Cardiovascular events and safety outcomes associated with ...

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Clin Transl Sci. 2021;00:1–13. | 1www.cts-journal.com

Received:22July2021 | Revised:24August2021 | Accepted:10September2021

DOI:10.1111/cts.13168

A R T I C L E

Cardiovascular events and safety outcomes associated with remdesivir using a World Health Organization international pharmacovigilance database

Se Yong Jung1 | Min Seo Kim2,3 | Han Li4 | Keum Hwa Lee5 | Ai Koyanagi6,7,8 | Marco Solmi9,10,11 | Andreas Kronbichler12 | Elena Dragioti13 | Kalthoum Tizaoui14 | Sarah Cargnin15 | Salvatore Terrazzino15 | Sung Hwi Hong16 | Ramy Abou Ghayda17 | Nam Kyun Kim18,19 | Seo Kyoung Chung20 | Louis Jacob6,21 | Joe- Elie Salem22 | Dong Keon Yon23 | Seung Won Lee24 | Karel Kostev25 | Ah Young Kim1 | Jo Won Jung1 | Jae Young Choi1 | Jin Soo Shin26 | Soon- Jung Park27 | Seong Woo Choi28 | Kiwon Ban29 | Sung- Hwan Moon27 | Yun Young Go30 | Jae Il Shin5 | Lee Smith31

1DivisionofPediatricCardiology,DepartmentofPediatrics,YonseiUniversityCollegeofMedicine,Seoul,Korea2CollegeofMedicine,KoreaUniversity,Seoul,Korea3SamsungAdvancedInstituteforHealthSciencesandTechnology(SAIHST),SamsungMedicalCenter,SungkyunkwanUniversity,Seoul,Korea4UniversityofFloridaCollegeofMedicine,Gainesville,Florida,USA5DepartmentofPediatrics,YonseiUniversityCollegeofMedicine,Seoul,Korea6ResearchandDevelopmentUnit,ParcSanitariSantJoandeDéu,UniversitatdeBarcelona,FundacióSantJoandeDéu,CIBERSAM,Barcelona,Spain7ICREA,Barcelona,Spain8InstitutodeSaludCarlosIII,CentrodeInvestigaciónBiomédicaenReddeSaludMental,CIBERSAM,Madrid,Spain9DepartmentofPsychiatry,UniversityofOttawa,Ottawa,Ontario,Canada10DepartmentofMentalHealth,TheOttawaHospital,Ottawa,Ontario,Canada11OttawaHospitalResearchInstitute(OHRI)ClinicalEpidemiologyProgram,UniversityofOttawa,Ottawa,Ontario,Canada12DepartmentofInternalMedicineIV,MedicalUniversityInnsbruck,Innsbruck,Austria13DepartmentofHealth,MedicineandCaringSciences,PainandRehabilitationCentre,LinköpingUniversity,Linköping,Sweden14LaboratoryMicroorganismesandActiveBiomolecules,SciencesFacultyofTunis,TunisElManarUniversity,Tunis,Tunisia15DepartmentofPharmaceuticalSciences,InterdepartmentalResearchCenterofPharmacogeneticsandPharmacogenomics(CRIFF),UniversityofPiemonteOrientale,Novara,Italy16YonseiUniversityCollegeofMedicine,Seoul,Korea17UrologyInstitute,UniversityHospitalsandCaseWesternReserveUniversity,Cleveland,Ohio,USA18DepartmentofPediatrics,EmoryUniversity,Atlanta,Georgia,USA19DivisionofCardiovascularSurgery,DepartmentofThoracicandCardiovascularSurgery,YonseiUniversityCollegeofMedicine,Seoul,Korea20CollegeofMedicine,EwhaWomansUniversity,Seoul,Korea21FacultyofMedicine,UniversityofVersaillesSaint-Quentin-en-Yvelines,Montigny-le-Bretonneux,France

ThisisanopenaccessarticleunderthetermsoftheCreativeCommonsAttribution-NonCommercialLicense,whichpermitsuse,distributionandreproductioninanymedium,providedtheoriginalworkisproperlycitedandisnotusedforcommercialpurposes.©2021TheAuthors.Clinical and Translational SciencepublishedbyWileyPeriodicalsLLConbehalfofAmericanSocietyforClinicalPharmacologyandTherapeutics.

SeYongJung,MinSeoKim,andHanLicontributedequallytothiswork.

NCT:NCT04314817

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22DepartmentofPharmacology,INSERM,CIC-1901Paris-Est,CLIPGalilée,UNICO-GRECOCardio-oncologyProgram,Pitié-SalpêtrièreHospital,AssistancePublique–HôpitauxdeParis,SorbonneUniversité,Paris,France23DepartmentofPediatrics,SeoulNationalUniversityChildren'sHospital,SeoulNationalUniversityCollegeofMedicine,Seoul,Korea24DepartmentofDataScience,SejongUniversityCollegeofSoftwareConvergence,Seoul,Korea25UniversityClinicofMarburg,Marburg,Germany26InfectiousDiseaseResearchCenter,KoreaResearchInstituteofChemicalTechnology,Daejeon,Korea27StemCellResearchInstitute,T&RBiofabCo.Ltd,Siheung,Korea28DepartmentofPhysiology,Ischemic/HypoxicDiseaseInstitute,SeoulNationalUniversityCollegeofMedicine,Seoul,Korea29DepartmentofBiomedicalSciences,CityUniversityofHongKong,HongKongSAR,China30DepartmentofInfectiousDiseasesandPublicHealth,CityUniversityofHongKong,HongKongSAR,China31TheCambridgeCentreforSportandExerciseSciences,AngliaRuskinUniversity,Cambridge,UK

CorrespondenceJaeIlShin,DepartmentofPediatrics,YonseiUniversityCollegeofMedicine,50-1Yonsei-ro,Seodaemun-gu,C.P.O.Box8044,Seoul03722,Korea.Email:[email protected]

Funding informationThisstudywassupportedbyanewfacultyresearchseedmoneygrantofYonseiUniversityCollegeofMedicinefor2021(2021-32-0049).Thefundershadnoroleinthedesign,analyses,orinterpretationofthestudy.

