癫痫病制订临床指南的目的.ppt

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1、关于癫痫病制订临床指南的目的现在学习的是第1页，共30页临床指南的存在问题临床指南的存在问题1.1.评估标准不统一评估标准不统一2.2.缺乏证据缺乏证据不存在的证据不存在的证据3.3.时间局限性时间局限性过时、更新过时、更新4.4.受到药厂的影响，有一定的利益因素受到药厂的影响，有一定的利益因素5.5.由少部分专家制定由少部分专家制定6.6.个体差异个体差异7.7.临床医生执行时困难临床医生执行时困难Shorvon S.Epilepsia 2006,4).10913 现在学习的是第2页，共30页制订指南原则制订指南原则透明：无利益驱动透明：无利益驱动公平：所有数据采用同样的评估标准公平：所有数

2、据采用同样的评估标准严格：评价方法严格可行严格：评价方法严格可行动态：不断更新动态：不断更新现在学习的是第3页，共30页抗癫痫治疗指南大事记抗癫痫治疗指南大事记发布机构 发布年限苏格兰临床指导协作组(SIGN)2003英国临床优化研究所（NICE）2004 美国神经学会（AAN）美国癫痫学会（AES）2004ILAE2006Payakachat et al.J Manag Care Pharma 2006现在学习的是第4页，共30页NICENICE指南指南对于抗癫痫药物使用的指证，药物选择，换药，停药对于抗癫痫药物使用的指证，药物选择，换药，停药等原则性问题均作出了相应推荐等原则性问题均作出了

3、相应推荐Ref:National Institute for Health and Clinical Excellence.Technology appraisalguidance 76:newer drugs for epilepsy in adults.Available at:http:/www.nice.org.uk/TA076guidance.Accessed July 5,2005.现在学习的是第5页，共30页NICENICE指南指南NICENICE在治疗中在治疗中尽可能选择单药治疗尽可能选择单药治疗不推荐常规监测看癫痫药物的血药浓度不推荐常规监测看癫痫药物的血药浓度停药原则停药原

4、则Ref:National Institute for Health and Clinical Excellence.Technology appraisalguidance 76:newer drugs for epilepsy in adults.Available at:http:/www.nice.org.uk/TA076guidance.Accessed July 5,2005.现在学习的是第6页，共30页NICENICE指南指南目前仍缺乏高质量的临床试验支持新药单药治疗比传统药物更有效研究中的药物副作用和耐受性并未提供足够多且一致的结果支持新药优于传统药物仅9项比较新药和老药单药治

5、疗新诊断癫痫患者生活质量的研究，未提供强有力的证据支持新药提高患者生活质量传统抗癫痫药物单药治疗费用更便宜Ref:National Institute for Health and Clinical Excellence.Technology appraisalguidance 76:newer drugs for epilepsy in adults.Available at:http:/www.nice.org.uk/TA076guidance.Accessed July 5,2005.http:/http:/http:/400-0059-826昆明军海脑科医院昆明军海脑科医院现在学习的是

6、第7页，共30页NICENICE指南指南首选单药治疗药物应为传统抗癫痫药物如丙戊酸钠或卡马西平，除如下原因:禁忌症与患者目前服用的药物有潜在的相互作用患者在既往治疗中对该药耐受性差患者处于准备生育期新型抗癫痫药物作为初始治疗的二线选择Ref:National Institute for Health and Clinical Excellence.Technology appraisalguidance 76:newer drugs for epilepsy in adults.Available at:http:/www.nice.org.uk/TA076guidance.Accessed

7、July 5,2005.现在学习的是第8页，共30页NICENICE指南指南NICENICE缺点缺点1.1.评定的证据标准和证据分类没有明确的描述评定的证据标准和证据分类没有明确的描述2.2.传统抗癫痫药没有进行同样的评估传统抗癫痫药没有进行同样的评估现在学习的是第9页，共30页Neurology.2004,62(8):1252-1260 Neurology.2004,62(8):1252-1260 Neurology.2004,62(8):1261-1273Neurology.2004,62(8):1261-1273现在学习的是第10页，共30页AANAAN指南指南1.AAN1.AAN指南有

