Sotalol Group Research Articles

Bleeding Associated With Antiarrhythmic Drugs in Patients With Atrial Fibrillation Using Direct Oral Anticoagulants: A Nationwide Population Cohort Study.

This study investigated drug-drug interactions in patients with atrial fibrillation taking both a direct oral anticoagulant (DOAC) and an antiarrhythmic drug. Using data from the National Health Insurance database (2012-2018), we identified 78 805 patients with atrial fibrillation on DOACs, with 24 142 taking amiodarone, 8631 taking propafenone, 2784 taking dronedarone, 297 taking flecainide, 177 taking sotalol, and 42 772 on DOACs alone. Patients with bradycardia, heart block, heart failure, mitral stenosis, prosthetic valves, or incomplete data were excluded. Propensity score matching compared those taking both DOACs and antiarrhythmic drugs with those on DOACs alone. There was an increased risk of major bleeding in patients concomitantly taking DOACs with amiodarone when compared with matched patients taking DOACs alone (hazard ratio [HR],1.13 [95% CI, 1.04-1.23]; P=0.0044), particularly in patients taking dabigatran (HR, 1.19 [95% CI, 1.03-1.38]; P=0.0175). No significant difference in bleeding risk was found for propafenone, dronedarone, flecainide, or sotalol. The small sample sizes in the flecainide and sotalol groups limit interpretation. Notably, intracranial bleeding risk was higher in patients on DOACs and amiodarone, regardless of age. Additionally, patients <80 years old taking dabigatran with amiodarone or propafenone had a higher risk of gastrointestinal bleeding. Concomitant use of DOACs with amiodarone, but not dronedarone or propafenone, increases the risk of major bleeding, particularly intracranial bleeding. This study provides new evidence to guide clinicians to tailor concomitant anticoagulation and antiarrhythmic therapy for patients with atrial fibrillation.

Comparative analysis of antiarrhythmic drugs following atrial fibrillation ablation

Abstract Background Atrial fibrillation (AF) ablation has become an established therapeutic modality for rhythm control. However, the optimal post-ablation pharmacological strategy remains uncertain. The present study addresses this gap by conducting a comparative analysis of four commonly used antiarrhythmic drugs (amiodarone, propafenone, sotalol, and flecainide), both as standalone treatments and in combination with beta blockers, to determine their impact on mortality, hospitalization rates, and AF recurrence. Methods A multi-center, retrospective cohort study was conducted, including patients who underwent successful AF ablation between 20010 to 2020. The study population was divided into groups based on the prescribed antiarrhythmic drug regimen: amiodarone, propafenone, sotalol, flecainide, and respective combinations with beta blockers. Patient demographics, comorbidities, and procedural details were collected. Endpoints included all-cause mortality, hospitalization due to cardiovascular events, MACE and AF recurrence. Results A total of 908 patients were included in this study. The mean age was 66 years old, and 33% (n=297) were female patients. Of 908 patients, 35% (n=316) were prescribed amiodarone, 34% (n=305) propafenone, 8% (n=76) sotalol, and 6%% (n=51) flecainide post AF ablation. Association with beta blockers were observed in 55% (n=496) of cases. Amiodarone group had a 0,3% (n=1) mortality, 9% (n=27) of hospitalizations, 2% (n=5) of major cardiovascular events (MACE) and 32% (n=101) of AF recurrence. Propafenone group had a 1,3% (n=4) mortality, 4% (n=12) hospitalizations, 2% (n=5) of MACE and 27% (n=81) of AF recurrence. Sotalol group had a 4% (n=3) mortality, 6% (n=4) of hospitalizations, 3% (n=2) of MACE and 44% (n=32) of AF recurrence. Flecainide group had 0 cases of death, 2% (n=1) of hospitalization, 0 cases of MACE and 35% of recurrence. Amiodarone is associated with a lower risk of death (p=0,018 OR 0,13). The presence of betablockers did not affect the endpoints, namely, death, hospitalization, MACE or AF recurrence. There were no other statistically significant associations between variables. Conclusion This study evaluated the effectiveness of common antiarrhythmics, such as amiodarone, propafenone, sotalol, and flecainide, with and without beta blockers, in the post-AF ablation setting. In this study, amiodarone showed a lower risk of death. There were no other statistically significant associations between either antiarrhythmic drug and each endpoint. The presence of betablocker therapy did not interfere with the endpoints. The findings contribute to the ongoing discourse on the optimal pharmacological strategy for AF management post-ablation. Further prospective studies with larger sample sizes are warranted to validate and refine these observations, paving the way for evidence-based guidelines in tailoring antiarrhythmic drug regimens for improved patient outcomes