AbstractOnOctober2020,theUSFoodandDrugAdministration(FDA)approvedremde-sivirasthefirstdrugforthetreatmentofcoronavirusdisease2019(COVID-19),increasing remdesivir prescriptions worldwide. However, potential cardiovas-cular(CV)toxicitiesassociatedwithremdesivirremainunknown.Weaimedtocharacterize theCVadversedrugreactions (ADRs)associatedwithremdesivirusing VigiBase, an individual case safety report database of the World HealthOrganization (WHO).DisproportionalityanalysesofCV-ADRsassociatedwithremdesivirwereperformedusingreportedoddsratiosandinformationcompo-nents. We conducted in vitro experiments using cardiomyocytes derived fromhumanpluripotentstemcellcardiomyocytes(hPSC-CMs)toconfirmcardiotoxic-ityofremdesivir.Todistinguishdrug-inducedCV-ADRsfromCOVID-19effects,werestrictedanalyses topatientswithCOVID-19and foundthat,afteradjust-ingformultipleconfounders,cardiacarrest(adjustedoddsratio[aOR]:1.88,95%confidenceinterval[CI]:1.08–3.29),bradycardia(aOR:2.09,95%CI:1.24–3.53),andhypotension(aOR:1.67,95%CI:1.03–2.73)wereassociatedwithremdesivir.InvitrodatademonstratedthatremdesivirreducedthecellviabilityofhPSC-CMsintime-anddose-dependentmanners.PhysiciansshouldbeawareofpotentialCVconsequencesfollowingremdesiviruseandimplementadequateCVmoni-toringtomaintainatolerablesafetymargin.

Study HighlightsWHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?Remdesiviruseisincreasing,butitscardiovascular(CV)adversedrugreactions(ADRs)remainlargelyunknown.Thetoxicityprofilederivesfromclinicaltrialswithconflictingresultsandofinsufficientsizetoidentifyrare,severeadverseCVreactions.WHAT QUESTION DID THIS STUDY ADDRESS?ThisstudyidentifiesCVADRsassociatedwithremdesivirbydisproportionalityanalysisusingVigiBase,aglobalindividualcasesafetyreportdatabase.WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?ThisstudyidentifiesthreepreviouslyunreportedputativeadverseCVreactions,namely,hypotension,cardiacarrest,andbradycardia,independentlyassociated

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| 3CARDIOVASCULAR EVENTS OF REMDESIVIR

INTRODUCTION

InDecember2019,thenovelsevereacuterespiratorysyn-dromecoronavirus2(SARS-CoV-2)wasidentifiedasthecausativeagentofoutbreakofpneumoniaandotherasso-ciatedsymptomslikecytokinestorm,1eventuallytermedcoronavirus disease 2019 (COVID-19).2 Remdesivir (GS-5734),aninhibitoroftheRNA-dependentRNApolymer-asesofSARS-CoV-1andMiddleEastrespiratorysyndrome(MERS)-CoV,3hasshownprotectiveeffectagainstSARS-CoV-2byeffectivelyinhibitingitsproliferationinvitro.4,5Subsequentrandomizedplacebo-controlledtrials(RCTs)and open-label trials have shown that remdesivir treat-mentloweredthemedianrecoverytimeofpatientswithCOVID-19,6–8 with some trials demonstrating decreasedmortality.6 Based on this supporting evidence, the USFood and Drug Administration (FDA) approved rem-desiviras the firstdrug treatmentagainstCOVID-19onOctober22,2020.9

Although the efficacy of remdesivir has been exten-sivelyinvestigated,theassociatedadverseevents(AEs)arenotwell-characterized.Becauseremdesivirhasnotbeenextensively used in clinical practice—other than againstEbola virus (EBOV) disease and COVID-19—sufficientsafety evidence has not been accumulated. At present,clinical trials on COVID-19 are the sole source of infor-mationoncardiovascular(CV)toxicitiesassociatedwithremdesivir, and recent RCTs have reported conflictingresults;someRCTshavereportedthatremdesivircausesmore seriousCVAEs than the standardcare,10whereasanother suggested that the CV AEs induced by remde-siviriscomparabletothatinducedbyplacebo.8AlthoughRCTs provide reliable information on drug efficacy, ob-servational studies with large sample size often outper-formRCTsincapturingrarebutfatalAEs,suchascardiacarrest or myocardial infarction.11 The increasing use ofremdesivir during the COVID-19 pandemic has createdanurgentneedtoelucidateitssafetyprofile,particularlyforCVAEsthatareofteninfrequentbutlethaltopatientswithCOVID-19.

Therefore, we conducted a large observational phar-macovigilancestudyusingtheWorldHealthOrganization(WHO) global database of individual case safety reports

(ICSRs),12 todetectCVsignalswithhighresolutionandcharacterize theCVAEsofremdesivir.TheVigiBase in-corporates thedataof20 million individuals frommorethan130countriesandasthelargestpharmacovigilancedatabase, it provides discriminating findings on drugsafety,asindicatedinourpreviousstudies.13–16

METHODS

Study design and data source

This large retrospective pharmacovigilance cohort studywasconductedusingdatafromVigiBase,theWHOglobaldeduplicated ICSR database,12 which contains recordsfromgreaterthan130countriesand20 millionindividuals,untilSeptember1,2020.Relevantadversedrugreaction(ADR)reportsfromacrosstheglobehavebeencollectedto thedatabasesince1967asper theWHOProgramforInternational Drug Monitoring (MDR), and is managedby the Uppsala Monitoring Center (UMC, Sweden).The data casemix was separated into case and non-casegroupsbasedonthetargetdrugof interest (remdesivir),whichwerethenusedforthedisproportionalityanalysis.VigiBaseacceptsreportsfromvariouscrediblesources,in-cludinghealthcareworkers,patients,andpharmaceuticalcompanies, and the sources are generally provided withpostmarketing notifications. We extracted remdesivir-associated ADR cases from the inception of the data-basetoAugust30,2020.TheethicscommitteeofYonseiUniversity Severance Hospital, Seoul, Korea, approvedthisstudyandgrantedawaiverofreviewfromtheformalinstitutionalreviewboard(no.4-2020-0868)andinformedconsentbecauseanonymousdatawereused.This studyhasbeenregisteredinclinicaltrial.govNCT04314817.