8、明确证据分类和证据评级指南有明确证据分类和证据评级2.2.以有效性作为主要评估指标以有效性作为主要评估指标3.3.缺点：缺点：未评估传统药物未评估传统药物 生活质量和成本效益未作为参考指标生活质量和成本效益未作为参考指标现在学习的是第11页，共30页抗癫痫临床治疗指南比较总结评价指标NICE指南AAN指南有效性安全性生活质量成本效益Payakachat et al.J Manag Care Pharma 2006http:/http:/http:/400-0120-772沈阳万佳癫痫医院沈阳万佳癫痫医院现在学习的是第12页，共30页Payakachat et al.J Manag Care P

9、harma 2006AEDs as Monotherapyof Partial/Mix GeneralizedTonic-Clonic SeizureANN*NICESIGNPhenobarital1st-Carbamazepine(generic Tegretol)Tegretol XR1st1st1stPhenytoin(generic Dilantin)1st1st-Valproic acid(generic Depakene)Divalproex(Depakote)Divalproex(Depakote ER)1st1st1stPrimidone(generic Mysoline)-G

10、abapentin(generic Neurontin)1st-Zonisamide)Zonegran)-Tiagabine(Gabitril)-Oxcarbazepine(Trileptal)1st2nd1stTopiramate(Topamax)1st2nd-Levetiracetam(Keppra)-Lamotrigine(Lamictal)1st2nd1st现在学习的是第13页，共30页NICE指南和AAN指南对于新药的使用推荐Lancet Neurol 2004;3:61821DrugDrugNewly diagnosed epilepsyNewly diagnosed epilep

11、syRefractory epilepsy Refractory epilepsy PartialPartialAbsenceAbsencePartialPartialPartialPartialIdiopathicIdiopathicSymptomatieSymptomatiemixedmixedmonotherapymonotherapygeneralisedgeneralisedgeneralisedgeneralisedUSUSUKUKUSUSUKUKUSUSUKUKUSUSUKUKUSUSUKUKUSUSUKUKFelbamate*Felbamate*NoNoNANANoNoNANA

12、YesYesNANAYesYesNANANoNoNANAYes Yes NANAGabapentinGabapentinYesYesNoNoNoNoNoNoYesYesYesYesNoNoNoNoNoNoNoNoNoNoNoNoLamotrigineLamotrigineYes Yes Yes|Yes|Yes Yes Yes|Yes|YesYesYes*Yes*YesYesYesYesNo No Yes*Yes*YesYesYes*Yes*LevetiracetamLevetiracetamNoNoNoNoNoNoNoNoYesYesYesYesNoNoNoNoNoNoNoNoNoNoNoNo

13、OxcarbazepineOxcarbazepineYesYesYesYesNoNoNoNoYesYesYesYesYesYesYesYesNoNoNoNoNoNoNoNoTiagabineTiagabineNoNoNoNoNoNoNoNoYesYesYes|Yes|NoNoNoNoNoNoNoNoNoNoNoNoTopiramateTopiramateYesYesYes Yes NoNoNoNoYesYesYes*Yes*YesYesYesYesYesYesYes*Yes*YesYesYes*Yes*VigabatrinVigabatrinNANANoNoNANANoNoNANAYesYes

14、NANANoNoNANANoNoNANAYesYesZonisamideZonisamideNoNoNANANo No NANAYes|Yes|NANANoNoNANANoNoNANANoNoNANANone of the drugs is recommended as first choice in newly diagnosed epilepsy by the UK guidelines(see text).NA=not available.*Patients Unresponsive to standard drugs in Whom the risk/benefit ratio sup

15、ports use;only patients 18 years;only patients 4 years with Lennox-Gastaut ayndrome;indication not approved FDA;only patients 6 years;|only patients 12 years;*only patients 2 years;only patients 16years;only generalized tonic-clonic seizures;in the UK the indications are limited to adjunctive use af

16、ter failure of all other appropriate drug combinations;only West ayndrome;|only adulte.现在学习的是第14页，共30页新药的严重新药的严重/非严重不良事件非严重不良事件Lancet Neurol 2004;3:61821AEDAEDSerious adverse vevntsSerious adverse vevntsNonserious adverseNonserious adverseFelbamateFelbamateAplastic anaemia,hepatotoxicityAplastic ana

