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RAAS Modulation in High-Risk Patients

RAAS Modulation in High-Risk Patients. ACEIs: Evolution of benefits. BP reduction. Cardioprotection. Vascular protection. Renal protection. Improved glycemic control (?). 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.

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RAAS Modulation in High-Risk Patients

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  1. RAAS Modulationin High-Risk Patients

  2. ACEIs: Evolution of benefits BP reduction Cardioprotection Vascular protection Renal protection Improved glycemic control (?) 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.

  3. Effect of ACEIs and ARBs on new-onset diabetes Meta-analysis of 12 randomized controlled trials Less likely to develop T2DM More likely to develop T2DM 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 Relative risk (95% CI) Abuissa H et al. J Am Coll Cardiol. 2005;46:821-6.

  4. HOPE, EUROPA, PEACE: Reduction in new-onset diabetes (placebo-controlled trials) n = 23,340 free from diabetes* at baseline Overall 14% RRR RR 0.86 (0.78–0.95) P = 0.0023 Ramipril 10 mg Perindopril 8 mg Trandolapril 4 mg (all trials) *Not a prespecified end point Dagenais GR et al. Lancet. 2006;368:581-8.

  5. TZDs blunt diabetes progression Diabetes Prevention Program (DPP) 15 Placebo Metformin 850 mg bid Cumulative incidence of diabetes (%) 10 Lifestyle Troglitazone400 mg/d* 5 0 0 0.5 1.0 1.5 Follow-up (years) n = 2343 1568 739 237 *Withdrawn from study after 1.5 yr DPP Research Group. Diabetes. 2005;54:1150-6.

  6. DPP: Long-term benefit of lifestyle intervention or metformin on diabetes prevention N = 3234 with IFG and IGT, without diabetes 40 Placebo P* 30 Metformin <0.001 31% Cumulative incidence of diabetes (%) 20 Lifestyle 58% <0.001 10 0 0 1.0 2.0 3.0 4.0 Years *vs placebo IFG = impaired fasting glucose IGT = impaired glucose tolerance DPP Research Group. N Engl J Med. 2002;346:393-403.

  7. DREAM: Background Diabetes REduction Assessment with ramipril and rosiglitazone Medication • Prevalence of T2DM continues to rise • Persons with diabetes are at risk for macro- and microvascular complications • Current options for diabetes prevention include: • Lifestyle intervention: ≥50% • Acarbose, metformin: 25%–30% • New approaches are needed DREAM Trial Investigators. Lancet. 2006;368:1096-105. N Engl J Med. 2006;355:1551-62.

  8. DREAM: Study design Randomized, double-blind 2 × 2 factorial designN = 5269 with IFG and/or IGT, free from CV disease Ramipril 15 mg/d vs placebo AND Rosiglitazone 8 mg/d vs placebo Primary outcome:Diabetes or death from any cause Secondary outcomes I: CV eventsCombined MI, stroke, CV death, revascularization, HF, angina, ventricular arrhythmia Secondary outcomesII: Renal eventsProgression to micro- or macroalbuminuria, or 30% CrCl Secondary outcomesIII: Glycemic statusGlucose levels,conversion to normoglycemia Follow-up: 3–5 years DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.

  9. DREAM: 2 × 2 factorial design Rosiglitazone Placebo Ramipril Ramipril + Rosiglitazone Ramipril + Placebo Placebo Rosiglitazone + Placebo Placebo + Placebo N = 5269 with IFG and/or IGT Ramipril: 5 mg × 2 months; 10 mg × 10 months; 15 mg thereafterRosiglitazone: 4 mg × 2 months; 8 mg thereafter DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.

  10. DREAM: Adjudicated HF Overnight (2 calendar days) hospitalization or ER attendance for 2 of the following criteria: • Signs/symptoms of HF • Radiologic evidence of HF • Need for IV/oral diuretic, vasodilator, and/or inotrope DREAM Trial Investigators. N Engl J Med. 2006;355:suppl appendix (epub).

  11. DREAM: Ramipril effect on new-onset diabetes or death 0.6 9% RRRHR 0.91 (0.81–1.03) P = 0.15 0.5 Placebo 0.4 Cumulative hazard rate 0.3 0.2 Ramipril 0.1 0.0 0 1 2 3 4 Follow-up (years) 26462623 25102498 22772287 12401218 200194 No. at riskPlaceboRamipril DREAM Trial Investigators. N Engl J Med. 2006;355:1551-62.

