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Role of raas inhibition in management of hypertension

hypertension

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Role of raas inhibition in management of hypertension

  1. 1.    Role of RAAS inhibition Role of RAAS inhibition  in the Management of in the Management of  HypertensionHypertension Dr KyawSoe Win MBBS, M Med Sc (Int Med), MRCPUK, FRCPE, FAsCC, FAPSIC Asso: Prof / Senoir Consultant Cardiologist Department of Cardiovascular Medicine Mandalay General Hospital Hot Topic In Hypertension  2013 12th  January 2013
  2. 2. RAAS:  Central Role in the Pathogenesis  of Cardiovascular Disease 
  3. 3. Ang II effect in target organ damage McFarlane SI et al. Am J Cardiol. 2003;91(suppl):30H-7. Angiotensinogen Angiotensin I Angiotensin II Renin ACE Aldosterone (Adrenal/CV tissues)  Stroke HF Kidney failure ↑BP VSMC Fat cells Reduced  baroreceptor  sensitivity
  4. 4. RAAS: Sites of intervention with RAAS modulators Angiotensinogen Angiotensin I Renin ACE inhibitors Angiotensin-converting enzyme (ACE) Angiotensin II AT1 receptor Angiotensin receptor blockers AT2 receptor Atherosclerosis, hypertension Vascular protection? Adapted from Nickenig G. Circulation. 2004;110:1013-20. Direct renin  inhibitor Aldosterone Aldo antagonist
  5. 5. Atherosclerosis-promoting actions of Ang II and protective effects of bradykinin ↑↑ VasodilationVasodilation ↑↑ ProstacyclinProstacyclin ↑↑ Nitric oxideNitric oxide ↑↑ tPAtPA ↑↑  VasoconstrictionVasoconstriction ↑↑ ICAM-1, VCAM-1ICAM-1, VCAM-1 ↑↑ Growth factorsGrowth factors ↑ Oxyradical formationOxyradical formation ↑ PAI-1PAI-1 ↑ Smooth muscle cellSmooth muscle cell proliferationproliferation ↑ Matrix degradationMatrix degradation Protection againstProtection against the effectsthe effects of Ang IIof Ang II ↑ Endothelial dysfunctionEndothelial dysfunction ↑ InflammationInflammation ↑ CoagulationCoagulation ↑ AtherogenesisAtherogenesis BradykininBradykinin Ang IIAng II Inactive peptidesInactive peptides Ang IAng I -- -- ACE inhibitor Ferrari R. Expert Rev Cardiovasc Ther. 2005;3:15-29.
  6. 6. AT1R blockade upregulates both Ang II levels and AT2R expression Ang I Strauss MH, Hall AS. Circulation. 2006;114:838-54. Ang II AT2 ACE ARB AT1 AT4 Ang I Ang II AT2 ACE ARB AT1 AT4 + Both physiologic and pathologic effects have been proposed  for AT2R stimulation Vasodilation Hypertrophy  Inflammation
  7. 7. Impaired NO synthase Ang II and mechanisms of atherosclerosis Jacoby DS, Rader DJ. Arch Intern Med. 2003;163:1155-64. IL-6 MCP-1 PDGF LOX-1 PAI-1 TF TGF-β VCAM ICAM Angiotensin II Lipid oxidation Thrombosis Inflammation Proliferation fibrosis Adhesion Endothelial dysfunction Endothelial dysfunction
  8. 8. PERTINENT: ACE inhibition ↑ NO via ↑ eNOS activity Ferrari R et al. www.europa-trial.org 0 1 2 3 4 2.5 3.5 2.4 2.9 3.3 Controls n = 45 Placebo n = 44 Placebo n = 44 Perindopril n = 43 Perindopril n = 43 P < 0.01* P < 0.05† Baseline 1 Year eNOS activity in HUVECs (pmol/min/ mg protein) Controls CAD patients * vs baseline † ∆ perindopril vs ∆ placebo PERindopril – Thrombosis, InflammatioN, Endothelial dysfunction and Neurohormonal activation Trial (substudy of EUROPA) HUVEC = human umbilical vein endothelial cell
  9. 9. Schwartzkopff B et al. Hypertension. 2000;36:220-5. 0 200 400 600 800 Periarteriolar collagen  P = 0.04 53% 558 ± 270 260 ± 173 µm2 0 2 4 6 8 Total  interstitial collagen P = 0.04 22% 5.5 ± 3.8 4.3 ± 3.2Vv% Pretreatment (n = 14) Post-treatment* (n = 14) Coronary reserve +67% P = 0.001 Baseline 2.1 3.5Perindopril *Perindopril 4–8 mg for 12 months ACEI normalizes structure of resistance arteries in CAD patients At treatment end (12 mo)
  10. 10. AT1 receptor blockade improves flow-mediated vasodilation 122 Hypertensive patients treated for 2 months *P < 0.05 vs baseline and vs placebo Koh KK et al. Am J Cardiol. 2004;93:1432-5. 0.15 1.14 1.66 1.32 0.0 0.5 1.0 1.5 2.0 Placebo (n = 30) Irbesartan 300 mg (n = 30) Losartan 100 mg (n = 31) Candesartan 16 mg (n = 31) ∆ FMD in brachial artery (%) 2.5 * * *
  11. 11. Inflammation IL-6 MCP-1 PDGF Inflammation Ang II and mechanisms of atherosclerosis Jacoby DS, Rader DJ. Arch Intern Med. 2003;163:1155-64. Impaired NO synthase LOX-1 PAI-1 TF TGF-β VCAM ICAM Lipid oxidation Thrombosis Proliferation fibrosis Endothelial dysfunction Adhesion Angiotensin II
  12. 12. ACE inhibition reduces oxidative stress and inflammation 20 Patients with type 2 diabetes Marketou ME et al. J Am Coll Cardiol. 2005;45 (suppl A):396A. Baseline Perindopril 4 mg x 6 mos * P < 0.05 vs baseline TNF-α IL-6Lipid peroxides 3.3 2.0 0 1 2 3 4 2.9 1.8 370 264 0 100 200 300 400 µmol/L pg/mL * * *
  13. 13. LOX-1 VCAM ICAM Jacoby DS, Rader DJ. Arch Intern Med. 2003;163:1155-64. Ang II and mechanisms of atherosclerosis IL-6 MCP-1 PDGF Impaired NO synthase PAI-1 TF TGF-β Thrombosis Inflammation Proliferation fibrosis Endothelial dysfunction Angiotensin II Lipid oxidationLipid oxidation AdhesionAdhesion
  14. 14. Ang II upregulates LOX-1 expression via lipoxygenase pathway * P < 0.0001 vs control † P < 0.0001 vs Ang II ‡ P < 0.05 vs Ang II Bai = baicalein (12-lipoxygenase inhibitor) Human vascular smooth muscle cells Limor R et al. Am J Hypertens. 2005;18:299-307. Ang II 10-7 mol/L+ losartan 10-5 mol/L 0 100 200 300 Control Ang II 10-7 mol/L Ang II 10-7 mol/L+ Bai 10-5 mol/L LOX-1 mRNA * † ‡ 400
  15. 15. TGF-β Jacoby DS, Rader DJ. Arch Intern Med. 2003;163:1155-64. Ang II and mechanisms of atherosclerosis IL-6 MCP-1 PDGF Impaired NO synthase LOX-1 PAI-1 TF VCAM ICAM Angiotensin II Lipid oxidation Thrombosis Inflammation Endothelial dysfunction Adhesion ProliferationProliferation fibrosis
  16. 16. HOPE: Dose-dependent effects of ramipril on LV mass and function 5.31 2.9 –1.9–3 0 2 4 68.21 7.86 –3.53–4 0 5 10 LV end-systolic volumeLV mass Lonn E et al. J Am Coll Cardiol. 2004;43:2200-6.Mean baseline LVEF 58%, all groups ∆ (mL) ∆ (g) PTrend = 0.001 PTrend = 0.03 N = 446 follow-up, 4 years Placebo Ramipril 2.5 mg Ramipril 10 mg
  17. 17. LIFE: Greater reduction in LV mass  with angiotensin receptor blockade  vs beta-blockade Devereux RB et al. Circulation. 2004;110:1456-62. Patients with hypertension and LVH Change in LV mass (g) –50 –20 Year –10 0 Losartan 50–100 mg (n = 457) Atenolol 50–100 mg (n = 459) –30 –40 1 2 3 4 5 Last visit P = 0.009 for all time points
