Atrial fibrillation is the most frequent sustained arrhythmia. Atrial fibrillation often recurs after restoration of normal sinus rhythm.
Antiarrhythmic drugs have been widely used to prevent recurrence.
Researchers have carried out a review was to determine the effects of long-term treatment with antiarrhythmic drugs on death, stroke, drug adverse effects and recurrence of atrial fibrillation in people who had recovered sinus rhythm after having atrial fibrillation.
The update has included one new study ( 100 participants ) and excluded one previously included study because of double publication.
The research has included 59 RCTs ( randomized controlled trials ) comprising 20,981 participants studying Quinidine, Disopyramide, Propafenone, Flecainide, Metoprolol, Amiodarone, Dofetilide, Dronedarone and Sotalol.
Overall, mean follow-up was 10.2 months.
High-certainty evidence from five RCTs has indicated that treatment with Sotalol was associated with a higher all-cause mortality rate compared with placebo or no treatment ( RR 2.23, 95% CI 1.03 to 4.81; participants = 1882 ).
The number need to treat for an additional harmful outcome ( NNTH ) for Sotalol was 102 participants treated for one year to have one additional death.
Low-certainty evidence from six RCTs has suggested that risk of mortality may be higher in people taking Quinidine ( RR 2.01, 95% CI 0.84 to 4.77; participants = 1646 ).
Moderate-certainty evidence showed increased RR for mortality but with very wide CIs ( confidence intervals ) for Metoprolol ( RR 2.02, 95% CI 0.37 to 11.05, 2 RCTs, participants = 562 ) and Amiodarone ( RR 1.66, 95% CI 0.55 to 4.99, 2 RCTs, participants = 444 ), compared with placebo.
Little or no difference in mortality was found with Dofetilide ( RR 0.98, 95% CI 0.76 to 1.27; moderate-certainty evidence ) or Dronedarone ( RR 0.86, 95% CI 0.68 to 1.09; high-certainty evidence ) compared to placebo / no treatment.
There were few data on mortality for Disopyramide, Flecainide and Propafenone, making impossible a reliable estimation for those drugs.
Withdrawals due to adverse events
All analysed drugs increased withdrawals due to adverse effects compared to placebo or no treatment ( Quinidine: RR 1.56, 95% CI 0.87 to 2.78; Disopyramide: RR 3.68, 95% CI 0.95 to 14.24; Propafenone: RR 1.62, 95% CI 1.07 to 2.46; Flecainide: RR 15.41, 95% CI 0.91 to 260.19; Metoprolol: RR 3.47, 95% CI 1.48 to 8.15; Amiodarone: RR 6.70, 95% CI 1.91 to 23.45; Dofetilide: RR 1.77, 95% CI 0.75 to 4.18; Dronedarone: RR 1.58, 95% CI 1.34 to 1.85; Sotalol: RR 1.95, 95% CI 1.23 to 3.11 ).
Certainty of the evidence for this outcome was low for Disopyramide, Amiodarone, Dofetilide and Flecainide; moderate to high for the remaining drugs.
Virtually all studied antiarrhythmics showed increased proarrhythmic effects ( counting both tachyarrhythmias and bradyarrhythmias attributable to treatment ) ( Quinidine: RR 2.05, 95% CI 0.95 to 4.41; Disopyramide: no data; Flecainide: RR 4.80, 95% CI 1.30 to 17.77; Metoprolol: RR 18.14, 95% CI 2.42 to 135.66; Amiodarone: RR 2.22, 95% CI 0.71 to 6.96; Dofetilide: RR 5.50, 95% CI 1.33 to 22.76; Dronedarone: RR 1.95, 95% CI 0.77 to 4.98; Sotalol: RR 3.55, 95% CI 2.16 to 5.83 ); with the exception of Propafenone ( RR 1.32, 95% CI 0.39 to 4.47 ) for which the certainty of evidence was very low and researchers were uncertain about the effect.
Certainty of the evidence for this outcome for the other drugs was moderate to high.
Eleven studies reported stroke outcomes with Quinidine, Disopyramide, Flecainide, Amiodarone, Dronedarone and Sotalol.
High-certainty evidence from two RCTs suggested that Dronedarone may be associated with reduced risk of stroke ( RR 0.66, 95% CI 0.47 to 0.95; participants = 5872 ). This result is attributed to one study dominating the meta-analysis and has yet to be reproduced in other studies.
There was no apparent effect on stroke rates with the other antiarrhythmics.
Recurrence of atrial fibrillation
Moderate- to high-certainty evidence, with the exception of Disopyramide which was low-certainty evidence, showed that all analysed drugs, including Metoprolol, reduced recurrence of atrial fibrillation ( Quinidine: RR 0.83, 95% CI 0.78 to 0.88; Disopyramide: RR 0.77, 95% CI 0.59 to 1.01; Propafenone: RR 0.67, 95% CI 0.61 to 0.74; Flecainide: RR 0.65, 95% CI 0.55 to 0.77; Metoprolol: RR 0.83 95% CI 0.68 to 1.02; Amiodarone: RR 0.52, 95% CI 0.46 to 0.58; Dofetilide: RR 0.72, 95% CI 0.61 to 0.85; Dronedarone: RR 0.85, 95% CI 0.80 to 0.91; Sotalol: RR 0.83, 95% CI 0.80 to 0.87).
Despite this reduction, atrial fibrillation still recurred in 43% to 67% of people treated with antiarrhythmics.
There is high-certainty evidence of increased mortality associated with Sotalol treatment, and low-certainty evidence suggesting increased mortality with Quinidine, when used for maintaining sinus rhythm in people with atrial fibrillation.
Investigators found few data on mortality in people taking Disopyramide, Flecainide and Propafenone, so it was not possible to make a reliable estimation of the mortality risk for these drugs.
However, investigators did find moderate-certainty evidence of marked increases in proarrhythmia and adverse effects with Flecainide.
Overall, there is evidence showing that antiarrhythmic drugs increase adverse events, increase proarrhythmic events and some antiarrhythmics may increase mortality.
Conversely, although they reduce recurrences of atrial fibrillation, there is no evidence of any benefit on other clinical outcomes, compared with placebo or no treatment. ( Xagena )
Valembois L et al, Cochrane Database Syst Rev 2019; Epub ahead of print