The Important Antihypertensive

Agent in Preventing the Progression

of Cardiovascular Demages

Djanggan Sargowo

Batu, 2004

HYPERTENSION

Worldwide 1 billion people

USA 50 million people
Prevalence will be higher if
there are no effective
preventions

HYPERTENSION
In INDONESIA complex problems:

Etiology
Prevention
Early detection
Management
Monitoring
Socio economic
Education
Income
Etc.
3

ETIOLOGY OF HYPERTENSION

Rudnie,Danilson & Sinclair (5.448 P. Hy)

Essential hypertension
Renal disease
Coarctasion of Aorta
Primary Aldosteronism
Cushings syndrome
Prehormacytoma
Oral Contraceptive induced

: 92,1 95,3 %
: 3,4 6,3 %
: 0 0,2 %
: 0 0,3 %
: 0,1 0,2 %
: 0 0,2 %
: 0,2 1 %
4

NATURAL HISTORY OF HYPERTENSION

Age

HEREDITY - ENVIRONMENT

Normotension

PRE - HYPERTENSION

0 - 30

EARLY HYPERTENSION

20 40

ESTABLISHED HYPERTENSION

30 50

UNCOMPLICATED

Accelerated
CARDIAC
Malignant Hypertrophy
course
Failure
Infarction

COMPLICATED

LARGE
VESSEL
Aneurysm
Dissection

CEREBRAL
Ischemia
Thrombosis
Hemorrhage

40

RENAL
Nephrosclerosis
Failure
5

CVD Risk Factors

Hypertension*
Cigarette smoking
Obesity* (BMI >30 kg/m2)
Physical inactivity
Dyslipidemia*
Diabetes mellitus*
Microalbuminuria or estimated GFR <60 ml/min
Age (older than 55 for men, 65 for women)
Family history of premature CVD
(men under age 55 or women under age 65)
*Components of the metabolic syndrome.

WHO-ISH (1999)
Klasifikasi Derajat Tekanan Darah menurut WHO-ISH 1999
yang diadaptasi dari JNC VI 1997

1
2
3
4
5
6
7

Kategori

Sistolik
(mmHg)

Diastolik
(mmHg)

Optimal
Normal
Normal Tinggi
Hipertensi derajat 1 (ringan)
Subgrup : perbatasan
Hipertensi derajat 2 (sedang)
Hipertensi derajat 3 (berat)
Hipertensi Sistolik
(Isolated Systolic Hypertension)

120
130
130 - 139
140 - 159
140 - 149
160 - 179
180
140

80
85
85 - 89
90 - 99
90 - 94
100 - 109
110
90
7

The hypertension to heart failure continuum

Hypertension
Hypertension
Coronary risk
factors

Coronary
Coronaryartery
artery
disease
disease

Myocardial
Myocardial infarction
infarction

LV
LVhypertrophy
hypertrophy
LV dilation

Remodelling

Diastolic

LV dysfunction

LV damage
Systolic

Heart
Heart failure
failure
Symptoms

Decreased tissue
perfusion

Increased
hospitalisations

Death

Hemodynamic overload
Hypertension

Myocardial Infarction

Hemodynamic Overload
Myocardial Remodeling
Myocardial Failure
9

Myocardial Remodeling
Systolic Overload
Hypertension
Aortic Stenosis

Diastolic Overload
Myocardial Infarction
Valvular Regurgitation

Concentric
Hypertrophy

Eccentric
Hypertrophy
10

Factors Controlling LVH in

Hypertension
BLOOD PRESSURE

AGE

EXERCISE
GENDER
COEXISTENT
CARDIAC
DISORDERS

ADRENERGI
C
SYSTEM

LVH

WEIGHT

INSULIN, GROWTH,
THYROID HORMON
RENINANGIOTENSIN
SYSTEM

11

Impaired
LV filling

Myocardial
Ischemia
Infarction

Sudden
death

Arrhythmia

Heart
failure
LVH
Impaired
contractility
12

The Cardiovascular Continuum

MI
Loss of
muscle

CAD

Endothelial dysfunction
Microvascular Disease
Atherosclerosis
&
LVH
Risk factors
Hyperlipidemia
HTN
Diabetes
Smoking
Insulin resistance

Neurohormonal
activation

LV
Remodeling
Ventricular dilation
HF
End-stage Microvascular
& Heart Disease

Adapted with permission from Dzau V, Braunwald E. Am Heart J. 1991;121:1244-1263.

