Study Antiarrhythmic Drugs

Class IC antiarrhythmic drugs such as flecainide or propafenone block the Na+ channel (open state propafenone open and inactivated state) with a very long dissociation time constant so that they alter normal action potential propagation. Flecainide increased mortality of patients recovering from myocardial infarction due to its proarrhythmic effects (CAST study). Action potential is shortened in Purkinje fibres but is prolonged in the ventricles. 

FIGURE 6-2. Algorithm for the treatment of acute (top portion) paroxysmal supraventricular tachycardia and chronic prevention of recurrences (bottom portion). Note For empiric bridge therapy prior to radiofrequency ablation procedures, calcium channel blockers (or other atrioventricular [AV] nodal blockers) should not be used if the patient has AV reentry with an accessory pathway. (AAD, antiarrhythmic drugs AF, atrial fibrillation AP, accessory pathway AVN, atrioventricular nodal AVNRT, atrioventricular nodal reentrant tachycardia AVRT, atrioventricular reentrant tachycardia DCC, direct-current cardioversion ECG, electrocardiographic monitoring EPS, electrophysiologic studies PRN, as needed VT, ventricular tachycardia.)... 

MUSTT (NEJM 1999) EP guided therapy (antiarrhythmic drugs and ICD) vs no therapy in patients with CAD, EF < 40%, asymptomatic NSVT and inducible VT with EP study 704 39 All cause mortality reduced by 55% in ICD arm (compared to control), arrhythmic death reduced by 73% <0.001 <0.001... 

Kuck KH, Cappato R, Siebels J, et al. Randomized comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from cardiac arrest the Cardiac Arrest Study Hamburg (CASH). Circulation. Aug 15 2000 102(7) 748-754. 

Nattel S, Kneller J, Zou R, Leon LJ. Mechanisms of termination of atrial fibrillation by Class I antiarrhythmic drugs evidence from clinical, experimental, and mathematical modeling studies. J Cardiovasc Electro-physiol 2 003 14(suppl) S133—S139. 

A systematic review of randomized controlled trials in patients with newly detected AF identified a number of antiarrhythmic drugs for which there was statistically significant evidence of benefit (I). In a limited number of comparative studies, flecainide was more effective than propafenone and procainamide, propafenone was superior to amiodarone, amiodarone was superior to quinidine, and quinidine was superior to sotalol. 

Another very successful apphcation of nonlinear dynamics to the heart is through mathematical modehng. An example in which a simple model based on coupled oscillators describes the dynamics of agonist induced vasomotion is in the work of de Brouwer et al. [586], where the route to chaos in the presence of verapamil, a class IV antiarrhythmic drug, is studied. 

Eckardt et al. (1998), Johna et al. (1998) proposed the isolated perfused rabbit heart as a model to study proarrhythmia induced by class III antiarrhythmic drugs. 

Jackman WM, Friday KJ, Anderson JL et al. (1988) The long QT syndromes A critical review, new clinical observation and a unifying hypothesis. Progr Cardiovasc Dis 31 115-172 Johna R, Mertens H, Haverkamp W et al. (1998) Clofilium in the isolated perfused rabbit heart A new model to study proarrhythmia by class III antiarrhythmic drugs. Basic Res Cardiol 93 127-135... 

Drug commonly induces an otherwise common illness this effect will not be discovered by informal clinical observation. If very common, it may be discovered in formal therapeutic trials and in case-control studies, but if only moderately common it may require observational cohort studies, e.g. proarrhythmic effects of antiarrhythmic drugs. 

Flecainide slows conduction in all cardiac cells including the anomalous pathways responsible for the Wolff-Parkinson-White (WPW) syndrome. Together with encainide and moricizine, it underwent clinical trials to establish if suppression of asymptomatic premature beats with antiarrhythmic drugs would reduce the risk of death from arrhythmia after myocardial infarction. The study was terminated after preliminary analysis of 1727 patients revealed that mortality in the groups treated with flecainide or encainide was 7.7% compared with 3.0% in controls. The most likely explanation for the result was the induction of lethal ventricular arrhythmias possibly due to ischaemia by flecainide and encainide, i.e. a proarrhythmic effect. In the light of these findings the indications for flecainide are restricted to patients with no evidence of structural heart disease. The most common indication, indeed where it is the drug of choice, is atrioventricular re-entrant tachycardia, such as AV nodal tachycardia or in the tachycardias associated with the WPW syndrome or similar conditions with anomalous pathways. This should be as a prelude to definitive treatment with radiofrequency ablation. Flecainide may also be useful in patients with paroxysmal atrial fibrillation. 

Northridge D 1996 Frusemide or nitrates for acute heart failure [see comments] Lancet 347 667-668 Peters N S et al 2002 Atrial fibrillation strategies to control, combat and cure. Lancet 359 593-603 Pitt B et al 2000 Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure randomised trial — the Losartan Heart Failure Survival Study ELITE II. [see comments] Lancet 355 1582-1587 Podrid P J 1999 Redefining the role of antiarrhythmic drugs. New England Journal of Medicine 340 1910-1912... 

Bashir Y, Thomsen PE, Kingma JH, Moller M, Wong C, Cobbe SM, Jordaens L, Campbell RW, Rasmussen HS, Camm AJ. Electrophysiologic profile and efficacy of intravenous dofetilide (UK-68,798), a new class III antiarrhythmic drug, in patients with sustained monomorphic ventricular tachycardia. Dofetilide Arrhythmia Study Group. Am J Cardiol 1995 76(14) 1040-4. 

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