Amiodarone for Sinus Tachycardia in Heart Failure

ABSTRACT & COMMENTARY

Synopsis: High resting heart rates in heart failure patients identify a subgroup that benefits from low-dose amiodarone therapy, especially if it reduces their heart rate at six months.

Source: Nul DR, et al. J Am Coll Cardiol 1997; 29:1199-1205.

Patients with heart failure often have inappropriate rapid heart rate, despite good control of their heart failure with ACE inhibitors, diuretics, and digoxin. Amiodarone can slow the sinus rate in addition to its antiarrhythmic properties. The Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (GESICA) trial, which randomized patients with heart failure not on other antiarrhythmics to low-dose amiodarone vs. placebo, showed a 28% reduction in all-cause mortality at two years, which was independent of ambient ventricular arrhythmias on entry and was associated with improved functional capacity, suggesting a benefit of amiodarone beyond its antiarrhythmic effect. Thus, the investigators retrospectively analyzed the mortality benefit of amiodarone in GESICA relative to baseline heart rate and its change during therapy. The 516 patients in GESICA were in NYHA functional classes II-IV, but all were symptomatic and had an ejection fraction less than 35%. After loading, the amiodarone dose was 300 mg, and follow-up was for two years. Heart rate was determined from physical examination at baseline and six months. The amiodarone and control groups were stratified at a mean resting heart rate of below 90 vs. ³ 90 beats/min.

In the baseline heart rate ³ 90 group, amiodarone decreased all-cause mortality to 38% vs. 62% in the control group (relative risk (RR) 0.55; P < 0.002). Also, sudden death was reduced (RR 0.46; P < 0.02), as was progressive heart failure (RR 0.6; P < 0.06). In the < 90 baseline heart rate group, amiodarone did not alter survival. The six-month follow-up heart rate data showed that in the baseline heart rate ³ 90 group, amiodarone reduced heart rate 13 ± 16 beats/min vs. an observed 8 ± 13 beats/min in the control group (P < 0.02). In the baseline heart rate < 90 group, there was an increase in heart rate that was greater in the control group 7 ± 12 vs. 2 ± 12 beats/min in the amiodarone group. Mortality in the ³ 90 group was lower on amiodarone therapy in those whose heart rate decreased at six months (22%) vs. the control patients (54%; P < 0.002). In the < 90 group, there were no mortality differences, regardless of heart rate changes at six months. Also, there were more patients in functional class I and II in the ³ 90 group treated with amiodarone at six months (51%) vs. the control patients (32%), and the proportion in class IV was also reduced by amiodarone as compared to control (18 vs 34%; P < 0.02). Patients in the < 90 group exhibited no differences in functional class between amiodarone and control. Nul and colleagues conclude that high resting heart rates in heart failure patients identify a subgroup that benefits from low-dose amiodarone therapy, especially if it reduces their heart rate at six months.

COMMENT BY MICHAEL H. CRAWFORD, MD

These results of the GESICA trial are interesting and provocative. Increased heart rate is a bad prognostic sign in heart failure, but in patients with severe heart failure (class III, IV), attempts to slow it with traditional beta-blockers often result in worsening heart failure. Whether this response would be seen in patients treated with carvedilol is unclear since trials with this drug have generally included patients with lesser degrees of heart failure and slower heart rates than those observed in GESICA. Thus, amiodarone may be the most appropriate additional treatment for severe heart failure patients with sinus tachycardia. Not only will it reduce heart rate, but ventricular performance and functional class may be enhanced. Also, amiodarone is a potent type III antiarrhythmic with few proarrhythmic effects. Possibly, for all these reasons, survival is enhanced.

In this study, benefit was confined to those with a baseline heart rate ³ 90 beats/min and if a reduction in heart rate was observed after six months of amiodarone. Thus, if amiodarone fails to reduce heart rate on physical examination at six months, an argument could be made to stop it at that point, if there was no other indication for it. Interestingly, benefit was proportional to the magnitude of resting baseline heart rate. Those in the highest quintile (³ 100 beats/min) had a 65% decrease in mortality rate, and those in the lowest (< 76 beats/min) had a nonsignificant trend toward increased mortality. Perhaps lower heart rates are a contradiction to amiodarone therapy. Whether the degree of heart rate lowering at six months was also related to survival benefit was not reported. Also, since a fixed dose was used in this study, we do not know if titrating the amiodarone dose to a reduced heart rate end point would be beneficial.

The major limitation of this study is that it is a retrospective analysis of a trial that did not specify heart rate stratification as a covariate. There were observed differences in the baseline characteristics of the heart rate < 90 and ³ 90 beats/min groups. The ³ 90 group was younger, had lower blood pressure, lower serum Na, lower ejection fraction, and had more class IV patients that were on more standard medications. Basically, they were a sicker group as might be expected. Of interest, about 10% of both heart rate groups were in atrial fibrillation at baseline, but no detailed analysis of this subgroup is provided. Also, the results did not seem to differ by etiology of heart failure.

The potential mechanism of this beneficial effect of amiodarone is unclear. Amiodarone may have non-competitive antiadrenergic effects, which could be beneficial in the same way beta-blockers are, but likely there are other effects as well. It is possible that slowing the heart rate alone is the primary benefit of amiodarone in heart failure patients. Clearly, the benefit was confined to those with fast rates whose rate decreased. Slowing the heart rate may increase ventricular filling, coronary blood flow, and the contractile state of the left ventricle. The observed increases in ejection fraction noted in this and other amiodarone trials (Circulation 1996;93:2128- 2134) and in beta-blocker trials (N Engl J Med 1996;334:1348-1355) support this concept. However, in my limited experience, amiodarone has a greater safety margin for reducing heart rate than do traditional beta- blockers in severe heart failure patients.