs alone. The disproportionality analysis of AAD-associated cardiac arrhythmias, including AAD monotherapies and concomitant use of pharmacokinetic interacting agents involving AADs, was conducted by using reporting odds ratio (ROR) and information component (IC) as detection of potential safety signals based on FAERS data from January 2016 to June 2022. We compared the clinical features of patients reported with AAD-associated arrhythmias between fatal and non-fatal groups, and further investigated the onset time (TTO) following different AAD regimens. A total of 11754 AAD-associated cardiac arrhythmias reports were identified, which was more likely to occur in the elderly (52.17%). Significant signals were detected between cardiac arrhythmia and all AAD monotherapies, with ROR ranging from 4.86 with mexiletine to 11.07 with flecainide. Regarding four specific arrhythmias in High Level Term (HLT) level, the AAD monotherapies with the highest ROR were flecainide in cardiac conduction disorders (ROR025 = 21.18), propafenone in rate and rhythm disorders (ROR025 = 10.36), dofetilide in supraventricular arrhythmias (ROR025 = 17.61), and ibutilide in ventricular arrhythmias (ROR025 = 4.91). Dofetilide/ibutilide, ibutilide, mexiletine/ibutilide and dronedarone presented no signal in the above four specific arrhythmias respectively. Compared with amiodarone monotherapy, sofosbuvir plus amiodarone detected the most significantly increased ROR in arrhythmias. The investigation showed the spectrum and risk of AAD-associated cardiac arrhythmias varied among different AAD therapies. The early identification and management of AAD-associated arrhythmias are of great importance in clinical practice.
PubMed: 37251345
DOI: 10.3389/fphar.2023.1170039 -
Current Treatment Options in... Nov 2019Left ventricular assist device (LVAD) implantation is a well-known treatment option for patients with advanced heart failure refractory to medical therapy and is... (Review)
Review
PURPOSE OF REVIEW
Left ventricular assist device (LVAD) implantation is a well-known treatment option for patients with advanced heart failure refractory to medical therapy and is recognized both as bridge to transplant and a destination therapy. The risk of ventricular arrhythmias (VAs) is common after LVAD implantation. We review the pathophysiology and recent advances in the management of VA in LVAD patients.
RECENT FINDINGS
VAs are most likely to occur in the early post-operative periods after LVAD implantation and a prior history of VA is the most important risk factor. Post-LVAD VAs are usually well tolerated with less morbidity and decreased risk of sudden cardiac death. However, risk of right heart failure in the setting of persistent VAs is being increasingly recognized. The mechanisms of post-LVAD VAs may vary depending on the time from LVAD implantation. Electrical remodeling may play an important role in the immediate post-implant phase. Preexisting myocardial scar and to a lesser extent mechanical irritation from the LVAD cannula are important in the later phases. Most LVAD patients have a previously placed implantable cardioverter-defibrillator (ICD). The benefit of implanting a new ICD in LVAD patients is unknown and should be individualized. For ICD programming, a conservative strategy with higher detection zones and prolonged time to detection is usually recommended aiming to minimize ICD shocks. More aggressive programming is appropriate if the VA results in hemodynamic instability. Antiarrhythmic drugs including amiodarone, mexiletine, and beta blockers are usually the first-line therapy for VAs. Catheter ablation has been shown to be safe and effective in LVAD recipients with recurrent VAs not responsive to antiarrhythmic drugs. LVAD-related VA is most frequently reentrant secondary to myocardial scar and usually well tolerated. Management options include antiarrhythmic drugs and catheter ablation.
PubMed: 31773322
DOI: 10.1007/s11936-019-0783-7 -
Acta Cardiologica May 2022The pharmacological therapy of ventricular arrhythmias in patients with unsuccessful or not feasible catheter ablation and contraindication or inefficacy to amiodarone...
BACKGROUND
The pharmacological therapy of ventricular arrhythmias in patients with unsuccessful or not feasible catheter ablation and contraindication or inefficacy to amiodarone and beta-blockers, is controversial. The present study investigated the effectiveness and tolerability of mexiletine in patients with recurrent ventricular arrhythmias and ischaemic heart disease, when the conventional antiarrhythmic therapy failed.
