PGS TS vothanhnhan UCTT trong NMCT

THUỐC ỨC CHẾ THỤ THỂ ANGIOTENSIN II
TRONG NHỒI MÁU CƠ TIM

PGS TS VÕ THÀNH NHÂN
ĐH Y Dược – BV Chợ Rẫy TPHCM
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Tiến Trình Bệnh Tim Mạch Là Dải Liên Tục

Myocardial
Infarction

CAD

Atherosclerosis

CV Risk Factors
•Diabetes
•Hypertension
•Hyperlipidemia
•Smoking

Loss of
contractility

Remodeling

Ventricular
Dilation
Congestive

Heart Failure

End-Stage
Heart Disease

Death

Adapted from Dzau V, Braunwald E. Am Heart J. 1991

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Hệ RAAS Trong Bệnh Tim Mạch : ACEI/ARB
Renin-Angiotensin System
Angiotensinogen
Renin
BKR

Bradykinin

• Vasodilation
•  Ischemia
•  Platelet agg
•  inotrope

Renin inhibitors

Angiotensin I
ACE/
BPF

NO

Non-Renin
•Tonin
•Cathepsin
Non-ACE
•Chymase

ACE inhibitors

Angiotensin II
Inactive
Peptides

Cross talk
AT I
• Vasoconstriction
• Cell growth
• Na+/H2O retention
• SNS activation

Enzymatic activity
Enzymatic blockade
Product/receptor stimulation

AT II
• Vasodilation
• Anti proliferation
•  Kinins

•  NO

RAAS MODULATORS:

Spironolactone
Eplerenone
Beta blockers

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AII Receptor Blocker

ACE Inhibitor

Blocks formation
of AII incompletely

↓ AII effects

& aldosterone

Blocks
AT-1R

Blocks Kininase II

↑ Kinins

More complete

Inhibition
of AII effects

PROTECTION

AT-2R
Free

Preserve
Antiproliferative
effect

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Vai Trò ACEI Trong Dãi Tim Mạch
GISSI-3, ISIS-4,
SAVE, AIRE
TRACE, SMILE

SOLVD-P

Myocardial
Infarction

Loss of
contractility

HOPE
EUROPA

PEACE
HOPE

Remodeling

SOLVD-T
Ventricular
Dilation

CAD

Congestive
Heart Failure

Atherosclerosis

End-Stage
Heart Disease

CV Risk Factors
Diabetes
Hypertension

Hyperlipidimia
Smoking

Micro-HOPE
PERSUADE

Death

ALLHAT
ANBP2

CONSENSUS
Adapted from Dzau V, Braunwald E. Am Heart J. 1991

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Vai Trò ARB Trong Dãi Tim Mạch
OPTIMAAL
VALIANT
ONTARGET
TRANSCEND
(2007)

Myocardial
Infarction

Remodeling
Ventricular
Dilation

CAD

VALHEFT
CHARM

Congestive

Heart Failure

Atherosclerosis

End-Stage
Heart Disease

CV Risk Factors
Diabetes
Hypertension

Hyperlipidimia
Smoking

PRIME
RENAAL

Loss of
contractility

Death

LIFE
VALUE
SCOPE

Adapted from Dzau V, Braunwald E. Am Heart J. 1991

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Tái Định Dạng Sau Nhồi Máu Cơ Tim:
Hoạt Hóa Hệ Renin–Angiotensin

Initial infarct

Infarct expansion
(hours to days)

Global remodelling
(days to months)

Modified from Jessup and Brozena. New Engl J Med 2003;348:2007–18

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PHÒNG NGỪA
THỨ PHÁT

 EUROPA
 HOPE
 PEACE
 QUIET

TRƯỚC

HIỆU QUẢ

Thử nghiệm về ức chế men chuyển trong bệnh

mạch vành
ĐIỀU TRỊ SAU
NMCTC

 CONSENSUS 1
 SOLVD

 AIRE
 SAVE

 TRACE
 GISSI 3
 ISIS 4
 CONSENSUS 2

THỜI GIAN SỬ DỤNG SAU NMCTC

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AIRE: Acute Infarction Ramipril Efficacy study

