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Role of RAAS Modulation: Recent Clinical Trials

VBWG. Role of RAAS Modulation: Recent Clinical Trials. CAD Diabetes ACEIs and ARBs. VBWG. Benefit of ACE inhibition in CAD. SOLVD SAVE AIRE TRACE. Post-MI, HF, LVEF <40%. HOPE. SOLVD (prev). High risk. EUROPA. All CAD patients. Bertrand ME . Curr Med Res Opin. 2004;20:1559-69.

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Role of RAAS Modulation: Recent Clinical Trials

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  1. VBWG Role of RAAS Modulation:Recent Clinical Trials • CAD • Diabetes • ACEIs and ARBs

  2. VBWG Benefit of ACE inhibition in CAD SOLVDSAVEAIRETRACE Post-MI, HF, LVEF <40% HOPE SOLVD (prev) High risk EUROPA All CAD patients Bertrand ME. Curr Med Res Opin. 2004;20:1559-69.

  3. VBWG EUROPA: EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease 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 EUROPA Investigators. Lancet. 2003;362:782-8.

  4. VBWG EUROPA: Baseline characteristics Perindopril (%) (n = 6110) Placebo (%) (n = 6108) EUROPA Investigators. Lancet. 2003;362:782-8.

  5. VBWG EUROPA: Concomitant medications Baseline (%) 3 Years (%)* *Concomitant medications recorded in 11,547 patients EUROPA Investigators. Lancet. 2003;362:782-8.

  6. VBWG EUROPA: Primary outcome CV death, MI, cardiac arrest 14 RRR 20% (95% CI: 9%–29%)AR 8.0% vs 9.9% P = 0.0003 12 Placebo 10 Perindopril 8 mg 8 Primary outcome (%) 6 20% 14% 4 P < 0.05 11% 2 10% 0 P = 0.35 0 1 2 3 4 5 Time (years) EUROPA Investigators. Lancet. 2003;362:782-8. Fox KM. Br J Cardiol. 2004;11:195-204. AR = absolute risk (perindopril vs placebo)

  7. VBWG EUROPA: Effect of ACEI on fatal/nonfatal MI and HF hospitalizations Fatal and nonfatal MI HF hospitalization 10 RRR 39%AR 1.0% vs 1.7% P = 0.002 RRR 24% AR 5.2% vs 6.8%P < 0.001 Placebo 2.0 Placebo 8 1.5 Perindopril8 mg Perindopril8 mg 6 Events (%) 1.0 4 0.5 2 0 0.0 0 1 2 3 4 5 0 1 2 3 4 5 Years Years EUROPA Investigators. Lancet. 2003;362:782–8. AR = absolute risk (perindopril vs placebo)

  8. EUROPA: Benefit of ACEI on primary and secondary outcomes 2.0 0.5 1.0 VBWG N = 12,218 Perindopril (%) (n = 6110) Placebo (%) (n = 6108) Favors perindopril Favors placebo 9.9 17.1 9.8 6.9 4.1 6.8 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 EUROPA Investigators. Lancet. 2003;362:782-8.

  9. EUROPA: Benefit of ACEI on selected secondary outcomes 2.0 0.5 1.0 VBWG N = 12,218 Perindopril (%) (n = 6110) Placebo (%) (n = 6108) Favors perindopril Favors placebo 6.0 0.2 1.7 9.8 1.7 5.6 0.1 1.6 9.4 1.0 Unstable angina Cardiac arrest Stroke Revascularization HF w/hospital admission EUROPA Investigators. Lancet. 2003;362:782-8.

  10. 0.5 1.0 2.0 VBWG EUROPA: Consistent benefits in predefined subgroups N = 12,218 Primary events (%) Perindopril(n = 6110) Placebo(n = 6108) Favors perindopril Favors placebo n 10,4391779 3948 4439 3831 8.2 6.9 6.5 6.9 10.7 10.18.8 8.9 8.1 12.9 MaleFemale≤55 56–65 ≥66 Age (years) EUROPA Investigators. Lancet. 2003;362:782-8.

  11. 0.5 1.0 2.0 VBWG EUROPA: Consistent benefits in predefined subgroups (continued) Primary events (%) Previous MINo previous MI Previous revascularizationNo previous revascularization HypertensionNo hypertension Diabetes mellitusNo diabetes mellitus 7910 4299 6709 5509 3312 8906 1502 10,716 Perindopril(n = 6110) Placebo(n = 6108) Favors perindopril Favors placebo n 8.9 6.4 6.6 9.6 9.8 7.3 12.6 7.4 11.3 7.3 8.0 12.2 12.0 9.1 15.59.0 EUROPA Investigators. Lancet. 2003;362:782-8.