Procedures and description of the pharmacovigilance cohort

As per the Medical Dictionary for Drug RegulatoryActivities(MedDRA)version23.1(Table S1),allrelevantCV-ADRs classified by group queries were prespecified

with remdesivir usage after sensitivity analysis and adjustment for multipleconfounders.HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR

TRANSLATIONAL SCIENCE?Patientswithpre-existingCVcomorbiditiesorreceivinghigherdosesofremde-sivirmaybenefitfromadditionalcardiacmonitoring.Furtherstudyiswarrantedtoconfirmthefindings.

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andextractedforanalysis.Currently,thereisaconsider-ablelackofspecificCVtoxicityreportsonremdesivirforits recent FDA approval (October 2020) and EmergencyUseAuthorization(EUA)fromtheFDA(2020)aswellasapprovalandconditionalmarketingauthorizationintheEuropeanUnionandverylowaccumulationofreal-worlddata. Consequently, we used some specific cardiac andvascular preferred terms (PTs) for the analysis. Of note,ICSRsassociatedwithremdesivirhavebeenaccruing inVigiBasesinceFebruary2020.Theindividualreportsin-cludedpatientcharacteristics(age,sex,andnationality),drug information (indications, dosage, regimen, admin-istrationroute,anddurationprescribed),ADR(reportedAE, MedDRA classification terms, time to onset, natureandseverityofADR,fetaloutcomes,andmortality),andgeneral administrative information (date of report, re-porter qualification, and country of origin). Because thetimetoADRonsetwasnotconsistentlyreportedforrem-desivir,weusedtreatmentdurationasanalternativetoas-sumetheonsetperiod.AccordingtotheWHOdefinition,a serious reaction was described as an ADR associatedwithdeath,life-threateningcondition,hospitaladmissionorprolongationofhospitalization, chronic incapacityorimpairment, andconsequencesdeemedclinically severebythereportingphysician.17

Sensitivity analysis

BecausethenaturaldiseasecourseofCOVID-19isknownto involve myocardial injury and further challenges theCV system,18,19 it is crucial to distinguish drug-inducedCV-ADRsfromCOVID-19inducedCVeffects.Therefore,wefurtherconductedasensitivityanalysisbycomparingtheeffectofremdesivirandotherdrugsexclusivelyintheCOVID-19 diagnosed population, offsetting the effect ofCOVID-19 in cases and non-cases. The COVID-19 sub-populationwasdefinedbyeachcaseofCOVID-19relatedMedDRAtermastheindicationofremdesiviruse.

Statistical analysis

As VigiBase incorporates a dataset comprising a largesamplesizecollectedworldwide,itprovidesagoodfitforthestudyofdisproportionality(alsoknownascase–non-case analysis), for which sufficient sample size is indis-pensable to warrant applicable power and resolution.20We used the analysis to determine whether the propor-tionofCVtoxicitiesreportedforremdesivirdiffersfromthatoccurring in thedrugcontrolgroup (fulldatabase).Whenpatientsexposedtoaparticularmedication(cases)haveahigherpercentageofADRsthanthosenotexposed

tothatdrug(non-cases),thelinkbetweentheadversere-actionandtheindividualactivedrugmaysuggestapos-sible safety concern. Information component (IC) andreportingoddsratio(ROR)are indicatorvaluesusedforthedisproportionatereportingdevelopedbyUMC,whereanIC0.25(thelowerendofa95%credibleinterval)greaterthan0or lowerconfidence interval (CI)ofRORgreaterthan1indicatessignificantassociationsofspecificADRswiththedrugs.RORwascalculatedusingthechi-square(χ2) test as per the well-established reporting method ofpharmacovigilancestudies.21Whenthefulldatabasewasnot used as a comparator and sensitivity analyses wereconducted, ROR was reported rather than the IC to ex-pressdisproportionality.15Multivariateoddsratios(ORs)with95%CIswerecalculatedusinga logistic regressionmodeltoconsiderprespecifiedvariables,suchasage,sex,and multiple COVID-19 treatment drugs, including hy-droxychloroquine,corticosteroid,lopinavir-ritonavir,andinterferon.22,23 Dexamethasone, hydrocortisone, predni-solone, and prednisone were included for corticosteroidvariableas indicated instudyprotocolandguideline forCOVID-19treatment.23,24

TheICcomparesobservedandexpectedvaluestoiden-tifyAEsthatareassociatedwithparticulardrugsusingtheBayesian neural network method developed by UMC.25Probabilistic logic in intelligent systems—proven usefulin controlling big data—is reliable for handling missingdata,andcanbeusedforcomplexvariables.25Itisoftenvulnerabletospontaneousvariabilityforrareeventswithlowexpectedcounts,butstatisticalshrinkagesafeguardsagainstspuriousassociationsandtheshrinkageobserved-to-expected(OE)ratiooffersabasicbutefficientstructurefor large-scale pattern exploration.26This sensitive algo-rithmallowstheidentificationofsignalssoonafterdrugapproval by a regulatory agency, therefore, we used thismethodtodetectearlysignalsofremdesivirandidentifyanypotentialrisk.

Thefollowingstatisticalformulawasused:

whereNexpected=[Ndrug×Nreaction]/Ntotal.Nexpectedrepresentsthenumberofcasereportsexpected

for the drug-effect combination, whereas Nobserved indi-catestheactualnumberofcasereportsforthedrug-effectcombination.Furthermore,NdrugandNreactionspecifythenumberofcasereportsforthedrugirrespectiveofAEsandfor the effect irrespective of drug, respectively.25,26 Ntotalcorrespondtothetotalnumberofcasereportsinthefulldatabase. Qualitative variables were described as count(percentage), and continuous variables were expressedasmedianwithinterquartilerange(IQR).Theremdesivirand full database cases were compared using theχ2 test

IC = log2([Nobserved + 0.5]∕[Nexpected + 0.5])

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| 5CARDIOVASCULAR EVENTS OF REMDESIVIR

orFisher’sexacttestforqualitativevariablesandtheun-paired Kruskal-Wallis test for continuous variables. Posthocpoweranalysesofthecomparisonsbetweentherem-desivirandfulldatabasecasesaswellastheremdesivirandCOVID-19caseswereperformedusingtheZtestofinde-pendentproportions.Alltestsweretwo-sided,andpvalueless than 0.05 was considered significant. All analyseswereconductedusingIBMstatisticalpackagefortheso-cialsciences(SPSS)version25.0(SPSSInc.)orRsoftware,version 3.6.0 (R Foundation for Statistical Computing).Power analyses were performed with G*Power, version3.1.9.6(Heinrich-Heine-Universität-Düsseldorf).

