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1、抗癫痫药物临床治疗指南新看点,华山医院俞丽云,抗癫痫药物临床治疗指南新看点,1,抗癫痫药物临床治疗指南新看点华山医院抗癫痫药物临床治疗指南新,制订临床指南的目的,应用指南是一种系统性阐述，用以帮助职业医师以及患者对于特定临床情况作出适当的医疗决定,抗癫痫药物临床治疗指南新看点,2,制订临床指南的目的 应用指南是一种系统性阐述，用以帮助职,临床指南的存在问题,1.评估标准不统一2.缺乏证据不存在的证据3.时间局限性过时、更新4.受到药厂的影响，有一定的利益因素5.由少部分专家制定6.个体差异7.临床医生执行时困难,Shorvon S.Epilepsia 2006,4).10913,抗癫痫药物临床
2、治疗指南新看点,3,临床指南的存在问题1.评估标准不统一Shorvon S.E,制订指南原则,透明：无利益驱动公平：所有数据采用同样的评估标准严格：评价方法严格可行动态：不断更新,抗癫痫药物临床治疗指南新看点,4,制订指南原则透明：无利益驱动抗癫痫药物临床治疗指南新看点4,抗癫痫治疗指南大事记,Payakachat et al.J Manag Care Pharma 2006,抗癫痫药物临床治疗指南新看点,5,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(,Welcome to the National Institute for Healthand Clinical Excel
3、lence websiteNICE is the independent organization responsible for providingnational guidance on the promotion of good health andthe prevention and treatment of ill health.On 1 April 2005 NICE joined with the Health Development Agency to becomethe new National Institute for Health and Clinical Excell
4、ence(also to be known as NICE).Clinical ExcellencePublic Health Excellence,NICE was set up as a Special Health Authority for England and Wales on 1 April 1999.Its role is to provide patients,health professionals and the public with authoritative,robust and reliable guidance on current best practice.
5、(http:/),抗癫痫药物临床治疗指南新看点,6,Welcome to the National Inst,NICE指南,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,Ref:National Institute for Health and Clinical Excellence.Technology appraisalguidance 76:newer drugs for epilepsy in adults.Available at:.Accessed July 5,2005.,抗癫痫药物临床治疗指南新看点,7,NICE指南对于抗癫痫药物使用的指证，药物选
6、择，换药，停药等,NICE在治疗中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停药原则,NICE指南,Ref:National Institute for Health and Clinical Excellence.Technology appraisalguidance 76:newer drugs for epilepsy in adults.Available at:.Accessed July 5,2005.,抗癫痫药物临床治疗指南新看点,8,NICE在治疗中NICE指南Ref:National In,NICE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
7、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:.Accessed July 5,2005.,抗癫痫药物临床治疗指南新看点,9,NICE指南Ref:National I
8、nstitute,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:.Accessed July 5,2005.,NICE指南,抗癫痫药物临床治疗指南新看点,10,首选单药治疗药
9、物应为传统抗癫痫药物如丙戊酸钠或卡马西平，除如,NICE缺点1.评定的证据标准和证据分类没有明确的描述2.传统抗癫痫药没有进行同样的评估,NICE指南,抗癫痫药物临床治疗指南新看点,11,NICE缺点NICE指南抗癫痫药物临床治疗指南新看点11,Neurology.2004,62(8):1252-1260,Neurology.2004,62(8):1261-1273,抗癫痫药物临床治疗指南新看点,12,Neurology.2004,62(8):1252-126,AAN指南,1.AAN指南有明确证据分类和证据评级2.以有效性作为主要评估指标3.缺点：未评估传统药物 生活质量和成本效益未作为参考指