  18. 18. PAI-1 TF Jacoby DS, Rader DJ. Arch Intern Med. 2003;163:1155-64. Ang II and mechanisms of atherosclerosis IL-6 MCP-1 PDGF Impaired NO synthase LOX-1 TGF-β VCAM ICAM Angiotensin II Lipid oxidation Inflammation Proliferation fibrosis Endothelial dysfunction AdhesionThrombosisThrombosis
  19. 19. Brown NJ et al. Hypertension. 2002;40:859-65.P = 0.043, drug × time interaction ACE inhibition (ramipril) AT1 receptor blockade (losartan) 10 0 –10 20 Week 1 –20 ∆ PAI-1 antigen (ng/mL) 30 Week 3 Week 4 Sustained decrease in PAI-1 antigen over time with ACEI vs ARB Week 6
  20. 20. Greater decrease in PAI-1 over time with ACEI vs ARB 85 Hypertensive diabetic patients treated for 12 weeks Fogari R et al. Am J Hypertens. 2002;15:316-20. 10 –10 5 0 –5 Losartan 50 mg 4 Perindopril 4 mg –10 P < 0.01 *P = 0.028 perindopril vs placebo ∆ PAI-1 ng/dL *
  21. 21. Change in PAI-1 antigen levels:  Differing effects of ARBs Koh KK et al. Atherosclerosis. 2004;177:155-60. % Change –40 20 40 60 Placebo 80 –20 0 Irbesartan 300 mg Losartan 100 mg Candesartan 16 mg P < 0.01 P = 0.012 P = 0.163 126 Patients with hypertension
  22. 22. Pretorius M et al. Circulation. 2003;107:579-85. *P < 0.05 vs baseline †P < 0.05 vs vehicle or baseline ‡P < 0.05 vs enalaprilat + vehicle HOE 140 = bradykinin B2 receptor antagonist Greater effect in women vs men Women (n = 7) Men (n = 5) Baseline ‡ HOE 140 + Enalaprilat HOE 140 2 1 0 3 Net tPA release (ng/min/ 100 mL) 2 1 0 Baseline *† Vehicle + Enalaprilat Vehicle 3 ACEI increases tPA release through endogenous bradykinin
  23. 23. tPA release: Differing effects of ACE inhibition vs AT1 receptor blockade Matsumoto T et al. J Am Coll Cardiol. 2003;41:1373-9.*P < 0.05 vs baseline 20 10 15 5 0.2 0 0 0.6 2.0 tPA antigen in coronary sinus (ng/mL) Bradykinin (µg/min) Perindopril 4 mg (n = 16) Losartan 50 mg (n = 15) Control (n = 14) P < 0.05 * * * * * * * 25
  24. 24. Antiatherosclerotic effect of RAAS modulation: Clinical and experimental evidence • Studies in several animal models of  atherosclerosis demonstrated reduced lesion  progression with ACE inhibitor or AT1 receptor  blocker1 • Regression of human carotid plaque demonstrated  with ramipril (SECURE2 ), losartan (LAARS3 ), and  fosinopril (PHYLLIS4 ) 1 Jacoby DS, Rader DJ. Arch Intern Med. 2003;163:1155-64. 2 Lonn E et al. Circulation. 2001:103;919-25. 3 Ludwig M et al. Clin Ther. 2002;24:1175-93. 4 Zanchetti A et al. Stroke. 2004;35:2807-12.
  25. 25. Lonn EM et al. Circulation. 2001;103:919-25. 0 0.005 0.010 0.015 0.020 0.025 Ramipril 10 mg Ramipril 2.5 mg Placebo 0.022 0.018 0.014 NS 37% Reduction P = 0.028 Mean maximum IMT slope (mm/y) SECURE  ACEI reduces atherosclerosis progression
  26. 26. ARB blunts MMP expression in human carotid plaques: Potential role in plaque stabilization 25.8 28.2 25.1 22.4 5.8 6.2 7.2 5.6 0 10 20 30 MMP-2 MMP-9 COX-2 mPGES-1 P < 0.0001 all comparisons ARB = AT1 receptor blockade MMP = matrix metalloproteinase % Positive staining Chlorthalidone Irbesartan Cipollone F et al. Circulation. 2004;109:1482-8. Carotid endarterectomy specimens
  27. 27. Role of RAAS Modulation: Evidence from Clinical Trials • CAD • Heart Failure
  28. 28. ACEIs: Evolution of benefits BP reduction Cardioprotection Improved glycemic control (?) Vascular protection Lonn E et al. Eur Heart J Suppl. 2003;5(suppl A):A43-8. DREAM Trial Investigators. N Engl J Med. 2006;355:1551-62. Renal protection
  29. 29. Benefit of ACE inhibition in CADBenefit of ACE inhibition in CAD EUROPA HOPE All CAD patientsAll CAD patients Post-MI, HF, LVEF <40% SOLVD SAVE AIRE TRACE SOLVD (prev) High risk Bertrand ME. Curr Med Res Opin. 2004;20:1559-69.
  30. 30. ACEI trials in CAD without HF: Primary outcomes HOPE Study Investigators. N Engl J Med. 2000;342:145-53. Pitt B et al. Am J Cardiol. 2001;87:1058-63. PEACE CV death/MI/CABG/PCI HOPE CV death/MI/stroke 15 5 10 0 20 0 Placebo Ramipril 10 mg Time (years) % 2 41 22% Risk reduction HR 0.78 (0.70–0.86) P < 0.001 3 Time (years) 12 4 10 0 1 3 4 14 0 Placebo Perindopril 8 mg 8 6 2 52 EUROPA CV death/MI/cardiac arrest 20% Risk reduction HR 0.80 (0.71–0.91) P = 0.0003 40 20 30 0 50 0 Placebo Quinapril 20 mg Time (years) 1 4% Risk increase HR 1.04 (0.89–1.22) P = 0.6 10 2 3 QUIET All CV events Time (years) Trandolapril 4 mg Placebo 30 20 10 15 5 1 2 3 4 5 25 0 6 4% Risk reduction HR 0.96 (0.88–1.06) P = 0.43 EUROPA Investigators. Lancet. 2003;362:782-8. PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68. % % %
  31. 31. HOPE EUROPA PEACE QUIET Antiplatelet agents (%) 76 92 91 73 β-Blockers (%) 40 62 60 26 Lipid-lowering agents (%) 29/49* 58/68† 70 0/14* Calcium antagonists (%) 47 32 36 0/7* Diuretics (%) 15 10 13 NA EUROPA Investigators. Lancet. 2003;362:782-8. HOPE Study Investigators. N Engl J Med. 2000;342:145-53. PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68. Pitt B et al. Am J Cardiol. 2001;87:1058-63. * at study end † at 3 yrs ACEI outcome trials in CAD patients  without HF: CV therapies at entry/during study 
  32. 32.  ACE inhibitor Key inclusion criteria    Primary          outcome EUROPA N = 12,218 (4.2 years) Perindopril 8 mg CAD No heart failure Age ≥18 years CV death, MI, cardiac arrest PEACE N = 8290 (4.8 years) Trandolapril 4 mg CAD LVEF ≥40% Age ≥50 years CV death, MI, coronary revascularization QUIET N = 1750 (2.25 years) Quinapril 20 mg PTCA, atherectomy Normal LVEF CV death, MI, coronary revasc, cardiac arrest, hosp for angina EUROPA Investigators. Lancet. 2003;362:782-8. HOPE Study Investigators. N Engl J Med. 2000;342:145-53. PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68. Pitt B et al. Am J Cardiol. 2001;87:1058-63. ACEI outcome trials in CAD patients without HF HOPE N = 9297 (4.5 years) Ramipril 10 mg Vascular disease (80% had CAD) LVEF ≥40%, or No heart failure Age ≥55 years CV death, MI, stroke
  33. 33. ACEI outcome trials in CAD patients without HF: Totality of trial evidence MI Stroke All-cause death Event rate (%) Favors ACEIACEI Revascularization Favors placeboPlacebo 7.5 6.4 2.1 15.5 8.9 7.7 2.7 16.3 0.86 0.86 0.77 0.93 0.0004 0.0004 0.0004 0.025 0.5 0.75 1.251 Odds ratio P Pepine CJ, Probstfield JL. Vasc Bio Clin Pract. CME Monograph; UF College of Medicine. 2004;6(3). HOPE, EUROPA, PEACE, QUIET