The effect of antiarrhythmic medications on the risk of cardiovascular outcomes in patients with atrial fibrillation and coronary artery disease

BackgroundWhile current guidelines recommend amiodarone and dronedarone for rhythm control in patients with atrial fibrillation (AF) and coronary artery disease (CAD), there was no comparative study of antiarrhythmic drugs (AADs) on the cardiovascular outcomes in general practice. MethodsThis study included patients with AF and CAD who received their first prescription of amiodarone, class Ic AADs (flecainide, propafenone), dronedarone or sotalol between January 2016 and December 2020. The primary outcome was a composite of hospitalization for heart failure (HHF), stroke, acute myocardial infarction (AMI), and cardiovascular death. We used Cox proportional regression models, including with inverse probability of treatment weighting (IPTW), to estimate the relationship between AADs and cardiovascular outcomes. ResultsAmong the AF cohort consisting of 8752 patients, 1996 individuals had CAD, including 477 who took dronedarone and 1519 who took other AADs. After a median follow-up of 38 months, 46.3% of patients who took dronedarone and 54.4% of patients who took other AADs experienced cardiovascular events. Compared to dronedarone, the use of other AADs was associated with increased cardiovascular events after adjusting for covariates (hazard ratio [HR] 1.531, 95% confidence interval [CI] 1.112–2.141, p = 0.023) and IPTW (HR 1.491, 95% CI 1.174–1.992, p = 0.012). The secondary analysis showed that amiodarone and class Ic drugs were associated with an increased risk of HHF. The low number of subjects in the sotalol group limits data interpretation. ConclusionFor patients with AF and CAD, dronedarone was associated with better cardiovascular outcomes than other AADs. Amiodarone and class Ic AADs were associated with a higher risk of cardiovascular events, particularly HHF.

Factors influencing early recurrence of atrial fibrillation among elderly patients following radiofrequency catheter ablation and the impact of different antiarrhythmic regimens.

Patients with atrial fibrillation (AF) who undergo radiofrequency catheter ablation (RFCA) necessitate the administration of antiarrhythmic drugs to prevent early recurrence. The clinical outcomes among these patients may be influenced by varying antiarrhythmic regimens. To identify the risk factors associated with early recurrence and compare the clinical outcomes among different antiarrhythmic regimens in elderly patients with AF following radiofrequency catheter ablation (RFCA) during a 3-month period. A retrospective observational study encompassed 420 elderly patients with AF following RFCA. Baseline data were collected during the initial postoperative visit and clinical outcomes were carefully monitored over a 3-month follow-up period. Logistic regression and Cox-proportional hazard regression analyses were performed to investigate the relationship between various antiarrhythmic regimens and the clinical outcomes. Multivariate logistic regression analysis revealed that age (p = 0.001), left atrial diameter (p < 0.001), left ventricular diameter (p = 0.015), reactive hyperemia index (RHI) (p < 0.001), antiarrhythmic drug (p < 0.001) and hs-cTnI (p = 0.017) were independent risk factors of early recurrence. Furthermore, in cox survival regression analysis model, survival rate of early recurrence in the amiodarone group was higher than in the propafenone group (HR 2.30, 95%CI 1.17-4.53, p = 0.016) and in the sotalol group (HR 3.60, 95%CI 2.17-5.95, p < 0.001). Compared to the amiodarone group, the incidence of liver dysfunction was lower in the dronedarone group (p = 0.046) and the propafenone group (p = 0.021). The incidence of bradyarrhythmia (p = 0.003), QT interval prolongation (p = 0.035) and atrioventricular transmission block (p = 0.021) were higher in the sotalol group than in the amiodarone group. RHI was identified as an independent risk factor for early recurrence among elderly AF patients after RFCA. Compared to amiodarone, propafenone and sotalol exhibited an elevated risk of early recurrence. Although there was no significant difference in early recurrence between amiodarone and dronedarone, dronedarone emerged as the preferred option due to its lower frequency of adverse drug reactions than amiodarone.

