role of ace inhibitors as secondary prevention in acs
DESCRIPTION
Dr. Nani Hersunarti, SpJP (K), FIHA. 3rd Pekanbaru Cardiology Update, August 25th 2013. Pangeran Hotel Pekanbaru. Learn more at PerkiPekanbaru.comTRANSCRIPT
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