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Update on the cardiovascular profile of fingolimod in the therapy of relapsing-remitting multiple sclerosis (MS)

Multiple Sclerosis and Related Disorders, July 2016, Pages 19 - 26

Abstract

Background

Fingolimod (FTY720) has been approved as the first oral representative of the class of sphingosine-1-phosphate (S1P) receptor modulators for the treatment of relapsing-remitting multiple sclerosis (MS). Besides inducing vaso-relaxation, fingolimod can also influence electrical conduction in the myocardium and vascular endothelium by having a transient negative chronotropic effect on the sinus node.

Methods

Cardiac safety and tolerability of fingolimod in the cardiac sense were reviewed by analysing the data collected from the FREEDOMS and TRANSFORMS studies –both relevant studies for marketing authorisation, from their extension studies, as well as the clinical data collected from a practice-related MS patient cohort with cardiovascular risk factors and corresponding co-medication (FIRST study).

Results

The safety analyses on file gave no indication of any increased cardiovascular risk. The 2–3 mmHg increase in blood pressure observed after the first dose of fingolimod has no therapeutic consequences. The first dose of 0.5 mg fingolimod resulted in an average decrease in heart rate of 7–8 beats/min. The onset of effect occurred approximately 1–2 h after the first dose and the nadir was reached after approximately 4–5 h. This negative chronotropic effect returned to normal after internalisation of the S1P1 receptors on maintenance therapy. There were no indications that patients with cardiac risk factors required closer observation beyond the monitoring recommended by the EMA following the first dose of fingolimod. Case study observations from the routine clinical setting show that patients accept this method of monitoring, which they assess as being a positive aspect of attentive medical care and concern.

Highlights

  • The safety analyses of fingolimod on file gave no indication of an increased cardiovascular.
  • Nor were there any indications that patients with cardiac risk factors need closer observation beyond the monitoring recommended by the EMA after the first dose of fingolimod.
  • Observations from routine clinical setting show high acceptance of this monitoring.

Keywords: Cardiovascular profile, Fingolimod, Relapsing-remitting, Multiple sclerosis (MS).

Fingolimod (FTY720) has been approved as the first oral representative of the group of sphingosine-1-phosphate (S1P) receptor modulators for treatment of relapsing-remitting multiple sclerosis (MS). As part of the clinical study more than 11,000 patients were treated, thus totalling an overall exposure period of approximately 19,000 patient-years. Besides its immunomodulatory action, fingolimod can affect angiogenesis, vaso-relaxation, and the electrical conduction in both the myocardium and vascular endothelium.

The European Medicines Agency (EMA) has issued recommendations for cardiovascular monitoring after the first application and reached a positive evaluation of the risk-benefit profile for fingolimod.

Fingolimod is a structural analogue of sphingosine, a physiologically naturally-occurring lysophospholipid in the human body. After oral application phosphorylation by sphingosine kinases forms the biologically active substance (S) fingolimod phosphate (FP), which acts as agonist at four (S1P1R, S1P3R, S1P4R, S1P5R) out of five known S1P-receptors following antagonistic activity of sphingosine-1-phosphate (S1P). Fingolimod exerts its effects relevant to MS by inhibiting the function of S1P1 receptors to favour conserved cysteines (CC)-chemokine receptor 7 (CCR7)-mediated retention of lymphocytes in lymph and potentially by directly targeting S1P-receptors in the central nervous system nodes (Brinkmann, 2010, Chun and Brinkmann, 2011, and Ocker et al, 2011). Sphingosine-1-phosphate (S1P) belongs to the family of bioactive lysophospholipids which as pleiotropic mediators are involved in many cell functions, such as proliferation, cytoskeletal organisation, migration and morphogenesis. S1P binds to five transmembrane receptors from the G-protein-coupled receptors (GPCR) family: S1P1 to S1P5. S1P3 receptors are common and are expressed in various tissues, e.g. neural cells, endothelial cells, atrial myocytes, smooth muscle cells. S1P4 receptors are present in lymphoid and haematopoietic tissues, while S1P5 receptors are located especially in the central nervous system (CNS), here mainly in the oligodendrocytes.

The signal transduction of S1P1 is mainly conducted by Gi/o class G proteins, while S1P2, S1P3 and S1P4 develop their effect via Gi, Gq, G12/13, and S1P5 via Gi and G12/13 (Brinkmann, 2007, Koyrakh et al, 2005, Sanna et al, 2004, Herr and Chun, 2007, Meyer zu Heringsdorf and Jakobs, 2007, and Chun and Hartung, 2010). This results in the activation of various intracellular signalling cascades; their mechanisms of action are not yet fully clarified. Gi impedes the cyclic adenosine monophosphate (cAMP)-dependent upregulation of the calcium (Ca2+) influx through the calcium channel by inhibiting adenylate cyclase. Gq increases the intracellular Ca2+ concentration, for example in smooth muscle cells. The GIRK channels (G protein-coupled inwardly-rectifying potassium ion {K} channels) in the sinoatrial (SA) and atrioventricular (AV) nodes and in the atrial myocytes are important direct targets of Gi/o(Bünemann et al, 1995 and Brinkmann, 2009) (Table 1).