  34. 34. HOPE, EUROPA, PEACE: Benefit of ACEIs across broad spectrum of risk Dagenais GR et al. Lancet. 2006;368:581-8. Trial Patients (n) Annual rates in placebo groups OR (95% CI) P -5 20 405 3015 35 Odds reduction (%) 25100 PEACE 8290 2.13 7 (-8 to 19) 0.328 HOPE total 9297 3.95 25 (16 to 32) 0.0001 HOPE lower risk 3083 2.17 18 (-4 to 35) HOPE med risk 3100 3.58 20 (3 to 33) HOPE high risk 3114 5.98 24 (12 to 34) EUROPA total 12,218 2.60 19 (8 to 28) 0.0007 EUROPA lower risk 3976 1.40 19 (-5 to 38) EUROPA med risk 3975 2.41 28 (11 to 41) EUROPA high risk 3975 4.00 10 (-4 to 22) AIRE 1986 22.6 24 (7 to 38) 0.0068 TRACE 1749 17.0 25 (9 to 33) 0.0028 SOLVD-P 4228 7.4 15 (2 to 27) 0.0252 SOLVD-T 2569 13.1 23 (10 to 33) 0.0009 SAVE 2231 9.8 20 (4 to 33) 0.0168 CV death,* nonfatal MI or stroke ACEI worse ACEI better *Or total mortality in AIRE, TRACE, SOLVD, SAVE trials
  35. 35. HOPE Study Investigators. N Engl J Med. 2000;342:145-53. EUROPA Investigators. Lancet. 2003;362:782-8. PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68. Pitt B et al. Am J Cardiol. 2001;87:1058-63. ACEI outcome trials in CAD patients without HF: Differences in baseline CV risk HOPE EUROPA PEACE Annualized event rate in placebo group (%/yr) CV death Nonfatal MI QUIET 1.8 1.0 0.8 0.7 2.7 1.5 1.1 2.0 0.0 1.0 2.0 3.0
  36. 36. EUROPA: EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease EUROPA Investigators. Lancet. 2003;362:782-8. Objective: Assess effects of the ACEI perindopril on CV risk in a broad-spectrum population with stable CAD and without HF Design: N = 12,218, age ≥18 years, with CAD/without HF at randomization Treatment: Perindopril 8 mg or placebo Follow-up: 4.2 years Primary outcome: CV death, nonfatal MI, cardiac arrest
  37. 37. EUROPA: Baseline characteristics EUROPA Investigators. Lancet. 2003;362:782-8. Female History of CAD – MI – PCI – CABG Documented CAD – Angiographic evidence (stenosis >70% ) 14.5 100 64.9 29.0 29.3 60.4 14.7 100 64.7 29.5 29.4 60.5 – Positive stress test (in men w/chest pain) History of stroke/TIA PVD Hypertension Diabetes Hypercholesterolemia 22.6 3.4 7.1 27.0 11.8 63.3 23.3 3.3 7.4 27.2 12.8 63.3 Placebo (%) (n = 6108) Perindopril (%) (n = 6110)
  38. 38. EUROPA: Concomitant medications Platelet inhibitors Beta-blockers Lipid-lowering agents Nitrates Calcium channel blockers Diuretics 92 62 58 43 32 9 91 63 69 NA NA NA EUROPA Investigators. Lancet. 2003;362:782-8. Baseline (%) 3 Years (%)* *Concomitant medications recorded in 11,547 patients
  39. 39. EUROPA Investigators. Lancet. 2003;362:782-8. Fox KM. Br J Cardiol. 2004;11:195-204. EUROPA: Primary outcome 12 4 10 0 1 3 4 14 0 Placebo Perindopril 8 mg8 6 2 52 Primary outcome (%) Time (years) 10% 11% 14% 20% CV death, MI, cardiac arrest RRR 20% (95% CI: 9%–29%) AR 8.0% vs 9.9% P = 0.0003 P < 0.05 P = 0.35 AR = absolute risk (perindopril vs placebo)
  40. 40. RRR 24% AR 5.2% vs 6.8% P < 0.001 EUROPA Investigators. Lancet. 2003;362:782–8. Fatal and nonfatal MI RRR 39% AR 1.0% vs 1.7% P = 0.002 2 4 Events (%) 0 10 6 8 0 1 2 3 4 5 Years Placebo Perindopril 8 mg 0.5 1.0 0.0 2.0 1.5 0 1 2 3 4 5 Years Placebo Perindopril 8 mg HF hospitalization EUROPA: Effect of ACEI on fatal/nonfatal MI and HF hospitalizations AR = absolute risk (perindopril vs placebo)
  41. 41. EUROPA Investigators. Lancet. 2003;362:782-8. 8.0 14.8 7.9 6.1 3.5 5.2 CV mortality, MI, cardiac arrest Total mortality, MI, UA, cardiac arrest CV mortality, MI Total mortality CV mortality Fatal/nonfatal MI Favors perindopril Favors placebo Perindopril (%) (n = 6110) Placebo (%) (n = 6108) 9.9 17.1 9.8 6.9 4.1 6.8 0.5 1.0 2.0 EUROPA: Benefit of ACEI on primary and secondary outcomes N = 12,218
  42. 42. EUROPA Investigators. Lancet. 2003;362:782-8. 5.6 0.1 1.6 9.4 1.0 Unstable angina Cardiac arrest Stroke Revascularization HF w/hospital admission Favors perindopril Favors placebo Perindopril (%) (n = 6110) Placebo (%) (n = 6108) 6.0 0.2 1.7 9.8 1.7 0.5 1.0 2.0 EUROPA: Benefit of ACEI on selected secondary outcomes N = 12,218
  43. 43. EUROPA: Benefit of perindopril was on top of recommended medications EUROPA Investigators. Lancet. 2003;362:782-8. 7.0 9.3 7.6 8.7 9.9 7.1 0.5 1.0 2.0 8.3 11.9 10.2 9.4 11.7 9.0 Lipid-lowering drug No lipid-lowering drug β-blockers No β-blockers Calcium channel blockers No calcium channel blockers Favors perindopril Favors placeboPerindopril (n = 6110) Placebo (n = 6108) Primary events (%)
  44. 44. EUROPA HOPE Age, mean (yrs) 60 66 BP (mm Hg) 137/82 139/79 Known CAD (%) MI (%) PVD (%) Stroke/TIA (%) Revascularization (%) Diabetes (%) Hypertension (%) Hypercholesterolemia (%) 100 65 7 3 58 12 27 63 80 53 43 11 44 39 47 66 EUROPA Investigators. Lancet. 2003;362:782-8. HOPE Study Investigators. N Engl J Med. 2000;342:145-53. EUROPA vs HOPE: Study populations
  45. 45. EUROPA vs HOPE: Inclusion criteria HOPE • Age ≥55 years • Females: 27% • No HF or LV dysfunction • High-risk of CV events with history of – CAD, stroke, or peripheral vascular disease – Diabetes + ≥1 CV risk factor (hypertension, dyslipidemia, smoking, microalbuminuria) EUROPA • Age ≥18 years • Females: 15% • No clinical HF • Documented CAD including – Previous MI, PCI/CABG – Angiographic evidence of CAD with/without previous coronary event – Positive stress test (men) EUROPA Investigators. Lancet. 2003;362:782-8. HOPE Study Investigators. N Engl J Med. 2000;342:145-53. HOPE patients were at higher risk than EUROPAHOPE patients were at higher risk than EUROPA
  46. 46. EUROPA vs HOPE: Event rates in placebo groups reflect differences in baseline risk 80% higher annual rate of CV and total mortality in HOPE80% higher annual rate of CV and total mortality in HOPE EUROPA Investigators. Lancet. 2003;362:782-8. HOPE Study Investigators. N Engl J Med. 2000;342:145-53. CV mortality Total mortality Annualized event rate in placebo groups (%) HOPEEUROPA 1.8 2.7 1.0 1.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0
  47. 47. Are all ACEIs the same: Survival post-MI by ACEI at discharge P < 0.001 log-rank 100 90 80 70 121086420 Months Captopril Ramipril Quinapril Fosinopril Lisinopril Enalapril Perindopril Unadjusted cumulative survival (%) N = 7512 Pilote L et al. Ann Intern Med. 2004;141:102-12. n = 421 n = 905 n = 276 n = 889 n = 2201 n = 2577 n = 243
  48. 48. Factors that may lead to divergent results in ACEI trials • Underdosing – Dose-related effects on vascular and myocardial tissue – Dose for CAD patients can’t be predicted from studies in HF or hypertension • Differences may exist among ACEIs • Differences in baseline risk (age, diabetes, HTN, PAD) • Inclusion of revascularization in primary outcome • Lack of power • Poor adherence to assigned treatment Pitt B et al. Am J Cardiol. 2004;87:1058-63. Yusuf S, Pogue J. N Engl J Med. 2005;352:937-8. Pitt B. N Engl J Med. 2004;351:2115-7. Pepine CJ, Probstfield JL. Vasc Bio Clin Pract. CME Monograph; UF College of Medicine. 2004;6(3).