Generation of human pluripotent stem cells- derived cardiomyocytes

The human pluripotent stem cells (hPSCs) lines, whichinclude both human embryonic stem cells (hESC: H9:Wicell)andhuman-inducedpluripotent stemcells (hiP-SCs: CMC-hiPSC-011: KNIH) were maintained with theStemMACS iPS-BREW XF, human (Miltenyi Biotec) onMatrigel (Corning).Forderivation into thecardiac line-age,hPSCswereplatedontoanMatrigel-coatedcellcul-turedish(Eppendorf)at140,000cells/cm2dish.Atday0,6 μM/mlCHIR99021(Tocris)wastreatedintotheculturedhPSCstogetherwithbovineserumalbumin(BSA;Sigma-Aldrich) and ascorbic acid (Sigma-Aldrich). After 48  h,2 μM/mlofC59,aWntinhibitor(StemgentInc.)wasfor48 h.Spontaneouslycontractingcardiaclinagecellsbegantoappearasearlyasdifferentiationday8.Subsequently,L-lacticacidwasadded into theculturemedia topurifycardiomyocytes(CM)-derivedhPSCs(hPSC-CMs).

Cell viability assay

Variousconcentrationsofremdesivir(MedChemExpress)wasaddedtohPSC-CMsfor24 hor48 h,andthecellvi-ability was determined using the CellTiter 96 AQueousOne Solution Cell Proliferation Assay (MTS; Promega)accordingtothemanufacturer’sinstructions.Absorbanceat490 nm(A490)wasmeasuredusingaSynergyTMH1multi-modemicroplatereader(Biotek).Allthecellviabil-ityassayswereperformedatleastthreetimes.

RESULTS

CV- ADR signals

ThenumberofADRsreportedforremdesivirwas2107byAugust30,2020,andatotalof22,728,189all-drugADRs

have been reported since the inception of the database.BecauseADRsassociatedwithremdesivirduringtheout-breakofEBOVwasnotreportedtoVigiBase,ADRsrelatedtoremdesivirwerefirstrecordedinVigiBaseinFebruary2020,aftertheoutbreakofCOVID-19.Thetotalnumberofall-drugADRscorrespondingtotheintervalofinterest(fromFebruary2020toAugust2020)was1,403,532.ThenumberofspecificCV-ADRsislistedinTable 1.ThetotalnumberofpatientswithCOVID-19includedinouranaly-siswas5408,andthesensitivityanalysisoftheCOVID-19population alone is described in Table  2. Median (IQR)drugtreatmentduration(days)rangedfrom0(0–4)daysforventricularfibrillationto4(1–5)daysforatrialfibrilla-tion(Table 3).TheindicationforremdesivirwasCOVID-19-positive for all reported patients. Post hoc poweranalysis of the closest proportion comparison (atrioven-tricularblock)revealedapowerof0.634,withthesecondclosestcomparison(myocarditis)revealingapower0.996.

Weidentifiedeightcandidatesamong37broadCVout-comeswhereCV-ADRsweresignificantlyhigherinrem-desivir thantheywereintheentiredatabase(non-cases;Table 1).Remdesivirwasassociatedwithhigherreportingofcardiacarrest(ROR:19.9,95%CI:16.1–24.5,IC0.25:3.19),bradycardia (ROR: 15.0, 95% CI: 12.0–18.9, IC0.25: 2.83),shock(ROR:17.8,95%CI:11.2–28.1,IC0.25:2.56),hypoten-sion(ROR:5.9,95%CI:4.7–7.3,IC0.25:1.76),atrialfibrilla-tion(ROR:7.3,95%CI:5.0–10.6,IC0.25:1.64),ventriculartachycardia(ROR:17.8,95%CI:9.5–33.4,IC0.25:1.58),ven-tricular fibrillation (ROR:22.1,95%CI:10.4–47.1, IC0.25:1.18), and acute myocardial infarction (AMI; ROR: 15.5,95%CI:8.0–30.0,IC0.25:1.06).Theresultswereconsistentwiththethoseofsensitivityanalysesrestrictedtothepa-tientswithCOVID-19only,exceptforcardiogenicshock,atrial fibrillation, and ventricular tachycardia (Table  2).Afterfurtheradjustmentforvariousconfounders,includ-ingcorticosteroiduse,cardiacarrest(adjustedOR[aOR]:1.88,95%CI:1.08–3.29),bradycardia(aOR:2.09,95%CI:1.24–3.53),andhypotension(aOR:1.67,95%CI:1.03–2.73)were significantly associated with the use of remdesivir.Posthocpoweranalysisoftheclosestproportioncompari-son(cardiogenicshock)revealedapowerof1.00.

Characteristics of patients

Remdesivir-associated CV toxicity is a novel clinical en-tity and represents a new problem for clinicians treatingCOVID-19,and, therefore, additionaldatawerecollectedtofacilitatethedescriptionoftheclinicalcharacteristicsofremdesivir-associated CV-ADR in the 2107 identified pa-tients (Table 3).AllCV-ADRsassociatedwithremdesiviroccurred more frequently in male patients (51.6%-90.0%)thaninfemalepatients.Cardiacarrest,cardiogenicshock,

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T A B L E 1 DisproportionalityanalysisinVigiBasefromtheinceptionofthedatabasetoAugust30,2020

RemdesivirFull database (since inception) IC/IC025

Full database (since February 2020) ROR (95% CI)

TotalnumbersofICSRsavailable 2107 22,728,189 1,403,532

NumbersofICSRsbycardiovascularADRsubgroups

Cardiacarrest 93 (4.41) 83,581 (0.37) 3.50/3.19 3340 (0.24) 19.9 (16.1– 24.5)

Bradycardia 79 (3.75) 90,496 (0.40) 3.16/2.83 3703 (0.26) 15.0 (12.0– 18.9)

