最新：钙离子拮抗剂治疗原发性高血压-中山医院-文档资料.ppt

作者简介,钱菊英 主任医师，硕士研究生导师。 现任复旦大学附属中山医院心内科副主任，内科教研室副主任，心导管室副主任。 长期从事心血管病的医教研工作，擅长各种心血管疾病的诊治，尤其在冠心病的介入诊治领域有颇深的造诣，每年主刀完成冠心病介入诊治手术500多例，是中山医院急性心肌梗死患者急症介入治疗抢救“绿色通道”的主要术者之一。 历年共发表第一作者论文30多篇，SCI收录9篇，主译专著1部，参编和参译专著13部。作为主要完成人曾获得国家和省部级科技进步奖共7项。,实线表示证据支持或推荐使用的组合; 虚线表示证据不足或必要时谨慎使用的组合,噻嗪类利尿剂,血管紧张素 受体拮抗剂,钙拮抗剂,ACE 抑制剂,-阻滞剂,-阻滞剂,CCB是目前各指南中推荐使用的五大类降压药物之一,CCB的种类,二氢吡啶类： 第一代：短效 第二代：长效制剂，非洛地平，尼卡地平，拜新同，尼索地平，依拉地平 第三代：长效制剂，氨氯地平，乐卡地平 非二氢吡啶类 维拉帕米 地尔硫卓,CCB的种类,阻断L-型通道 二氢吡啶类：血管扩张作用强，对血管通透性无或有增加作用，对心肌收缩和传导无或仅轻微影响 短效： 长效制剂，对心肌收缩轻微影响：非洛地平，尼卡地平，拜新同，尼索地平，依拉地平 长效制剂，对心肌收缩无影响：氨氯地平，乐卡地平 非二氢吡啶类：血管扩张作用相对小，降低血管通透性，抑制心肌收缩力和传导 维拉帕米 地尔硫卓,CCB降低收缩期高血压最有效,Am J Hypentens 2001,14:241,CCB降压的临床试验,Lancet June 2004,amlodipine ± perindopril,Atenolol ± bendroflumethiazide,19,257 hypertensive patients,PROBE design,ASCOT Design,ASCOT：Amlodipine group is better than Atenolol group,(amlodipine ± perindopril vs Atenolol ± bendroflumethiazide ),* P0.05,-35,-30,-25,-20,-15,-10,-5,0,*,*,*,*,*,*,*,Non fatal MI+ Fatal CHD,CV death,All mortality,All CHD,fatal/ nonfatal stroke,All CHD+ intervention,New onset DM,Renal impairment,Dahlof B, Sever P, et al. Lancet. 2005;366:895-906.,*,Percentage of reduction %,ASCOT: CV events reduction,Major Outcomes in High Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic,The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),The ALLHAT Collaborative Research Group Sponsored by the National Heart, Lung, and Blood Institute (NHLBI),JAMA. 2002;288:2981-2997,0.20 0.15 0.10 0.05 0.00,0 1 2 3 4 5 6 7,With CHD,amlodipine Lisinopril.,time（y）,L/A 1.06(0.99-1.32) 0.69,RR(95%Cl) P,Cumulative CHD,0.20 0.15 0.10 0.05 0.00,0 1 2 3 4 5 6 7,Without CHD,氨氯地平 Lisinopril.,L/A 0.98(0.88-1.13) 0.78,RR(95%Cl) P,tiem（y）,Frans H.H. Leenen et al. Hypertension. 2006;48:374-384.,ALLHAT: for patients with CHD at baseline, amlodipine has similar effect of prevention of MI as ACEI,JAMA 2004,Placebo-controlled, multicenter, randomised, double-blind, comparative, parallel trial,CAMELOT: Study Design,Results BP Data,BP reductions in the amlodipine and enalapril groups were statistically significant vs placebo (P0.001) There was no statistically significant difference between amlodipine and enalapril,CAMELOT ResultsCumulative Event Rates,Cumulative events, proportion,Months,0,6,12,18,24,0,0.25,0.20,0.15,0.10,0.5,placebo enalapril amlodipine,No. at risk Placebo 655 588 558 525 488 Enalapril 673 608 572 553 529 Amlodipine 663 623 599 574 535,31% Risk reduction for amlodipine vs placebo (P=0.003) 19% Risk reduction for amlodipine vs enalapril (P=0.10) 15% Risk reduction for enalapril vs placebo (P=0.16),Rates for coronary revascularisation,27% reduction,Rates for hospitalisation for angina,42% reduction,CAMELOT ResultsSubgroup Analyses amlodipine vs placebo,All patients,Lipid-lowering therapy Treated with statin Not treated with statin Age Age mean,Hazard Ratio (95% CI),amlodipine,placebo,2-year event rates,30.9% 0.003 16.6% 23.1%,33.9% 0.002 16.9% 24.5% 4.1% 0.91 15.2% 15.5% 22.9% 0.07 17.2% 21.9% 49.3% 0.006 14.8% 26.8% 26.8% 0.03 17.4% 23.0% 42.8% 0.03 14.0% 23.2% 32.2% 0.03 15.0% 21.4% 29.6% 0.04 18.3% 24.7%,0.5,0.75,1.0,1.5,2.0,Favors