Randomized antiarrhythmic drug therapy in survivors of cardiac arrest (the CASCADE study)

doi:10.1016/0002-9149(93)90673-Z

The American Journal of Cardiology

Volume 72, Issue 3, 1 August 1993, Pages 280-287

https://doi.org/10.1016/0002-9149(93)90673-Z Get rights and content

Abstract

The Cardiac Arrest in Seattle: Conventional Versus Amiodarone Drug Evaluation (CASCADE) study evaluated antiarrhythmic drug treatment of survivors of out-of-hospital ventricular fibrillation (VF) not associated with a Q-wave myocardial infarction who were at especially high risk of recurrence of VF. Therapy was randomized to empiric treatment with amiodarone versus treatment with other antiarrhythmic drugs guided by electrophysiotogic testing, Holter recording, or both (conventional therapy). The primary end points of the study were cardiac mortality, resuscitated cardiac arrest due to documented VF, or complete syncope followed by a shock from an implanted automatic defibrillator.

Two hundred twenty-eight patients were enrolled in the study, and baseline characteristics were similar in the patients treated with amiodarone and with conventional therapy. Two hundred two patients (89%) were men with an average age of 62 years. Coronary artery disease was the most common underlying condition (188 of 228, 82%), and in coronary patients, 153 of 188 (81%) had experienced a prior myocardial infarction before the index VF event. Mean left ventricular ejection fraction was 0.35, and 102 patients (45%) had a prior history of congestive heart failure.

Survival free of cardiac death, resuscitated VF, or syncopal defibrillator shock for the entire population was 75% at 2 years (amiodarone, 82%; conventional, 69%), 59% at 4 years (amiodarone, 66%; conventional, 52%), and 46% at 6 years (amiodarone, 53%; conventional, 40%); p = 0.007. The survival free of cardiac death and sustained ventricular arrhythmias was 65% at 2 years (amiodarone, 78%; conventional, 52%), 43% at 4 years (amiodarone, 52%; conventional, 36%), and 30% at 6 years (amiodarone, 41%; conventional, 20%); p < 0.001.