Cardiogenicshock 19 (0.90) 16,292 (0.07) 3.28/2.56 737 (0.05) 17.8 (11.2– 28.1)

Hypotension 86 (4.08) 215,210 (0.95) 2.01/1.76 10,194 (0.73) 5.9 (4.7– 7.3)

Atrialfibrillation 28 (1.33) 60,278 (0.27) 2.23/1.64 2624 (0.19) 7.3 (5.0– 10.6)

Ventriculartachycardia 10 (0.47) 13,208 (0.06) 2.61/1.58 385 (0.03) 17.8 (9.5– 33.4)

Ventricularfibrillation 7 (0.33) 9482 (0.04) 2.44/1.18 218 (0.02) 22.1 (10.4– 47.1)

Acutemyocardialinfarction 9 (0.43) 17,645 (0.08) 2.15/1.06 397 (0.03) 15.5 (8.0– 30.0)

Sinustachycardia 19(0.90) 213,580(0.94) −0.06/−0.78 10,467(0.75) NA

Hypertension 13(0.62) 176,559(0.78) −0.32/−1.21 7910(0.56) NA

Pulmonaryembolism 10(0.47) 75,522(00.33) 0.49/−0.54 2074(0.15) NA

Chestpain 7(0.33) 319,538(1.41) −2.00/−3.27 23,265(1.66) NA

ElectrocardiogramQTcorrectedintervalprolonged

4(0.19) 21,278(0.09) 0.86/−0.87 1746(0.12) NA

Ischemicstroke 3(0.14) 9860(0.04) 1.31/−0.74 429(0.03) NA

Systolicdysfunction 2(0.09) 970(0.00) 2.08/−0.51 189(0.01) NA

Atrialflutter 2(0.09) 5118(0.02) 1.36/−1.22 200(0.01) NA

Supraventriculartachycardia 2(0.09) 8478(0.04) 0.96/−1.63 249(0.02) NA

Bundlebranchblockright 2(0.09) 2731(0.01) 1.73/−0.86 105(0.01) NA

Jugularveinthrombosis 2(0.09) 1010(0.00) 2.07/−0.51 29(0.00) NA

Vertebralarteryobstruction 1(0.05) 123(0.00) 1.55/−2.55 5(0.00) NA

Cerebralhemorrhage 1(0.05) 36,338(0.16) −1.37/−5.16 1373(0.01) NA

Deepveinthrombosis 1(0.05) 58,504(0.26) −1.98/−5.78 1276(0.01) NA

Lacunarinfarction 1(0.05) 1543(0.01) 1.22/−2.58 20(0.00) NA

Rightventricledysfunction 1(0.05) 405(0.00) 1.48/−2.32 31(0.00) NA

Sinusnodedysfunction 1(0.05) 1972(0.01) 1.13/−2.66 34(0.00) NA

Transientischemicattack 1(0.05) 24,093(0.11) −0.87/−4.66 653(0.05) NA

Atrioventricularblock 1(0.05) 8770(0.04) 0.19/−3.61 232(0.02) NA

Rightventricularfailure 1(0.05) 7102(0.03) 0.37/−3.43 195(0.01) NA

Coronaryarterystenosis 1(0.05) 2651(0.01) 1.01/−2.79 38(0.00) NA

Carotidarteryocclusion 1(0.05) 1994(0.01) 1.13/−2.67 51(0.00) NA

STsegmentelevation 1(0.05) 1837(0.01) 1.16/−2.64 67(0.00) NA

Hypertensiveurgency 1(0.05) 132(0.00) 1.55/−2.25 16(0.00) NA

Torsadedepointes 1(0.05) 5583(0.02) 0.56/−3.24 154(0.01) NA

Myocarditis 1(0.05) 7340(0.03) 0.34/−3.45 411(0.03) NA

Pulmonaryhypertension 1(0.05) 16,720(0.07) −0.45/−4.25 514(0.04) NA

Syncope 1(0.05) 124,759(0.55) −3.00/−6.81 4259(0.30) NA

Palpitations 1(0.05) 215,552(0.95) −3.77/−7.57 14,559(1.04) NA

Note: Valuesaren(%)unlessotherwiseindicated.Informationcomponent(IC)andits95%credibilityintervallowerendpoint(IC025)comparingcardiacADRsassociatedwithremdesivirversusentiredatabaseinVigiBase(frominceptiononNovember14,1967,toAugust30,2020).ApositiveIC025value(>0)isthetraditionalthresholdusedforstatisticalsignaldetection(inbold).Forsignificantsignals,RORandits95%CIwerealsocalculatedusingentiredatabasefromFebruary1,2020,toAugust30,2020,ascomparator(contemporarycontrolgroupforremdesivir,firstremdesivirreportinFebruary2020).Abbreviations:ADR,adversedrugreaction;CI,confidenceinterval;ICSR,individualcasesafetyreport;NA,notapplicable;ROR,reportingoddsratio.

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| 7CARDIOVASCULAR EVENTS OF REMDESIVIR

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term

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idth

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Page 8

8 | JUNG et al.

TA

BL

E 3

C

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epor

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(66.

7)

Page 9

| 9CARDIOVASCULAR EVENTS OF REMDESIVIR

hypotension, and ventricular fibrillation were the com-monlyreportedCV-ADRsinpatientsagedbetween45and74 years.Bradycardia,atrialfibrillation,ventriculartachy-cardia,andAMIprimarilyoccurredinpatientsgreaterthan75 yearsofage.TheproportionsofseriousCV-ADRsweregenerallyhigh,rangingfrom80%forventriculartachycar-diato100%forcardiogenicshock,hypotension,AMI,andventricular fibrillation. Almost all cases were reported aspartofclinicalcareandnotclinicaltrials,andmostweread-ditionallyreportedbyhealthprofessionals(Tables S2–S9).

Outcomes

Theoverlapsbetween identifiedCV-ADRsare shown inFigure 1andTable 4.AMIcaseswere frequentlyassoci-atedwithconcurrentconditions(Table 4),suchascardiacarrest (33.3%) and, in rare cases, ventricular tachycar-dia (11.1%). Ventricular fibrillation was often associ-ated with cardiac arrest (42.8%). Most of these eight CVeventsoccurredwithotherseriousADRs,exceptforatrialfibrillation.

