1、更多医学精品 尽在医学吧,http:/ 除了停药还能作些什么？,中国医学科学院 阜外心血管病医院,Adverse effects of statins: Strategies beyond discontinuation,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,WHO2008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,CHD: Severe challe
2、nge in developing countries,奠定了他汀类药物的临床广泛与强化应用的基础,5项经典他汀类里程碑临床试验,CARE n=4,159 TC 5.4 mmol/l,LIPID n=9,014 TC 5.6 mmol/l,WOS n=6,595 TC 7.0 mmol/l,4S n=4,444 TC 6.8 mmol/l,冠心病 + 胆固醇高,冠心病+ 胆固醇不高,无冠心病 胆固醇高,TexCAPS n=6,605 TC 5.7 mmol/l,无冠心病 胆固醇不高,LDL-C降低 35 25 32 26 23,34 24 23 31 35,Landmark studies o
3、f statin-related clinical trials,LDL-C降低 事件减少,优化药物治疗是现代冠心病治疗主流,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):537-46.,Current strategies of medication therapy for coronary heart disease,他汀促进强化调脂与靶目标概念诞生,Target of lower-density cholesterol followi
4、ng lipid-lowering therapy,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 Therapy an long-term important issue,2002,2006,他汀应用需要格外关注药物的安全性,药物间相互作用肌毒性与肝毒性,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（Discontinuation),Special attention on safety issue of statin therapy,临床要点,他汀类药物相互作用的可能风险,合并高血压， 同时
5、服用钙离子拮抗剂，辛伐他汀, 阿托伐他汀慎重使用（定期监测CK) 合并房颤，辛伐他汀, 阿托伐他汀应在监测CK下慎用 心衰患者，辛伐他汀, 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，联合使用氯吡格雷，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,Possible risk of drugs when co-administration with statin,他汀类药物应用的肌毒性问题,肌病：他汀类药物最严重的不良反应Mechanism: Gemonic variation 表现：肌痛或肌无力，伴有CK升高至正常上限10倍以上，也
6、可有发热和全身不适症状发生率：大约是0.1%，且与剂量有关危害：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,Statin-associated myopathy: an important issue,他汀类药物肌毒性的临床认知,The clinician should suspect a toxic myopathy when a patient without a pre-existing muscle disease develops myalgia, fatigue, weakness or myoglobinuria, temporally connect
7、ed to the administration of a statin or exposure to a myotoxic substance.,Dalakas MC. J Neurol Neurosurg Psychiatry 2009;80:832-838.,Statin-related toxic myopathy: clinical recognition,他汀类药物肌肉症状的基本定义,1. Pasternak R et al. Circulation 2002;106:102428 2. Ucar M et al. Drug Saf 2000;22:44157,Definition
8、 of statin-associated myopathy,澳大利亚报道他汀类药物致肌病的危险因素,Australian Adverse Drug Reactions Bulletin. 2004 Feb；23（1）,Risk factors of statin-related myopathy in Australia,他汀类副作用:除了停药还能作些什么？,减量与间断应用 (reduce dose and nondaily dosing regimes)他汀类药物之间的转换应用 (statin switching)非他汀降脂药物的替换应用(nonstatin alternatives)他汀
9、与降脂药物联合应用 (combination of ow-dose statin and others) 保护性药物的联合应用 (coenzyme Q10 supplementation),Adverse effects of statins: Strategies beyond discontinuation,他汀类副作用:除了停药还能作些什么？,减量与间断应用Reduce dose and nondaily dosing regimes,Adverse effects of statins: Strategies beyond discontinuation,（治疗组76,359；安慰剂7