10、标,抗癫痫药物临床治疗指南新看点,13,AAN指南1.AAN指南有明确证据分类和证据评级抗癫痫药物,抗癫痫临床治疗指南比较总结,Payakachat et al.J Manag Care Pharma 2006,抗癫痫药物临床治疗指南新看点,14,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,Payakachat et al.J Manag Care Pharma 2006,抗癫痫药物临床治疗指南新看点,15,Payakachat et al.J Manag Care,NICE指南和AAN指南对于新药的使用推荐,Lancet Neurol 2004;3:61821,DrugNe
11、wly diagnosed epilepsyRefractory epilepsy PartialAbsencePartialPartialIdiopathicSymptomatiemixedmonotherapygeneralisedgeneralisedUSUKUSUKUSUKUSUKUSUKUSUKFelbamate*NoNANoNAYesNAYesNANoNAYes NAGabapentinYesNoNoNoYesYesNoNoNoNoNoNoLamotrigineYes Yes|Yes Yes|YesYes*YesYesNo Yes*YesYes*LevetiracetamNoNoN
12、oNoYesYesNoNoNoNoNoNoOxcarbazepineYesYesNoNoYesYesYesYesNoNoNoNoTiagabineNoNoNoNoYesYes|NoNoNoNoNoNoTopiramateYesYes NoNoYesYes*YesYesYesYes*YesYes*VigabatrinNANoNANoNAYesNANoNANoNAYesZonisamideNoNANo NAYes|NANoNANoNANoNA,None of the drugs is recommended as first choice in newly diagnosed epilepsy b
13、y the UK guidelines(see text).NA=not available.*Patients Unresponsive to standard drugs in Whom the risk/benefit ratio supports 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 yea
14、rs;only patients 16years;only generalized tonic-clonic seizures;in the UK the indications are limited to adjunctive use after failure of all other appropriate drug combinations;only West ayndrome;|only adulte.,抗癫痫药物临床治疗指南新看点,16,NICE指南和AAN指南对于新药的使用推荐Lancet Ne,新药的严重/非严重不良事件,Lancet Neurol 2004;3:61821,
15、AEDSerious adverse vevntsNonserious adverseFelbamateAplastic anaemia,hepatotoxicityGastrointestinal disturbancse,anorexia,insomniaGabapentinAggresion*Weight gain,peripheral cedema,behavioural changes LamotrigineRash,including Stevens Johnson and toxic epidermal necrolysisTics and insomnia(high risk
16、for children,also more common with concomitantvaiproic-acid use and low with slow titration);hypereensitivityreactions,including hepatic and renal failure,DIC,and arthritisLevetiracetamNoneIrritability/behaviour changeOxcarbazepineHyponatraemia(more common in elderly people),rashNoneTiagabineNonconv
17、ulsive status epilepticusDizziness,astheniaTopiramate Nephrolithiasis,open angle glaucoma,hypohidrosis,Metabolic acidosis,weight loss,depression,psychosislanguage dysfunxtion,paraesthesiaVigabatrinVisual field defects,psychosis,depressionWeight gainZonisamideRash,renal calculi,hypohidrosis Irritabil
18、ity,photosensitivity,weight lossAED=antieptic drug;DIC=disseminated intravascular coagulation.*Mosthy in cognitively impaired patients;predominantly children.,抗癫痫药物临床治疗指南新看点,17,新药的严重/非严重不良事件Lancet Neurol 200,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）原因：1.证据的评估标准 2.制定指南的目的差异,临床医生在应用指南时特别注意,抗癫痫药物临床治疗指南新看点,18,临床