  49. 49. • Cumulative evidence supports ACE inhibitors for stable CAD patients with/without clinical signs of HF • Not all ACE inhibitors can be assumed to have comparable effects for all indications – Dose and individual properties of ACEIs are important • Benefit may depend on risk level – Benefit may be less in patients with well controlled risk factors • Randomized clinical trial evidence and guidelines should guide selection of effective ACE inhibitor and dose for CAD patients without HF Pitt B. N Engl J Med. 2004;351:2115-7. ACEI outcome trials in CAD patients without HF: Clinical implications
  50. 50. • Totality of clinical trial evidence supports ACEI for treatment of stable CAD patients with/without HF • Benefits have been shown in patients at all levels of risk • All ACEIs may not have comparable effects for all indications • Consider evidence and guidelines in selection of an ACEI and dose. • Both ramipril and perindopril reduce risk of CV events in stable CAD patients without HF – Ramipril 10 mg has proven efficacy in CAD patients ≥55 yrs – Perindopril 8 mg has proven efficacy in CAD patients ≥18 yrs Pitt B. N Engl J Med. 2004;351:2115-7. EUROPA Investigators. Lancet. 2003;362:782-8. HOPE Study Investigators. N Engl J Med. 2000;342:145-53. PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68. Should all patients with stable CAD without HF receive an ACEI? Interpreting evidence
  51. 51. Evidence-based medicine: Updated guide-lines for ACEI in CAD patients without HF “ACE inhibitors should be used as routine secondary prevention for patients with known CAD, particularly in diabetics without severe renal disease.” . . . R.J. Gibbons et al. “The HOPE trial…confirms that the ACE inhibitor ramipril reduced CV death, MI, and stroke in patients who were at high risk for, or had, vascular disease in the absence of heart failure.” . . . R.J. Gibbons et al. EUROPA “showed that an ACE inhibitor can have a vasculoprotective effect in patients at lower risk than those enrolled in the HOPE study.” . . . V. Snow et al. Gibbons RJ et al. 2002 ACC/AHA Practice Guidelines. www.acc.org; July 2005. Snow V et al. Ann Intern Med. 2004;141:562-7.
  52. 52. Role of RAAS Modulation in CAD Patients with heart failure
  53. 53. ACE inhibition in CAD: Short-term trials in acute MI Odds ratio (95% CI) 220/3044 (7.23%) 570/9682 (5.89%) 2035/29,028 (7.01%) 676/7460 (9.06%) CONSENSUS-II* Test for Heterogeneity: χ2 5.8 (2p = 0.1) df = 3 Deaths (n)/Randomized (n) GISSI-3 ISIS-4 CCS-1 Total Control O-E Variance 1.0 1.25 1.50.750.5 727/7489 (9.71%) 650/9712 (6.69%) 192/3046 (6.30%) 2171/29,022 (7.48%) 3501/49,214 (7.11%) 3740/49,269 (7.59%) 14.07 –39.06 –68.22 –24.14 –117.35 96.05 285.83 975.33 317.85 1675.06 ACEI ACEI better Control better Odds reduction (± SD) 7 ± 2 Treat Eff: χ2 (2p = 0.004) ACE Inhibitor MI Collaborative Group. Circulation. 1998;97:2202-12.*IV infusion followed by oral therapy
  54. 54. ACE inhibition in CAD: Long-term trials in post-MI LV dysfunction and HF AIRE Study Investigators. Lancet. 1993;342:821-8. Køber L et al. N Engl J Med. 1995;333:1670-6. SOLVD Investigators. N Engl J Med. 1991;325:293-302. SOLVD Investigators. N Engl J Med. 1992;327:685-91. Pfeffer MA et al. N Engl J Med. 1992;327:669-77. AIRE TRACE SOLVD (Treatment) SAVE 0.002 0.001 0.0036 0.019 0 5 10 15 20 25 Risk reduction in total mortality (%) P 30 SOLVD (Prevention) 0.30 27% 22% 8% 16% 19%
  55. 55. Aldosterone blockade and AT1 receptor blockade: Trials in post-MI/LV dysfunction or HF Pitt B et al. N Eng J Med. 1999;341:709-17. Pitt B et al. N Eng J Med. 2003;348:1309-21. Pitt B et al. N Eng J Med. 2003;349:1893-906. VALIANT Months Captopril Valsartan 0.4 0.1 0.2 6 12 24 30 36 0.3 0.0 Probability of event 0% RR V vs C HR 1.00 (0.90–1.11) P = 0.98 RALES 0.75 0.60 1.00 0 Placebo Spironolactone Months Probability of survival 24 366 30% Risk reduction RR 0.70 (0.60–0.82) P < 0.001 30 0.00 12 18 0.90 0.45 180 Valsartan/captopril 22 10 2 6 24 300 Eplerenone Months 18 14 6 3612 EPHESUS 15% Risk reduction RR 0.85 (0.75–0.96) P = 0.008 Cumulative incidence (%) Placebo 0 18 2% RR V/C vs C HR 0.98 (0.89–1.09) P = 0.73)
  56. 56. EPHESUS: New subgroup analysis Pitt B et al. Am J Cardiol. 2006;97(suppl):26F-33F. N = 6632 with post-MI LVSD, mean follow-up 16 months Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study History of hypertension All-cause mortality CV mortality/hospitalization Sudden cardiac death History of diabetes All-cause mortality CV mortality/hospitalization Sudden cardiac death LVEF ≤30% All-cause mortality CV mortality/hospitalization Sudden cardiac death P 0.001 0.002 0.022 0.127 0.03 0.641 0.012 0.001 0.01 0.2 1.0 1.2 1.8 Eplerenone better Placebo better 1.4 1.60.4 0.6 0.8 Odds ratio (95% Cl)
  57. 57. Greenberg B et al. Am J Cardiol. 2006;97(suppl):34F-40F. EMPHASIS-HF: Study design Eplerenone + standard therapy N = 2584 with NYHA class II chronic systolic HF Results in 2010 Placebo + standard therapy Primary end point: CV death, hosp for HF Follow-up: 4 years Effect of Eplerenone in Chronic Systolic Heart Failure
  58. 58. EMPHASIS-HF: Major results EMPHASIS-HF Outcome Eplerenone (%) Placebo (%) Adjusted hazard ratio (95% CI) p Cardiovascular death/heart-failure hospitalization 18.3 25.9 0.63 (0.54–0.74) <0.001 Cardiovascular death 10.8 13.5 0.76 (0.61–0.94) 0.01 Heart-failure hospitalization 12.0 18.4 0.58 (0.47–0.70) <0.001 Hospitalization for hyperkalemia 0.3 0.2 1.15 (0.25–5.31) 0.85 NYHA Class II HF (N=2737) LV EF < 30% Eplerenone 25-50mg QD vs. Placebo
  59. 59. Greenberg B et al. Am J Cardiol. 2006;97(suppl):34F-40F. TOPCAT: Study design Spironolactone N ≅ 4500 with HF and LVEF >45% Results anticipated 2011 Placebo Primary end point: CV death, hosp for HF Follow-up: ≥2 years Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Enrollment: 3445 Study Start Date: August 2006 Estimated Study Completion Date: June 2013 Estimated Primary Completion Date: June 2013
