Predicting mortality after myocardial infarction from the response of RR variability to antiarrhythmic drug therapy.
OBJECTIVE
This study was designed to test the hypothesis that antiarrhythmic drugs that decrease RR variability will predict all-cause mortality during follow-up after myocardial infarction.


BACKGROUND
RR variability, a noninvasive indicator of autonomic nervous system activity, predicts death after acute myocardial infarction independently of other risk predictors and changes substantially in response to some drugs. A previous study in patients with chronic heart disease and frequent ventricular premature complexes reported that flecainide decreased vagal modulation of RR intervals but amiodarone did not. The investigators of that study speculated that changes in RR variability during antiarrhythmic drug therapy predict an increased mortality rate during long-term drug treatment. To explore this hypothesis further, we compared the effects of encainide and flecainide, which increase long-term mortality substantially, on RR variability with the effects of placebo and moricizine, which have no significant effect on mortality during long-term treatment of unsustained ventricular arrhythmias after myocardial infarction.


METHODS
The 24-h power spectral density was computed from the baseline electrocardiographic recordings and drug evaluation tapes, and six frequency domain measures of RR variability were calculated: ultra-low frequency (< 0.0033 Hz), very low frequency (0.0033 to < 0.04 Hz), low frequency (0.04 to < 0.15 Hz) and high frequency power (0.15 to < 0.40 Hz), plus total power (< 0.40 Hz) and the ratio of low to high frequency power. Changes in power spectral measures were related to drug treatment and to mortality.


RESULTS
In the placebo group, values for RR interval and RR variability increased because of recovery from the effects of acute myocardial infarction. Contrasting placebo treatment with all three active antiarrhythmic drug treatments taken together showed that of all the measures of RR variability, only NN50, pNN50 and low frequency power changed significantly during drug treatment (Bonferroni adjusted p value < 0.025); these variables all decreased during drug therapy. Contrasting encainide and flecainide with moricizine, we found that the encainide and flecainide groups taken together showed a larger decrease in dLF than moricizine, but the difference was of borderline significance (Bonferroni adjusted p value < 0.08). Survival was significantly worse in the groups treated with encainide and flecainide than in the groups treated with placebo or moricizine (relative risk > 2.0, adjusted p < 0.05). The antiarrhythmic drug-induced change in measures of RR variability was not a significant predictor of all-cause mortality during a year of follow-up after myocardial infarction.


CONCLUSIONS
Encainide, flecainide and moricizine all caused a decrease in RR variability in patients studied approximately 1 month after acute myocardial infarction. Encainide and flecainide caused a significant increase in mortality rates; placebo and moricizine did not. Baseline measurements of RR variability also predicted all-cause mortality after myocardial infarction. The decrease in RR variability produced by the three antiarrhythmic drugs did not predict mortality during follow-up.
Bigger
J T
JT
Department of Medicine, School of Public Health, Columbia University, New York, New York 10032.
Rolnitzky
L M
LM
Steinman
R C
RC
Fleiss
J L
JL
D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D005117:Cardiac Complexes, Premature / Q000188:drug therapy*; D015716:Electrocardiography, Ambulatory / Q000379:methods*; D016700:Encainide / Q000627:therapeutic use; D005260:Female; D005424:Flecainide / Q000627:therapeutic use; D005500:Follow-Up Studies; D006329:Heart Conduction System / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016293:Moricizine / Q000627:therapeutic use; D009203:Myocardial Infarction / Q000401:mortality*; D012307:Risk Factors; D012815:Signal Processing, Computer-Assisted
D000889:Anti-Arrhythmia Agents; D016293:Moricizine; D005424:Flecainide; D016700:Encainide