METHODS
We enrolled all consecutive patients with unsuccessful/not feasible catheter ablation and ineffective/contraindicated amiodarone or beta-blockers, which started the mexiletine treatment for refractory ventricular tachycardia (VT) or ventricular fibrillation (VF) between January 2010 and January 2020. The primary endpoint was the total number of VT/VF episodes after the beginning of mexiletine therapy. The 2 secondary endpoints were the overall number of therapies released by implantable cardioverter-defibrillators (ICDs) and the discontinuation of the pharmacological therapy. The events occurring during the mexiletine treatment period were compared with those observed in a matched duration interval before the initiation of therapy.
RESULTS
Thirty-four consecutive patients (27 males, 79.4%; mean age 74.0 ± 9.5 years) with ischaemic heart disease were finally analysed. The median of mexiletine treatment was 26.5 months (interquartile range: 18.75-38.25 months). After the mexiletine start, VT/VF episodes and ICD interventions significantly decreased (respectively: 74 vs 33 episodes, = 0.002; 116 vs 52 interventions, = 0.02) in comparison with a matched period without mexiletine. Six patients (13.9%) discontinued the treatment because of severe side effects.
CONCLUSIONS
The treatment period following the mexiletine start was associated with a significant reduction of ventricular arrhythmias. The rate of side effects requiring dosage reduction or interruption was not neglectable.
Topics: Aged; Aged, 80 and over; Amiodarone; Anti-Arrhythmia Agents; Cohort Studies; Coronary Artery Disease; Defibrillators, Implantable; Female; Humans; Male; Mexiletine; Middle Aged; Myocardial Ischemia; Tachycardia, Ventricular; Ventricular Fibrillation
PubMed: 34006205
DOI: 10.1080/00015385.2021.1926628 -
European Journal of Hospital Pharmacy :... Nov 2016Myotonia is found in a number of muscle diseases, including myotonic dystrophy and non-dystrophic myotonia. The resulting symptoms of myotonia can interfere with daily... (Review)
Review
INTRODUCTION
Myotonia is found in a number of muscle diseases, including myotonic dystrophy and non-dystrophic myotonia. The resulting symptoms of myotonia can interfere with daily activities such as walking or climbing the stairs. Due to the rarity of both these conditions, pharmacological treatment of myotonia is largely anecdotal and is led by specialist clinicians who tend to favour the use of mexiletine, a class 1b antiarrhythmic sodium antagonist.
OBJECTIVE
To identify and review randomised controlled trials in order to assess the efficacy and safety of use of mexiletine in myotonic dystrophy and non-dystrophic myotonia for two different patient cases.
SEARCH METHODS
The literature search was conducted using MEDLINE, EMBASE and The Cochrane Library (from January 1990 to December 2014). Specialist neurology centres were also contacted.
SELECTION CRITERIA
All randomised controlled trials between January 1990 and December 2014 which compared the use of mexiletine for the treatment of myotonia in patients who suffer from myotonic dystrophy and non-dystrophic were included in this review. Primary outcome: reduction of clinical myotonia.
RESULTS
Two randomised controlled trials were included for review. Both studies are underpowered; however, there is evidence to support the use of mexiletine for the improvement of clinical myotonia.
CONCLUSIONS
Larger randomised controlled trials are required, which look at the functional effect of myotonia as a primary outcome (ie, stair test) and the long-term use of mexiletine. This is needed to establish the ongoing efficacy and safety of the long-term use of mexiletine in the management of myotonia.
PubMed: 31156883
DOI: 10.1136/ejhpharm-2015-000839 -
The Cochrane Database of Systematic... Aug 2015Coronary artery disease is a major public health problem affecting both developed and developing countries. Acute coronary syndromes include unstable angina and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Coronary artery disease is a major public health problem affecting both developed and developing countries. Acute coronary syndromes include unstable angina and myocardial infarction with or without ST-segment elevation (electrocardiogram sector is higher than baseline). Ventricular arrhythmia after myocardial infarction is associated with high risk of mortality. The evidence is out of date, and considerable uncertainty remains about the effects of prophylactic use of lidocaine on all-cause mortality, in particular, in patients with suspected myocardial infarction.
OBJECTIVES
To determine the clinical effectiveness and safety of prophylactic lidocaine in preventing death among people with myocardial infarction.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 3), MEDLINE Ovid (1946 to 13 April 2015), EMBASE (1947 to 13 April 2015) and Latin American Caribbean Health Sciences Literature (LILACS) (1986 to 13 April 2015). We also searched Web of Science (1970 to 13 April 2013) and handsearched the reference lists of included papers. We applied no language restriction in the search.
