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ACE INHIBITION IN CVD

DR.dr. Zainal M Department of Cardiology Faculty of Medicine UPN Veteran jakarta

The Global Burden of Cardiovascular Disease in The 21st Century

Total deaths* Cardiovascular disease Ischaemic heart disease Cerebrovascular disease

Number (millions) % of total deaths

0
* Estimated deaths by 2020

10

20

30

40

50

60

70

80

Neal B, et al. Eur Heart J 2002; 4(Suppl. F): F2-F6.

Cardiovascular Challenges For The 21st Century

Rapidly increasing numbers of middle-aged and elderly people 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.

Lifestyles and Characteristics Increase The Risk of Coronary Artery Disease


Modifiable Non-modifiable

Diets high in fat, cholesterol, and/or calories


Smoking Excess alcohol consumption Sedentary lifestyle and/or obesity High blood pressure Raised LDL-cholesterol and triglyceride levels Hyperglycaemia/diabetes Thrombogenic factors

Age and gender Family history of CAD or other atherosclerotic disease at early age (<55 years men, <65 years women) Personal history of CAD or other atherosclerotic disease

Third Joint Task Force of European and other Societies on Cardiovascular Disease Prevention in Clinical Practice. Eur Heart J 2003; 24: 1601-10.

Relationship Between Risk Factors & Coronary Artery Disease


50 40 30 20 10 0 HBP(150-160) HDL (33-35) Chol (240-262) Cigarettes Diabetes LVH + + + + + + + + + + + + + + + + + + + + + Women Men

Kannel WB. Eur Heart J 1992; 13(Suppl. G): 34-42.

The Chain of Events Leading to End-Stage Heart Disease


Myocardial ischaemia Coronary thrombosis Myocardial infarction Arrhythmias/ loss of muscle

Coronary artery disease

Remodelling

Atherosclerosis LVH

Ventricular dilatation

Risk factors (cholesterol, high blood pressure, diabetes, insulin resistance)

Congestive heart failure

End-stage heart disease

Adapted from Dzau V, Braunwald E. Am Heart J 1991; 121: 1244-63.

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 years 6.8 million hypertensives

Hypertension in INDONESIA
Based on Survey of Household Health (SKRT 1995) is 8,3 % per 100 population Women > men Based on bordeline hypertension criteria (140/90159/94 mmHg), the prevalence is 4,8-18,8%. Based on WHO report for last 10 years, hospitalized patient due to hypertension in Semarang increased by 10 fold. In North Sumatera demonstrate of 3 - 9,17% from the population

ESH 2003 & JNC VII


ESH-ESC BP Classification Optimal BP <120 / <80 BP <120/<80 JNC VII BP Classification Normal

Normal
High normal Grade 1 Hypertension (mild)

120-129 / 80-84
130-139 / 85-89 140-159 / 90-99

120-129 /80-84
130-139 / 85-89 140-159 / 90-99

Prehypertension
Prehypertension Stage 1 Hypertension

Grade 2 Hypertension (moderate)


Grade 3 Hypertension (severe) Isolated Systolic Hypertension

160-179 /100-109
> 160 / > 100 > 180 / >110 > 140 < 90

Stage 2 Hypertension

Isolated Systolic Hypertension

Impact of High Normal Blood Pressure on CVD Risk


14 12 High Normal

10
8 6 4 2 0 0
No. at risk Optimal Normal High Normal

Normal

Optimal

Time (years)
995 1039 879 973 1012 857

10

12

1005 1059 903

962 982 819

934 952 795

892 892 726

454 520 441

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

Benefit of Hypertension Treatment

Benefit of Hypertension Treatment

Meta-Analysis: Lower Systolic BP Results in Slower Rates of Decline in GFR in Patients with/out DM
SBP (mm Hg)
130
0

134

138

142

146

150

154

170

180

GFR (mL/min/y)

-2

r = 0.69; P < 0.05


-4 -6 -8 -10 -12

Untreated hypertension

-14
Parving HH et al. Br Med J. 1989. Viberti GC et al. JAMA. 1993. Klahr S et al. N Eng J Med. 1994. Hebert L et al. Kidney 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.