amlodipine,Favors placebo,% Relative Risk Reduction,P value,0.25,Amlodipine versus Nifedipine,SAME STRENGTH,Journal of Human Hypertension 2002; 16: 805813.,-20.1,-11.7,-21.8*,-12.1*,-25,-20,-15,-10,-5,0,Day SBP,Day DBP,Norvasc(n=97),Adalat GITS(n=104),*p=0,26;*p=0.72 *p=0,44;*p=0.38,BPmmHg,-20.4,-18.3*,-11.7,-10.2*,Night SBP,Night DBP,Key clinical trails of CCBs on CV events reduction,ASCOT: vs atenolol ALLHAT: vs hydro- vs irbesartan VALUE: vs valsartan CASE-J: vs candesartan ACCOMPLISH: vs hydrochlorothiazide ,INSIGHT: vs hydrochlorothiazide × ACTION: vs placebo ×,Norvasc,Adalat GITS,Norvasc on MI,Franz H. Messerli et al. Hypertension. 2006;48:359-361.,0.20 0.15 0.10 0.05 0.00,0 1 2 3 4 5 6 7,With CHD,amlodipine Lisinopril.,time（y）,L/A 1.06(0.99-1.32) 0.69,RR(95%Cl) P,Cumulative CHD,0.20 0.15 0.10 0.05 0.00,0 1 2 3 4 5 6 7,Without CHD,氨氯地平 Lisinopril.,L/A 0.98(0.88-1.13) 0.78,RR(95%Cl) P,ALLHAT: for patiens with CHD at baseline, amlodipine has similar effect of prevention of MI as ACEI,tiem（y）,Frans H.H. Leenen et al. Hypertension. 2006;48:374-384.,Time to first occurrence of clinical events,0.0,0.2,0.4,0.6,0.8,1.0,0,2,4,6,年,Survival %,nifedipine GITS placebo,All cause mortality (p=0.41),Primary efficacy end point (death,MI, RA, HF, CVA, PREV,P=0.54),Primary safety end point (death, MI, CVA, p=0.86),Philip A Poole-Wilson,et al. Lancet 2004; 364: 84957,all cause mortality and MI were not significantly reduced by nifedipine GITS,Philip A Poole-Wilson,et al. Lancet 2004; 364: 84957,310,1.25 (0.073),118,146,Peripheral revascularisation,0.78 (0.10),99,77,Fatal stroke,0.71 (0.015),121,86,New onset hear failure,0.86 (0.18),174,150,Refractory angina,1.04 (0.62),257,267,MI,1.07 (0.41),291,All cause mortality,RR (p ),Placebo (n=3840),nifedipine GITS(n=3825),Individual component of end points,Change in mean heart rate and blood pressure,Poole-Wilson PA et al. Lancet 2004; 364: 849-57,0,1,2,3,4,5,6,Follow-up (years),Nifedipine Placebo,140,mmHg,80,b/min,Heart rate,SBP,p 0.0001,p 0.0001,p 0.0001,DBP,Time to first occurrence of clinical events,Avoiding Cardiovascular Events through COMbination Therapy in Patients LIving with Systolic Hypertension,Kenneth Jamerson1, George L. Bakris2, Bjorn Dahlof3, Bertram Pitt1, Eric J. Velazquez4, and Michael A. Weber5 for the ACCOMPLISH Investigators University of Michigan Health System, Ann Arbor, MI1; University of Chicago-Pritzker School of Medicine, Chicago, IL2; Sahlgrenska University Hospital, Gothenburg, Sweden3; Duke University School of Medicine, Durham, NC4; SUNY Downstate Medical College, Brooklyn, NY5,ACCOMPLISH: 一项独特的高血压研究,传统的高血压研究: 以单药治疗起始, 逐渐加药以致血压达标 ACCOMPLISH: 以单片复方药物治疗起始治疗高危高血压 某些特殊复方药物组合可能有降压外器官保护作用,ACCOMPLISH: Design,Jamerson KA et al. Am J Hypertens. 2003;16(part2)193A,*Beta blockers; alpha blockers; clonidine; (loop diuretics).,14 Days,Day 1,Month 1,Month 2,Year 5,Screening,Amlodipine 5 mg + benazepril 20 mg,Randomization,Benazepril 40 mg + HCTZ 12.5 mg,Benazepril 40 mg + HCTZ 25 mg,Free add-on antihypertensive agents*,Month 3,Free add-on antihypertensive agents*,Amlodipine 5 mg + benazepril 40 mg,Amlodipine 10 + benazepril 40 mg,Benazepril 20 mg + HCTZ 12.5 mg,Titrated to achieve BP140/90 mmHg; 130/80 mmHg in patients with diabetes or renal insufficiency,Primary Endpoint,心血管发病率与死亡率: 心因性死亡 非致死性心梗 非致死性卒中 因不稳定性心绞痛入院 冠脉重建术 (PCI or CABG) 猝死后心脏复苏 (Resuscitated sudden death),Jamerson KA et al. Am J Hypertens. 