  12. VBWG EUROPA: Benefit of perindopril was on top of recommended medications Favors perindopril Primary events (%) Favors placebo Perindopril(n = 6110) Placebo(n = 6108) Lipid-lowering drugNo lipid-lowering drug -blockersNo -blockers Calcium channel blockersNo calcium channel blockers 7.09.3 7.68.7 9.97.1 8.311.9 10.29.4 11.79.0 0.5 1.0 2.0 EUROPA Investigators. Lancet. 2003;362:782-8.

  13. VBWG EUROPA: Risk reduction with perindopril stratified by baseline systolic BP level N = 12,218 Baseline SBP (mm Hg) <120 120 to <140 140 0 5 10 Primaryendpoint relative riskreduction withperindopril(%) 15 17 20 18 25 No interaction between treatment and SBP: P = 0.464 30 35 40 39 Remme WJ. Circulation. 2004;110(suppl):III-628.

  14. VBWG EUROPA: Systolic BP reduction during run-in did not affect risk reduction during trial N = 12,218 RRR 20% RRR 18% 12 n = 1841 n = 4263 10 n = 1804 n = 4303 8 Primaryevent(%) 6 4 2 0 SBP decrease during run-in No SBP decrease during run-in Placebo Perindopril Run in = 4 weeks when all patients receivedperindopril 8 mg Remme WJ. Circulation. 2004;110(suppl):III-628.

  15. 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) VBWG EUROPA vs HOPE: Inclusion criteria 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) HOPE patients were at higher risk than EUROPA EUROPA Investigators. Lancet. 2003;362:782-8.HOPE Study Investigators. N Engl J Med. 2000;342:145-53.

  16. VBWG EUROPA vs HOPE: Study populations EUROPA Investigators. Lancet. 2003;362:782-8. HOPE Study Investigators. N Engl J Med. 2000;342:145-53.

  17. VBWG EUROPA vs HOPE: Event rates in placebo groups reflect differences in baseline risk 3.0 2.7 2.5 2.0 1.8 Annualized event rate in placebo groups (%) 1.5 1.5 1.0 1.0 0.5 0.0 CV mortality Total mortality EUROPA HOPE 80% 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.

  18. VBWG EUROPA vs HOPE: Treatment more intensive in EUROPA than in HOPE Baseline medication 100 92 75 80 62 57 60 % 39 40 28 20 0 Antiplateletdrugs* Beta-blockers Lipid-loweringdrugs EUROPA HOPE EUROPA Investigators. Lancet. 2003;362:782-8.HOPE Study Investigators. N Engl J Med. 2000;342:145-53. *Mostly aspirin

  19. VBWG EUROPA: Clinical implications • In optimally treated CAD patients, perindopril 8 mg significantly reduced • CV mortality + nonfatal MI + cardiac arrest: 20% • CV mortality + nonfatal MI: 19% • Fatal + nonfatal MI: 24% • Heart failure hospitalization: 39% • Benefits exhibited on top of recommended therapy (aspirin, -blockers, lipid-lowering agents) • Benefits consistent across all predefined subgroups • Baseline BP and changes in BP had no significant impact on outcome Treatment with perindopril should be considered in all CAD patients, including patients at low risk EUROPA Investigators. Lancet. 2003;362:782-8.Remme WJ. Circulation. 2004;110(suppl):III-628.

  20. VBWG PEACE: Prevention of Events with Angiotensin Converting Enzyme inhibition Objective: Assess effect of ACEI in patients with stable CAD and normal/slightly reduced LV function Design: N = 8290 randomized Treatment: Trandolapril 4 mg or placebo Follow-up: 4.8 years Primary outcome: CV death, nonfatal MI, CABG, PCI PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.

  21. VBWG PEACE: Primary outcome CV death, MI, CABG/PCI; N = 8290 30 4% Risk reduction HR 0.96 (0.88–1.06) P = 0.43 Placebo 25 Trandolapril 4 mg 20 Patients(%) 15 10 5 0 0 1 2 3 4 5 6 Time (years) PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.

  22. VBWG EUROPA vs PEACE: Differences in compliance 3 Years 93 100 81 74.5 80 68.6 60 Patients (%) 40 20 0 On study ACEI At targetACEI dose EUROPA (perindopril 8 mg) PEACE (trandolapril 4 mg) EUROPA Investigators. Lancet. 2003;362:782-8. PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.