  60. 60. RAAS Modulation in Patients With Diabetes
  61. 61. Potential role of RAAS activation in metabolic syndrome and diabetes Adapted from Henriksen EJ, Jacob S. J Cell Physiol. 2003;196:171-9. Paul M et al. Physiol Rev. 2006;86:747-803. RAAS activation Skeletal muscle Pancreatic β cells ↑MetS ↑T2DM MetS = metabolic syndrome T2DM = type 2 diabetes Obesity
  62. 62. RAAS activation in obesity Engeli S et al. Hypertension. 2005;45:356-62. Circulating RAAS, N = 38 menopausal women *P < 0.05 Renin (ng/l) ACE (U/l) Aldosterone (ng/l) Ang II (nmol/l) Lean Obese 0 3 6 12 9 0 15 30 60 45 0 90 0.00 0.05 0.10 30 60 Lean Obese Lean Obese Lean Obese * * *
  63. 63. Obesity Volume expansion Arterial hypertension Sharma AM. Hypertension. 2004;44:12-19. ↑LeptinRenal medullary compression ↑RAAS activation Sodium reabsorption Renal vasodilation ↑SNS activation SNS = sympathetic nervous system RAAS activation contributes to obesity-related hypertension
  64. 64. Adipocyte and vasculature interactionsAdipocyte and vasculature interactions Courtesy of W. Hseuh; 2005. IL-6 PAI-1 TNF-α Adiponectin Leptin Insulin sensitivity Insulin resistance Vascular inflammation Endothelial dysfunction Angiotensinogen FFA Visfatin
  65. 65. Furuhashi M et al. Hypertension. 2003;42:76-81. • Insulin sensitivity, BMI, and HDL-C independent determinants of adiponectin concentrations • ACEI and ARB increased insulin sensitivity and adiponectin (P < 0.05) • Changes in insulin sensitivity correlated with changes in adiponectin (r = 0.59, P < 0.05) *P < 0.05 N = 16 with essential hypertension and insulin resistance RAAS blockade increases adiponectin 6 4 10 Adiponectin (µg/mL) 0 8 2 Before After Before After 6 4 10 0 8 2 Temocapril 4 mg (n = 9) Candesartan 8 mg (n = 7) * *
  66. 66. ACEIs: Potential mechanisms of improved glucose metabolism Henriksen EJ, Jacob S. J Cell Physiol. 2003;196:171-9. Angiotensin I ACE/Kininase II Degradation products ↑Nitric oxide Angiotensin II ↓Angiotensin II ACE inhibitors Bradykinin ↑Bradykinin ↑Skeletal muscle blood flow ↑Glucose metabolism
  67. 67. Effect of ACEIs and ARBs on new-onset diabetes Abuissa H et al. J Am Coll Cardiol. 2005;46:821-6. Meta-analysis of 12 randomized controlled trials CAPPP STOP-2 HOPE LIFE ALLHAT ANBP2 SCOPE ALPINE CHARM SOLVD VALUE PEACE All pooled ACEI pooled ARB pooled 0.79 (0.67–0.94) 0.96 (0.72–1.27) 0.66 (0.51–0.85) 0.75 (0.63–0.88) 0.70 (0.56–0.86) 0.66 (0.54–0.85) 0.81 (0.61–1.02) 0.13 (0.03–0.99) 0.78 (0.64–0.96) 0.26 (0.13–0.53) 0.77 (0.69–0.86) 0.83 (0.72–0.96) 0.75 (0.69–0.82) 0.73 (0.63–0.84) 0.77 (0.71–0.83) 0.125 0.25 0.5 1 2 4 8 Less likely to develop T2DM Relative risk (95% CI) More likely to develop T2DM
  68. 68. HOPE, EUROPA, PEACE: Reduction in new- onset diabetes (placebo-controlled trials) 0 2 4 6 8 10 12 14 HOPE EUROPA PEACE Pooled data New-onset diabetes (%) Placebo ACEI Dagenais GR et al. Lancet. 2006;368:581-8. n = 23,340 free from diabetes* at baseline Ramipril 10 mg Perindopril 8 mg Trandolapril 4 mg Overall 14% RRR RR 0.86 (0.78–0.95) P = 0.0023 (all trials) *Not a prespecified end point
  69. 69. PERSUADE: PERindorpil SUbstudy of coronary Artery disease and DiabEtes: The diabetic substudy of EUROPA Objective: Investigate the effect of long-term treatment with perindopril added to standard therapy on CV events in diabetic patients with CAD and without heart failure Population: N = 1502 with known diabetes at randomization Treatment: Perindopril 8 mg (n = 721) or placebo (n = 781) Follow-up: 4.2 years Daly CA et al. Eur Heart J. 2005;26:1369-78.
  70. 70. PERSUADE: Primary outcome Cumulative frequency (%) Perindopril 8 mg Placebo 2 3 4 510 Years from randomization 0 4 8 12 16 20 RRR: 19% 95% CI: –7% to 38% P = 0.13 CV death, MI, cardiac arrest Daly CA et al. Eur Heart J. 2005;26:1369-78.
  71. 71. PERSUADE: Clinical implications • Perindopril 8 mg once daily reduced CV events in patients with CAD and diabetes • Relative risk reduction in primary and secondary outcomes with perindopril was similar to EUROPA • Results extend the benefit of ACEI shown in MICRO- HOPE to a lower-risk population with diabetes and CAD Daly CA et al. Eur Heart J. 2005;26:1369-78.
  72. 72. HOPE Study Investigators. Lancet. 2000;355:253-9. 3.0 2.5 2.0 1.5 1.0 0.5 0 1 2 3 4.5 Placebo Ramipril 10 mg Mean albumin- creatinine ratio Years P = 0.001 P = 0.02 0 10 20 30 40 Overt nephro- pathy CV deathStrokeMI Risk reduction (%) P = 0.027 P = 0.0001 P = 0.007 P = 0.01 22 33 37 24 N = 3577 (32% with microalbuminuria) MICRO-HOPE: ACEI improves renal and CV outcomes in type 2 diabetes
  73. 73. HOPE Study Investigators. Lancet. 2000;355:253-9. Daly CA et al. Eur Heart J. 2005. In press. PERSUADE (N = 1502) CV death/MI/cardiac arrest MICRO-HOPE (N = 3577) CV death/MI/stroke MICRO-HOPE, PERSUADE: Primary outcome Placebo Ramipril 10 mg 25 20 15 10 5 0 % Follow-up (years) 0 1 2 3 4 5 25% Risk reduction RR 0.75 (0.64–0.88) P = 0.0004 20 15 10 5 0 0 1 2 3 4 5 Follow-up (years) Placebo Perindopril 8 mg 19% Risk reduction P = 0.131 25
  74. 74. MICRO-HOPE, PERSUADE: Consistency of benefit HOPE Study Investigators. Lancet. 2000;355:253-9. Daly CA et al. Eur Heart J. 2005. In press. Primary outcome Total mortality CV mortality All MI Stroke 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 Favors ACEI Favors placebo Relative risk (95% CI) MICRO-HOPE (N = 3577) PERSUADE (N = 1502)
  75. 75. Effects of ACEI on endothelial function: EUROPA substudies • PERTINENT: PERindopril Thrombosis, InflammatioN, Endothelial dysfunction and Neurohormonal activation Trial – Determined the mechanisms by which the ACEI perindopril improved outcomes in patients with stable coronary artery disease • PERFECT: PERindopril-Function of the Endothelium in Coronary artery disease Trial – Evaluated whether long-term administration of perindopril improves endothelial dysfunction Ferrari R. ESC 2004; Munich. Bots ML et al. Cardiovasc Drugs Ther. 2002;16:227-36.