Mortality and ventricular arrhythmias in patients with atrial fibrillation on sotalol

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Karolinska Institue at Stockholm South hospital. Background In atrial fibrillation (AF), anti-arrhythmic drugs are an option for rhythm control. Guidelines regarding treatment with sotalol varies worldwide. The risk of serious adverse events in AF patients on sotalol is estimated from small studies, with short follow-up, not designed for mortality analysis. Purpose To evaluate mortality in patients with a rhythm control strategy for AF. Methods In Swedish registries, 7473 sotalol-treated and 107255 patients on betablockers underwent cardioversion or were diagnosed with paroxysmal AF between 2006 and 2017. Mortality and ventricular arrhythmias were estimated in unadjusted, and propensity score matched cohorts. Results Mean follow up was 474 (SD 599) and 481 (SD 515) days in sotalol/betablocker respectively. Crude all-cause mortality was lower in the sotalol group (HR 0.3 CI 0.3-0.4), also in multi-adjusted analysis (HR 0.6 CI 0.5-0.6). In the propensity-matched comparison, HR remained lower on sotalol (0.6 CI 0.5-0.7). Ventricular arrhythmias were more common among patients on sotalol (1.5 vs 1,0%, p&amp;lt;0,001. 1,1% vs 0,8%/100 personyears). There were no significant differences in CPR or sudden cardiac death. Conclusions This real-world data did not show increased mortality in sotalol-treated patients. Ventricular arrhythmias were relatively rare. Careful patient selection and follow-up probably reduce the proarrhythmic risk during sotalol-treatment.

Safe electrophysiologic profile of the neprilysin-inhibitor sacubitril in combination with different antiarrhythmic drugs

Abstract Background Observational clinical data suggest a direct effect of sacubitril on cardiac electrophysiology. However, data concerning the impact of combination of sacubitril with antiarrhythmic drug therapy is sparse. Purpose We aimed at characterizing the electrophysiologic effects of a combination therapy of sacubitril with the class III-drug sotalol and the class IB-agent mexiletine in a sensitive, experimental whole-heart model. Methods and results 25 isolated rabbit hearts were retrogradely perfused. Hearts were treated with mexiletine (25 μM, 13 hearts) or sotalol (100 μM, 12 hearts) after generating baseline data. Eight endo- and epicardial monophasic action potentials and ECG recordings demonstrated an abbreviation of action potential duration (APD90, −21 ms, p&amp;lt;0.01) and no significant changes of QT interval (+10ms, p=ns) after administration of mexiletine. Spatial dispersion of repolarization (SDR) remained stable after mexiletine treatment (+6 ms, p=ns) whereas effective refractory periods (ERP) were significantly prolonged (+80 ms, p&amp;lt;0.01). Sotalol prolonged cardiac repolarization (APD90: +1 ms, p=ns; QT: +24 ms, p&amp;lt;0.01) and amplified spatial dispersion (+19 ms, p&amp;lt;0.01) without changing ERP (+8 ms, p=ns). Additional treatment with sacubitril (5 μM) led to a significant reduction of APD90 (−12 ms, p&amp;lt;0.01), QT interval (−20 ms, p&amp;lt;0.01) and ERP (−23 ms, p&amp;lt;0.01) in the presence of a stable SDR (−4 ms, p=ns) in the mexiletine group. In the sotalol group, additional administration of sacubitril abbreviated APD90 (−9 ms, p&amp;lt;0.05) and QT interval (−13 ms, p&amp;lt;0.01) and reduced ERP (−18 ms, p&amp;lt;0.01) without affecting SDR (−3 ms, p=ns). Ventricular vulnerability was assessed by a predefined pacing protocol employing premature extra stimuli and burst stimulation. After lowering the potassium concentration, 30 episodes of torsade de pointes tachycardia were observed after sotalol treatment (vs. 0 episodes under baseline, p&amp;lt;0.05). Additional sacubitril treatment significantly suppressed torsade de pointes tachycardia (8 episodes, p&amp;lt;0.05) in the sotalol-group. No proarrhythmic effect was observed after mexiletine treatment (8 episodes vs. 3 episodes under baseline conditions, p=ns). Additional sacubitril treatment did not increase ventricular vulnerability (32 episods, p=ns). Conclusion Sacubitril in combination with antiarrhythmic drugs demonstrates a safe electrophysiologic profile. In class IB- and class III-pretreated hearts, sacubitril abbreviates cardiac repolarization duration and effective refractory periods without changing spatial dispersion of repolarization. Thereby, sacubitril reduces the occurrence of torsade de pointes-tachycardia in antiarrhythmic pretreated hearts. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Deutsche Stiftung für Herzforschung (to G.F.)

