Survival with oral d-Sotalol in patients with left ventricular dysfunction after myocardial infarction: Rationale, design, and methods (the SWORD trial)

doi:10.1016/S0002-9149(99)80717-6

The American Journal of Cardiology

Volume 75, Issue 15, 15 May 1995, Pages 1023-1027

https://doi.org/10.1016/S0002-9149(99)80717-6 Get rights and content

Abstract

Impaired left ventricular function after acute myocardial infarction (AMI) is associated with an increased risk of death. Despite recent advances in the management of these patients, sudden death accounts for up to 50% of this mortality, and effective treatment strategies have yet to be identified. Preliminary trials with amiodarone have offered promise that drugs that prolong action potential duration by blocking the potassium channel may be useful in reducing this mortality. The Survival With Oral d-Sotalol (SWORD) trial is a multicenter, multinational study which tests the hypothesis that the class III agent d-sotalol will reduce all-cause mortality in high-risk survivors of AMI. The trial will enroll 6,400 patients with left ventricular dysfunction (ejection fraction ≤40%) and a recent (6 to 42 days) or a remote (>42 days) AMI with overt heart failure (New York Heart Association class II or III). In approximately 500 centers throughout the world, men and women aged ≥18 years will be enrolled and randomized to placebo or d-sotalol (200 mg/day). The minimal follow-up will be 18 months. The trial has a 90% power to detect a 20% reduction in all-cause mortality. The rationale, design, and trial methods are described.

References (26)

R Kato et al.
Electrophysiologic effects of the levo- and dextrorotatory isomers of sotalol in isolated cardiac muscle and their in vivo pharmacokinetics
J Am Coll Cardiol
(1986)
AW Gomoll et al.
Comparative β-blocking activities and electrophysiologic actions of racemic sotalol and its optical isomers in anesthetized dogs
Eur J Pharmacol
(1986)
DL Kuchar et al.
Prediction of serious arrhythmic events after myocardial infarction: signal-averaged electrocardiogram, Holter monitoring and radionuclide ventriculography
J Am Coll Cardiol
(1987)
J Steinberg et al.
Predicting arrhythmic events after acute MI using the signal-averaged electrocardiogram
Am J Cardiol
(1992)
RE Kleiger et al.
Decreased heart rate variability and its association with increased mortality after acute myocardial infarction
Am J Cardiol
(1987)
The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators
Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure
Lancet
(1993)
F Burkart et al.
Effect of antiarrhythmic therapy on mortality in survivors of myocardial infarction with asymptomatic complex ventricular arrhythmias: Basel antiarrhythmic study of infarct survival (BASIS)
J Am Coll Cardiol
(1990)
HC Doval et al.
Randomized trial of low dose amiodarone in severe congestive heart failure
Lancet
(1994)
E Patterson et al.
Antifibrillatory properties of the beta-adrenergic receptor antagonists nadolol, sotalol, atenolol, and propranolol in the anesthetized dog
Pharmacology
(1984)
E Vanoli et al.
Sympathetic activation, ventricular repolarization, and Ik_r blockade: implications for the antifibrillatory efficacy of k+ channel blockers
J Am Coll Cardiol
(1995)

SU Yasuda et al.

d-Sotalol reduces heart rate in vivo through a β-adrenergic receptor-independent mechanism

Clin Pharmacol Ther

(1993)

The early termination of clinical trials: causes, consequences and control with special reference to trials in the field of arrhythmias and sudden death

Circulation

(1994)

KKG Lan et al.

Discrete sequential boundaries for clinical trials

Biometrika

(1983)

Cited by (112)

