关键词： 普罗帕酮；莫雷西嗪；美西律；治疗结果；药物副反应报告系统

【摘要】目的对三种我国最常用的抗心律失常药：普罗帕酮(Pr)、莫雷西嗪(Mo)、美西律(Me)进行较长期的治疗观察，考察其疗效及血药浓度在治疗中的作用。方法对1403例15～80岁非心肌梗塞的心律失常患者进行随机分组及安慰剂(Pl)对照治疗，剂量从300 mg/d开始，不超过1200 mg/d，有效者随访不少于6个月，疗效及不良反应用临床及Holter法评定。结果(1)室性心律失常924例，有效率Pr、Mo、Me、Pl分别为：66.8%、72.7%、64.2%、20.5%；室上性心律失常479例，有效率Pr、Mo、Pl分别为：71.2%、60.4%、23.2%。各药与安慰剂疗效相比差异有显著性(P＜0.0001)，但各药之间相比差异无显著性(P＞0.05)。(2)不同病因、不同病程之间相比，各组之间疗效差异无显著性。(3)三种药的最佳治疗剂量均在400～800 mg/d。(4)不同血药浓度之间疗效差异无显著性。(5)Pr、Mo、Me的不良反应发生率分别为17.7%、36.5%、35.5%。(6)Pr、Mo、Me的心脏不良反应占不良反应的百分比分别为：28.4%、17.5%、4.8%，心脏不良反应以Pr、Mo多见；Pr有2例室性早搏增多，Me有1例阵发性室性心动过速增多，Mo组1例死于心力衰竭，未发现有严重室性心律失常而致严重心脏事件。消化道反应与神经系统的不良反应以Me、Mo多见，不同剂量组间的不良反应发生率差别不显著。(7)Pr、Mo不良反应与血药浓度无明显关系，Me高血药浓度时不良反应发生率高。结论本研究显示三种抗心律失常药对室性心律失常、室上性心律失常有较好的疗效；血药浓度不能有效地反映疗效；三种药物虽有一定的心脏不良反应，致心律失常的不多见，具有一定的安全性，但对心功能不全者应用时应谨慎，对非心肌梗塞患者的抗心律失常治疗相对安全。

reappraisal of the efficacy and safety of propafenone, mexiletine and moricizineZhu Junren¹, Li Zhishan¹, Tao Ping², You Kai³, Qi Wenhang⁴, Yin Qiuxi⁵, Huang Dejia⁵, Zhou Daxin¹. (1: Zhong Shan Hospital, Shanghai Medical University, Shanghai 200032; 2:Fu Wai Hospital, CAMS&PUMC; 3: Beijing Union Hospital, CAMS&PUMC; 4: Rui Jin Hospital, Shanghai Second Medical University; 5: First Affiliated Hospital, West China Medical University)

【Abstract】ObjectiveTo investigate the long term efficacy and safety of propafenone, mexiletine and moricizine in nonmyocardial infarction patients with arrhythmia. MethodTaking placebo as the control, 1403 patients, aged 15-80 years, with multiple ventricular or atrial premature beats, or paroxysmal atrial flutter or fibrillation for more than 3 months of duration, entered the study and were randomized to treatment groups with any of the three drugs or placebo. Etiologically the patients were divided into non-infarction coronary artery disease, primary cardiomyopathy or myocarditis, rheumatic heart disease, hypertension, and unknown cause groups. The initial dose was 300 mg/day for any drug. The dosage was titrated later on but not more than 1200 mg/day. Patients with treatment failure with one drug was switched randomly to another drug. Arrhythmias were assessed by Holter monitoring. The duration of follow-up was 6-48(28.3±8) months.Results(1) The effective rates for ventricular arrhythmias in patients given propafenone (n=337), moricizine (n=246), mexiletine (n=229) and placebo (n=112) were 66.8%, 72.7%, 64.2% and 20.5%, respectively. The effective rates for supraventricular arrhythmias in patients given propafenone (n=271),moricizine (n=144) and placebo(n=64) were 71.2%, 60.4% and 23.4%, respectively. The difference was significant (P＜0.001) between any drug group and placebo group but insignificant (P＞0.05) between any two drug groups; (2) No difference in effective rate was noted among groups of different etiology or duration of arrhythmias; (3) The optimal dosage was 400-800 mg/day for any drug ; (4) There was no definite relationship between blood drug concentration and the efficacy of treatment with each of the 3 drugs; (5) The occurrence rates of adverse reactions were 17.7%, 36.6%, 35.5% and 5.3% for propafenone, moricizine, mexiletine and placebo, respectively, in which cardiovascular reactions accounted for 28.4%, 17.5% and 4.8% in the three-drug treatment groups. No significant difference in the occurrence rate of adverse reactions was found among different drug treatment groups; (6) There were more cardiac adverse reactions in the propafenone group and morcizine group than those in mexiletine. Increase of VPCs occurred in 2 cases treated with propafenone, and paroxysms of VT increased in 1 case treated with mexiletine. The only one death was due to left heart failure in the moricizine group. There were more adverse reaction of gastrointestinal tract in mexiletine group and moricizine group than those in propafenone, and more side-effects of nervous system in the mexiletine group and morcizine group than those in propafenone; (7) The occurrence of adverse reactions was not correlated with the blood levels of propafenone or moricizine, while higher blood levels of mexiletine accompanied with higher rates of adverse reactions. ConclusionPropafenone, moricizine and mexiletine are effective in the treatment of arrhythmias in patients not suffered from myocardial infarction. The long term effective rate is 60-70%, and there is no definite relationship between blood drug concentration and the efficacy of treatment with any of the 3 drugs. The arrhythmogenic effect was rarely observed in these patients. In contrast to the condition in CAST, the use of antiarrrhythmic drugs is relatively safe in patients not suffered from myocardial infarction.