Remdesivir induced cardiotoxicity on hPSC- CMs in vitro

Toexaminewhetherremdesivircould inducecardiotox-icity in the human heart within the range of half maxi-maleffectiveantiviralconcentration (EC50), theculturehPSC-CMs were treated with increasing concentrationsofremdesivir,andthecellviabilitywasmeasuredat24 hand48 haftertreatmentusingcellproliferationassay.Weobserved that remdesivir treatment induced substantialcytotoxic effects in CMs derived from both hESCs andhiPSCs(Figure 2).Inaddition,treatmentwithremdesivirforalongertime(48 h)demonstratedsignificantlylowercell viability of hPSCS-CMs as compared to 24  h post-treatment, indicatingtime-anddose-dependentreactionandpotentialinducedcardiotoxicitybyremdesivir.Thesefindings are consistent with previous reports of dose-dependentremdesivirtoxicity.27

DISCUSSION

OnOctober22,2020,theFDAapprovedremdesivirasthefirst drug to treat hospitalized patients with COVID-19,andtheapprovalmayhaverapidlyincreasedremdesiviruseworldwide.Thelargeincreaseinremdesivirdemandand associated ADR reports warrant urgent pharma-covigilant evaluations of this drug.28,29 We conducted aclinical characterization of CV-ADRs disproportionally

Car

diac

arr

est

(n =

 93)

Bra

dyca

rdia

(n

 = 7

9)C

ardi

ogen

icsh

ock

(n =

 19)

Hyp

oten

sion

(n

 = 8

6)A

. fib

(n =

 28)

VT

(n =

 10)

AM

I (n 

= 9

)V

. fib

(n =

 7)

Dru

gtr

eatm

ent

dura

tion

81 (8

7.1)

61 (7

7.2)

16 (8

4.2)

74 (8

6.0)

23 (8

2.1)

8 (8

0.0)

8 (8

8.9)

7 (1

00.0

)

Med

ian

days

(IQ

R,

min

-max

)2.

0(0

.0–4

.0,

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13.0

)4.

0(0

.0–4

.0,

0.0–

10.0

)2.

0(0

.0–4

.0,

0.0–

9.0)

3.0

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–4.0

,0.

0–10

.0)

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(1.0

–5.0

,0.

0–9.

0)2.

0(0

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.0,

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8.0)

1.0

(0.0

–3.5

,0.

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0)0.

0(0

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Indi

catio

ns86

(92.

5)64

(81.

0)19

(100

.0)

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4.5)

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2.1)

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9 (1

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(100

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VID

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e: V

alue

sare

n(%

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/N(%

),un

less

oth

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ise

indi

cate

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vaila

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dat

ais

men

tione

din

bol

dan

dto

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ws.

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vere

AD

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asd

efin

eda

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thre

aten

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cau

sing

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sten

tors

igni

fican

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ty,o

rre

quir

ing

hosp

italiz

atio

n(fi

rsto

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long

ed)o

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usin

gde

ath.

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atio

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,adv

erse

dru

gre

actio

n;A

.fib

,atr

ialf

ibri

llatio

n;A

MI,

acut

em

yoca

rdia

linf

arct

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CO

VID

-19,

cor

onar

viru

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ease

201

9;IC

SR,i

ndiv

idua

lcas

esa

fety

repo

rt;I

QR

,int

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era

nge;

min

-max

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inim

um-m

axim

um;V

.fib

,ven

tric

ular

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illat

ion;

VT,

ven

tric

ular

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dia.

TA

BL

E 3

(C

ontin

ued)

Page 10

10 | JUNG et al.

related to remdesivir using the international pharma-covigilancedatabase(VigiBase),whichincludesinforma-tion from over 130 countries and 20  million individualsuntilSeptember1,2020.Tothebestofourknowledge,thisisthefirstpopulation-basedpharmacovigilancestudyon

the CV-ADRs of remdesivir. In this study, we compara-tivelyanalyzedCV-ADRsreported tobeassociatedwithremdesivirtreatmentandthosefortheentiredataset,andidentifiedeightCV-ADRscandidatesthatweredispropor-tionatelyassociatedwithremdesiviramong37broadCV

F I G U R E 1 Overlapbetweencardiovascularentities.AMI,acutemyocardialinfarction

T A B L E 4 OverlapofcardiacADRassociatedwithremdesivir

Cardiac arrest

Atrial fibrillation

Ventricular tachycardia

Acute myocardial infarction

Ventricular fibrillation

Cardiacarrest(n=93) 2/93(2.2) 2/93(2.2) 3/93(3.2) 3/93(3.2)

Atrialfibrillation(n=28) 2/28(7.1) 0/28(0.0) 0/28(0.0) 0/28(0.0)

Ventriculartachycardia(n=10) 2/10 (20.0) 0/10(0.0) 1/10(10.0) 1/10(10.0)

Acutemyocardialinfarction(n=9) 3/9 (33.3) 0/9(0.0) 1/9(11.1) 0(0.0)

Ventricularfibrillation(n=7) 3/7 (42.8) 0/7(0.0) 1/7(14.3) 0/7(0.0)

Note: Valuesareexpressedasn/N(%).AlthoughweadoptedtheoverlapratebetweencardiacarrestandpulselessactivityfromthereporteddatatoVigiBase,allpulselesselectricalactivityisregardedapartofcardiacarrestregardlessofpropernotificationtoVigiBasebydefinition.Inbold,whenoverlapis≥20%.Abbreviation:ADR,adversedrugreaction.

