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

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

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

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, etal. AHRQ Comparative Effectiveness ReviewNo. 18. October 2009.

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.

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

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

MAJOR CLINICAL OUTCOME TRIALS

OF ACE INHIBITORS

ALLHATANBP2INVEST

HOPEEUROPAPEACE QUIET

GISSI-3ISIS-4

AIRESAVESOLVD-PreventionTRACE

SOLVD-Treat

CONSENSUS

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

13

HOPEDOSE-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.

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

HOPE AND EUROPAOVERVIEW

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.

HOPE AND EUROPATREATMENT BENEFIT ON

PRIMARY AND SELECTED SECONDARY OUTCOMES

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

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.

PEACETREATMENT EFFECT ON PRIMARY OUTCOME

PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.

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.

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.

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.

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.

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.

GISSI-3PRIMARY END-POINTS

GISSI 3 Study Group. Am Coll Cardiol. 1996;27:37-44.

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

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

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

Take Home Message

THANK YOU