Table 1

Expression, signal transduction and biological action of the S1P receptor family (Brinkmann, 2007 and Koyrakh et al, 2005; Herr and Chun, 2007 and Sanna et al, 2004; Meyer zu Heringsdorf and Jakobs, 2007; Bünemann et al, 1995, Brinkmann, 2009, and Chun and Hartung, 2010).

 

Receptor G Protein Expression (mRNA) Functions
S1P1 Gi Ubiquitous
  • Emigration of lymphocytes from peripheral lymphoid tissues
  • Astrocytic function
  • Embryonic cardiovascular and neural development
  • Reinforcing of the endothelial barrier function
  • Vaso-dilation
S1P2 Gi, Gq, G12/13 Endothelial cells, smooth muscle cells
  • Embryonic cardiovascular development
  • Reinforcing of the endothelial barrier function
  • Vaso-constriction
S1P3 Gi, Gq, G12/13 Ubiquitous
S1P4 Gi, Gq, G12/13 Lymphocytes
  • Unknown (migration?, Inhibition of proliferation and
  • cytokine production in T cells?)
S1P5 Gi, G12/13 CNS (oligodendrocytes, NK cells), spleen
  • Maturation, survival and function of oligodendrocytes
  • Phagocytic activity and migration of microglial cells
  • Astrocytic function
  • Emigration of NK cells
  • Myelination?
  • Emigration from the bone marrow and peripheral lymphoid tissue?

1. Fingolimod’s mechanism of action

Fingolimod is principally phosphorylated by sphingosine kinase-2 (SphK2) to form fingolimod phosphate (FP) and, like S1P, is discharged from the cells by active transport mechanisms. Fingolimod, as the first molecule to be used therapeutically, targets the sphingosine phosphate receptor group. Following oral administration, fingolimod is phosphorylated by SphK2 to form the active substance (S) fingolimod-phosphate (FP), and binds itself with low affinity to S1P1R, S1P4R, S1P5R as well as to S1P3R (Maceyka et al., 2012). Fingolimod acts as a functional antagonist of the S1P receptors. The drug binds to the receptor, thereby triggering both internalisation and degradation of the receptor. Induced by the internalisation of the S1P1 receptor, its mechanism of action is primarily based on the reduction of the number of MS-relevant lymphocyte populations in the periphery - CCR7+ naive T-cells (Tn) and autoreactive pathogenic central memory T cells (TCM). The emigration of the lymphocyte populations which is important for defending against infection - CCR7- effector memory T cells (TEM) – is not impaired by fingolimod (Brinkmann et al, 2010, Mehling et al, 2008, and Metzler et al, 2008).

1.1. Approval status and clinical observations

Fingolimod is licensed as a first-line treatment for relapsing remitting multiple sclerosis, the most common form of the disease, in the USA, Canada, Australia, New Zealand, Switzerland and Russia. In Australia, the license also pertains to patients with secondary progressive MS (SPMS) with residual inflammatory activity (Broadley et al, 2014 and Freedman et al, 2013).

According to the latest extension of indication Fingolimod is approved by the European Medicines Agency (EMA) in the European Union (EU) for

or

Until September 2015, more than 125,000 patients worldwide – having an overall exposition of more than 240,800 patient-years – were treated with fingolimod. Cardiac safety data are available from controlled clinical studies of more than 3,000 MS patients (Gold et al, 2014 and Kappos et al, 2010). As the studies have shown, the first application can result in transient bradycardia or, in rare cases, even in a delay or blockade of atrioventricular conduction (AV block). The monitoring of patients over 6 h was included as a condition for the approval in March 2011. Subsequent to one unexplained death of a patient within 24 h after the first dose in November 2011, the EMA issued for a re-evaluation of fingolimod and potential cases of interest with unwanted cardiovascular incidents were reviewed. In this context, all available information about the application of fingolimod was collected and re-evaluated (Rote-Hand-Brief zu Gilenya, 2012). The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) acknowledged the positive benefit-risk profile for fingolimod on April 20th, 2012 and updated the recommendations for the first dose observation (EMA-Press release, 2012). In the course of this process, the manufacturing company again referred to the drug contraindications and warnings that had been newly integrated into the information for healthcare professionals. According to this information, the application of fingolimod is not recommended for patients with second-degree or higher AV block, sick sinus syndrome or sinoatrial block, as well as in patients with a pre-existing, prolonged QT interval. Additionally, it should not be used with patients showing a history of known bradycardia, recurrent syncope, ischaemic diseases, uncontrolled hypertension or sleep apnoea. Furthermore, the use of fingolimod is not recommended with patients who are already taking antiarrhythmic medication (e.g. Class I a and Class III antiarrhythmics) or bradycardia-inducing antihypertensive drugs (e.g. calcium antagonists [CA], also known as calcium-channel blockers) (Rote-Hand-Brief zu Gilenya, 2012).