F I G U R E 2 RedemsivirelicitscardiotoxiceffectsinhPSC-CMs(a)andhiPSC-CMs(b).CardiotoxicityanalyseswasperformedusinghPSC-CMs(hESC-CMsandhiPSC-CMscelllines)inthepresenceofvariousconcentrationsofremdesivir.After24and48 hpost-treatment,cellviabilitywasdeterminedbyusingtheCellTiter96AQueousOneSolutionCellProliferationAssay(MTS,Promega).Thedatarepresentthemean(±SD)ofatleasttwoindependentexperimentsperformedintriplicate.CC50,50%cytotoxicconcentration;hESC-CMs,cardiomyocytederivedfromhumanembryonicstemcells;hiPSC-CMs,cardiomyocytesderivedfromhumanembryonicstemcells

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outcomes;thesewerecardiacarrest,bradycardia,shock,hypotension, atrial fibrillation, ventricular tachycardia,ventricularfibrillation,andAMI(Table 1).Todistinguishdrug-inducedCV-ADRs fromCOVID-19-inducedCVef-fects,18,19 we further restricted the analysis to patientswithCOVID-19andtheresultswereconsistent,exceptforcardiogenicshock,atrialfibrillation,andventriculartach-ycardia.However,theeffectsizes(ROR)ofallCV-ADRsweresmallerthanthoseoftheresultsoftheoverallpopu-lation,indicatingthattheRORsofCV-ADRsderivedfromtheoveralldatabasewereoverestimated,perhapsduetothe intrinsic COVID-19 CV deleterious effects (Tables  1and2).After furtheradjustment forpotentialconfound-ers(i.e.,corticosteroiduse),cardiacarrest(aOR:1.88,95%CI:1.08–3.29),bradycardia(aOR:2.09,95%CI:1.24–3.53),andhypotension(aOR:1.67,95%CI:1.03–2.73)weresig-nificantlyassociatedwiththeuseofremdesivir.

TheprevalenceintheVigiBaseforcardiacarrest,bra-dycardia, and severe hypotension was reported to be ashighas3.58%,3.64%,and3.97%,respectively,inpatientswith COVID-19 taking remdesivir, whereas they were0.97%, 1.75%, and 1.25%, respectively, in patients withCOVID-19takingotherdrugs(Table 2);therateofcardiacarrestandserioushypotensionwithremdesivir reportedinthisstudywasmarginallyhigherthanthepooledinci-dencerateofcardiacarrestandseverehypotensionfromclinicaltrials(1.3%and1.0%,respectively,asdescribedinTable S10).7,8,10,30,31Thediscrepanciescouldbeexplainedinpartbydifferencesintheincludedcases.Ofnote,thetotal number of remdesivir users in VigiBase (2107 pa-tients) corresponds to a total number of any ADRs re-ported on remdesivir (e.g., hepatotoxicity) and does notincluderemdesiviruserswithoutanyADRs;therefore,ac-tualADRratemaybemuchlowerinthegeneralpopula-tionandtheprevalenceratesreportedinVigiBaseshouldnotbetakenasabsoluteprevalenceratesinthereal-worldsettings.

GileadSciencesbegandevelopingremdesivirasearlyas2009asanagentagainstRNA-basedviruseswithhightransmission potential.32 Early studies mainly focusedon the efficacy of remdesivir against SARS and EBOV,becauseitprotectedprimatekidneyepithelialcells fromSARS-induced cytotoxicity,32 and significantly improvedthesurvivalofEBOV-infectedprimatemodels.33,34Theef-fectivenessofremdesivirwaspreservedtovaryingdegreesagainstvariousotherviruses,includingthehumanimmu-nodeficiencyvirus(HIV),MERS-CoV,anddeltacoronavi-ruses.3,35Althoughremdesivirdemonstrateseffectivenessagainst several viruses, it was not extensively used inmainstreamclinicalpracticeuntilitwasrepurposedasapotentialtherapeuticagentforCOVID-19in2020,andwassubsequentlyintegratedintoclinicalpracticeasaspecifictreatment.28 In addition, parallel studies evaluating its

effectiveness in reducing mortality and time-to-recoveryhavebeenconducted.8,10,30

Numerous efficacy studies and increased applicationofremdesivirhavenotbeenmatchedbypopulation-basedsafetyevaluations.Asremdesivirisarelativelynovelagentinthemarket,itsADRevaluationissubstantiallylackingcompared to other repurposed drug agents used to man-ageCOVID-19.Todate,afewclinicaltrialshavereportedmajor CV-ADRs associated with remdesivir (Tables S10andS11),7,8,10,30,31butthesetrialshaveinvestigatedeffectsonly in severalhundredpatients,whichmaynotcapturerarebutfatalCV-ADRsand,thus,thesefindingscannotbeextrapolatedtolargepopulations.Pharmacovigilancestud-iesusingVigiBase,withICSRsfrom20 millionindividuals,areuniquelypoisedtoidentifyADRsthatclinicaltrialsmaynotdetect,asdemonstratedinpreviousstudies.13–16,36Thepresentstudyrepresentsthefirstlarge-casepharmacovigi-lanceevaluationofremdesivirandprovidesnovelinsightsintoremdesivirADRclinicalspectrums.

GiventhatCOVID-19cancausemyocardialinjuryandchallengestheCVsystembyinflammatoryactivationandhypoxia,18,19itisuncertainifthehigherratesofCVeventsinpatients taking remdesivirarecausedbyadverse reac-tions of remdesivir or by severe COVID-19. To confirmthebiologicalcausation,wedesignedinvitroexperimentsusing hPSC-CM and found that remdesivir indeed re-ducedcellviabilityofhPSC-CMs;thecytotoxiceffectofthedrugincreasedwiththeescalationofdosage.Someofourgrouppreviouslydemonstratedthatremdesivirhashigherpotency for reducing cell viability, whereas less likely tointroduce arrhythmogenic risk compared with hydroxy-chloroquine,albeitbothdrugseventuallycausecardiotox-icityandarrhythmogenicriskathighconcentration27;ourindependentexperimentshereinreplicatedthefindingsde-notedbyChoietal.underamock-infectedcontrolsetting.Althoughtheexperimentswerelimitedtoinvitroandthedataalonedonotguaranteetheextrapolationoftheresultsto clinical settings, they provided a biological plausibilityforourobservationalfindings.Altogether,ourfindingsatthe population-level captured cardiotoxicity associatedwithremdesivirdistinguishedfromtheCOVID-19naturalcourses,andthesefindingsmayhelpphysiciansbeawareofpotentialCVadverseconsequencesfollowingremdesivir.

