Tối Ưu Hóa Điều Trị Tăng Huyết Áp với Thuốc chẹn thụ thể AT1 Liệu Pháp Phối Hợp Thuốc Cùng Viên PGS.TS Phạm Mạnh Hùng Tổng thư ký – Hội Tim Mạch Việt nam Khi cần phối hợp thuốc? • Bệnh nhân có nguy tim mạch cao – Nhiều yếu tố nguy cơ, ĐTĐ – Tiền sử có bệnh tim mạch • Tăng huyết áp (> 160/100) • Huyết áp mục tiêu thấp – ĐTĐ, Bệnh thận mạn, tiền sử Đột quị, Nhồi máu tim • Tất yếu tố Lựa chọn thuốc giảm biến cố tim mạch Mức huyết áp Lựa chọn thuốc kiểm soat huyết áp tốt kéo dài Kiểm soát huyết áp hiệu Giảm nguy Bênh/Nguy tim mạch Phân tầng nguy tim mạch chọn lựa chiến lược điều trị ESC Guidelines 2007 Eur Heart J 2007;28:1462-1536 Remodelling Ventricular ARB có phải “thuốc lý tưởng”? Dilatation Myocardial Infarction Chronic Phối hợp thuốc ARB có phải the “phối Heart hợp Atherosclerosis Failure ưu”, bệnh nhân cần hạ áp thêm? and LVH tối Tiêu chí End-Stage thuốc lý tưởng Phối hợp ARB “Phối hợp tối ưu”? Risk Factors Heart Disease Diabetes Hypertension Hyperlipidemia Dạng Smoking thuốc phối hợp (SPC) “phối hợp tối ưu” ? Death Chiến lược điều trị ?SPC Thuốc Effectively lower BP Lower CV risk ???ARB ESC Guidelines 2007 Eur Heart J 2007;28:1462-1536 Khuyến cáo ESHESC phối hợp thuốc điều trị tăng huyết áp Diuretics Angiotensin receptor blockers (ARBs) b-blockers Lựa chọn thuốc cho bệnh nhân nguy cao? a-blockers Calcium channel blockers (CCBs) Angiotensin-converting enzyme (ACE) inhibitors Preferred combination Less frequently used/ combination used as necessary Task Force of ESH–ESC J Hypertens 2007;25:1105–87 Copyright © 2007, with permission from Lippincott Williams and Wilkins Lợi ích thuốc ức chế men chuyển (ACEi) chuỗi bệnh lý tim mạch khẳng định rõ Remodelling Myocardial Infarction Atherosclerosis and LVH Risk Factors Diabetes Hypertension Ventricular Dilatation Chronic Heart Failure SAVE ,AIRE TRACE,SMILE SOLVD ISIS GISSI HOPE CAPP EUROPA End-Stage Heart Disease and Death CONSENSUS Death Tiêu chí cho thuốc chẹn thụ thể AT1 (ARB) lý tưởng cho bệnh nhân tăng huyết áp có yếu tố nguy cao … Hạ huyết áp hiệu … Remodelling Đã Myocardial Infarction chứng minh Atherosclerosis and LVH Ventricular Dilatation lợi ích lâm sàng chuỗi Chronic bệnh lý tim mạch Heart Failure Ít không thua ACE-I? Risk Factors Diabetes Hypertension Hyperlipidemia Smoking End-Stage Heart Disease Liệu ARB có giống nhau? Death Tỷ lệ ngưng thuốc tác dụng phụ BP Lowering Efficacy Cough ARBs hạ huyết áp tương đương dung nạp tốt ACEi Ann Intern Med 2008;148:16-29 ARBs thuốc có tỷ lệ tuân trị cao Diuretics 1.83 βB 1.64 α-blockers 1.23 CCBs 1.08 ACE-Is 1.00 ARBs 0.92 0.5 - 1.0 + 2.0 Cause-specific HR (95% CI) for discontinuation* * Relative to ACE-I after y of treatment 10 Corrrao et al J Hypertens 2008;26:819–824 Losartan + Amlodipine FDC*: Dose-Finding Study Additional Efficacy Results Mean SBP Reductions at weeks (n=320) Losartan 50 mg 100 mg Amlodipine mg 10 mg Amlo/Losartan FDC* 5/50 mg 5/100 mg Amlo/Losartan FDC* 10/50 mg 10/100 mg Mean change, mm