Background: First dose observation for cardiac effects is required for fingolimod. Previous results in patients with relapsing remitting multiple sclerosis (RRMS) suggest that transient bradycardia and conduction abnormalities during the observation phase are rare, benign and reversible. Prior analyses corroborate these findings. The present large scale dataset allows subgroup analyses for differences in the incidence of cardiac findings depending on patient characteristics. Methods: START was an open-label, multi-center study that enrolled 6,998 RRMS patients. Primary endpoints were incidence of bradycardia (heart rate < 45 bpm) and second-/third-degree atrioventricular (AV) block during treatment initiation. Subgroup analyses were performed according to age, gender, body mass index (BMI), baseline expanded disability status scale (EDSS), and concomitant medication to determine the impact of these variables on cardiac outcomes parameters. Results: 63 patients (0.9%) developed bradycardia (<45 bpm), 120 patients (1.7%) had a second-degree Mobitz I (Wenkebach) block and/or 2:1 AV block. One case of an asymptomatic third-degree AV block occurred. No Mobitz II AV block was observed. After 1 week, no second-/third-degree AV block was observed. The incidence of second- or third-degree AV blocks was significantly higher in older patients (≥50 years; p = 0.014 vs. patients 35-49 years). Second- or third-degree AV blocks were more frequent in females (87.5% of all patients with a second- or third-degree AV block; p < 0.001), while bradycardia occurred more often in males (58.7% of all bradycardia events; p < 0.001). Furthermore, patients with a BMI below 25 had a higher incidence of second- or third-degree AV block. Conclusions: In summary, transient bradycardia and AV conduction abnormalities after the first dose of fingolimod were rare and asymptomatic. When compared to females, male patients might have a higher risk for bradycardia during treatment initiation, presumably due to a lower resting heart rate. Furthermore, a low heart rate before treatment initiation, low body weight, or low BMI possibly increases the risk for bradycardia. Second- or third-degree AV blocks were more frequent in females, older patients and patients with a low BMI. Nevertheless, these cardiac events remained rare and benign, confirming the favorable cardiac safety profile of fingolimod upon treatment initiation in MS patients without cardiovascular comorbidities.

中文翻译：

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芬戈莫德首次可预测心脏预后的剂量后，对心电图评估和心脏事件进行全面监测。

背景：芬戈莫德需要对心脏效应进行首次剂量观察。复发性缓解型多发性硬化症（RRMS）患者的先前结果表明，观察期短暂性心动过缓和传导异常罕见，良性且可逆。先前的分析证实了这些发现。当前的大规模数据集允许根据患者特征对亚组进行心脏发现发生率差异的分析。方法：START是一项开放式，多中心研究，招募了6,998名RRMS患者。主要终点是治疗开始期间心动过缓的发生率（心率<45 bpm）和房室二/三度房室传导阻滞。根据年龄，性别，体重指数（BMI），基线残疾状况扩大量表（EDSS）进行亚组分析，并用药物来确定这些变量对心脏预后参数的影响。结果：63例患者（0.9％）发生心动过缓（<45 bpm），120例患者（1.7％）患有二度Mobitz I（Wenkebach）阻滞和/或2：1 AV阻滞。发生一例无症状的三度房室传导阻滞。没有观察到Mobitz II AV阻滞。1周后，未观察到二级/三级房室传导阻滞。老年患者中二级或三级房室传导阻滞的发生率显着更高（≥50岁；与35-49岁患者相比，p = 0.014）。女性发生二级或三级房室传导阻滞的频率更高（占所有患有二级或三级房室传导阻滞的患者的87.5％； p <0.001），而男性的心动过缓发生率更高（占所有心动过缓事件的58.7％； p <0.001）。此外，BMI低于25的患者发生二级或三级房室传导阻滞的发生率较高。结论：总之，首次服用芬戈莫德后的短暂性心动过缓和AV传导异常罕见且无症状。与女性相比，男性患者在治疗开始期间心动过缓的风险可能较高，大概是由于静息心率较低。此外，治疗开始前的低心率，低体重或低BMI可能会增加心动过缓的风险。女性，老年患者和BMI较低的患者更常发生二级或三级房室传导阻滞。然而，这些心脏事件仍然罕见且良性，这证实了芬戈莫德在无心血管合并症的MS患者中开始治疗后的良好心脏安全性。