Multifactorial approaches to enhance maturation of human iPSC-derived cardiomyocytes
2023, Journal of Molecular Liquids
Cardiovascular diseases are the leading cause of death worldwide. Several strategies – small molecules, gene therapy, surgeries, cardiac rehabilitation – have been developed to treat patients with cardiac disorders or to prevent the disease. A novel promising tool is the application of induced pluripotent stem cell-derived human cardiomyocytes; however, their clinical application is hampered by their fundamentally immature characteristics. Although several approaches were recently proven to support certain aspects of cardiac maturation, it has been discovered that any kind of stimulus itself is insufficient to induce proper maturation of these cardiomyocytes. Therefore, researchers have developed multifactorial approaches linking biotechnology, life sciences and material sciences toolsets. In this review, we summarise the current state-of-the-art methodologies in cardiac differentiation and maturation with the application of biocompatible materials and automated cell culture systems combined with various electrical, mechanical, topological, and biochemical stimuli.
R-on-T and the initiation of reentry revisited: Integrating old and new concepts
2022, Heart Rhythm
Initiation of reentry requires 2 factors: (1) a triggering event, most commonly focal excitations such as premature ventricular complexes (PVCs); and (2) a vulnerable substrate with regional dispersion of refractoriness and/or excitability, such as occurs during the T wave of the electrocardiogram when some areas of the ventricle have repolarized and recovered excitability but others have not. When the R wave of a PVC coincides in time with the T wave of the previous beat, this timing can lead to unidirectional block and initiation of reentry, known as the R-on-T phenomenon. Classically, the PVC triggering reentry has been viewed as arising focally from 1 region and propagating into another region whose recovery is delayed, resulting in unidirectional conduction block and reentry initiation. However, more recent evidence indicates that PVCs also can arise from the T wave itself. In the latter case, the PVC initiating reentry is not a separate event from the T wave but rather is causally generated from the repolarization gradient that manifests as the T wave. We call the former an “R-to-T” mechanism and the latter an “R-from-T” mechanism, which are initiation mechanisms distinct from each other. Both are important components of the R-on-T phenomenon and need to be taken into account when designing antiarrhythmic strategies. Strategies targeting suppression of triggers alone or vulnerable substrate alone may be appropriate in some instances but not in others. Preventing R-from-T arrhythmias requires suppressing the underlying dynamic tissue instabilities responsible for producing both triggers and substrate vulnerability simultaneously. The same principles are likely to apply to supraventricular arrhythmias.
The Increasing Role of Rhythm Control in Patients With Atrial Fibrillation: JACC State-of-the-Art Review
2022, Journal of the American College of Cardiology
Citation Excerpt :
For example, observational results from Canada also showed little difference in mortality until 4 years post-treatment initiation for rhythm or rate control, after which, long-term results progressively favored rhythm control, with mortality decreasing in the rhythm-control group after year 5.62 Initial enthusiasm for AADs was dampened after their association with excess mortality in patients with prior myocardial infarction, impaired left ventricular function, and ventricular ectopy, likely attributable to their proarrhythmic or negative inotropic effects, in the CAST (Cardiac Arrhythmia Suppression Trial), CAST II, SWORD (Survival With Oral d-Sotalol in Patients With Left Ventricular Dysfunction After Myocardial Infarction), and ALIVE (Azimilide Post-Infarct Survival Evaluation) studies in the 1990s.63-66 However, this was followed by the evaluation of AADs for rhythm control in patients with AF and the development of more atrial-specific AADs in the early 21st century.50-54
The considerable mortality and morbidity associated with atrial fibrillation (AF) pose a substantial burden on patients and health care services. Although the management of AF historically focused on decreasing AF recurrence, it evolved over time in favor of rate control. Recently, more emphasis has been placed on reducing adverse cardiovascular outcomes using rhythm control, generally by using safe and effective rhythm-control therapies (typically antiarrhythmic drugs and/or AF ablation). Evidence increasingly supports early rhythm control in patients with AF that has not become long-standing, but current clinical practice and guidelines do not yet fully reflect this change. Early rhythm control may effectively reduce irreversible atrial remodeling and prevent AF-related deaths, heart failure, and strokes in high-risk patients. It has the potential to halt progression and potentially save patients from years of symptomatic AF; therefore, it should be offered more widely.
Oral procainamide as pharmacological treatment of recurrent and refractory ventricular tachyarrhythmias: A single-center experience
2021, Heart Rhythm O2
Citation Excerpt :
Antiarrhythmic drugs are usually prescribed long-term for the prevention of recurrences, and amiodarone commonly represents the first-line therapy. However, although amiodarone and sotalol have been clearly demonstrated to reduce recurrent ventricular arrhythmias,6,7 they have been limited by tolerance and side effects.8,9 As a matter of fact, long-term therapy with amiodarone is commonly associated with severe organ damage.
Antiarrhythmic therapy for recurrent ventricular arrhythmias in patients who have undergone catheter ablation, and in whom amiodarone and/or beta-blockers were ineffective or contraindicated, is a controversial issue.
The present study sought to evaluate the efficacy and tolerability of oral procainamide in patients with recurrent ventricular arrhythmias when the standard therapy strategy had failed.
All patients treated with procainamide for recurrent ventricular tachycardia (VT) or ventricular fibrillation (VF) in our institution between January 2010 and May 2019 were enrolled. The primary endpoint was the total number of implantable cardioverter-defibrillator (ICD) interventions after the beginning of procainamide therapy. Secondary endpoints were the total number of VTs and VFs recorded on the ICDs’ controls and discontinuation of therapy. The events occurring during procainamide treatment were compared with a matched-duration period before the initiation of therapy with procainamide. Patients therefore served as self-controls.