Hg -6 –7 -12 –16 -18 –15.5 -24 –23.6 –24C,D –25.7A,B -30 A C P < 0.0001 vs losartan 50 mg; B P = 0.0229 vs losartan 100 mg; P = 0.0035 vs amlodipine mg; DP –25.9 –28.7 = 0.0092 vs amlodipine mg The change from baseline blood pressure at weeks was P < 0.0001 in each of the treatment arms Data on file, MSD * COZAAR XQ, MSD 48 Losartan + Amlodipine FDC*: Dose-Finding Study Additional Efficacy Results Response Rates FDC vs Monotherapies Amlodipin/Losartan FDC 5/50 mg (n=38) 86.8% p-value vs components Amlodipine mg (n=40) 77.5% p=0.3794 Losartan 50 mg (n=38) 50% p=0.0011 Amlodipin/Losartan FDC 5/100 mg (n=41) 92.7% p-value vs components Amlodipine mg (n=40) 77.5% p=0.0667 Losartan 100 mg (n=40) 72.5% p=0.0201 *The rate of patients who achieved any of the following predefined targets: 1) SBP 10 mm Hg from baseline Data on file, MSD * COZAAR XQ, MSD 49 Losartan + Amlodipine FDC : Dose-Finding Study Safety Profile Results Amlodipine mg Losartan 50 mg Losartan 100 mg FDC Amlo/Losar 5/50 mg FDC Amlo/Losar 5/100 mg (22.5%) (23.7%) (17.5%) (13.2%) (17.1%) 11 11 (27.3%) (18.2) 0 Mild (45.5%) (36.4%) (37.5%) (44.4%) (71.4%) Moderate (36.4%) (63.6%) (62.5%) (33.3%) (28.6%) Severe (18.2%) 0 (22.2%) AEs leading to discontinuation (18.2%) (27.3%) 0 (14.3%) Drug-related AEs (27.3%) (36.4%) (25%) (33.3%) (57.1%) 0 0 Subjects with AEs Number of AEs Number of serious AEs Severity of AEs Deaths Data on file, MSD 50 Losartan + Amlodipine FDC* in Uncontrolled on Losartan 100 mg Study Design  Objective Evaluate the efficacy and safety of Amlodipine/Losartan FDC 5/100 mg vs losartan 100 mg in patients with essential hypertension inadequately controlled on losartan 100 mg  Study Design 8-week, multicenter, randomized, double-blind phase III clinical study Patients (N = 142)  Adults ≥18 years with essential hypertension  Not controlled* on losartan 100 mg monotherapy *siDBP ≥ 90 mm Hg if drug-treated or ≥ 95 mm Hg if drug-naïve Data on file, MSD *COZAAR XQ, MSD weeks randomized, double-blind period 32 days run-in treatment period (losartan 100 mg once daily) Losartan 100 mg (n = 72) once daily Amlo/Losartan FDC 5/100 mg (n = 70) once daily siDBP = sitting diastolic blood pressure siSBP = sitting systolic blood pressure Primary Endpoint Mean change in siDBP at weeks Selected 2nd Endpoints  Mean change in siSBP at weeks  Response** rates  Safety profile **Defined as siSBP10 mm Hg from baseline 51 Losartan + Amlodipine FDC in Uncontrolled on Losartan 100 mg Inclusion and Exclusion Criteria  Selected Inclusion Criteria – Patients 18 years of age or older with essential hypertension (DBP ≥ 90 mm Hg if drug-treated or ≥ 95 mm Hg if drug-naïve) – Non-responders to weeks of treatment with losartan 100 mg monotherapy (sitting DBP≥ 90)  Selected Exclusion Criteria – Secondary hypertension – A difference in sitting systolic BP measurements ≥20 mm Hg or diastolic BP ≥10 mm Hg between the highest and lowest measurements after measurements – Known