10、1,962）,Law MR. Br Med J 2003;326:1423,长期治疗是他汀获益的必要条件,58项他汀临床试验荟萃分析的结果,Benefits of statin therapy derived from long-term administration,他汀突然撤除会增加心血管事件,Circulation 2002; 105:1446-1542.,Withdrawal of Statins: 增加ACS患者心血管事件发生率 可能机制之一炎症因子反弹？,Li J-J, et al. Med Hypo 2006; 66:478.,Increased mortality after
11、withdrawing a statin therapy,他汀撤除事件增加的可能机制：炎症“反弹”,_Time Median CRP(mg/dl) Mean CRP(mg/dl) IL-6 (pg/dl)_ Baseline 0.15 0.300.10 8.4 0.6 6 weeks 0.10 0.220.09 6.7 0.4 WithdrawalDay 1 0.10 0.210.09 6.8 0.5 Day 3 0.14 0.270.14 7.7 0.6 Day 7 0.16 0.310.15 8.7 0.8 _,Li J-J, et al. Clin Chim Acta 2006;366:
12、273-279.,Increased mortality after withdrawing a statin therapy,AtoZ 研究中不良事件发生率与剂量关系,de Lemos JA, et al. JAMA 2004;292:1307-1316.,辛伐他汀40或80mg/日 安慰剂辛伐他汀20mg/日AST或ALT3倍ULN 19/2132（0.9） 8/2068（0.4）横纹肌溶解# 3/2230（0.1） 0/2230（0）肌病 9/2263（0.4） 1/2230（0.04）因肌肉方面不良反应 而停药 41/2263（1.8） 34/2230（1.5）,Rate of adv
13、erse effects occurred in A to Z study,不良反应类型,TNT研究不良事件发生率与剂量关系,La Rosa JC et al. N Engl J Med 2005;352:1425-1435.,不良反应类型,Safety issue of high-dose statin administration in TNT study,他汀小剂量应用有效性的证据,对象：106名高脂血症妇女方法：Atorvastatin 10mg/d 3-6 m 指标：LDL-C, CRP, TPA/PAI-1, Sex steroidproduction结论：low-dose has
14、 no influence on endocrinological status except effectivein LDL-C and inflammatory markers,Evidence of reduced and nondaily dosing statin regimes,Ushiroyama T, et al. Int J Cardiol 2006;113:66-75.,MEGA研究小剂量普伐他汀在日本成年人胆固醇升高一级预防治疗有效,研究背景：8214例中度高脂血症的患者，接受限制总胆固醇和饱和脂肪酸的饮食，每周吃3次鱼，一组服用10-20mg普伐他汀，一组不服用普伐他汀
15、治疗随访时间：5.3年结果： 服用10mg20mg普伐他汀可以使冠心病的危险约降低30,Nakamura H, et al. Lancet 2006;368:1155-1163.,Mega study: low-dose pravastatin decreases CVE in Japanese,血脂康降低老年MI高血压患者CVE,研究设计：多中心、随机、安慰剂对照对象：1530老年高血压患者（65 yrs) with MI 接受二种降压方案治XZK or或安慰剂治疗，随访4.5年结果与结论： XZK（含洛伐他汀10mg 明显降低老年心梗后高血压患者的心血管事件,Li J-J,Lu Z-L,
16、et al. J Clin Pharmacol 2009; 47:947-956.,Xuezhikang decrease CVE in Chinese hypertensive elderly with MI,他汀类副作用:除了停药还能作些什么？,他汀类药物之间的转换应用 Statin switching,Adverse effects of statins: Strategies beyond discontinuation,Statin switching: a case report,Case report: 1 59-year-old women withheart transpla
17、ntation 4 years eralier.Pravastatin 20mg/d for 4 yearsAfter switching from pravastatin tosimvastatin, she developed severe muscularweakness until repeat hemodialysis,Sochman J, Podzimkova M. Int J Cardiol 2005;99:145-146.,Statin switching: basic mechanism,Ballantyne C et al. Arch Intern Med 2003;163