Effect of Alpinia Officinarum Rhizome Extract on Fertility and Sexual Behavior of Adult Male Albino Rats Treated with Sotalol

Background: Infertility in cardiovascular patients is not only attributed to pathogenesis of the disease but, also to the used therapeutic drugs. Beta blockers which are corner stone in treatment of these patients are reported to affect fertility and sexual behavior in patients using them. Alpinia officinarum (A. officinarum) rhizome extracts are widely used for their antioxidant and anti-inflammatory effects to improve oxidative stress which affects organs due to using different drugs or pathogenesis of different diseases. Objective: The current work aimed to study effect of Alpinia officinarum rhizome extract on improving the reproductive function and sexual behavior of adult male Albino rat treated with Sotalol. Materials and Methods: Fifty adult male Albino rats were categorized into five groups. Group I control, group II (A. officinarum group) received A. officinarum extract at a dose of 200mg/kg/day in olive oil orally by gastric tube for 21 days, group III (Sotalol group) received Sotalol at a dose of 3mg/kg/day orally by gastric tube for 21 days, group IV (protected group) received the extract then Sotalol and group V (treated group) received Sotalol then the extract. Then fifty adult female rats were used for assessment of sexual behavior through observing mount latency and frequency. Results: Sotalol induced testicular destruction in the form of shedding of germinal epithelium, hyaline deposition, decreased sperm count with decreased testosterone level, increased oxidative stress in the form of decreased Serum superoxide dismutase (SOD) level and increased Serum malondialdehyde (MDA) level. Deterioration of sexual behavior in the form of increased mount latency and decreased mount frequency was noticed in the Sotalol group. A. officinarum extract produced a great preservation of testicular structure and sexual behavior in the protected group (IV) together with improvement in the treated group (V). Conclusion: Sotalol induced destructive effects on the testicular structure, function and sexual behavior which were greatly improved by using A. officinarum extract.

Risk of interstitial lung disease in patients treated for atrial fibrillation with dronedarone versus other antiarrhythmics.

PurposeTo compare risks of interstitial lung disease (ILD) between patients treated with dronedarone versus other antiarrhythmics.MethodsParallel retrospective cohort studies were conducted in the United States Department of Defense Military Health System database (DoD) and the HealthCore Integrated Research Database (HIRD). Study patients were treated for atrial fibrillation (AF) with dronedarone, amiodarone, sotalol, or flecainide. Propensity score matching was employed to create analysis cohorts balanced on baseline variables considered potential confounders of treatment decisions. The study period of July 20, 2008 through September 30, 2014 included a 1‐year baseline and minimum 6 months of follow‐up, for patients with drugs dispensed between July 20, 2009 and March 31, 2014. Suspect ILD outcomes were reviewed by independent adjudicators. Cox proportional hazards regression compared risk of confirmed ILD between dronedarone and each comparator cohort. A sensitivity analysis examined the effect of broadening the outcome definition.ResultsA total 72 ILD cases (52 DoD; 20 HIRD) were confirmed among 27 892 patients. ILD risk was significantly higher among amiodarone than dronedarone initiators in DoD (HR = 2.5; 95% CI = 1.1–5.3, p = 0.02). No difference was detected in HIRD (HR = 1.0; 95% CI = 0.4–2.4). Corresponding risks in sotalol and flecainide exposure groups did not differ significantly from dronedarone in either database.ConclusionsILD risk among AF patients initiated on dronedarone therapy was comparable to or lower than that of amiodarone initiators, and similar to that of new sotalol or flecainide users. This finding suggests that elevated ILD risk associated with amiodarone does not necessarily extend to dronedarone or other antiarrhythmic drugs.

Comparative clinical outcomes of dronedarone and sotalol in Asian patients with atrial fibrillation: a nationwide cohort study

We aimed to evaluate the effectiveness and safety of dronedarone versus sotalol in real-world practice in Asian patients with atrial fibrillation (AF). Using the Korean nationwide claims database from August 2013 to December 2016, we identified patients with AF recently prescribed dronedarone or sotalol and analyzed the hospitalization risk and all-cause death until December 2017. Overall, 3119 and 1575 patients treated with dronedarone and sotalol, respectively, were included. After propensity score weighting, no significant differences were observed between the treatment groups. Dronedarone use was associated with a lower risk of all-cause hospitalization than sotalol use (hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.70–0.88). The dronedarone group demonstrated a significantly lower risk of cardiovascular (CV) hospitalization than the sotalol group (HR 0.62, 95% CI 0.53–0.72); however, no significant difference was observed in non-CV hospitalization. No difference in the risk of all-cause death was observed between groups. The dronedarone group was significantly less likely to receive nonpharmacological treatment for AF than the sotalol group (HR 0.63, 95% CI 0.51–0.77). In a large-scale population of Asian patients with AF, dronedarone was associated with a lower risk of CV hospitalization and a lower need for nonpharmacological treatment for AF than sotalol.

Effect of sotalol on heart rate, QT interval, and atrial fibrillation cycle length in horses with atrial fibrillation.

