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

Abstract

IntroductionFingolimod 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.MethodsThe 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.ResultsMore 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.ConclusionAltogether, 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.FundingNovartis Pharma GmbH, Nürnberg, Germany.

Roles and regulation of protein phosphatase 2A (PP2A) in the heart

“…LB-100 has also been used in mice to successfully prevent vascular disease, including arterial dysfunction and increased blood pressure in the context of diet-induced obesity [78]. Interestingly, FTY720 (fingolimod), an activator of PP2A has also been associated with bradycardia and blood pressure reduction in patients treated for multiple sclerosis [81–83]. Further, treatment with FTY720 protected mice from ischemia-reperfusion injuries and mitigated hypertrophy following transverse aortic constriction [84–86].…”

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

“…The conduction abnormalities were typically transient, asymptomatic, and resolved within 24 h on treatment. START was a prospective study that aimed to assess the cardiac safety of fingolimod first dose in detail in a much larger cohort compared to previous studies in daily practice treatment circumstances (14,(16)(17)(18)(19)(20)(21)(22). The study followed the EU label first-dose observation recommendation by obtaining a Holter ECG for 6 h in addition to clinical monitoring and pre-/post first dose 12-lead ECG.…”

Comprehensive review of cardiovascular toxicity of drugs and related agents

“…These first‐dose effects are infrequent, mostly asymptomatic and resolve spontaneously in the majority of cases. ECG monitoring during the first 6 hrs after drug administration is considered to be the standard . Interestingly, fingolimod can acutely cause slight transient hypotension due to the activation of the eNOS pathway, but this is sometimes followed by a small increase in blood pressure (+3/1 mmHg of systolic/diastolic blood pressure)…”

“…ECG monitoring during the first 6 hrs after drug administration is considered to be the standard. 346,347 Interestingly, fingolimod can acutely cause slight transient hypotension due to the activation of the eNOS pathway, but this is sometimes followed by a small increase in blood pressure (+3/1 mmHg of systolic/diastolic blood pressure). 348 Other drugs, such as lithium and carbamazepine might also cause rhythm disturbances, but the underlying mechanisms are not known.…”