2. Cardiovascular effects of fingolimod

2.1. Effect on the myocardium

Transient agonistic activation of S1P1 receptors by FP leads to the activation of GIRK channels and subsequent negative chronotropic effects on the SA node and the upper fibres of the AV node triggered by fingolimod (Brinkmann, 2007). Due to its physiologically established key role in the context of vagal bradycardia, the GIRK channel-mediated current is also called acetylcholine-induced ionic channel (IKACh). Further studies on GIRK - knockout mouse models indicate the possibility of the involvement of further mechanisms such as the hyperpolarisation-activated ion current (Murakami, et al., 2010). The ion current activated by hyperpolarisation – designated If (also: Ih) – through so-called HCN channels (hyperpolarisation-activated cyclic nucleotide-gated cation channels) represents the most important mechanism for electrical pacemaker activity in both the heart and the CNS. In the heart, it is responsible for the autonomous, repetitive impulse formation as well as for the specific processes in regard to conduction in the AV node (Baruscotti et al., 2005). Clinically, these effects are transient because the receptor is rapidly desensitised and internalised. The effects seem limited to supraventricular structures, most probably due to a relatively weak expression of GIRK channels in ventricular myocytes (Beckmann et al., 2008).

In addition to the regulation of cell migration and the control of the endothelial cell barrier, a further direct agonistic effect of Fingolimod-P takes place – a vasodilation of vessels (Brinkmann, 2007). After S1P1 receptors are down-modulated, S1P activates the S1P2/3 receptors, thus leading to an imbalance of S1P signalling and a stronger activation of Rho kinase pathways occurs – resulting in both SMC-constriction of smooth muscle cells (SMCs) and decrease of endothelial barriers. This is the likely explanation for the mild increase in blood pressure and low incidence rate of macular edema (McVerry and Garcia, 2004, Salomone, 2008, and Uehata, 1997).

2.2. First-dose cardiac monitoring

In course of the re-evaluation of fingolimod the EMA recommended a continuous observation after the first dose (EMA-Press release, 2012). According to the summary of product characteristics (SPC), an ECG is required prior to and 6 h after the first dose of fingolimod and continuous cardiac monitoring during the first six hours is recommended (Table 2). Furthermore, as recommended with the first dose, monitoring is recommended if the treatment is interrupted as follows:

  • for one or several days during the first two weeks of treatment.
  • for more than seven days during the third and fourth weeks of treatment.
  • for more than two weeks after one month of treatment.

Table 2

First-dose cardiac monitoring with the first dose of fingolimod (Gold et al., 2014).

 

SPC
Prior to and 6 hours after the first dose
  • 12-lead baseline electrocardiogram (ECG) for all patients prior to the first dose
During the first 6 hours after the first dose
  • Continuous ECG monitoring recommended
  • Hourly pulse and blood pressure checks
Criteria for discharge During the 6 h of observation
  • No third-degree atrioventricular (AV) block
12-lead ECG after 6 h:
  • Heart rate>45 beats per minute
  • No Mobitz type I second-degree AV block (Wenckebach periodicity)
  • Heart-rate corrected QT (QTc) interval <500 ms
Extended monitoring In patients with indicators of clinically relevant cardiac effects during the first 6 hours who do not meet the criteria for discharge, monitoring should be prolonged until resolution, or at least overnight.
If pharmacological treatment is required during the 6 hours after the first dose, extended overnight monitoring is indicated. The measures outlined for the first dose should be performed anew with the second dose of fingolimod.
If the heart rate is at its lowest 6 hours after the first dose, extended monitoring for at least 2 further hours until the heart rate increases again.

If the interruption of treatment is for a shorter period of time than indicated above, treatment with the next dose should be continued as planned. In patients who required pharmacological intervention during the first dose, and who were monitored overnight in a medical facility, it is recommended that the first-dose cardiac monitoring is repeated with the second dose too (Gold et al., 2014).

