西洛他唑的研究及存在的问题

西洛他唑的最新研究及存在的问题1Newprogression——CSPSⅡ2Combination3

AnnouncementsAboutCilostazol

Cilostazol(Pletaal®):1988improvementofischemicsymptomsincludingulcers,painandcoldnessassociatedwithchronicarterialobstructionastheindicationinJapan.InApril2003,secondarypreventionofcerebralinfarction(excludingcardiogeniccerebralembolism)wasapprovedastheadditionalindication.主要试验1.

CilostazolStrokePreventionStudy:aplacebocontrolledtrialdouble-blindtrialforsecondarypreventionofcerebralinfarction2.

ARandomizedDouble-blindStudyOfCilostazolAndAspirin(CilostazolStrokePreventionStudyII:CSPSII)3.

EffectofCilostazolintheAcuteLacunarInfarctionBasedonPulsatilityIndexofTranscranialDoppler1.CilostazolStrokePreventionStudy（CSPS）

试验对象：采用随机、双盲、安慰剂对照的方法，平均随访2年，病例来自日本183个临床研究所，1052例受试者参与试验。

西洛他唑组：526例

安慰剂组：526例

排除标准：既往有脑出血病史；既往或未来可能有心源性脑栓塞或任何相关的并发症；严重的脑梗死导致日常生活能力丧失，生活不能自理者；痴呆；对西洛他唑有禁忌证者。

入选标准：年龄＜80岁；在1992年4月～1996年3月患脑梗死的患者，如果该患者在随机入选前1～6个月发生脑梗死也符合入选标准；并无严重的并发症；颈内动脉系统及基底动脉系统的脑梗死均包括在研究范围中。

方法：治疗组接受西洛他唑100mg，2/d口服，对照组采用安慰剂口服。

平均随访时间：治疗组651.8d安慰剂组569.7d

主要终点事件：脑梗死复发，其次是心肌梗死、颅内出血、短暂性脑缺血发作（TIA）、心绞痛、肺栓塞、静脉血栓形成以及死亡。

2组人群的基线特征包括年龄、性别、临床资料（卒中的类型、梗死灶大小、糖尿病、高血压、心脏病等病史）相匹配。

结果：关于终点事件，西洛他唑组有30例脑梗死复发，安慰剂组有57例，年发病率2组分别为3.37％和5.78％。

西洛他唑组与安慰剂组相比脑梗死复发的相对危险度显著降低（41.7％，可信区间为9.2％～62.5％），有显著的统计学意义（P=0.015)。GUIDELINESFORMODERATESTROKEGUIDELINESFORSEVERESTROKE2.CilostazolStrokePreventionStudyII(CSPSII)Background:Theefficacyofaspirinandotherantiplateletsinsecondarypreventionofcerebralinfarctionhasbeen

demonstratedinvariousstudiesandmeta-analyses,mostlyconductedintheUSandEU.

Alongwithaspirin,ticlopidine,

andclopidgrel,cilostazolisrecommendedforsecondarypreventionofnoncardiogeniccerebralinfarctioninthe

JapaneseGuidelinesfortheManagementofStroke.Objective:Thisstudywasdesignedtodemonstratecilostazol’snon-inferioritytoaspirininsecondarypreventionof

strokeinJapanesepatients.Design:Thisisamulti-center,randomized,double-blindstudytoconfirmthesafetyandefficacyofcilostazolin

Japanesecerebralinfarctionpatientscomparedwithaspirin.cilostazol(100mg,twicedaily)aspirin(81mg,oncedaily).Populationstudied:

Patientswhosufferedcerebralinfarctionwithin26weekspriortoenrollmentandwhose

symptomswerestablethereafterwererandomlyassignedtoreceiveeithercilostazoloraspirin.ThestudyperiodisfromDecember2003——December2008,withindividualpatienttreatment

andobservationbeingbetween1and5years.OutcomeMeasures:Theprimaryendpointisoccurrence：stroke(cerebralinfarction,cerebralhemorrhage,or

subarachnoidhemorrhage).Thesecondaryendpoints：recurrenceofcerebralinfarction,occurrenceofischemic

cerebraldisorder,occurrenceofall-causedeath,andoccurrenceof

cerebralinfarction,cerebralhemorrhage,subarachnoidhemorrhage,transientischemicattack,anginapectoris,

myocardialinfarction,cardiacfailure,andhemorrhagerequiringhospitalization.Intherandomized,double-blindstudyofnearly2,700patientswithnon-cardioembolicischemicstroke,thosetreatedwithcilostazolwere25.7%lesslikelytosufferfromastrokethanthosewhoreceivedaspirin.Strokesoccurredin82of1,337cilostazol-treatedpatientsandin119of1,335aspirin-treatedpatients（riskratio≤1.33）.Ahemorrhagicstrokeorhemorrhagethatrequiredhospitalizationoccurredin23patientstakingcilostazoland57ofthosereceivingaspirin-asignificantdifference（p＜0.001）.CombinationManagementofperipheralarterialdisease(PAD)requiresstandardatheroscleroticriskmanagementinterventions.However,PADisoften

complicatedbywalkingpain(intermittentclaudication[IC]),whichrequiressymptom-specifictherapiesaswell.Thus,allPADpatients

areencouragedtotakeantiplateletagentstoreducetheassociatedrisksofmajorcardiovascularevents,andthosewithICmayalsorequire

treatmentwithcilostazol.

Ascriteriaforinclusioninthetrial,26patients(71.4%

males;meanage65.9years)wereidentifiedwhohadPAD

withIC,anABI<0.90,andnocontraindicationstothestudy

drugs.AnnouncementsAntiplateletAgentsSarpogrelateandCilostazolAffect

Experimentally-inducedVentricularArrhythmiasandMortalityMaleSprague–DawleyratsCardiovascToxicol(2008)8:127–135pretreatedwitheitherSARorCIL(5mg/kg/day)for2weeksEpigiven4,8,16,32,and64lg/kgat10minintervalsoruntildeathoftheanimals；Saline-treatedanimalsservedascontrolsCoronaryOcclusionResults1outof17

SAR-pretreatedratshadanepisodeofsinglePVC4outof17CIL-pretreatedratshadanaverageof1.25

episodesofsinglePVCs.Among12controlanimals,2rats

developed1episodeofsinglePVC.SARandCILpretreatmentshadno

significanteffectsonthebaselineECGvariablesincluding

QTandQTcintervals.Table1

ECGvariablesofcontrol,SAR-treated,andCIL-treated

animalsunderbaselineconditionsTable2

Variablesofearly

ventriculararrhythmiasin

control,SAR-pretreated,and

CIL-pretreated

animalsafter

inducingcoronaryartery

occlusionTable3

Incidenceandonsettimeofventriculararrhythmiasincontrol,SAR-pretreated,andCIL-pretreatedanimalsuponadministrationof

cumulativedosesofEpiTable4

Incidenceandnumberofsingleprem