A total of 34 consecutive patients (32 male, 94.1%; mean age 74.4 ± 9.7 years) were included in the retrospective analysis. The mean time of procainamide treatment was 12.9 ± 13.7 months (median 9 [2–20] months). The mean dose of procainamide was 1207 ± 487 mg/day. Procainamide therapy significantly decreased ICD interventions (median 5 [0–22.5] vs 15.5 [3–32.25], P < .05). Procainamide also decreased the total number of VT/VF episodes (median 5.5 [0.75–30] vs 19 [7.5–30], P < .05). Only 3 patients (8.8%) presented severe side effects (dyspnea or hypotension), requiring discontinuation of therapy.
Oral procainamide was associated with a significant decrease in ICD therapies and ventricular arrhythmias, showing an acceptable profile of tolerability.
Molecular determinants of pro-arrhythmia proclivity of d- and l-sotalol via a multi-scale modeling pipeline
2021, Journal of Molecular and Cellular Cardiology
Citation Excerpt :
A fascinating and puzzling example of isomerism to impact cardiac safety is the antiarrhythmic sulfonamide drug sotalol. The d-isomer was infamously shown in the SWORD (Survival With ORal D-sotalol) clinical trial [16] to increase mortality and risk of sudden cardiac death in patients, leading to its withdrawal [17]. The racemic mixture comprising d- and l-sotalol, however, is widely used as an effective antiarrhythmic – although not entirely without risk [18–29].
Drug isomers may differ in their proarrhythmia risk. An interesting example is the drug sotalol, an antiarrhythmic drug comprising d- and l- enantiomers that both block the hERG cardiac potassium channel and confer differing degrees of proarrhythmic risk. We developed a multi-scale in silico pipeline focusing on hERG channel – drug interactions and used it to probe and predict the mechanisms of pro-arrhythmia risks of the two enantiomers of sotalol. Molecular dynamics (MD) simulations predicted comparable hERG channel binding affinities for d- and l-sotalol, which were validated with electrophysiology experiments. MD derived thermodynamic and kinetic parameters were used to build multi-scale functional computational models of cardiac electrophysiology at the cell and tissue scales. Functional models were used to predict inactivated state binding affinities to recapitulate electrocardiogram (ECG) QT interval prolongation observed in clinical data. Our study demonstrates how modeling and simulation can be applied to predict drug effects from the atom to the rhythm for dl-sotalol and also increased proarrhythmia proclivity of d- vs. l-sotalol when accounting for stereospecific beta-adrenergic receptor blocking.
Mechanisms of flecainide induced negative inotropy: An in silico study
2021, Journal of Molecular and Cellular Cardiology
Citation Excerpt :
While important progress has been made recently via safety pharmacology studies designed to screen drugs for pro-arrhythmia, the primary focus has been on determining the extent to which drugs cause repolarization abnormalities [1,2]. In particular, the emphasis has been on the proclivity for drugs to block the cardiac potassium channel hERG, an infamously promiscuous drug target [3–5]. More recently, studies have begun to take into account the simultaneous effects of drugs on multiple cardiac ion channel.
It is imperative to develop better approaches to predict how antiarrhythmic drugs with multiple interactions and targets may alter the overall electrical and/or mechanical function of the heart. Safety Pharmacology studies have provided new insights into the multi-target effects of many different classes of drugs and have been aided by the addition of robust new in vitro and in silico technology. The primary focus of Safety Pharmacology studies has been to determine the risk profile of drugs and drug candidates by assessing their effects on repolarization of the cardiac action potential. However, for decades experimental and clinical studies have described substantial and potentially detrimental effects of Na⁺ channel blockers in addition to their well-known conduction slowing effects. One such side effect, associated with administration of some Na⁺ channel blocking drugs is negative inotropy. This reduces the pumping function of the heart, thereby resulting in hypotension. Flecainide is a well-known example of a Na⁺ channel blocking drug, that exhibits strong rate-dependent block of I_Na and may cause negative cardiac inotropy. While the phenomenon of Na⁺ channel suppression and resulting negative inotropy is well described, the mechanism(s) underlying this effect are not. Here, we set out to use a modeling and simulation approach to reveal plausible mechanisms that could explain the negative inotropic effect of flecainide. We utilized the Grandi-Bers model [1] of the cardiac ventricular myocyte because of its robust descriptions of ion homeostasis in order to characterize and resolve the relative effects of QRS widening, flecainide off-target effects and changes in intracellular Ca²⁺ and Na⁺ homeostasis. The results of our investigations and predictions reconcile multiple data sets and illustrate how multiple mechanisms may play a contributing role in the flecainide induced negative cardiac inotropic effect.

View all citing articles on Scopus

^☆: This study was supported by a grant from Bristol-Myers Squibb, Princeton, New Jersey.

^∗: See appendix for participating centers.

View full text

Survival with oral d-Sotalol in patients with left ventricular dysfunction after myocardial infarction: Rationale, design, and methods (the SWORD trial)☆

Abstract

J Am Coll Cardiol

Eur J Pharmacol

J Am Coll Cardiol

Am J Cardiol

Am J Cardiol

Lancet

J Am Coll Cardiol

Lancet

Antifibrillatory properties of the beta-adrenergic receptor antagonists nadolol, sotalol, atenolol, and propranolol in the anesthetized dog

Pharmacology

Sympathetic activation, ventricular repolarization, and Ikr blockade: implications for the antifibrillatory efficacy of k+ channel blockers

J Am Coll Cardiol

d-Sotalol reduces heart rate in vivo through a β-adrenergic receptor-independent mechanism

Clin Pharmacol Ther

The early termination of clinical trials: causes, consequences and control with special reference to trials in the field of arrhythmias and sudden death

Circulation

Discrete sequential boundaries for clinical trials

Biometrika

Sympathetic activation, ventricular repolarization, and Ik_r blockade: implications for the antifibrillatory efficacy of k+ channel blockers