Since two deaths have been reported at the clinic in relationship to sotalol treatment the question

Fråga: Since two deaths have been reported at the clinic in relationship to sotalol treatment the questioner wants to know what is documented regarding sotalol and cardiovascular side effects, as well as its place in therapy.

Sammanfattning: In total there are 162 adverse effects reported in Sweden due to the treatment with sotalol. Of these, 104 (62 %) are classified as cardiovascular disorders. Gastro-intestinal diseases are the second most common adverse effect with totally 15 reported cases (3). The outcome regarding end-points such as death, heart failure, stroke etc differs between the studies included in this overview, and due to the different study designs it is difficult to evaluate if sotalol is associated with a higher incidence of these end-points or not.

In most cases, sotalol was not superior to any other drug, neither in the prevention of atrial fibrillation, nor in the treatment of tachyarrhythmias, but sotalol administration or rhythm-control management is generally not considered as first-line treatment.

Svar: Sotalol is a non-selective beta-blocking agent as well as a class III antiarrhythmic agent Sotalol is an isomer of which the L-isomer excerts the beta-blocking effect while both D- and L-sotalol have equally potent class III antiarrhythmic effects (1). Sotalol has a relatively low lipid solubility compared to other beta-blockers and its oral bioavailability is high (1). It is almost entirely (80-90%) eliminated as unchanged drug by the kidneys, why dose adjustment in patients with decreased renal sufficiency is required. Since sotalol has no substantial protein binding the risk of pharmacokinetic drug interactions is very low. The half-life of sotalol ranges between 10 and 20 hours. The main indication for sotalol is ventricular arrhythmias and supraventricular arrhythmias, and the normal dose is usually 160 to 320 mg daily (1-2).

Sotalol has been associated with cardiovascular side effects, especially torsades de pointes, and in the Swedish adverse drug reaction registry (SWEDIS) there are 49 cases of sotalol related torsades de pointes. All but six of these patients recovered, for four the outcome was unknown at the time of the report and two died due to other causes. In total there are 103 reports of cardiovascular adverse events with sotalol (3). In the WHO database one death has been reported in relation to sotalol treatment (4). In SWEDIS there are a total of 10 cases. Three of which were unrelated to the drug treatment, and one where the combination of diltiazem, rofecoxib as well as sotalol was suspected (3).

A summary of the current opinions about the therapeutic use and effect of sotalol is given below: According to one review article the use of sotalol in patients with atrial fibrillation can be recommended only for patients who are using low doses of sotalol, having a low risk for torsades de pointes and who are ECG monitored. The risk of side effects is decreased if the drug is started after cardioversion (5). Compared to placebo, sotalol decreased the incidence of myocardial reinfarction, in a study on totally 1456 patients suffering from arrhythmias, although the mortality was relatively high during the first week. The overall mortality rate was 7.3 and 8.9 % for sotalol and placebo, respectively. The benefit from sotalol was seen later in the follow-up period. The treatment was considered to be safe in these patients, but still other beta-adrenergic antagonists would be the preferred treatment (6).

When evaluating the use of sotalol (160 to 320 mg daily) and quinidine in a study with 98 and 85 patients, respectively, suffering from chronic atrial fibrillation, it was concluded that sotalol was as effective as quinidine in maintaining the sinus rhythm after cardioversion. Sotalol was however better tolerated. Sotalol was more effective in suppressing unsustained ventricular arrhythmias than both propranolol and procainamide, but as effective as quinidine (6). It was not reported whether the doses of sotalol and quinidine used were equipotent. The overall mortality rate was not reported either.

In the United States sotalol has been widely used for atrial fibrillation (AF) although it was only approved for ventricular arrhythmias. Today, only one sotalol product has been approved for atrial fibrillation by the FDA. When using sotalol in the treatment of atrial fibrillation, most recommendations suggest it to be used only in the absence of structural heart disease or heart failure. In patients with hypertension together with left ventricular hypertrophy the risk of torsades de pointes is increased. When initiating sotalol treatment it is recommended to monitor patients until steady-state has been reached. When treating atrial fibrillation the approach of many physicians, at least in the United States, is to start at a dose of 80 mg x3 the first day, 120 mg x 2 the second day and 160 mg twice daily the next day or 2. The patient is then discharged at a dose of 120 mg twice daily. A later increase to 160 mg x2 can be performed when necessary (7).

In a meta-analysis of 42 trials, evaluating the use of beta-blockers, amiodarone or sotalol for preventing postoperative AF, it was concluded that the efficacy of sotalol, amiodarone and beta-blockers were quite similar (8). The hospital length of stay (LOS), which was also evaluated, did not decrease to any significant extent, neither with sotalol treatment nor beta-blockers. Amiodarone, however, reduced the LOS significantly by 0.91 days. The authors conclude that beta-blockers should be considered as the first-line treatment for prevention of postoperative AF, even though amiodarone and sotalol are appropriate alternatives (8). There was no evidence that prophylactic treatment against stroke would be of any benefit.

Another meta-analysis, including 10 studies, which compared amiodarone and sotalol treatments as prophylaxis against atrial fibrillation/flutter (AFF) after heart surgery came to the conclusion that sotalol is as effective as amiodarone in reducing AFF (9). The numbers of side effects requiring drug discontinuations were fewer in patients treated with amiodarone, but when the two treatments were compared with each other no significant differences were observed (9). In two of the sotalol studies the incidence of adverse effects (mainly bradycardia and hypertension) ranged between 10 and 24%, while none of the amiodarone studies reported any differences in the incidence of adverse effects between treatment and placebo groups (9). Neither sotalol nor amiodarone had any effect on the duration of hospitalization and both treatments were regarded as equally effective regarding the prevention of AFF (9).

Several studies have been performed on the effects of sotalol in sustained ventricular arrhythmias. In one of these studies, where programmed electrical stimulation was used, sotalol completely prevented the reinduction of tachycardia in 33 patients (31%) out of 106, and in 29 (27%) it slowed the tachycardia. In 44 patients (42%) sotalol did not have any measurable effects (6). In another study, doses of 240 to 640 mg of sotalol daily, prevented induction of ventricular tachycardia or fibrillation in 42% of totally 172 patients (6).

The conclusions from one study, performed on 486 patients with sustained ventricular tachyarrhythmias, were that the risks of death from any cause, cardiac cause or death from arrhythmia, were significantly lower in patients treated with sotalol than with any of the other antiarrhythmic drugs administered, ie imipramine, mexiletine, pirmenol, procainamide, propafenone and quinidine. Sotalol was also demonstrated to be the most effective drug, and the one associated with the lowest number of adverse effects as well as with the lowest number of discontinuations. However, seven of totally ten episodes of torsades de pointes occurred in patients receiving sotalol. The overall efficacy (as defined by the authors) was significantly better for sotalol, in comparison with the other treatment groups. These data must however be cautiously interpreted since the patients were highly selected, and six of the seven drugs were calcium-channel blockers, which are known not to be particularly effective in treating sustained tachycardia or to prevent sudden death. Furthermore neither placebo nor other beta-adrenergic antagonists were included (6, 10).

It has been shown that D-sotalol is more effective in prolonging atrial action potentials than ventricular action potentials, suggesting D-sotalol to be more effective for supra-ventricular arrhythmias than ventricular arrhythmias (11). In an extensive trial (SWORD) the survival with oral D-sotalol was investigated in patients previously surviving a myocardial infarction (MI), and having a left ventricular ejection fraction (LVEF) of < 40%. The study had to be discontinued in advance due to an increase in mortality rate in the D-sotalol group compared to the placebo group. When analysing the results, the mortality was hii