An Anti ti-Hy Hype perte tensi sive ve Tr Treat atment Specia Sp ial l At Atte tenti tion on to to AC ACE In Inhib ibit itor or
Quy uy mô mô c ủ a v ấ n đ ề Tử vong bệnh tim mạch: > 4 triệu chết ở Châu Âu (2000) Bệnh tim mạch: 43% của tất cả tử vong ở đàn ông và 55% tử vong ở phụ nữ Nguyên nhân chính của nhập viện: 2557/100000 dân (2002)
Actuality 2010: Tăng huyết áp vẫn là nguyên nhân gây tử vong hàng đầu. 17 triệu cas tử vong mỗi năm; giảm trung bình 5 năm tuổi thọ của bệnh nhân. WHO 2010
T ỉ l ệ hi hi ệ n m n m ắ c tăng huy ế t á t áp d ự báo vào năm 2020 Prevalence 2000 Predicted Prevalence 2025 350 300 250 Milions 200 150 100 50 0 Established Latin Former Middle East China India Other Asia & Sub-saharan market America & socialist crescent Islands Africa economies the economies Caribbeans > 500 triệu người bị tăng huyết áp vào năm 2025 * Estimated number of individuals aged >20 years with BP >140/90 mmHg in 2000 and predicted number of affected individuals in 2025. Kearney PM, et al. Lancet 2005;365:217-23.
Sử dụng thuốc hạ áp để giảm bệnh tim mạch Để giảm 10 mm Hg trong HATT hay 5 mm Hg trong HATTr: Biến cố bệnh mạch vành Đột quỵ -22 to 25% -36 to 41% Law MR et al, BMJ. 2009; 338: b1665.
Current Situation of Blood Pressure Management
Hypertension Management: Hypertension Awareness, Treatment & Control in Various Countries awareness treatment BP control 70 < 140/90 mmHg 60 50 % of population 40 30 20 10 0 USA Canada Italy Sweden Spain Germany England Wolf-Maier et al 2004 7
Control Status of BP Levels in Treated Hypertensive Patients J-HOME study Hypertensive patients Total hypertensive patients (n=3,400) complicated with diabetes (n=466) Good control a) Good control e) 19.1% 25.1% (n=648) Poor control d) (n=117) 43.4% (n=1,477) Masked hypertension b) Poor control f) 22.9% 74.9% (n=777) (n=349) White coat hypertension c) 14.7% (n=498) a) home BP < 135/85 mmHg clinic BP < 140/90 mmHg b) home BP ≥ 135/85 mmHg clinic BP < 140/90 mmHg c) home BP < 135/85 mmHg clinic BP ≥ 140/90 mmHg d) home BP ≥ 135/85 mmHg clinic BP ≥ 140/90 mmHg e) home BP < 130/80 mmHg clinic BP < 130/80 mmHg f) home BP ≥ 130/80 mmHg clinic BP ≥ 130/80 mmHg Obata et al. J Hypertens 2005;23:1653-1660. Obata et al. Diabetes Res Clin Pract 2006;73:276-283. modified
Development of Anti-hypertensive Therapies Effectiveness Tolerability 1940s 1950 1957 1960s 1970s 1980s 1990s 2004+ Direct Alpha ACE ARBs Others? vasodilators blockers inhibitors Aliskiren Thiazide Peripheral diuretics sympatholytics Central alpha 2 DHP CCBs Ganglion agonists blockers Non-DHP Veratrum CCBs alkaloids Beta blockers
Origin of RAS Research
The Discovery of Renin 1896 • ‘ A [rabbit] kidney was pulverized with 21 mL of water. Injection into jugular vein. Within 80 seconds, there is a rise in mean arterial pressure from 62 – 67 mmHg to 100 mmHg, i.e. an increase by ca. 50%. ’ Experiment 1B, 8. November 1896 Robert Adolf Armand Tigerstedt (ca. 1910) Tigerstedt R, Bergman PG. 1898
114 Years of RAAS Research 1898 Tigerstedt R. Finding of renin 1954 Simpson & Tait : Struct. Ident. of aldosterone 1955 Skeggs : Isol. of horse Ang Ⅱ 1956 Sequencing 1960 Kagawa , Develop. of spirolactone 1966 Arakawa : Isol.& synth. of human Ang Ⅰ 1969 Haber : RIA for PRA 1970 Bumpus : Peptide ARB: Goodfriend : finding of Ang Ⅱ -R 1975 Misono&Inagami : Isol. of mouse renin 1977 Ondetti : ACE inhibitor captopril 1982 Furukawa : Non-peptide ARB 1983 Imai : Cloning of human renin 1984 Kageyama : human Aogen 1990 Urata : Isol. of human heart chymase 1991 Cloning 1991 Hubert : Cloning of human ACE Sasaki/Murphy : Cloning of mouse AT 1 R Timmermans : Develop. of losartan (AIIA, ARB) 1993 Kanbayashi/Mukoyama : Cloning of rat AT 2 R 2003 Wood : Develop. of aliskiren (non-peptide renin inhibitor)
114 Years of RAAS Research 1898 Tigerstedt R. Finding of renin 1954 Simpson & Tait : Struct. Ident. of aldosterone 1955 Skeggs : Isol. of horse Ang Ⅱ 1956 Sequencing 1960 Kagawa , Develop. of spirolactone 1966 Arakawa : Isol.& synth. of human Ang Ⅰ 1969 Haber : RIA for PRA 1970 Bumpus : Peptide ARB: Goodfriend : finding of Ang Ⅱ -R 1975 Misono&Inagami : Isol. of mouse renin 1977 Ondetti : ACE inhibitor captopril 1982 Furukawa : Non-peptide ARB 1983 Imai : Cloning of human renin 1984 Kageyama : human Aogen 1990 Urata : Isol. of human heart chymase 1991 Cloning 1991 Hubert : Cloning of human ACE Sasaki/Murphy : Cloning of mouse AT 1 R Timmermans : Develop. of losartan (AIIA, ARB) 1993 Kanbayashi/Mukoyama : Cloning of rat AT 2 R 2003 Wood : Develop. of aliskiren (non-peptide renin inhibitor)
