THUỐC ỨC CHẾ THỤ THỂ ANGIOTENSIN II TRONG NHỒI MÁU CƠ TIM PGS TS VÕ THÀNH NHÂN ĐH Y Dược – BV Chợ Rẫy TPHCM Tiến Trình Bệnh Tim Mạch Là Dải Liên Tục Myocardial Infarction CAD Atherosclerosis CV Risk Factors •Diabetes •Hypertension •Hyperlipidemia •Smoking Loss of contractility Remodeling Ventricular Dilation Congestive Heart Failure End-Stage Heart Disease Death Adapted from Dzau V, Braunwald E Am Heart J 1991 Hệ RAAS Trong Bệnh Tim Mạch : ACEI/ARB Renin-Angiotensin System Angiotensinogen Renin BKR Bradykinin • Vasodilation •  Ischemia •  Platelet agg •  inotrope Renin inhibitors Angiotensin I ACE/ BPF NO Non-Renin •Tonin •Cathepsin Non-ACE •Chymase ACE inhibitors Angiotensin II Inactive Peptides Cross talk AT I • Vasoconstriction • Cell growth • Na+/H2O retention • SNS activation Enzymatic activity Enzymatic blockade Product/receptor stimulation AT II • Vasodilation • Anti proliferation •  Kinins •  NO RAAS MODULATORS: Spironolactone Eplerenone Beta blockers AII Receptor Blocker ACE Inhibitor Blocks formation of AII incompletely ↓ AII effects & aldosterone Blocks AT-1R Blocks Kininase II ↑ Kinins More complete Inhibition of AII effects PROTECTION AT-2R Free Preserve Antiproliferative effect Vai Trò ACEI Trong Dãi Tim Mạch GISSI-3, ISIS-4, SAVE, AIRE TRACE, SMILE SOLVD-P Myocardial Infarction Loss of contractility HOPE EUROPA PEACE HOPE Remodeling SOLVD-T Ventricular Dilation CAD Congestive Heart Failure Atherosclerosis End-Stage Heart Disease CV Risk Factors Diabetes Hypertension Hyperlipidimia Smoking Micro-HOPE PERSUADE Death ALLHAT ANBP2 CONSENSUS Adapted from Dzau V, Braunwald E Am Heart J 1991 Vai Trò ARB Trong Dãi Tim Mạch OPTIMAAL VALIANT ONTARGET TRANSCEND (2007) Myocardial Infarction Remodeling Ventricular Dilation CAD VALHEFT CHARM Congestive Heart Failure Atherosclerosis End-Stage Heart Disease CV Risk Factors Diabetes Hypertension Hyperlipidimia Smoking PRIME RENAAL Loss of contractility Death LIFE VALUE SCOPE Adapted from Dzau V, Braunwald E Am Heart J 1991 Tái Định Dạng Sau Nhồi Máu Cơ Tim: Hoạt Hóa Hệ Renin–Angiotensin Initial infarct Infarct expansion (hours to days) Global remodelling (days to months) Modified from Jessup and Brozena New Engl J Med 2003;348:2007–18 PHÒNG NGỪA THỨ PHÁT  EUROPA  HOPE  PEACE  QUIET TRƯỚC HIỆU QUẢ Thử nghiệm ức chế men chuyển bệnh mạch vành ĐIỀU TRỊ SAU NMCTC  CONSENSUS  SOLVD  AIRE  SAVE  TRACE  GISSI  ISIS  CONSENSUS THỜI GIAN SỬ DỤNG SAU NMCTC AIRE: Acute Infarction Ramipril Efficacy study - TRIAL DESIGN - Design Multicenter, multinational, randomized, double-blind, placebo-controlled Patients 2006 patients, aged >18 years, with evidence of heart failure 3–10 days after MI; patients with severe heart failure (usually NYHA class IV) or ongoing ischemia excluded Follow up and primary endpoint Average 15 months follow up Primary endpoint all-cause mortality Treatment Placebo or ramipril initiated at 2.5 mg twice daily; increased to mg twice daily after days if tolerated Lancet 1993;342:821–8 SAVE: Survival