Comparative efficacy and safety of wenxin granule combined with antiarrhythmic drugs for atrial fibrillation: A protocol for a systematic review and network meta-analysis.

BACKGROUND: The combination of Chinese patent medicine Wenxin Granules (WXG) and antiarrhythmic drugs has been widely used in the treatment of atrial fibrillation (AF), but the results are controversial. This study will conduct a network meta-analysis (NMA) based on data from randomized controlled trials to evaluate the efficacy and safety of WXG combined with ADDs (amiodarone, metoprolol, propafenone, bisoprolol, or other antiarrhythmic drugs) in the treatment of AF, which will perform comparisons or rankings of efficacy among the currently available therapeutic schemes in order to provide evidence to determine the optimal threshold and treatment regimen to AF patients. METHODS AND ANALYSIS: A comprehensive systematic literature search will be conducted in Cochrane Library, PubMed, Web of Science, EMBASE, Chinese Biomedical Literature Database (SinoMed), Chinese National Knowledge Infrastructure (CNKI), and WanFang database for randomized controlled trials about the WXG with ADDs. The NMA will be conducted following the PRISMA-NMA guidelines. Statistical analyses will be conducted by using Stata software (version 14.0) and RevMan software (version 5.3). RESULTS: The results of this NMA will provide a high-quality evidence for the efficacy of WXG combined with ADDs in the treatment of AF, and a ranking of the therapeutic classes will also be presented. CONCLUSION: The protocol will provide updated evidence for the application of WXG for AF.

Evaluation of metoprolol versus diltiazem for rate control of atrial fibrillation in the emergency department.

OBJECTIVE: The purpose of this study was to compare the effectiveness and safety of the metoprolol and diltiazem administration in the Emergency Department (ED) for rate control of supraventricular tachycardia. METHODS: This was a retrospective cohort study of adult patients who presented to the ED with ventricular rates ≥120 beats per minute (bpm) and who received bolus doses of either intravenous metoprolol or intravenous diltiazem. The primary outcome was achievement of rate control, defined as heart rate < 110 bpm, at two hours after administration of the last bolus dose of metoprolol or diltiazem. Safety outcomes included occurrence of hypotension, defined as systolic blood pressure < 90 mmHg or diastolic blood pressure < 60 mmHg, and bradycardia, defined as heart rate < 60 bpm. RESULTS: There were 166 patients receiving metoprolol and 183 patients receiving diltiazem included in the study. The primary outcome, rate control at two hours after the last bolus dose of metoprolol or diltiazem was similar between the two groups (45.8% vs 42.6%, p = 0.590, respectively). The percentage of patients achieving rate control was also similar (47.0% vs 41.6%, p = 0.333) at one hour. At 0.5 h HR had a significantly greater numerical (diltiazem: 29.3 ± 23.1 bpm vs metoprolol: 21.8 ± 18.9 bpm, p = 0.012) and percent decrease (21.1% vs 15.94%, p = 0.014) in the diltiazem group compared to metoprolol. There was no significant difference in occurrence of bradycardia in the two groups (diltiazem: 3.83% vs metoprolol: 1.2%, p = 0.179). More patients in the diltiazem group compared to the metoprolol group experienced hypotension (39.3% vs 23.5%, p = 0.002). The difference in systolic hypotension events was not significantly different (9.29% vs 5.42%, p = 0.221), while the difference in diastolic hypotension events was significantly different (37.7% vs 22.3%, p = 0.002). CONCLUSION: There was no difference in acute rate control effectiveness two hours after the last bolus dose of diltiazem and metoprolol for supraventricular tachycardias. There was a significantly higher occurrence of hypotension in the diltiazem group which was driven by higher rates of diastolic blood pressures less than 60 mmHg.

Amiodarone and/or lidocaine for cardiac arrest: A Bayesian network meta-analysis.

