Valembois Lucie, Audureau Etienne, Takeda Andrea, Jarzebowski Witold, Belmin Joël, Lafuente-Lafuente Carmelo
Service de Gériatrie à Orientation Cardiologique et Neurologique, Groupe Hospitalier Pitié-Salpêtrière-Charles Foix, AP-HP, Université Pierre et Marie Curie, 7 avenue de la République, Ivry-sur-Seine, France, 94200.
Cochrane Database Syst Rev. 2019 Sep 4;9(9):CD005049. doi: 10.1002/14651858.CD005049.pub5.
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 mortalityHigh-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 eventsAll 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.ProarrhythmiaVirtually 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.StrokeEleven 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 fibrillationModerate- 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.
AUTHORS' CONCLUSIONS: 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.
心房颤动是最常见的持续性心律失常。心房颤动在恢复正常窦性心律后常复发。抗心律失常药物已被广泛用于预防复发。这是对先前于2006年、2012年和2015年发表的一篇综述的更新。
确定抗心律失常药物长期治疗对心房颤动恢复窦性心律的患者的死亡、中风、药物不良反应及心房颤动复发的影响。
我们于2019年1月更新了对Cochrane系统评价数据库、医学期刊数据库和荷兰医学文摘数据库的检索，并于2019年2月更新了对美国国立医学图书馆临床试验注册库和世界卫生组织国际临床试验注册平台的检索。我们检查了检索到的文章、近期综述和荟萃分析的参考文献列表。
两位作者独立选择随机对照试验（RCT），这些试验比较了任何抗心律失常药物与对照（不治疗、安慰剂、控制心率的药物）或与另一种抗心律失常药物，试验对象为患有心房颤动且已恢复窦性心律的成年人，窦性心律恢复可为自发恢复或通过任何干预恢复。我们排除了术后心房颤动。
两位作者独立评估质量并提取数据。如果合适，我们使用Mantel-Haenszel风险比（RR）及95%置信区间（CI）对研究进行汇总。所有结果均在随访一年时或最接近的时间点计算得出。
本次更新纳入了一项新研究（100名参与者），并排除了一项先前纳入的研究，原因是该研究存在重复发表情况。最终，我们纳入了59项RCT，共20981名参与者，研究了奎尼丁、丙吡胺、普罗帕酮、氟卡尼、美托洛尔、胺碘酮、多非利特、决奈达隆和索他洛尔。总体而言，平均随访时间为10.2个月。
五项RCT的高确定性证据表明，与安慰剂或不治疗相比，索他洛尔治疗与更高的全因死亡率相关（RR 2.23，95%CI 1.03至4.81；参与者 = 1882）。索他洛尔导致额外有害结局的需治疗人数（NNTH）为治疗一年有102名参与者会额外出现一例死亡。六项RCT的低确定性证据表明，服用奎尼丁的人死亡风险可能更高（RR 2.01，95%CI 0.84至4.77；参与者 = 1646）。中度确定性证据显示，与安慰剂相比，美托洛尔（RR 2.02，95%CI 0.37至11.05，2项RCT，参与者 = 562）和胺碘酮（RR 1.66，95%CI 0.55至4.99，2项RCT，参与者 = 444）的死亡率RR增加，但置信区间非常宽。与安慰剂/不治疗相比，我们发现多非利特（RR 0.98，95%CI 0.76至1.27；中度确定性证据）或决奈达隆（RR 0.86，95%CI 0.68至1.09；高确定性证据）的死亡率几乎没有差异。关于丙吡胺、氟卡尼和普罗帕酮的死亡率数据很少，无法对这些药物进行可靠估计。
与安慰剂或不治疗相比，所有分析的药物因不良反应导致的停药率均增加（奎尼丁：RR 1.56，95%CI 0.87至2.78；丙吡胺：RR 3.68，95%CI 0.95至14.24；普罗帕酮：RR 1.62，95%CI 1.07至2.46；氟卡尼：RR 15.41，95%CI 0.91至260.19；美托洛尔：RR 3.47，95%CI 1.48至8.15；胺碘酮：RR 6.70，95%CI 1.91至23.45；多非利特：RR 1.77，95%CI 0.75至4.18；决奈达隆：RR 1.58，95%CI 1.34至1.85；索他洛尔：RR 1.95，95%CI 1.23至3.11）。丙吡胺、胺碘酮、多非利特和氟卡尼这一结局的证据确定性较低；其余药物的证据确定性为中度至高。
几乎所有研究的抗心律失常药物均显示致心律失常作用增加（包括归因于治疗的快速性心律失常和缓慢性心律失常）（奎尼丁：RR 2.05，95%CI 0.95至4.41；丙吡胺：无数据；氟卡尼：RR 4.80，95%CI 1.30至17.77；美托洛尔：RR 18.14，95%CI 2.42至135.66；胺碘酮：RR 2.22，95%CI 0.71至6.96；多非利特：RR 5.50，95%CI 1.33至22.76；决奈达隆：RR 1.95，95%CI 0.77至4.98；索他洛尔：RR 3.55，95%CI 2.16至5.83）；普罗帕酮除外（RR 1.32，95%CI 0.39至4.47），其证据确定性非常低，我们对其效果不确定。其他药物这一结局的证据确定性为中度至高。
11项研究报告了奎尼丁、丙吡胺、氟卡尼、胺碘酮、决奈达隆和索他洛尔的中风结局。两项RCT的高确定性证据表明，决奈达隆可能与中风风险降低相关（RR 0.66，95%CI 0.47至0.95；参与者 = 5872）。这一结果归因于一项在荟萃分析中占主导地位的研究，尚未在其他研究中得到重复验证。其他抗心律失常药物对中风发生率无明显影响。
中度至高确定性证据表明，除丙吡胺为低确定性证据外，所有分析的药物，包括美托洛尔，均可降低心房颤动复发率（奎尼丁：RR 0.83，95%CI 0.78至0.88；丙吡胺：RR 0.77，95%CI 0.59至1.01；普罗帕酮：RR 0.67，95%CI 0.61至0.74；氟卡尼：RR；0.65，95%CI 0.55至0.77；美托洛尔：RR 0.83，95%CI 0.68至1.02；胺碘酮：RR 0.52，95%CI 0.46至0.58；多非利特：RR 0.72，95%CI 0.61至0.85；决奈达隆：RR 0.85，95%CI 0.80至0.91；索他洛尔：RR 0.83，95%CI 0.80至0.87）。尽管复发率有所降低，但接受抗心律失常药物治疗的患者中仍有43%至67%会复发心房颤动。
有高确定性证据表明，索他洛尔治疗会增加死亡率，低确定性证据表明奎尼丁用于维持心房颤动患者的窦性心律时会增加死亡率。我们发现服用丙吡胺、氟卡尼和普罗帕酮的人的死亡率数据很少，因此无法对这些药物的死亡风险进行可靠估计。然而，我们确实发现有中度确定性证据表明氟卡尼的致心律失常作用和不良反应显著增加。总体而言，有证据表明抗心律失常药物会增加不良事件、增加致心律失常事件，且一些抗心律失常药物可能会增加死亡率。相反，尽管它们可降低心房颤动的复发率，但与安慰剂或不治疗相比，没有证据表明对其他临床结局有任何益处。
