Elsevier

The Lancet

Volume 348, Issue 9019, 6 July 1996, Pages 7-12
The Lancet

Articles
Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction*

https://doi.org/10.1016/S0140-6736(96)02149-6Get rights and content

Summary

Background

Left ventricular dysfunction after myocardial infarction is associated with an increased risk of death. Other studies have suggested that a potassium-channel blocker might reduce this risk with minimal adverse effects. We investigated whether d-sotalol, a pure potassium-channel blocker with no clinically significant beta-blocking activity, could reduce all-cause mortality in these high-risk patients.

Methods

Patients with a left ventricular ejection fraction of 40% or less and either a recent (6–42 days) myocardial infarction or symptomatic heart failure with a remote (>42 days) myocardial infarction were randomly assigned d-sotalol (100 mg increased to 200 mg twice daily, if tolerated) or matching placebo twice daily.

Findings

After 3121 of the planned 6400 patients had been recruited, the trial was stopped. Among 1549 patients assigned d-sotalol, there were 78 deaths (5·0%) compared with 48 deaths (3·1%) among the 1572 patients assigned placebo (relative risk 1·65 [95% CI 1·15–2·36], p=0·006). Presumed arrhythmic deaths (relative risk 1·77 [1·15–2·74], p=0·008) accounted for the increased mortality. The effect was greater in patients with a left ventricular ejection fraction of 31–40% than in those with lower (≤30%) ejection fractions (relative risk 4·0 vs 1·2, p=0·007).

Interpretation

Among the 1549 patients evaluated, administration of d-sotalol was associated with increased mortality, which was presumed primarily to be due to arrhythmias. The prophylactic use of a specific potassium-channel blocker does not reduce mortality, and may be associated with increased mortality in high-risk patients after myocardial infarction.

Introduction

Survivors of myocardial infarction (MI) face an increased risk of sudden cardiac death.1 When MI is recent, depressed left ventricular function,2 ventricular ectopic activity,3 signal-averaged late potentials,4 low heart rate variability,5 and low baroreflex sensitivity6 identify patients at highest risk. When MI is remote, the risk of sudden cardiac death remains substantial7 but high-risk patients are not easy to define. Left ventricular dysfunction is regarded as the best predictor of total mortality.

Beta-adrenergic blockers provide some protection from all-cause mortality and sudden cardiac death after MI.8 However, these drugs are used infrequently in patients with impaired ventricular function.9, 10 Results with flecainide, encainide, and moricizine in the Cardiac Arrhythmia Suppression Trials (CAST),9, 11, 12 together with previous results for other class I antiarrhythmic drugs,13 have shown that sodium-channel-blocking agents are associated with increased rather than decreased all-cause mortality and sudden cardiac death despite suppression of arrhythmia. Results with class III antiarrhythmic drugs were expected to be different. Studies of the class III antiarrhythmic amiodarone after MI14, 15 and in congestive heart failure16 established that amiodarone was at least safe and may have improved survival.17 Because amiodarone prolongs action potential duration by potassium-channel blockade, it has been proposed that other potassium-channel blockers, lacking the toxicity of amiodarone, might also be protective. Such extrapolation may be unwarranted because amiodarone has other ion-channel effects, including sodium-channel and calcium-channel blockade, as well as non-competitive alpha-adrenergic and beta-adrenergic blockade, and it is a coronary vasodilator.18

Among available potassium-channel blockers, d-sotalol has been most widely used. It is the dextrorotatory optical isomer of the racemate d, l-sotalol,19 and blocks Ikr, the rapid component of the delayed-rectifier current. d-sotalol lacks clinically significant beta-blocking activity20, 21 and would be expected to be well tolerated by patients with severe left ventricular dysfunction. Antifibrillatory activity of d-sotalol has been shown in some experimental models22 but not in others.23 The Survival With Oral d-Sotalol (SWORD) trial was a multinational, multicentre, placebo-controlled, randomised, double-blind trial of d-sotalol to test the hypothesis that a drug with a pure potassium-channel-blocking action reduces all-cause mortality in patients with previous MI and left ventricular dysfunction.

Section snippets

Patients and methods

SWORD24 was a randomised, double-blind, placebo-controlled, trial of oral d-sotalol at 546 centres, of which 406 actually enrolled patients, most of whom were outpatients. Eligible patients were men and women 18 years or older, with left ventricular ejection fraction 40% or less (measured by echocardiography, radionuclide angiography, or contrast ventriculography) and either a recent (6–42 days) MI or a remote (>42 days) MI with overt heart failure (New York Heart Association class II or III).

Results

By Nov 1, 1994, after 2·3 years of recruitment, the SWORD trial had enrolled 3121 patients with mean follow-up of 148 days. At that time, the data and safety monitoring board recommended termination of the trial because an interim analysis showed increased mortality among patients assigned d-sotalol that crossed the prespecified advisory statistical boundary (observed Z=−2·75).

The trial originally intended to recruit two patients with recent MI for each one with remote MI. However, at the time

Discussion

This study has shown a significant adverse association of d-sotalol with all-cause mortality in patients with recent and remote MI and left ventricular systolic dysfunction. These findings may have implications for the use of other class III potassium-channel-blocking antiarrhythmic drugs. These implications are all the more important given that SWORD was not a trial for suppression of frequent or complex ventricular ectopy but a secondary prevention trial. Furthermore, the SWORD trial was

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