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Discussion
Main Findings
The main results of this study are: (1) bepridil was more effective than amiodarone in achieving sinus conversion (85% vs 35%, p<0.01) in patients with persistent AF; (2) the rate of sinus rhythm maintenance after conversion was higher in group B than in group A (75% vs 50%, p<0.01); and (3) no TdP or cardiac death was observed in the study, although one group B patient developed acute interstitial pneumonia requiring steroid therapy.
Conversion Effect on Sinus Rhythm
The prospect of spontaneous conversion to sinus rhythm is usually difficult in long persisting AF. Pharmacological conversion may also decline even if class Ic or Class III drugs are administered. According to a study by Kochiadakis et al on patients with chronic AF, conversion was achieved in 16 (47%) of 34 patients receiving amiodarone and in 13 (40.6%) of 32 patients receiving propafenone. In the SAFE-T study, 665 patients with persistent AF were randomly assigned to three groups and treated with amiodarone (267), sotalol (261) or placebo (137). After 28 days of drug administration, spontaneous sinus conversion was obtained in 27.1% of the patients receiving amiodarone, 24.2% of the patients receiving sotalol and 0.8% of the placebo controls. These results indicate that the pharmacological conversion is limited in patients with persistent AF.
The multi-ion channel blocker bepridil has recently drawn attention for its favourable sinus conversion effects in patients with persistent AF, both when administered alone or in combination with class I drugs. Several studies have reported a good rate of conversion to sinus rhythm by low dose bepridil. In our previous study, bepridil alone achieved a conversion rate of 58%. In a study by Fujiki et al, bepridil alone or in combination with aprindine restored sinus rhythm in 69% of 32 patients with persistent AF. Imai et al reported that the combined use of flecainide with bepridil was effective in patients in whom bepridil alone failed to bring about conversion. In the first part of their study, the administration of bepridil alone to 32 patients with persistent AF restored sinus rhythm in only nine patients. Next, when flecainide and bepridil were administered in combination in the remaining 23 patients, sinus conversion was obtained in 22 patients (96%).
While the high conversion effects from these studies are certainly significant, we should point out that the studies were observational and open labelled. Validation of the utility of bepridil for persistent AF would require a multicentre, randomised, placebo-controlled, double-blind study (J-BAF study). In a population of 90 patients, sinus conversion was achieved in 3.4% of the placebo control, 37.5% of the patients receiving 100 mg/day and 69% of the patients receiving 200 mg/day.
When Perelman et al compared the effects of amiodarone and bepridil in 24 patients with AF, conversion to sinus rhythm was achieved in four (40%) of 10 patients receiving amiodarone and in nine (64%) of 14 patients receiving bepridil. In our study, conversion was achieved in 85% of the patients receiving bepridil and 35% of the patients receiving amiodarone. The results from both studies suggest that bepridil is superior to amiodarone for pharmacological sinus conversion in persistent AF. We propose two factors that may at least partly explain the difference in efficacy between bepridil and amiodarone: (1) the ultra rapid (Ik-ur) K current observed exclusively in the atrium is specifically blocked by bepridil, and not by amiodarone and (2) the combined inhibition of Ikr and Ik-ur by bepridil is synergistic and produces an action potential prolongation effect much larger than the sum of the effects of individual channel blockades.
Maintenance Effect of Sinus Rhythm
Randomised, placebo-controlled, multicentre studies to assess amiodarone have already been conducted. In the CTAF study by Roy et al, AF recurred in 71 (35%) of 201 patients receiving amiodarone (mean follow-up of 16 months) versus 127 (63%) of 201 patients receiving sotalol or propafenone. The SAFE-T study compared the rate of sinus rhythm maintenance in patients treated with amiodarone, sotalo and placebo over a much longer period. Amiodarone maintained sinus rhythm in 50% of the patients over a follow-up of almost 30 months and was significantly more effective than both sotalol and placebo. The only data available on bepridil treatment are observational. It would be difficult to attempt a simple comparison of effectiveness between amiodarone and bepridil using only the data now available. In our randomised study, sinus rhythm was maintained in 50% of the group A patients and 75% of the group B patients over an average follow-up of 12 months. As we have already reported, bepridil was significantly more effective than amiodarone in both restoring and maintaining it.
In a study with a long-term follow-up, Shiga et al reported that bepridil might not improve the clinical outcome. Another point of concern when using bepridil is clinical safety: bepridil should only be used under the careful observation of an arrhythmia specialist, and only for selected cases of persistent AF with appropriate indications.
Safety Analysis
Previous investigators warned that the relatively strong potassium-channel-blocking effects of bepridil sometimes render serious adverse complications such as TdP, complications whose risks, they concluded, outweighed the benefits. Yet the bepridil doses their patients received (ranging from 200 mg to 600 mg of per day) suggest that TdP may have been induced not by the type of agent, but high dosages. In the J-BAF study, one patient receiving 200 mg of bepridil per day died of ventricular tachycardia (VT). This patient, however, showed no QT prolongation, and his serum K was 4.2 mmol/l upon hospitalisation. The data were insufficient to clearly implicate bepridil overdose as the cause of VT in this patient, and QT prolongation and bradycardia were conspicuous in this patient even when the patient received the 200 mg/day dose. Hence, the J-BAF authors warned that the indication should be restricted for patients with certain backgrounds, even when administering bepridil at a low dose. The patients in our study who received a maximum dose of 200 mg/day showed no signs of TdP, though four of them did show marked QT prolongation. In light of these experiences, we also recommend careful follow-up of patients receiving even a low dose of bepridil (<200 mg/day) with close observation of the QT interval and serum potassium levels.
On the other hand, we observed no serious adverse complications in our group A patients. The only side effects found were minor conditions such as hypothyroidism and bradycardia. We note, with interest, that interstitial pneumonia, the most common adverse effect of amiodarone, developed in one of the bepridil-treated patients in this study. Sporadic cases of bepridil-induced interstitial pneumonia have been reported, and some of them have required steroid pulse therapy. This adverse complication should be always kept in mind when administering amiodarone and bepridil.
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