内科-神经内科-癫痫治疗指南新看点33张课件

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华山医院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 2019,4).10913 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

2、准严格：评价方法严格可行动态：不断更新制订指南原则透明：无利益驱动抗癫痫治疗指南大事记Payakachat et al. J Manag Care Pharma 2019抗癫痫治疗指南大事记Payakachat et al. J Welcome to the National Institute for Healthand Clinical Excellence websiteNICE is the independent organization responsible for providingnational guidance on the promotion of good healt

3、h andthe prevention and treatment of ill health. On 1 April 2019 NICE joined with the Health Development Agency to becomethe new National Institute for Health and Clinical Excellence(also to be known as NICE). Clinical ExcellencePublic Health Excellence NICE was set up as a Special Health Authority

4、for England and Wales on 1 April 2019. Its role is to provide patients, health professionals and the public with authoritative, robust and reliable guidance on current best practice. (.uk/)Welcome to the National InstNICE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 Heal

5、th and Clinical Excellence. Technology appraisalguidance 76: newer drugs for epilepsy in adults. Available at:.uk/TA076guidance. Accessed July 5, 2019.NICE指南对于抗癫痫药物使用的指证，药物选择，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. Technol

6、ogy appraisalguidance 76: newer drugs for epilepsy in adults. Available at:.uk/TA076guidance. Accessed July 5, 2019.NICE在治疗中NICE指南Ref: National InNICE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: Nati

7、onal Institute for Health and Clinical Excellence. Technology appraisalguidance 76: newer drugs for epilepsy in adults. Available at:.uk/TA076guidance. Accessed July 5, 2019.NICE指南Ref: National Institute 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

8、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:.uk/TA076guidance. Accessed July 5, 2019.NICE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NICE缺点NICE指南Ne

9、urology. 2019,62(8):1252-1260 Neurology. 2019,62(8):1261-1273Neurology. 2019,62(8):1252-126AAN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AAN指南1. AAN指南有明确证据分类和证据评级抗癫痫临床治疗指南比较总结Payakachat et al. J Manag Care Pharma 2019抗癫痫临床治疗指南比较总结Payakachat et al.Payakachat et al. J Manag Ca

10、re Pharma 2019Payakachat et al. J Manag CareNICE指南和AAN指南对于新药的使用推荐Lancet Neurol 2019; 3: 61821DrugNewly diagnosed epilepsyRefractory epilepsy PartialAbsencePartialPartialIdiopathicSymptomatiemixedmonotherapygeneralisedgeneralisedUSUKUSUKUSUKUSUKUSUKUSUKFelbamate*NoNANoNAYesNAYesNANoNAYes NAGabapentin

11、YesNoNoNoYesYesNoNoNoNoNoNoLamotrigineYes Yes|Yes Yes|YesYes*YesYesNo Yes*YesYes*LevetiracetamNoNoNoNoYesYesNoNoNoNoNoNoOxcarbazepineYesYesNoNoYesYesYesYesNoNoNoNoTiagabineNoNoNoNoYesYes|NoNoNoNoNoNoTopiramateYesYes NoNoYesYes*YesYesYesYes*YesYes*VigabatrinNANoNANoNAYesNANoNANoNAYesZonisamideNoNANo

12、NAYes|NANoNANoNANoNANone 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 supports use; only patients 18 years; only patients 4 years with Lennox-Gastaut

13、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 after failure of all other appropriate drug combinations; only West

14、ayndrome; | only adulte. 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 2019; 3: 61821AEDSerious adverse vevntsNonserious adverseFelbamateAplastic anaemia, hepatotoxicityGastrointestinal disturbancse, anorexia, insomniaGabapentinAggresion*Weight gain, peripheral cedema, behavioural changes

15、 LamotrigineRash, including Stevens Johnson and toxic epidermal necrolysisTics and insomnia(high risk for children, also more common with concomitantvaiproic-acid use and low with slow titration); hypereensitivityreactions, including hepatic and renal failure, DIC, and arthritisLevetiracetamNoneIrri

16、tability/behaviour changeOxcarbazepineHyponatraemia (more common in elderly people), rashNoneTiagabineNonconvulsive status epilepticusDizziness, astheniaTopiramate Nephrolithiasis, open angle glaucoma, hypohidrosis,Metabolic acidosis, weight loss,depression, psychosislanguage dysfunxtion, paraesthes

17、iaVigabatrinVisual field defects, psychosis, depressionWeight gainZonisamideRash, renal calculi, hypohidrosis Irritability, photosensitivity, weight lossAED=antieptic drug; DIC=disseminated intravascular coagulation. * Mosthy in cognitively impaired patients; predominantly children. 新药的严重/非严重不良事件Lan

18、cet Neurol 201 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可能加重某些癫痫综合征的抗痫药物Ref: Epilepsia. 39(Suppl. 3):S15-S18, 2019Topiramate Vigabatrin0246810ClonazepamClobazamSodium Valproate(德巴金

19、)CarbamazepineBarbexaclonePrimidonePhenobarbitalEthosuximideSulthiameOxcarbazepinePhenytoinLamotrigineGabapentinElger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Ref: Epilepsia. 39(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

20、新抗癫痫药在癫痫治疗的综合作用中明显优于其它药物临床医生在应用指南时特别注意 认识的更新研究A: 基线的人口学资料和临床表现Ref: SANAD研究结果研究A: 基线的人口学资料和临床表现Ref: SANAD研究研究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继续治疗的比例研究A:治疗无效的时间, 意向性治疗集-O- LTG继续治疗结论 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

21、分性发作的患者可考虑为第一线药物Ref: SANAD研究结果结论 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:基线的人口学资料和临床表现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

22、发作或未分类的发作的患者可考虑为第一线药物结论 研究 B丙戊酸的疗效显著高于拉莫三嗪和托吡酯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 0%10%20%30%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 yearPati

23、ents with epilepsy (n-525) 60%50%40%30%20%Patients63%37%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 oxcarbazepine, 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 antiepilept