  76. 76. PERTINENT: Study design Endothelial cell (EC) studiesEndothelial cell (EC) studies ECs incubated with serum from CADECs incubated with serum from CAD patients at baseline and at 1 year*patients at baseline and at 1 year* Plasma studiesPlasma studies Measure substances in plasma thatMeasure substances in plasma that modulate ecNOS and apoptosismodulate ecNOS and apoptosis Ang IIAng II BradykininBradykinin TNF-TNF-αα von Willebrand factorvon Willebrand factor ecNOSecNOS EC apoptosis rateEC apoptosis rate *Human umbilical vein ECs ecNOS = EC nitric oxide synthase Ferrari R. ESC 2004; Munich. Levels measured at baseline vs 1 year Objective:Objective: Evaluate effects of perindopril on endothelial function and markers ofEvaluate effects of perindopril on endothelial function and markers of inflammation and thrombosis in EUROPA subgroup of CAD patientsinflammation and thrombosis in EUROPA subgroup of CAD patients EUROPA substudy
  77. 77. ↑ ecNOS activity ↓ Endothelial cell apoptosis ↓ Ang II ↑ Bradykinin ↓ TNF-α ↓ von Willebrand factor Ferrari R. ESC 2004; Munich.*Incubated with patients’ serum Endothelial cells* Patients’ plasma EUROPA substudy • The only significant correlation was between bradykinin and ecNOS • Results suggest perindopril modifies inflammation and thrombosis and endothelial function through bradykinin- dependent mechanisms PERTINENT: Effects of treatment with perindopril for 1 year
  78. 78. PERFECT: Study design Objective: Determine effect of perindopril on brachial artery endothelial function in patients with stable CAD and without clinical HF Design: Double-blind randomized controlled trial Population: N = 333 at 20 centers Treatment: Perindopril 8 mg or placebo Follow-up: 3 years Primary outcome: Change in flow-mediated vasodilation of brachial artery assessed over 36 months EUROPA substudy Bots ML et al. J Am Coll Cardiol. 2005;45A(suppl):409A. Bots ML et al. Cardiovasc Drugs Ther. 2002;16:227-36.
  79. 79. • Mean FMD* increased (baseline vs 36 months) Perindopril 2.7% to 3.3% (+37%) Placebo 2.8% to 3.0% (+7%) • Endothelial function (rate of change per 6 months) Perindopril 0.14% (P < 0.05 vs baseline) Placebo 0.02% (P = 0.74 vs baseline) (P = 0.07 for perindopril vs placebo) • Conclusion: Part of the beneficial effect of perindopril on CV morbidity and mortality in the EUROPA study may be explained by improvement in endothelial function *Brachial artery vasodilation in response to reactive hyperemia Bots ML et al. J Am Coll Cardiol. 2005;45A(suppl A):409A. PERFECT: ACEI and endothelial function EUROPA substudy
  80. 80. Effects of ARBs in type 2 diabetes: Renal and CV outcomes Lewis EJ et al. N Engl J Med. 2001;345:851-60. Brenner BM et al. N Engl J Med. 2001;345:861-9. Parving HH et al. N Engl J Med. 2001;345:870-8. *Doubling of baseline serum creatinine, end-stage renal disease (IDNT, RENAAL): progression to diabetic nephropathy (IRMA-2) Study (N) ARB Primary outcome: Renal disease progression* Secondary outcomes (CV) Average duration (years) IDNT (N = 1715) Irbesartan 300 mg/d vs amlodipine 10 mg ↓20% vs placebo, (P = 0.02) and ↓23% vs amlodipine (P = 0.006) Combined CV outcomes: NS 2.6 RENAAL (N = 1514) Losartan 100 mg/d vs placebo† ↓16% (P = 0.02) CV morbidity and mortality: NS HF hospitalization ↓32% 3.4 IRMA-2 (N = 590) Irbesartan 150– 300 mg vs placebo ↓39% with 150 mg (P = 0.08) ↓70% with 300 mg (P < 0.001) Nonfatal CV events: NS 2
  81. 81. Clinical trials of ARBs: CV outcomes Similar ↓ Greater ↓ with amlodipine (2.0/1.6 mm Hg) Losartan vs atenolol Valsartan vs amlodipine Essential HTN N = 9193 (4.8 years) Essential HTN, high CV risk N = 15,245 (4.3 years) LIFE (2002) VALUE (2004) BPTreatment Patients (Follow-up)Trial (year) HTN = hypertension 13% ↓ in primary outcome (CV death, MI, stroke) with ARB (P = 0.021) driven by 25% ↓ in stroke (P = 0.001) No difference in CV death/MI CV outcomes Primary outcome similar at study end Trend favors amlodipine at 3 and 6 months Difficult to interpret due to BP difference Dahlöf B et al. Lancet. 2002;359:995-1003. Julius S et al. Lancet. 2004;363:2022-31.
  82. 82. LIFE: Effects of ARB vs β-blockade on primary outcome and components Dahlöf B et al. Lancet. 2002;359:995-1003. N = 9193 with hypertension and ECG-LVH LIFE = Losartan Intervention for Endpoint Reduction in Hypertension 16 Proportion of patients with first event (%) 12 8 4 0 60 18 30 5442 66 Atenolol Losartan Primary composite endpoint (CV death/MI/stroke) Adjusted RR 13.0% P = 0.021 (losartan vs atenolol) Time (months) 5 10 Risk increase (%) 0 5 10 15 20 25 Primary outcome components (Losartan vs atenolol) Risk reduction (%) P = 0.206 CV death P = 0.491 Stroke MI P = 0.001
  83. 83. LIFE: Comparison of treatment effects in overall population vs with diabetes Patients with hypertension and LVH Dahlöf B et al. Lancet. 2002;359:995-1003. Lindholm LH et al. Lancet. 2002;359:1004-10. 0.5 1.0 1.5 Overall (n = 9193) Diabetes (n = 1195) 0.206 0.028 0.001 0.204 0.491 0.373 Favors losartan 50–100 mg Favors atenolol 50–100 mg P CV death Stroke MI Hazard ratio
  84. 84. VALUE: Similar treatment effects on primary outcome at study end 14 4 2 0 Proportion of patients with first event (%) 0 12 3018 24 54 60 66 Time (months) 6 8 10 12 6 36 42 48 HR = 1.03; 95% CI 0.94–1.14; P = 0.49 Valsartan-based regimen Amlodipine-based regimen Julius S et al. Lancet. 2004;363:2049-51
  85. 85. Time interval (mos) ∆ SBP (mm Hg) Odds ratio Odds ratio Favors valsartan Favors amlodipine Favors valsartan Favors amlodipine Primary outcome Myocardial infarction 0.5 1.0 2.0 4.0 0.5 1.0 2.0 4.0 All study 2.2 0–3 3.8 3–6 2.3 6–12 2.0 12–24 1.8 24–36 1.6 Study end 1.7 36–48 1.4 Julius S et al. Lancet. 2004;363:2022-31. VALUE: SBP and outcome differences during consecutive time periods VALUE = Valsartan Antihypertensive Long-Term Use Evaluation
