型固定劑量降壓制劑arbhctz.ppt

新型固定劑量降壓制劑ARB/HCTZ 臨床應(yīng)用的中國(guó)專家共識(shí),北京大學(xué)人民醫(yī)院 孫寧玲,我們面臨的巨大挑戰(zhàn)：三高三低 94%高血壓患者血壓不達(dá)標(biāo)!,2004年中國(guó)居民營(yíng)養(yǎng)與健康狀況調(diào)查報(bào)告,三高,三低,0,5,10,15,20,25,30,35,知曉率,治療率,控制率,百分比（）,30.2,24.7 ,6.1 ,薈萃分析61項(xiàng)回顧性觀察研究 涵蓋1百萬(wàn)人（40-89歲）,控制心血管危險(xiǎn)降壓是關(guān)鍵,Lewington et al. Lancet. 2002;360:19031913,利尿劑治療高血壓的作用 1、 利尿劑減輕體內(nèi)鈉負(fù)荷，減少鈉在阻力動(dòng)脈管壁中的含量，降低血管收縮的反應(yīng)性。 2、能增強(qiáng)其它降壓藥物的降壓效應(yīng)，增加血管順應(yīng)性。 3、能夠減輕左心室肥厚 4、可弱化對(duì)低鹽飲食的限制,幾項(xiàng)主要使用利尿劑的高血壓治療研究,1. EWPHE. Lancet. 1985; 1: 1349-1354 2. STOP. Lancet. 1991; 338: 1281-1285 3. SHEP. JAMA. 1991; 265: 3255-3264,EWPHE,STOP,SHEP,病例數(shù),840,1627,4736,隨訪（年）,12,4,4.5,收縮壓,160,180,160,-,36,-,47,-,36,心性事件減少（,%,）,-,32,-,40,-,32,平均年齡,SBP Response to 2-Drug Combinations That Include or Do Not Include a Diuretic,With HCTZ,Without HCTZ,SBP 140 mmHg, %,P=0.002,Materson, et al. J Human Hypertens. 1995;9:791-795.,77,46,0,20,40,60,80,100,2007年ESC/ESH降壓藥物的選擇,降壓治療的主要獲益源自降低血壓本身。 五大類降壓藥物： 噻嗪類利尿劑 鈣拮抗劑 血管緊張素轉(zhuǎn)換酶 (ACE) 抑制劑 血管緊張素受體阻滯劑 (ARB) -阻滯劑,Myocardial infarction,Heart failure,End-stage heart disease,Plaque rupture,Risk factors,Hypertension Hyperlipidemia Diabetes,Atherosclerosis,Endothelial dysfunction,Coronary artery disease,Dilatation/Remodeling,Angiotensin II,The cardiovascular continuum,Potential effects of AT1-receptor blockade,ANG II,ANG II,ANG II,ANG II,ARB,AT1,AT2,ANG II,Vasodilation? Pathological Growth Apoptosis,Vasodilation Pathological growth Apoptosis Sodium & water retention Neurohumoral activation Reactive oxygen species Pro-inflammatory processes,厄貝沙坦: 劑量反應(yīng)和耐受性,安慰劑對(duì)照試驗(yàn)匯總結(jié)果。 *谷值坐位舒張壓 90 mm Hg 或從基線下降10 mm Hg。 Man in抰 Veld AJ. J Hypertens. 1997;15(suppl 7):S27-S33.,總的治療 反應(yīng)率* %,(n=539),(n=277),(n=357),(n=216),厄貝沙坦 (mg/天),扣除安慰劑作 用的不良反應(yīng) (% 病例數(shù)),(n=641),(n=297),(n=516),(n=282),Low-does Polypill vs Standard-dose Monotherapy:Effect on Systolic BP,N=108 with hypertension,drug naive; 4-week treatment,Mahmud A. Feely J. Hypertension 2007:49;272-5.,0,-5,-10,-15,-20,-25,-30,Comb (n=22),Capt 100mg (n=22),Amlo 5mg (n=20),Aten 50mg (n=20),Bend 2.5mg (n=22),P0.01vs monotherapies,SBP (mmHg),單藥治療控制率低，多數(shù)使用聯(lián)合治療,“超過(guò)2/3的高血壓病人需要兩種或兩種以上不同類別的藥物而不是只用一個(gè)藥物來(lái)有效控制血壓” JNC 7,“血壓控制在140/90mmHg以內(nèi)的病人中的60使用了兩種或兩種以上的藥物，只有30的病人使用了一種藥物?！?ALLHAT 研究,“隨機(jī)臨床試驗(yàn)證明，大多數(shù)高血壓病人為控制血壓須用兩種或兩種以上降壓藥” 中國(guó)高血壓防治指南（2005修訂版）,選擇藥物組合有差別,ARB加小劑量利尿劑持續(xù)用藥比例最高，放棄治療或轉(zhuǎn)藥比例最低,100,90,80,70,60,50,40,30,20,10,0,0,3,6,9,12,15,18,21,24,27,自治療開(kāi)始的時(shí)間（月）,21%,17%,患者比率（%）,固定復(fù)方制劑 2片藥物同時(shí)服用,固定復(fù)方制劑較2片藥物同服依從性高,復(fù)方固定復(fù)方制劑在指南中被推薦,“固定復(fù)方制劑常常在更低的組方劑量下能更好的控制血壓，導(dǎo)致的副作用也更少” “固定復(fù)方制劑會(huì)更加方便和簡(jiǎn)化治療方案，也會(huì)比單獨(dú)處方不同的藥物花費(fèi)少?！?JNC 7,“近來(lái)多類新型降壓藥問(wèn)世，新型固定復(fù)方制劑涌現(xiàn)如海捷亞等。既有不同作用機(jī)制藥物對(duì)降壓協(xié)同作用，也使不良反應(yīng)最小化?！?中國(guó)高血壓防治指南（2005修訂版）,新型固定復(fù)方制劑,氯沙坦/氫氯噻嗪 （海捷亞） 纈沙坦/氫氯噻嗪 （復(fù)代文） 厄貝沙坦/氫氯噻嗪 （安博諾）（依倫平）,強(qiáng)效快速，控制血壓 耐受性好，與安慰劑相似 獨(dú)特保護(hù), 獨(dú)特的腦卒中保護(hù),新型固定復(fù)方制劑:氯沙坦/氫氯噻嗪,ARB氯沙坦+小劑量利尿劑,聯(lián)合用藥-降壓更快速,使用海捷亞第一周 即可降低SBP16mmHg,Adapted from Julian Critchley A.J.H. et al., Current Therapeutic Research 57:392-407, 1996,氯沙坦 + HCTZ (N=426),氨氯地平 + HCTZ (N=419),*,*,*,*,基線,治療周,Volpe et al Vol. 25, No. 5, 2003, Page(s) 1469-1489,*P0.001 vs. 基線,坐位收縮壓 (mmHg),聯(lián)合用藥強(qiáng)效降壓：,171.9,148.9,144.7,143.8,171.2,151.3,146.2,143.8,140,145,150,155,160,165,170,175,0,6,12,18,提高血壓控制率,對(duì)已經(jīng)用纈沙坦單藥治療失敗者，海捷亞血壓控制率（SiDBP 90 mmHg）高達(dá)72！,ARB纈沙坦+小劑量利尿劑,-8.6,-8.8,-7.2,-7.3,-11.8,-16.5,-18,-16,-14,-12,-10,-8,-6,-4,-2,0,纈沙坦,80mg,HCTZ 12.5mg,復(fù)代文 （纈沙坦80mg/HCTZ 12.5mg）,舒張壓,收縮壓,復(fù)代文（纈沙坦/氫氯噻嗪）降壓療效顯著,JR Benz, HR Black, A Graff, et al，J Hum Hypertens, Dec 1998; 12(12): 861-6.,Benz在871例輕中度高血壓患者中進(jìn)行的雙盲安慰劑對(duì)照研究,與基線相比 血壓的改變 mmHg,復(fù)代文（纈沙坦/氫氯噻嗪）的降壓療效優(yōu)于雙倍劑量氫氯噻嗪,Schmidt,et al. Blood Press2001;10:230,與基線相比 血壓的改變 mmHg,-16,-14,-12,-10,-8,-6,-4,-2,0,HCTZ 25mg,收縮壓,舒張壓,復(fù)代文 （纈沙坦80mg/HCTZ 12.5mg）,- 5.7,- 6.8,- 14.9,- 11.2,Schmidt在217 例輕中度高血壓患者中進(jìn)行的雙盲安慰劑對(duì)照研究,-17.1,-15.7,-17,-11.7,-13.1,-12.8,-12.3,-12.5,-18,-16,-14,-12,-10,-8,-6,-4,-2,0,98,周,114,周,130,周,146,周,血壓下降平均值,(mmHg),收縮壓,舒張壓,SG Chrysant,DG Wombolt,et al.Current Therapeutic Research.1998(59):762-772,長(zhǎng)期服用復(fù)代文（纈沙坦/氫氯噻嗪），降壓療效穩(wěn)定,Chrysant 對(duì)73例服用復(fù)代文（纈沙坦/氫氯噻嗪）的原發(fā)性高血壓患者（33-77歲）進(jìn)行的3年降壓療效研究。