3. Phase III studies

3.1. FREEDOMS, FREEDOMS II, TRANSFORMS study concept and background

Both the efficacy and safety of administering 0.5 mg fingolimod once daily were examined in the Phase III studies, FREEDOMS (Gold et al., 2014), FREEDOMS II (Calabresi et al., 2014) – in comparison to placebo – and also in TRANSFORMS (Cohen et al., 2010) – as a head-to-head-comparison to intramuscular interferon beta-1a. The duration of treatment was 24 months and 12 months, respectively (FREEDOMS, FREEDOMS II and TRANSFORMS). Patients with indicators of possible cardiac comorbidities were excluded. The intake of Class III antiarrhythmic agents (antiarrhythmic drugs) which affect the heart rate, such as beta-blockers (Class II) or calcium antagonists (Class IV) were permitted. The demographic details of the participants and their cardiovascular history are documented in the respective original publications (Calabresi et al, 2014, Cohen et al, 2010, and Gold et al, 2014).

3.2. FREEDOMS, FREEDOMS II, TRANSFORMS: study population and workflow

In both the Phase III studies relevant for approval (FREEDOMS und TRANSFORMS), 12-lead ECGs were carried out with the first application (before the administration of fingolimod and 6 h after intake). Likewise, in the first 6 h, blood pressure and heart rate were checked. In the FREEDOMS II study, which was predominantly executed in the USA, further investigations were performed at the request of the American Food and Drug Authority (e.g. additional 24-h Holter ECG monitoring following the initial t intake of fingolimod as well as again after 3 months).

In FREEDOMS and TRANSFORMS, 18.0% of patients with fingolimod 0.5 mg and 15% of patients in FREEDOMS II did not meet the criteria for release from monitoring after being monitored for six hours and needed extra monitoring. The specifics are listed as follows:

  • Heart rate >55 beats/min or >80% of baseline.
  • No bradycardia symptoms.
  • Nadir of heart rate modulation is exceeded.
  • No new, clinically relevant changes in the ECG in the last six hours.

3.3. FREEDOMS, FREEDOMS II, TRANSFORMS: results and cardiovascular events

The first dose of 0.5 mg fingolimod resulted in an average decrease in heart rate of 7–8 beats/minute (FREEDOMS and TRANSFORMS) and 8.5 beats/min (FREEDOMS II), thus resulting in a pooled average 8.1 beats/min (Fig. 1). The fall in heart rate began approximately 1–2 h after the first dose; the nadir was reached after 4–5 h. This negative chronotropic effect returned to normal after internalisation of the S1P1 receptors during maintenance therapy (DiMarco et al., 2014).

Fig. 1:

Fig. 1

Influence of 0.5 mg fingolimod on the heart rate after the first dose of fingolimod: short- and long-term effects (DiMarco et al., 2014).

 

The first dose of fingolimod 0.5 mg resulted in a prolongation of the PR interval of 4.5 ms. A first-degree AV block was discovered on the first day of fingolimod administration in 4.7% of the cases. A Mobitz Type I (Wenckebach periodicity), second-degree AV-block occurred in 0.2% of the study participants under fingolimod 0.5 mg treatment (DiMarco et al., 2014).

During the whole observation period, only a few cases of first-degree AV-block and second-degree AV-block (Mobitz Type I) occurred (Table 2). These events were transient, asymptomatic, and required no treatment. The view of the clinical investigators is that the observed increase of fewer clinically-relevant pauses of 2–3 s, as seen in the 24-h Holter ECG monitoring after the first administration, most likely denote sinus arrhythmias with bradycardias. Most of the observed AV blocks were similarly categorised as not being clinically relevant (DiMarco et al., 2014).

3.4. Extension studies, results and cardiovascular events

The safety data of an ongoing open extension study (2201E1) of an international , double-blind, randomised Phase II study (core study 2201) show no relevant effects on heart rate, atrioventricular conduction or left ventricular pump function from fingolimod, after treatment for a total duration of 60 months. Regular intake of fingolimod resulted in a stable rise in blood pressure of 2–3 mmHg (Izquierdo et al., 2014). Similarly the TRANSFORMS extension study revealed no new evidence beyond the findings to date after treatment for a total duration of 24 months (Khatri et al., 2011).

In addition to the findings of controlled clinical studies, a large volume of experimental and clinical data support the role of the sympathetic nervous system in the initiation of lethal cardiac arrhythmias. Vagal activation is then appreciated as the most physiological tool to inhibit excessive sympathetic activation (Vanoli et al., 2014).

4. FIRST study

4.1. FIRST, study concept and background

The single-arm, open-label, FIRST Phase III b study (NCT01497262) evaluated the safety and tolerability profile of fingolimod in patients with relapsing forms of MS in a broader, real-world population (aged 18–65 years, EDSS 0–6.5) (Gold et al., 2014). Further, the study included patients with certain cardiac risk factors, such as a history or presence of recurrent symptomatic bradycardia and/or Mobitz I second-degree AV-block, a resting pulse of 45–54 bpm, BB or CA intake, diagnosed controlled diabetes possibly including certain pulmonary conditions, as well as all patients previously excluded from the Phase II and III trials. At the discretion of the investigator, treatment initiation and the following 6h-Holter ECG monitoring could be performed either on-site (in the clinic or office setting) or off-site. Monitoring off-site was not made available to those patients with cardiac risk factors thus requiring to be monitored on-site.

