14th International Congress
THE "NEW FRONTIERS"
OF ARRHYTHMIAS 2000

Jan. 29 - Feb. 5, 2000
Marilleva, Trento, Italy

RT-90

Calcium-channel-blockers and efficacy of external cardioversion of persistent atrial fibrillation. Prevention of electrical remodeling?

Giovanni Luca Botto, Roberto Bonatti, Giuseppe De Nittis, Mario Susta, Franco Tettamanti, Alessandro Politi, Tiziana Broffoni, Giovanni Ferrari.
Department of Cardiology, S. Anna Hospital, Como, Italy

Atrial fibrillation is a self-perpetuating arrhythmia¹ causing electrophysiological changes that are mediated by rate-induced intracellular calcium overload¹. Calcium-channel-blockers have been demonstrated to be effective in preventing atrial electrical remodeling^3,4. Aim of the present study was to evaluate the effect of the concomitant use of calcium blocking agents on the efficacy of electrical cardioversion of persistent atrial fibrillation and on the occurence of very early relapses of the arrhythmia.

The population of this retrospective study was 437 consecutive patients, who underwent, in our institution, external cardioversion for stable atrial fibrillation between June ‘93 and December ‘98. Standard clinical criteria were used to select patients for cardioversion⁵, we excluded patients with: 1) hemodynamically unstable atrial fibrillation in which cardioversion needs to be performed urgently; 2) left atrium dimension, measured with M-mode echocardiography, >60 mm; 3) arrhythmia duration either >2 years or of unknown duration; 4) untreated thyrotoxicosis.

External cardioversion was performed according to our previously published strategy⁶.

We define technical failure the inability of interrupting the arrhythmia and clinical failure the early relapse of atrial fibrillation 48 hour after successful cardioversion.

All patients with an arrhythmia duration >72 hours received anticoagulation with warfarin for at least 3 weeks prior to attempted cardioversion and continued for at least 4 weeks after restoration of sinus rhythm⁷.

Patient population was divided in two groups: Group A received calcium-channel-blocking drugs before electrical cardioversion and 48 hours after, Group B didn’t receive them. The group of calcium blockers consisted of verapamil, diltiazem, gallopamil and dihydropyridines. Pharmacological antiarrhythmic treatment was not randomized and some physicians began this treatment prior to cardioversion while others started immediately after cardioversion was accomplished.

Data were expressed as mean±SD. Continuous variables were compared by using Student’s t-test for independent samples. A chi-square test was used to determine the 2-tailed statistical significance of associations in 2 by 2 tables. A p value <0.05 was considered statistically significant.

The mean age of the study population was 62±12 years (range 26-80 years). One-hundred-thirty-five pts (31%) were treated with calcium blockers before electrical cardioversion and 48 hours after (Group A), while 302 pts (69%) didn’t receive them (Group B).

The group of calcium-channel-blocker drugs consisted of 54/135 patients (40%) who received non-dihydropyridinic drugs (verapamil n=33, diltiazem n=16, and gallopamil n=5) and 81/135 (60%) patients who received dihydropyridines (nifedipine n=27, amlodipine n=33, felodipine n=16, and others n=5).

The two groups were well matched with no significant differences in age, male/female ratio, body weight, left atrial dimension, left ventricular function, history of previous atrial fibrillation episodes, arrhythmia duration, and concomitant antiarrhythmic treatment (Tab. I). The prevalence of arterial hypertension or coronary disease was higher in Group A patients [arterial hypertension 49/135 (36%) vs 74/302 patients (25%), p<0.05; coronary disease 18/135 (13%) vs 15/302 (5%) patients, p<0.0001].

Overall, external cardioversion was effective in interrupting the arrhythmia in 402/437 (91.9%) patients. There were no complications related to the electrical procedure.

The main results are reported in table II. The rate of interruption of atrial fibrillation was higher in patients who received calcium blocking drugs compared to patients who didn’t receive them [Group A 130/135 (96%) patients vs Group B 270/302 (90%) patients; p=0.043].