2003;16(part2)193A.,ACCOMPLISH 入选标准,男性, 女性 55 岁 SBP 160 mmHg 或正在接受高血压治疗 心血管及肾脏损害依据,Baseline Demographics,*Denmark, Finland, Norway or Sweden,ACCOMPLISH 研究提前中止 DSMB Oct 17 2007,在研究进展到60%时, 提前到达预先设定的有效性指标, 因此研究提前中止. 末次病人数据采集: 2008年1月24日,Systolic Blood Pressure Over Time,mm Hg,Month,5731 5387 5206 4999 4804 4285 2520 1045 5709 5377 5154 4980 4831 4286 2594 1075,Patients,*Mean values are taken at 30 months F/U visit,129.3 mmHg,130mmHg,Difference of 0.7 mmHg p0.05*,DBP: 71.1,DBP: 72.8,ACCOMPLISH: Exceptional Control Rates with Initial Combination Therapy,ACEI / HCTZ N=5733,Control rate (%),CCB / ACEI N=5713,10,20,30,40,50,60,70,80,90,P0.001 at 30 months follow-up,Control defined as 140/90 mmHg,Kaplan Meier for Primary Endpoint,Cumulative event rate,HR (95% CI): 0.80 (0.72, 0.90),Time to 1st CV morbidity/mortality (days),p = 0,650,526,.0,0,0,2,INTERIM RESULTS Mar 08,Primary Endpoint and Components,Composite CV mortality/morbidity Cardiovascular mortality Non-fatal MI Non-fatal stroke Hospitalization for unstable angina Coronary revascularization procedure Resuscitated sudden death,Incidence of adjudicated primary endpoints, based upon cut-off analysis date 3/24/2008 (Intent-to-treat population),Risk Ratio (95%),Favors CCB / ACEI,Favors ACEI / HCTZ,0.80 (0.720.90) 0.81 (0.62-1.06) 0.81 (0.63-1.05) 0.87 (0.67-1.13) 0.74 (0.49-1.11) 0.85 (0.74-0.99) 1.75 (0.73-4.17),INTERIM RESULTS Mar 08,Primary and Other Endpoints,Composite CV mortality/morbidity Primary w/o revascularization Hard CV endpoint (CV death, non-fatal MI, non-fatal stroke) All cause mortality,Incidence of adjudicated primary endpoints, based upon cut-off analysis date 3/24/2008 (Intent-to-treat population),Risk Ratio (95%),0.80 (0.720.90) 0.79 (0.680.92) 0.80 (0.680.94) 0.90 (0.751.08),Favors CCB / ACEI,Favors ACEI / HCTZ,INTERIM RESULTS Mar 08,Conclusions,ACCOMPLISH achieved exceptional BP control with combination therapy providing a new option for cardiovascular risk reduction to millions of patients with hypertension. The results of ACCOMPLISH provide compelling evidence for initial combination therapy with ACEI / CCB and challenge current diuretic-based guidelines.,CCB常见副作用,对血管扩张作用强的CCB：发生率10-20% 头痛，头晕，或头重脚轻感，面部潮红，周围水肿 维拉帕米主要副作用：便秘，发生率25%,Calcium-antagonist drugs. N Engl J Med 1999; 341:1447.,参考文献：Manufacturers Data Sheets And Summaries Of Product Characteristics 2005中国高血压防治指南,CCB安全性更高,二氢吡啶类CCB无严重不良反应,外周水肿,维拉帕米较少。 与血管扩张，毛细血管循环压力增加，渗出增加有关。 利尿剂合用，不能减少 ACEI，ARB合用，发生减少：与静脉扩张有关，毛细血管循环压力减少。,Am J Hypertens 2001 Sep;14(9 Pt 1):963-8.,适应人群,病例选择：没有绝对的适应证和禁忌证 长效药物常用于合并冠心病的患者 合并COPD的患者 维拉帕米、地尔硫卓常用于合并房颤快速室率和心绞痛患者,应用注意事项,心功能：维拉帕米，地尔硫卓在服用-阻滞剂的患者、严重左室收缩功能不全，病窦综合症，II-III度房室传导阻滞禁忌 在心衰的患者，氨氯地平、非洛地平用于治疗心绞痛或高血压是安全的。,Circulation 1995; 92: 1326-31.,二氢吡啶类CCB-基层指南唯一推荐用药,降压作用强 安全性高，适用广泛 无绝对禁忌证 无糖脂代谢不良反应 不良反应率低且无严重不良反应 联合治疗的基础用药 唯一可与其他四种降压药联合使用的药物 临床证据充分,小结,CCB是临床常用的降压药物 适应人群广 无绝对禁忌证，相对安全,谢谢观赏！,