BackgroundBased on its pharmacokinetic profile and electrophysiological effects in healthy horses, sotalol potentially could be used as a long‐term PO antiarrhythmic drug in horses.ObjectivesTo evaluate the effect of sotalol on heart rate (HR), QT interval, atrial fibrillatory rate, and success of cardioversion in horses with naturally occurring chronic atrial fibrillation (AF).AnimalsTwenty‐eight horses referred for transvenous electrical cardioversion of AF were treated with 2 mg/kg sotalol PO q12h for 3 days before cardioversion, and 13 horses underwent the same protocol without sotalol administration.MethodsRetrospective study. Before and after sotalol or no treatment, the HR was measured at rest and during an exercise test. The QT interval and atrial fibrillation cycle length (AFCL) were measured at rest using tissue Doppler velocity imaging.ResultsIn the control group, no significant differences were found between the 2 examinations. In the sotalol group, the HR at rest and during exercise was significantly lower after sotalol treatment, whereas the QT interval and AFCL measured by tissue Doppler increased significantly. Cardioversion to sinus rhythm was achieved in 25/28 horses in the sotalol group and all horses in the control group, but the median number of shocks and energy at cardioversion were significantly lower in the sotalol group.Conclusions and Clinical ImportanceIn horses with AF, sotalol administration results in class III antiarrhythmic effects and β‐blocking activity, with moderate HR reduction during exercise.

Wenxin Keli versus Sotalol for Paroxysmal Atrial Fibrillation Caused by Hyperthyroidism: A Prospective, Open Label, and Randomized Study.

We aimed to compare effectiveness of Wenxin Keli (WK) and sotalol in assisting sinus rhythm (SR) restoration from paroxysmal atrial fibrillation (PAF) caused by hyperthyroidism, as well as in maintaining SR. We randomly prescribed WK (18 g tid) or sotalol (80 mg bid) to 91 or 89 patients. Since it was not ethical not to give patients antiarrhythmia drugs, no control group was set. Antithyroid drugs were given to 90 patients (45 in WK group, 45 in sotalol group); 131I was given to 90 patients (46 in WK group, 44 in sotalol group). Three months later, SR was obtained in 83/91 or 80/89 cases from WK or sotalol groups (P = 0.762). By another analysis, SR was obtained in 86/90 or 77/90 cases from 131I or ATD groups (P = 0.022). Then, we randomly assigned the successfully SR-reverted patients into three groups: WK, sotalol, and control (no antiarrhythmia drug was given) groups. After twelve-month follow-up, PAF recurrence happened in 1/54, 2/54, and 9/55 cases, respectively. Log-Rank test showed significant higher PAF recurrent rate in control patients than either treatment (P = 0.06). We demonstrated the same efficacies of WK and sotalol to assist SR reversion from hyperthyroidism-caused PAF. We also showed that either drug could maintain SR in such patients.

Antiarrhythmic Effect of Ranolazine in Combination with Class III Drugs in an Experimental Whole‐Heart Model of Atrial Fibrillation

Ranolazine is evaluated for antiarrhythmic therapy of atrial fibrillation (AF). The electrophysiologic mechanisms of ranolazine in combination with class III drugs were studied in an isolated whole-heart model of stretch-related AF. Thirty rabbits were fed with amiodarone (50mg/kg/day, n=10), dronedarone (50mg/kg/day, n=10), or placebo (n=10) for 6weeks. Subsequently, in isolated hearts, AF was induced by high-rate atrial pacing and acute atrial dilatation. In placebo-treated hearts, d,l-sotalol (50μM) was acutely administered. Ranolazine (10μM) was additionally infused in all groups. Chronic amiodarone (+26±7ms, P<0.05) or dronedarone (+22±4ms, P<0.05) as well as acute application of d,l-sotalol (+20±3ms, P<0.05) increased atrial action potential duration (aAPD90 ). Additional treatment with ranolazine did not significantly change aAPD90 (P=ns). Class III drugs did not affect interatrial conduction time, while ranolazine significantly increased it (amiodarone group: +15±3ms, dronedarone group: +11±3ms, sotalol group: +15±6ms; P<0.05 each). Ranolazine led to an additional increase in atrial effective refractory period (aERP), thus leading to an enhanced atrial postrepolarization refractoriness (aPRR, +17±6ms, +21±4ms and +16±8ms, P<0.05, respectively). Acute atrial dilatation increased AF incidence compared with baseline. Amiodarone-pretreated hearts showed a lower incidence of AF. Additional infusion of ranolazine further diminished AF. Dronedarone or acute infusion of sotalol did not significantly suppress AF, while additional treatment with ranolazine in these groups also reduced AF incidence. In this study, ranolazine on top of class III antiarrhythmic therapy had a beneficial effect. The increase in interatrial conduction time and marked atrial aPRR suppressed AF. These results shed further light on a potential therapeutic benefit of ranolazine on top of conventional antiarrhythmic therapy for rhythm control in AF.