  86. 86. Direct Renin Inhibitor Aliskerin pre-clinical data
  87. 87. Aliskerin preclinical data Summary • Aliskerin demonstrates organ protective effects in animal models • Renoprotection comparable with ACEIs and ARBs • LVH reductions comparable with ARBs • Suppresses markers of renal damage in diabetic nephropathy • Atherogenesis prevention
  88. 88. Direct Renin Inhibitor Aliskerin Clinical data
  89. 89. Direct Renin Inhibitor Aliskerin Outcome data
  90. 90. EFFECT OF THE DIRECT RENIN INHIBITOR ALISKIREN ON LEFT VENTRICULAR REMODELING FOLLOWING MYOCARDIAL INFARCTION WITH LEFT VENTRICULAR DYSFUNCTION ASPIRE Trial Scott D. Solomon, MD, FACC, Sung Hee Shin, MD, Amil Shah, MD, Lars Kober, MD, Aldo P. Maggioni, MD, Jean Rouleau, MD, FACC, John J. V. McMurray, MD, FACC, Roxzana Kelly, Allen Hester, Marc A. Pfeffer, MD, PhD, FACC for the Aliskiren Study in Post-MI Patients to Reduce Remodeling (ASPIRE) investigators Brigham and Women’s Hospital, Boston, MA; Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark; ANMCO Research Center, Firenze, Italy; University of Montreal, Montreal, Canada; Western Infirmary, Glasgow, Scotland; Novartis Pharmaceuticals, East Hanover, NJ
  91. 91. Cardiovascular Outcomes ASPIRE Trial Endpoint Placebo n=397 n (%) Aliskiren n=423 n (%) CV Death 6 (1.5) 13 (3.1) Resuscitated Sudden Death 4 (1.0) 1 (0.2) HF Hospitalization 17 (4.3) 12 (2.8) Myocardial Infarction 16 (4.0) 11 (2.6) Stroke 2 (0.5) 7 (1.7) Any of the above 34 (8.6) 39 (9.2) No Significant between group differences
  92. 92. Conclusions ASPIRE Trial • In high risk post-MI patients with LV systolic dysfunction, the addition of aliskiren to a standard optimal medical regimen, including an ACE-I or an ARB, did not result in benefit with respect to ventricular remodeling compared to placebo and was associated with more adverse events • Although ASPIRE utilized a surrogate endpoint, and was not powered to assess hard clinical outcomes, these results do not provide support for testing the use of aliskiren in a morbidity and mortality trial in the high-risk post-MI population • Ongoing outcomes trials with aliskiren in patients with heart failure and diabetic kidney disease are well underway and will further assess the role for direct renin inhibition in these populations
  93. 93. Evidence of Dual RAA inhibition
  94. 94. RAAS: Pathways of ACE inhibition and angiotensin receptor blockade Dzau V. J Hypertens. 2005;23(suppl 1):S9-S17. ACE inhibitor Bradykinin/NO Inactive fragments Chymase, tPA, cathepsin ‘Angiotensin II escape’ ARB AT1 receptor AT2 receptor Angiotensin I Angiotensin II
  95. 95. ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61. ONTARGET: Study design Ramipril 10 mg Telmisartan 80 mg N = 25,620 ≥55 years with coronary, cerebrovascular, or peripheral vascular disease, or diabetes + end-organ damage Results in 2007 Ramipril 10 mg + telmisartan 80 mg Primary end point: CV death, MI, stroke, hosp for HF Secondary end point: Newly diagnosed diabetes ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial
  96. 96. ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61. TRANSCEND: Study design Telmisartan 80 mg N = 5776 ACEI-intolerant ≥55 years with coronary, cerebrovascular, or peripheral vascular disease, or diabetes + end-organ damage Results in 2007 Placebo Primary end point: CV death, MI, stroke, hosp for HF Secondary end point: Newly diagnosed diabetes Telmisartan Randomized AssessmeNt Study in aCE iNtolerant subjects with cardiovascular Disease
  97. 97. Yusuf S et al. N Engl J Med 2008: 358:1547-1559. ONTARGET: Key results Outcome Ramipril, n=8576 (%) Telmisartan, n=8542 (%) Combination, n=8502 (%) CV death/MI/ stroke/ CHF hospitalizationa 16.5 16.7 16.3 CV death/MI/strokeb 14.1 13.9 14.1 MI 4.8 5.2 5.2 Stroke 4.7 4.3 4.4 CHF hospitalization 4.1 4.6 3.9 CV death 7.0 7.0 7.3 Any death 11.8 11.6 12.5 Renal impairment 10.2 10.6 13.5 a. Primary end point b. Primary end point in the HOPE trial
  98. 98. Yusuf S et al. N Engl J Med 2008: 358:1547-1559. ONTARGET: Key results Outcome Risk ratio (95% CI), telmisartan vs ramipril Risk ratio (95% CI), combination therapy vs ramipril CV death/MI/ stroke/ CHF hospitalizationa 1.01 (0.94–1.09) 0.99 (0.92–1.07) CV death/MI/strokeb 0.99 (0.91–1.07) 1.00 (0.93–1.09) MI 1.07 (0.94–1.22) 1.08 (0.94–1.23) Stroke 0.91 (0.79–1.05) 0.93 (0.81–1.07) CHF hospitalization 1.12 (0.97–1.29) 0.95 (0.82–1.10) CV death 1.00 (0.89–1.12) 1.04 (0.93–1.17) Any death 0.98 (0.90–1.07) 1.07 (0.98–1.16) Renal impairment 1.04 (0.96–1.14) 1.33 (1.22–1.44) a. Primary end point b. Primary end point in the HOPE trial
  99. 99. ONTARGET: Reasons for permanent discontinuations Yusuf S et al. N Engl J Med 2008: 358:1547-1559. Outcome Ramipril (%) Telmisartan (%) Combination (%) p, telmisartan vs ramipril p, combination therapy vs ramipril Hypotensive symptoms 1.7 2.7 4.8 <0.001 <0.001 Syncope 0.2 0.2 0.3 0.49 0.03 Cough 4.2 1.1 4.6 <0.001 0.19 Diarrhea 0.1 0.2 0.5 0.20 <0.001 Angioedema 0.3 0.1 0.2 0.01 0.30 Renal impairment 0.7 0.8 1.1 0.46 <0.001
  100. 100. Conclusions: Telmisartan vs. Ramipril 1. Telmisartan is clearly “non-inferior” to ramipril,with most ( 95-100%) of the benefits preserved 2. Consistent results on a range of: • Secondary outcomes • Subgroups 3. Telmisartan exhibits slightly superior overall tolerability: • Less cough and angioneurotic edema • More mild hypotensive symptoms, but no difference in severe hypotensive symptoms, such as syncope
  101. 101. Conclusions: Telmisartan plus Ramipril vs. Ramipril 1. Combination therapy does not reduce the primary outcome to a greater extent compared to ramipril alone and has higher adverse events. Implications • Telmisartan is as effective as ramipril, with a slightly better tolerability. • Combination therapy is not superior to ramipril, and has increased side effects.