Death

13

HYPERTENSION
THE LATEST GUIDELINES:
The
TheSeventh
SeventhReport
Reportof
ofthe
the
JOINT
JOINTNATIONAL
NATIONALCOMMITTEE
COMMITTEE
on
onPrevention,
Prevention,Detection,
Detection, Evaluation,
Evaluation,and
andTreatment
Treatment
of
of High
High Blood
Blood Pressure
Pressure(JNC
(JNCVII)
VII)(May,
(May,2003)
2003)
2003
2003Guidelines
Guidelinesfor
forthe
themanagement
management of
of hypertension
hypertension
from
fromEuropean
EuropeanSociety
Societyof
of Hypertension
Hypertension
European
EuropeanSociety
Societyof
of Cardiology
Cardiology(ESH
(ESHESC
ESC2003)
2003)
(June,
(June,2003)
2003)
14

JNC VII
NEW GUIDELINES IN JNC VII:
1. Classification and Management of
Blood Pressure for Aduls
2. Patient Evaluation
3. Treatment

15

1. Classification and
Management of
Blood Pressure for
Adults
16

Classification of Hypertension
JNC V (1988)

Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Presure (JNC)

BP Range, mmHg

Category

BDP
< 85

Normal BP

85 89

High normal BP

90 104

Mild Hypertension

105 114

Moderate hypertension

> 115

Severe Hypertension

SBP, when
DBP < 90 mmHg
< 140

Normal BP

140 159

Borderline isolated systolic H.

> 160

Isolated systolic Hypertension

17

JNC VI (1997)
Blood Presure
Normal
Normal high
Stafe 1
Stage 2
Stage 3

Systolic
( mmHg )
< 130

Diastolic
( mmHg )
< 85

130 139
140 159
160 179
> 180

85 89
90 99
100 109
> 110

18

JNC VII
Blood Presure
(mmHg)

Normal

SBP

DBP

< 120

and

< 80

Prehypertension

120 139

or

80 89

Stage 1 H.

140 159

or

90 99

Stage 2 H.

> 160

or

> 100

19

The Aims of Hypertension

Management
Decrease mortality and morbidity
Restore blood pressure to normal levels1
Maintain blood pressure at TD < 140/90
mmHg2
1. 1999 World Health Organisation-International Society of Hypertension Guidelines for the Management of
Hypertension.
2. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of
High Blood Pressure

20

The Ideal of Antihypertension Drug

Decrease cardiac output

Decrease systemic peripheral resistense
Maintain the normal cardiac output
Maintain organ perfussion

21

Cardioprotective Effect of
Antihypertension Drugs
Prevents atherosclerosis
progression Prevents hearth
attacks
Prevent and regression of LVH
Does not increase risk factors
22

2.a. Management of treatment :

- Based on Risk Stratification
- We start with antihypertensive drugs:
Very High Risk
High Risk
Moderate Risk ( if BP didnt after
3 months non-pharmocology treatment)
Low Risk (if BP didnt after
3 - 12 months non-pharmocology treatment)

23

Risk Stratification and Treatment (JNC-VI)

Risk Group B
(At Least 1 Risk
Risk Group A
Factor, Not Including
Blood Pressure Stages (No Risk Factors Diabetes; No
(mmHg)
No TOD/CCD)
TOD/CCD)

Risk Group C
(TOD/CCD and/or
Diabetes, With or
Without Other Risk
Factors)

High-normal
(130-139/89-89)

Lifestyle
modification

Drug therapy

Stage 1
(140-159/90-99)

Lifestyle
Lifestyle
modification
modification
(up to 12 months) (up to 6 months)

Drug therapy

Stages 2 and 3
(> 160/> 100)

Drug therapy

Drug therapy

Lifestyle
modification

Drug therapy

For example, a patient with diabetes and a blood pressure of 142/94 mmHg plus left ventricular
hypertrophy should be classified as having stage 1 hypertension with target organ disease (left
ventricular hypertrophy) and with another major risk factor (diabetes). This patient would be categorized
as Stage 1, Risk Group C, and recommended for immediate initiation of pharmacologic treatment. 24

2. PATIENT
EVALUATION
25

2. PATIENT EVALUATION:
2.1. To asses lifestyle and identify
other cardiovascular risk
factors or concomitant
disorders that may effect
prognosis and guide treatment

