他汀类药物的副作用除了停药还能作些什么?.pdf
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1、他汀类药物的副作用除了停药还能作些什么?Adverse effects of statins:Strategies beyond discontinuation中国医学科学院 阜外心血管病医院Fu Wai Cardiovascular Hospital,CAMS Disclosure(讲前声明)No any interest was involved in this Lecture冠心病:发展中国家的严峻挑战CHD:Severe challenge in developing countries口 WH02008年报告:心血管病死亡占全球死亡31%,排名第一(传染病29%)17,00万/年死于
2、动脉粥样硬化性疾病 80%分布在低中等收入国家包括中国 我国每年死于冠心病的人数达250万5项经典他汀类里程碑临床试验Landmark studies of statin-related clinical trialsLDL-C降低15.9/13.222.62.8TexCAPS n=6,605 TC 5.7 mmol/lWOS n=6,595 TC 7.0 mmol/l冠心病+胆固醇高35%25%冠心病+9胆固醇不高无冠心病 胆固醇高卜无冠心病4 胆固醇不高32%26%23%事件减少34%24%23%31%35%奠定了他汀类药物的临床广泛与强化应用的基础优化药物治疗是现代冠心病治疗主流Curr
3、ent strategies of medication therapy for coronary heart disease药物危险性减少(%)5年事件发生率(%)无药物治疗020.0阿司匹林2515.0B受体阻滞剂2511.3AC日258.4他汀类药物305.9同时使用上述4种药物,可使总的死亡危险性减少70%5年中,每治疗7位患者,便可减少1例主要心血管事件Yusuf et al.Rev Cardiovasc Med.2003;4(suppl 3):537-4 6.他汀促进强化调脂与靶目标概念诞生Target of lower-density cholesterol following
4、lipid-lowering therapy危险等级彳氐危:(10年危险性 24 0 LDL-C160TC200LDL-C130TC 1 60 LDL-C 100TC120LDL-O8 0治疗开始(mg)TC270 LDL-C190TC 24 0 LDL-C 160TC 1 60 LDL-C 100TC160LDL-C8 0目标值(mg)TC24 0LDL-C160TC200LDL-C130TC160LDL-C100TC120LDL-C8 0中国成人血脂异常防治指南委员会,中华心血管病杂志2007;35:390-413.Safety Issue of Statin Therapyan long
5、-term important issueJournal at the Auxiican College of Cardiok*0 3202 by fhe Amwicin Cclkyjc of Caudiolo空 Foundurjou and the Amerkan Heut AMoeution Piihlitlxd ly Elsevier Science I DC2002ACC/AHAHLBI CLI NI CAL ADVI SORY ON STATI NSACC/AHA/NHLBI Clinical Advisor y on th e Use and Sate tv of Statins2
6、006Final Conclusions and Recommendations of th e National Lipid Association Statin Safety Assessment Task For ceJames M.McKenney.Ph ar mD/*Michael H.Davidson.MD,1,Ter r y A.Jacobson.MD?and John R.Guyton.MDdWRITING COMMITTEE MEMBERSRI CHARD C.PASTERNAK,MD,FACC,FAHA SI DNEY C.SMI TH Jr,MD,FACC,FAHA C.
7、NOEL BAI REY-MERZ,MD,FACCSCOTT M.GRUNDY,MD.PhUJAMES 1.CLEEMAN,MD CLAUDE LENFANT,MD,FA5TABLE OF CONTENTSI ncidence of Adver se Events.S69Mech anism of Myopath y.570Bdselme Measur emeots-.一一一一一570Monitor ing tor Adsr fse Reacuom and Adjusting Th er apy 571AsTOptcmatK Patients With CK Ekva口0n.S71I ncr
8、eased Risk States tor SutJ D-I nduced Myopath y-571Clinical Pr ecautions 一一一一371and Blood I nstitute(ACC/AHAN soty is intended co summar ize for pH under standing of statin use,pr ovide updated r ecommendations H of statins,including cautions,contr.monitor ing for statin ther apy.Ie pqj age r he app
9、r opr iate use of statins,.potential in pr oper ly selected pati.with established cor onan,h ear t di辽 at high r isk for developing CHDi myopathy infor mation compiled by fr om clinical tr ials,and summar ies11 leased r epor t of r h e Adult Tftatnienfl the National Ch olester ol Education2I NTRODUC
10、TI ON I n th e liter atur e,th e gener al ter mir flh jpThis art icle sumnKiri/csIhc final conclusions of t he Nat ional lipid AsMKiafion(NLA)St at in Safet y Task Force,based on a review and independent research of New Drug Applicat ion(NDA)informat ion.US Food and Drug Administ rat ion(FDA)Adverse
11、 Event Report ing Syst em(APRS)dat a,cohort and cliniud t rial result s,and analysis ut administ rat ive claims dat akbc informat ion and t he assessment of it s 4 Expert Panels,which focused nn issues of st at in safet y wit h reg ard t o liver,musde.renal,and neurolog ic syst ems.Pract ical g uida
12、nce in t he form of recommendat ions Io healt h profcKsionals who manag e t he coronary art ery disease risk of pat ient s wit h Mat in t herapv is provided.2006 Elsevier Inc.All rig ht s reserved.(Am J Cardiol 2006:Q7|siippl|:89C-Q4()In t he sect ions t hat follow,t he Nat ional Lipid Associat ion
