KYOTO, Japan — Fingolimod (Gilenya, Novartis), used to treat relapsing-remitting multiple sclerosis (RRMS), is known to reduce cardiac autonomic modulation and baroreflex sensitivity at rest, as well as to dampen cardiovagal responses to autonomic challenges. A lingering question has been whether these impaired autonomic effects are permanent or reversible.
A new study indicates that several months after fingolimod discontinuation, responses no longer differed from prefingolimod baseline responses and are thus reversible.
Speaking here at the XXIII World Congress of Neurology (WCN), Professor Max Hilz of the Department of Neurology at the University of Erlangen-Nuremberg, Germany, said that “major studies” have sought to identify the cause of the very rare cases of clinically relevant bradycardia or arrhythmia “or in 0.4% [of patients] even cardiac problems such as conduction block.”
Estimates are that up to 2% of patients may have some impairment of cardiac autonomic modulation when receiving fingolimod.
Professor Hilz explained that the autonomic effects of the drug are related to its similar structure to sphingosine-1-phosphate (S1P). Fingolimod exerts its actions, both intended effects on lymphocytes in RRMS and unintended effects on cardiac cells, through the S1P receptor. In the case of autonomic effects, activation of the receptor causes potassium efflux from cardiomyocytes, with the resulting hyperpolarization slowing depolarization and thus leading to bradycardia.
He said this effect is usually not clinically relevant, except that over time and in the presence of fingolimod this receptor is desensitized and even degraded. So the question arises: When the drug is withdrawn, is the heart’s ability to respond to changing demands permanently affected?
“What our data show, is no, that’s not the case,” he told Medscape Medical News.
Drug Discontinuation
In this investigation, he studied 10 patients with RRMS who were receiving fingolimod 0.5 mg/day for 6 months or longer (range, 7 – 24.4 months; median, 17.3 months) but then discontinued the drug because of clinical or radiographic relapse, adverse effects, or other reasons.
Patients were 9 women and 1 man, with a mean age of 35.8 years. The mean disease duration was 94.9 ± 86.1 months, the median Expanded Disability Status Scale score was 2.0, and the multiple sclerosis functional composite score was 0.1 ± 0.3.
The investigators assessed cardiovascular autonomic modulation by recording and analyzing oscillations in autonomic function before and during fingolimod therapy and after drug discontinuation. Patients were assessed at rest and during a challenge.
Autonomic challenge maneuvers were metronomic deep breathing (6 cycles/min of 5 seconds of inspiration, 5 seconds of expiration), Valsalva maneuver (15 seconds at 40 mm Hg), and active standing up from a supine position.
Assessments were done before initiation of fingolimod, after at least 6 months on the drug, and at least 6 months after drug discontinuation (median, 11.6 months; interquartile range, 7.6 – 16.6 months).
Several measures were significantly different during drug therapy compared with before initiation of the drug (P value for 2 vs 1 [per table below]) but recovered after the drug was discontinued (P value 3 vs 2) and were not significantly different from the values before the drug was started (P value 3 vs 1).