And Ventricular Enlargement study - TRIAL DESIGN - Design Multicenter, randomized, double-blind, placebo-controlled Patients 2231 patients, aged 21–80 years, with left ventricular dysfunction (ejection fraction 12 hours and < 10 days Maximum tolerated dose Stepwise titration Target Doses • Signs or symptoms of CHF or LVD Randomize (N = 14,500) Captopril Captopril 5050 mgmg tid Primary end point: Secondary end points: Other end points: Pfeffer MA et al Am Heart J 2000;140;727-750 Valsartan 160 mg bid C C 50 50mg mgtid tid++ VV80 80mg mgbidbid All-cause mortality CV death, MI, or HF Safety and tolerability 30 VALIANT: Phác đồ liều lượng Randomization 12 hours – 10 days post-MI Captopril (tid) Valsartan (bid) Captopril (tid) + Valsartan (bid) STEP I C 6.25 mg V 20 mg C 6.25 mg V 20 mg STEP II C 12.5 mg V 40 mg C 12.5 mg V 20 mg STEP III C 25 mg V 80 mg C 25 mg V 40 mg STEP IV C 50 mg V 160 mg C 50 mg V 80 mg Step III by discharge Step IV by months 31 VALIANT OPTIMAAL Comparators Valsartan 160 mg bid Captopril 50 mg tid Valsartan 80 mg bid+ captopril 50 mg tid Losartan 50 mg qd Captopril 50 mg tid Endpoint All-cause mortality (event-driven trial) All-cause mortality (event-driven trial) Patients 14,703 with AMI, HF and/or LVD 5,477: AMI and HF; LVEF 65 mm; new ant Q-wave MI/ LBBB; reinfarction and old ant Q waves Age 18 years 50 years Events 2850 ( = 0.15, P = 0.86) 938 ( = 0.20, P = 0.95) Completion 2003 2002 32 Am Heart J 2000;140;727–734 Am J Cardiol 1999;83:477–481 Mortality by Treatment 0.3 Captopril Valsartan Probability of Event 0.25 Valsartan + Captopril 0.2 0.15 0.1 0.05 Valsartan vs Captopril: HR = 1.00; P = 0.982 Valsartan + Captopril vs Captopril: HR = 0.98; P = 0.726 Months Captopril 4909 Valsartan 4909 Valsartan + Cap 4885 4428 4464 4414 12 4241 4272 4265 18 4018 4007 3994 24 2635 2648 2648 30 1432 1437 1435 364 357 382 36 33 Pfeffer, McMurray, Velazquez, et al N Engl J Med 2003;349 VALIANT: TỬ SUẤT VÀ BỆNH SUẤT TIM MẠCH Hazard Ratio (97.5% CI) p noninferiority margin (noninferiority) CV Death 0.001 (1657 events) CV Death or MI 0.00001 CV Death or HF 0.0001 (2234 events) (2661 events) CV Death, MI, or HF 0.000001 (3096 events) Noninferiority not Demonstrated Noninferiority Val Superior to Cap 0.8 Cap Superior to Val Favors Valsartan 1.13 Favors Captopril 1.2 34 VALIANT Patients +/- Beta-blocker Hazard ratios (95% CI) tử vong tim mạch, nhồi máu tim, suy tim Favors Valsartan Favors Captopril p Valsartan vs Captopril: (interaction) No Beta-Blocker (n = 2907) 0.48 Beta-Blocker (n = 6911) Combination vs Captopril: No Beta-Blocker (n = 2910) Beta-Blocker (n = 6882) 0.56 0.5 Pfeffer M et al N Engl J Med 2003;349:1893-906 Favors Combination Favors Captopril 35 Mortality in SAVE, TRACE, AIRE and VALIANT Hazard Ratio for Mortality SAVE TRACE AIRE Combined VALIANT (imputed placebo) 0.5 Favors Active Drug Pfeffer MA et al N Engl J Med 2003;349:1893-1906 Favors Placebo 36 VALIANT: Hazard Ratios (95% CI) tử vong tim mạch, nhồi máu tim, suy tim P-Value (interaction) # of Pts Median Age Sex < 65 ³ 65 Male Female Prior MI No Yes DM No Yes SBP £ median > median Serum £ median Cr > median Killip I Class II III IV BetaNo Blocker Yes Overall 4618 5200 6738 3080 7088 2730 7564 2254 5632 4182 4970 4837 2718 4747 1687 619 2907 6911 0.5 0.96 0.55 0.93 0.12 0.71 0.67 0.84 0.48 Favors Valsartan Favors Captopril Pfeffer, McMurray, Velazquez, et al N Engl J Med 2003;349:1893–1906 # of Pts 4675 5119 6768 3026 7085 2709 7528 2266 5642 4149 4908 4878 2805 4675 1655 618 2910 6882 0.5 Favors Combination1 P-Value (interaction) 1.00 0.47 0.26 0.85 0.68 0.92 0.11 0.56 Favors Captopril37 Các tác dụng phụ gây ngưng điều trị Captopril 3.5 Valsartan Valsartan + Captopril * P < 0.05 Valsartan vs Captopril †P < 0.05 Valsartan + Captopril vs Captopril % of Patients 2.5 † * 1.5 † * * 0.5 * n= Hypotension 201 Renal Causes 154 Hyperkalemia 23 Cough 253 Skin Rash 90 Taste Disturbance 46 Angioedema 34 38 VALIANT: KẾT LUẬN Trên bệnh nhân sau nhồi máu tim có suy tim rối loạn chức thất trái :  Valsartan hiệu captopril việc giảm :  Tử vong Tử vong tim mạch, nhồi máu tim nhập viện suy tim  Valsartan điều trị thay hiệu cho ACEI  Valsartan kết hợp với captopril:  Không làm giảm thêm tử suất  Tăng tác dụng phụ 39 Diovan® ARB Duy Nhất Có Chỉ Định Sau NMCT Và Ở BN Suy Tim Powerful Efficacy in BP Control1 Significantly Reduced CV Mortality in Proven Benefits Beyond BP Control2,3,4 Post-MI Efficacy in Stage Hypertension More than Efficacy in Stage Hypertension 55 Efficacy Trials1 DIOVAN clinical trials program involves more than 55,000 Significantly Reduced HF Hospitalizations in Heart Failure patients Data on file, Novartis Pharmaceuticals Corporation Pfeffer MA et al N Engl J Med 2003;349:1893–1906 Cohn JN et al N Engl J Med 2001;345:1667–1675 Maggioni A et al J Am Coll Cardiol 2002;40:1414–1421 40 Valsartan làm giảm tỉ lệ tái hẹp stent sau đặt stent thường so với ACEi 41 Peters et al Int J Cardiol 2005;98:331-335 KẾT LUẬN ACEI: có vai trò quan trọng điều trị BN sau NMCT cấp ARB: Hiện có Valsartan có chứng có lợi ACEI điều trị BN sau NMCT cấp 42 CÁM ƠN QUÝ ĐỒNG NGHIỆP 43 [...]... double-blind, placebo-controlled, 2 x 2 x 2 factorial study Patients: 58,050 patients hospitalized within 24h of suspected acute MI; patients with cardiogenic shock or persistent severe hypertension excluded Follow up and primary end point: Median 15 months follow up Primary endpoint all-cause mortality Treatment: All patients received three study treatments, each being randomly assigned to active or placebo within... noninferiority margin (noninferiority) CV Death 0.001 (1657 events) CV Death or MI 0.00001 CV Death or HF 0.0001 (2234 events) (2661 events) CV Death, MI, or HF 0.000001 (3096 events) Noninferiority not Demonstrated Noninferiority Val Superior to Cap 0.8 Cap Superior to Val 1 Favors Valsartan 1.13 Favors Captopril 1.2 34 VALIANT Patients +/- Beta-blocker Hazard ratios (95% CI) đối với tử vong do tim... trandolapril Captopril – most extensively studied with survival benefits in both early, short-term and long-term, higher-risk trials 15 ACEI Nào Được Nghiên Cứu Nhiều Nhất ? 