ACE-Inhibitors in CVD

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ACE INHIBITION IN CVD

DR.dr. Zainal M

Department of Cardiology Faculty of Medicine

UPN Veteran

jakarta


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The Global Burden of Cardiovascular

Disease in The 21st Century

Neal B, et al. Eur Heart J2002; 4(Suppl. F): F2-F6.

Cerebrovascular disease

Ischaemic heart disease

Cardiovascular disease

Total deaths*

% of total deaths

Number (millions)

0 10 20 30 40 50 60 70 80

* Estimated deaths by 2020


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Cardiovascular Challenges

For The 21st Century

Rapidly increasing numbers of middle-aged and elderlypeople worldwide

Higher rates of heart disease and stroke

Increased urbanization, undesirable nutritional habits,and sedentary lifestyles

A rise in obesity

Higher prevalence of diabetes

Increased cardiovascular disease

Tobacco epidemic

Increased cardiovascular disease

WHO. The World Health Report, 1999.Neal B, et al. Eur Heart J 2002; 4(Suppl. F): F2-F6.


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Lifestyles and Characteristics Increase The

Risk of Coronary Artery Disease

Modifiable

Diets high in fat, cholesterol, and/or calories

Smoking

Sedentary lifestyle and/or obesity

High blood pressure

Raised LDL-cholesterol and triglyceride levels

Thrombogenic factors

Non-modifiable

Age and gender

Family history of CAD or other atheroscleroticdisease at early age(


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Relationship Between Risk Factors &

Coronary Artery Disease

Kannel WB. Eur Heart J1992; 13(Suppl. G): 34-42.

HBP(150-160) + + + + + +

HDL (33-35) - + + + + +Chol (240-262) - - + + + +

Cigarettes - - - + + +

Diabetes - - - - + +

LVH - - - - - +

0

10

20

30

40

50

Men

Women


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The Chain of Events Leading

to End-Stage Heart Disease

Adapted from Dzau V, Braunwald E.Am Heart J1991; 121: 1244-63.

Coronary arterydisease Remodelling

AtherosclerosisLVH

Ventriculardilatation

Myocardialischaemia

Coronarythrombosis

Myocardialinfarction

Arrhythmias/loss of muscle

Risk factors (cholesterol,high blood pressure,

diabetes, insulin resistance)

End-stage heartdisease

Congestiveheart failure


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Prevalence of Hypertension:Over The World

In US and developed country, the data showed 1 among 4 person in the range of age 18-50 yo

1 from 2 person who over 50 yo Cheng et al in Taiwan reported the data of

6,2%

In Philippines, from 80 M Filipinos, 17%

prevalence among those over 15 years6.8million hypertensives


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Hypertension in INDONESIA

Based on Survey of Household Health (SKRT1995) is 8,3 % per 100 population

Women > men

Based on bordeline hypertensioncriteria (140/90-159/94 mmHg), the prevalence is 4,8-18,8%.

Based on WHO report for last 10 years,hospitalized patient due to hypertension inSemarang increased by 10 fold.

In North Sumatera demonstrate of 3 - 9,17%from the population


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ESH 2003 & JNC VIIESH-ESC

BP Classification

BP BP JNC VII

BP Classification

Optimal 110

Isolated SystolicHypertension

Isolated SystolicHypertension

> 140 < 90


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Impact of High Normal Blood Pressureon CVD Risk

No. at riskOptimal 1005 995 973 962 934 892 454Normal 1059 1039 1012 982 952 892 520High Normal 903 879 857 819 795 726 441

0 2 4 6 8 10 12

0

2

4

6

8

10

1214

Time (years)

HighNormal

Normal

Optimal

Framingham Study, Vasan RS et al. N Engl J Med 2001; 345: 1291-1297


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Benefit of Hypertension Treatment


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Benefit of Hypertension Treatment


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Meta-Analysis: Lower Systolic BP Results in Slower

Rates of Decline in GFR in Patients with/out DM

130 134 138 142 146 150 154 170 180

r= 0.69; P< 0.05

SBP (mm Hg)

GFR(mL/min/y)

Untreated

hypertension

0

-2

-4

-6

-8

-10

-12

-14Parving HH et al. Br Med J. 1989.VibertiGC et al. JAMA . 1993.Klahr S et al. N Eng J Med. 1994.Hebert L et al. Kidn ey Int. 1994.Lebovitz H et al. Kidney Int. 1994.

