Review question
We reviewed the evidence about the effect of antiarrhythmic medicines on mortality (death), stroke, side effects that cause people to stop taking the medicine and recurrences of irregular heartbeat, in people who had recovered normal heart rhythm after having atrial fibrillation (a type of irregular heartbeat).
Background
Atrial fibrillation is a disease where the heart rhythm is irregular (called arrhythmia) and often, but not always, too fast. Atrial fibrillation may produce complications, either in the heart (heart failure, fainting) or in other organs by causing embolisms. Embolisms are blood clots that form in the cavities of the heart which may then travel to other places, for example the brain.
Atrial fibrillation can be reverted, restoring normal heart rhythm, by using medicines or a controlled electrical shock. However, a major problem is that atrial fibrillation frequently recurs. A variety of medicines have been used to avoid these recurrences and keep the normal heart rhythm.
Study characteristics
This is an update of a review previously published in 2006, 2012 and 2015, and includes results of a search for new studies in January 2019. We found 59 studies testing various antiarrhythmic drugs and involving 20,981 participants. The average age of participants was 65 years. The most frequent diseases were hypertension (high blood pressure) and diseases of the arteries and valves of the heart. We found studies for nine medicines: quinidine, disopyramide, propafenone, flecainide, metoprolol, amiodarone, dofetilide, dronedarone and sotalol.
Key results and certainty of the evidence
High-certainty evidence from five studies found that deaths from any cause were twice as high in people taking sotalol compared with people taking a placebo (dummy treatment) or no treatment. We calculated that one extra person would die for every 102 people taking sotalol for one year. Evidence for quinidine was low certainty, but the average effect across six studies suggested that people who took quinidine may have a higher risk of death compared with people taking no treatment or placebo. However, the evidence was not strong enough to rule out the possibility that there was no increased risk of death with quinidine. We found few data on mortality for disopyramide, flecainide and propafenone, meaning that we are uncertain of the effect of these drugs on mortality. We found no clear evidence that the other medicines we studied had any effect on risk of death.
We found that people taking any of these medicines were more likely to stop taking them due to side effects, compared with people not taking them. We are less certain of the results for disopyramide, amiodarone, dofetilide and flecainide because the low-certainty evidence mostly came from small studies with design limitations. Evidence was moderate or high for the other medicines.
One particular side effect of antiarrhythmic medications is proarrhythmia, which means that people have new or more frequent problems with irregular heartbeats. We found high-certainty evidence that people taking quinidine or metoprolol had a higher risk of proarrhythmia than people taking no treatment or placebo. Moderate-certainty evidence indicated a similar increased risk for flecainide, amiodarone, dofetilide, dronedarone and sotalol. Evidence from these studies was moderate certainty due to problems with study limitations, smaller size or imprecise results. We are uncertain of the effect of propafenone on proarrhythmia as we only had very low-certainty evidence for this medicine. None of the disopyramide studies reported how many people had proarrhythmia.
We found high-certainty evidence that dronedarone may reduce the risk of stroke. There was no evidence of an effect of sotalol (moderate-certainty evidence); amiodarone, flecainide, quinidine (all low-certainty evidence) or disopyramide (very low-certainty evidence) on risk of stroke. No studies reported risk of stroke with propafenone, metoprolol or dofetilide.
Moderate- to high-certainty evidence, except disopyramide which was low certainty, showed that all the medicines we assessed reduced recurrence of atrial fibrillation, compared with not taking any treatment or taking a placebo. However, atrial fibrillation still recurred in about half of participants (43% to 67%) treated with antiarrhythmics.
Overall, It is unclear whether long-term treatment with antiarrhythmic medicines carries benefits that outweigh their risks for this group of people.
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. We 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, we 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.
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. This is an update of a review previously published in 2006, 2012 and 2015.
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.
We updated the searches of CENTRAL, MEDLINE and Embase in January 2019, and ClinicalTrials.gov and WHO ICTRP in February 2019. We checked the reference lists of retrieved articles, recent reviews and meta-analyses.
Two authors independently selected randomised controlled trials (RCTs) comparing any antiarrhythmic drug with a control (no treatment, placebo, drugs for rate control) or with another antiarrhythmic drug in adults who had atrial fibrillation and in whom sinus rhythm was restored, spontaneously or by any intervention. We excluded postoperative atrial fibrillation.
Two authors independently assessed quality and extracted data. We pooled studies, if appropriate, using Mantel-Haenszel risk ratios (RR), with 95% confidence intervals (CI). All results were calculated at one year of follow-up or the nearest time point.
This update included one new study (100 participants) and excluded one previously included study because of double publication. Finally, we included 59 RCTs comprising 20,981 participants studying quinidine, disopyramide, propafenone, flecainide, metoprolol, amiodarone, dofetilide, dronedarone and sotalol. Overall, mean follow-up was 10.2 months.
All-cause mortality
High-certainty evidence from five RCTs 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 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 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.
We found little or no difference in mortality 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.
Proarrhythmia
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 we were uncertain about the effect. Certainty of the evidence for this outcome for the other drugs was moderate to high.
Stroke
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.