  12. DREAM: Ramipril effect on glycemia 1.60 16% increaseHR 1.16 (1.07–1.27) P = 0.001 1.20 Ramipril Cumulative hazard rate of conversion to normoglycemia 0.80 Placebo 0.40 0.0 1 2 3 4 0 Follow-up (years) 26462623 24942487 20902060 876791 145127 No. at riskPlaceboRamipril FPG < 110 mg/dL and 2-h glucose < 140 mg/dL DREAM Trial Investigators. N Engl J Med. 2006;355:1551-62.

  13. DREAM: Rosiglitazone effect on primary end point 0.6 Placebo 60% RRR HR 0.40 (0.35–0.46) P < 0.0001 0.5 0.4 Cumulative hazard rate 0.3 0.2 Rosiglitazone 0.1 0.0 0 1 2 3 4 Follow-up (years) No. at riskPlaceboRosiglitazone 26342635 24702538 21502414 11481310 177217 DREAM Trial Investigators. Lancet. 2006;368:1096-105.

  14. DREAM: Conversion to normoglycemia with rosiglitazone N = 5269 71% increaseHR 1.71 (1.571.87)P < 0.0001 *FPG < 110 mg/dL and 2-h glucose < 140 mg/dL DREAM Trial Investigators. Lancet. 2006;368:1096-105.

  15. DREAM: Safety Ramipril vs placebo • No adverse hepatic effects • Alanine aminotransferase (ALT) levels 1.1 U/L at 1 year (P = 0.004) Rosiglitazone vs placebo • Increased incidence of HF* (0.5% vs 0.1%, P = 0.01) • No cases of fatal HF • No difference for other CV events • Increased incidence of peripheral edema(6.8% vs 4.9%, P = 0.003) • 4.9-lb weight gain (P < 0.0001) • Increased hip circumference (0.71 in, P < 0.0001) • No difference in waist circumference • Decreased waist-hip ratio (P < 0.0001) • No adverse hepatic effects • ALT levels 4.2 U/L at 1 year (P < 0.0001) DREAM Trial Investigators.N Engl J Med. 2006;355:1551-62; Lancet. 2006;368:1096-105. *Adjudicated

  16. DREAM: Clinical implications Ramipril • No significant effect on new-onset diabetes • Improved glucose metabolism; further research is needed • Routine use for diabetes prevention cannot be recommended • When ACEIs are indicated, improved glucose metabolism may be additional benefit Rosiglitazone • Provides evidence that pharmacologic intervention is an option for treatment of prediabetes • Benefit/risk: Of 1000 individuals treated for 3 years, ~144 cases of new-onset diabetes could be prevented with excess of 4–5 HF cases DREAM Trial Investigators.N Engl J Med. 2006;355:1551-62; Lancet. 2006;368:1096-105.

  17. Evolution of ACE inhibition for treating patients with CHD CHD without HF or LV dysfunction Severe HF Low LVEF Acute MI SOLVD-Prevent SOLVD-Treat SAVE AIRE GISSI-3 ISIS-4 CCT* CONSENSUS II QUIET HOPEEUROPAPEACE CONSENSUS 1987 1991–1993 1992–1995 1999–2004 Adapted from Yusuf S, Lonn E. Eur Heart J. 1998;19(suppl J):J36-44.Lonn EM et al. Circulation. 1994;90:2056-69. *Chinese Captopril Trial

  18. Meta-analyses show consistency of ACEI benefit in preventing CV events Randomized, placebo-controlled trials in patients with CAD without HF or LV dysfunction Danchin N et al. Arch Intern Med. 2006.Al-Mallah MH et al. J Am Coll Cardiol. 2006.Dagenais GR et al. Lancet. 2006.

  19. EUROPA, HOPE, PEACE, QUIET: Treatment effect on CV end points EUROPA CV death/MI/cardiac arrest* HOPECV death/MI/stroke* Placebo 15 20 Placebo 20% RRR HR 0.80 (0.71–0.91) P = 0.0003 22% RRR HR 0.78 (0.70–0.86) P < 0.001 15 10 10 Ramipril 10 mg Perindopril 8 mg 5 5 0 0 0 1 2 3 4 5 0 1 2 3 4 Patients (%) PEACECV death/MI/CABG/PCI* QUIETCV death/MI/cardiac arrest† Placebo 8 30 Placebo 5 4% RRR HR 0.96 (0.88–1.06) P = 0.43 13% RRR HR 0.87 (0.59–1.29) 20 Trandolapril 4 mg 3 10 Quinapril 20 mg 1 0 0 0 1 2 3 1 2 3 4 5 6 Time (years) *Primary end point†Secondary end point EUROPA Investigators. Lancet. 2003; HOPE Study Investigators. N Engl J Med. 2000;PEACE Trial Investigators. N Engl J Med. 2004; Pitt B et al. Am J Cardiol. 2001.

