Role of ACE Inhibitors as Secondary Prevention in ACS

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Dr. Nani Hersunarti, SpJP (K), FIHA. 3rd Pekanbaru Cardiology Update, August 25th 2013.
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Role of ACE Inhibitors as Secondary Prevention in ACS

  1. 1. Dr. Nani Hersunarti, SpJP(K) ROLE OF ACE-INHIBITORS AS SECONDARY PREVENTION IN ACS Department of Cardiology and Vascular Medicine Faculty of Medicine Universitas Indonesia National Cardiovascular Center Harapan Kita
  2. 2. EPIDEMIOLOGY • Worldwide, coronary artery disease (CAD) is the single most frequent cause of death • Over 7 millions people every year die from CAD, accounting for 12.8% of all deaths • Every 6 sixth man and seventh women in Europe will die from myocardial infarction
  3. 3. BETA-BLOCKERS REPRESENT 2 OF 7 RX STEPS THAT SHOULD BE PROVIDED IN ALL ACUTE MYOCARDIAL INFARCTIONS • Aspirin - Early Administration • Aspirin at Discharge • Beta-Blocker - Early Administration • Beta-Blocker at Discharge • ACE or ARB at Discharge if LV Systolic Dysfunction • Statin – Early Administration • Timely Initiation of Reperfusion • Life-Style Modification
  4. 4. PHARMACOLOGIC EFFECTS OF ANTAGONISTS ON THE RAA-SYSTEM Angiotensinogen Renin Angiotensin I Angiotensin II Kininogen Bradykinin Inactive Angiotensin-converting enzyme Kalllikrein Kininase II Legend Reaction Stimulatory signal Inhibitory effect Angiotensin- converting enzyme inhibitor Angiotensin II- receptor blocker Angiotensin II Type I Receptors Vasodilation Decreased peripheral vascular resistance Aldosterone secretion Increased Na+ and H2O reabsorption Vasoconstriction Increased peripheral vascular resistance Decreased peripheral vascular resistance Ceconi C, et al. Cardiovasc Res 2007;73:237-46; Faxon DP, et al. Circulation 2004;109:2617-2625; Schmidt-Ott KM, et al. Regul Pept 2000; 93:65-77; Song JC, White CM. Pharmacotherapy 2000;20:130-9; Song JC, White CM. Clin Pharmacokinet 2002;41:207-24; Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.
  5. 5. ROLE OF ANGIOTENSIN II IN ATHEROSCLEROSIS Angiotensine II Vasoconstriction Neurohormonal activation Angiogenesis ↑ Reactive oxygen species ↑ Endothelial dysfunction Fatty Streak Advanced plaques Plaque rupture A T H E R O S C L E R O S I S Apoptosis ↑ Growth ↑ Inflammation ↑ Blood Pressure ↑ Werner N, Nickenig G. Eur Heart J. 2003; 5(suppl A): A9-A13.
  6. 6. RATIONALE OF ACE INHIBITORS • Anti-atherosclerotic - reduction VSMC proliferation • Plague rupture reduction • Improvement of vascular endothelial function • Enhanced fibrinolysis • Modulation of neurohormonally-induced arterial vasoconstriction • LVH reduction • Angiotensin II reduction / Bradykinin increased
  7. 7. ANTI-ISCHEMIC MECHANISMS OF ACE INHIBITOR Myocardium Optimizing oxygen supply/demand Preload and afterload ↓ Left ventricular mass↓ Attenuation sympathetic nervous system stimulation Anti-hypertensive activity Vascular Anti-atherogenic Anti-proliferative effects (vascular smooth muscle cells) Improved endothelial function Plaque stabilization Enhanced fibrinolysis
  8. 8. MAJOR CLINICAL OUTCOME TRIALS OF ACE INHIBITORS ALLHAT ANBP2 INVEST HOPE EUROPA PEACE QUIET GISSI-3 ISIS-4 AIRE SAVE SOLVD-Prevention TRACE SOLVD-Treat CONSENSUS
  9. 9. HOPE (HEART OUTCOMES PREVENTION EVALUATION) • 9297 patients with evidence of vascular disease • Ramipril or placebo and followed for 1 year • Ramipril significantly : • Reduced MI, stroke and death • less need revascularization, fewer complications of diabetes, less heart failure or worsening angina, and smaller incidence of new-onset diabetes • Gives benefit in patients with or without evidence of coronary artery disease, with or without history of MI and EF >40% Yusuf S, et al. (2000). N Engl J Med 342:145-153
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  12. 12. HOPE DOSE-DEPENDENT EFFECTS OF RAMIPRIL ON LV MASS AND FUNCTION Mean baseline LVEF 58% in all groups Lonn E et al. J Am Coll Cardiol. 2004;43:2200-6.
  13. 13. EUROPA (EUROPEAN TRIAL ON REDUCTION OF CARDIAC EVENTS WITH PERINDOPRIL IN STABLE CORONARY ARTERY DISEASE) • 12,218 patients randomized with previous MI, angiographic evidence of coronary disease, coronary revascularization, or a positive exercise test • Perindopril or placebo and followed for 4.2 years • Perindopril significantly reduced : • Cardiovascular death • MI • Cardiac arrest The EROPA Investigators (2003). Lancet 362:782-788
