Electrocardiographic assessments and cardiac events after fingolimod first dose - a comprehensive monitoring study.

BACKGROUND: First dose observation for cardiac effects is required for fingolimod, but recommendations on the extent vary. This study aims to assess cardiac safety of fingolimod first dose. Individual bradyarrhythmic episodes were evaluated to assess the relevance of continuous electrocardiogram (ECG) monitoring. METHODS: START is an ongoing open-label, multi-center study. At the time of analysis 3951 patients were enrolled. The primary endpoints are the incidence of bradycardia (heart rate < 45 bpm) and second-/third-degree AV blocks during treatment initiation. The relevance of Holter was assessed by matching ECG findings with the occurrence of clinical symptoms as well as by rigorous analysis of AV blocks with regard to the duration of pauses and the minimal heart rate recorded during AV block. RESULTS: Thirty-one patients (0.8%) developed bradycardia (<45 bpm), 62 patients (1.6%) had second-degree Mobitz I and/or 2:1 AV blocks with a lowest reading (i.e. mean of ten consecutive beats) of 35 bpm and the longest pause lasting for 2.6 s. No Mobitz II or third-degree AV blocks were observed. Only one patient complained about mild chest discomfort and fatigue. After 1 week, there was no second-/third-degree AV block. CONCLUSIONS: Continuous Holter ECG monitoring in this large real-life cohort revealed that bradycardia and AV conduction abnormalities were rare, transient and benign. No further unexpected abnormalities were detected. The data presented here give an indication that continuous Holter ECG monitoring does not add clinically relevant value to patients' safety. TRIAL REGISTRATION: NCT01585298 ; registered April 23, 2012.

A Comprehensive Monitoring Study on Electrocardiographic Assessments and Cardiac Events After Fingolimod First Dose-Possible Predictors of Cardiac Outcomes.

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.

Cardiac Safety Profile of First Dose of Fingolimod for Relapsing-Remitting Multiple Sclerosis in Real-World Settings: Data from a German Prospective Multi-Center Observational Study.

INTRODUCTION: Fingolimod was the first oral therapy approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). Due to its action on cardiac sphingosine 1-phosphate receptors, fingolimod is leading to a transient decrease in heart rate (HR) and the occurrence of rare and asymptomatic self-limited atrioventricular (AV) blocks. This German non-interventional clinical study aimed to assess the cardiac safety profile in RRMS patients during at least 6 h after the initial treatment or restart after interruption of fingolimod in real-world settings. METHODS: The GoCARD study (German National Health Authorities, BfArM, CFTY720DDE18, NIS334) was a prospective, multi-center non-interventional study which was conducted in neurological and other medical practices or hospitals, qualified to routinely assess electrocardiogram (ECG) findings. Data were collected through interviews, clinical evaluations (notably ECGs), and laboratory tests. Medical history, vital signs, and a 12-lead ECG were assessed before fingolimod administration. After the first dose, a 6 h ECG was performed and vital signs (blood pressure and HR) were measured hourly. The occurrence of bradycardia (HR ≤45 beats per minute [BPM]), AV blocks (2nd degree Mobitz type I or higher), and corrected QT interval (QTc) intervals was also documented. RESULTS: More than 95% of physicians adhered to the cardiac monitoring recommendations. The observation of 217 patients in 42 study centers showed that while 35.9% of the patients had any cardiac risk profile, none of them experienced a bradycardia during the 6 h post-dose observation. Overall, only 1.8% of all patients displayed bradycardia (HR ≤45 BPM) during 6 h after treatment initiation. Moreover, in this cohort, none of the patients showed a new or persistent onset AV block (2nd degree Mobitz type I or higher) or QTc ≥500 ms. CONCLUSION: Altogether, these data confirm that the first-dose observation after fingolimod initiation is usually uneventful (even in patients with pre-existing cardiovascular risk factors of this cohort) and that the rarely observed events remained asymptomatic and self-limited. FUNDING: Novartis Pharma GmbH, Nürnberg, Germany.