SciELO - Scientific Electronic Library Online

 
vol.72 issue9Incidence of basilar invagination in patients with tonsillar herniation ? a case control craniometrical studyThe influence of decompressive craniectomy on the development of hydrocephalus: a review author indexsubject indexarticles search
Home Pagealphabetic serial listing  

Services on Demand

Journal

Article

  • text new page (beta)
  • English (pdf)
  • Article in xml format
  • How to cite this article
  • SciELO Analytics
  • Curriculum ScienTI
  • Automatic translation

Indicators

Related links

Share


Arquivos de Neuro-Psiquiatria

Print version ISSN 0004-282X

Arq. Neuro-Psiquiatr. vol.72 no.9 São Paulo Sept. 2014

http://dx.doi.org/10.1590/0004-282X20140102 

Trick of the trade

The real-life experience with cardiovascular complications in the first dose of fingolimod for multiple sclerosis

A experiência da vida real com complicações cardiovasculares na primeira dose de fingolimode

Yara Dadalti Fragoso1 

Christian Cardoso Arruda2 

Walter Oleschko Arruda3 

Joseph Bruno Bidin Brooks1 

Alfredo Damasceno4 

Carlos Augusto de Albuquerque Damasceno5 

Alessandro Finkelsztejn6 

Juliana Finkelsztejn6 

Paulo Diniz da Gama7 

Maria Cristina Brandão Giacomo8 

Sidney Gomes9 

Marcus Vinicius Magno Goncalves10 

Andre Palma da Cunha Matta11 

Marilia Manprim de Morais12 

Enedina Maria Lobato de Oliveira12 

Yuna Ribeiro13 

Henry Koiti Sato14 

Carlos Bernardo Tauil13 

1Departamento de Neurologia, Universidade Metropolitana de Santos, Santos SP, Brazil

2Departamento de Neurologia, Universidade Positivo, Curitiba PR, Brazil

3Departamento de Neurologia, Universidade Federal do Paraná, Curitiba PR, Brazil

4Departamento de Neurologia, Universidade Estadual de Campinas, Campinas SP, Brazil

5Departamento de Neurologia, Universidade Federal de Juiz de Fora, Juiz de Fora MG, Brazil

6Departamento de Neurologia, Hospital de Clínicas de Porto Alegre, Porto Alegre RS, Brazil

7Departamento de Neurologia, Pontifícia Universidade Católica Sorocaba, Sorocaba SP, Brazil

8Clínica Holus MedService, Sao Paulo SP, Brazil

9Departamento de Neurologia, Hospital Beneficência Portuguesa de São Paulo, Sao Paulo SP, Brazil

10Departamento de Neurologia, Centro Hospitalar Unimed, Joinville SC, Brazil

11Departamento de Neurologia, Universidade Federal Fluminense, Niterói RJ, Brazil

12Departamento de Neurologia, Universidade Federal de São Paulo, Sao Paulo SP, Brazil

13Departamento de Neurologia, Hospital de Base do Distrito Federal, Brasília DF, Brazil

14Departamento de Neurologia, Instituto de Neurologia de Curitiba, Curitiba PR, Brazil

ABSTRACT

Fingolimod is a new and efficient treatment for multiple sclerosis (MS). The drug administration requires special attention to the first dose, since cardiovascular adverse events can be observed during the initial six hours of fingolimod ingestion. The present study consisted of a review of cardiovascular data on 180 patients with MS receiving the first dose of fingolimod. The rate of bradycardia in these patients was higher than that observed in clinical trials with very strict inclusion criteria for patients. There were less than 10% of cases requiring special attention, but no fatal cases. All but one patient continued the treatment after this initial dose. This is the first report on real-life administration of fingolimod to Brazilian patients with MS, and one of the few studies with these characteristics in the world.

Key words: multiple sclerosis; fingolimod; bradycardia; adverse event

RESUMO

Fingolimode é um tratamento novo e eficaz para esclerose múltipla (EM). A administração desta droga requer atenção especial para a primeira dose, uma vez que eventos adversos cardiovasculares podem ser observados nas seis horas iniciais da ingestão de fingolimode. O presente estudo consistiu de uma revisão de dados cardiovasculares de 180 pacientes com EM ao receberem a primeira dose de fingolimode. A taxa de bradicardia nestes pacientes foi maior do que aquele observada em estudos clínicos que tem critérios de inclusão muito rigorosos para seleção de pacientes. Menos de 10% dos casos necessitou de atenção especial, mas não houve casos fatais. Todos os pacientes exceto por um continuaram o tratamento após esta dose inicial. Este é o primeiro relato de dados de administração de fingolimode na vida real de pacientes brasileiros com EM, e um dos poucos trabalhos com estas características no mundo.

Palavras-Chave: esclerose múltipla; fingolimode; bradicardia; evento adverso

The efficacy of fingolimod, the innovative oral drug therapy for multiple sclerosis (MS) has been shown in clinical trials and in medical practice1. It is widely recommended that, during the first dose of fingolimod, patients should be on an appropriate medical environment capable to deal with potential cardiovascular complications1,2. Transient effects on heart rate are explained by transient agonism of sphingosine-1P receptors in atrial myocytes3. As yet, there has been no report on the safety of the first dose of fingolimod in Brazilian patients with MS where the protocol recommends medical observation and cardiovascular monitoring for at least six hours. In fact, except for results on clinical trials with very strict inclusion criteria for patients4, there are few reports on the real life experience with the first dose of fingolimod2,5.

