Dr. Nani Hersunarti, SpJP (K), FIHA. 3rd Pekanbaru Cardiology Update, August 25th 2013. Pangeran Hotel Pekanbaru. Learn more at PerkiPekanbaru.com

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. 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. 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

5. 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.

6. 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.

7. 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

8. 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

9. 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

10. 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

12. 12

13. 13

14. 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.

15. 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

16. 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.

17. 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.

18. 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.

19. PEACE
TREATMENT EFFECT ON PRIMARY OUTCOME
PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.

20. 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.

21. 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.

22. 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.

23. 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.

24. 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.

25. GISSI-3
PRIMARY END-POINTS
GISSI 3 Study Group. Am Coll Cardiol. 1996;27:37-44.

28. 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

29. 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

30. 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

31. Take Home Message

32. THANK YOU