Abstracts

The efficacy of fingolimod, the innovative oral drug therapy for multiple sclerosis (MS) has been shown in clinical trials and in medical practice¹1 . Thomas K, Ziemssen T. Management of fingolimod in clinical practice. Clin Neurol Neurosurg. 2013;115(Suppl 1):S60-S64.. 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 complications¹1 . Thomas K, Ziemssen T. Management of fingolimod in clinical practice. Clin Neurol Neurosurg. 2013;115(Suppl 1):S60-S64.^,22 . 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.. Transient effects on heart rate are explained by transient agonism of sphingosine-1P receptors in atrial myocytes³3 . 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.. 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 patients⁴4 . 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., there are few reports on the real life experience with the first dose of fingolimod²2 . 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.^,55 . 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..

Retrospective data were collected for 180 patients aged over 18 years diagnosed with MS according to the revised McDonald criteria⁶6 . 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.. 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 asystole⁷7 . Espinosa PS, Berger JR. Delayed fingolimod-associated asystole. Mult Scler 2011;17:1387-1389.. 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 3^rd and 4^th hours of observation showed a significant (P<0.001) lower heart rate than other time points.

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 dose⁸8 . 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.. The study of Ontaneda et al. which dealt with clinical practice data also demonstrated 1% rate of bradycardia as a complication of fingolimod initiation²2 . 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.. A recent Italian study reported 2% cardiovascular adverse events in patients taking the first dose of fingolimod, mainly bradycardia and atrio-ventricular block⁵5 . 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.. 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 fingolimod⁹9 . Singer BA. Initiating oral fingolimod treatment in patients with multiple sclerosis. Ther Adv Neurol Disord 2013;6:269-275.. 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

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