Effect of dofetilide in patients with recent myocardial infarction and left-ventricular dysfunction: a randomised trial

doi:10.1016/S0140-6736(00)03402-4

The Lancet

Volume 356, Issue 9247, 16 December 2000, Pages 2052-2058

https://doi.org/10.1016/S0140-6736(00)03402-4 Get rights and content

Summary

Background

Arrhythmias cause much morbidity and mortality after myocardial infarction, but in previous trials, antiarrhythmic drug therapy has not been convincingly effective. Dofetilide, a new class III agent, was investigated for effects on all-cause mortality and morbidity in patients with left-ventricular dysfunction after myocardial infarction.

Methods

In 37 Danish coronary-care units, 1510 patients with severe left-ventricular dysfunction (wall motion index ≤1·2, corresponding to ejection fraction ≤0·35) were enrolled in a randomised, double-blind study comparing dofetilide (n=749) with placebo (n=761). The primary endpoint was all-cause mortality. Secondary endpoints included cardiac and arrhythmic mortality and total arrhythmic deaths. Analyses were by intention to treat.

Findings

No significant differences were found between the dofetilide and placebo groups in all-cause mortality (230 [31%] vs 243 [32%]), cardiac mortality (191 [26%] vs 212 [28%]), or total arrhythmic deaths (129 [17%] vs 140 [18%]). Atrial fibrillation or flutter was present in 8% of the patients at study entry. In these patients, dofetilide was significantly better than placebo at restoring sinus rhythm (25 of 59 vs seven of 56; p=0·002). There were seven cases of torsade de pointes ventricular tachycardia, all in the dofetilide group.

Interpretation

In patients with severe left-ventricular dysfunction and recent myocardial infarction, treatment with dofetilide did not affect all-cause mortality, cardiac mortality, or total arrhythmic deaths. Dofetilide was effective in treating atrial fibrillation or flutter in this population.

Introduction

Survivors of acute myocardial infarction have high rates of subsequent morbidity and mortality,¹ especially when left-ventricular dysfunction is present.2, 3, 4, 5, 6, 7 Long-term treatment with angiotensin-converting-enzyme (ACE) inhibitors has improved survival after myocardial infarction by reducing the number of deaths attributed to progressive heart failure.⁸ Atrial fibrillation is one important factor increasing morbidity and mortality; in one study, survivors of myocardial infarction with atrial fibrillation were more likely to die from presumed arrhythmias than of heart failure.⁹ ACE inhibitors may help to prevent the development of atrial fibrillation, but they have little or no effect on the risk of sudden, unexplained, and presumably arrhythmic death.8, 10, 11, 12, 13

With the exception of β-blockers, prophylactic antiarrhythmic therapy has not been successful in lowering all-cause mortality after myocardial infarction.¹⁰ In the Cardiac Arrhythmia Suppression Trial (CAST), mortality increased in patients given prophylactic therapy with encainide and flecainide, and the results with moricizine were inconclusive.14, 15, 16, 17 To date, amiodarone is the only extensively studied agent used for its antiarrhythmic properties that is not associated with increased mortality in survivors of myocardial infarction. In the Basel Antiarrhythmic Study of Infarct Survival, prophylactic use of amiodarone decreased the risk of death in patients who had had a myocardial infarction.¹⁸ This finding has not been confirmed in larger double-blind, placebo-controlled trials.19, 20 In both the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT) and the European Myocardial Infarct Amiodarone Trial (EMIAT), amiodarone was associated with lower numbers of arrhythmic deaths but it had no effect on all-cause mortality.19, 20 Although amiodarone does not adversely affect left-ventricular performance,21, 22 its use is limited by significant adverse effects.23, 24 Especially in patients with left-ventricular dysfunction, antiarrhythmic treatment can increase the risk of death, and at present there is no safe treatment available for atrial fibrillation.

Dofetilide, a new class III antiarrhythmic agent, selectively inhibits the rapid component of the delayed rectifier potassium current, which prolongs the effective refractory period.25, 26 It does not affect cardiac conduction or sinus-node function.27, 28 It is effective in the treatment of supraventricular arrhythmias,29, 30, 31, 32 and decreased the frequency of hospital admission in patients with severe congestive heart failure without affecting mortality.³³ Dofetilide is haemodynamically neutral,²⁷ and it has no significant extracardiac toxic effects. Clearance of dofetilide is about 50% renal and 50% hepatic, and plasma concentration strongly depends on renal function.

The Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND)-MI study was designed to find out whether long-term treatment with dofetilide affects mortality and morbidity in survivors of myocardial infarction with left-ventricular dysfunction.

Section snippets

Patients

The design of the DIAMOND-MI study, including stopping rules, has been published previously.³⁴ The trial was carried out at 37 coronary-care units in Denmark. Patients had to be at least 18 years old, and women had to be postmenopausal or using effective contraception. All patients provided written informed consent. Consecutive patients admitted to hospital with a recent (within 7 days) myocardial infarction were screened for left-ventricular dysfunction. The diagnosis of a myocardial

Results

Study investigators screened 8272 consecutive patients admitted with a myocardial infarction. 2376 (29%) were eligible for the trial on the basis of left-ventricular systolic function (figure 1). 866 of the eligible patients were excluded because they met an exclusion criterion or did not provide informed consent. The remaining 1510 patients (64% of those eligible, according to wall motion index) were randomly assigned dofetilide or placebo. The groups were well balanced in terms of baseline

Discussion

Long-term treatment with dofetilide in patients with severe left-ventricular dysfunction after myocardial infarction did not increase or reduce the risk of death when the drug dose was adjusted in relation to the patient's renal function and provided that the patient was monitored in hospital for at least the first 3 days of treatment. This finding was consistent across all subgroups examined. Long-term treatment with dofetilide had a neutral effect on the secondary endpoints of cardiac

References (37)

WB Kannel et al.
Prognosis after initial myocardial infarction: the Framingham study
Am J Cardiol
(1979)
J Berning et al.
Early estimation of risk by echocardiographic determination of wall motion index in an unselected population with acute myocardial infarction
Am J Cardiol
(1990)
FI Marcus et al.
Mechanism of death and prevalence of myocardial ischemic symptoms in the terminal event after acute myocardial infarction
Am J Cardiol
(1988)
A Hjalmarson
Effects of beta blockade on sudden cardiac death during acute myocardial infarction and the postinfarction period
Am J Cardiol
(1997)
S Goldstein
Clinical studies on beta blockers and heart failure preceding the MERIT-HF Trial
Am J Cardiol
(1997)
AL Waldo et al.
Effect of d-sotalol on mortality in patients with left-ventricular dysfunction after recent and remote myocardial infarction
Lancet
(1996)
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)
JA Cairns et al.
For the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators. Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT
Lancet
(1997)
DG Julian et al.
Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT
Lancet
(1997)
BN Singh
Amiodarone: historical development and pharmacologic profile
Am Heart J
(1983)

VR Vorperian et al.

Adverse effects of low dose amiodarone: a meta-analysis

J Am Coll Cardiol

(1997)

ML Sedgwick et al.

Clinical and electrophysiologic effects of intravenous dofetilide (UK-68,798), a new class III antiarrhythmic drug, in patients with angina pectoris

Am J Cardiol

(1992)

HL Greene et al.

Classification of deaths after myocardial infarction as arrhythmic or nonarrhythmic (The Cardiac Arrhythmia Pilot Study)

Am J Cardiol

(1989)

L Køber et al.

An echocardiographic method for selecting high risk patients shortly after acute myocardial infarction, for inclusion in multi-centre studies

Eur Heart J

(1994)

HD White et al.

Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction

Circulation

(1987)

KE Hammermeister et al.

Variables predictive of survival in patients with coronary disease: selection by univariate and multivariate analyses from the clinical, electrocardiographic, exercise, arteriographic, and quantitative angiographic evaluations

Circulation

(1979)

ML Stadius et al.

Risk stratification for 1 year survival based on characteristics identified in the early hours of acute myocardial infarction: the Western Washington Intracoronary Streptokinase Trial

Circulation

(1986)

Risk stratification andsurvival after myocardial infarction

N Engl J Med

(1983)

Cited by (283)