- TRIAL DESIGN -

Design
Multicenter, multinational, randomized, double-blind, placebo-controlled
Patients
2006 patients, aged >18 years, with evidence of heart failure
3–10 days after MI; patients with severe heart failure (usually
NYHA class IV) or ongoing ischemia excluded

Follow up and primary endpoint
Average 15 months follow up. Primary endpoint all-cause mortality
Treatment
Placebo or ramipril initiated at 2.5 mg twice daily; increased to
5 mg twice daily after 2 days if tolerated

Lancet 1993;342:821–8

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SAVE: Survival And Ventricular Enlargement study

- TRIAL DESIGN -

Design
Multicenter, randomized, double-blind, placebo-controlled
Patients
2231 patients, aged 21–80 years, with left ventricular dysfunction (ejection fraction
<40%), but no overt heart failure or symptoms of myocardial ischemia, 3–16 days after
MI
Follow up and primary endpoint
Average 3.5 years follow up. Primary endpoint all-cause mortality
Treatment
Placebo or captopril, initially titrated from 12.5 mg to 25 mg three-times daily before
leaving hospital, increasing to maximum 50 mg three-times daily if tolerated
N Engl J Med 1992;327:669–77.

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TRACE: TRandolapril Cardiac Evaluation

- TRIAL DESIGN -

Design
Multicenter, randomized, double-blind, placebo-controlled
Patients
1749 patients with left ventricular systolic dysfunction (wall-motion index <1.2, ejection fraction
<35%) <7 days after MI

Follow up and primary endpoint
2.0–4.1 years follow up. Primary endpoint all-cause mortality
Treatment
Matched placebo or once-daily trandolapril 1 mg for 2 days, increased to 2 mg after 2 days,
increased to 4 mg after 4 weeks; reduced to 1– 2 mg daily if highest dose not tolerated

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N Engl J Med 1995; 333:1670–6


All-Cause Mortality
AIRE

SAVE

TRACE

Clinical and/or

radiographic signs of
HF

Radionuclide
EF ≤40%

Echocardiography
EF ≤35%

0.40

Placebo

0.35
0.30
Cumulative
Mortality

ACE-I

0.25
0.20
0.15

Placebo: 866/2971 (29.1%)
ACE-I: 702/2995 (23.4%)
OR: 0.74 (0.66–0.83)

0.10

0.05
Years

ACE-I
Placebo

0

0

2995
2971

2250
2184

1

161
1521

Adapted from Flather MD et al. Lancet. 2000;355:1575-1581.

2

892
853

3

223
138

4

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ISIS-4: Fourth International Study of Infarct Survival

- TRIAL DESIGN -

Design: Multicenter, multinational, randomized, partial double-blind, placebo-controlled, 2 x 2 x 2
factorial study
Patients: 58,050 patients hospitalized within 24h of suspected acute MI; patients with
cardiogenic shock or persistent severe hypertension excluded
Follow up and primary end point: Median 15 months follow up. Primary endpoint all-cause
mortality
Treatment: All patients received three study treatments, each being randomly assigned to active
or placebo within each treatment:
• Oral captopril 50mg twice daily or placebo, for 28 days (blinded)
• Oral controlled-release isosorbide mononitrate 60mg twice daily or placebo, for 28 days
(blinded)
• Intravenous magnesium sulfate as 8 mmol bolus over 15 min then 72 mmol over 24 h, or no
infusion (open)
Lancet 1995; 345: 669–85.

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ISIS-4: Fourth International Study of Infarct Survival

- SUMMARY -

In patients with suspected or definite acute MI:
• Early treatment with captopril reduced all-cause mortality at 35 days
and during long-term follow up
• Mononitrate conferred no survival advantage in the short or long term
• Magnesium conferred no survival advantage, in contrast with earlier
and smaller studies

Lancet 1995; 345: 669–85.