Arrhythmogenic right ventricular cardiomyopathy in boxer dogs: a retrospective study of survival

The aim of the present study was to retrospectively evaluate survival in a population of 62 boxer dogs with arrhythmogenic right ventricular cardiomyopathy (ARVC), without left ventricular systolic failure, based...

First Direct Comparison of the Late Sodium Current Blocker Ranolazine to Established Antiarrhythmic Agents in an Ischemia/Reperfusion Model

There are few safe antiarrhythmics for ischemic heart disease. Whereas ranolazine is a promising late INa blocker with antiarrhythmic effects, and devoid of pro-arrhythmic properties, there are no direct comparisons between ranolazine and other antiarrhythmic agents in an ischemia/reperfusion setting. HYPOTHESIS AND METHODS: To determine whether ranolazine was as effective as sotalol and lidocaine to reduce ischemia/reperfusion-induced arrhythmias, anesthetized rats were subjected to 5 minutes of proximal left coronary artery occlusion plus 5 minutes of reperfusion, which causes severe ventricular arrhythmias. At 21 minutes prior to coronary occlusion, rats (n = 20 per group) were randomized to receive either sotalol (intravenous [IV] bolus 5 mg/kg, 10 mg/kg per hour infusion), lidocaine (IV bolus 2.5 mg/kg, 2.5 mg/kg/hr infusion), ranolazine (IV bolus 3.3 mg/kg, 3.2 mg/kg per hour infusion), or saline (control). The incidence of ventricular arrhythmias in the sotalol (S), lidocaine (L), ranolazine (R), and control (C) groups was 7/20, 10/20, 9/20, and 16/20, respectively (P = .01 S vs C, P = .10 L vs C, and P = .048 R vs C). Duration of ventricular tachycardia (VT) episodes was reduced from 15.5 seconds (mean) in C to 1.3 seconds in S, 1.4 sec in L and 0.09 sec in R (P < .05 for S vs C and R vs C by Wilcoxon test). The number of rats with any (≥ 10 seconds) sustained VT was 3 in C versus 1, 0, and 0 in the S, L, and R groups, respectively. Two rats in C had reversible ventricular fibrillation versus 0 in the S, L, and R groups. The number of ventricular premature beats (VPBs) per rat was 10.9 in C, 2.3 in S, 4.9 in L, and 5.7 in R (P < .05 for S, L, or R vs C). P = NS for R versus L or S for all analyses. In this first head-to-head comparison of R vs other antiarrhythmic agents at therapeutic doses in an ischemia/reperfusion model, ranolazine (which lacks pro-arrhythmic effects) was as effective as either sotalol or lidocaine to reduce reperfusion-induced ventricular arrhythmias.

Identifying Drug-Induced Repolarization Abnormalities from Distinct ECG Patterns in Congenital Long QT Syndrome

The electrocardiographic QT interval is used to identify drugs with potential harmful effects on cardiac repolarization in drug trials, but the variability of the measurement can mask drug-induced ECG changes. The use of complementary electrocardiographic indices of abnormal repolarization is therefore warranted. Most drugs associated with risk are inhibitors of the rapidly activating delayed rectifier potassium current (I(Kr)). This current is also inhibited in the congenital type 2 form of the long QT syndrome (LQT2). It is therefore possible that electrocardiographic LQT2 patterns might be used to identify abnormal repolarization patterns induced by drugs. To develop distinct T-wave morphology parameters typical of LQT2 and investigate their use as a composite measure for identification of d,l-sotalol (sotalol)-induced changes in T-wave morphology. Three independent study groups were included: a group of 917 healthy subjects and a group of 30 LQT2 carriers were used for the development of T-wave morphology measures. The computerized measure for T-wave morphology (morphology combination score, MCS) was based on asymmetry, flatness and notching, which are typical ECG patterns in LQT2. Blinded to labels, the new morphology measures were tested in a third group of 39 healthy subjects receiving sotalol. Over 3 days the sotalol group received 0, 160 and 320 mg doses, respectively, and a 12-lead Holter ECG was recorded for 22.5 hours each day. Drug-induced prolongation of the heart rate corrected QT interval (QTcF) was compared with changes in the computerized measure for T-wave morphology. Effect sizes for QTcF and MCS were calculated at the time of maximum plasma concentrations and for maximum change from baseline. Accuracy for separating baseline from sotalol recordings was evaluated by area under the receiver operating characteristic curves (AUCs) using all recordings from the time immediately post-dose to maximum change. MCS separated baseline recordings from sotalol treatment with higher accuracy than QTcF for the 160 mg dose: (AUC) 84% versus 72% and for the 320 mg dose: (AUC) 94% versus 87%, p < 0.001. At maximum serum-plasma concentrations and at maximum individual change from baseline, the effect sizes for QTcF were less than half the effect sizes for MCS, p < 0.001. Effect sizes at peak changes of the mean were up to 3-fold higher for MCS compared with QTcF, p < 0.001. In subjects receiving sotalol, T-wave morphology reached similarity to LQT2, whereas QTcF did not. Distinct ECG patterns in LQT2 carriers effectively quantified repolarization changes induced by sotalol. Further studies are needed to validate whether this measure has general validity for the identification of drug-induced disturbed repolarization.