26

2. PATIENT EVALUATION
2.2. To reveal identifiable causes
of high Blood Pressure
2.3. To assess the presence or
absence of target organ
damage and CVD
27

3. TREATMENT

28

ESH ESC 2003

NEW GUIDELINES IN ESH-ESC 2003:
1. Classification and Risk Stratification
2. Treatment
2.1. Management of treatment
2.2. Indication & contra-indication of 6
antihypertensive drugs
29

1999 WHO-ISH Guidelines for Initiation

of Anti-Hypertensive Treatment
The six classes of antihypertensive agents
listed in the new WHO/ISH guidelines :

Diuretics
Beta-blockers
ACE Inhibitors

Calcium antagonists
Alpha-blockers
Angiotensin II Receptor Blockers

Guidelines Subcommitte 1999 WHO-Intl Society of Hypertension. Guidelines for

Management of Hypertension. J Hypertens 1999;17:151-83

30

JNC
JNCVII
VII
2003
2003

Classification and Management

of BP for adults

Lifestyle
BP
SBP* DBP*
classification mmHg mmHg modification

JAMA.2003;289

Initial drug therapy

Without compelling
indication

Normal

<120

and
<80

Encourage

Prehypertens
ion

120
139

or 80
89

Yes

No antihypertensive
drug indicated.

Stage 1
Hypertension

140
159

or 90
99

Yes

Thiazide-type diuretics
for most. May consider
ACEI, ARB, BB, CCB,
or combination.

Stage 2
Hypertension

>160

or >100

Yes

With compelling
indications

Drug(s) for
compelling
indications.

Drug(s) for the

compelling
indications.
Other
Two-drug combination antihypertensive
drugs (diuretics,
for most (usually
ACEI, ARB, BB,
thiazide-type diuretic
CCB) as needed.
and ACEI or ARB or
31
BB or CCB).

JNC
JNCVII
VII
2003
2003
2003

Compelling indications
Heart Failure
Post Myocardial Infarction
High Coronary Art. Disease Risk
Diabetes
Chronic Kidney Disease
Recurrent Stroke Prevention
JAMA.2003;289

32

Lifestyle Modifications to
Prevent and Manage Hypertension
Reduce weight

Increase
physical
activity

Moderate consumption of:

alcohol
sodium
saturated fat
cholesterol

Maintain adequate intake of dietary:

potassium
calcium
magnesium

(JNC VI. Arch Intern Med. 1997)

Avoid tobacco
33

Development of Antihypertensive Drugs

Reserpin (1949)

1950
HCT (1958)

1960

Diuretics

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

Beta blockers

1970
CCBs
1-blockers
ACE-inhibitors

Nifedipin (1975)
Prazosin (1977)

1980

Captopril (1981)

1990

Losartan (1995)
Valsartan

AT1-antagonists

2000

34

INDICATIONS FOR INDIVIDUAL DRUG CLASSES

Compelling
indications
Heart failure

Diuretic -blocker

Post-MI
High coronary
disease risk
Diabetes

Chronic
kidney disease
Stroke
prevention

ACE
inhibitor

ARB

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

CCB

35

JNC
JNCVII
VII
2003
2003

Hypertension
Hypertension
Without
Without
Compelling
Compellingindication
indication

Stage 1 Hypertension
Syst. 140 159 OR
Diast. 80 90 mmHg

Stage 2 Hypertension
Syst. > 160 mmHg OR
Diast > 100 mmHg

Thiazide type diuretics

for most

2 Drug Combination
for most

May consider ACE inh,

ARB, CCB, Betablocker
Or Combination

Usualy thiazide type with

ACE inh. or ARB or Beta
Blocker or CCB

JAMA.2003;289

36

Treatment Algorithm for Adults with Systolic-Diastolic

Hypertension without another compelling indication
TARGET <140/90 mmHg
INITIAL TREATMENT AND MONOTHERAPY

Lifestyle modification
therapy

Thiazide

ACE-I

ARB

Long-acting
DHP-CCB

Betablocker
Alpha-blocker
as initial
monotherapy

2003 Canadian Hypertension Education Program Recommendations.

37

JNC
JNCVII
VII
2003
2003
JAMA. 2003;289

Hypertension
With
Compelling Indication
Drugs for the compelling indications.

PRICE
HEART
FAILURE /
LV DYSFUNCTION

Diuretic

Betablocker
Ec : Maintate
( Tanabe )

ACE inh / ARB.