140 # of Trial Patients (,000s) 120 100 80 60 40 20 0 Captopril Enalapril Lisinopril Ramipril Other ACEI are not included because of total sample size 16 HIỆU QUẢ CỦA ACEI TRONG NMCTC GISSI Lancet 1994; 343:1115–22 ISIS-4 Collaborative Group... active-controlled mortality trial with 3 parallel treatment groups Eligible Patients (SAVE/AIRE or TRACE eligible) • Acute MI > 12 hours and < 10 days Maximum tolerated dose Stepwise titration Target Doses • Signs or symptoms of CHF or LVD Randomize (N = 14,500) Captopril Captopril 5050 mgmg tid Primary end point: Secondary end points: Other end points: Pfeffer MA et al Am Heart J 2000;140;727-750 Valsartan 160 mg... 0.362 Đột tử hoặc ngưng tim Số lần nhập viện 23 OPTIMAAL: Tử Suất Do Mọi Nguyên Nhân Tử suất trên bn nguy cơ cao sau NMCT cấp 20% 30% Captopril better Dickstein K, et al Lancet 2002; 360:752-60 10% 10% Losartan better 24 Tử Suất Chung 25 losartan (n=499 events) captopril (n=447 events) Event rate (%) 20 15 10 5 0 losartan (n) captopril (n) Relative Risk = 1.13 (0.99 to 1.28); p=0.069 0 6 12 18 Month... nên dùng cho dân số bn này - ACEI vẫn là thuốc lựa chọn hàng đầu cho các bn bị NMCT cấp có biến chứng 26 VALIANT: Valsartan in Treating Post-Myocardial Infarction VALIANT = VALsartan In Acute myocardial iNfarcTion Pfeffer MA et al N Engl J Med 2003;349:1893-1906 27 Qui mô nghiên cứu NC lớn nhất về tính bảo vệ tim trên BN sau NMCT 16,000 14,703 14,000 12,000 10,000 8,000 5,477 6,000 4,000 2,000 2,231 1,986... có tốt hơn hoặc “không kém hơn” so với captopril trong cải thiện thời gian sống thêm  Mức tin cậy 86-95% nhằm phát hiện 15-17.5% giảm nguy cơ tử vong do mọi nguyên nhân  Ngưỡng được xem ‘không kém hơn’ là 1.13 (bảo đảm ít nhất 55% lợi ích sống thêm của thuốc ức chế men chuyển)  Thêm Valsartan vào Captopril có tốt hơn Captopril một mình hay không trong việc cải thiện sống thêm 29 VALIANT: thiết kế... iNfarction Trial 19 OPTIMAAL: Captopril sv Losartan Sau NMCT Cấp > 50 years; acute MI and clinical/radiologic signs of heart failure EF < 35%/LVEDd > 65 mm; new anterior Q waves/LBBB Re-infarction and old anterior Q waves Event-driven (target 937 deaths) ~3 years Captopril 50 mg 3 times daily (n = 2733) Primary end point Secondary end point Other end points Losartan 50 mg daily (n = 2744) All-cause mortality... qd Captopril 50 mg tid Endpoint All-cause mortality (event-driven trial) All-cause mortality (event-driven trial) Patients 14,703 with AMI, HF and/or LVD 5,477: AMI and HF; LVEF 65 mm; new ant Q-wave MI/ LBBB; reinfarction and old ant Q waves Age 18 years 50 years Events 2850 ( = 0.15, P = 0.86) 938 ( = 0.20, P = 0.95) Completion 2003 2002 32 Am Heart J 2000;140;727–734 Am J Cardiol...TRACE: TRandolapril Cardiac Evaluation - TRIAL DESIGN - Design Multicenter, randomized, double-blind, placebo-controlled Patients 1749 patients with left ventricular systolic dysfunction (wall-motion index