18、:553564Corsini A. Cardiovasc Drugs Ther 2003;17:257277,Drug interactions between statin and other medications,相对亲水性 *,Statin switching: basic mechanism,Buckett et al., (2000); McTaggart et al., (2001),相对亲脂性 *,瑞舒伐他汀,西立伐他汀,辛伐他汀,氟伐他汀,阿托伐他汀,普伐他汀,* log D at pH 7.4,肝外扩散分布少,肝内 CYP代谢少,Cell-selective action
19、of Water-loving and water-hating statin,普伐他汀,ML-236B,静注C14标记美百乐镇及 ML-236B 后大鼠全身放射显影照片,Arai M, et al. Annu Rep Sankyo Res Lab 1988;1:40.,普伐他汀在肝脏高度选择性分布,High-degree selective action in liver following pravastatin administration,The rate of occurrence of muscular symptoms with high dosage statin therap
20、y varied depending on the statinLescol XL treatment was associated with a significantly lower risk of muscular symptoms compared with pravastatin, atorvastatin and simvastatin,PRIMO研究:他汀类药物剂量和肌肉症状风险,Bruckert B et al. Cardiovasc Drugs Ther 2006;19:403-414.,(N=7924),Statin dosing and statin-relating m
21、yopathy in PRIMO study,FDA报道他汀发生肌毒性事件,FDA report data on file,Statin-related toxic myopathy: Are all statins same?,他汀类副作用:除了停药还能作些什么？,非他汀降脂药物的替换应用Nonstatin alternatives,Adverse effects of statins: Strategies beyond discontinuation,非他汀降脂药物替换应用的临床选择,烟酸多廿烷醇Red yeast rice （血脂康）3- 脂肪酸依折麦布,Clinical select
22、ion of nonstatin lipid-lowering drugs,烟酸类调脂药物的作用特点与应用,B族维生素(vitamin B3), 大剂量有降脂作用；适用高TG血症，低HDL-C血症或以TG升高为主混合型高脂血症 速释剂烟酸不良反应明显，现已不用。缓释型烟酸不良反应明显减轻，较易耐受 临床试验CDP,CLAS-I,FATS,HATS,ARBITER2等证实，烟酸降低主要冠脉事件减少总死亡率 常见不良反应：颜面潮红、高血糖、高尿酸（或痛风）、上消化道不适等。绝对禁忌证为慢性肝病和严重痛风；相对禁忌证为溃疡病、肝毒性和高尿酸血症,Clinical features and appli
23、cation of Niacin-derived drugs,Study on extended niacin application,Design: Randomized, double-blind, placebo controlled multicenter, 24-week trial Drug: Combination of Niacin 2000mg/laropiprant 40mg Results: LDL-C 18%Incidence and intensity of flushing were significantly reduced compared with Niaci
24、n 2000mg alone. Conclusion: Combination of Niacin/laropiprant was generally well tolerated by adults with dyslipidemia.,Perry CM. Drugs 2009;69:1665-1679.,多廿烷醇调脂治疗临床应用文献汇总,作用机制：通过腺苷酸激酶选择性阻断HMG-CoA还原酶的活性（他汀完全阻断HMG-CoA合成酶）调脂作用：10 mg/d: LDL-C 17%; HDL-C +5%20mg/d: LDL-C 24%; HDL-C +18%证据：1）肝酶异常者（ALT45U
25、/L）应用无恶化现象2）迄今无肌病及肌溶解报道,J Gerontol Med Sci 2001;13:1-9; Curr Ther Res 1996;57:118-127.,Red yeast rice（红曲） for dislipidemia in a statin- intolerant patients: a randomize trial,Design （设计）: Randomized, controlled trial Patients（患者）: 62 名他汀肌病停药者 Therapy （治疗）: Rid yeast rice 1800mg (Sylvan bioproducts,
26、Kittanning, Pennsylvania) or placebo (n=31 respectively) Bid Follow-up（随访）: 24 weeks, primary outcome: LDL-C; secondary outcome: TC, HDL-C, TG, Liver enzyme, CK, weight, Results （结果）: LDL-C减少: 1.11mmol/L vs 0.28 mmol/L at 12 wks, 0.93 mmol/L vs 0.39 mmol/L at 24 wks Conclusion （结论）: Red yeast rice m