INTRODUCTION: Although available studies have not demonstrated that antiarrhythmic drugs could increase long-term survival or survival with favorable neurological outcome, some studies have shown that the rate of hospital admission is higher with amiodarone or lidocaine than with placebo. To study the effects of antiarrhythmic drugs during cardiac arrest, a meta-analysis was conducted to assess the efficacy of amiodarone and/or lidocaine. METHODS: We searched studies from inception until Jan 21, 2020. The primary endpoint was survival to hospital discharge in cardiac arrest, and the secondary endpoints were survival to hospital admission/24 h and favorable neurological outcome. RESULTS: A total of 9 studies were included. In head-to-head studies, amiodarone (odds ratio [OR] 2.96, 95% credible interval [CrI] 1.02-8.53) and lidocaine (OR 3.12, 95% CrI 1.08-9.98) had superior effects on survival to hospital admission/24 h compared to the combination of the two drugs. In terms of survival to hospital discharge, amiodarone (OR 1.18, 95% CrI 1.03-1.35) and lidocaine (OR 1.22, 95% CrI 1.06-1.41) were more effective than placebo. Amiodarone (OR 1.20, 95% CrI 1.02-1.41) was significantly better than placebo in favorable neurological outcome. However, there was no significant difference in other pairwise comparisons. The surface under cumulative ranking curve (SUCRA) revealed that lidocaine was the most effective therapy for survival to hospital admission (84.1%) and discharge (88.4%), while amiodarone was associated with a more favorable neurological outcome (88.2%). CONCLUSIONS: Lidocaine had the best effect on both survival to hospital admission and discharge, while amiodarone was associated with a more favorable neurological outcome. TRIAL REGISTRATION: This study is registered with PROSPERO, number CRD42020171049.

Esmolol Compared with Amiodarone in the Treatment of Recent-Onset Atrial Fibrillation (RAF): An Emergency Medicine External Validity Study.

BACKGROUND: Recent-onset atrial fibrillation (RAF) is the most frequent supraventricular dysrhythmia in emergency medicine. Severely compromised patients require acute treatment with injectable drugs OBJECTIVE: The main purpose of this external validity study was to compare the short-term efficacy of esmolol with that of amiodarone to treat severe RAF in an emergency setting. METHODS: This retrospective survey was conducted in mobile intensive care units by analyzing patient records between 2002 and 2013. We included RAF with (one or more) severity factors including: clinical shock, angina pectoris, ST shift, and very rapid ventricular rate. A blind matching procedure was used to constitute esmolol group (n = 100) and amiodarone group (n = 200), with similar profiles for age, gender, initial blood pressure, heart rate, severity factors, and treatment delay. The main outcome measure was the percentage of patients with a ventricular rate control defined as heart frequency ≤ 100 beats/min. More stringent (rhythm control) and more humble indicators (20% heart rate reduction) were analyzed at from 10 to 120 min after treatment initiation. RESULTS: Patient characteristics were comparable for both groups: age 66 ± 16 years, male 71%, treatment delay < 1 h 36%, 1-2 h 29%, > 2 h 35%, chest pain 61%, ST shift 62%, ventricular rate 154 ± 26 beats/min, and blood pressure 126/73 mm Hg. The superiority of esmolol was significant at 40 min (64% rate control with esmolol vs. 25% with amiodarone) and for all indicators from 10 to 120 min after treatment onset. CONCLUSION: In "real life emergency medicine," esmolol is better than amiodarone in the treatment of RAF.

Treatment Strategies for Atrial Fibrillation With Left Ventricular Systolic Dysfunction　- Meta-Analysis.

BACKGROUND: Atrial fibrillation (AF) frequently coexists with heart failure (HF) with reduced ejection fraction (EF). This meta-analysis compared AF control strategies, that is, rhythm vs. rate, and catheter ablation (CA) vs. anti-arrhythmic drugs (AAD) in patients with AF combined with HF.Methods and Results:The MEDLINE, EMBASE, and CENTRAL databases were searched, and 13 articles from 11 randomized controlled trials with 5,256 patients were included in this meta-analysis. The outcomes were echocardiographic parameters (left ventricular EF, LVEF), left atrial (LA) size, and left ventricular end-systolic volume, LVESV), clinical outcomes (mortality, hospitalization, and thromboembolism), exercise capacity, and quality of life (QOL). In a random effects model, rhythm control was associated with higher LVEF, better exercise capacity, and better QOL than the rate control. When the 2 different rhythm control strategies were compared (CA vs. AAD), the CA group had significantly decreased LA size and LVESV, and improved LVEF and 6-min walk distance, but mortality, hospitalization, and thromboembolism rates were not different between the rhythm and rate control groups. CONCLUSIONS: In AF combined with HF, even though mortality, hospitalization and thromboembolism rates were similar, a rhythm control strategy was superior to rate control in terms of improvement in LVEF, exercise capacity, and QOL. In particular, the CA group was superior to the AAD group for reversal of cardiac remodeling.

Antiarrhythmic drug therapy during cardiopulmonary resuscitation: should we use it?