無(wú)患者因藥物相關(guān)副作用退出研究,*Mean reductions from baseline at end point (12 weeks) in patients with mild to moderate essential hypertension. Mallion JM et al. Blood Press. 2003;12(suppl 1):36-43.,Diovan and Co-Diovan: Dose-Responsive Efficacy,ARB厄貝沙坦+小劑量利尿劑,厄貝沙坦/HCTZ（安博諾） 和單個(gè)藥物治療的劑量反應(yīng),-16,-14,-12,-10,-8,-6,-4,-2,0,SeDBP 變化 (mmHg),Kochar M et al. Am J Hypertens 1999;12:797-805.,每組患者數(shù) n = 40,安慰劑,HCTZ 12.5 mg,厄貝沙坦 150 mg 安搏維,厄貝沙坦 150 mg HCTZ 12.5 mg 安博諾,-3.5,-6.2,-10.2,-15.0,降壓的達(dá)標(biāo)的%,0,10,20,30,40,50,60,70,80,90,100,反應(yīng)率,(%),83.5%,( DBP85 mmHg),安博諾,150mg/ HCTZ 12.5mg,(DBP90 mmHg),94.35%,Littlejohn T III et al. Clin Exp Hypertens 1999;21:1273-95.,厄貝沙坦/HCTZ（安博諾）治療 的長(zhǎng)期治療反應(yīng),正常化者* 有反應(yīng)者,*Trough SeDBP 90 mmHg 正?；蜉^基礎(chǔ)值下降 of 10 mmHg,0,20,40,60,80,100,80,83,81,87,90,87,患者 (%),月,6,12,24,N = 1,006,兩制劑其血漿中厄貝沙坦經(jīng)時(shí)濃度：,說(shuō)明兩制劑的藥代動(dòng)力學(xué)參數(shù)相近。且兩制劑的參數(shù)Cmax、AUC0-24、AUC0-和Tmax經(jīng)統(tǒng)計(jì)學(xué)檢驗(yàn)均無(wú)顯著性差異(P0.05)。 （備注： AUC0-分別為13.021.96gh/ml和13.122.38gh/ml。 ）,國(guó)產(chǎn)厄貝沙坦/氫氯噻嗪（依倫平）與進(jìn)口厄貝沙坦/氫氯噻嗪 （安博諾）生物等效性比較,兩制劑其血漿中氫氯噻嗪經(jīng)時(shí)濃度：,說(shuō)明兩制劑的藥代動(dòng)力學(xué)參數(shù)相近。且兩制劑的參數(shù)Cmax、AUC0-24、AUC0-和Tmax經(jīng)統(tǒng)計(jì)學(xué)檢驗(yàn)均無(wú)顯著性差異(P0.05)。 （備注: AUC0-分別為773.13127.05ngh/ml和750.26150.62ngh/ml）,國(guó)產(chǎn)厄貝沙坦/氫氯噻嗪（依倫平）與進(jìn)口厄貝沙坦/氫氯噻嗪 （安博諾）生物等效性比較,試驗(yàn)結(jié)果表明：受試制劑-南京正大天晴制藥有限公司研制的依倫平與參比制劑賽諾菲安萬(wàn)特制藥股份有限公司生產(chǎn)的安博諾具有生物等效性。,國(guó)產(chǎn)厄貝沙坦/氫氯噻嗪（依倫平）與進(jìn)口厄貝沙坦/氫氯噻嗪 （安博諾）生物等效性比較,血壓下降,利尿劑 或 CCB,利鈉 和 血管擴(kuò)張,RAAS 激活,聯(lián)合治療的機(jī)制,聯(lián)合治療,對(duì)利尿劑長(zhǎng)期應(yīng)用的擔(dān)心 是否增加了糖尿病的風(fēng)險(xiǎn)？ 是否增加了低血鉀現(xiàn)象？,如何看待利尿劑長(zhǎng)期應(yīng)用的安全性？