American College of Cardiology -- Anaheim, California

The Trials Guiding Current Approaches to Ventricular Arrhythmias and Sudden Death


To date, at least two clinical trials, Integrelin to Manage Platelet Aggregation to Combat Thrombosis (IMPACT) and Cardiac Arrhythmia Suppression Trial (CAST), have shown that class Ic antiarrhythmic agents, and possibly all drugs that slow conduction, may be deleterious to patients after myocardial infarction (MI) and, by extension, any type of left ventricular (LV) dysfunction. Dr. Gunther Breidhardt, speaking at the American College of Cardiology 46th Annual Scientific Session, examined the question of whether or not antiarrhythmic drugs, which certainly do suppress arrhythmia, are also effective in improving survival and, if they are, whether implantable cardioverter defibrillators (ICD) may prove even more effective.

Trials Comparing Antiarrhythmic Agents
Whereas all currently available class Ic antiarrhythmic agents have been shown to actually increase mortality in patients with serious ventricular arrhythmias following MI, clinical trials of class III antiarrhythmics (specifically amiodarone) have demonstrated that the latter may be effective in improving survival in the subgroup of patients with nonischemic etiology. Later trials have not corroborated this finding, although some have indicated a reduced risk of sudden cardiac death and/or a possible increased risk in noncardiac death for patients with nonischemic etiology. Patients without serious arrhythmias have been shown to enjoy better survival rates, but studies indicate no differences in survival for placebo-controlled patients vs amiodarone-treated patients with complex arrhythmias.

Two South American trials with a significant proportion of patients with nonischemic-etiology included in the cohort have shown a significant improvement in total mortality in patients taking amiodarone. Although some studies have shown significant differences in arrhythmia mortality in post-MI patients, only one study (from Switzerland) has shown a significant difference in total mortality. Dr. Breidhardt remarked that there appears to be a tendency towards improvement as far as sudden death is concerned, but total mortality appears to be mostly unaffected.

Whereas amiodarone appears ineffective for patients with poor LV function, it does seem to play a significant role in treating patients with better LV function. The Cardiac Arrest in Seattle: Conventional versus Amiodarone Drug Evaluation (CASCADE) trial compared amiodarone to conventional antiarrhythmic therapies, mostly class I drugs, and demonstrated superior event curves for amiodarone. However, there is a paucity of data to substantiate these findings. The ability to suppress inducible arrhythmias of racemic (D-L) sotalol – which has both class II (ß-blockade) and III (potassium channel blockade) antiarrhythmic properties – appears to be dose related. Although there is a lack of randomised trials comparing D-L sotalol to placebo, and no data to demonstrate the real potential benefit of the drug, it has been shown more effective than class I agents in preventing recurrence of arrhythmia and improving total survival.

D sotalol, a pure class III drug, was expected to show great promise but clinical trials assessing it have been prematurely halted by the Data Safety Monitoring Board (DSMB) in response to an excessive occurrence of mortality in subgroups of patients early or remote after MI. Preliminary findings have demonstrated that D sotalol was unable to improve prognosis in patients with ejection fractions below 40% and recent or remote MI with overt heart failure (class 2 or 3). Since it did result in decreased survival rates, other protocols have also been halted. (Although other pure class III drugs are currently being studied, the only conclusions which have been reached so far is that they appear to do no harm, since trials examining them have not been stopped by the DSMB.) Given these findings, it may be postulated that it is the ß-blocking property of D-L sotalol which confers its effectiveness. The role of ß-blockers in preventing sudden death in cardiac patients is unclear, however Dr. Breidhardt suggested that they may not be as effective as newer agents. He also pointed out that they still have not been indicated for use by patients with documented ventricular tachycardia, ventricular fibrillation, or with cardiac arrest.

ICD Trials
Although the results of randomised trials comparing defibrillators against antiarrhythmic drugs have yet to be published, several previous studies have indicated their possible superiority. Some of these studies have also demonstrated that immediate ICD use has been associated with improved survival in patients with documented ventricular tachycardia, ventricular fibrillation, or cardiac arrest.