Fingolimod effects on left ventricular function in multiple sclerosis

Abstract

Background:

Cardiovascular side effects such as bradycardia and atrioventricular block were observed during the early clinical trials of fingolimod in multiple sclerosis, and one cardiovascular- linked death has been reported in the post-marketing period.

Objective:

To investigate the medium-term effects of fingolimod on heart function in order to obtain further insights into its cardiac safety profile.

Methods:

The study involved 53 patients starting treatment with fingolimod 0.5 mg daily and 25 patients treated with natalizumab 300 mg monthly. Cardiac function was assessed by means of echocardiography at baseline (T0), and after one (T1), six (T6), and (in the case of the fingolimod group) 12 months (T12).

Results:

Mean left ventricular ejection fraction significantly decreased and end-systolic volume increased from T0 to T1 (p=0.005) and T6 (p=0.0001) in the fingolimod but not the natalizumab group, although a slight increase was observed at T12. A similar decrease in ejection fraction was also observed after six months in nine patients switched from natalizumab to fingolimod.

Conclusion:

Fingolimod significantly reduces left ventricular systolic function in MS patients. This effect has no clinical consequences in subjects without previous cardiac disorders, but suggests that more caution is required in patients with current or previous heart failure.

Keywords

Fingolimod multiple sclerosis left ventricular systolic function drug safety drug side effects ventricular ejection fraction cardiotoxicity

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References

Koch-Henriksen

Sorensen

. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol 2010; 9: 520–532.

Chun

Brinkmann

. A mechanistically novel, first oral therapy for multiple sclerosis: the development of fingolimod (FTY720, Gilenya). Discov Med 2011; 12: 213–228.

Kappos

Radue

O’Connor

. A placebo controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010; 362: 387–401.

Calabresi

Radue

Goodin

. 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: 545–56; Erratum: Lancet Neurol 2013; 13: 536.

Cohen

Barkhof

Comi

. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010; 362: 402–415.

Chun

Hartung

. Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin Neuropharmacol 2010; 33: 91–101.

Brinkmann

. FTY720 (fingolimod) in multiple sclerosis: therapeutic effects in the immune and the central nervous system. Br J Pharmacol 2009; 158: 1173–1182.

Brinkmann

Baumruker

. Pulmonary and vascular pharmacology of sphingosine 1-phosphate. Curr Opin Pharmacol 2006; 6: 244–250.

Mazurais

Roberts

Gout

. Cell type-specific localization of human cardiac S1P receptors. J Histochem Cytochem 2002; 50: 661–669.

10.

Liliom

Sun

Bunemann

. Sphingosylphosphocholine is a naturally occurring lipid mediator in blood plasma: a possible role in regulating cardiac function via sphingolipid receptors. Biochem J 2001; 355: 189–197.

11.

Koyrakh

Roman

Brinkmann

. The heart rate decrease caused by acute FTY720 administration is mediated by the G protein-gated potassium channel I. Am J Transplant 2005; 5: 529–536.

12.

Schmouder

Serra

Wang

. FTY720: placebo-controlled study of the effect on cardiac rate and rhythm in healthy subjects. J Clin Pharmacol 2006; 46: 895–904.

13.

Collins

Cohen

O’Connor

. Long-term safety of oral fingolimod (FTY720) in relapsing multiple sclerosis: integrated analyses of phase 1 and 3 studies (P843). Mult Scler 2010; 16: S295.

14.

Gialafos

Gerakoulis

Grigoriou

. Intermittent atrioventricular block following fingolimod initiation Case Rep Neurol Med 2014: 1–4. DOI: 10.1155/2014/191305.

15.

Pelletier

Hafler

. Fingolimod for multiple sclerosis. N Engl J Med 2012; 366: 339–347.

16.

Espinosa

Berger

. Delayed fingolimod-associated asystole. Mult Scler 2011; 17: 1387–1389.

17.

Food and Drug Administration. FDA drug safety communication: safety review of a reported death after the first dose of multiple sclerosis drug Gilenya (fingolimod). http://www.fda.gov/Drugs/DrugSafety/ucm284240.htm (accessed 20 December 2011).

18.

European Medicines Agency. European Medicines Agency starts review of Gilenya (fingolimod) 2012. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/public_health_alerts/2012/01/human_pha_detail_000050.jsp&mid=WC0b01ac058001d126 (accessed 25 October 2012).

19.

Laroni

Brogi

Morra

. EAP Investigators. Safety of the first dose of fingolimod for multiple sclerosis: results of an open-label clinical trial. BMC Neurol 2014; 14: 65.

20.

Ward

Jones

Goldman

. Overview and safety of fingolimod hydrochloride use in patients with multiple sclerosis. Expert Opin Drug Saf 2014; 13: 989–98.

21.

Rossi

Rocchi

Studer

. The autonomic balance predicts cardiac responses after the first dose of fingolimod. Mult Scler 2015; 21: 206–216.

22.

Schiller

Shah

Crawford

. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr 1989; 2: 358–367.

23.

Quiñones

Otto

Stoddard

. Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. Recommendations for quantification of Doppler echocardiography: a report from the Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr 2002; 15: 167–184.

24.

O’Connor

. Safety, tolerability, and efficacy of oral therapies for relapsing-remitting multiple sclerosis. CNS Drugs 2013; 27: 591–609.

25.

Schmouder

Hariry

David

. Placebo-controlled study of the effects of fingolimod on cardiac rate and rhythm and pulmonary function in healthy volunteers. Eur J Clin Pharmacol 2012; 68: 355–362.

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