Cost of Hospital Admission for Antiarrhythmic Drug Initiation in Atrial Fibrillation

Initiation of some rhythm-control therapies for atrial fibrillation (AF) requires an inpatient hospital stay and telemetry monitoring, adding to the cost burden of AF. However, specific cost data for inpatient initiation of AF therapies are lacking. To examine costs associated with initiating sotalol or dofetilide in the inpatient setting in the US. This retrospective cohort study used data from billing/discharge records in the Premier Perspective Database for adults with a primary diagnosis of AF, hospitalized between January 2002 and September 2007. Patients had to have received 4 or more sotalol doses or 5 or more dofetilide doses starting within 2 days of admission (with >/=1 dose within 3 days of discharge). Patients admitted solely for AF drug initiation were identified by excluding patients who were admitted on an emergency basis, received care in the emergency department, or underwent major surgical procedures. The primary outcome was direct medical costs for in-hospital services during the stay. Among 7290 patients included in the analysis (4847 sotalol, 2443 dofetilide), mean total inpatient costs per patient were $3278 in the sotalol group and $3610 in the dofetilide group. The greatest costs were for room/board ($1874 sotalol, $1985 dofetilide) and cardiology/electrocardiograms ($394 sotalol, $443 dofetilide). Pharmacy costs were $230 and $201 per patient in the sotalol and dofetilide groups, respectively. The admission of patients for in-hospital initiation of AF rhythm-control therapy represents a high cost burden in the US.

D,l-Sotalol Reverses Abbreviated Atrial Refractoriness and Prevents Promotion of Atrial Fibrillation in a Canine Model With Left Ventricular Dysfunction Induced by Atrial Tachypacing

This study evaluated antiarrhythmic effects of d,l-sotalol in a canine atrial fibrillation (AF) model with left ventricular dysfunction. Thirteen beagles (Sotalol group n=7 and Control group n=6) were subjected to atrial tachypacing (ATP) (400 beats/min) with intact atrioventricular conduction for 4 weeks. Oral d,l-sotalol (2 mg/kg) was administered 1 week after starting ATP and continued throughout the experiment. One week after starting ATP, atrial effective refractory periods (AERPs) were shortened in both groups. However, d,l-sotalol treatment gradually prolonged AERP, resulting in a significant prolongation of AERP compared with the Control group at 4 weeks (Control 76 +/-4 and Sotalol 126 +/-5 ms, p<0.01). d,l-Sotalol treatment showed lower AF inducibility and shorter AF duration at 4 weeks. In the control group, expressions of L-type Ca(2+) channel alpha1c and Kv4.3 mRNA were downregulated by 46.2% and 43.0%, respectively, after 4 weeks of ATP; d,l-sotalol treatment did not affect these changes. d,l-Sotalol treatment prolonged AERP, even after atrial electrical remodeling had developed, and prevented AF perpetuation without affecting downregulated expression of L-type Ca(2+) channel alpha1c and Kv4.3 mRNA in an ATP-induced canine AF model.

Alternatives to amiodarone: search for the Holy Grail

Atrial fibrillation (AF) is the most common heart rhythm disturbance, effecting more than six million individuals in North America, Europe, and Japan. Atrial fibrillation is associated with increased morbidities, including thrombo-embolism, stroke, and decreased cardiac function. However, some patients experience debilitating symptoms and decreased quality of life for which elimination of the arrhythmia is an important goal. Although AF ablation is quickly expanding to treat some of these patients, first-line therapy remains antiarrhythmic drugs (AADs). Furthermore, there are many patients with symptomatic AF who are not candidates for ablation due to associated comorbidity. Thus, there remains a great interest in pursuing novel AAD therapy. In spite of numerous available AADs and introduction of new alternatives, the most effective available antiarrhythmic remains amiodarone. 1‐3 No oral AAD to date has proven efficacy superior to amiodarone for long-term maintenance of sinus rhythm. 4 This is in part due to the fact that amiodarone has several mechanisms of action on cardiac conduction. In addition to traditional class III effects, amiodarone also has beta-blocker, calcium channel blocker, and sodium channel blockade effects. The iodine moiety may also have independent antiarrhythmic effects. In the Canadian Trial of Atrial Fibrillation (CTAF), 1 amiodarone was shown to be superior to both class Ic (propafenone) and other class III (sotalol) AADs. After 1 year, the calculated probability of remaining in sinus rhythm was 69% for patients on amiodarone compared with only 39% in the sotalol/propafenone group. In another study by Singh et al., 2 amiodarone was again shown to be superior to sotalol, with a median time to recurrence of 487 days compared with 74 days in the sotalol group. Furthermore, amiodarone is effective in reducing AF burden without causing proarrhythmia, particularly in patients with congestive heart failure or structural heart disease. 5 Amiodarone has been shown to be effective in preventing AF in heart failure patients. 5 Only dofetilide has been shown to have a comparable efficacy profile in heart failure, but with a 3.3%