,海捷亞: 不影響血鉀 / 血糖代謝,1 Adapted from Ruilope LM et al Blood Pressure 5:32-40, 1996 2 Adapted from JNC Arch Intern Med 157:2413-2446, 1997,血鉀,血糖,NS,NS,12周時(shí)，礦物質(zhì)參數(shù)自基線*的平均改變,-0.1,-0.2,-0.8,-0.6,-0.4,-0.2,0,自基線的平均改變值,(mmol/L),科素亞,50mg,(n=59),海捷亞,(n=55),LIFE研究中氫氯噻嗪的使用率,Adapted from Dahlf B J Ann Intern Med 2004;364:413414.,使用氫氯噻嗪患者的比例 ,100,80,60,0,40,20,研究月份,48,60,24,36,12,0,阿替洛爾組 氯沙坦組,72,N=9193,降壓獲益及藥物本身的獲益,1、 強(qiáng)化降壓達(dá)標(biāo)才能獲得可能的器官 保護(hù)作用。 2、在降壓達(dá)標(biāo)后不同的藥物是有差別的。,LIFE: 服用藥物患者%,氯沙坦 阿替洛爾 50 mg 9% 10% 50 -100mg 含氫氯噻嗪在內(nèi)的其它治療* 68% 63% 中斷研究 23% 27% 平均劑量 82 mg 79 mg,*排除ACEIs, AIIAs, beta blockers. Dahlf B et al Lancet 2002;359:995-1003.,LIFE: 相似的降壓效果,研究月份,收縮壓,舒張壓,平均動(dòng)脈壓,mmHg,阿替洛爾 145.4 mmHg,氯沙坦 144.1 mmHg,阿替洛爾 80.9 mmHg,氯沙坦 81.3 mmHg,Dahlf B et al Lancet 2002;359:995-1003.,阿替洛爾 102.4 mmHg,氯沙坦 102.2 mmHg,Proportion of patients with first event (%),0,2,4,6,8,10,12,14,16,0,6,12,18,24,30,36,42,48,54,60,66,Adjusted Risk Reduction: 13.0%, p = 0.021,Time (months),Change from baseline (%) in LVH determined by electrocardiography,-18,-16,-14,-12,-10,-8,-6,-4,-2,0,p 0.0001,p 0.0001,4.4%,10.2%,15.3%,9.0%,Atenolol Losartan,Dahlf B et al. Lancet 2002;359:9951003.,LVH regression and primary endpoint,Atenolol,Losartan,Cornell Voltage-Duration Product,Sokolow-Lyon Voltage,Composite of CV Death, stroke and MI,LIFE 研究,VALUE: Major Study End Points in 5006 Patient Pairs (N = 10,012) on Diovan- or Amlodipine-Based Therapies Using Serial Median Matching,Composite cardiac events,Stroke,Death,Myocardial infarction,Heart failure,0.6,0.8,1.0,1.2,1.4,Favours Diovan,Favours amlodipine,*P0.05. Weber MA et al. Lancet. 2004;363:2047-2049.,有利于氨氯地平,VALUE:初步結(jié)果顯示，與全球結(jié)果相比， 亞洲人群從以纈沙坦為基礎(chǔ)的治療方案中獲益更多。,主要終點(diǎn)的危險(xiǎn)比和 95% CIs 總組 (n=15,245) vs 亞洲人群 (n=441),有利于纈沙坦,風(fēng)險(xiǎn)比,0.25,0.5,1,2,4,+,#,總組主要聯(lián)合終點(diǎn)* 亞洲人群主要聯(lián)合終點(diǎn) 總組心梗 亞洲人群心梗 總組充血性心衰 亞洲人群充血性心衰 總組中風(fēng) 亞洲人群腦卒中 總組全因死亡 亞洲人群總死亡 總組心源性死亡 亞洲人群心源性死亡,* 心源性死亡和發(fā)病率 + P0.05 # P=0.054,Julius S et al. Lancet. 