  14. 14. HOPE AND EUROPA OVERVIEW Study (Follow up) ACE inhibitor Key inclusion criteria Primary outcome HOPE N = 9297 (4.5 years) Ramipril 10 mg Vascular disease* (80% had CAD) LVEF ≥40% Age ≥55 years CV death, MI, stroke EUROPA N = 12,218 (4.2 years) Perindopril 8 mg CAD No heart failure Age ≥18 years CV death, MI, cardiac arrest *CV disease, peripheral artery disease, stroke or diabetes + ≥1 CV risk factor HOPE Investigators. N Engl J Med. 2000;342:145-53. EUROPA Investigators. Lancet. 2003;362:782-8.
  15. 15. HOPE AND EUROPA TREATMENT BENEFIT ON PRIMARY AND SELECTED SECONDARY OUTCOMES HOPE Investigators. N Engl J Med. 2000;342:145-53. EUROPA Investigators. Lancet. 2003;362:782-8.
  16. 16. PEACE (PREVENTION OF EVENTS WITH ANGIOTENSIN CONVERTING ENZYME INHIBITION) • 8290 patients randomized • Trandolapril or placebo and followed for 4,8 years • Trandolapril non significantly reduced primary outcome compared with placebo PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.
  17. 17. PEACE TREATMENT EFFECT ON PRIMARY OUTCOME PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.
  18. 18. HOPE, EUROPA, PEACE, QUIET CV EVENT RATE IN PLACEBO GROUP HOPE Investigators. N Engl J Med. 2000;342:145-53. EUROPA Investigators. Lancet. 2003;362:782-8. PEACE Investigators. N Engl J Med. 2004;351:2058-68. Pitt B. et al. Am J Cardiol. 2001;87:1058-63.
  19. 19. HOPE, EUROPA, PEACE, QUIET CV THERAPIES AT BASELINE HOPE EUROPA PEACE QUIET Antiplatelet agents* (%) 76 92 91 73 β-Blockers (%) 40 62 60 26 Lipid-lowering agents (%) 29 58 70 0 Calcium channel blockers (%) 47 32 36 0 Diuretics (%) 15 10 13 NA *Mostly aspirin HOPE Investigators. N Engl J Med. 2000;342:145-53. EUROPA Investigators. Lancet. 2003;362:782-8. PEACE Investigators. N Engl J Med. 2004;351:2058-68. Pitt B. et al. Am J Cardiol. 2001;87:1058-63.
  20. 20. HOPE, EUROPA, PEACE, QUIET CLINICAL IMPLICATIONS • Cumulative evidence supports ACE inhibitors for a broad range of CAD patients • Not all ACE inhibitors can be assumed to have comparable effects on vascular protection • – Medication adherence and dosage are important • Evidence-based medicine should guide use • – Ramipril 10 mg (HOPE) • – Perindopril 8 mg (EUROPA) Pitt B. N Engl J Med. 2004;351:2115-7.
  21. 21. 1-YEAR SURVIVAL IN POST-MI PATIENTS ACCORDING TO ACEI RX AT DISCHARGE N = 7512 *Unadjusted Pilote L et al. Ann Intern Med. 2004;141:102-12.
  22. 22. GISSI-3 (GRUPPO ITALIANO PER LO STUDIO DELLA SOPRAVVIVENZANELL’LINFARTO MIOCARDIO) • 18,895 patients of acute MI • Lisinopril, nitates, lisinopril + nitrates, or placebo and followed for 6 weeks • Either lisinopril alone or with nitrates significantly reduced : • Mortality • Clinical symptoms of Heart Failure • EF <35% • Myocardial dyskinesis GISSI 3 Study Group. Am Coll Cardiol. 1996;27:37-44.
  23. 23. GISSI-3 PRIMARY END-POINTS GISSI 3 Study Group. Am Coll Cardiol. 1996;27:37-44.
  24. 24. CONTRAINDICATIONS TO ACE-I USE DURING ACUTE MYOCARDIAL INFARCTION • Hypotension, • Shock • Bilateral renal artery stenosis • History of worsening of renal function with ACE inhibitor/ARB exposure • Renal failure • Drug allergy ACCF/AHA Guideline for The Management of ST-Elevation Myocardial Infarction, 2013 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation, 2012
  25. 25. DOSAGES OF ACE-INHIBITORS AFTER MYOCARDIAL INFARCTION • Lisinopril 2.5 to 5 mg/d to start; titrate to10 mg/d or higher as tolerated • Captopril 6.25 to 12.5 mg 3 times/d to start; titrate to 25 to 50 mg 3 times/d as tolerated • Ramipril 2.5 mg twice daily to start; titrate to5 mg twice daily as tolerated • Trandolapril test dose 0.5 mg; titrate up to 4 mg daily as tolerated • Enalapril 2.5 mg twice daily to start; titrate to 10 to 20 mg twice daily ACCF/AHA Guideline for The Management of ST-Elevation Myocardial Infarction, 2013 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation, 2012
  26. 26. SUMMARY • ACE-inh should be administered within 24 hours of onset of Acute MI • ACE-inh attenuate LV remodelling and reduce the risk of subsequent MI • ACE-inh have indirect anti-ischemic effect by lessening the afterload on the myocardial oxygen demand by decreasing adrenergic activation, and by improving endothelial function • ACE-inh give benefit on MI patient with diabetes
  27. 27. Take Home Message
  28. 28. THANK YOU

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