27、ay be a treatment optionfor dislipidemic patients who cannot tolerate statin therapy,Becher DJ, et al. Ann Intern Med 2009;150:830-839.,Omega-3-fatty acids (-3-脂肪酸): an cardiovascular agent,Lipid-related effects: dose-dependently reduce blood TG Pleiotropic effects: favorable effects on inflammatory
28、 process, endothelial dysfunction, platelet aggregation and arrhythmogenesis Administration: used alone or used in combination with statin MACE: need further study and more evidence,Dimitrow PP, et al. Mini Rev Med Chem 2009;9:1030-1039.,他汀类副作用:除了停药还能作些什么？,小剂量他汀与降脂药物联合应用Combination of low-dose stati
29、n and other lipid-lowering drugs,Adverse effects of statins: Strategies beyond discontinuation,小剂量他汀与其它调脂药物联合应用,Bile acid sequestrants （多价螯合剂） (Cholestyramine, colestipol, colesevelam) Ezetimibe Niacin Plant sterols（植物固醇） Fibrate (fenofibrate, bezafibrate, gemfibrozil) Omega-3-fatty acids （-3-脂肪酸）,C
30、ombination of low-dose statin and other lipid-lowering drugs,小剂量他汀与其它调脂药物联合应用,目的：维持达标水平,降低不良反应与事件 原则：小剂量他汀与另外一种降脂药物组成,Combination of low-dose statin and other lipid-lowering drugs,It has to stated that for most of these combination therapies data on cardiovascular outcomes are still lacking.,Fundam
31、Clin Pharmacol 2009;14:88-94.,临床上可供选择的联合治疗模式,小剂量他汀类治疗,* = 增加肌病危险性,Grundy S, Am J Cardiol 2002;90:1135-38,Models of lipid-lowering combination therapy,依折麦布+辛伐他汀:显著降低LDL-C,Davidson,et al. J Am Coll Cardiol 2002;40:2125,More reduction of LDL-C levels following EZE+Simvastatin,依折麦布联合他汀治疗更有效降低CRP,Thomas
32、P, et al., Am J Cardiol 2007;99:17061713.,12 weeks therapy,More reduction of CRP levels following EZE+Simvastatin,HATS:辛伐他汀与烟酸联用显著改善冠脉狭窄和心血管事件,Zhao X et al. J Am Coll Cardiol. 2002;39:242A;1130-73.,Change in Stenosis, %,CVD Event Rate, %,*,90% Reduction,*,代谢综合征 n = 69,非代谢综合征 n = 77,40% Reduction,代谢综
33、合征n = 77,非代谢综合征 n = 83,*,Placebo,Niacin + Simvastatin,More reduction of MACE following niacin+simvastatin,他汀类副作用:除了停药还能作些什么？,非他汀类降脂药物联合应用Combination of non-statin lipid-lowering drugs,Adverse effects of statins: Strategies beyond discontinuation,非他汀降脂药物联合应用的临床方向,Niacin-resin or fibrate-niacinExtende
34、d-release niacin/laropipranSqualene synthase inhibitor （角鲨烯合成酶抑制剂）Microsomal triglyceride transfer proteininhibitor （微粒体甘油三脂转运蛋白抑制剂）antisense apolipoprotein B （反义载脂蛋白B）,Novel nonstatin strategies to lower LDL-C,Curr Atheroscler Rep 2009;11:67-70.,Extended niacin/laropiprant application,Design: Rando
35、mized, double-blind, placebo controlled multicenter, 24-week trial Drug: Combination of Niacin 2000mg/laropiprant 40mg Results: LDL-C 18%Incidence and intensity of flushing were significantly reduced compared with Niacin 2000mg alone. Conclusion: Combination of Niacin/laropiprant was generally well