PURPOSE OF REVIEW: The optimal antiarrhythmic drug therapy (amiodarone or lidocaine) in the treatment of ventricular fibrillation/pulseless ventricular tachycardia (VF/pVT) cardiac arrest that is refractory to defibrillation is uncertain. This article reviews the evidence for and against these drugs, alternatives treatments for refractory VF/pVT and aims to define the role of antiarrhythmic drugs during cardiopulmonary resuscitation (CPR). RECENT FINDINGS: A large randomized controlled trial that compared amiodarone, lidocaine and saline 0.9% sodium chloride for the treatment of refractory VF/pVT out-of-hospital cardiac arrest reported no difference in survival to hospital discharge or neurological outcome. In patients with witnessed arrest, survival was improved with antiarrhythmic drugs compared to saline. SUMMARY: The benefit of antiarrhythmic drugs appears to be for those patients in whom initial early CPR and defibrillation attempts fail and the antiarrhythmic drug is given early. There does not appear to be any clear survival benefit for any one particular drug and other factors such as availability and cost should be considered when deciding which drug to use. Furthermore, other interventions (e.g. percutaneous coronary intervention and extra-corporeal CPR) may provide additional survival benefit when defibrillation attempts and antiarrhythmic drugs are not effective.

[Which drugs are useful during resuscitation? Which are not?]. / Welche Medikamente sind bei der Reanimation sinnvoll? Welche nicht?

INTRODUCTION: Cardiopulmonary resuscitation represents a therapeutic challenge. Evidence-based guidelines, which were updated in 2015, give detailed advice on how to treat the patient. METHODS: Basic life support consists of cardiopulmonary resuscitation (30 chest compressions interrupted briefly to provide to 2 ventilations) and, if ventricular tachyarrhythmia is present, urgent cardiac defibrillation. Administration of drugs is one of the aspects of advanced life support. Vasopressors (adrenaline, vasopressin) aim to optimize coronary and cerebral perfusion. Antiarrhythmic drugs (amiodarone or lidocaine, when amiodarone is not available) are given during cardiac arrest to treat specific cardiac arrhythmias, mainly ventricular fibrillation and ventricular tachycardia. CONCLUSION: However, even in current guidelines, there is growing ambivalence towards drug treatment in the setting of cardiopulmonary resuscitation. This is mainly due to a paucity of robust clinical data. Most of the studies that have addressed the efficacy and safety of drugs during resuscitation are observational studies; however, a few small randomized controlled studies also exist. Recently, two large randomized controlled studies addressing the efficacy and safety of adrenaline versus placebo and amiodarone or lidocaine versus placebo have started. Both are currently recruiting patients. The hope is that the results of these studies will help to better define the role of drugs administered during cardiopulmonary resuscitation.

[Therapy of inherited diseases of platelet function. Interdisciplinary S2K guideline of the Permanent Paediatric Committee of the Society of Thrombosis and Haemostasis Research (GTH e. V.)]. / Therapie hereditärer Thrombozytopathien. Interdisziplinäre S2K-Leitlinie der Ständigen Kommission Pädiatrie der Gesellschaft für Thrombose- und Hämostaseforschung e. V.

Inherited disorders of platelet function are a heterogeneous group. For optimal prevention and management of bleeding, classification and diagnosis of the underlying defect are highly recommended. An interdisciplinary guideline for a diagnostic approach has been published (AWMF # 086-003 S2K; Hämostaseologie 2014; 34: 201-212). Underlying platelet disorder, platelet count, age and clinical situation modify treatment. Exclusive transfusion of platelet concentrates may be inappropriate as potentially adverse effects can outweigh its benefit. A stepwise and individually adjusted approach for restitution and maintenance of haemostasis is recommended. Administration of antifibrinolytics is generally endorsed, but is of particular use in Quebec disease. Restricted to older children, desmopressin is favourable in storage pool disease and unclassified platelet disorders. Although licensed only for patients with Glanzmann thrombasthenia and alloantibodies, in clinical practice rFVIIa is widely used in inherited platelet disorders with severe bleeding tendency. This guideline aims at presenting the best available advice for the management of patients with inherited platelet function disorders.

Quality by design (QbD) based development and validation of an HPLC method for amiodarone hydrochloride and its impurities in the drug substance.

The USP monograph describes an HPLC method for seven impurities in the amiodarone drug substance using a L1 column, 4.6mm×150mm, 5µm packing (PF listed ODS2 GL-Science, Inertsil column) at 30°C with detection at 240nm. The standard contains 0.01mg/mL of amiodarone, and USP specified impurities D and E with a resolution requirement of NLT 3.5 between peaks D and E. Impurities in a 5mg/mL sample are quantitated against the standard. Impurity A peak elutes just before peak D. We observed two problems with the method; the column lot-to-lot variability resulted in unresolved A, D, and E peaks, and peak D in the sample preparation eluted much later than that in the standard solution. Therefore, optimization experiments were conducted on the USP method following the QbD approach with Fusion AE™ software (S-Matrix Corporation). The resulting optimized conditions were within the allowable changes per USP 〈621〉. Lot-to-lot variability was negligible with the Atlantis T3 (Waters Corporation) L1 column. Peak D retention time remained constant from standard to sample. The optimized method was validated in terms of accuracy, precision, linearity, range, LOQ/LOD, specificity, robustness, equivalency to the USP method, and solution stability. The QbD based development helped in generating a design space and operating space with knowledge of all method performance characteristics and limitations and successful method robustness within the operating space.