SELECTION CRITERIA
We included randomised controlled trials assessing the effects of prophylactic lidocaine for myocardial infarction. We considered all-cause mortality, cardiac mortality and overall survival at 30 days after myocardial infarction as primary outcomes.
DATA COLLECTION AND ANALYSIS
We performed study selection, risk of bias assessment and data extraction in duplicate. We estimated risk ratios (RRs) for dichotomous outcomes and measured statistical heterogeneity using I(2). We used a random-effects model and conducted trial sequential analysis.
MAIN RESULTS
We identified 37 randomised controlled trials involving 11,948 participants. These trials compared lidocaine versus placebo or no intervention, disopyramide, mexiletine, tocainide, propafenone, amiodarone, dimethylammonium chloride, aprindine and pirmenol. Overall, trials were underpowered and had high risk of bias. Ninety-seven per cent of trials (36/37) were conducted without an a priori sample size estimation. Ten trials were sponsored by the pharmaceutical industry. Trials were conducted in 17 countries, and intravenous intervention was the most frequent route of administration.In trials involving participants with proven or non-proven acute myocardial infarction, lidocaine versus placebo or no intervention showed no significant differences regarding all-cause mortality (213/5879 (3.62%) vs 199/5848 (3.40%); RR 1.02, 95% CI 0.82 to 1.27; participants = 11727; studies = 18; I(2) = 15%); low-quality evidence), cardiac mortality (69/4184 (1.65%) vs 62/4093 (1.51%); RR 1.03, 95% CI 0.70 to 1.50; participants = 8277; studies = 12; I(2) = 12%; low-quality evidence) and prophylaxis of ventricular fibrillation (76/5128 (1.48%) vs 103/4987 (2.01%); RR 0.78, 95% CI 0.55 to 1.12; participants = 10115; studies = 16; I(2) = 18%; low-quality evidence). In terms of sinus bradycardia, lidocaine effect is imprecise compared with effects of placebo or no intervention (55/1346 (4.08%) vs 49/1203 (4.07%); RR 1.09, 95% CI 0.66 to 1.80; participants = 2549; studies = 8; I(2) = 21%; very low-quality evidence). In trials involving only participants with proven acute myocardial infarction, lidocaine versus placebo or no intervention showed no significant differences in all-cause mortality (148/2747 (5.39%) vs 135/2506 (5.39%); RR 1.01, 95% CI 0.79 to 1.30; participants = 5253; studies = 16; I(2) = 9%; low-quality evidence). No significant differences were noted between lidocaine and any other antiarrhythmic drug in terms of all-cause mortality and ventricular fibrillation. Data on overall survival 30 days after myocardial infarction were not reported. Lidocaine compared with placebo or no intervention increased risk of asystole (35/3393 (1.03%) vs 14/3443 (0.41%); RR 2.32, 95% CI 1.26 to 4.26; participants = 6826; studies = 4; I(2) = 0%; very low-quality evidence) and dizziness/drowsiness (74/1259 (5.88%) vs 16/1274 (1.26%); RR 3.85, 95% CI 2.29 to 6.47; participants = 2533; studies = 6; I(2) = 0%; low-quality evidence). Overall, safety data were poorly reported and adverse events may have been underestimated. Trial sequential analyses suggest that additional trials may not be needed for reliable conclusions to be drawn regarding these outcomes.
AUTHORS' CONCLUSIONS
This Cochrane review found evidence of low quality to suggest that prophylactic lidocaine has very little or no effect on mortality or ventricular fibrillation in people with acute myocardial infarction. The safety profile is unclear. This conclusion is based on randomised controlled trials with high risk of bias. However (disregarding the risk of bias), trial sequential analysis suggests that additional trials may not be needed to disprove an intervention effect of 20% relative risk reduction. Smaller risk reductions might require additional higher trials.
Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Bradycardia; Humans; Lidocaine; Myocardial Infarction; Randomized Controlled Trials as Topic; Ventricular Fibrillation
PubMed: 26295202
DOI: 10.1002/14651858.CD008553.pub2 -
Europace : European Pacing,... Nov 2022While mexiletine has been used for over 40 years for prevention of (recurrent) ventricular arrhythmias and for myotonia, patient access has recently been critically...