2004;363:2022-2031.,VALUE: Diovan-Based Therapy Significantly Reduces Risk for New-Onset Diabetes,Study Design,W0 Visit 1 Enrolment of hypertensive patients untreated or uncontrolled by monotherapy,R,HCTZ : 12.5 mg od - 5 weeks,W4 Visit 2 Exclusion if SBP 140 mm Hg (office),W13 Visit 4 Final evaluation,5 weeks,8 weeks,Phase 1,Phase 2,COSIMA Study,COSIMA：, BP final - baseline (mm Hg),HBPM (average of all values),DBP,SBP,Office BP (trough),DBP,SBP,P0.001,P0.01,2.8(26%),-16,-12,-8,-4,0,2.2(30%),-16,-12,-8,-4,0,P0.05,P0.01,3.2(28%),1.4(21%),G. Bobrie et al. Archives Mal Coeur Vaiss 2004 (12): p96 and p116,-9.6,-7.4,-13.4,-10.6,-8.2,-6.8,-14.8,-11.6,Significantly More Patients Normalised on Irbesartan Combination Therapy*,% Patients,P0.0001,Office,HBPM,P0.05,Normal HBPM values: SBP 135 mm Hg and DBP 85 mm Hg,Normal office values: SBP 140 mm Hg and DBP 90 mm Hg,19.6%,10.3%,Data on file,52.9%,33.3%,51.5%,41.2%,*The PP results are consistent with the ITT results 8 week study,COSIMA Study,Minimum 4 weeks,1,005 Uncontrolled on Single Antihypertensive Agent,INCLUSIVE: Study Design,Multicenter (119 sites across the US), prospective, open-label, single-arm study,Screening,Intent-to-treat (ITT) population, n = 736. Week 18 aggregate data for irbesartan/HCTZ 150/12.5 mg and 300/25 mg include all patients whose BP was controlled from baseline. Entry criteria at screening were SBP 140 mmHg, 130 mmHg in type 2 diabetes; entry criterion at each stage of the study was DBP 70-109 mmHg; mean DBP at baseline = 91.3 mmHg. Some patients were at goal DBP at baseline. * Goal: SBP 140 mmHg, DBP 90 mmHg, except patients with type 2 diabetes: SBP 130 mmHg, DBP 80 mmHg. BP = blood pressure; DBP = diastolic blood pressure; SBP = systolic blood pressure.,DBP Goal,SBP Goal,INCLUSIVE Blood Pressure Goal Attainment at Week 18,ITT population; T2DM, type 2 diabetes mellitus,Elderly (n=184),African- American (n=157),Hispanic/ Latino (n=110),T2DM (n=227),Metabolic syndrome (n=345),Women (n=370),Men (n=366),130 mm Hg,73%,73%,72%,75%,82%,73%,56%,0,20,40,60,80,100,Patients Controlled (%),Elderly (n=184),African- American (n=157),Hispanic/ Latino (n=110),T2DM (n=227),Metabolic syndrome (n=345),Women (n=370),Men (n=366),80 mm Hg,80%,96%,78%,83%,86%,77%,63%,0,20,40,60,80,100,Patients Controlled (%),SBP 亞組達(dá)標(biāo)率,DBP 亞組達(dá)標(biāo)率,130,80,INCLUSIVE,ARB聯(lián)合利尿劑的優(yōu)勢(shì),血管緊張素 I,血管緊張素 （肝）,血管緊張素 II,ARB AT1 受體拮抗劑,Adapted from: de Gasparo et al. Pharmacol Rev. 2000; 52: 415,ACE,ARB作用示意圖,血管舒張 抗增殖作用 凋亡,Clinical Significance of AT1 Receptor Blockade,A II,AT2,BP,Atherosclerosis,Endothelial Function,Neuroendocrine,LVH,Cardioprotection Vasculoprotection Renoprotection,AT1 receptor blockade,A II binding at the AT2 receptor,ARB,LVH=left ventricular hypertrophy.,AT1,氯沙坦有效逆轉(zhuǎn)向心性LVH,氯沙坦可使47.4%患者LVMI恢復(fù)正常，向心性LVH比例從38.9%降至6.7% 向心性LVH的危險(xiǎn)性比離心性LVH高,38.9%,6.7%,47.4%,CVF = 9.8%,CVF = 2.7%,氯沙坦抑制膠原合成和心肌纖維化,基線,氯沙坦治療12個(gè)月,CVF = 膠原容量比例,Diez et al. Circulation 2002;105:25122517.,Baseline,During Treatment,3.95,3.9,3.85,3.8,3.75,3.7,3.65,P0.001,Losartan Atenolol,LIFE 研究,Months in LIFE,Left Atria diameter (cm),3.55,3.6,3.65,3.7,3.75,3.8,3.85,3.9,3.95,4,0,12,24,36,48,60,Losartan,Atenolol,P=0.86,P=0.003,P=0.077,P=0.025,P=0.002,P=0.01,科素亞與阿替洛爾治療對(duì)左房?jī)?nèi)徑的影響,纈沙坦 vs氨氯地平: 纈沙坦改善內(nèi)皮功能,60,40,20,0,10,30,50,70,62%*,13%,% 乙酰膽堿刺激后前臂血流量的改變,纈沙坦,氨氯地平,Adapted with permission from Tzemos N et al. Am J Hypertens. 2001;14:A66-A67.0,*P 0.05 vs 基線,代文增加內(nèi)皮NO的產(chǎn)生和釋放，改善血管內(nèi)皮功能,Klingbeil AU, et al. Am J Hypertens 2003;16:1238,0.6,0.4,0.2,0,0.2,代文 80 mg HCTZ 25 mg 安慰劑,NG-單甲基-L-精氨酸刺激后前臂血流量變化* (mL/min/100 mL),服用氫氯噻嗪治療無(wú)明顯變化,0.6 (n=20),0.2 (n=20),(n=20),p0.05 vs安慰劑,Valsartan Improves Insulin Sensitivity in Hypertensive Patients,Top C, et al. J Internat Med Res. 2002;30:1520.,Normotensive (20) Hypertensive (20) Pre-Treatment Hypertensive Post-Treatment (valsartan 80 mg),Fasting Insulin (uIU/mL),0,65,70,75,80,85,90,95,纈沙坦,安慰劑,100,p=0.009,無(wú)事件概率 (%),13.2%,一級(jí)聯(lián)合終點(diǎn),0,65,70,75,80,85,90,95,100,p0.00001,纈沙坦,安慰劑,27.5%,心衰再住院率,* p0.00002,無(wú)事件生存率,纈沙坦 n = 185,安慰劑 n = 181,44%,未使用ACEI組代文可使一級(jí)聯(lián)合終點(diǎn)降低44%,Val- HeFT 的主要終點(diǎn)事件,Val-HeFT: 左室功能的超聲心動(dòng)指標(biāo),纈沙坦,安慰劑,LVIDd/BSA變化 (cm/m2),EF變化 (%),2.0,3.0,4.0,5.0,0.12,0.08,0.04,0.00,4 Months,12 Months,18 Months,24 Months,P 0.0001,P 0.001,P 0.0001,P = 0.031,P 0.