De Vecchis Renato, Ariano Carmelina
Unit of Preventive Cardiology and Rehabilitation, S. Gennaro dei Poveri Hospital, Naples, Italy -
Division of Geriatrics, Casa di Cura "Sollievo della Sofferenza", San Giovanni Rotondo, Foggia, Italy.
Minerva Cardioangiol. 2019 Apr;67(2):163-171. doi: 10.23736/S0026-4725.18.04719-9. Epub 2018 Sep 26.
The efficacy and safety profiles of the dronedarone were rather praised when the molecule was placed on the market (2009). However, there are today some safety concerns (in particular, risk of liver toxicity) that have led to limit the use of this drug to paroxysmal or persistent atrial fibrillation, and to exclude it from therapy protocols for ventricular tachyarrhythmias. The aim of the present study was to explore some efficacy and safety endpoints concerning dronedarone, by analyzing the evidence derived from quantitative evaluation (meta-analysis) of literature data.
We comprised in the meta-analysis exclusively randomized controlled trials (RCTs) that reported relevant clinical outcomes with dronedarone. In addition, eligible RCTs had to have randomized 100 patients at least in order to have adequate statistical power, and they had to have clearly reported the outcomes of interest. Primary efficacy outcomes were a) all-cause mortality,b) major acute cardiovascular events and c) worsening heart failure. Secondary outcomes of interest were ventricular tachyarrhythmias, stroke and systemic embolism. We performed a number of sensitivity analyses to better ascertain the sources of heterogeneity. We also performed a number of subgroup analyses.
At the end of the selection process, the studies regarded suitable for meta-analysis were seven. Dronedarone use was not associated with any significant advantage as regards all-cause mortality(pooled odds ratio =1.31; 95% CI: 0.78 to 2.18; P= 0.31) and major cardiovascular events (pooled odds ratio=1.45; 95% CI: 0.7 to 3.01; P=0.28), as well as regarding the endpoint" worsening heart failure" (pooled odds ratio =1.32; 95% CI: 0.87 to 2.01; P= 0.20). Moreover, using subgroup analyses, in patients with permanent AF, dronedarone use was associated with increased all-cause mortality compared to placebo(P=0.03),as well as with higher risk of major acute cardiovascular events (P=0.04) and episodes of worsening heart failure(P=0.02). In addition, when data from ATHENA study were excluded, dronedarone use was associated with increased all-cause mortality (post exclusion pooled odds ratio=1.77; 95% CI: 1.15 to 2.72; P=0.0089), increased risk of major cardiovascular events (post exclusion pooled odds ratio=2.16; 95% CI: 1.34 to 3.47; P= 0.0014) and increased risk of worsening heart failure(post exclusion pooled odds ratio= 1.618; 95% CI: 1.14 to 2.3; P=0.006).
In our meta-analysis, dronedarone did not provide any significant benefit with regard to all-cause mortality and major cardiovascular events, as well as regarding the risk of worsening heart failure. Sensitivity analyses then showed that the exclusion of a study, namely ATHENA study, caused a shift in the overall odds ratio, so as to convert the dronedarone use to the ominous role of predictor of higher mortality, worse cardiovascular morbidity and increased risk of worsening heart failure. Thus, dronedarone should be used with caution as second-line medication and exclusively for the secondary prevention of paroxysmal or persistent atrial fibrillation, in patients without signs or symptoms of cardiac decompensation, preferably for limited periods of time and under assiduous clinical and laboratory surveillance.
2009年决奈达隆上市时，其疗效和安全性备受赞誉。然而，如今出现了一些安全问题（尤其是肝毒性风险），这使得该药物的使用仅限于阵发性或持续性心房颤动，并且被排除在室性快速心律失常的治疗方案之外。本研究的目的是通过分析文献数据定量评估（荟萃分析）得出的证据，探讨一些与决奈达隆有关的疗效和安全性终点。
我们纳入荟萃分析的仅为报告了决奈达隆相关临床结局的随机对照试验（RCT）。此外，符合条件的RCT必须至少随机分配100名患者，以便有足够的统计效力，并且必须明确报告感兴趣的结局。主要疗效结局为：a）全因死亡率，b）主要急性心血管事件，c）心力衰竭恶化。感兴趣的次要结局为室性快速心律失常、中风和系统性栓塞。我们进行了多项敏感性分析，以更好地确定异质性的来源。我们还进行了多项亚组分析。
在筛选过程结束时，认为适合进行荟萃分析的数据有7项。在全因死亡率（合并比值比=1.31；95%置信区间：0.78至2.18；P=0.31）、主要心血管事件（合并比值比=1.45；95%置信区间：0.7至3.01；P=0.28）以及“心力衰竭恶化”这一终点方面（合并比值比=1.32；95%置信区间：0.87至2.01；P=0.20），使用决奈达隆未显示出任何显著优势。此外，通过亚组分析发现，在永久性房颤患者中，与安慰剂相比，使用决奈达隆会增加全因死亡率（P=0.03），以及增加主要急性心血管事件风险（P=0.04）和心力衰竭恶化发作风险（P=0.02）。此外，当排除ATHENA研究的数据后，使用决奈达隆与全因死亡率增加（排除后合并比值比=1.77；95%置信区间：1.15至2.72；P=0.0089）、主要心血管事件风险增加（排除后合并比值比=2.16；95%置信区间：1.34至3.47；P=0.0014）以及心力衰竭恶化风险增加（排除后合并比值比=1.618；95%置信区间：1.14至2.3；P=0.006）相关。
在我们的荟萃分析中，决奈达隆在全因死亡率、主要心血管事件以及心力衰竭恶化风险方面未提供任何显著益处。敏感性分析表明，排除一项研究（即ATHENA研究）导致总体比值比发生变化，从而使决奈达隆的使用转变为更高死亡率、更差心血管发病率和心力衰竭恶化风险增加的不良预测因素。因此，决奈达隆应谨慎用作二线药物，仅用于阵发性或持续性心房颤动的二级预防，适用于无心脏失代偿体征或症状的患者，最好在有限时间内使用，并进行密切的临床和实验室监测。