17、emia,hepatotoxicityGastrointestinal disturbancse,anorexia,insomniaGastrointestinal disturbancse,anorexia,insomniaGabapentinGabapentinAggresion*Aggresion*Weight gain,peripheral cedema,behavioural changes Weight gain,peripheral cedema,behavioural changes LamotrigineLamotrigineRash,including Stevens Jo

18、hnson and toxic epidermal necrolysisRash,including Stevens Johnson and toxic epidermal necrolysisTics and insomniaTics and insomnia(high risk for children,also more common with concomitant(high risk for children,also more common with concomitantvaiproic-acid use and low with slow titration);hypereen

19、sitivityvaiproic-acid use and low with slow titration);hypereensitivityreactions,including hepatic and renal failure,DIC,and arthritisreactions,including hepatic and renal failure,DIC,and arthritisLevetiracetamLevetiracetamNoneNoneIrritability/behaviour changeIrritability/behaviour changeOxcarbazepi

20、neOxcarbazepineHyponatraemia(more common in elderly people),rashHyponatraemia(more common in elderly people),rashNoneNoneTiagabineTiagabineNonconvulsive status epilepticusNonconvulsive status epilepticusDizziness,astheniaDizziness,astheniaTopiramate Topiramate Nephrolithiasis,open angle glaucoma,hyp

21、ohidrosis,Nephrolithiasis,open angle glaucoma,hypohidrosis,Metabolic acidosis,weight loss,Metabolic acidosis,weight loss,depression,psychosisdepression,psychosislanguage dysfunxtion,paraesthesialanguage dysfunxtion,paraesthesiaVigabatrinVigabatrinVisual field defects,psychosis,depressionVisual field

22、 defects,psychosis,depressionWeight gainWeight gainZonisamideZonisamideRash,renal calculi,hypohidrosis Rash,renal calculi,hypohidrosis Irritability,photosensitivity,weight lossIrritability,photosensitivity,weight lossAED=antieptic drug;DIC=disseminated intravascular coagulation.*Mosthy in cognitivel

23、y impaired patients;predominantly children.AED=antieptic drug;DIC=disseminated intravascular coagulation.*Mosthy in cognitively impaired patients;predominantly children.现在学习的是第15页，共30页临床医生在应用指南时特别注意临床医生在应用指南时特别注意 上述各抗癫痫药治疗指南的差异在于单药上述各抗癫痫药治疗指南的差异在于单药治疗的推荐上（新药与传统药）治疗的推荐上（新药与传统药）原因：原因：1.1.证据的评估标准证据的评估标

24、准 2.2.制定指南的目的差异制定指南的目的差异现在学习的是第16页，共30页临床医生在应用指南时特别注意临床医生在应用指南时特别注意要特别注意癫痫药物加重癫痫发作要特别注意癫痫药物加重癫痫发作http:/http:/http:/400-0120-772沈阳万佳癫痫医院沈阳万佳癫痫医院现在学习的是第17页，共30页可能加重某些癫痫综合征的抗痫药物可能加重某些癫痫综合征的抗痫药物药物综合症可能加重的情况卡马西平失神癫痫肌阵挛、失神发作青少年肌阵挛癫痫肌阵挛性发作进行性肌阵挛癫痫肌阵挛中央回癫痫CSWS.肌阵挛苯巴英钠失神癫痫失神发作进行性肌阵挛癫痫小脑综合症，肌阵挛苯巴比妥失神癫痫大剂量时失神发

25、作苯二氮卓类药物LGS强直性发作氨已烯酸失神癫痫失神发作伴肌阵挛的癫痫肌阵挛加巴喷丁失神癫痫失神发作伴肌阵挛的癫痫肌阵挛拉莫三嗪严重的肌阵挛癫痫大剂量时 GTCS青少年肌阵挛癫痫肌阵挛性发作现在学习的是第18页，共30页Ref:Epilepsia.39(Suppl.3):S15-S18,1998Topiramate Vigabatrin0246810ClonazepamClobazamSodium Valproate(Sodium Valproate(德巴金德巴金德巴金德巴金 )CarbamazepineBarbexaclonePrimidonePhenobarbitalEthosuximid