13、NLA|S(a(in Safet y Task Force draws from t he ext ensive evidence so superbly pivsent ed and analyzed by t he scient ist s and expert s who aut hored(he preceding art icles In t his supplenienl.The Task Force herein offers whal It believes t o he a summary ol final conclusions t hat can he made base
14、d on t his evidence and provides piaciical g uidance in t he form of recommendahons t o healt h pt oiessinals who nunag e t he coronary art eiy disease risk of pat ient s wit h st at in t herapy*The Liver and St alin Salet)-Wc IALT and/or AST 3 t imes t he ULN is mosl oft en t ransient and will reso
15、lve spont aneously In 70%of cases even if t he skuin and dose are coniinued unchang ed 工To more accurat ely ident ify palieni wit h a persisleni liver t est abnormalit y,some inveslig at ors have adopt ed a more rig orous definit ion,eg.ALT or AST 3 t imes t he ULN on 2 consecut ive occasions When t
16、 his det lnihon is applied.t he number of paiient s wit h a sig nificant elevat ion drops from 300 per 100.000 person-years t o 110 per 100.000 person-years?Reduct ion in t he dose or wit hdrawal of t he st at in reg ukirly result s in a ret urn ot t he elevat ed enzyme levels lo normal wit houl adv
17、erse sequelae.外心血管病度眄竽1金他汀应用需要格外关注药物的安全性Special attention on safety issue of statin therapy药物间相互作用肌毒性与肝毒性临床要点他汀类药物的副作用机制尚不十分清楚 严重不良反应绝对停用(Discontinucition)他汀类药物相互作用的可能风险Possible risk of drugs when co-administration with statin口合并高血压,同时服用钙离子拮抗剂,辛伐他汀邛可 托伐他汀慎重使用(定期监测CK)口合并房颤,辛伐他汀,阿托伐他汀应在监测CK下慎用口心衰患者,辛伐
18、他汀,阿托伐他汀应在定期监测CK及 地高辛浓度下慎重使用 PCI术后,联合使用氯毗格雷,辛伐他汀,阿托伐他汀 应在定期监测CK下慎重使用他汀应尽量避免与烟酸类和贝特类药物合用他汀类药物应用的肌毒性问题Statin-associated myopathy:an important issue口肌病:他汀类药物最严重的不良反应 Mechanism:G emonic variation口表现:肌痛或肌无力,伴有CK升高至正常上 限10倍以上,也可有发热和全身不适症状口发生率:大约是0.1%,且与剂量有关 口危害:肌病未能及时被发现,仍旧继续用药,则可能导致横纹肌溶解和急性肾功能衰竭他汀类药物肌毒性的
19、临床认知Statin-related toxic myopathy:clinical recognitionTh e clinician sh ould suspect a toxic myopath y wh en a patient without a pre-exis ting muscle disease develops myalgia,fatigue,weakness or myoglobinuria,tempor ally connected to th e administr ation of a statin or exposur e to a myotoxic substa
20、nce.Dalakas MC.J Neurol Neurosurg Psychiat ry 2009;80:832-838.例心血管他汀类药物肌肉症状的基本定义Definition of statin-associated myopathy肌毒性表现基本定义肌病肌肉的任何疾病肌痛肌肉疼痛或疲软不伴CK升局肌炎有肌肉症状伴CK升高肌溶解有肌肉症状伴CK显著升高(以超过正 常高限ULN 1。倍以上并伴肌酎升高 为典型)1.Pasternak R et al.Circulation 2002;106:1024-282.Ucar M et al.Drug Saf 2000;22:4 4 1-57澳大利
21、亚报道他汀类药物致肌病的危险因素Risk factors of statin-related myopathy in Australia通过CYP3A4代谢而抑制他 汀类药物代谢的物质通过其他作用方式抑制他汀 类药物代谢的药物疾病状态高龄环抱素、钙离子拮抗剂,大环内 酯类抗生素、毗咯抗真菌类药物、蛋白酶抑制剂、葡萄柚果汁吉非贝齐糖尿病、甲状腺功能减退、肾和肝脏疾病 7 0岁大剂量服用他汀类药物Australian Adverse Drug Reactions Bulletin.2004 Feb;23(1)他汀类副作用:除了停药还能作些什么?Adverse effects of statins:
22、Strategies beyond discontinuation 减量与间断应用(r educe dose and nondaily dosing r egimes)他汀类药物之间的转换应用(statinswitch ing)非他汀降脂药物的替换应用(nonstatin alter natives)他汀与降脂药物联合应用(combination of ow-dose statin and oth er s)保护性药物的联合应用(coenzymeQI0 supplementation)外心血管他汀类副作用:除了停药还能作些什么?Adverse effects of statins:Strate
23、gies beyond discontinuation减量与间断应用Reduce dose and nondaily dosing regimes长期治疗是他汀获益的必要条件Benefits of statin therapy derived from long-term administration58项他汀临床试验荟萃分析的结果(治疗组76,359;安慰剂71,962)试验时间危险性降低()第6年以后36(26-4 5)Law MR.Br Med J 2003;326:14 23他汀突然撤除会增加心血管事件Increased mortality after withdrawing a st
24、atin therapy8 6 4 41 41 41(一工*-otOE力2 w 8 6St at ins discont inuedNo st at insSt at in cont inuedWithdrawal of Statins:增加ACS患者心血管事件发生可能机制之一炎症因子反弹?10 15 20 25 3030-day follow-up penodCirculation 2002;105:1446-1542.Li J-J,et al.Med Hypo 2006;66:478.他汀撤除事件增加的可能机制:炎症“反弹,Increased mortality after withdra
25、wing a statin therapyTime Median CRP(mg/dl)Mean CRP(mg/dl)IL-6(pg/dl)Baseline0.150.300.108.4 0.66 weeks0.100.220.096.7 0.4WithdrawalDay 10.100.210.096.8 0.5Day 30.140.270.147.7 0.6Day 70.160.310.158.7 0.8Li J-J,et al.Clin Chim Acta 2006;366:273-279.AtoZ研究中不良事件发生率与剂量关系Rate of adverse effects occurred
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