hypersensitivity to dihydropyridine CCBs or ARBs – Mean sitting SBP ≥ 200 mm Hg or mean sitting DBP ≥ 120 mm Hg at screening and mean siSBP ≥ 180 mm Hg or mean sitting DBP ≥ 120 mm Hg after weeks of losartan potassium 100 mg treatment – Clinically significant renal, metabolic, or hepatic disease – Severe heart disease or severe neurovascular disease – Uncontrolled diabetes mellitus – Pregnant or nursing women Data on file, MSD 52 Losartan + Amlodipine FDC* in Uncontrolled on Losartan 100 mg Mean Reductions in DBP (Primary Endpoint) and SBP Mean BP Reductions at weeks (N=142) Mean DBP Reductions Mean SBP Reductions Amlo/Losartan FDC 5/100 mg Losartan 100 mg Amlo/Losartan FDC 5/100 mg Losartan 100 mg Mean change (mm Hg) -3 –3.2 –3.4 -9 –11.7 –13.4 -15 P < 0.0001 P < 0.0001 Data on file, MSD *COZAAR XQ, MSD 53 Losartan + Amlodipine FDC* in Uncontrolled on Losartan 100 mg Losartan 100 mg Additional Efficacy Results Blood Pressure Response Rates* 100 Amlo/ Losartan FDC P < 0.0008 5/100 mg 80 Patients, % 90% Losartan 100 mg 60 66.7% 40 20 *The rate of patients who achieved any of the following predefined targets: 1) systolic BP 10 mm Hg from baseline Data on file, MSD *COZAAR XQ, MSD 54 Losartan + Amlodipine FDC* in Uncontrolled on Losartan 100 mg Safety Profile Results (After Randomization) Amlo/Losartan FDC 5/100 mg (n=70) Losartan 100 mg (n=72) P value 21 (30.0%) 16 (22.2%) 0.2911 Number of AEs 25 25 Number of serious AEs (1.4%) 0.2306 19 (27.1%) 15 (20.8%) 0.5294 (2.9%) (1.4%) 0 AEs leading to discontinuation (1.4%) 0.4930 Drug-related AEs (7.1%) (12.5%) 0.2844 0 Subjects with AEs Severity of AEs Mild Moderate Severe Deaths Data on file, MSD *COZAAR XQ, MSD 55 Losartan + Amlodipine FDC* in Uncontrolled on Amlodipine mg Study Design  Objective Compared the efficacy and safety of Amlodipine/Losartan FDC 5/50 mg to amlodipine 10 mg in patients with essential hypertension inadequately controlled on amlodipine mg  Study Design 8-week, multicenter, randomized, double-blind phase III clinical study Patients (N = 184) 32 days run-in treatment period (amlodipine camsylate mg daily)  Adults ≥18 years with essential hypertension  Not controlled* on amlodipine mg monotherapy *siDBP ≥ 90 mm Hg if drug-treated or ≥ 95 mm Hg if drug-naïve weeks randomized, double-blind period Amlodipine 10 mg (n = 92) once daily Amlo/Losartan 5/50 mg (n = 92) once daily siDBP = sitting diastolic blood pressure siSBP = sitting systolic blood pressure Primary Endpoint Mean change in siDBP at weeks Selected 2nd Endpoints  Mean change in siSBP at weeks  Response** rates  Safety profile **Defined as siSBP10 mm Hg from baseline Kang S-M et al Clin Ther 2011;33(12):1953-1963 *COZAAR XQ, MSD 56 Losartan + Amlodipine FDC* in Uncontrolled on Amlodipine mg Inclusion and Exclusion Criteria  Selected Inclusion Criteria – Adults aged 18 or older with essential hypertension with uncontrolled essential hypertension [a sitting DBP ≥90 mm Hg in drug-treated