26、eSulthiameOxcarbazepinePhenytoinLamotrigineGabapentinElgerElger等等等等 对对对对 10061006例局灶性癫痫例局灶性癫痫例局灶性癫痫例局灶性癫痫（包包包包括括括括单单单单药药药药和和和和添添添添加加加加治疗）荟萃分析治疗）荟萃分析治疗）荟萃分析治疗）荟萃分析抗癫痫药物恶化发作癫痫患者发作增加的百分比癫痫患者发作增加的百分比现在学习的是第19页，共30页临床医生在应用指南时特别注意临床医生在应用指南时特别注意治疗要个体化治疗要个体化,要特别关注特殊人群要特别关注特殊人群:儿童、妇儿童、妇女、老人女、老人现在学习的是第20页，共30

27、页临床医生在应用指南时特别注意临床医生在应用指南时特别注意 认识的更新认识的更新 SANAD试验发现丙戊酸和其它新抗癫痫药在癫痫发现丙戊酸和其它新抗癫痫药在癫痫治疗的综合作用中明显优于其它药物治疗的综合作用中明显优于其它药物现在学习的是第21页，共30页研究研究A:A:基线的人口学资料和临床表现基线的人口学资料和临床表现CBZ(n=378)GBP(n=377)LTG(n=378)OXC(n=210)TPM(n=378)Total(n=1721)性别,n(%)男女208(55)170(45)207(55)170(45)208(55)170(45)111(53)99(47)208(55)170(4

28、5)942(55)779(45)治疗史,n(%)未治疗单药治疗(效果差)发作较少后最近发作309(81.8)60(15.9)9(2.4)306(81.2)60(15.9)11(2.9)308(81.5)61(16.1)9(2.4)181(86.2)25(11.9)4(1.9)308(81.5)60(15.9)10(2.7)1412(82.1)266(15.5)43(2.5)病史,n(%)高热惊厥 其他急性症状性发作 1o 级亲属患癫痫 27(7.1)6(1.6)39(10.3)16(4.2)15(4.0)44(11.7)25(6.6)18(4.8)38(10.1)7(3.3)8(3.8)24(

29、11.4)17(4.5)13(3.4)34(9.0)92(5.4)60(3.5)179(10.0)癫痫综合征,n(%)特发性部分性症状性或隐源性部分性特发性全面性其他综合征未分类4(1.1)338(89.4)3(0.8)2(0.5)31(8.2)5(1.3)333(88.6)3(0.8)0(0)35(9.3)6(1.6)330(88.0)4(1.1)0(0)35(9.3)3(1.4)180(85.7)5(2.4)1(0.5)21(10.0)6(1.6)322(85.4)7(1.9)1(0.3)41(10.9)24(1.4)1503(87.6)22(1.3)4(0.2)163(9.5)平均年龄

30、标准差,岁39.2 18.337.8 17.936.8 18.340.1 18.038.4 18.638.3 18.3 Ref:SANAD研究结果研究结果现在学习的是第22页，共30页研究研究A:治疗无效的时间治疗无效的时间,意向性治疗集意向性治疗集 Log-Rank Chi-square=22.150,df=3,p0.0001-O-LTG-O-CBZ-O-TPM-O-GBP时间时间(天天)继续治疗的比例继续治疗的比例继续治疗的比例继续治疗的比例Ref:SANAD研究结果研究结果现在学习的是第23页，共30页结论 研究 A拉莫三嗪治疗无效的比例显著低于卡马西平拉莫三嗪治疗无效的比例显著低于卡马

31、西平,加巴喷丁加巴喷丁,托吡酯托吡酯拉莫三嗪的疗效与卡马西平相似且并不低于拉莫三嗪的疗效与卡马西平相似且并不低于卡马西平卡马西平拉莫三嗪对于部分性发作的患者可考虑为第一线拉莫三嗪对于部分性发作的患者可考虑为第一线药物药物Ref:SANAD研究结果研究结果现在学习的是第24页，共30页LTG(n=239)TPM(n=239)VPS(n=238)Total(n=716)性别,n(%)男女142(59)97(41)142(59)97(41)143(60)95(40)427(60)289(40)治疗史,n(%)未治疗单药治疗(效果差)发作较少后最近发作210(87.9)19(8.0)10(4.2)20