Ec: Tanapress
( Tanabe )

CCB* Ec :
Herbesser CD
( Tanabe )

METABOLIC ( ec : DM )/ COPD

C.H.D /
ANGINA
CCB* : Calcium
Channel Blocker

38

The Renin-Angiotensin System

Alternate Pathway

Local

Circulating

Tissue

Liver

Angiotensinogen
Renin inhibitors

Renin

Non Renin pathways

- t-PA
- Cathepsin G
- Tonin

Angiotensin I
ACE inhibitor

Converting enzyme

Non-ACE pathways
- Chymase
- CAGE
- Cathepsin G

Angiotensin II
AII receptor blockers

Angiotensin
receptors

39

ACE INHIBITOR (ACEI)

Indikasi Spesifik dari ACEI

Hipertensi ringan, sedang, berat

Hipertensi disertai hipertropi ventrikel kiri
Gagal jantung kiri
Miokard infark disertai remodeling
Diabetes disertai mikroalbuminuria
Hipertensi disertai
Penyakit vaskuler perifer
Penyakit jalan nafas obstruktif menahun
Depresi
40

TANAPRESS Selectively Inhibit RAA System

41

Inhibitory effects on tissue ACE activity

ACE Activity in the Thoracic Aorta
(nmol/min/mg protein)

12

P < 0.05

10
8
6
4
2
0
Control

Captopril
(5 mg/kg/day)

Enalapril

Imidapril

(5 mg/kg/day) (5 mg/kg/day)

Subjects : Young male SHRs (n = 7 8)

Method

: Inhibition of ACE activity was measured 9 days after stopping

administration of ACEIs for 10 weeks.

Kubo M et al. Jpn J Pharmacol 57(4): 517-26 (1991)

42

43

44

Change
Changein
inExercise
ExerciseDuration
Duration
after
after12
12weeks
weekstreatment
treatmentwith
withIMIDAPRIL
IMIDAPRIL

Change
Changein
inPhysical
PhysicalWorking
WorkingCapacity
Capacity(PWC)
(PWC)
after
after12
12weeks
weekstreatment
treatmentwith
withIMIDAPRIL
IMIDAPRIL

45

TANAPRESS Optimally Control Blood Pressure

With Once Daily Regimen

46

TANAPRESS Reduce Urinary Albumin Excretion at Similar Degress

Compared to Captopril in Diabetic Patients with Hypertension

47

AT1-receptor blockers:
improving heart function

Reducing hypertension [1]

Reducing LV hypertrophy/improving
LV relaxation
Antagonising adverse effects of
elevated neurohormones
Reducing aldosterone levels
Maintaining renal function

Goodfriend et al. N Engl J Med 1996; 334: 164954

2. Swedberg et al. J Card Failure 1999; 5: 27682
1

48

Role of ARBs in
The Cardiovascular Continuum
MI

CAD
Endothelial dysfunction
Microvascular Disease
Atherosclerosis
&
LVH

OPTIMAAL
VALIANT

ONTARGET
TRANSCEND
LIFE

VALUE
Risk factors
SCOPE
Hyperlipidemia
Hipertensi
NAVIGATOR
Diabetes
Smoking
Insulin resistance

Loss of
muscle

LV
Remodeling
Elite II
Val-HeFT
CHARM
RENAAL
IDNT
IRMA-2
MARVAL

Ventricular dilation
HF

End-stage Microvascular
& Heart Disease

Death

49

Compelling Indications for

Individual Drug Classes
Compelling Indication

Initial Therapy Options

Clinical Trial Basis

Heart failure

THIAZ, BB, ACEI, ARB,

ALDO ANT

ACC/AHA Heart Failure

Guideline, MERIT-HF,
COPERNICUS, CIBIS,
SOLVD, AIRE, TRACE,
ValHEFT, RALES

Postmyocardial
infarction

BB, ACEI, ALDO ANT

ACC/AHA Post-MI
Guideline, BHAT,
SAVE, Capricorn,
EPHESUS

High CAD risk

THIAZ, BB, ACE, CCB

ALLHAT, HOPE,
ANBP2, LIFE,
CONVINCE
50

THE CARDIOVASCULAR CONTINUUM

Myocardial
infarction
Coronary
thrombosis
Myocardial
ischaemia
CAD
Atherosclerosis
LVH