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ACE Inhibitor Comparator Myocardial
Infarction Trials
MI Trials With Mortality Benefit
Broad

(early, short-term)

GISSI 3
lisinopril
ISIS 4
captopril
Chinese-Cap captopril

Long Term

(higher risk, long-term)

SAVE
AIRE
TRACE

captopril
ramipril
trandolapril

Captopril – most extensively studied with survival benefits in both
early, short-term and long-term, higher-risk trials
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ACEI Nào Được Nghiên Cứu Nhiều Nhất ?
140

# of Trial Patients
(,000s)

120
100

80
60

40
20

0

Captopril

Enalapril

Lisinopril

Ramipril

Other ACEI are not included because of total sample size

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HIỆU QUẢ CỦA ACEI TRONG NMCTC

GISSI. Lancet 1994; 343:1115–22.
ISIS-4 Collaborative Group. Lancet 1995; 345: 669–85.

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Nghiên cứu về ARB sau Nhồi Máu Cơ Tim

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ARB: BN sau Nhồi Máu Cơ Tim
* OPTIMAAL

OPtimal Trial In Myocardial infarction with
the Angiotensin II Antagonist Losartan

* VALIANT
VALsartan In Acute myocardial iNfarction Trial
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OPTIMAAL: Captopril sv Losartan Sau NMCT Cấp
> 50 years; acute MI and clinical/radiologic signs of heart failure
EF < 35%/LVEDd > 65 mm; new anterior Q waves/LBBB
Re-infarction and old anterior Q waves

Event-driven
(target 937 deaths)
~3 years

Captopril
50 mg 3 times daily
(n = 2733)
Primary end point
Secondary end point
Other end points

Losartan
50 mg daily
(n = 2744)

All-cause mortality
Sudden cardiac death or resuscitated arrest

Fatal and nonfatal myocardial infarction
Safety and tolerability

Dickstein K et al. Lancet. 2002;360:752-760.

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OPTIMAAL: Các tiêu chuẩn đưa vào nghiên cứu
NMCT cấp

Clinical/
radiographic
signs of HF

LVEF < 35% or LVEDD
> 65 mm

New Q wave anterior MI or
new LBBB or re-MI with prior
anterior Q waves
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OPTIMAAL: Phác đồ liều lượng
Losartan
12.5 mg qd

Losartan
25 mg qd

Losartan 50 mg qd

Randomization
(N=5,004)
Captopril
12.5 mg tid

Captopril
25 mg tid

Dickstein K, Kjekshus J. Am J Cardiol 1999; 83(4):477-81.

Captopril 50 mg tid

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OPTIMAAL: các kết quả chính
Tiêu chí

Losartan (n)

Captopril (n)

Odds ratio

p

Tử suất

499

447

1.13 (0.99 – 1.28)

0.069

được cứu sống

239

203

1.19 (0.99 – 1.34)

0.073

Nhồi máu cơ tim

384

379

1.03 (0.89 – 1.18)

0.72

Đột quị

140

132

1.07 (0.84 – 1.36)

0.587

Tử vong tim mạch

420

363

1.17 (1.01 – 1.34)

0.032

1,806

1,774

1.03 (0.97 – 1.10)

0.362

Đột tử hoặc
ngưng tim

Số lần nhập viện

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OPTIMAAL: Tử Suất Do Mọi Nguyên Nhân
Tử suất trên bn nguy cơ cao sau NMCT cấp

20%

30%

Captopril better
Dickstein K, et al. Lancet 2002; 360:752-60.

10%

10%
Losartan better
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Tử Suất Chung
25

losartan (n=499 events)
captopril (n=447 events)

Event rate (%)

20

15
10
5
0

losartan (n)
captopril (n)

Relative Risk = 1.13 (0.99 to 1.28); p=0.069
0

6

12

18
Month

24

30

36

2744
2733

2504

2534

2432
2463

2390
2423

2344
2374

2301
2329

1285
1309

Dickstein K et al.Lancet 2002

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