19、医生在应用指南时特别注意抗癫痫药物临床治疗指南新看,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,抗癫痫药物临床治疗指南新看点,19,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抗,可能加重某些癫痫综合征的抗痫药物,抗癫痫药物临床治疗指南新看点,20,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,Ref:Epilepsia.39(Suppl.3):S15-S18,1998,Elger等对1006例局灶性癫痫（包括单药和添加治疗）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,抗癫痫药物临床治疗指南新看点,21,Ref:Epilepsia.3
20、9(Suppl.3):S,临床医生在应用指南时特别注意,治疗要个体化,要特别关注特殊人群:儿童、妇女、老人,抗癫痫药物临床治疗指南新看点,22,临床医生在应用指南时特别注意治疗要个体化,要特别关注特殊人群,临床医生在应用指南时特别注意,认识的更新 SANAD试验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,抗癫痫药物临床治疗指南新看点,23,临床医生在应用指南时特别注意 认识的更新抗癫痫药物临床治,研究A:基线的人口学资料和临床表现,Ref:SANAD研究结果,抗癫痫药物临床治疗指南新看点,24,研究A:基线的人口学资料和临床表现CBZGBPLTGOXC,研究A:治疗无效的
21、时间,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(天),继续治疗的比例,Ref:SANAD研究结果,抗癫痫药物临床治疗指南新看点,25,研究A:治疗无效的时间,意向性治疗集-O-LTG时间,结论 研究 A,拉莫三嗪治疗无效的比例显著低于卡马西平,加巴喷丁,托吡酯拉莫三嗪的疗效与卡马西平相似且并不低于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药物,Ref:SANAD研究结果,抗癫痫药物临床治疗指南新看点,26,结论 研究 A拉莫三嗪治疗无效的比例显著低于卡马西平,加,研究B:基线的人
22、口学资料和临床表现,Ref:SANAD研究结果,抗癫痫药物临床治疗指南新看点,27,LTGTPMVPSTotal 性别,n(%)治疗史,研究B: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,时间(天),Ref:SANAD研究结果,抗癫痫药物临床治疗指南新看点,28,研究B:治疗无效的时间-O-VPS继续治疗的比例时间(天,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为第一线药物,抗癫痫药物临床治疗指南新看点,
23、29,结论 研究 B丙戊酸的疗效显著高于拉莫三嗪和托吡酯抗癫痫药,传统抗癫痫药与新型抗癫痫药在疗效上无显著差异,Kwan P,Brodie MJ.N Engl Med.2000;342:314-315,289 were receiving an established drug(155 were receiving carbamazepine,125 valproate sodium,8 phenytoin,and 1 ethosuximide),134 were taking one of the newer antiepileptic drugs(99 were receiving lam
24、otrigine,15 gabapentin,7 oxcarbazepine,9 tiagabine,3 topiramate,and 1 vigabatrin).,抗癫痫药物临床治疗指南新看点,30,传统抗癫痫药与新型抗癫痫药在疗效上无显著差异Kwan P,传统抗癫痫药与新型抗癫痫药在疗效上无显著差异,N Engl J Med 2000;342:314-9.,470 patients has never receivedAn antiepileptic drug before(64%seizure-free),Epilepsy was not controlled by1st antiepi
25、leptic drug in 248;168 receved an established drugand 80 received a new drug,69 Had intolerableSide effects(41%seizure-free),29 Had an idiosyncratic reaction(55%seizure-free),37 Had other reasonsFor stopping treatment(62%seizure-free),Figure 3.Outcome in 470 Previously Untreated Patients.The status
26、of patients at the time of the last clinic visit is given in parentheses.,Epilepsy was controlled by 1st antiepileptic drug in 222(47%seizure-free);151 received an established drug(47%seizure-free)and 71 received a new drug(47%seizure-free),Treatment wasIneffective in 113(11%seizure-free),抗癫痫药物临床治疗指南新看点,31,传统抗癫痫药与新型抗癫痫药在疗效上无显著差异N Engl J,总结,传统抗癫痫药物如丙戊酸钠、卡马西平、苯妥英钠仍旧是新诊断癫痫患者的首选单药治疗药物除非新药在疗效、成本效益和生活质量上能显示出其优越性，否则他们仍将作为二线用药,Payakachat et al.J Manag Care Pharma 2006,抗癫痫药物临床治疗指南新看点,32,总结传统抗癫痫药物如丙戊酸钠、卡马西平、苯妥英钠仍旧是新诊断,