  23. VBWG ACEI trials in CAD without HF: Primary outcomes EUROPA CV death/MI/cardiac arrest HOPECV death/MI/stroke 14 20 Placebo Placebo 12 15 10 22% Risk reduction HR 0.78 (0.70–0.86) P < 0.001 20% Risk reduction HR 0.80 (0.71–0.91) P = 0.0003 Ramipril 10 mg 8 % % 10 6 Perindopril 8 mg 4 5 2 0 0 0 1 2 3 4 5 0 1 2 3 4 Time (years) Time (years) PEACECV death/MI/CABG/PCI QUIETAll CV events Placebo 50 30 Quinapril 20 mg 40 25 4% Risk increase HR 1.04 (0.89–1.22) P = 0.6 20 4% Risk reduction HR 0.96 (0.88–1.06) P = 0.43 30 Trandolapril 4 mg % % Placebo 15 20 10 10 5 0 0 1 2 3 4 5 6 0 1 2 3 Time (years) Time (years) HOPE Study Investigators. N Engl J Med. 2000;342:145-53. Pitt B et al. Am J Cardiol. 2001;87:1058-63. EUROPA Investigators. Lancet. 2003;362:782-8. PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.

  24. VBWG ACEI trials in CAD patients without HF: Key baseline characteristics EUROPA HOPE PEACE QUIET N 12,218 9297 8290 1750 Follow-up (yrs) 4.2 4.5 4.8 2.3 ACEI/dose (mg) P-8 R-10 T-4 Q-20 Age (yrs) 60 66 64 58 Men (%) 85 73 82 82 CAD/Cor rev (%) 100/55 80/44 100/72 100/100 Diabetes (%) 12 39 17 16 Hypertension (%) 27 47 46 47 Prior MI (%) 65 53 55 49 Ejection fraction (%) NA NA 58 59 PVD (%) 7 43 NA 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.

  25. VBWG EUROPA, HOPE, PEACE, QUIET: Totality of trial evidence Event rate (%) P ACEI Placebo Favors ACEI Favors placebo 0.0004 All-cause death 7.5 8.9 0.86 6.4 7.7 0.0004 MI 0.86 2.1 2.7 0.0004 Stroke 0.77 Revascularization 15.5 16.3 0.025 0.93 0.5 0.75 1 1.25 Odds ratio Pepine CJ, Probstfield JL. Vasc Bio Clin Pract. CME Monograph; UF College of Medicine. 2004;6(3).

  26. EUROPA, HOPE, PEACE, QUIET: CV therapies at entry/during study VBWG 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 3 yrs †at study end

  27. VBWG ACEI outcome trials in CAD patients without HF: BP at entry/during study 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. *Run-in BP maintained during study†at study end ‡at 3 years

  28. VBWG HOPE, EUROPA, PEACE, QUIET: Differences in baseline CV risk 3.0 2.7 2.0 2.0 1.8 Annualized event rate in placebo group (%/yr) 1.5 1.1 1.0 1.0 0.8 0.7 0.0 CV death Nonfatal MI 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. HOPE PEACE QUIET EUROPA

  29. VBWG EUROPA, HOPE: Consistent benefit of ACEI on CV outcomes Event rate (%) 14.0 17.8 8.0 9.9 6.1 8.1 3.5 4.1 9.9 12.3 4.8 6.2 3.4 4.9 1.6 1.7 0.8 1.3 0.1 0.2 Favors ACE inhibitor Favors Placebo ACEI Placebo Composite outcome CV mortality Myocardial infarction Stroke Cardiac arrest HOPE(ramipril 10 mg) EUROPA(perindopril 8 mg) 0.5 1.0 1.5 Hazard ratio EUROPA Investigators. Lancet. 2003;362:782-8. HOPE Study Investigators. N Engl J Med. 2000;342:145-53.

  30. VBWG Should all patients with stable CAD without HF receive an ACEI? Interpreting evidence • 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.

  31. VBWG 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 ofheart 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.

  32. VBWG ACP guidelines for ACEI in chronic stable angina or asymptomatic CAD • Symptomatic patients with chronic stable angina (Level of evidence: A) • Asymptomatic patients – CAD with systolic dysfunction (Level of evidence: A) – Diabetes with CAD (Level of evidence: A) – Diabetes without CAD (Level of evidence: B) Snow V et al. Ann Intern Med. 2004;141:562-7.

  33. VBWG 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.

  34. VBWG PERSUADE: Primary outcome CV death, MI, cardiac arrest 20 RRR: 19% 95% CI: –7% to 38% P = 0.13 Placebo 16 Perindopril8 mg 12 Cumulative frequency (%) 8 4 0 0 1 2 3 4 5 Years from randomization Daly CA et al. Eur Heart J. 2005;26:1369-78.