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Long term risk of recurrence among survivors of sudden cardiac arrest: A systematic review and meta-analysis
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With a growing number of survivors of sudden cardiac arrest globally, their natural disease progression is of interest. This systematic review and meta-analysis aimed to determine the risk of recurrence after sudden cardiac arrest and its associated risk factors.
Medline, Embase, Cochrane Library and Scopus were searched from inception to October 2021. Studies involving survivors of an out-of-hospital sudden cardiac arrest event of any non-traumatic aetiology were included. Meta-analyses of proportions using the random-effects model estimated the primary outcome of first recurrent sudden cardiac arrest incidence as well as secondary outcomes including cumulative incidence of recurrence at 1-year and incidence of second recurrence among survivors of first recurrence. A recurrent episode was defined as a sudden cardiac arrest that occurs 28 or more days after the index event. Subgroup and meta-regression analyses were conducted for predetermined variables. The Newcastle-Ottawa Scale was used to assess risk of bias for most studies.
35 studies of moderate to high quality comprising a total of 7186 survivors were analysed. The pooled incidence of first recurrence was 15.24% (32 studies; 95%CI, 11.01–19.95; mean follow-up time, 41.3 ± 29.3 months) and second recurrence was 35.03% (3 studies; 95%CI, 19.65–51.93; mean follow-up time, 161.1 ± 54.3 months). At 1-year, incidence of recurrence was 10.62% (3 studies; 95%CI, 0.25–30.42). Subgroup analyses found no significant difference (p = 0.204) between incidence of first recurrence published from 1975-1992 and 1993–2021, and between studies with mean follow-up time of <24 months, 24–48 months, and >48 months. On meta-regression, initial shockable rhythm increased incidence of first recurrence (p = 0.01).
15.24% of sudden cardiac arrest survivors experienced a recurrence, and of these, 35.03% experienced a second recurrence. Most recurrences occurred in the first year. Initial shockable rhythm increased this risk. Despite the limitations of inter-study heterogeneity, these findings can still guide intervention and follow-up of sudden cardiac arrest survivors.
The role of amiodarone in contemporary management of complex cardiac arrhythmias
2020, Pharmacological Research
Amiodarone is an iodinated benzofuran derivative, a highly lipophilic drug with unpredictable pharmacokinetics. Although originally classified as a class III agent due to its ability to prolong refractoriness in cardiac regions and prevent/terminate re-entry, amiodarone shows antiarrhythmic properties of all four antiarrhythmic drug classes. Amiodarone is a potent coronary and peripheral vasodilator and can be safely used in patients with left ventricular dysfunction after myocardial infarction or those with congestive heart failure or hypertrophic cardiomyopathy. Its use is regularly accompanied with QT and QTc-interval prolongation but rarely with ventricular proarrhythmia. It is the most powerful pharmacological agent for long-term sinus rhythm maintenance in patients with atrial fibrillation. Amiodarone, particularly if co-administered with beta-blockers, reduces the rate of arrhythmic death due to ventricular tachyarrhythmias in patients with heart failure, but its benefit on cardiovascular and overall survival in these patients is uncertain. In addition, amiodarone is an important adjuvant drug for the reduction of shocks in patients with an implantable cardioverter-defibrillator. Over the past 40 years, amiodarone became the most prescribed antiarrhythmic. Nevertheless, the slow onset of its antiarrhythmic action requires a loading dose while the high risk of non-cardiac toxicity and common drug-drug interactions limit its long-term use. Furthermore patients treated with amiodarone require a close supervision by the treating physician. Therefore amiodarone is generally considered a secondary therapeutic option. Long-term treatment with amiodarone should be based on the use of minimal doses for satisfactory arrhythmia outcome and serial screening for thyroid, liver and pulmonary toxicity.
Antidysrhythmic electrophysiology and pharmacotherapy
2018, Cardiac Intensive Care
Treatment of Ventricular Arrhythmias and Use of Implantable Cardioverter-Defibrillators to Improve Survival in Older Adult Patients with Cardiac Disease
2017, Heart Failure Clinics
Citation Excerpt :
The patient population was composed of survivors of cardiac arrest caused by VF who also had VT/VF inducible at EPS and/or at least 10 VPB/h, couplets, or VT on Holter. The conventional therapy group was started on AAD and progressed through the list until a response was seen on repeat testing.26,27 As the ICD became more readily available and reports of efficacy appeared, as well as a high mortality on interim analysis of CASCADE, the protocol was changed midstudy to include ICD implantation if surgically feasible (early devices required sternotomy and did not have the capability to store electrograms from treated arrhythmias for confirmation of arrhythmia detection).27
Hopes and disappointments with antiarrhythmic drugs
2017, International Journal of Cardiology