36、tolerated by adults with dyslipidemia.,Perry CM. Drugs 2009;69:1665-1679.,Raising HDL-C with niacin and fibrates: a comparative review,Design: A head-to-head comparative study Drug: Combination of Niacin 2,000mg/Gemfibrozil 1,200mg compared with Niacin or Fibrate trial alone Indexes: TC/HDL-C, Lp (a
37、) and fibrinogen Conclusion: Combination therapies of Niacin plus a resin are effective, well tolerated, and safe.,Sprecher D, Am J Cardiol 2001;86(suppl 1):46-50.,他汀类副作用:除了停药还能作些什么？,保护性药物的联合应用Coenzyme Q10 supplementation,Adverse effects of statins: Strategies beyond discontinuation,保护性药物联合应用的临床证据,B
38、r J Clin Pharmacol 1996;42:333-337.Ann Intern Med 2002;137:581-585.Arch of Neurol 2004;61:889-892. Eur J Clin Invest. 2005;35:251-258.Am J Cardiol 2004;94:1306-1310.Georgian Medical News 2005(1):20-24.,Clinical application of statin with preventive drugs,辅酶Q10与他汀类药物的机制关系,HMG-CoA,甲酸戊酸,异戊烯焦磷酸,焦磷酸法呢酯,辅
39、酶Q10(CoQ10),多醇,胆固醇,鲨烯,HMGCoA还原酶,HMGCoA还原酶抑制剂,乙酰辅酶A,+,Possible Mechanism of Co-Q10 and statins,他汀类药物与对辅酶Q10水平影响,Br J Clin Pharmacol 1996, 42:333,高胆固醇血症患者(21岁-76岁，n=80） 40名接受他汀类药物治疗，20名接受贝特类药物，20名没有药物治疗，20名健康对照者 入住及试验一周后采集血样,辛伐他汀,贝特类,未治疗组,健康对照组,e P0.05 vs 未治疗组,h P0.05 vs 健康对照组,Decreased levels of Co-Q
40、10 in patients treated with statin,辅酶Q10水平,Statin-induced myopathy is associated with mitochondrion dysfunction,他汀性肌病与线粒体功能异常,Ann Intern Med. 2002,137:581-585,A,C,E服用他汀类药物肌肉活检图 B、D、F停药后肌肉活检图,阿托伐他汀对辅酶Q10水平的影响,Decreased levels of Co-Q10 in patients treated with atorvastatin,Archives of Neurology Vol.6
41、1(6):889-892,* P0.01 与基线水平相比,治疗后的天数,2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0,基线 14 30,辅酶Q10的浓度(ug/mL),1.26,0.67,0.62,*,*,N=34 阿托伐他汀80mg/天 疗程30天,辛伐他汀对辅酶Q10水平的影响,Effects of simvatstatin on plasma levels of Co-Q10,European Journal of Clinical Investigation. 2005, 35: 251258,辅酶Q10水平(nmol/L),时间（月）,N=21
42、辛伐他汀20mg/天 疗程6个月，期间测定辅酶Q10的浓度 停药一个月后，再测定体内辅酶Q10水平,150012501000750500,0 1 2 3 4 5 6 7,*P0.05, 与基线相比,vs服用他汀类药物的患者 DT值, # p=0.002, $ p=0.12,DT值,14位高脂血症患者51-79岁，他汀类药20mg/天，疗程 3-6个月 10名患者出现心室舒张功能恶化 再加用辅酶Q10 300mg/天 (100mg/次，tid)后，患者心肺功能得到恢复,Silver MA, et al. Am J Cardiol 2004, 94:1306-1310,192#,209$,242,
43、基线,他汀类药物,他汀类药物+ 辅酶Q10,Statin plus Co-Q10 reverse statin-induced ventricular dysfunction,辅酶Q10逆转他汀引起的心室舒张功能,基线,他汀类药物+辅酶Q10,他汀类药物组,小结:他汀副作用除了停药可以选择策略,减量与间断应用 他汀类药物之间的转换应用 非他汀降脂药物的替换应用小剂量他汀与降脂药物联合应用 保护性药物的联合应用,温馨提示：上述策略的循证证据十分有限，本内容仅供学术研讨,Summary: Adverse effects of statins: Strategies beyond discontinuation,Thank you for your attention!,Building insights, break boundaries,更多医学精品 尽在医学吧,http:/