Moschio G et al. N Engl J Med. 1996.Bakris GL et al. Kidney Int. 1996.Bakris GL. Hypertension. 1997.GISEN Group. Lancet. 1997.

Bakri s et al. Am J K idn ey Dis. 2000;36:646


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Mortality is Reduced When

Blood Pressure is Controlled*

Benetos A, et al.Arch Intern Med2002; 162: 577-81.

RF adjusted cardiovascular

relative risk1.66[1.042.64] 2.35[1.035.35]

CVD mortality CAD mortality0

4

5

6

7

8

Cardiovascula

rdeaths(%)

1

2

3

Uncontrolled

Controlled

***

***

***p


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35 40 %mean reduction instroke

20 25 %decrease inMI incidence

> 50 %reduction inCHF

(LANCET 2000)

BENEFITS OF BP LOWERING


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BENEFITS OF BP LOWERING

Stage I Hypertensive Patients with CVD Risk Factors

Sustained 12-mmHg decrease in systolic BP for 10 yearsprevents 1 death for every 11 patients treated

Stage I Hypertensive Patients with CVD or TOD

Sustained 12-mmHg decrease in systolic BP for 10 years

prevents 1 death for every 9 patients treated

Adapted from THE JNC7 REPORT 2003


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Antihypertensive Therapy

Antihypertensive therapy should

Lower blood pressure effectively

Have a favourable safety profile

Reduce cardiovascular morbidity and mortality

Five drug categories

Diuretics

Beta-blockers

ACE inhibitors Calcium channel blockers

Angiotensin-receptor blockers

Third Joint Task Force of European and other Societies on Cardiovascular Disease Prevention in Clinical Practice.Eur Heart J2003; 24: 1601-10.


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1950

1960

1970

1980

Diuretics

Beta blockers

CCBs

1-blockersACE-inhibitors

1990

2000AT-antagonists/ARB

?

Reserpin (1949)

HCT (1958)

Verapamil (1963)

Furosemide (1964)

Propanolol (1965)

Nifedipin (1975)

Prazosin (1977)

Captopril (1981)

Losartan (1995)

Valsartan

Development of Antihypertensive Drugs

Bisoprolol (1988)

Diltiazem (1980)

Amlodipine (1987)


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Lifestyle Modification

Lifestyle Modification Aproximate SBPReduction

______________________________________________________________

Weight reduction 5-20 mmHg/10 kg weight loss

Adopt DASH eating plan 8-14 mmHg

Dietary sodium reduction 2- 8 mmHg

Physical activity 4- 9 mmHg

Moderation of alcohol 2- 4 mmHgconsumption


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Therapeutic Strategies of Hypertension

ESH-ESC Guidelines 2003

Add a

third drug

at low dose

Choose between

Single agent

at low dose

2 drug combination

at low dose

Previous agent

at full dose

Switch to different

Agent at low dose

Previous

combination

at full dose

2-3 drug combination

3 drug combination

at effective dose

If goal BP not achieved

If goal BP not achieved

J.hypertension 2003 ,21, 1011 - 1053


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Algorithm of Hypertension Treatment

Not at Goal Blood Pressure (100

mmHg)

2-drug combination for most

Stage 1 Hypertension

(SBP 140159 or DBP 9099

mmHg)

mono or combination.

Without Compelling

Indications

Not at Goal

Blood Pressure

Optimize dosages or add additional drugs

until goal blood pressure is achieved.

Consider consultation with hypertension

specialist.

JNC 7 , Jama May 21,2003


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Diuretics

Mean arterial pressure Lipid profile Unfavourable

Insulin resistance or

Secondary prevention Limited

Primary prevention

Adapted from a slide produced by Hess, B. 1999.