Table. Autonomic Function Before, During, and After Stopping Fingolimod Therapy
| Measurea | 1: Before | 2: During | 3: After Discontinuation | P Value: 2 vs 1 | P Value: 3 vs 2 | P Value: 3 vs 1 |
|---|---|---|---|---|---|---|
| RRI-SD at rest (msec) | 37.1 ± 13.1 | 23.6 ± 10.2 | 33.6 ± 15.3 | .036 | .043 | .617 |
| RRI-total powers (msec2) | 1340.2 ± 1031.1 | 563.1 ± 506.9 | 1064.2 ± 894.4 | .047 | .017 | .799 |
| RRI-LF-powers (ms2) at rest | 994.9 ± 732.5 | 389.7 ± 368.9 | 808.3 ± 645.5 | .037 | .022 | .959 |
| BRS (msec/mm Hg) at rest | 6.9 ± 3.4 | 4.2 ± 2.6 | 6.3 ± 3.1 | .047 | .047 | .386 |
| E/I ratios | 1.42 ± 0.18 | 1.23 ± 0.15 | 1.40 ± 0.31 | .015 | .023 | .798 |
| aBRS = baroreflex sensitivity; E/I ratio = expiratory/inspiratory ratio during 6 cycle/min metronomic deep breathing (a measure of parasympathetic cardiac regulation); RRI-SD= electrocardiogram R-R interval standard deviation (a measure of total cardiac autonomic modulation); RRI total powers = electrocardiogram R-R interval (a measure of total cardiac autonomic modulation); RRI-LF-powers = electrocardiogram R-R interval low frequency powers (a measure of sympathetic cardiac autonomic modulation). | ||||||
Professor Hilz concluded that fingolimod reduced cardiac autonomic modulation and baroreflex sensitivity at rest and dampened cardiovagal responses to autonomic challenges, but these effects no longer differed from baseline values once fingolimod had been stopped for several months.
He noted that patients who developed prolonged slowing of heart rate upon starting fingolimod already had abnormal autonomic function. “We do assume this is related to the central autonomic network that can be afflicted by MS-typical lesions…. So if this system that works very rapidly is compromised because the wiring is compromised then, of course, a drug that at the level of the heart slows heart rate may not be counter-regulated as quickly.
“So I think there is no major concern that fingolimod itself has ‘cardiotoxic effects,’ but it has more to do with the fact that these are multiple sclerosis patients who have specific lesions,” he said.
Professor Hilz advised that physicians should always monitor the heart rate and blood pressure of their patients receiving fingolimod and if possible assess heart rate variability with easy bedside tests for this purpose. For example, metronomic deep breathing of 6 cycles/min will increase parasympathetic modulation and slow the heart rate, can be done to see whether this effect is more prominent in a patient receiving fingolimod.
Another simple test he cited is the sustained hand grip test, compressing something as common as a rubber ball, first at full strength and then at one-third strength. Squeezing a rolled-up and partially inflated blood pressure cuff is a good way to see what a full strength grip is and then have the patient squeeze at one-third strength.
“If you do that for 3 to 5 minutes, blood pressure goes up by at least 10 millimeters of mercury,” he said. “Patients who are over-responsive to fingolimod show prolonged recovery times of slowing of heart rate. This response to a hand grip test might be exaggerated. Their diastolic blood pressure might go up much more.”
He said it is always good to take a patient’s complaints seriously and get an electrocardiogram and measure heart rate and blood pressure at rest and then again during some challenge.
Although the various tests revealed cardiac autonomic dysfunction, Professor Hilz noted that none of the patients in the study had any symptoms related to the changes.
John England, MD, professor and chairman of the Department of Neurology at Louisiana State University School of Medicine, New Orleans, and editor-in-chief of the Journal of Neurological Sciences, cautioned that just because this study didn’t show significant adverse effects doesn’t mean that there can’t be.
“If you cause bradycardia and cardiac issues in some patients who are predisposed to cardiac disease, there could be serious problems of a cardiac sort, even death,” he told Medscape Medical News.
Although it does not appear to be a frequent problem, it is still a concern enough so that “we do need to be careful with drugs like fingolimod,” he said. He also noted that clinicians are supposed to monitor patients with electrocardiograms after the first dose to make sure that they do not have a serious adverse outcome before continuing the medicine.
With a large array of drugs now available to treat RRMS, he noted, if a patient has an adverse effect to one drug, there are several other choices.
Professor Hilz has received compensation from Genzyme, A Sanofi, and Novartis Pharma Germany and has received research support from the Rolf and Hubertine Schiffbauer Foundation, Bayer Health Care, and Novartis. Dr England has disclosed no relevant financial relationships.
XXIII World Congress of Neurology (WCN). Abstract 533. Presented September 19, 2017.
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