Bakris et al. Am J Kidney Dis. 2000;36:646

Mortality is Reduced When Blood Pressure is Controlled*


Cardiovascular deaths (%)
8 7 6 5 4 3 2 1 0 *** *** Controlled Uncontrolled

CVD mortality
RF adjusted cardiovascular 1.66[1.042.64] relative risk

CAD mortality
2.35[1.035.35] ***p<0.001 v uncontrolled group

Benetos A, et al. Arch Intern Med 2002; 162: 577-81.

* Study conducted in hypertensive men

(LANCET 2000)
35 40 % mean reduction in stroke

20 25 % decrease in MI incidence
> 50 % reduction in CHF

BENEFITS OF BP LOWERING

Stage I Hypertensive Patients with CVD Risk Factors Sustained 12-mmHg decrease in systolic BP for 10 years prevents 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

BENEFITS OF BP LOWERING
Adapted from THE JNC7 REPORT 2003

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 J 2003; 24: 1601-10.

Development of Antihypertensive Drugs


Reserpin (1949)
1950 HCT (1958) 1960

Diuretics Beta blockers

Verapamil (1963)
Furosemide (1964) Propanolol (1965)

1970
Nifedipin (1975)

CCBs 1-blockers ACE-inhibitors

Diltiazem (1980) 1980 Captopril (1981) Amlodipine (1987) Bisoprolol (1988) Losartan (1995) 1990 Valsartan

Prazosin (1977)

AT-antagonists/ARB

2000 ?

Lifestyle Modification
Lifestyle Modification Aproximate SBP Reduction

___________________________________________________ ___________

Weight reduction Adopt DASH eating plan Dietary sodium reduction

5-20 mmHg/10 kg weight loss 8-14 mmHg 2- 8 mmHg

Physical activity
Moderation of alcohol consumption

4- 9 mmHg
2- 4 mmHg

Therapeutic Strategies of Hypertension ESH-ESC Guidelines 2003


J.hypertension 2003 ,21, 1011 - 1053

Choose between Single agent at low dose 2 drug combination at low dose If goal BP not achieved Previous agent at full dose Switch to different Agent at low dose Previous combination at full dose Add a third drug at low dose

If goal BP not achieved


2-3 drug combination 3 drug combination at effective dose

Algorithm of Hypertension Treatment


Lifestyle Modifications Not at Goal Blood Pressure (<140/90 mmHg)
(<130/80 mmHg for those with diabetes or chronic kidney disease)

Initial Drug Choices


Without Compelling Indications With Compelling Indications

Stage 1 Hypertension (SBP 140159 or DBP 9099 mmHg) mono or combination.

Stage 2 Hypertension
(SBP >160 or DBP >100 mmHg) 2-drug combination for most

Drug(s) for the compelling indications


Other antihypertensive drugs

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

Diuretics
Mean arterial pressure Lipid profile Insulin resistance Primary prevention
Unfavourable or

Secondary prevention

Limited
Decrease Increase No effect Evidence for efficacy

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

Beta-Blockers
Mean arterial pressure Lipid profile Insulin resistance Primary prevention
Unfavourable

(MI)

Secondary prevention

Decrease Increase No evidence for efficacy Evidence for efficacy

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

Calcium Channel Blockers


Mean arterial pressure Lipid profile Insulin resistance Primary prevention
Neutral

(non-DHPs only) (non-DHPs only)

Secondary prevention

Decrease No effect Evidence for efficacy

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

Angiotensin-Receptor Blockers
Mean arterial pressure Lipid profile Insulin resistance Primary prevention
Neutral Some evidence

Secondary prevention

Some evidence
Decrease

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

ACE Inhibitors
Mean arterial pressure Lipid profile Insulin resistance Primary prevention
Neutral

Secondary prevention

Decrease Evidence for efficacy

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

MECHANISM OF ACTION :

Angiotensinogen

K in in o g e n K a lik r e in

Angiotensin I ACE

B r a d ik in in
ACE

ACE INHIBITOR
Angiotensin II

P e p tid a In a k tif

Antihypertensive Agents: Summary of Efficacy


Diuretics Betablockers ACE inhibitors Calcium channel blockers Angiotensinreceptor blockers

Mean arterial pressure

Lipid profile
Insulin resistance Primary prevention Secondary prevention

Unfavourable Unfavourable Neutral


or

Neutral

Neutral
Some evidence Some evidence

(non-DHPs) (non-DHPs)