  102. 102. •The combination of aliskiren (Rasilez) with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) has been associated with serious adverse cardiovascular and renal outcomes in a recent large clinical trial (ALTITUDE). •This combination is now contraindicated in: diabetic patients (type I or type II); and non-diabetic patients with an estimated glomerular filtration rate (eGFR) <60 mL/min per 1•73 m2 •In all other patient groups, aliskiren in combination with an ACE inhibitor or an ARB is not recommended •Any use of aliskiren (either as monotherapy or in combination with other medicines) is no longer recommended in any patient with severe renal impairment: eGFR <30 mL/min per 1•73 m2
  103. 103. RAA inhibition ? ACEI ? ARB ? DRI Evidences from Recent Analysis
  104. 104. Aliskiren in Hypertension Clinical summary •Aliskerin provides long- term suppression of PRA •Aliskerin effectively reduces PRA from baseline as monotherapy, and blocks the rise in PRA seen during treatment with other antihypertensives such as ARB •Aliskerin monotherapy provides dose-dependent reductions in DBP and SBP •Additional BP lowering when combined with other antihypertensives but more side effects
  105. 105. Meta-analyses show consistency of ACEI benefit in preventing CV events No. of trials N Relative risk reduction (%) CV death MI Danchin, 2006 7 33,960 19 18 Al-Mallah, 2006 6 33,500 17 16 Dagenais, 2006 3 29,805 18 18 Danchin N et al. Arch Intern Med. 2006. Al-Mallah MH et al. J Am Coll Cardiol. 2006. Dagenais GR et al. Lancet. 2006. Randomized, placebo-controlled trials in patients with CAD without HF or LV dysfunction
  106. 106. Meta-analysis of trials comparing ARB vs placebo, non-ACEI comparators, or ACEI Strauss MH, Hall AS. Circulation. 2006;114:838-54. 9 of 11 trials show excess MI for ARB Trial ARB n/N (MI) Control n/N (MI) ELITE 3/352 4/370 DETAIL 9/120 6/130 ELITE II 31/1578 28/1574 IDNT 39/579 66/1136 CHARM-Alt 75/1013 48/1015 SCOPE 70/2477 63/2460 RENAAL 50/751 68/762 LIFE 198/4605 188/4588 VALUE 369/7649 313/7596 OPTIMAAL 384/2744 379/2733 VALIANT 587/4909 559/4909 Total 26,777 27,273 0.5 1.0 1.5 2.0 Odds ratio (95% Cl) Favors ARB Favors control 1.08 (1.01–1.16)
  107. 107. Meta-analyses of ACEI and ARB trials StraussStrauss TsuyukiTsuyuki VolpeVolpe VerdecchiaVerdecchia N ACEIACEI 150,943150,943 ARBARB 55,05055,050 ARBARB 68,71168,711 ARBARB 56,25456,254 ARBARB 64,38164,381 MIMI ↓↓14%14% (P < 0.00001)(P < 0.00001) Event Rate 5.8%Event Rate 5.8% ↑8% (P = 0.03)(P = 0.03) Event Rate 6.3%Event Rate 6.3% ↑3% (P = ns) ↑4% (P = ns) ↑2% (P = ns) CV deathCV death ↓↓12%12% (P < 0.0005)(P < 0.0005) Event Rate 8.4%Event Rate 8.4% ↑↑1% (P = ns) Event Rate 9.2%Event Rate 9.2% NA NA ↓1% Strauss MH, Hall AS. Circulation. 2006. Tsuyuki RT, McDonald MA. Circulation. 2006. Volpe M et al. J Hypertension. 2005. Verdecchia P et al. Eur Heart J. 2005. Relative risk
  108. 108. ACEIs vs ARBs: Comparative effect on stroke, HF, and CHD Turnbull F. 15th European Meeting on Hypertension. 2005. Adapted by Strauss MH, Hall AS. Circulation. 2006;114:838-54.CHD = MI and CV death Blood Pressure Lowering Treatment Trialists’ Collaboration meta-analysis N = 137,356; 21 randomized clinical trials ACEI ARB Stroke -1% (9% to -10%) HF 10% (10% to 0%) CHD 9% (14% to 3%) Stroke 2% (33% to -3%) HF 16% (36% to -5%) CHD -7% (7% to -24%) 30% 0 30% Decrease Increase Stroke P = 0.6 HF P = 0.4 CHD P = 0.001 Risk RRR (95%)
  109. 109. Eur Heart J 2012 Van Vark LC, Bertrand M, Fox K, Mourad JJ, Boersma E, et al. Eur Heart J 2012; published online April 17.
  110. 110. All-cause mortality: effect of ACE inhibitors ASCOT-BPLA ADVANCE HYVET Overall 1.03 (0.90-1.15) 0.90 (0.75-1.09) 0.99 (0.62-1.58) 1.32 (0.61-2.86) 0.89 (0.81-0.99) 0.86 (0.75-0.98) 0.79 (0.65-0.95) 0.90 (0.84-0.97) ACE inhibitor better Control better Random effects model HR (95% CI) P N= 76 6150.50 0.75 1.33 2.01 HR (log scale) 0.03 0.03 0.02 0.87(0.81-0.93) 0.004 <0.001 ALLHAT (lisinopril) ANBP-2 (enalapril) pilot HYVET (lisinopril) JMIC-B (lisinopril, enalapril) (perindopril) Van Vark LC, Bertrand M, Fox K, Mourad JJ, Boersma E, et al. Eur Heart J 2012; published online April 17.
  111. 111. All-cause mortality: effect of ARBs RENAAL (losartan) IDNT (irbesartan) LIFE (losartan) SCOPE (candesartan) VALUE (valsartan) MOSES (eprosartan) JIKEI HEART (valsartan) PRoFESS (telmisartan) TRANSCEND (telmisartan) CASE-J (candesartan) HIJ-CREATE (candesartan) KYOTO HEART (valsartan) NAVIGATOR (valsartan) Overall HR (log scale) Control betterARB better 0.50 0.75 1.33 2.01 1.03 (0.83-1.29) 0.92 (0.69-1.23) 0.88 (0.77-1.01) 0.96 (0.81-1.14) 1.04 (0.94-1.14) 1.07 (0.73-1.57) 1.09 (0.64-1.85) 1.03 (0.93-1.14) 1.05 (0.91-1.22) 0.85 (0.62-1.16) 1.18 (0.83-1.67) 0.76 (0.40-1.30) 0.90 (0.77-1.05) 0.99 (0.94-1.04) Random effects model HR (95% CI) P N=82 383 0.683 Van Vark LC, Bertrand M, Fox K, Mourad JJ, Boersma E, et al. Eur Heart J 2012; published online April 17.
  112. 112.  Among RAAS inhibitors, only ACE inhibitors have demonstrated a significant 10% mortality reduction in hypertensive patients (P=0.004).  No significant reduction in all-cause mortality could be demonstrated with ARBs (HR, 0.99 (0.95-1.04); P=0.683).  The difference in treatment effect between ACE inhibitors and ARBs was statistically significant (P-value for interaction 0.036).  The largest mortality reductions were observed in ASCOT-BPLA, ADVANCE, and HYVET, which studied the ACE inhibitor perindopril (pooled HR, 0.87 [0.81-0.93]; P<0.001).  Because of the high prevalence of hypertension, the widespread use of ACE inhibitors may result in an important gain in lives saved. Van Vark LC, Bertrand M, Fox K, Mourad JJ, Boersma E, et al. Eur Heart J 2012; published online April 17.
  113. 113. Savarese G,et al.J Am Coll Cardiol.In press.doi:10.1016/i.iacc.2012.10.011
  114. 114. Savarese G,et al.J Am Coll Cardiol.In press.doi:10.1016/i.iacc.2012.10.011
  115. 115. Savarese G,et al.J Am Coll Cardiol.In press.doi:10.1016/i.iacc.2012.10.011 Conclusion From Saverese G,et alConclusion From Saverese G,et al Meta-analysisMeta-analysis End Points ACEI ARB Composite outcome -14.9% p=0.001 -7% p=0.005 CV death -10% p=0.112 No benefit MI -17.7% p<0.001 -9.5% NS Stroke -19.6% p=0.004 -9.1% p=0.011 All cause death -8.3% p=0.008 No benefit New-onset HF -20.5% p=0.001 No benefit New-onset DM -13.7% p=0.012 -10.6% P<0.001
  116. 116. RAAS modulation in high-risk patients: Summary • Opportunity for greater use of RAAS modulation in patients at high risk for CV events • ACEIs reduce CV death, MI, HF, and stroke across a broad range of patients with vascular disease – With/without LVSD or HF – With/without other proven CV therapies – Annual event rates of 1.4%–22.6% in untreated groups • ARBs reduce HF and stroke • ACEIs may be considered in all patients with vascular disease • ARBs are an alternative in ACEI-intolerant patients • Dual RAAS inhibition is not better than single therapy and causes more side effects
  117. 117. AHA/ACC secondary-prevention guidelines: ACEIs and ARBs ACEIs • All patients with LVEF ≤40%, hypertension, diabetes, or chronic kidney disease (IA) • Consider for all other patients (IB) • Optional: Lower-risk, post-revascularization patients with normal LVEF and well-controlled risk factors (IIaB) ARBs • ACEI-intolerant patients with HF or post-MI LVEF ≤40% (IA) • Consider in DM and other ACEI-intolerant patients (IB) • Consider use in combination with ACEIs in systolic
  118. 118. Thank You

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