AIMS
While mexiletine has been used for over 40 years for prevention of (recurrent) ventricular arrhythmias and for myotonia, patient access has recently been critically endangered. Here we aim to demonstrate the effectiveness and safety of mexiletine in the treatment of patients with (recurrent) ventricular arrhythmias, emphasizing the absolute necessity of its accessibility.
METHODS AND RESULTS
Studies were included in this systematic review (PROSPERO, CRD42020213434) if the efficacy or safety of mexiletine in any dose was evaluated in patients at risk for (recurrent) ventricular arrhythmias with or without comparison with alternative treatments (e.g. placebo). A systematic search was performed in Ovid MEDLINE, Embase, and in the clinical trial registry databases ClinicalTrials.gov and ICTRP. Risk of bias were assessed and tailored to the different study designs. Large heterogeneity in study designs and outcome measures prompted a narrative synthesis approach. In total, 221 studies were included reporting on 8970 patients treated with mexiletine. Age ranged from 0 to 88 years. A decrease in ventricular arrhythmias of >50% was observed in 72% of the studies for pre-mature ventricular complexes, 64% for ventricular tachycardia, and 33% for ventricular fibrillation. Electrocardiographic effects of mexiletine were small; only in a subset of patients with primary arrhythmia syndromes, a relative (desired) QTc decrease was reproducibly observed. As for adverse events, gastrointestinal complaints were most frequently observed (33% of the patients).
CONCLUSIONS
In this systematic review, we present all the currently available knowledge of mexiletine in patients at risk for (recurrent) ventricular arrhythmias and show that mexiletine is both effective and safe.
Topics: Humans; Infant, Newborn; Infant; Child, Preschool; Child; Adolescent; Young Adult; Adult; Middle Aged; Aged; Aged, 80 and over; Mexiletine; Arrhythmias, Cardiac; Ventricular Fibrillation; Electrocardiography; Heart Ventricles
PubMed: 36036670
DOI: 10.1093/europace/euac087 -
Pharmacology Research & Perspectives Aug 2021Prolongation of the cardiac action potential (AP) and early after depolarizations (EADs) are electrical anomalies of cardiomyocytes that can lead to lethal arrhythmias...
Prolongation of the cardiac action potential (AP) and early after depolarizations (EADs) are electrical anomalies of cardiomyocytes that can lead to lethal arrhythmias and are potential liabilities for existing drugs and drug candidates in development. For example, long QT syndrome-3 (LQTS3) is caused by mutations in the Na 1.5 sodium channel that debilitate channel inactivation and cause arrhythmias. We tested the hypothesis that a useful drug (i.e., mexiletine) with potential liabilities (i.e., potassium channel inhibition and adverse reactions) could be re-engineered by dynamic medicinal chemistry to afford a new drug candidate with greater efficacy and less toxicity. Human cardiomyocytes were generated from LQTS3 patient-derived induced pluripotent stem cells (hIPSCs) and normal hIPSCs to determine beneficial (on-target) and detrimental effects (off-target) of mexiletine and synthetic analogs, respectively. The approach combined "drug discovery" and "hit to lead" refinement and showed that iterations of medicinal chemistry and physiological testing afforded optimized compound 22. Compared to mexiletine, compound 22 showed a 1.85-fold greater AUC and no detectable CNS toxicity at 100 mg/kg. In vitro hepatic metabolism studies showed that 22 was metabolized via cytochrome P-450, as previously shown, and by the flavin-containing monooxygenase (FMO). Deuterated-22 showed decreased metabolism and showed acceptable cardiovascular and physicochemical properties.
Topics: Animals; Behavior, Animal; Cells, Cultured; Female; Humans; Induced Pluripotent Stem Cells; Liver; Long QT Syndrome; Male; Mexiletine; Mice, Inbred BALB C; Myocytes, Cardiac; Rats, Sprague-Dawley; Seizures; Mice; Rats
PubMed: 34327875
DOI: 10.1002/prp2.828 -
Frontiers in Neurology 2022Non-dystrophic myotonias (NDMs) are skeletal muscle ion channelopathies caused by or mutations. This study aimed to describe the clinical, myopathological, and genetic...
INTRODUCTION
Non-dystrophic myotonias (NDMs) are skeletal muscle ion channelopathies caused by or mutations. This study aimed to describe the clinical, myopathological, and genetic analysis of NDM in a large Chinese cohort.