Limited

Decrease Increase No effect Evidence for efficacy No evidence for efficacy

JNC VII - Basis for The Compelling Indications for Individual Drug Classes
High-risk condition with compelling indications Diuretic
HF Post MI High Coronary disease Risk DM Chronic Kidney Disease Recurrent Stroke prevention

Recommended drugs
Beta Blocker

AR ACE I B

AldosteCCB rone antagonist

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

Possible Combinations of Antihypertensive Agents


Diuretics

Beta-blockers

Angiotensin- receptor blockers

Alpha-blockers

Calcium channel blockers

ACE inhibitors
Guidelines Committee. J Hypertens 2003; 21: 1011-53.

ACE Inhibitor Lisinopril and Study

ATLAS

- Assessment of Treatment with

Lisinopril and Survival Study


Comparative 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

ATLAS: Conclusion
A non-significant 8% risk reduction in primary endpoint of all-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% risk reduction 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 established the therapeutic strategy for physicians to increase the dose of lisinopril in heart failure

ACUTE MYOCARDIAL INFARCTION


Once daily Lisinopril may be used for the treatment of hemodynamically stable patients within 24 hours of an acute myocardial infarction, to prevent the subsequent development of left ventricular dysfunction or heart failure and to improve survival
Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin and beta-blockers

GISSI-3
Gruppo 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 Lancet 1994; 343: 1115-1122

GISSI-3: Results
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
GISSI-3 Study Group. Lancet 1994; 343: 1115-1122

EUCLID
EUrodiab Controlled trial of Lisinopril in Insulin dependent Diabetes
Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependant diabetes and normoalbuminurea or microalbuminurea EUCLID Study Group

Lancet 1997; 349: 1787-1792

EUCLID
EUrodiab 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. Lancet 1997; 349: 1787-1792

EUCLID: Conclusions
In Type 1 diabetes patients without hypertension Lisinopril slows the progression of renal disease in normoalbuminuric and microalbuminuric patients
Greatest benefits were seen in microalbuminuric patients

EUCLID Study Group. Lancet 1997; 349: 1787-1792

EUCLID
EUrodiab Controlled trial of Lisinopril in Insulin dependent Diabetes Effect of lisinopril on progression of retinopathy in normotensive people with Type 1 diabetes

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

Lancet 1998; 351: 28-31

EUCLID
Retinopathy data
Retinopathy, a diabetic complication which shares the risk factors of nephropathy 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
Chaturvedi N, Sjolie A-K, Stephenson JM et al. Lancet 1998; 351: 28-31

EUCLID: Conclusions Retinopathy data

In Type 1 diabetes patients without hypertension lisinopril slows the progression of retinopathy independent of the degree of renal disease

Chaturvedi N, Sjolie A-K, Stephenson JM et al. Lancet 1998; 351: 28-31

Achieving Success in

Management of Hypertension

Barriers To Achieve BP Goals


Poor compliance Under aggressiveness of physician in HT treatment Wrong medication ; not proper combination ; medication interfering risk with BP control White coat HT Pseudo HT Secondary HT

Patterns Of Compliance: Antihypertensive Therapy

Noncompliant 33% Adequate 56% Perfect 11%

(Noncompliance is characterized by patients who Meredith PA: Clinical Relevance of Pharmacokinetics in Cardiovascular Therapy Symposium, February 25, 1994. take 40-80% of doses and by drug holidays)

Factors to Consider in the Choice of an Antihypertensive Drug

Antihypertensive effects Safety Patient acceptance Cost Number of doses per day Need for laboratory follow-up Mechanism of action Potential interaction with other drugs Additional salutary effects

Epstein M, Oster JR. In: Hypertension. A Practical Approach. 1984:112-118

General Guidelines to Improve Patient Adherence to Antihypertensive Therapy


Be aware of signs of patient non-adherence to antihypertensive therapy. Establish the goal of therapy; to reduce blood pressure to non-hypertensive levels with minimal or no adverse effects. Educate patients about the disease, and involve them and their families in its treatment. Have them measure blood pressure at home. Maintain contact with patients; consider telecommunication. Keep care inexpensive and simple.

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, in sufficient doses to achieve the goal of therapy. Encourage a positive attitude about achieving therapeutic goals. Consider using nurse care management.

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