[Tachycardiac arrhythmia in children without congenital heart diseases]. / Tachykarde Herzrhythmusstörungen bei Kindern ohne angeborene Herzfehler.

Based on invasive electrophysiological studies and ablation procedures of tachycardias in children and adolescents, the understanding and knowledge of the different tachycardia substrates have significantly increased in recent years. This article describes the underlying pathophysiological mechanisms together with the expected changes in electrocardiogram (ECG) of the four most common types of supraventricular tachycardia in children and adolescents without congenital heart defects: atrioventricular reentrant tachycardia, atrioventricular nodal reentrant tachycardia, focal atrial tachycardia and permanent junctional reentrant tachycardia. Furthermore, idiopathic ventricular tachycardia is described. The incidence, clinical symptoms, natural course and prognosis of each particular tachycardia will be specified . The pharmacological and interventional treatment will be the focus of other reports in this issue. Finally, the current recommendations for the approach to asymptomatic children and adolescents with preexcitation are discussed according to the current guidelines.

Dispersive liquid-liquid microextraction of propranolol enantiomers from human plasma based on the solidification of a floating organic droplet.

BACKGROUND: A dispersive liquid-liquid microextraction based on the solidification of a floating organic droplet was developed and validated for the extraction of propranolol enantiomers from human plasma. The studied enantiomers were extracted from diluted and alkalized plasma samples using 1-undecanol as the extracting solvent. HPLC-fluorescence detection analyses were carried out on a chiral column, using n-hexane-ethanol (80:20, v/v) plus 0.2% triethylamine as the mobile phase, at a flow rate of 0.8 ml/min. The significant factors in the microextraction procedure, including extracting and disperser solvents volume, solution pH and salt contents were optimized by using a central composite design and the response surface methodology. RESULTS: Under optimized conditions, the mean recoveries were approximately 14% with linear responses over the 0.5-100 ng/ml concentration range for both enantiomers. The LOQ was 0.5 ng/ml (S/N = 10). Intra-day (n = 5) and inter-day (n = 3) assay precision (1 and 50 ng/ml) showed RSD lower than 8 and 9.5% for studied enantiomers, respectively. Finally, the method was successfully used for the determination of propranolol enantiomers in plasma samples obtained after single drug administration of racemic propranolol tablet to three healthy volunteers. The plasmatic concentrations of (-)-(S)-PROP were higher than those of (+)-(R)-PROP in all times after oral administration of the racemic drug. CONCLUSION: The obtained results proved that the proposed method is a powerful technique for sample preparation, providing suitable recoveries, efficient cleanup, high selectivity and sensitivity and low consumption of organic solvent for determination of the studied enantiomers in plasma samples after oral administration of the racemic drug to volunteers.

Tablet splitting and weight uniformity of half-tablets of 4 medications in pharmacy practice.

BACKGROUND: Tablet splitting is a common practice for multiple reasons including cost savings; however, it does not necessarily result in weight-uniform half-tablets. OBJECTIVES: To determine weight uniformity of half-tablets resulting from splitting 4 products available in the Jordanian market and investigate the effect of tablet characteristics on weight uniformity of half-tablets. METHODS: Ten random tablets each of warfarin 5 mg, digoxin 0.25 mg, phenobarbital 30 mg, and prednisolone 5 mg were weighed and split by 6 PharmD students using a knife. The resulting half-tablets were weighed and evaluated for weight uniformity. Other relevant physical characteristics of the 4 products were measured. RESULTS: The average tablet hardness of the sampled tablets ranged from 40.3 N to 68.9 N. Digoxin, phenobarbital, and prednisolone half-tablets failed the weight uniformity test; however, warfarin half-tablets passed. Digoxin, warfarin, and phenobarbital tablets had a score line and warfarin tablets had the deepest score line of 0.81 mm. CONCLUSION: Splitting warfarin tablets produces weight-uniform half-tablets that may possibly be attributed to the hardness and the presence of a deep score line. Digoxin, phenobarbital, and prednisolone tablet splitting produces highly weight variable half-tablets. This can be of clinical significance in the case of the narrow therapeutic index medication digoxin.