Retrospective data were collected for 180 patients aged over 18 years diagnosed with MS according to the revised McDonald criteria6. These patients were closely monitored during the first dose of fingolimod. Each MS Unit had obtained authorization by the Ethics Committee to proceed with the treatment with fingolimod. Patients were informed that they should contact their doctor in case of any signs or symptoms beyond the observation period (minimum six hours).

Gender, age, cardiac rate and blood pressure were registered for all cases. There were 132 women and 48 men, with an average age of 36.8 years (median=36 years, range=19 to 66 years). Five patients had high blood pressure and four patients had right or left branch block before medication. They were kept under observation for longer than six hours and did not develop complications. Two patients had sinus tachycardia and two other patients had sinus bradycardia at the first ECG registration. They did not develop complications. Twelve other patients (6.7%) were kept under medical observation for longer than six hours due to symptomatic bradycardia, while three of them (1.7%) needed to be in intensive care units for developing right branch block or second-degree atrioventricular block. There were no cases of other severe complications and no cases of death among these patients during or after the initial dose, despite the description of possible delayed asystole7. At present, 99.4% of the patients reported here continue the treatment with fingolimod.

Figure shows a summary of data regarding cardiac rate, systolic and diastolic blood pressure up to six hours for all patients. When assessed by one-way ANOVA, the 3rd and 4th hours of observation showed a significant (P<0.001) lower heart rate than other time points.

Figure Average values and standard deviation for the heart rate of 180 patients undergoing the first dose of fingolimod. Data registered over six hours of medical observation. *P<0.001 in relation to other time points (A). Average values and standard deviation for the systolic (upper values) and diastolic (lower values) blood pressure of 180 patients undergoing the first dose of fingolimod. Data registered over six hours of medical observation (B). 

Figure also shows the variation in systolic and diastolic blood pressure during the observation period of six hours. There were no isolated cases of marked hypo or hypertension peaks during the whole observation period. When assessed by one-way ANOVA, no significant differences in either systolic or diastolic blood pressure were observed.

The FREEDOMS clinical trial of fingolimod and its extensions showed less than 1% cases of bradycardia during the first dose8. The study of Ontaneda et al. which dealt with clinical practice data also demonstrated 1% rate of bradycardia as a complication of fingolimod initiation2. A recent Italian study reported 2% cardiovascular adverse events in patients taking the first dose of fingolimod, mainly bradycardia and atrio-ventricular block5. The Italian study used a method similar to ours, reporting the results of daily medical practices. For Brazilian patients in the real life series this observation was higher, even though there was a return to normal cardiac rate after a period of up to ten hours in all but three cases.

It is imperative to register the cardiovascular parameters during the first dose of fingolimod9. A much larger retrospective and prospective Brazilian database should be created in order to observe cardiovascular parameters in patients receiving the first dose of fingolimod in our country.

Acknowledgments

The authors are grateful to all cardiologists who graciously sent data from patients seen at first dose clinical units in Brazil.

References

. Thomas K, Ziemssen T. Management of fingolimod in clinical practice. Clin Neurol Neurosurg. 2013;115(Suppl 1):S60-S64. [ Links ]

. Ontaneda D, Hara-Cleaver C, Rudick RA, Cohen JA, Bermel RA. Early tolerability and safety of fingolimod in clinical practice. J Neurol Sci. 2012;323:167-172. [ Links ]

. Bünemann M, Liliom K, Brandts BK, et al. A novel membrane receptor with high affinity for lysosphingomyelin and sphingosine 1-phosphate in atrial myocytes. EMBO J. 1996;15:5527-5534. [ Links ]

. Sanna M, Liao J, Jo E, et al. Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate. J Biol Chem 2004;279:13839-13848. [ Links ]

. Laroni A, Brogi D, Morra VB, et al. Safety of the first dose of fingolimod for multiple sclerosis: results of an open-label clinical trial. BMC Neurol 2014;14:65. [ Links ]

. Polman CHR, Reingold SC, Banwell B et al. Dianosticcriteria for multiple sclerosis: 2010 Revisions to the Mac Donald criteria. Ann Neurol 2011;69:292-302. [ Links ]

. Espinosa PS, Berger JR. Delayed fingolimod-associated asystole. Mult Scler 2011;17:1387-1389. [ Links ]

. Kappos L, Radue EW, O’Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010;362:387-401. [ Links ]

. Singer BA. Initiating oral fingolimod treatment in patients with multiple sclerosis. Ther Adv Neurol Disord 2013;6:269-275. [ Links ]

Received: March 31, 2014; Revised: May 10, 2014; Accepted: June 13, 2014

Correspondence: Yara Dadalti Fragoso; Departamento de Neurologia, Universidade Metropolitana de Santos; Rua da Constituição, 374; 11015-470 Santos SP, Brasil; E-mail: yara@bsnet.com.br

Conflict of interest: The pharmaceutical company producing and commercializing fingolimod will only have acess to these data after publication.

Creative Commons License This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.