Decrease

IncreaseNo effect

Evidence for efficacy


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Beta-Blockers

Mean arterial pressure Lipid profile Unfavourable

Insulin resistance

Secondary prevention (MI)

Primary prevention

S Decrease

Increase

No evidence for efficacy




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Calcium Channel Blockers

Mean arterial pressure Lipid profile Neutral

Insulin resistance

Secondary prevention (non-DHPs only)

Primary prevention (non-DHPs only)

Decrease

No effectEvidence for efficacy



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Angiotensin-Receptor Blockers


Insulin resistance

Secondary prevention Some evidence

Primary prevention Some evidence

Decrease



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ACE Inhibitors


Insulin resistance

Secondary prevention Primary prevention

Decrease




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MECHANISM OF ACTION :

ACE

Angiotensin II

Angiotensin I

Angiotensinogen

K a l i k r e in

A C E

P e p t i d a

I n a k t i f

B r a d ik i n i n

K i n in o g e n

ACE INHIBITOR


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Antihypertensive Agents: Summary

of Efficacy

Mean arterial pressure Lipid profile Unfavourable Unfavourable Neutral Neutral Neutral

Insulin resistance or

Secondary prevention Limited (non-DHPs)Primary prevention (non-DHPs)

Someevidence

Diuretics Beta- ACE Calcium Angiotensin-blockers inhibitors channel receptor

blockers blockers

DecreaseIncrease

No effect

Evidence for efficacyNo evidence for efficacy

Some

evidence


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JNC VII - Basis for The Compelling Indications

for Individual Drug Classes

High-risk condition withcompelling indications

Recommended drugs

Diu-

retic

Beta

Block-

er

ACE IAR

BCCB

Aldoste-

rone

antagonist

HF

Post MI

High Coronary disease Risk

DM

Chronic Kidney Disease

Recurrent Stroke prevention

The JNC VII Report. JAMA, 2003; 289: 2560-2572


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ACE Inhibitor

Lisinopriland Study


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ATLAS - Assessment of Treatment withLisinopril and Survival StudyComparative effects of low and high doses of the

angiotensin-converting enzyme inhibitor, lisinopril, on

morbidity and mortality in chronic heart failure

Packer M et al.

Circulation 1999; 100: 2312-2318


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ATLAS: Conclusion

A non-significant 8% risk reduction in primary endpoint ofall-cause mortality with high dose lisinopril

A highly statistically significant 12% risk reduction in

secondary endpoint of all-cause mortality & all-cause

hospitalization with high dose lisinopril. An 8-10% riskreduction in all other secondary endpoints

Both high and low doses of lisinopril were well tolerated;

adverse events were not unexpected and were within label

Additional costs associated with high dose lisinopril were

offset by the reduction costs associated with hospitalizations

ATLAS has establ ished the therapeutic s trategy fo r phy sicians toincrease the dose of l is ino pr i l in heart fai lure


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ACUTE MYOCARDIAL INFARCTION

Once daily Lisinoprilmay be used for the treatmentof hemodynamically stable patients within 24 hoursof an acute myocardial infarction, to prevent the

subsequent development of left ventriculardysfunction or heart failure and to improve survival

Patients should receive, as appropriate, thestandard recommended treatments such asthrombolytics, aspirin and beta-blockers


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GISSI-3Gruppo Italiano per lo Studio della Sopravvienza nellInafarto

Miocardico 3

Effects of lisinopril and transdermal glyceryl trinitrate singly

and together on 6-week mortality and ventricular function

after acute myocardial infarction

GISSI-3 Study Group

Lancet1994; 343: 1115-1122

GISSI 3 R l


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GISSI-3: Results

GISSI-3 Study Group. Lancet1994; 343: 1115-1122

TOLERABILITY

All therapies were well tolerated although persistent hypotension and

renal dysfunction were significantly more common with lisinopril

However, neither were associated with an increase in mortality or in

severe renal failure

OTHER RESULTS

The 11% reduction in the risk of death at 6 weeks translates into a

saving of 8 lives per 1,000 patients treated

This is clinically meaningful since it is achieved in patients already

receiving other treatment know to improve survival following an MI

(thrombolytics, aspirin and beta-blockers)

Lisinopril therefore provides an additional life-saving benefit over an

above that already achieved with standard coronary care unit

treatments


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EUCLIDEUrodiab Controlled trial of Lisinopril in Insulindependent Diabetes