patients and ≥95 mm Hg in drug-naïve patients] – Non-responders to weeks of treatment with open-label amlodipine mg monotherapy (DBP ≥90 mm Hg)  Selected Exclusion Criteria – Secondary hypertension – A difference in sitting systolic BP measurements ≥20 mm Hg or diastolic BP ≥10 mm Hg between the highest and lowest measurements after measurements – Known hypersensitivity to dihydropyridine CCBs or ARBs – Mean sitting SBP ≥ 200 mm Hg or mean sitting DBP ≥ 120 mm Hg at screening and mean siSBP ≥ 180 mm Hg or mean sitting DBP ≥ 120 mm Hg after weeks of amlodipine mg treatment – Clinically significant renal, metabolic, or hepatic disease – Severe heart disease or severe neurovascular disease – Uncontrolled diabetes mellitus – Pregnant or nursing women Data on file, MSD Kang S-M et al Clin Ther 2011;33(12):1953-1963 57 Losartan + Amlodipine FDC* in Uncontrolled on Amlodipine mg Mean Reductions in DBP (Primary Endpoint) and SBP Mean BP Reductions at weeks (N=183) Mean DBP Reductions Amlo/Losartan FDC 5/50 mg Amlodipine 10 mg Mean SBP Reductions Amlo/Losartan FDC 5/50 mg Amlodipine 10 mg Mean change (mm Hg) -3 -9 –8.9 –9.4 P = NS –12.2 –13.4 -15 P = NS Kang S-M et al Clin Ther 2011;33(12):1953-1963 *COZAAR XQ, MSD 58 Losartan + Amlodipine FDC* in Uncontrolled on Amlodipine mg Additional Efficacy Results Blood Pressure Response Rates* 100 Amlo/Losartan FDC 5/50 mg P < 07960 Amlodipine 10 mg 80 Patients, % 89.1% 87.9% 60 40 20 *The rate of patients who achieved any of the following predefined targets: 1) systolic BP 10 mm Hg from baseline Kang S-M et al Clin Ther 2011;33(12):1953-1963 59 Losartan + Amlodipine FDC* in Uncontrolled on Amlodipine mg Safety Profile Results Subjects with AEs Number of AEs Number of serious AEs Amlo/Losartan FDC 5/50 mg (n=92) Amlodipine 10 mg (n=92) P value 20 (21.7%) 24 (26.1%) 0.49 38 31 - (1.1%) (1.1%) 1.00 Severity of AEs Mild 0.6907 15 (16.3%) 21 (22.8%) Moderate (3.3%) (2.2%) Severe (2.2%) (1.1%) (2.2%) 0.50 (6.5%) 10 (10.9%) 0.30 0 AEs leading to discontinuation Drug-related AEs Deaths Kang S-M et al Clin Ther 2011;33(12):1953-1963 60 Thuốc chẹn thụ thể AT1 liệu pháp phối hợp thuốc: Kết luận • Cần kiểm soát huyết áp tốt /mục tiêu huyết áp thấp bệnh nhân nguy tim mạch cao ĐTĐ , tiền sử bệnh tim mạch • Liệu pháp phối hơp thuốc ( từ đầu) giúp cho kiểm soát huyết áp tốt bệnh nhân nguy cao • Phối hợp chẹn thụ thể AT1 (ARB)là lựa chọn tối ưu( đặc biệt phối hợp ARB + CCB) • Tiêu chí lựa chọn phối hợp ARB CCB gồm – Dung nạp tốt – Hiệu kiểm soát huyết áp 24h – Đã có chứng minh hiệu bảo vệ tim mạch cac thuốc thành phần phối hợp Làm tối ưu hóa liệu pháp chẹn thụ thể AT1 bệnh nhân tăng huyết áp?: Kết luận Dạng thuốc phối hợp cố định liều bước tiến quản lý tăng huyết áp thập niên vừa qua Phối hợp thuốc viên (SPC) “bước nhảy vọt” điều trị THA thời gian qua:  chiến lược chứng minh làm giảm huyết áp  thông qua chế compliance/persistence  giảm giá thành / nhập viện  giảm biến cố tim mạch !!!!!!