Risk factors

smoking,hypertension
cholesterol, diabetes

Arrhythmia &
loss of muscle

Adrenergic
blockade

Remodelling
Ventricular
dilatation
Congestive
heart failure

Death
51

ACTIVATION AND BLOCKADE OF

NEUROHUMORAL SYSTEM IN CHF
RAA System

SNS System

Angiotensin II

Noradrenalin

ACE-I

-Blocker

Hypertrophy, apoptosis, ischemia,

arrhythmia, remodelling, fibrosis
52

WHERE -BLOCKERS WORK

Sudden
Sudden
death
death
Angina
Angina
Ventricular
Ventricular
arrhythmias
arrhythmias

Hypertension
Hypertension
Coronary
Coronary
artery
artery
disease
disease

Diabetes
Diabetes

Hyperlipidemia
Hyperlipidemia
Hypertrophic
Hypertrophic
cardiomyopathy
cardiomyopathy

Myocardial
Myocardial
infarction
infarction

Cardiac
Cardiac
rupture
rupture

LV
LV
dysfunction
dysfunction

Atrial
Atrial
fibrillation
fibrillation

Mechanical
Mechanical
death
death

Heart
Heart
failure
failure

Pump
Pump
failure
failure

53

Antihypertensive

Anti-ischemic

-blocking
-blocking
agents
agents
Antiarrythmic

Treatment for heart failure

54

Not all -BLOCKERS are the same !

NON
SELECTIVE
ISA Nadolol

ISA +
Pindolol

Propanolol
Penbutolol
Timolol

Alprenolol

Sotalol Oxprenolol

SELECTIVE
ISA Atenolol

ISA +
Acebutolol

Non-selective wit
alfa-blocking activ
Labetolol
Bucindolol
Carvedilol

Esmolol Celiporlol
Metoprolol

Bisoprolol
Bisoprolol
Betaxolol

55

All- Caused Mortality

34%

p < 0.0001

Sudden Death

44%

p < 0.0011

Hospitalization Due To Worsening

Heart Failure

36%

p < 0.0001

All- Caused Hospitalization

20%

p < 0.0006

CIBIS II
Diabetic (%)
Renal impairment(%)
NYHA IV (%)
Elderly (mean age-year)
Antiarrhytmic drug (%)
*no data

12
33
17
61
15

MERIT-HF
25
*
3
64
0

COPERNICUS

*
*
100
63
18

Modified from:CIBIS II,Lancet,Vol.353,1999

56

Treatment Algorithm for Adults with Systolic-Diastolic

Hypertension without another compelling indication
TARGET <140/90 mmHg
INITIAL TREATMENT AND MONOTHERAPY

Lifestyle modification
therapy

Thiazide

ACE-I

ARB

Long-acting
DHP-CCB

Betablocker
Alpha-blocker
as initial
monotherapy

2003 Canadian Hypertension Education Program Recommendations.

57

METABOLISM OF VARIOUS -BLOCKER

%
100

50

Atenolol Bisoprol
ol

Betaxolol Metoprolol

Balanced clearance

Metabolites
Unchanged
substance

Leopold G.J.Cardiovasc. Pharmacol. 1986; 8(Suppl.

11): 16-20

58

Survival Rate of Bisoprolol

Survival

34% reduction in all-cause mortality with bisoprolol

Bisoprolol
p 0,0001

placebo
200

400

600

800

Time after inclusion (days)

CIBIS-II, Lancet, Vol. 353, 1999

59

BISOPROLOL : NEUTRAL EFFECT ON

LIPID METABOLISM
8
7

Mmol/l

6
5
4
3
2
1
Start

1 Year

Total cholestrol

2 Years
Triglycerides

3 Years

4 Years

HDL-cholesterol

5 Years
LDL-cholesterol

Frithz G.5th Internat Symposium on Cardiovascular Pharmacotherapy,Minneapolis,Abstract 1993

60

BISOPROLOL :
Neutral Effect on Glucose Metabolism
Glucose (mg/dl)
170

HbA1 (%)
10

160

150
140

130

120

110
A

A: Initial Value B: after 2 weeks of C: after 2 weeks of

Bisoprolol
placebo
Janka HU etal.J Cardiovasc Pharmacol 1986; 8

61

BISOPROLOL : Circadian rhythm

(mmHg)