Study limitations

Ourstudyhassomelimitationsthatareworthnoting.First,althoughweconductedasensitivityanalysiswithpatientswithCOVID-19andsubsequentmultivariableanalysestominimize the confounding effect on CV outcomes by thenatureofCOVID-19,somedegreesofconfoundingmayper-sistasabias.Remdesivirtrialshavedemonstratedgreatest

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12 | JUNG et al.

efficacy in moderate to severe COVID-19.22 It is possiblethattheCV-ADRsfromcasesthatwarrantremdesivirtreat-mentreflectmoresevereunderlyinginfectionratherthandrugtoxicity.AlthoughotherdrugsusedtotreatCOVID-19atthetime,suchaslopinavir-ritonavir,37interferon,37anddexamethasone,23 were either used primarily for or mosteffectiveinmoderatetosevereinfection,thepossibilityofthisbiascouldnotbeentirelyeliminated.Wefurthercon-ductedexperimentalresearchtounderstandthegenuineef-fectofthedrugonhPSC-CMs,yettheresultsareprimarilylimitedtoinvitroandthusshouldnotbeoverinterpreted.Second, national drug authorities may have overlookedsomedrug-inducedCV-ADRcasesandnotincludedtheseeventsinVigiBase, introducingpotentialreportingbiases.Inaddition,comorbiditieswerenotcompletelyreportedtoVigiBaseandthusadjustmentforthebaselinecharacteris-ticswaslimited.DisproportionalityanalysesareprimarilyusedtogenerateADRsignalsinanexploratorymannerandcannotbeinterpretedtoquantifytheriskofanygivenADR.However,thecountermeasureofthisstudyliesonthemostextensiveADRdatatodatethatincludeICSRsfrommorethan130nations,whichhelpsclassifyrarebutfatalADRs.Nevertheless,ourresultsfromVigiBasewouldbebettertobevalidatedbyimportantpharmacovigilancedababaseasFDAAEreportingsystem.Third,thedosageofremdesivirusedforinvitroexperimentsmaydifferfromthatusedfortreatment. As such, the experimental dosages should betakensimplyasinferencesofadose-responserelationshipandevidenceofcausality,andnotactualtherapeuticeffectmeasures.Last,ourstudydidnotbeginwithtotalexposuredataforremdesivirbut,rather,reliesondisproportionalityanalysesbetweenADRsofremdesivirandthetotalnumberofADRsreportedtothedatabase.However,theadvantageofVigiBaseandthemethodsusedinthisstudy(dispropor-tionateanalysis)hasbeenwell-establishedthroughnumer-ous studies13–16,36 and may provide reliable and sufficientevidencetosupportpotentialsafetyconcernswiththein-creasedadministrationofremdesivir.

STUDY HIGHLIGHTS

RemdesivirisadministeredforCOVID-19,butCVsafetydataarelimited,conflicting,andderivefromasmallse-lection of clinical trials. This study attempts to identifyandquantifyadverseCVoutcomesassociatedwithrem-desiviruse.Wefindthatremdesivirputativelyassociatedwithcardiacarrest,bradycardia,andhypotension,whichhasbeeninpartvalidatedinvitroasacytotoxiceffectonhPSC-derivedcardiomyocytes.Cliniciansshouldbeawareof potential CV consequences following remdesivir use,albeit infrequent. Adequate cardiac monitoring shouldbeinstitutedtomaintainatolerablesafetymarginwhen

usingremdesiviruntilfurthermatchedprospectiveobser-vationalstudiesconfirmtheCVsafetyofremdesivir.

ACKNOWLEDGEMENTSThe authors appreciate members of the custom searchteam at the Uppsala Monitoring Centre (Uppsala,Sweden) research section, who were invaluable to thesuccessful performance of this study. The supplied datafromVigiBasewasobtainedfromvarioussourcesandthelikelihoodofacausalrelationshipwasnotthesameinallreports.Finally,theresultsandconclusionsofthisstudydonotrepresenttheopinionoftheWHO.

CONFLICT OF INTERESTAllauthorshavenoconflictofinterest.

AUTHOR CONTRIBUTIONSJ.I.S.,S.Y.J.,M.S.K.,H.L.,K.H.L.,S.C.,S.H.H.,S.K.C.,L.J.,J.S.,D.K.Y.,S.W.L.,K.K.,A.Y.K.,K.B.,andL.S.wrotethemanuscript.J.I.S.,S.Y.J.,M.S.K.,A.Ko.,M.S.,A.Kr.,R.A.G.,N.K.K.,L.J.,J.S.,D.K.Y.,S.W.L.,K.K.,J.W.J.,andJ.Y.C.de-signedtheresearch.J.I.S.,S.Y.J.,M.S.K.,H.L.,E.D.,K.T.,S.C.,S.T.,N.K.K.,J.S.S.,S.J.P.,S.W.C.,K.B.,S.H.M.,Y.Y.G.,and L.S. performed the research. J.I.S., S.Y.J., M.S.K.,K.H.L.,A.Ko.,A.Kr.,S.H.H.,R.A.G.,N.K.K.,J.S.,D.K.Y.,S.W.L., and K.B analyzed the data. J.I.S., S.Y.J., M.S.K.,H.L.,M.S.,E.D.,J.S.,J.S.S.,S.J.P.,S.W.L.,andK.B.contrib-uted new reagents/analytical tools. This manuscript hasbeenreviewedandapprovedbyallauthors.

ORCIDSe Yong Jung  https://orcid.org/0000-0003-1337-563XKeum Hwa Lee  https://orcid.org/0000-0002-1511-9587Ai Koyanagi  https://orcid.org/0000-0002-9565-5004Andreas Kronbichler  https://orcid.org/0000-0002-2945-2946Salvatore Terrazzino  https://orcid.org/0000-0002-4909-1121Louis Jacob  https://orcid.org/0000-0003-1071-1239Joe- Elie Salem  https://orcid.org/0000-0002-0331-3307Dong Keon Yon  https://orcid.org/0000-0003-1628-9948Seung Won Lee  https://orcid.org/0000-0001-5632-5208Jae Il Shin  https://orcid.org/0000-0003-2326-1820

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SUPPORTING INFORMATIONAdditional supporting information may be found in theonlineversionofthearticleatthepublisher’swebsite.

How to cite this article:JungSY,KimMS,LiH,etal.CardiovasculareventsandsafetyoutcomesassociatedwithremdesivirusingaWorldHealthOrganizationinternationalpharmacovigilancedatabase.Clin Transl Sci.2021;00:1–13.doi:10.1111/cts.13168