PMID- 34950154
OWN - NLM
STAT- MEDLINE
DCOM- 20220228
LR  - 20220228
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 12
DP  - 2021
TI  - 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.
PG  - 795574
LID - 10.3389/fimmu.2021.795574 [doi]
LID - 795574
AB  - BACKGROUND: All 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). METHODS: We 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. RESULTS: Seventeen 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; I(2), 75.6%). Notably, 
      the high-risk cardiovascular AEs associated with S1PRMs were primarily 
      bradyarrhythmia (RR, 2.92; 95% CI, 1.91-4.46; I(2), 30.8%) and hypertension (RR, 
      2.00; 95% CI, 1.49-2.67; I(2), 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; I(2), 0.0%), while siponimod 
      was associated with a higher risk of bradyarrhythmia only (RR, 2.75; 95% CI, 
      1.75-4.31; I(2), 0.0%). No significant inter-subgroup differences were observed 
      (P(interaction) > 0.05). CONCLUSIONS: S1PRM 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 REGISTRATION: The PROSPERO ID is 
      CRD42020183215.
CI  - Copyright (c) 2021 Zhao, Lv, Gu, Ma and Zhong.
FAU - Zhao, Zhao
AU  - Zhao Z
AD  - Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China.
FAU - Lv, Yang
AU  - Lv Y
AD  - Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China.
AD  - The First Affiliated Hospital, College of Clinical Medicine of Henan University 
      of Science and Technology, Luoyang, China.
FAU - Gu, Zhi-Chun
AU  - Gu ZC
AD  - Department of Pharmacy, Ren Ji Hospital, Shanghai Jiao Tong University School of 
      Medicine, Shanghai, China.
FAU - Ma, Chun-Lai
AU  - Ma CL
AD  - Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China.
FAU - Zhong, Ming-Kang
AU  - Zhong MK
AD  - Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China.
LA  - eng
PT  - Journal Article
PT  - Meta-Analysis
PT  - Research Support, Non-U.S. Gov't
PT  - Systematic Review
DEP - 20211207
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (Azetidines)
RN  - 0 (Benzyl Compounds)
RN  - 0 (Indans)
RN  - 0 (Oxadiazoles)
RN  - 0 (Sphingosine 1 Phosphate Receptor Modulators)
RN  - 0 (Sphingosine-1-Phosphate Receptors)
RN  - G926EC510T (Fingolimod Hydrochloride)
RN  - RR6P8L282I (siponimod)
RN  - Z80293URPV (ozanimod)
SB  - IM
MH  - Azetidines/adverse effects/*therapeutic use
MH  - Benzyl Compounds/adverse effects/*therapeutic use
MH  - Bradycardia/*epidemiology
MH  - Drug-Related Side Effects and Adverse Reactions/*epidemiology
MH  - Fingolimod Hydrochloride/adverse effects/*therapeutic use
MH  - Humans
MH  - Hypertension/*epidemiology
MH  - Indans/adverse effects/*therapeutic use
MH  - Multiple Sclerosis
MH  - Oxadiazoles/adverse effects/*therapeutic use
MH  - Randomized Controlled Trials as Topic
MH  - Risk
MH  - Sphingosine 1 Phosphate Receptor Modulators/adverse effects/*therapeutic use
MH  - Sphingosine-1-Phosphate Receptors/metabolism
PMC - PMC8688957
OTO - NOTNLM
OT  - Sphingosine 1-phosphate receptor modulators
OT  - bradyarrhythmia
OT  - cardiovascular adverse events
OT  - hypertension
OT  - meta-analysis
OT  - multiple sclerosis
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2021/12/25 06:00
MHDA- 2022/03/01 06:00
PMCR- 2021/01/01
CRDT- 2021/12/24 05:47
PHST- 2021/10/15 00:00 [received]
PHST- 2021/11/18 00:00 [accepted]
PHST- 2021/12/24 05:47 [entrez]
PHST- 2021/12/25 06:00 [pubmed]
PHST- 2022/03/01 06:00 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2021.795574 [doi]
PST - epublish
SO  - Front Immunol. 2021 Dec 7;12:795574. doi: 10.3389/fimmu.2021.795574. eCollection 
      2021.