1、抗癫痫药物临床治疗指南新看点,华山医院俞丽云,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,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,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,抗癫痫治疗指南大事记,Payakachat et al. J Manag Care Pharma 2
2、006,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. (http:/www.nice.org.uk/),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
3、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.,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 E
4、xcellence. Technology appraisalguidance 76: newer drugs for epilepsy in adults. Available at:http:/www.nice.org.uk/TA076guidance. Accessed July 5, 2005.,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: Nat
5、ional 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.,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: Nat
6、ional 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.,NICE指南,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,Neurology. 2004,62(8):1252-1260,Neurology. 2004
7、,62(8):1261-1273,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标,抗癫痫临床治疗指南比较总结,Payakachat et al. J Manag Care Pharma 2006,Payakachat et al. J Manag Care Pharma 2006,NICE指南和AAN指南对于新药的使用推荐,Lancet Neurol 2004; 3: 61821,DrugNewly diagnosed epilepsyRefractory epilepsy PartialAbse
8、ncePartialPartialIdiopathicSymptomatiemixedmonotherapygeneralisedgeneralisedUSUKUSUKUSUKUSUKUSUKUSUKFelbamate*NoNANoNAYesNAYesNANoNAYes NAGabapentinYesNoNoNoYesYesNoNoNoNoNoNoLamotrigineYes Yes|Yes Yes|YesYes*YesYesNo Yes*YesYes*LevetiracetamNoNoNoNoYesYesNoNoNoNoNoNoOxcarbazepineYesYesNoNoYesYesYes
9、YesNoNoNoNoTiagabineNoNoNoNoYesYes|NoNoNoNoNoNoTopiramateYesYes NoNoYesYes*YesYesYesYes*YesYes*VigabatrinNANoNANoNAYesNANoNANoNAYesZonisamideNoNANo NAYes|NANoNANoNANoNA,None of the drugs is recommended as first choice in newly diagnosed epilepsy by the UK guidelines (see text). NA=not available. *Pa
10、tients 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 years; only patients 16years; only generalize
11、d 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.,新药的严重/非严重不良事件,Lancet Neurol 2004; 3: 61821,AEDSerious adverse vevntsNonserious adverseFelbamateAplastic anaemia, hepatotoxicit
12、yGastrointestinal disturbancse, anorexia, insomniaGabapentinAggresion*Weight gain, peripheral cedema, behavioural changes LamotrigineRash, including Stevens Johnson and toxic epidermal necrolysisTics and insomnia(high risk for children, also more common with concomitantvaiproic-acid use and low with
13、 slow titration); hypereensitivityreactions, including hepatic and renal failure, DIC, and arthritisLevetiracetamNoneIrritability/behaviour changeOxcarbazepineHyponatraemia (more common in elderly people), rashNoneTiagabineNonconvulsive status epilepticusDizziness, astheniaTopiramate Nephrolithiasis
14、, open angle glaucoma, hypohidrosis,Metabolic acidosis, weight loss,depression, psychosislanguage dysfunxtion, paraesthesiaVigabatrinVisual field defects, psychosis, depressionWeight gainZonisamideRash, renal calculi, hypohidrosis Irritability, photosensitivity, weight lossAED=antieptic drug; DIC=di
15、sseminated intravascular coagulation. * Mosthy in cognitively impaired patients; predominantly children.,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,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,可能加重某些癫痫综合征的抗痫药物,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
16、分析,抗癫痫药物恶化发作,癫痫患者发作增加的百分比,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,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,研究A: 基线的人口学资料和临床表现,Ref: SANAD研究结果,研究A:治疗无效的时间, 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,结论 研究 A,拉莫三嗪治疗无效
17、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,研究B:基线的人口学资料和临床表现,Ref: SANAD研究结果,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,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,传统抗癫痫
18、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 lamotrigine, 15 gabapentin, 7 o
19、xcarbazepine, 9 tiagabine, 3 topiramate, and 1 vigabatrin).,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 antiepileptic drug in 248;168 receved an established drugand 80 received a
20、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 of patients at the time of the last clinic visit is given in par
21、entheses.,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),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,