2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines
2024, Journal of the American College of Cardiology
The “2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Patients With Atrial Fibrillation” provides recommendations to guide clinicians in the treatment of patients with atrial fibrillation.
A comprehensive literature search was conducted from May 12, 2022, to November 3, 2022, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. Additional relevant studies, published through November 2022, during the guideline writing process, were also considered by the writing committee and added to the evidence tables, where appropriate.
Atrial fibrillation is the most sustained common arrhythmia, and its incidence and prevalence are increasing in the United States and globally. Recommendations from the “2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation” and the “2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation” have been updated with new evidence to guide clinicians. In addition, new recommendations addressing atrial fibrillation and thromboembolic risk assessment, anticoagulation, left atrial appendage occlusion, atrial fibrillation catheter or surgical ablation, and risk factor modification and atrial fibrillation prevention have been developed.
Combining pharmacokinetic and electrophysiological models for early prediction of drug-induced arrhythmogenicity
2023, Computer Methods and Programs in Biomedicine
In silico methods are gaining attention for predicting drug-induced Torsade de Pointes (TdP) in different stages of drug development. However, many computational models tended not to account for inter-individual response variability due to demographic covariates, such as sex, or physiologic covariates, such as renal function, which may be crucial when predicting TdP. This study aims to compare the effects of drugs in male and female populations with normal and impaired renal function using in silico methods.
Pharmacokinetic models considering sex and renal function as covariates were implemented from data published in pharmacokinetic studies. Drug effects were simulated using an electrophysiologically calibrated population of cellular models of 300 males and 300 females. The population of models was built by modifying the endocardial action potential model published by O'Hara et al. (2011) according to the experimentally measured gene expression levels of 12 ion channels.
Fifteen pharmacokinetic models for CiPA drugs were implemented and validated in this study. Eight pharmacokinetic models included the effect of renal function and four the effect of sex. The mean difference in action potential duration (APD) between male and female populations was 24.9 ms (p<0.05). Our simulations indicated that women with impaired renal function were particularly susceptible to drug-induced arrhythmias, whereas healthy men were less prone to TdP. Differences between patient groups were more pronounced for high TdP-risk drugs. The proposed in silico tool also revealed that individuals with impaired renal function, electrophysiologically simulated with hyperkalemia (extracellular potassium concentration [K⁺]_o = 7 mM) exhibited less pronounced APD prolongation than individuals with normal potassium levels. The pharmacokinetic/electrophysiological framework was used to determine the maximum safe dose of dofetilide in different patient groups. As a proof of concept, 3D simulations were also run for dofetilide obtaining QT prolongation in accordance with previously reported clinical values.
This study presents a novel methodology that combines pharmacokinetic and electrophysiological models to incorporate the effects of sex and renal function into in silico drug simulations and highlights their impact on TdP-risk assessment. Furthermore, it may also help inform maximum dose regimens that ensure TdP-related safety in a specific sub-population of patients.
2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines
2022, Journal of the American College of Cardiology
The “2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure” replaces the “2013 ACCF/AHA Guideline for the Management of Heart Failure” and the “2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure.” The 2022 guideline is intended to provide patient-centric recommendations for clinicians to prevent, diagnose, and manage patients with heart failure.
A comprehensive literature search was conducted from May 2020 to December 2020, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from MEDLINE (PubMed), EMBASE, the Cochrane Collaboration, the Agency for Healthcare Research and Quality, and other relevant databases. Additional relevant clinical trials and research studies, published through September 2021, were also considered. This guideline was harmonized with other American Heart Association/American College of Cardiology guidelines published through December 2021.
Heart failure remains a leading cause of morbidity and mortality globally. The 2022 heart failure guideline provides recommendations based on contemporary evidence for the treatment of these patients. The recommendations present an evidence-based approach to managing patients with heart failure, with the intent to improve quality of care and align with patients’ interests. Many recommendations from the earlier heart failure guidelines have been updated with new evidence, and new recommendations have been created when supported by published data. Value statements are provided for certain treatments with high-quality published economic analyses.
Endocardial Scar-Homogenization With vs Without Epicardial Ablation in VT Patients With Ischemic Cardiomyopathy
2022, JACC: Clinical Electrophysiology
In this study, the authors investigated the ablation success of scar homogenization with combined (epicardial + endocardial) vs endocardial-only approach for ventricular tachycardia (VT) in patients with ischemic cardiomyopathy (ICM) at 5 years of follow-up.