METHODS
We reviewed the clinical manifestations, laboratory results, electrocardiogram, electromyography, muscle biopsy, genetic analysis, treatment, and follow-up of 20 patients (from 18 families) with NDM.
RESULTS
Cases included myotonia congenita (MC, 17/20) and paramyotonia congenita (PMC, 3/20). Muscle stiffness and hypertrophy, grip and percussion myotonia, and the warm-up phenomenon were frequently observed in MC and PMC patients. Facial stiffness, eye closure myotonia, and cold sensitivity were more common in PMC patients and could be accompanied by permanent weakness. Nine MC patients and two PMC patients had cardiac abnormalities, mainly manifested as cardiac arrhythmia, and the father of one patient died of sudden cardiac arrest. Myotonic runs in electromyography were found in all patients, and seven MC patients had mild myopathic changes. There was no difference in muscle pathology between MC and PMC patients, most of whom had abnormal muscle fiber type distribution or selective muscle fiber atrophy. Nineteen variants were found in 17 MC patients, among which c.795T>G (p.D265E) was a new variant, and two variants were found in three PMC patients. The patients were treated with mexiletine and/or carbamazepine, and the symptoms of myotonia were partially improved.
CONCLUSIONS
MC and PMC have considerable phenotypic overlap. Genetic investigation contributes to identifying the subtype of NDM. The muscle pathology of NDM lacks specific changes.
PubMed: 35350395
DOI: 10.3389/fneur.2022.830707 -
Current Cardiology Reports Sep 2017Ventricular tachycardia occurrence in implantable cardioverter defibrillator (ICD) patients may result in shock delivery and is associated with increased morbidity and... (Review)
Review
PURPOSE OF REVIEW
Ventricular tachycardia occurrence in implantable cardioverter defibrillator (ICD) patients may result in shock delivery and is associated with increased morbidity and mortality. In addition, shocks may have deleterious mechanical and psychological effects. Prevention of ventricular tachycardia (VT) recurrence with the use of antiarrhythmic drugs or catheter ablation may be warranted. Antiarrhythmic drugs are limited by incomplete efficacy and an unfavorable adverse effect profile. Catheter ablation can be effective but acute complications and long-term VT recurrence risk necessitating repeat ablation should be recognized. A shared clinical decision process accounting for patients' cardiac status, comorbidities, and goals of care is often required.
RECENT FINDINGS
There are four published randomized trials of catheter ablation for sustained monomorphic VT (SMVT) in the setting of ischemic heart disease; there are no randomized studies for non-ischemic ventricular substrates. The most recent trial is the VANISH trial which randomly allocated patients with ICD, prior infarction, and SMVT despite first-line antiarrhythmic drug therapy to catheter ablation or more aggressive antiarrhythmic drug therapy. During 28 months of follow-up, catheter ablation resulted in a 28% relative risk reduction in the composite endpoint of death, VT storm, and appropriate ICD shock (p = 0.04). In a subgroup analysis, patients having VT despite amiodarone had better outcomes with ablation as compared to increasing amiodarone dose or adding mexiletine. There is evidence for the effectiveness of both catheter ablation and antiarrhythmic drug therapy for patients with myocardial infarction, an implantable defibrillator, and VT. If sotalol is ineffective in suppressing VT, either catheter ablation or initiation of amiodarone is a reasonable option. If VT occurs despite amiodarone therapy, there is evidence that catheter ablation is superior to administration of more aggressive antiarrhythmic drug therapy. Early catheter ablation may be appropriate in some clinical situations such as patients presenting with relatively slow VT below ICD detection, electrical storms, hemodynamically stable VT, or in very selected patients with left ventricular assist devices. The optimal first-line suppressive therapy for VT, after ICD implantation and appropriate programming, remains to be determined. Thus far, there has not been a randomized controlled trial to compare catheter ablation to antiarrhythmic drug therapy as a first-line treatment; the VANISH-2 study has been initiated as a pilot to examine this question.
Topics: Amiodarone; Anti-Arrhythmia Agents; Catheter Ablation; Defibrillators, Implantable; Electric Countershock; Humans; Randomized Controlled Trials as Topic; Sotalol; Tachycardia, Ventricular; Treatment Outcome
PubMed: 28900864
DOI: 10.1007/s11886-017-0924-0