Regulatory pathways for development of antiarrhythmic drugs for management of atrial fibrillation/flutter.

New antiarrhythmic drugs are urgently required for the treatment of atrial fibrillation (AF), an increasingly common sustained cardiac arrhythmia seen predominantly in the elderly population. Pharmaceutical companies are generally interested in this important group of patients and a relatively large number of antiarrhythmic agents are under development for several indications relating to AF, predominantly rhythm and rate management. Because of the significant clinical consequences of the arrhythmia, it has been recognized that controlled trials in patients with AF should assess the effect of therapy in several major outcome domains such as mortality, morbidity, and hospitalization, with an emphasis on stroke and heart failure. As part of a regular series of meetings, the European Society of Cardiology recently met with European regulators and representatives of the pharmaceutical industry to review the current status of medical therapies for AF. Special attention has been paid to the debate on the relevant clinical endpoints in future AF trials and their implications for drug indications. The need for large-scale major cardiovascular outcome and comparator studies for the approval of drugs designed to manage rhythm and/or control the rate has been discussed. The requirements for appropriate ancillary studies, including quality of life and left ventricular function assessment and cost-effectiveness analysis, have been identified. This article reports the discussions that were held.

Ivabradine, a novel heart rate slower: is it a sword of double blades in patients with idiopathic dilated cardiomyopathy?

OBJECTIVE: To prospectively assess the safety and efficacy of ivabradine in patients with idiopathic dilated cardiomyopathy. METHODS: We included 35 patients with idiopathic dilated cardiomyopathy with an ejection fraction (EF) <40% and heart rate >70 beats/min despite optimal medical therapy, according to the international guidelines in this prospective, non-randomized, single-arm, open-label safety study. Ivabradine was used as an add-on therapy to the maximally tolerated b-blocker in an increasing titrated dose till a target dose of 15 mg/day or resting heart rate of 60 beats/min for 3 months. During follow-up period the safety, patient tolerance and efficacy of this drug were assessed. All patients underwent 12-lead resting electrocardiography and Holter monitoring at inclusion and after 3 months. Statistical analysis was accomplished using paired t-test and Pearson correlation analysis. RESULTS: We found a significant reduction in the resting heart rate by a mean of 25.9 ± 9.4%, without a significant change of blood pressure. There was no prolongation of PR, QTc or QRS durations. Ventricular ectopic activity showed significant reduction (p<0.001). There was a significant correlation between the resting heart rate, NYHA and left ventricular ejection fraction (p<0.001 for both). One patient developed photopsia and decompensation was observed in another patient. CONCLUSION: Ivabradine is a safe and effective drug in reducing resting heart rate, improving NYHA functional class without undesirable effects on conduction parameters or ectopic activity.

Vernakalant hydrochloride: A novel atrial-selective agent for the cardioversion of recent-onset atrial fibrillation in the emergency department.

OBJECTIVES: Vernakalant is a relatively atrial-selective antiarrhythmic agent that has been shown to successfully convert atrial fibrillation (AF) to normal sinus rhythm for some patients whose onset of dysrhythmia occurred less than 7 days previously. This study sought to evaluate the efficacy and safety of vernakalant for patients with recent-onset AF. METHODS: This was a post hoc analysis of patients with recent-onset AF (> 3 to ≤ 48 hours) enrolled in the double-blind, placebo-controlled Atrial arrhythmia Conversion Trial (ACT) I and the open-label ACT IV trials. The studies enrolled adults presenting with AF to 78 emergency departments (ED) and cardiac clinics in six countries. Patients received a 10-minute intravenous infusion of vernakalant or placebo, followed by an additional infusion if necessary. Efficacy assessments included conversion to sinus rhythm within 90 minutes and median time to conversion. Safety evaluations included telemetry, Holter monitoring, and adverse events (AEs). RESULTS: Of the 290 patients, 229 received vernakalant, 61 received placebo, and the overall mean age was 59 years. The vernakalant and placebo groups were similar. Of all patients given vernakalant, 136 (59.4%) converted to sinus rhythm within 90 minutes, compared with three (4.9%) placebo patients. The median time to conversion with vernakalant was 12 minutes (interquartile range = 7-24.5 minutes). Clinically significant bradycardia and hypotension were uncommon, and no cases of torsade de pointes or ventricular fibrillation occurred. CONCLUSIONS: Vernakalant rapidly converted recent-onset AF to sinus rhythm in over half of patients, was well tolerated, and has the potential to offer an important therapeutic option for rhythm control of recent-onset AF in the ED.