During 48-hour follow-up 20/130 (15%) patients in Group A and 39/272 (14%) patients in Group B had a relapse of atrial fibrillation (p=ns). Furthermore the number of patients who mantained sinus rhythm at the end of the follow-up was not significantly different between the two group (Group A 110/135 (81%) patients vs Group B 233/302 (77%) patients; p=ns).

There were no differences in mean DC-shock energy requirements between the two groups: Group A patients 456±271 Joules vs Group B patients 423±273 Joules (p=ns).

Only one patient (0.2%) with a prostetic mitral valve experienced an embolic event 37 hours after successful cardioversion while he was correctly anticoagulated.

Recent animal experiments have shown that artificially maintained atrial fibrillation induces a long term shortening of the atrial refractory period^1,2. Also in humans, shorter episodes of artificially induced atrial fibrillation shortened the refractory period significantly⁸. This electrical remodeling of the atria results in a shorter wavelenght of the traveling impulses that a determinant for the induction and maintainance of these reentrant arrhythmias: the smaller the wavelenght, the easier atrial fibrillation was induced and maintained⁹. These findings may explain the facilitation for maintenance of long standing atrial fibrillation and the increased vulnerability for arrhythmia recurrences after cardioversion.

The same animal studies have suggested that intracellular calcium play a pivotal role in the process of electrical remodeling of the atria. In a dog model of atrial fibrillation, pacing induced electrical remodeling was blocked by the administration of verapamil and, in contrast, atrial pacing during hypercalcemia resulted in a delay of recovery from electrical remodeling².

Tieleman et al documented that the use of calcium-lowering drugs (including beta-blocking agents) during AF appeared to reduce recurrences of the arrhythmia after successful electrical cardioversion³ and De Simone et al demonstrated the beneficial effect of verapamil in reducing the incidence of early recurrences of atrial fibrillation also in patients already receiving propafenone⁴.

The result of the present study is in agreement with the animal studies, but this is not the case with the latter two clinical studies. We observed a lower rate of unsuccessful cardioversion in patients with atrial fibrillation treated with calcium blockers before the electrical procedure: intracellular calcium-lowering drugs reduce electrical remodelling, which in turn would lead to a longer wavelenght that is easier to interrupt compared to a shorter one. In contrast we did not observe any difference in early recurrences of the arrhythmia in patients treated with calcium blockers compared to those who didn’t receive these drugs. If verapamil blocks electrical remodeling one would expect a more rapid recovery of electrophysiological parameters to baseline value after cardioversion, leading to a lower incidence of relapse of atrial fibrillation. The conclusion of Tieleman et al’s study is in good agreement with this statement. In this latter study, antiarrhythmic medication was administered only in 30/61 patients (33%) while in our study 291/437 patients (67%) received antiarrhythmic drugs during the follow-up. Antiarrhythmic drugs are effective in reducing early recurrences after successful cardioversion¹⁰, and this result could conceal the action of calcium-channel-blocking drugs in this setting.

This is a retrospective study on the maintenance of sinus rhythm after external cardioversion of persistent atrial fibrillation. Administration of both calcium blocking drugs and antiarrhythmic medication was not randomized: for this reason our results may be influenced by a selection bias.

In conclusion the pre-treatment with calcium-channel-blocking drugs could be is useful in reducing technical failure of electrical cardioversion of persistent atrial fibrillation, while no effects are detectable on the prevention of early relapses of the arrhythmia after restoring sinus rhythm in patients mostly receiving antiarrhythmic drugs. More randomized studies are mandatory to confirm the present data.

TABLE I – Patient clinical characteristics

Data are expressed as mean value±SD unless otherwise indicated. AF=atrial fibrillation; LA=left atrium; LV=left ventricular; EF=ejection fraction.

TABLE II – Main results

*p=0.047 vs sinus rhythm; **p=0.043 vs clinical failure+sinus rhythm; Gr. A=calcium blocking drug group; Gr. B=no calcium blocking drug group.