  20. HOPE, EUROPA, PEACE: Overview HOPE Study Investigators. N Engl J Med. 2000. EUROPA Investigators. Lancet. 2003. PEACE Trial Investigators. N Engl J Med. 2004. *or diabetes + ≥1 CV risk factor

  21. HOPE, EUROPA, PEACE: Reduction in all-cause mortality Favors ACEI Favors placebo 0.6 1.0 1.4 Odds ratio (95% CI) Dagenais GR et al. Lancet. 2006;368:581-8.

  22. HOPE, EUROPA: Benefit consistent across ancillary therapy 4-year rates in placebo groups ACEI better ACEI worse Patients (n) Subgroup P* 0.003 0.651 0.139 0.078 AntiplateletsNo antiplatelets Lipid-lowering agentsNo lipid-lowering agents -blockersNo -blockers RevascularizationNo revascularization 18,3313184 948912,026 11,32310,192 10,39411,123 13.217.9 10.616.4 13.414.3 11.516.0 0.5 0.6 0.7 0.8 0.9 1.0 1.1 Odds ratio (95% CI) *For interactionCV death, nonfatal MI, or stroke Adapted from: Dagenais GR et al. Lancet. 2006;368:581-8.

  23. HOPE, EUROPA: Benefit of ACEIs consistent across baseline combinations ACEI better ACEI worse P* 0.5 0.6 0.7 0.8 0.9 1.0 1.1 Odds ratio (95% CI) *For interactionCV death, nonfatal MI, or stroke Dagenais GR et al. Lancet. 2006;368:581-8.

  24. Benefit of ACEIs in patients with/withoutLVD or HF Favors ACEI Favors placebo 0.6 1.0 1.4 Odds ratio (95% CI) *HOPE, EUROPA, PEACE†SAVE, AIRE, TRACE, SOLVD Dagenais GR et al. Lancet. 2006;368:581-8.

  25. EUROPA: Consistent risk reduction regardless of baseline risk Relative risk reduction 12% 32% 17% Relative baseline risk *CV death and nonfatal MI Deckers JW et al. Eur Heart J. 2006;27:796-801.

  26. HOPE, EUROPA, PEACE: Benefit of ACEIs across broad spectrum of risk CV death,* nonfatal MI or stroke ACEI worse ACEI better -5 0 5 10 15 20 25 30 35 40 Odds reduction (%) *Or total mortality in AIRE, TRACE, SOLVD, SAVE trials Dagenais GR et al. Lancet. 2006;368:581-8.

  27. ACEIs in vascular disease: Conclusions • ACEIs reduce mortality, MI, HF, and stroke in patients with vascular disease with/without LVSD or HF • Benefit in addition to antiplatelet agents, β-blockers, and lipid-lowering agents • Combining ACEIs with these agents provides greatest benefit • Benefit in patients across a broad range of risk for CV events • Annual rate in placebo groups of 1.4%–22.6% • Consider ACEIs in all patients with vascular disease • Assess risk/benefits and tolerability • Use doses proven in clinical trials Dagenais GR et al. Lancet. 2006;368:581-8. Fox K et al. Eur Heart J. 2006;27:2154-7.

  28. ACEIs and elevated serum creatinine in renal insufficiency • Creatinine elevations are modest and self-limiting • ≤30% above baseline • Stabilize within 2 to 4 weeks • If BP is controlled, elevation after 4 weeks is unlikely • Causes • Effective circulating volume (most common) • Bilateral renal stenosis • Withdraw ACEI only if creatinine is >30% above baseline or K ≥21.9 mg/dL (5.6 mmol/L) Bakris GL, Weir MR. Arch Intern Med. 2000;160:685-93.

  29. HOPE: CV end point by baseline creatinine Primary end point* Myocardial infarction 80 60 60 50 Events 40 per 1000 40 30 person- 20 20 years (n) 10 0 0 <1.4 ≥1.4 <1.4 ≥1.4 Creatinine concentration Creatinine concentration (mg/dL) (mg/dL) All patients Placebo Ramipril 10 mg *CV death, MI, stroke Mann JFE et al. Ann Intern Med. 2001:134:629-36.