4.2. FIRST, study population and workflow

Altogether, 2417 patients were included in the study; 2215 received at least one dose of fingolimod. 73.4% of the participants were women, the average Expanded Disability Status Scale (EDDS) was 2.4 and the duration of disease since its first manifestation was 9.3 years. 2054 patients (85%) had been pre-treated with first-line, disease-modifying drugs. 296 patients (12.2%) had a positive cardiac history (recurrent symptomatic bradycardia, resting pulse rate of 45–54 beats per minute (bpm), history of a positive tilt test for vasovagal syncope, and history or presence of Mobitz type I second-degree AV block on the screening or baseline ECG. Concomitant medication with Betablockers and other heart rate lowering drugs was permitted). 120 patients (5.0%) received BBs or CAs as co-medication options. 50.5% of patients took their first dose after leaving the investigators’ site and were monitored at home using Holter-ECG telemetry following the preliminary cardiology examination, while 49.5% of patients had on-site first dose monitoring. The medication for the rest of the patients was adjusted in outpatient hospital wards. Altogether, 2282 patients (94.4%) completed the study as planned, 135 (5.6%) prematurely discontinued the treatment, mostly due to adverse events (2.8%), pathological laboratory results (1.1%) or because of participation consent withdrawal in the study. Four patients (0.2%) discontinued fingolimod due to a cardiac AE; none of these patients had pre-existing cardiac conditions or had been co-medicated with BBs or CAs (Gold et al., 2014).

4.3. FIRST, results and cardiovascular events

The frequency of cardiac events altogether hardly differed between patients with and those without pre-existing cardiac risk factors (2.4% versus 2.0%) in the first two days after the first dose of fingolimod. All the measured ECG changes were clinically asymptomatic. Palpitations and bradycardias (each 0.6%) were documented most frequently. Bradycardias occurred more often in patients with cardiac risk factors (1.4% versus 0.5%) and under co-medication with antihypertensive drugs which cause bradycardia (such as BB and CA) – in 3.5% versus 0.5% of cases, respectively (Table 3). Most types of bradycardia were asymptomatic and normalised spontaneously therefore not requiring medical treatment (Gold et al., 2014).

Table 3

Lowest heart rate ≤6 h and ECG findings 6 h after the first dose of fingolimod, intramuscular interferon beta-1a and placebo: Pooled data of the Phase III studies, TRANSFORMS, FREEDOMS and FREEDOMS II (DiMarco et al., 2014).

 

Number of patients n (%) Fingolimod 0,5 mg n=212 (%) Placebo n=773 (%) Intramuscular interferon beta-1a n=431 (%)
Lowest heart rate ≤6 h
(beats/min)
  • <35
0 (0.0) 0 (0.0) 1 (0.2)
  • 35–39
0 (0.0) 0 (0.0) 0 (0.0)
  • 40–44
17 (1.4) 2 (0.3) 0 (0.0)
  • 45–54
223 (18.4) 39 (5.0) 11 (2.6)
  • 55–64
608 (50.2) 304 (39.3) 141 (32.7)
  • ≥65
361 (29.8) 428 (55.4) 276 (64.0)
ECG recordings performed 1190 763 419
All ECG abnormalities 86 (7.2) 33 (4.3) 19 (4.5)
First-degree AV block 56 (4.7) 13 (1.7) 12 (2.9)
Mobitz Type I second-degree AV-block 2 (0.2) 0 (0.0) 0 (0.0)
Mobitz Type I, 2:1 second-degree AV- block 0 (0.0) 0 (0.0) 0 (0.0)
Mobitz Type II second-degree AV-block 0 (0.0) 0 (0.0) 0 (0.0)

After six hours, 40 of 1219 patients (3.3%) being monitored in the hospital outpatient wards required one hour extended monitoring. Among them, there were 15/271 patients with pre-existing cardiac conditions and 3/78 patients had been co-medicated with bradycardic antihypertensives. 31/40 patients were discharged after prolonged monitoring (total duration lasting 7 h); of these, 12/15 had pre-existing cardiac diseases and 3/3 had been co-medicated with bradycardic anti-hypertensives. The remaining 9 patients were monitored for a maximum of 3 more hours, as only then did they meet the discharge criteria (heart rate <80% with baseline before the first dose of fingolimod 0.5 mg or the lowest measured dose). 1/8 patients had symptomatic bradycardia and was in fact readmitted the next day, but was discharged again without any intervention or extended observation (Gold et al., 2014).

The co-medication had no significant impact on the dynamics of heart rate. After the first dose of fingolimod, the heart rate of patients receiving BB or CA co-medication dropped by a maximum of 7.3 beats/minute in comparison to a maximum of 7.2 beats/min in patients receiving no BB/CA co-medication. The incidence of AV blockade was low and of a benign nature – irrespective of whether or not the patients showed cardiac risk factors. Mobitz Type II second-degree AV-block or third-degree AV-block did not occur (Gold et al., 2014).

5. Phase IV studies

5.1. EPOC, study concept and background

In the single-arm, multi-centre Phase IV Study called EPOC (Evaluate Patient OutComes; NCT01216072), the outcome of the physician and patient evaluation of switching to Fingolimod after previous treatment with disease-modifying basic therapeutic drugs was evaluated. 783 patients took part (75.9% women; average age 46.0 years). The primary endpoint was the change in treatment satisfaction on the standardized and validated TSQM questionnaire (Treatment Satisfaction Questionnaire for Medication). The secondary endpoints were, inter alia, the TSQM subscales for effectiveness, side effects and convenience (Calkwood et al., 2014). The observation period extended over 6 months. Exclusion criteria were consistent with those described in the fingolimod Phase III clinical trials.

5.2. EPOC, results and cardiovascular events

The average heart rate prior to the first dose of fingolimod was 74.1 beats/min. Following the intake of fingolimod, the heart rate dropped on average by 8.3 beats/min. The nadir was reached after 5 h. 8 patients (1%) developed symptomatic bradycardia, which was usually associated with sensations of dizziness and disappeared again after medical intervention. Second-degree heart block after the first dose was not detected in any of the 139 patients with an ECG (17.8%) (Hughes et al., 2013).

5.3. START, study concept and background

The prospective, open, multicentre Phase IV Study called START took place in more than 250 centres in Germany and explored the cardiac safety of fingolimod at the initiation of treatment – this included ECG monitoring as well as the monitoring of both heart rate and blood pressure,. The patients were assessed during a total of three visits: (1) before initiation of treatment, (2) 6 h after initiation of treatment with a Holter-ECG, and (3) approximately a week later for an ECG check and laboratory testing (Limmroth et al., 2015).

In the third interim analysis, 3951 patients (70.3% women: average age 39.3 years; average EDSS 2.8) were evaluated. The heart rate dropped on average by 11.8 beats/min. The nadir was reached after 4.0 h. 3920 patients (99.2%) showed no signs of bradycardia. In 21 patients (0.5%), the heart rate dropped right down to <45 beats/min during the 6-h monitoring. Within the first 6 h, the heart rate returned to normal in 93.5% of the patients (±11.9%) of the baseline level. No patient had <45 bpm at the time the study was concluded (approximately 7 days after initiating fingolimod treatment). The necessity for extended ambulatory monitoring (6+2 h) was indicated in 7.4% of the cases and1.1% of the patients was monitored overnight as inpatients. No patient required pharmacological intervention due to the occurrence of bradycardia (Limmroth et al., 2015).

5.4. START, results and cardiovascular events

The ECG measurements did not show any prolongation of the corrected QT interval using Fridericia's equation (QTcF) to >500 ms in any patient. 96 of the 3951 patients (2.4%) experienced an AV block I0 (PR-interval >200 ms) even before fingolimod treatment was initiated. 206 patients (5.2%) had an AV block I0 6 h after the first dose and 99 patients (2.5%) experienced an AV block I0 after approximately 7 days of the said dose. 98.4% of patients suffered no second- or third-degree AV block after initiation of fingolimod treatment. 60 patients (1.5%) did indeed show an AV Block Mobitz Type I (Wenckebach) and 18 (0.5%) patients experienced an 2:1 AV block. No second AV Block Mobitz Type II (Mobitz) or third-degree AV block were recorded (Limmroth et al., 2015).

6. Discussion

Particularly high demands are placed on the safety profile of medications, especially in part due to the potential necessity to be taken by patients on the long-term, perhaps even for the rest of their lives. This is partially due to the fact that healthcare-associated adverse events do not trigger any interventions that detract from the risk/benefit profile of such first-line therapies. The cardiac effects observed in regard to the first dose of fingolimod give no indication of the need to a reassess therapeutic safety. Furthermore, long-term data analyses did not show any significant effects on blood pressure (Izquierdo et al, 2014, Khatri et al, 2011, Kappos et al, 2015, and Cohen et al Disease Long-term safety of fingolimod: An interim analysis of the LONGTERMS cohort; AAN 2015, Washington, USA; S4006).

The observed rise in blood pressure of 2–3 mm Hg correlating with the first dose of fingolimod is of no therapeutic significance. This rise falls within the normal range of blood pressure changes caused by other factors as well as lifestyle aspects inherently influencing blood pressure levels, for example nutrition, weight and co-medications.

The increase in cardiac abnormalities observed in patients with cardiovascular medications which are known to induce bradycardia (BBs and CAs) is principally based on or can be explained by the slight amplification of the drop in heart rate caused by fingolimod as well as by the increased occurrence of ventricular extrasystoles. The ventricular extrasystoles do not usually warrant treatment, but for those affected, they can be quite disturbing (Kennedy et al, 1985 J 24 and Santangeli and Marchlinski, 2015 J 14). The drop in heart rate after the first dose of fingolimod can be considered a classic, first-dose side-effect. As a result, the S1P receptors are internalised in the conduction system of the atrium as well as in other compartments and organ systems. With further intake of fingolimod, they are no longer expressed on the cell surface. As a result, the effect ceases after the first dose.

The lower degrees of AV block observed during fingolimod treatment- first-degree AV block and Mobitz Type I (Wenckebach periodicity) second-degree AV block – affect the conduction systems associated with the atria. The ventricular plane remains unaffected. These lower degrees of AV block are usually asymptomatic and require no treatment (Table 4 and Table 5). They stand in direct contrast to higher-degree AV-blocks, such as Mobitz Type II second-degree AV-block (Mobitz Type II block) and third-degree AV block. Higher-degree AV blocks did not occur during fingolimod treatment of the approval studies.

Table 4

Adverse cardiac events in >1 patient on day1 and/or day 2 (FIRST study) (Gold et al., 2014).

 

Number of patients n (%) Safety population n=2415 (%) Without cardiac risk factors n=2120 (%) With cardiac risk factors n=295 (%) Without co-medication {BB, CA} n=2295 (%) With co-medication {BB, CA} n=120 (%)
Cardiac events overall 49 (2.0) 42 (2.0) 7 (2.4) 42 (1.8) 7 (5.8)
Palpitations 14 (0.6) 14 (0.7) 0 (0.0) 14 (0.6) 0 (0.0)
Bradycardia 15 (0.6) 11 (0.5) 4 (1.4) 11 (0.5) 4 (3.5)
Tachycardia 2 (0.1) 1 (0.0) 1 (0.3) 2 (0.1) 0 (0.0)
Cardiovascular disorders 3 (0.1) 3 (0.1) 0 (0.0) 3 (0.1) 0 (0.0)
Angina Pectoris 3 (0.1) 2 (0.1) 1 (0.3) 2 (0.1) 1 (0.8)
Mobitz type I second-degree AV block 5 (0.2) 5 (0.2) 0 (0.0) 5 (0.2) 0 (0.0)
Ventricular extrasystoles 4 (0.2) 3 (0.1) 1 (0.3) 2 (0.1) 2 (1.7)
Ventricular tachycardias 1 (0.0) 1 (0.0) 0 (0.0) 1 (0.0) 0 (0.0)
Cardiac disorders 1 (0.0) 1(0.0) 0 (0.0) 1 (0.0) 0 (0.0)
Sinus bradycardia 1 (0.0) 1(0.0) 0 (0.0) 1 (0.0) 0 (0.0)
AV block 1 (0.0) 1 (0.0) 0 (0.0) 1 (0.0) 0 (0.0)

BB=Beta-blockers.

CA=Calcium antagonists.

Table 5

Classification and need for treatment of AV blocks.

 

First-degree AV block Each impulse arising in the sinus node is relayed, but the conduction is slowed down. There is no real block, but only a delay. This results in prolongation of the PR interval (>0.2 s) on the ECG. First-degree AV block does not cause symptoms and does not require treatment.
Second-degree AV block Some impulses from the sinus node are not relayed. It is possible that, in a regular pattern, only every 2nd, 3rd or 4th atrial beat is relayed to the ventricle (thus producing 2:1, 3:1 or 4:1 AV blocks). In this connection, two different forms with different prognoses can be distinguished
Mobitz Type I second-degree AV-block (Wenckebach) The PR interval lengthens progressively until conduction of one atrial impulse fails to reach the ventricles (Wenckebach periodicity). The block generally occurs in the area of the AV node. The prognosis is generally good in the absence of organic heart disease. Symptoms do not usually occur.
Mobitz Type II second-degree AV-block The PR interval is constant in the ECG. However, there will be the occasional regular loss of conduction to the ventricles (loss of a QRS complex). Frequently every second or third atrial impulse is not conducted to the ventricle. The block occurs mainly distal to the AV node in the bundle of His. The Mobitz type II second-degree AV block occurs much less frequently than the Wenckebach periodicity. Nevertheless, many patients are asymptomatic.
Third-degree AV-block (complete heart block) There is a temporary or even permanent disturbance of impulse conduction. The sinus node action potentials are not relayed. The ventricles contract in step with secondary structures, such as the AV node. Atrial and ventricular actions are no longer properly coordinated. There is a complete AV dissociation. Symptoms ranging from mere dizziness through to syncopes (Stokes-Adams attacks) can occur as the brain does not receive sufficient oxygen levels owing to the inadequate pumping capacity of the heart.