【Key words】propafenonemoricizinemexiletinetreatment outcomeadverse drug reaction reporting system

1989年美国CAST(cardiac arrhythmia suppression trial, CAST)研究的结果发现，某些抗心律失常药物［恩卡尼(encainide)、氟卡尼(flecainide)、莫雷西嗪(moricizine)］在急性心肌梗塞后患者中应用时，因致心律失常导致死亡率增加^［1］。该研究引起全世界的关注，恩卡尼为此而停止使用，氟卡尼的使用也受到严格限制；但抗心律失常药在非心肌梗塞患者中的疗效及安全性未有较系统的报道。为此，对三种在我国最常用的抗心律失常药：普罗帕酮(propafenone,简称Pr)、莫雷西嗪(简称Mo)、美西律(mexiletine,简称Me)，在非心肌梗塞患者中进行较大样本、随机安慰剂(placebo,简称Pl)对照的较长时期的治疗观察，考察其疗效和安全性。并了解血药浓度在上述三种抗心律失常药治疗中的作用。

资料与方法

一、观察对象

1.入选要求：15～80岁的心律失常患者，心功能不差于Ⅱ级(MYHA分类)，早搏病程超过3个月无改善趋向且具备随访条件者。(1)室性早搏(室早)原因不明者≥30次/时，有器质性心脏病者≥10次/时；(2)阵发性室性心动过速(室速)；(3)房性早搏(房早)平均≥60次/时；(4)阵发性室上性心动过速(室上速)、心房颤动(房颤)或扑动(房扑)，平均发作1次/日以上。

2.除外条件：(1)心肌梗塞，(2)对药物过敏者，(3)心肌炎患者病程在2个月以内者，(4)Q-T间期延长综合征，(5)肥厚性心肌病，(6)严重肝、肾疾病，(7)严重疾病试验期间影响寿命者，(8)孕妇。

患者按病因分为非心肌梗塞的冠心病、原发性心肌病及心肌炎、风湿性心脏病(简称风心病)、高血压病、原因不明等组。进入研究的患者共1403例，男性692例，女性711例，年龄15～80岁(平均49.95±13.14岁)。

二、观察方法

进入研究前停服抗心律失常药物1周(胺碘酮2周)进行必要的检查、病史询问，查清病因，同时进行24小时动态心电图检查，然后随机给予Pr、Mo、Me、Pl治疗。剂量均从300 mg/d开始，疗效不佳时渐增剂量，但不超过1200 mg/d。达最大剂量2周无效者停药3～5天，随机改服另一种药物。有效病例每月随访一次，随访不少于3个月。随访期间，每3～6个月复查动态心电图一次，随访期间着重观察疗效、不良反应、死亡率。为了解疗效与血药浓度、不良反应的关系以及依从性，部分病人测定稳态血药浓度。

1403例中，室性心律失常924例，室上性心律失常479例。按治疗方法区分，室性心律失常患者中337例给予Pr治疗，246例给予Mo治疗，229例给予Me治疗，112例给予Pl治疗；室上性心律失常患者中271例给予Pr治疗，144例给予Mo治疗，64例给予Pl治疗。给予Pr治疗的337例室性心律失常患者中220例曾使用过Me、Pr、Mo、胺碘酮、丙