Inhibition of the Na +/Ca 2+ exchanger suppresses torsades de pointes in an intact heart model of long QT syndrome-2 and long QT syndrome-3

Long QT syndrome (LQTS) is associated with sudden cardiac death resulting from torsades de pointes (TdP), which are triggered by early afterdepolarizations (EADs). The cardiac Na(+)/Ca(2+) exchanger (NCX) has been suggested to work as a trigger for EADs. The purpose of this study was to test the hypothesis that inhibition of NCX with a newly developed selective NCX inhibitor (SEA0400) reduces TdP. In 34 Langendorff-perfused rabbit hearts, the I(Kr)-blocker sotalol (100 microM; n = 18) as well as veratridine (0.5 microM; n = 16), an inhibitor of sodium channel inactivation, led to a significant increase in monophasic action potential (MAP) duration thereby mimicking LQTS2 and LQTS3. In bradycardic hearts, recordings of eight MAPs demonstrated an increased dispersion of repolarization (sotalol: 67%; veratridine: 89%; P <.05). After lowering of potassium concentration, sotalol (56%) and veratridine (63%) induced TdP. Perfusion with SEA0400 (1 microM) suppressed EADs in 15 of 16 sotalol hearts and in seven of 13 veratridine hearts. SEA0400 significantly shortened MAP duration and reduced dispersion of repolarization in both groups (P <.05). This reduced TdP incidence in the sotalol group (100%) and in the veratridine group (77%). To investigate the effects of NCX inhibition on the cellular level, we used a computer model of the rabbit ventricular myocyte. I(Na) and I(Kr) were modified to mimic the effects of veratridine and sotalol, respectively. Consistent with our in vitro experiments, reduction of NCX activity accelerated repolarization of the cellular action potential and prevented EADs. In an intact rabbit heart model of LQT2 and LQT3 as well as in a computer model of the rabbit cardiac myocyte, inhibition of NCX is effective in preventing TdP due to a suppression of EADs, a reversion of action potential prolongation, and a reduction of dispersion of repolarization. Our observations suggest a therapeutic benefit of selective NCX inhibition in LQTS.

Effects of Antiarrhythmic Drugs on Inappropriate Shocks in Patients With Implantable Cardioverter Defibrillators

Patients with atrial fibrillation (AF) or congestive heart failure (CHF) are more vulnerable to inappropriate shocks from implantable cardioverter-defibrillators (ICDs), but the effect of antiarrhythmic drugs in these patients remains unknown. A total of 55 patients with AF and/or CHF (New York Heart Association functional class > or =III) who had ICDs were divided into 3 groups [amiodarone (n=24), sotalol (n=12), beta-blocker (n=19)] and the cumulative rates of inappropriate shocks were compared. The baseline characteristics of the 3 groups were not significantly different. The 4-year event rate of inappropriate shocks was 27.3% in the amiodarone group, 54.3% in the sotalol group, and 70.6% in the beta-blocker group (amiodarone vs beta-blocker: log-rank p=0.003; sotalol vs beta-blocker: log-rank p=0.16; amiodarone vs sotalol: log-rank p=0.29). Amiodarone reduced the risk of inappropriate shocks significantly as compared with beta-blockers (hazard ratio (HR) 0.17; 95% confidence interval (CI) 0.05-0.64; p=0.008), whereas sotalol did not (HR 0.57; 95%CI 0.19-1.68; p=0.3). Amiodarone was discontinued in 4 patients (16.7%) because of pulmonary toxicity and the dose was reduced in 4 patients (16.7%) because of a thyroid function abnormality. Amiodarone is more effective than sotalol or beta-blockers in preventing inappropriate ICD shocks in patients with AF or CHF, but it has a significant risk of drug-related adverse effects.