Randomised placebo-controlled trial of lisinopril innormotensive patients with insulin-dependant diabetes and

normoalbuminurea or microalbuminurea

EUCLID Study Group

Lancet1997; 349: 1787-1792

EUCLID


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EUCLIDEUrodiab Controlled trial of Lisinopril in Insulin

dependent Diabetes

Morbidity and mortality are high in IDDM (Type 1

diabetes) due to renal and cardiovascular

complications.These are related to urinary albumin

content

ACE inhibitors benefit patients with raised albumin

excretion but their effect on normo-albuminuria is

unknown

EUCLID investigated whether once-daily lisinopril

reduced the progression of renal disease in patients

with Type 1 diabetes

EUCLID Study Group. Lancet1997; 349: 1787-1792


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EUCLID: Conclusions

EUCLID Study Group. Lancet1997; 349: 1787-1792

In Type 1 diabetes patients without hypertension

Lisinopril slows the progression of renal disease

in normoalbuminuric and microalbuminuricpatients

Greatest benefits were seen in microalbuminuric

patients


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EUCLIDEUrodiab Controlled trial of Lisinopril in Insulindependent Diabetes

Effect of lisinopril on progression of retinopathy in

normotensive people with Type 1 diabetes

Chaturvedi N, Sjolie A-K, Stephenson JM et al.

Lancet1998; 351: 28-31

EUCLID


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EUCLID

Chaturvedi N, Sjolie A-K, Stephenson JM et al. Lancet1998; 351: 28-31

Retinopathy data

Retinopathy, a diabetic complication which shares the risk factors ofnephropathy

Diabetic retinopathy is the leading cause of blindness in people

aged 30-69 years

Retinopathy Assessment

Retinopathy was assessed from two 45-50 degree fundus

photographs from each eye, using the EURODIAB-Hammersmith

grading system

Retinopathy was classified into 5 groups (none to proliferative)according to the worst eye

Retinal photographs were taken at baseline and 24 months, and

were graded by a single observer, who was blinded concerning

treatment status

EUCLID: Conclusions


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EUCLID: Conclusions

Retinopathy data

Chaturvedi N, Sjolie A-K, Stephenson JM et al. Lancet1998; 351: 28-31

In Type 1 diabetes patients without hypertension

lisinopril slows the progression of retinopathyindependent of the degree of renal disease


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Achieving Success inManagement of Hypertension


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Barriers To Achieve BP

Goals Poor compliance

Under aggressiveness of physician in HT

treatment Wrong medication ; not proper

combination ; medication interfering riskwith BP control

White coat HT

Pseudo HT

Secondary HT

Patterns Of Compliance:


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Patterns Of Compliance:

Antihypertensive Therapy

Meredith PA: Clinical Relevance of Pharmacokinetics in Cardiovascular Therapy Symposium, February 25, 1994.

Noncompliant

33%

Adequate

56%

Perfect

11%

(Noncompliance is characterized by patients who

take 40-80% of doses and by drug holidays)


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General Guidelines to Improve Patient

Adherence to Antihypertensive Therapy

Be aware of signs of patient non-adherence toantihypertensive therapy.

Establish the goal of therapy; to reduce blood

pressure to non-hypertensive levels withminimal or no adverse effects.

Educate patients about the disease, andinvolve them and their families in itstreatment. Have them measure blood pressureat home.

Maintain contact with patients; considertelecommunication.

Keep care inexpensive and simple.

G l G id li t I P ti t


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General Guidelines to Improve Patient

Adherence to Antihypertensive Therapy

Encourage lifestyle modification. Integrate pill-taking into routine activities of daily

living Prescribe medications according to pharmacologic

principles, favoring long-acting formulations. Be willing to stop unsuccessful therapy and try a

different approach Anticipate adverse effects, and adjust therapy to

prevent, minimize, or ameliorate side effects.

To add effective and tolerated drugs, stepwise, insufficient doses to achieve the goal of therapy. Encourage a positive attitude about achieving

therapeutic goals. Consider using nurse care management.


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ACE-Inhibitors in CVD

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