Angiotensin II Direct and indirect effects in organ damage Glomerular filtration rate Renal failure Proteinuria Angiotensin II Glomerulosclerosis Aldosterone release Left ventricular hypertrophy Fibrosis Remodelling Apoptosis Heart failure/ AT 1 Death myocardial Vasoconstriction receptor infarction Vascular hypertrophy Endothelial dysfunction Atherosclerosis Stroke Hypertension New-onset diabetes
The proven benefits of ACE inhibitors across the cardiovascular continuum Remodelling Ventricular Dilatation Chronic Myocardial Heart Infarction SAVE ,AIRE Failure TRACE,SMILE End-Stage SOLVD Atherosclerosis Heart ISIS 4 and LVH GISSI 3 Disease and Death CONSENSUS HOPE Risk Factors CAPP Diabetes Death EUROPA Hypertensio n
ACE inhibitor trials Primary Treatment Secondary prevention after MI prevention CONSENSUS I SOLVD AIRE SAVE TRACE HOPE GISSI-3 EUROPA ISIS-4 ASCOT ADVANCE QUIET CONSENSUS II Before AMI AMI After AMI PEACE
ARB : SELECTIVE • Provides highly selective blockade of Ang II directly at AT1 receptor ARBs ANGIOTENSIN II selective block at AT1 receptor AT1 AT2 - Proliferation - Anti proliferation - Vasoconstriction - Vasodilation - Increase sympathetic tone - Coronary flow Beneficial Effect Deleterious Effect
Emerging benefits of the ARBs across the cardiovascular continuum Remodelling Ventricular Myocardial Dilatation Infarction Chronic OPTIMAAL Heart VALIANT Atherosclerosis Failure and LVH ONTARGET ELITE 2 End-Stage Risk Factors Val-HeFT Heart Diabetes LIFE CHARM Hypertension Disease SCOPE Hyperlipidemia VALUE Smoking Death NAVIGATO RSMOOTH
Comparision of Antiypertensive Effects Ave. Rate of Efficacy No. of study Kind of drugs 68.7 % (64.4-73.1) Diuretic 6 64.7 % (56.4-76.0) Beta-blocker (including Alpha/Beta-blocker) 16+4 63.7 % (52.7-76.5) Alpha-blocker 5 83.0 % (76.8-90.0) Calcium antagonist 11 73.4 % (65.0-80.8) ACE inhibitor 11 78.9 % (69.7-84.7) ARB 5 Efficacy rates mainly on essential hypertension from insertions of respective drugs excluding slow release formulas
European Heart Journal 2012 Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin – angiotensin – aldosterone system inhibitors involving 158 998 patients
Background and aim • Background and Aim － Renin – angiotensin – aldosterone system (RAAS) inhibitors are well established for the reduction in cardiovascular morbidity, but their impact on all-cause mortality in hypertensive patients is uncertain. － Objective of this study was to analyze the effects of RAAS inhibitors as a class of drugs, as well as of angiotensin-converting enzyme (ACE) inhibitors and AT1 receptor blockers (ARBs) separately, on all-cause mortality. Laura C. van Vark et al.:European Heart Journal 2012
Method Randomized controlled trials, published between 1 st January, 2000 1 st March, 2011, are included in meta-analysis (n=20). Laura C. van Vark et al.:European Heart Journal 2012
All-cause mortality and Cardiovascular mortality In all 20 trials grouped together, all-cause mortality was reduced significantly by 5% by the treatment with an RAAS inhibition. In addition, the cardiovascular mortality was significantly reduced by 7%. Laura C. van Vark et al.:European Heart Journal 2012
Angiotensin-converting enzyme inhibitors vs. AT1 receptor blockers ACEI ARB The all-cause mortality reduction in the overall group of RAAS inhibitors in the previous slide was completely driven by the beneficial effect of the ACE inhibitors. Laura C. van Vark et al.:European Heart Journal 2012
Major Large Scale Clinical Trials using ACE Inhibitors Renal Cardiac Cardiovascul Hypertension Cardiac disorder Infarction ar disease failure ALLHAT CONSENSUS CONSENSUS II Lewis HOPE ISIS 4 ANBP 2 (D) V-HeFT II AIPRI EUROPA GISSI 3 ABCD SOLVD REIN PEACE SAVE FACET ELITE II AASK (ARB) AIRE UKPDS BENEDICT CAPPP ( B&D) TRACE Significant and won SMILE STOP2 HT Equivalent OPTIMAAL TOMHS ns. Against placebo
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