Acute Efficacy of Antiarrhythmic Drugs in ARVCD

Criteria to evaluate the acute efficacy of antiarrhyth-mic therapy are difficult to define because they may vary with specific clinical situation, arrhythmia characteristics, and appropriateness of test modalities to assess treatment effect.

The largest experience on acute and long-term efficacy of antiarrhythmic drug therapy in ARVC/D was first published in 1992 by Wichter et al. [37] and included 191 patients with 608 drug tests in their latest updated series [25]. To assess the acute efficacy of antiarrhythmic drugs during serial testing (Fig. 18.3), the following criteria were used:

1. Complete efficacy of antiarrhythmic therapy was defined as total suppression of inducible VT during electrophysiologic study or suppression and control of incessant VT or VT storms and clusters (i.e., resulting in frequent ICD shocks). In non-inducible VT, complete efficacy was considered as a reduction of ventricular ectopy >90% on Holter and exercise tests and no residual nonsustained or sustained VT.

2. Partial efficacy of antiarrhythmic therapy was considered if VT was rendered more difficult to induce during electrophysiologic study or if only nonclinical VT was induced on the drug. In non-inducible VT at baseline, partial efficacy was de

Fig. 18.3 • Efficacy rates of different antiarrhythmic drugs for treatment of VT in ARVC/D (n=191 patients, n=608 tests). Adapted from [25] with permission from Urban & Vogel GmbH. AAD,anti-arrhythmic drugs p-blockers Amiodarone Combinations

Na+-blockers Sotalol Verapamil

119 tests p-blockers Amiodarone Combinations

Na+-blockers Sotalol Verapamil

119 tests

Fig. 18.3 • Efficacy rates of different antiarrhythmic drugs for treatment of VT in ARVC/D (n=191 patients, n=608 tests). Adapted from [25] with permission from Urban & Vogel GmbH. AAD,anti-arrhythmic drugs fined as a reduction of ventricular ectopy on Holter or exercise testing by <90% but >70%. 3. Drug failure was defined as unchanged VT induction during electrophysiologic study, in-hos-pital VT recurrence, or failure to control incessant or frequent VT recurrences (VT storms or clusters). In noninducible VT, no significant reduction or even an increase of ventricular ectopy on Holter or exercise testing was considered a drug failure.

In the studies by Wichter et al. [25,37],complete antiarrhythmic drug efficacy was demonstrated in 62% of 191 patients and partial efficacy in another 13% of patients, resulting in a total overall acute efficacy of 75%. Multivariate analysis identified extensive right ventricular dysfunction as an independent predictor of antiarrhythmic drug failure [25].

Sotalol

Sotalol in a dosage of 320 mg to 480 mg/day (up to 640 mg/day in selected cases) was identified as the most effective drug in these studies [25, 37], resulting in a 68% overall acute success rate defined as the combination of complete and partial efficacy. All but one patient with inducible VT not responding to oral sotalol or combinations with sotalol proved refractory to all other antiarrhythmic agents tested (including amiodarone). Therefore, it was recommended that nonpharmacological therapy without further serial drug testing should be considered in sotalol nonresponders and inducible VT. Side effects requiring withdrawal of sotalol treatment were rare (5.5%) and mostly occurred within the first days of therapy.

Amiodarone

Amiodarone alone or in combination with ^-block-ers was reported with similar or less favorable results when compared with sotalol. Of twelve patients receiving both drugs successively, one out of eight so-talol nonresponders was effectively treated with amiodarone, whereas two out of nine amiodarone nonresponders were effectively treated with sotalol [37]. However, given the high incidence of serious side effects of amiodarone during long-term treatment, amiodarone should not be recommended as a first line drug in a young patient with ARVC/D. Therefore, sotalol or nonpharmacological treatment options should be considered prior to initiation of amiodarone therapy.

Class-1

Class-1 antiarrhythmic drugs have been demonstrated to be effective during electrophysiological testing in the treatment of life-threatening ventricular tachyarrhythmias in various underlying heart diseases. Most available data refer to postmyocardial infarction ventricular tachyarrhythmias, less frequently to patients with dilated cardiomyopathy. However, in patients with ARVC/D, varying results have been reported [20, 25, 34-36]. In the study by Wichter et al. [25], class-1 antiarrhythmic drugs proved effective in only a minority of patients with ARVC/D (18%), although some patients received three or more different class-1 drugs successively without satisfactory antiarrhythmic efficacy. Class-1c agents appeared to be slightly more effective than class-1a and class-1b drugs [37].

Beta-Blockers and Verapamil

Beta-blockers and verapamil have been reported to be effective in patients with idiopathic VT of right or left ventricular origin. In patients with ARVC/D, both ^-blockers and verapamil are usually not effective in suppressing VT induction and recurrence in the clinically dominant VT underlying reentrant mechanisms. However, when tested in a small proportion of ARVC/D patients with nonre-entrant VT and presumed mechanisms of triggered activity or abnormal automaticity, ^-blockers and verapamil demonstrated overall efficacy rates of 25% and 44%, respectively [25].

Drug Combinations

Combinations of antiarrhythmic drugs may result in electrophysiologic and antiarrhythmic properties that may be different from the action of individual agents. Drug combinations may cause enhanced or decreased antiarrhythmic efficacy but may also increase or decrease the incidence of side effects. In this regard, the experiences with antiarrhythmic drug combinations in patients with ARVC/D are limited and not very promising.

In ARVC/D, drug combinations with class-1 drugs and amiodarone or sotalol were effective in a minority of patients in whom the individual drugs had previously failed, whereas combinations of two class-1 drugs and class-1 drugs with ^-blockers were not effective in any of these patients [25, 37]. This contrasts with the results of several authors from

France who reported satisfactory therapeutic effects of combined therapy with class-1 agents and P-blockers [20,34,35].

The combination of amiodarone with P-blockers may be more effective than using individual drugs. In a study by Leclercq et al. [20], all of the six patients previously insufficiently treated by class-1 agents, amiodarone or P-blockers alone, or by combinations of class-1 agents with P-blockers or amiodarone, proved to be effectively treated with the combination of amiodarone and P-blockers. These observations should be viewed in light of the positive results with high dosages of sotalol. Both therapeutic regimens consist of a combination of class-3 antiarrhythmic properties plus P-blockade, which appears to act synergistically in patients with ARVC/D. This may be due to the strong catecholamine dependence as a triggering factor for ventricular arrhythmia in many of these patients, uncovered by stress tests or isoprenaline infusion. Similar efficacy rates of sotalol and a combination of amiodarone with P-blockers in patients with ARVC/D were confirmed in other studies [34, 35].

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