32、9(87.5)20(8.4)10(4.2)209(87.8)21(8.8)8(3.4)628(87.7)60(8.4)28(3.9)病史,n(%)高热惊厥 其他急性症状性发作 1o 级亲属患癫痫 16(6.7)9(3.8)53(22.2)22(9.2)6(2.5)38(15.9)21(8.8)6(2.5)38(16.0)59(8.2)21(2.9)129(18.0)癫痫综合征,n(%)特发性部分性症状性或隐源性部分性特发性全面性其他综合征未分类1(0.4)18(7.5)145(60.7)9(3.8)66(27.6)2(0.8)11(4.6)147(61.8)12(5.0)66(27.7)0(0

33、)20(8.4)150(63.0)9(3.8)59(24.8)3(0.4)49(6.9)442(61.8)30(4.2)191(26.7)平均年龄 标准差,岁22.8 14.322.3 13.322.5 14.522.5 14.0研究研究B B:基线的人口学资料和临床表现基线的人口学资料和临床表现基线的人口学资料和临床表现基线的人口学资料和临床表现Ref:SANAD研究结果研究结果现在学习的是第25页，共30页研究研究B:治疗无效的时间治疗无效的时间Log-Rank Chi-square=10.117,df=2,p=0.006-O-VPS-O-LTG-O-TPM继续治疗的比例继续治疗的比例继续

34、治疗的比例继续治疗的比例时间时间(天天)Ref:SANAD研究结果研究结果现在学习的是第26页，共30页结论 研究 B丙戊酸的疗效显著高于拉莫三嗪和托吡酯丙戊酸的疗效显著高于拉莫三嗪和托吡酯丙戊酸和拉莫三嗪的耐受性高于托吡酯丙戊酸和拉莫三嗪的耐受性高于托吡酯丙戊酸对于全身发作或未分类的发作的患者可考虑丙戊酸对于全身发作或未分类的发作的患者可考虑为第一线药物为第一线药物现在学习的是第27页，共30页传统抗癫痫药与新型抗癫痫药在传统抗癫痫药与新型抗癫痫药在疗效上无显著差异疗效上无显著差异Kwan P,Brodie MJ.N Engl Med.2000;342:314-315 0%10%20%30%

35、40%50%60%70%80%Patients seizure free for 1 yearTraditional AED(n=289)New AED(n=134)Patients treated with 1 AED P=NS67%69%70%10%0%PersistentseizuresSeizure freefor1 yearPatients with epilepsy(n-525)60%50%40%30%20%Patients63%37%289 were receiving an established drug(155 were receiving carbamazepine,12

36、5 valproate sodium,8 phenytoin,and 1 ethosuximide),134 were taking one of the newer antiepileptic drugs (99 were receiving lamotrigine,15 gabapentin,7 oxcarbazepine,9 tiagabine,3 topiramate,and 1 vigabatrin).现在学习的是第28页，共30页传统抗癫痫药与新型抗癫痫药在疗效上无传统抗癫痫药与新型抗癫痫药在疗效上无显著差异显著差异N Engl J Med 2000;342:314-9.470 p

37、atients has never received470 patients has never receivedAn antiepileptic drug before An antiepileptic drug before(64%seizure-free)(64%seizure-free)Epilepsy was not controlled byEpilepsy was not controlled by1 1stst antiepileptic drug in 248;antiepileptic drug in 248;168 receved an established drug1

38、68 receved an established drugand 80 received a new drugand 80 received a new drug69 Had intolerable69 Had intolerableSide effectsSide effects(41%seizure-free)(41%seizure-free)29 Had an idiosyncratic 29 Had an idiosyncratic reactionreaction(55%seizure-free)(55%seizure-free)37 Had other reasons37 Had

39、 other reasonsFor stopping treatmentFor stopping treatment(62%seizure-free)(62%seizure-free)Figure 3.Outcome in 470 Previously Untreated Patients.Figure 3.Outcome in 470 Previously Untreated Patients.The status of patients at the time of the last clinic visit is given in parentheses.The status of pa

40、tients at the time of the last clinic visit is given in parentheses.Epilepsy was controlled by 1Epilepsy was controlled by 1stst antiepileptic antiepileptic drug in 222(47%seizure-free);drug in 222(47%seizure-free);151 received an established drug(47%seizure-free)151 received an established drug(47%seizure-free)and 71 received a new drug(47%seizure-free)and 71 received a new drug(47%seizure-free)Treatment wasTreatment wasIneffective in 113Ineffective in 113(11%seizure-free)(11%seizure-free)现在学习的是第29页，共30页感谢大家观看现在学习的是第30页，共30页