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

Volker Limmroth, Tjalf Ziemssen, Michael Lang, Stephan Richter, Bert Wagner, Judith Haas, Stephan Schmidt, Kathrin Gerbershagen, Christoph Lassek, Luisa Klotz, Olaf Hoffmann, Christian Albert, Katrin Schuh, Monika Baier-Ebert, Guillaume Wendt, Heinke Schieb, Susanne Hoyer, Ralf Dechend, Wilhelm Haverkamp, Volker Limmroth, Tjalf Ziemssen, Michael Lang, Stephan Richter, Bert Wagner, Judith Haas, Stephan Schmidt, Kathrin Gerbershagen, Christoph Lassek, Luisa Klotz, Olaf Hoffmann, Christian Albert, Katrin Schuh, Monika Baier-Ebert, Guillaume Wendt, Heinke Schieb, Susanne Hoyer, Ralf Dechend, Wilhelm Haverkamp

Abstract

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.

Keywords: Atrioventricular conduction; Bradycardia; Cardiac effects; Electrocardiogram; Fingolimod; First dose.

Figures

Fig. 1
Fig. 1
Visit schedule
Fig. 2
Fig. 2
Patient disposition
Fig. 3
Fig. 3
Changes in heart rate after the first dose of fingolimod. The time course of heart rate during the first 6 hours after fingolimod intake is presented for the overall population, patients with bradycardia and patients with second-degree AV block (absolute values and SD)

References

    1. Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):402–15. doi: 10.1056/NEJMoa0907839.
    1. Calabresi PA, Radue EW, Goodin D, Jeffery D, Rammohan KW, Reder AT, et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13(6):545–56. doi: 10.1016/S1474-4422(14)70049-3.
    1. Kappos L, Radue EW, O’Connor P, Polman C, Hohlfeld R, Calabresi P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387–401. doi: 10.1056/NEJMoa0909494.
    1. Brinkmann V, Davis MD, Heise CE, Albert R, Cottens S, Hof R, et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem. 2002;277(24):21453–7. doi: 10.1074/jbc.C200176200.
    1. Brinkmann V, Billich A, Baumruker T, Heining P, Schmouder R, Francis G, et al. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov. 2010;9(11):883–97. doi: 10.1038/nrd3248.
    1. Chun J, Hartung HP. Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin Neuropharmacol. 2010;33(2):91–101. doi: 10.1097/WNF.0b013e3181cbf825.
    1. Camm J, Hla T, Bakshi R, Brinkmann V. Cardiac and vascular effects of fingolimod: mechanistic basis and clinical implications. Am Heart J. 2014;168(5):632–44. doi: 10.1016/j.ahj.2014.06.028.
    1. DiMarco JP, O’Connor P, Cohen JA, Reder AT, Zhang-Auberson L, Tang D, et al. First-dose effects of fingolimod: Pooled safety data from three phase 3 studies. Mult Scler Relat Disord. 2014;3(5):629–38. doi: 10.1016/j.msard.2014.05.005.
    1. Schmouder R, Serra D, Wang Y, Kovarik JM, DiMarco J, Hunt TL, et al. FTY720: placebo-controlled study of the effect on cardiac rate and rhythm in healthy subjects. J Clin Pharmacol. 2006;46(8):895–904. doi: 10.1177/0091270006289853.
    1. Gold R, Comi G, Palace J, Siever A, Gottschalk R, Bijarnia M, et al. Assessment of cardiac safety during fingolimod treatment initiation in a real-world relapsing multiple sclerosis population: a phase 3b, open-label study. J Neurol. 2014;261(2):267–76. doi: 10.1007/s00415-013-7115-8.
    1. Rolf L, Muris AH, Damoiseaux J, van Daele M, Hupperts R. Paroxysmal atrial fibrillation after initiation of fingolimod for multiple sclerosis treatment. Neurology. 2014;82(11):1008–9. doi: 10.1212/WNL.0000000000000218.
    1. van Pesch V, Marchandise S, El Sankari S, Sindic C. Ventricular arrhythmia in a male MS patient on fingolimod. Acta Neurol Belg. 2015;115(1):77–9. doi: 10.1007/s13760-014-0297-8.
    1. Castillo-Trivino T, Lopetegui I, Alarcon-Duque JA, Lopez de Munain A, Olascoaga J. Ventricular tachycardia on chronic fingolimod treatment for multiple sclerosis. J Neurol Neurosurg Psychiatry. 2015. doi:10.1136/jnnp-2014-310013.
    1. Rosini JM, Rajasimhan S, Fellows SE, Nomura JT. Delayed cardiac dysrhythmias after fingolimod administration. Am J Emerg Med. 2015;33(7):987 e1-3. doi: 10.1016/j.ajem.2014.12.037.
    1. Sellner J, Holl B, Wipfler P, Chroust V, Pilz G, Winhard M, et al. Delayed third degree atrioventricular block with pacemaker placement in a multiple sclerosis patient on fingolimod treatment. Neurology. 2014;82:10 Suppl 1. doi: 10.1212/WNL.0000000000000246.
    1. Espinosa PS, Berger JR. Delayed fingolimod-associated asystole. Mult Scler. 2011;17(11):1387–9. doi: 10.1177/1352458511410344.
    1. DePaula RS, Antelmi I, Vincenzi MA, Andre CD, Artes R, Grupi CJ, et al. Cardiac arrhythmias and atrioventricular block in a cohort of asymptomatic individuals without heart disease. Cardiology. 2007;108(2):111–6. doi: 10.1159/000095950.
    1. Nada A, Gintant GA, Kleiman R, Gutstein DE, Gottfridsson C, Michelson EL, et al. The evaluation and management of drug effects on cardiac conduction (PR and QRS intervals) in clinical development. Am Heart J. 2013;165(4):489–500. doi: 10.1016/j.ahj.2013.01.011.
    1. Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA, 3rd, Freedman RA, Gettes LS, et al. 2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation. 2013;127(3):e283–352. doi: 10.1161/CIR.0b013e318276ce9b.
    1. Zeltser D, Justo D, Halkin A, Rosso R, Ish-Shalom M, Hochenberg M, et al. Drug-induced atrioventricular block: prognosis after discontinuation of the culprit drug. J Am Coll Cardiol. 2004;44(1):105–8. doi: 10.1016/j.jacc.2004.03.057.
    1. Osmonov D, Erdinler I, Ozcan KS, Altay S, Turkkan C, Yildirim E, et al. Management of patients with drug-induced atrioventricular block. Pacing Clin Electrophysiol. 2012;35(7):804–10. doi: 10.1111/j.1540-8159.2012.03410.x.
    1. Scheinman MM. Atrioventricular nodal conduction and refractoriness. Pacing Clin Electrophysiol. 1993;16(3 Pt 2):592–8. doi: 10.1111/j.1540-8159.1993.tb01631.x.
    1. Katz AM. Calcium channel diversity in the cardiovascular system. J Am Coll Cardiol. 1996;28(2):522–9. doi: 10.1016/0735-1097(96)00170-2.
    1. Egom EE, Kruzliak P, Rotrekl V, Lei M. The effect of the sphingosine-1-phosphate analogue FTY720 on atrioventricular nodal tissue. J Cell Mol Med. 2015. doi:10.1111/jcmm.12549.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться