Risk for Cardiovascular Adverse Events Associated With Sphingosine-1-Phosphate Receptor Modulators in Patients With Multiple Sclerosis: Insights From a Pooled Analysis of 15 Randomised Controlled Trials

Abstract

BackgroundAll agents engaging sphongosine-1-phospate receptors (S1PRs) will have some cardiovascular effect. This study aimed to elucidate the risk of cardiovascular adverse events (AEs) in patients with multiple sclerosis (MS) treated with S1PR modulators (S1PRMs).MethodsWe systematically searched the PubMed, EMBASE, and Cochrane Library databases for randomised controlled trials (RCTs) published through January 5, 2021. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using the random-effects model. Sensitivity analyses and meta-regression were performed.ResultsSeventeen RCTs (12 for fingolimod; 3 for ozanimod; 2 for siponimod) involving 13,295 patients were included. Compared with the control treatment, S1PRMs significantly increased the risk of cardiovascular AEs (RR, 2.21; 95% CI, 1.58–3.10; I2, 75.6%). Notably, the high-risk cardiovascular AEs associated with S1PRMs were primarily bradyarrhythmia (RR, 2.92; 95% CI, 1.91–4.46; I2, 30.8%) and hypertension (RR, 2.00; 95% CI, 1.49–2.67; I2, 56.5%). Subgroup analysis results were consistent with the primary outcomes except that ozanimod was associated with a higher risk of hypertension only (RR, 1.76; 95% CI, 1.10–2.82; I2, 0.0%), while siponimod was associated with a higher risk of bradyarrhythmia only (RR, 2.75; 95% CI, 1.75–4.31; I2, 0.0%). No significant inter-subgroup differences were observed (Pinteraction > 0.05).ConclusionsS1PRM use increased the risk of cardiovascular AEs by 1.21 times in patients with MS, and increased risks for bradyarrhythmia and hypertension were at 2.92- and 2.00-fold, respectively. These findings can help clinicians assess the risk of cardiovascular AEs in patients treated with S1PRMs.Systematic Review RegistrationThe PROSPERO ID is CRD42020183215.

Demographic Patterns of MS Patients Using BRISA: An MS-Specific App in Germany

“…This could be attributed to the associated adverse effects. A pooled analysis of 15 randomized control trials with S1PRMs showed an increased risk of bradyarrhythmia and hypertension in MS patients [ 31 ]. As a result, clinicians assess the benefit-to-risk ratio before prescribing S1PRMs.…”

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“…They included 17 studies including 13,295 patients and found that these S1P receptor modulators were associated with an increased risk of overall cardiovascular events (risk ratio (RR), 2.21; 95% CI, 1.58–3.10), primarily bradyarrhythmia (RR, 2.92; 95% CI, 1.91–4.46) and hypertension (RR, 2.00;95% CI, 1.49–2.67). However, in subgroup analysis, ozanimod was only associated with hypertension, but not bradyarrhythmia 102 . Notably, there seems to be no increased risk of MACE with the use of S1P receptor modulators.…”

“…101 Fingolimod is a nonselective S1P receptor modulator, and consequently, it has been shown consistently to increase the risk of bradycardia in most clinical trials among patients with multiple sclerosis. 102 In three phase 3, placebo-controlled trials in patients with multiple sclerosis, after the first dose, fingolimod produced a transient, dose-dependent decrease in mean heart rate after 4-5 h, with a maximum reduction of 8-11 beats per minute below the baseline. 103 Symptomatic bradycardia at treatment initiation was reported in 0.6% (fingolimod 0.5 mg) and 2.1% (fingolimod 1.25 mg) of patients, whereas AV block was less frequent: Mobitz type I, second-degree AV block occurred in 0.2% and 1% of patients, respectively.…”

“…The same meta-analysis by Zhao et al did not find differences in either coronary artery disease or heart failure between S1P receptor modulators and placebo. 102 Data on real-world evidence use of ozanimod in multiple sclerosis are still lacking. However, a large-scale cohort study in Germany is ongoing, which will shed some light on the cardiovascular safety profile ozanimod has and its association with conduction abnormalities.…”

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“…As of now, they do not have any major safety concerns although do have some known off target effects. For example, by modulating S1P receptor in the myocardium, ozanimod has chronotropic effects causing a transitory dose-dependent bradycardia [42]. They show potential for use biologic-naı ¨ve and exposed patients and are a potential alternative therapeutic option in UC patients with moderate disease.…”