Best ablation approach to achieve long-term success rate in VT patients with ICM is not known yet.
Consecutive ICM patients undergoing VT ablation at our center were classified into group 1: endocardial + epicardial scar homogenization and group 2: endocardial scar homogenization. Patients with previous open heart surgery were excluded. Epicardial ablation was performed despite being noninducible after endocardial ablation in all group 1 patients. All patients underwent bipolar substrate mapping with standard scar settings defined as normal tissue >1.5 mV and severe scar <0.5 mV. Noninducibility of monomorphic VT was the procedural endpoint in both groups. Patients were followed up every 4 months for 5 years with implantable device interrogations.
A total of 361 patients (group 1: n = 70 and group 2: n = 291) were included in the study. At 5 years, 81.4% (n = 57/70) patients from group 1 and 66.3% (n = 193/291) from group 2 were arrhythmia-free (P = 0.01) Of those patients, 26 of 57 (45.6%) and 172 of 193 (89.1%) from group 1 and group 2 respectively were on anti-arrhythmic drugs (AAD) (log-rank P < 0.001). After adjusting for age, sex, and obstructive sleep apnea, endo-epicardial scar homogenization was associated with a significant reduction in arrhythmia-recurrence (HR: 0.48; 95% CI: 0.27-0.86; P = 0.02).
In this series of patients with ICM and VT, epicardial substrate was detected in all group 1 patients despite being noninducible after endocardial ablation. Moreover, combined endo-epicardial scar homogenization was associated with a significantly higher success rate at 5 years of follow-up and a substantially lower need for antiarrhythmic drugs after the procedure compared with the endocardial ablation alone.
Antiarrhythmic agents and torsades de pointes
2022, Torsades de Pointes
Many antiarrhythmic drugs inhibit potassium currents, particularly the rapid component of the delayed rectifier potassium current (I_Kr). Some antiarrhythmic drugs also inhibit other potassium channels, including the slow component of the delayed rectifier potassium current (I_Ks), the inward rectifier potassium current (I_K1) and the transient outward current (I_to). Inhibition of these currents delay ventricular repolarization, which can prolong the QT interval and increase the risk of torsades de pointes (TdP). In addition, some antiarrhythmic drugs also augment late sodium current (I_Na-L), which also prolongs ventricular repolarization and increases the risk of TdP. Antiarrhythmic agents that prolong the QT interval and are associated with an increased risk of TdP include Vaughan Williams class IA drugs (quinidine, procainamide, disopyramide), class IC agents (flecainide, propafenone), and class III drugs (ibutilide, dofetilide, sotalol, amiodarone, dronedarone).
Safety of rapid switching from amiodarone to dofetilide in atrial fibrillation patients with an implantable cardioverter–defibrillator
2019, Heart Rhythm
Dofetilide is a class III antiarrhythmic drug commonly used for treatment of atrial fibrillation. Drug guidelines mandate a 3-month waiting period before initiating dofetilide after amiodarone use. Whether patients with an implantable cardioverter–defibrillator (ICD) can be rapidly switched from amiodarone to dofetilide is not known.
The purpose of this study was to evaluate whether rapid switching from amiodarone to dofetilide is safe in atrial fibrillation patients with an ICD.
In this retrospective observational study, we assessed the feasibility and the short- and long-term safety of rapid switching from amiodarone to dofetilide in hospitalized atrial fibrillation with an ICD.
The study included a total of 179 patients who were followed for 12.6 ± 2.2 months. All patients had drug initiation during hospitalization. Dofetilide resulted in successful cardioversion in 66% (118/179). Twenty percent of patients (36/179) required dofetilide dose adjustments in the initiation phase because of QT prolongation and decreased creatinine clearance. A total of 6.1% of patients (11/179) required drug discontinuation. The incidence of torsades de pointes was 1.1% (2/179) during initiation. One patient (0.5%) had self-terminating ventricular tachycardia at follow-up. No other significant adverse events were noted during follow-up.
Atrial fibrillation patients with an ICD can be rapidly switched to dofetilide after 7 days of discontinuation of amiodarone without significant arrhythmia-related complications. Prospective studies with large sample sizes, especially of women, should be performed to further validate these findings.

View all citing articles on Scopus

View full text

ArticlesEffect of dofetilide in patients with recent myocardial infarction and left-ventricular dysfunction: a randomised trial

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Patients

Results

Discussion

Am J Cardiol

Am J Cardiol

Am J Cardiol

Am J Cardiol

Am J Cardiol

Lancet

J Am Coll Cardiol

Lancet

Lancet

Am Heart J

J Am Coll Cardiol

Am J Cardiol

Am J Cardiol

An echocardiographic method for selecting high risk patients shortly after acute myocardial infarction, for inclusion in multi-centre studies

Eur Heart J

Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction

Circulation

Variables predictive of survival in patients with coronary disease: selection by univariate and multivariate analyses from the clinical, electrocardiographic, exercise, arteriographic, and quantitative angiographic evaluations

Circulation

Risk stratification for 1 year survival based on characteristics identified in the early hours of acute myocardial infarction: the Western Washington Intracoronary Streptokinase Trial

Circulation

Risk stratification andsurvival after myocardial infarction

N Engl J Med

Articles
Effect of dofetilide in patients with recent myocardial infarction and left-ventricular dysfunction: a randomised trial