Bradycardias are clearly of lesser importance in life-threatening arrhythmias, causing only ≤20% of all events. Ventricular tachycardia is considerably more frequent and may result in a hyper-dynamic pump failure with subsequent syncopes and perhaps even sudden cardiac death. (Bayés de Luna et al., 1989) However, rhythm disorders accompanied by tachycardia were not observed during the treatment with 0.5 mg fingolimod. Patients with structural heart disease have are especially at an increased risk of sudden cardiac death. This may particularly occur in cases with acute or chronic coronary heart disease (CHD), pre-existing heart failure, as well as those with dilated or hypertrophic cardiomyopathy (Zipes et al., 2006). These patients differ quite clearly from the "typical” MS patient - young, female, without general medical vascular comorbidities and co-medication. On the contrary, they are characterised by a low prevalence of cardiac risk factors or existing beta-blocker therapies, as the very low incidence of heart rhythm disorders with bradycardia during treatment with fingolimod in the approval studies have shown.

The safety profile of the FIRST and the EPOC studies corresponds to the safety profile observed in the phase III studies with fingolimod (Gold et al, 2014 and Calkwood et al, 2014). The transient and benign nature of the vagomimetic effects of fingolimod after the initial dose justifies a widespread application in clinical routine practice. This should be in compliance with the exclusion criteria defined by the regulatory authorities and in compliance with the advised monitoring after initial application, as recommended in the summary of product characteristics (Summary of product characteristics Gilenya, 2015).

7. Recommendations from the cardiological point of view

Cardiological monitoring by observing blood pressure and conducting ECG-monitoring is obligatory for the first 6 h after the first application of fingolimod as well as when the therapy is interrupted for a defined period of time. The same applies for the second dose of fingolimod in those patients previously having required pharmacological intervention during their first-dose monitoring and overnight monitoring in a medical facility.

Prior to commencement of treatment with fingolimod, a thorough history regarding the presence of cardiovascular risk factors or pre-existing impairment and of the intake of appropriate co-medication is compulsory. At-risk patients are assumed when pre-existing symptoms such as the occurrence of dyspnea and or chest-pain, new palpitations with or without syncope are present. At-risk patients should be seen and looked after by way of consultation by a cardiologist.

8. Conclusion for clinical practice

Due to its immunomodulatory impact, fingolimod can affect angiogenesis, vaso-relaxation, and features of conduction via S1P1 and S1P3 receptors in the myocardium and vascular endothelium. General medical and cardiology monitoring should be carried out on a regular basis in MS patients, irrespective of their medication, as part of their primary medical care treatment programme. The recommendations of the European Medicines Agency (EMA) regarding cardiology monitoring after the first application, after interruption of the treatment, and as part of regular monitoring, all reflect these requirements. Safety analyses of Phase III studies, extension studies covering up to seven years of observation, and clinical data from a representative MS patient cohort present no evidence of an increased cardiovascular risk linked to fingolimod. The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has acknowledged this with its positive assessment of the benefit-risk profile of fingolimod and the recent label extension.

Conflict of interests

V. Limmroth works as a consultant for Novartis and is Principal Investigator (PI) of the START-study.

Acknowledgement

We would like to thank Professor Dr Lutz Pott, M. D., Department for Cellular Physiology of the Ruhr-University Bochum, for his critical review of the section on receptor physiology. We would also like to thank Dr Alexander Kretzschmar for his editorial support.

References

Footnotes

a Department of Cardiology, Rhythmology and Internal Intensive Care Cologne-Merheim Hospital, Academic Hospital of the University of Cologne, Ostmerheimerstr. 200, 51109 Köln, Germany

b Department of Neurology und Palliative Medicine, Cologne-Merheim Hospital Cologne-Merheim Hospital, Academic Hospital of the University of Cologne, Germany

Correspondence to: Ruhr-University Bochum, Universitätsstraße 150, 44801 Bochum, Germany.


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  • Prof Timothy Vartanian

    Timothy Vartanian, Professor at the Brain and Mind Research Institute and the Department of Neurology, Weill Cornell Medical College, Cornell...
  • Dr Claire S. Riley

    Claire S. Riley, MD is an assistant attending neurologist and assistant professor of neurology in the Neurological Institute, Columbia University,...
  • Dr Rebecca Farber

    Rebecca Farber, MD is an attending neurologist and assistant professor of neurology at the Neurological Institute, Columbia University, in New...

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