Ventricular arrhythmias such as sustained ventricular tachycardia and ventricular fibrillation account for two thirds of sudden cardiac deaths. Most ventricular tachyarrhythmias have well understood mechanisms such that it is theoretically possible to conceive of an antiarrhythmic drug-based intervention that would prevent arrhythmias that cause sudden cardiac death. Pharmaceutical agents which interfere with ion channel activity are known as antiarrhythmic drugs.
Acute experiments showing antiarrhythmic effects in the basic science laboratory have often not translated into clinical effectiveness. Evidence of efficacy has been difficult to assess and appears to be sparse. However, proarrhythmia is common and complicates assessment of the potential value of antiarrhythmic drugs. Important studies such as the Cardiac Arrhythmia Suppression Trial and the Survival With ORal d-sotalol study confirmed that antiarrhythmic drugs could kill rather than cure patients at risk of sudden cardiac death, and spelled the death knell for widespread use of antiarrhythmic drugs for the primary prevention of sudden cardia death in high risk patients.
However, when the implantable cardioverter defibrillator was introduced into clinical practice the situation changed - a drug that generally suppressed ventricular tachyarrhythmias was needed, but safety concerns were alleviated because the ICD could reverse proarrhythmic adverse effects. The accent changed towards the development of drugs that might reduce the prevalence or the symptomatic burden of ventricular arrhythmias. Similarly, antiarrhythmic drug development progressed towards finding an agent that might reduce symptoms associated with recurrent atrial fibrillation rather than for the treatment of ventricular arrhythmia.
In recent times the goal of antiarrhythmic therapy has changed again. No longer is it thought necessary to develop blockbuster therapies, but to concentrate on the specific mechanisms of cardiac arrhythmias in individuals and to develop therapies that can be specifically engineered to help carefully defined phenotypes. Personalised or precision medicine is now guiding the development of antiarrhythmic agents that are directed to very specific targets and arrhythmia mechanisms and are without off-target effects that may compromise their efficacy.
The value of antiarrhythmic medical therapy has raised great hopes which have been followed by disillusionment. Now hopes and needs are rising again, and we are better prepared to make this therapy successful. If we understand the arrhythmias we may be able to design effective and uncomplicated therapy.
Amiodarone Discontinuation or Dose Reduction Following Catheter Ablation for Ventricular Tachycardia in Structural Heart Disease
2017, JACC: Clinical Electrophysiology
This study sought to examine long-term outcomes in patients with structural heart disease in whom amiodarone was reduced/discontinued after ventricular tachycardia (VT) ablation.
VT in patients with structural heart disease increases morbidity and mortality. Amiodarone can decrease VT burden, but long-term use may result in organ toxicities and possibly increased mortality. Catheter ablation can also decrease VT burden. Whether amiodarone can be safely reduced/discontinued following ablation remains unknown.
We studied consecutive patients undergoing VT ablation from 2008 to 2011, typically followed by noninvasive programmed stimulation several days later. Patients were divided into 3 groups by amiodarone use: group A—amiodarone reduced/discontinued following ablation; group B—amiodarone not reduced; group C—not on amiodarone at time of ablation. Baseline characteristics and outcomes were compared between groups.
Overall, 231 patients (90% male; mean age: 63.4 ± 12.9 years; 53.7% ischemic cardiomyopathy) were included (group A: 99 patients; group B: 29 patients; group C: 103 patients). Group B patients were older with more advanced heart failure. Group A patients less frequently had inducible VT at the end of ablation or noninvasive programmed stimulation. In follow-up, 1-year VT-free survival was similar between groups (p = 0.10). Mortality was highest in group B (p < 0.001). Higher amiodarone dose after ablation (hazard ratio: 1.23; 95% confidence interval: 1.03 to 1.47; p = 0.02) was independently associated with shorter time to death.
After successful VT ablation, as confirmed by noninducibility at the end of ablation and noninvasive programmed stimulation, amiodarone may be safely reduced/discontinued without an unacceptable increase in VT recurrence. Reduction/discontinuation of amiodarone should be considered an important goal of VT ablation.

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^☆: The pilot study was supported in part by grants from the Medic I Foundation, Seattle, Washington, and Wyeth-Ayerst Laboratories, Philadelphia, Pennsylvania. The full study was supported in part by Grant RO1 HL31472 from the National Heart, Lung, and Blood Institute, Public Health Service, Department of Health and Human Services, Bethesda, Maryland.

^∗: See Appendix.

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Randomized antiarrhythmic drug therapy in survivors of cardiac arrest (the CASCADE study)☆

Abstract

J Am Coll Cardiol

J Am Coll Cardiol

Am J Cardiol

Am J Cardiol

J Am Coll Cardiol

Controlled Clin Trials

Controlled Clin Trials

Am J Cardiol

J Am Coll Cardiol

Am J Cardiol

Am J Cardiol

Am J Cardiol

Am J Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

Recurrent ventricular fibrillation and modes of death in survivors of out-of-hospital ventricular fibrillation

N Engl J Med