The purpose of this network meta-analysis was to analyze the safety and efficacy of different class III AADs in the treatment of AF. The results showed that several ADDs have obvious therapeutic effects with minimal incidence of adverse events. We found that vernakalant had the best therapeutic effect with the least incidence of adverse reactions.
AF is a type of atrial tachyarrhythmia that is characterized by rapid and disordered atrial electrical activity. These irregularities shorten ventricular diastole and further reduce cardiac output, leading to a decrease in blood pressure and coronary perfusion. This induces or aggravates myocardial ischemia and leads to tachycardia cardiomyopathy. Heart rhythm and rate control can alleviate AF symptoms and improve prognosis . Class III AADs have been shown to be an effective clinical strategy for treating patients with AF. Class III ADDs not only control heart rhythm or rate, but also significantly reduce the occurrence of adverse events [2, 4–34]. Previous studies that investigated the efficacy of class III AADs in the treatment of AF patients were limited to direct comparisons only. While the results obtained in those studies may be accurate and reliable, the interventions were one-sided without indirect comparison. We addressed this limitation by conducting a network meta-analysis. We retrieved articles reporting RCTs from PubMed and other databases that discussed the role of class III AADs in treating AF patients between 2014 and 2019. The chief six ADD interventions obtained from 31 articles included: 80.6% amiodarone (25), 6.4% dronedarone (2), 38.7% ibutilide (12), 6.4% nifekalant (2), 6.4% sotalol (2), and 6.4% vernakalant (2). Our network meta-analysis showed the efficacy of different class III AADs in treating patients with AF. Among them, amiodarone, ibutilide, nifekalant, and vernakalant were considered to be effective, and amiodarone, ibutilide, nifekalant, sotalol, and vernakalant were found to be safe.
Dronedarone has a similar chemical structure to amiodarone and is thus referred to as a second-generation amiodarone. Further research conducted by Guerra et al., confirmed that dronedarone is the most effective AAD for treating AF and is even tolerated by patients who previously presented with an inability to tolerate other AADs . According to Ezekowitz et al., dronedarone can prevent the occurrence of AF .However, there are studies that indicate that dronedarone treatment in patients with AF is less effective compared to amiodarone[36, 37]. From our results we are unable to conclude if dronedarone is superior to conventional treatment for managing AF. This may be due to a lack of relevant literature and research methods.
Previous studies showed that the treatment efficacy and incidence of adverse reactions differed in patients with AF who were administered class III AADs. For example, Ding et al., reported that ibutilide was more effective compared to amiodarone, but the incidence of adverse reactions did not differ statistically . Dai et al., found no significance differences in treatment effect between nifekalant and amiodarone, but did report that nifekalant improved AF clinical symptoms more quickly compared to amiodarone . Qin et al., showed that both amiodarone and sotalol were more effective compared to dronedarone for controlling heart rhythm . Kriz et al., reported that there was no significant difference in the efficacy of ibutilide, vernakalant, and amiodarone . However, it is important to note that none of these studies confirmed which of the class III ADDs was the most efficient and safest for treating AF. Our results showed that vernakalant had the best therapeutic effects, followed by ibutilide and nifekalant; vernakalant also resulted in the least incidence of adverse reactions, followed by sotalol and ibutilide. In our analysis of six class III AADs, we did not find any data on the adverse reactions of dronedarone. Previous studies showed that the occurrence of adverse reactions in dronedarone were similar compared to amiodarone, with a decreased incidence of thyroid toxicity, lung toxicity, and ophthalmia .Thus, the incidence of adverse reactions of dronedarone are not better compared to vernakalant, although there was a lack of sorting probability for the dronedarone data. Based on the above findings, we conclude that vernakalant is the best class III AAD for treating AF.
The efficacy and occurrence of adverse reactions of different class III AADs were determined by the effect of the drug on different potassium channel subtypes, blocking other ion channels, and myocardial site of drug selective action. The main ion current during myocardial cell repolarization is potassium ion outflow, which includes fast activation of delayed rectification current (Ikr), slow activation of delayed rectification current (Iks), ultrafast delayed rectification current (Ikur), transient outward potassium current (Ito), acetylcholine-sensitive potassium current (IkAch), and inward rectifier potassium current (IKir) . It has been found that blocking IKr will lead to negative frequency-dependent regulation of action potential duration (APD), resulting in slower heart rate due to prolonged APD. Excessive prolongation of APD induces early-posterior potential and tip torsional ventricular tachycardia, which increases the risk of death. Its representative drugs include sotalol, nifekalant, and ibutilide. In contrast, blocking IKs will lead to positive frequency-dependent regulation of APD. APD and effective refractory period (ERP) are significantly prolonged with increases in heart rate. At the same time, decreases in heart rate will prolong the APD and ERP to a lower rate. Thus, the pro-arrhythmogenic effect of these drugs is weaker compared to the IKr blocker. Its representative compounds include HMR-1556 and Chromanol 293B. Blocking IKr and IKs represent amiodarone, dronedarone, respectively [40, 41]. Apart from the above-mentioned potassium currents, Ikur is the chiefly formed potassium current and is formed by vernakalant. Ikur is the main current during APD repolarization in cardiomyocytes .Vernakalant acts on Kv1.5 ion channels and has high selectivity in the atrium. It also only acts on human atrial myocytes, not ventricular myocytes . Finally, vernakalant blocks Ito, IkAch, delayed sodium channel current (INa), and other multi-ion channels . Therefore, there is justification that vernakalant has the best therapeutic effect and safety among other AADs.
The plot in our study was symmetrical and roughly funnel-form in shape, but does not allow us to exclude all potential biases for the following reasons: 1) We could not elaborate on all diseases that cause AF mentioned in the included 31 articles. For instance valvular heart disease [5, 8, 10, 12, 17, 20, 22, 23, 26, 29, 34], hypertensive heart disease [10, 12, 20, 22, 25, 26, 28, 30, 32–34], coronary heart disease [10, 12, 20, 22, 25, 26, 28–30, 32–34], and dilated cardiomyopathy [12, 28]were treated differently. More specifically, coronary heart disease was treated with lipid-lowering and antiplatelet drugs, and hypertension was treated with pressure reducing drugs.2) AF classification was randomly mixed in the included 31 articles, and the literature included a collection of paroxysmal AF [4, 7, 9, 10, 13, 14, 18, 20, 22, 24, 31, 32], persistent AF [5–7, 15, 16, 22, 25, 26, 28], and permanent AF. The literature also included duration of AF [4, 6, 8, 14–16, 18, 22, 23, 26–30, 32–34],treatment course, efficacy judgment (conversation rate, effective rate), and drug administration. In addition, the sample size, quality of the selected documents, unknown languages, and geographical location bias may have influenced heterogeneity of the included studies. Due to these shortcomings in our meta-analysis, we recommend further detailed research with large sample evidence-based tests and a multicenter study.