  35. VBWG PERSUADE and EUROPA: Comparable outcomes Perindopriln = 6110 n = 721 Placebon = 6108 n = 781  RRR (%) EUROPA PERSUADE Favors perindopril Favors placebo 488 603 20 CV mortality, nonfatal MI,cardiac arrest 91 121 19 375 420 11 Total mortality 73 93 15 215 249 14 CV mortality 47 60 16 320 418 24 Fatal and nonfatal MI 56 78 23 212 273 23 Non–Q-wave infarction 37 60 34 98 102 4 Stroke 18 23 15 63 103 39 Heart failure 13 26 46 0.5 1.0 2.0 EUROPA PERSUADE Daly CA et al. Eur Heart J. 2005;26:1369-78.

  36. VBWG PERSUADE and MICRO-HOPE: Consistency of benefit Favors ACEI Favors placebo Primary outcome Total mortality MICRO-HOPE (N = 3577) CV mortality PERSUADE (N = 1502) All MI Stroke 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 Relative risk (95% CI) Daly CA et al. Eur Heart J. 2005;26:1369-78. HOPE Study Investigators. Lancet. 2000;355:253-9.

  37. VBWG 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.

  38. VBWG Are all ACEIs the same? Survival 1-year post-MI by ACEI at discharge N = 7512, Canadian pharmacy database 100 90 Unadjusted cumulativesurvival(%) Ramipril n = 905 Perindopril n = 243 Lisinopril n = 2201 80 Enalapril n = 2577 Quinapril n = 276 Fosinopril n = 889 Captopril n = 421 P < 0.001 log-rank 0 2 4 6 8 10 12 Months Pilote L et al. Ann Intern Med. 2004;141:102-12. Reference = ramipril

  39. VBWG Multiple mechanisms of ACEI in atherosclerotic CVD Vasculoprotective effects • Direct antiatherogenic • Enhance endogenous fibrinolysis • Inhibit platelet aggregation • Antimigratory for mononuclear cells •  Matrix formation • Improve endothelial function • Antioxidant • Anti-inflammatory • Protection from plaque rupture • Improved arterial compliance and tone Blood pressure lowering Cardioprotective effects •  Preload and afterload •  LV mass •  Sympathetic stimulation •  Reperfusion injury • Improved myocardial remodeling Metabolic syndrome • Lipid neutral • Improved glucose metabolism Lonn E et al. Eur Heart J. 2003;5(suppl):A43-8.

  40. VBWG Clinical trials of ARBs: CV outcomes Trial (year) Patients (Follow-up) Treatment BP CV outcomes LIFE (2002) VALUE (2004) Essential HTN N = 9193 (4.8 years) Essential HTN, high CV risk N = 15,245 (4.3 years) Losartan vs atenolol Valsartan vs amlodipine Similar  Greater  with amlodipine (2.0/1.6 mm Hg) 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 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. HTN = hypertension

  41. MI VBWG LIFE: Effects of ARB vs -blockade on primary outcome and components N = 9193 with hypertension and ECG-LVH Primary composite endpoint(CV death/MI/stroke) Primary outcome components (Losartan vs atenolol) 16 10 Adjusted RR 13.0% P = 0.021 (losartan vs atenolol) Riskincrease(%) 5 12 CV death Stroke 0 Proportionof patientswith firstevent (%) P = 0.491 Atenolol 8 5 Losartan 10 Riskreduction(%) P = 0.206 4 15 20 0 25 0 6 18 30 42 54 66 P = 0.001 Time (months) LIFE = Losartan Intervention for Endpoint Reduction in Hypertension Dahlöf B et al. Lancet. 2002;359:995-1003.

  42. VBWG VALUE: Similar treatment effectson primary outcome at study end 14 Valsartan-based regimen 12 10 Proportionof patientswith firstevent (%) 8 6 Amlodipine-based regimen 4 2 HR = 1.03; 95% CI 0.94–1.14; P = 0.49 0 0 6 12 18 24 30 36 42 48 54 60 66 Time (months) Julius S et al. Lancet. 2004;363:2049-51

  43. VALUE: SBP and outcome differencesduring consecutive time periods VBWG Primary outcome Myocardial infarction Timeinterval(mos) ∆ SBP(mm Hg) Favorsvalsartan Favorsamlodipine Favorsvalsartan Favorsamlodipine All study 2.2 0–3 3.8 3–6 2.3 6–12 2.0 12–24 1.8 24–36 1.6 36–48 1.4 Study end 1.7 0.5 1.0 2.0 4.0 0.5 1.0 2.0 4.0 Odds ratio Odds ratio VALUE = Valsartan Antihypertensive Long-Term Use Evaluation Julius S et al. Lancet. 2004;363:2022-31.

  44. VBWG Evidence of benefit: ACEI vs ARB Evidence from clinical trials supports the use of ACEIsvs ARBs in a broader range of high-risk conditions JNC 7. JAMA. 2003;289:2560-72.

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