180
160
140
120

SBP

100
80

DBP

60

3 5
7
9 11
Last day of placebo

13

After 4 weeks of Bisoprolol

15

17

19

21

23

62

Bisoprolol : Dose-dependent blood

pressure reduction in hypertensives
mmHg
0

28

56

84

mmHg
Days
28
0

-10

-10

-20

-20

-30

-30

-40

SBP

-40
5 mg

10 mg

56

84

Days

DBP
20 mg Bisoprolol

Kirsten,R.,et al.;J. Cardiovasc. Pharmacol. 8(Suppl.11)

(1986):S 11

63

RECENT STUDIES REPORTING INCREASED

RISK WITH ANTIHYPERTENSIVE DRUGS
Short acting Calcium Antagonist-particulary at high
doses-increase MI risk in Hypertensive patients
(Psaty et. Al. JAMA 1995; 274 : 629-625)
Short acting Nifedipine increase mortality risk in
patients with CHD
(Furberg et al. Circulation 1995; 92:1326-1331)
Short - acting nifedipine has not approved by the Food
and Drug Administration of USA for the treatment of
hypertension.
(Bassett et al. Journal of Hypertension 1997; 15:915-923)
64

PREVENT: Hospitalization for Unstable Angina

and Major Vascular Procedures by Treatment

Cumulative Event/
Procedure Rate (%)

Documented Unstable Angina/

Congestive Heart Failure

Any Revascularization

30.0

30.0

25.0

25.0
Placebo (n=408)

20.0

35%

15.0

Placebo

20.0

43%

15.0

P=.01 10.0

10.0
5.0

Amlodipine besylate (n=417)

P=.001

5.0

Amlodipine besylate

0.0

0.0
0

12

18 24

30 36

Months of Follow-up

12

18 24

30 36

Months of Follow-up

Pitt et al. Circulation.

Circulation. 2000;102:15032000;102:1503-1510.

65

EFFEK KARDIOPROTEKTIF CALSIUM ANTAGONIST

MENURUNKAN KEBUTUHAN OKSIGEN MIOKARDIUM
Menurunkan Tekanan Darah
Menurunkan Denyut Jantung
MENEKAN KERUSAKAN SEL MIOKARDIUM AKIBAT
INFLIKS ION CA++ YANG BERLEBIHAN KE DALAM SEL
Menekan peningkatan ion Ca++ di dalam sel miokardium
Menekan penurunan ATP & CP di dalam sel miokardium
MENINGKATKAN PENYEDIAAN OKSIGEN MIOKARDIUM
Menghilangkan spasme koroner
Meningkatkan aliran darah sub-endokardium
Menurunkan denyut jantung
(memperpanjang periode diastolik)
Menekan sklerosis koroner
EFEK : Anti Aritmia

66

Placebo (n=294)
50

Amlodipine (n=291)

40
30
20
10
0

67

Articel
Diltiazem in the management of acute myocardial
infarction treated with trombolythic agents ;
a randomized controlled trial
William E Boden et al for the INTERCEPT study group

THE LANCET Vol 355

May 20

2000 1751 -1756

68

INTERCEPT : Purpose
THE INCOMPLETE
INFARCTION

TRIAL OF
EUROPEAN
RESEARCH
COLLABORATORS
EVALUATING
PROGNOSIS
POST-THROMBOLYSIS

BACKGROUND
Diltiazem reduces

Non-fatal reinfarction,
Refractory ischaemia after nonQ-wave myocardial infarction
(acute coronary syndrome).

PURPOSE

To evaluate whether diltiazem

would reduce cardiac events in
patients after acute MI treated
initially with thrombolytic agents.

BODEN WE et al . LANCET 2000; 355: 1751-175669

INTERCEPT : RESULTS (1)

Primary endpoint
Number of events
Diltiazem

Hazard
Placebo Ratio

95% CI

P
Value

All CV events

97

131

0.79

0.61-1.02

0.07

Non fatal CV
events

90

125

0.76

0.58-1.00

0.05

Refractory
ischaemia

74

103

0.76

0.56-1.02

0.07

All recurrent
ischaemia

116

153

0.80

0.63-1.02

0.07

Need PTCA /
CABG

46

75

0.67

0.46-0.96

0.03

PTCA / CABG

30

53

0.61

0.39-0.96

0.03

alone

BODEN WE et al . LANCET 2000 ; 355 : 1751-175670

INTERCEPT : RESULTS (2)

1.20
1.10

Diltiazem reduced non-fatal cardiac death, non-fatal

reinfarction or refractory ischemia, and the need for
PTCA / CABG in Acute Myocardial Infarction (AMI).
Cardiac death
+ Non-fatal
reinfarction +
Refractory
ischemia