  30. Meta-analysis of trials comparing ARB vs placebo, non-ACEI comparators, or ACEI 9 of 11 trials show excess MI for ARB Favors ARB Favors control 1.08 (1.01–1.16) 0.5 1.0 1.5 2.0 Odds ratio (95% Cl) Strauss MH, Hall AS. Circulation. 2006;114:838-54.

  31. Meta-analyses of ACEI and ARB trials Relative risk 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.

  32. ACEIs vs ARBs: Comparative effect on stroke, HF, and CHD Blood Pressure Lowering Treatment Trialists’ Collaboration meta-analysisN = 137,356; 21 randomized clinical trials ACEI RRR (95%) StrokeP = 0.6 Stroke -1% (9% to -10%) HF 10% (10% to 0%) HF P = 0.4 CHD 9% (14% to 3%) ARB CHD P = 0.001 Stroke 2% (33% to -3%) HF 16% (36% to -5%) CHD -7% (7% to -24%) 30% 0 30% Decrease Increase Risk Turnbull F. 15th European Meeting on Hypertension. 2005.Adapted by Strauss MH, Hall AS. Circulation. 2006;114:838-54. CHD = MI and CV death

  33. EPHESUS: New subgroup analysis N = 6632 with post-MI LVSD, mean follow-up 16 months P 0.001 0.002 0.022 0.127 0.03 0.641 0.012 0.001 0.01 Eplerenone better Placebo better 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 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 Odds ratio (95% Cl) Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Pitt B et al. Am J Cardiol. 2006;97(suppl):26F-33F.

  34. Role of RAAS modulation continues to evolve Vascular diseaseDiabetes IFG/IGT IGT Heart failure ONTARGETTRANSCEND EMPHASIZE-HFTOPCAT DREAM NAVIGATOR 2006 2007 2008 2011 ONTARGET/TRANSCEND Investigators. Am Heart J. 2004.Skyler JS. Clin Diabetes. 2004.Greenberg B et al. Am J Cardiol. 2006.

  35. ONTARGET: Study design ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial N = 25,620≥55 years with coronary, cerebrovascular, or peripheral vascular disease, or diabetes + end-organ damage Ramipril 10 mg Telmisartan 80 mg Ramipril 10 mg + telmisartan 80 mg Primary end point:CV death, MI, stroke, hosp for HF Secondary end point:Newly diagnosed diabetes Results anticipated in 2007 ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.

  36. TRANSCEND: Study design Telmisartan Randomized AssessmeNt Study in aCE iNtolerant subjects with cardiovascular Disease N = 5776 ACEI-intolerant≥55 years with coronary, cerebrovascular, or peripheral vascular disease, or diabetes + end-organ damage Telmisartan 80 mg Placebo Primary end point:CV death, MI, stroke, hosp for HF Secondary end point:Newly diagnosed diabetes Results anticipated in 2007 ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.

  37. ONTARGET/TRANSCEND: Baseline medical conditions vs HOPE ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.

  38. ONTARGET/TRANSCEND: Baseline medications vs HOPE ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.

  39. NAVIGATOR: Study design Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research N = 9150 with IGT≥50 years with prior CV disease or≥55 years with CV risk factorsRandomized, double-blind 2 × 2 factorial design Valsartan vs placebo AND Nateglinide* vs placebo Primary end points:CV events, new-onset diabetes NAVIGATOR Trial Steering Committee. Diabetes. 2003;52(suppl 1):A505.Skyler JS. Clin Diabetes. 2004;22:162-6. *Insulin secretagogue

  40. EMPHASIZE-HF: Study design Effect of Eplerenone in Chronic Systolic Heart Failure N = 2584 with NYHA class II chronic systolic HF Eplerenone+ standard therapy Placebo+ standard therapy Primary end point:CV death, hosp for HF Follow-up: 4 years Results anticipated 2010 Greenberg B et al. Am J Cardiol. 2006;97(suppl):34F-40F.

  41. TOPCAT: Study design Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist N  4500 with HF and LVEF >45% Spironolactone Placebo Primary end point:CV death, hosp for HF Follow-up: ≥2 years Results anticipated 2011 Greenberg B et al. Am J Cardiol. 2006;97(suppl):34F-40F.

  42. 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 Dagenais GR et al. Lancet. 2006. Strauss MH, Hall AS. Circulation. 2006. Smith SC et al. Circulation. 2006.

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