ACE-Inhibitors in CVD
Transcript of 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
Evidence for efficacy
Adapted from a slide produced by Hess, B. 1999.
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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
Adapted from a slide produced by Hess, B. 1999.
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Angiotensin-Receptor Blockers
Mean arterial pressure Lipid profile Neutral
Insulin resistance
Secondary prevention Some evidence
Primary prevention Some evidence
Decrease
Adapted from a slide produced by Hess, B. 1999.
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ACE Inhibitors
Mean arterial pressure Lipid profile Neutral
Insulin resistance
Secondary prevention Primary prevention
Decrease
Evidence for efficacy
Adapted from a slide produced by Hess, B. 1999.
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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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