Cardiac death
+ Non-fatal
reinfarction +
All recurrent
ischemia

21%
P= 0.07

19%
P= 0.07

Cardiac death
+ Non-fatal
reinfarction +
PTCA/CABG

Non-fatal
reinfarction
+
Refractory
ischemia

Non-fatal
reinfarction
+ All
recurrent
ischemia

Non-fatal
reinfarction
+
PTCA/CAB
G

PTCA/CAB
G

24%
P= 0.05

20%
P= 0.05

33%
P= 0.03

39%
P= 0.03

1.00
0.90
0.80
0.70
0.60
0.50

29%
P= 0.05

BODEN WE et al . LANCET 2000; 355 : 1751-1756 71

INTERCEPT : CONCLUSION
The INTERCEPT showed that diltiazem reduce all
composite endpoints of non-fatal cardiac events:
reinfarction (21%),
refractory ischemia (24%),
recurrent ischemia (20%),
the need for PTCA/CABG (39%).
The implications of the INTERCEPT findings are
important to cardiovacular therapeutics of Heart rate
lowering Calcium Antagonists - Diltiazem

in the

management of ACS.
BODEN WE et al . LANCET 2000 ; 355 : 1751-1756 72

NORDIL : The NORdic DILtiazem Study

A Prospective Intervention Trial of
Ca-Antagonist Therapy in Hypertension

N O R D IL

As Evidenced based Medicine

( Lancet 2000 )

73

NORDIL Relative risk

Relative risk
(95%CI)

Primary endpoint

1.00
(0.87-1.15)

0.97

Stroke
(fatal and non-fatal)

0.80
(0.65-0.99)

0.04

Myocardial infarction
(fatal and non-fatal)

1.16
(0.94-1.14)

0.17

Diltiazem
0.5

/D
1.0

2.0

Adjusted for age, sex, diabetes, blood pressure and smoking

THE LANCET Vol 356 July 29

2000 359-365

74

Stroke
%
5

Conventional
Diltiazem

Patients with
event

4
3
2

1
0

5 Years

75

Myocardial infarction
Patients with event

%
5

Conventional
Diltiazem

4
3
2
1
0

3
Years

76

The NORDIL Study

- Stroke and MI in subgroups Stroke % 6

5
4
3
2
1
Patients at risk
-blockers/diuretics
Diltiazem
MI

DBP < 105

DBP 105
%6
Percentage
5
of patients
4
with stroke
3
(above) and
2
MI (below)
1
p = 0.030
n.s.
0
0
0 1 2 3 4 5
0 1 2 3 4 5
2493
2427
1545
-bl/diur
2974
2868 2002
1516
2501
2450
2905
2823 1978
Diltiazem
%6
5
4
3
2
n.s. 1
0
0 1 2 3 4 5
0 1 2 3
2493
2433
2974
2889
1543
1509
2501
2905
2445
2820

%6
5
4
3
2
1
0

Patients at risk
-blockers/diuretics
Diltiazem

n.s.
4 5
2022
1971

77

Conclusion
NORDIL study showed:
( 10.881 patients 50 74 years old , follow up 4.5 years )

Diltiazem was as effective as the beta-blocker and/or

diuretics in preventing CV mortality and morbidity.

Diltiazem ( Herbesser ) reduced fatal and non-fatal

stroke 20% more than conventional therapy.
78

Combination Drugs of
Hypertension
Diuretics

ACE Inhibitor (ARB)

- blocker

C.C. Blocker

79

PERCENTAGE OF PATIENTS WHO

NEEDED COMBINATION THERAPY
COOPE
INSIGHT
MRC1
NORDIL
STOP1
Syst-Eur
Average
0

10

20

30

40
50
60
70
% OF PATIENTS

80

90

100
80

POSSIBLE COMBINATIONS OF DIFFERENT

CLASSES OF ANTIHYPERTENSIVE AGENTS
DIURETICS

BETHA
BLOCKERS

AT1- RECEPTOR
BLOCKERS

ALFA
BLOCKERS

CALCIUM
ANTAGONISTS
ACE
INHIBITORS

81

Efective drug combinations

Diuretic and -blocker
Diuretic and ACE Inhibitor or AIIRA
Calcium antagonist (dihydropyridine)
and -blocker.
Calcium antagonist and ACE inhibitor.
-Blocker and -blocker

82

Thank
You

83