Targeting Blood Pressure Targeting Blood Pressure for Cardiovascular Risk for Cardiovascular Risk

PreventionPrevention

Dr. Aulia Sani, SpJP (K), FJCC, FIHA, FAsCCDepartemen Kardiologi dan Kedokteran Vaskuler FKUI / Pusat Jantung Nasional Harapan Kita, Jakarta

Dr. Aulia Sani, SpJP (K), FJCC, FIHA, FAsCCDepartemen Kardiologi dan Kedokteran Vaskuler FKUI / Pusat Jantung Nasional Harapan Kita, Jakarta

NAMANAMA : Dr AULIA SANI SPJP ( K ),FJCC,FIHA : Dr AULIA SANI SPJP ( K ),FJCC,FIHA

USIAUSIA : 65 TAHUN : 65 TAHUN

ISTRIISTRI : NY NERRY A SANI : NY NERRY A SANI

ANAKANAK : 2 PUTRI: 2 PUTRI

PEKERJAAN :PEKERJAAN :

STAFF PENGAJAR BAGIAN KARDIOLOGI & KEDOKTERAN STAFF PENGAJAR BAGIAN KARDIOLOGI & KEDOKTERAN VASKULER FKUI / PUSAT JANTUNG NASIONAL HARAPAN VASKULER FKUI / PUSAT JANTUNG NASIONAL HARAPAN KITAKITA

DIREKTUR PENUNJANG MEDIK & REHABILITASI PJNHK DIREKTUR PENUNJANG MEDIK & REHABILITASI PJNHK 1994-19981994-1998

DIRUT PJNHK TAHUN 1998 – 2005DIRUT PJNHK TAHUN 1998 – 2005

CURICULUM VITAE

ORGANISASI :ORGANISASI :

KETUA PERKUMPULAN VASKULER INDONESIAKETUA PERKUMPULAN VASKULER INDONESIA DEWAN PEMBINA YAYASAN JANTUNG INDONESIA PUSAT SEJAK 2003DEWAN PEMBINA YAYASAN JANTUNG INDONESIA PUSAT SEJAK 2003 ANGGOTA PERKIANGGOTA PERKI ANGGOTA IDIANGGOTA IDI ANGGOTA DEWAN PAKAR PDUIANGGOTA DEWAN PAKAR PDUI

PENDIDIKAN :PENDIDIKAN :

RESEARCH CARDIOLOGY ON HEART RESEARCH CENTER MELBOURNE RESEARCH CARDIOLOGY ON HEART RESEARCH CENTER MELBOURNE AUSTRALIA 1998AUSTRALIA 1998

TRAINING HOSPITAL ON HOSPITAL FOR MEDICAL TRAINING ( JCNI, TOKYO TRAINING HOSPITAL ON HOSPITAL FOR MEDICAL TRAINING ( JCNI, TOKYO JPN )JPN )

SPAMEN / LAN RI 1998SPAMEN / LAN RI 1998 ADVANCE CARDIOLOGY TRAINING IN TORANOMON HOSPITAL TOKYO ADVANCE CARDIOLOGY TRAINING IN TORANOMON HOSPITAL TOKYO

JAPAN 1994 – 1995.JAPAN 1994 – 1995. CARDIAC REHABILITATION TRAINING IN HOEHENRIED HOSPITAL, BENRIED CARDIAC REHABILITATION TRAINING IN HOEHENRIED HOSPITAL, BENRIED

GERMAN 1991.GERMAN 1991. PROGRAM STUDI ILMU PENYAKIT JANTUNG DAN PEMBULUH DARAH 1981-PROGRAM STUDI ILMU PENYAKIT JANTUNG DAN PEMBULUH DARAH 1981-

19841984 TRAINING ON ADVANCE MULTISLISH CITY / SCAI ( SOCIETY CARDILOGY TRAINING ON ADVANCE MULTISLISH CITY / SCAI ( SOCIETY CARDILOGY

ASSOSIATION ON INTERVENTION ) PHOENIC USA, FEEBRUARY 2006ASSOSIATION ON INTERVENTION ) PHOENIC USA, FEEBRUARY 2006

Clinical history:Clinical history:

““Hypertension is, very largely, an Hypertension is, very largely, an asymptomatic condition until and asymptomatic condition until and

unless it is very severe”unless it is very severe”

Contribution of CV Risk Factors to Contribution of CV Risk Factors to Burden of Disease Mortality*Burden of Disease Mortality*

0 5 10 15 20

Percentage of Mortality Attributable to Risk Factors

*Based on The World Health Report 2003. Yach et al. JAMA. 2004;291:2616-2622.

Developing

countries Developed countries

Blood pressure

Tobacco

Underweight

Alcohol

Cholesterol

Unsafe sex

OverweightUnsafe water, sanitation,

hygieneLow fruit and vegetable intake

Indoor smoke from solid fuels

Physical inactivity

Hypertension With Other CV Risk Hypertension With Other CV Risk Factors Increases Risk of MIFactors Increases Risk of MI

Od

ds

Rat

io (

95%

CI)

Od

ds

Rat

io (

95%

CI)

512512

256256

128128

6464

3232

1616

88

44

22

11Smk(1)

DM(2)

HTN(3)

ApoB/A1(4)

1+2+3 All 4 +Obes +PS All RFs

2.92.9(2.6-3.2)(2.6-3.2)

2.42.4(2.1-2.7)(2.1-2.7)

1.91.9(1.7-2.1)(1.7-2.1)

3.33.3(2.8-3.8)(2.8-3.8)

13.013.0(10.7-15.9)(10.7-15.9)

42.342.3(33.2-54.0)(33.2-54.0)

68.568.5(53.0-88.6)(53.0-88.6)

1182.982.9(132.6-252.2)(132.6-252.2)

333.7333.7(230.2-483.9)(230.2-483.9)

Smk=smoking; DM=diabetes mellitus; HTN=Hypertension; Obes=abdominal obesity; PS=psychosocial; RF=risk factor; MI=myocardial infarction.Yusuf S et al. Lancet. 2004; 364:937-952.

Economic Burden of Economic Burden of Cardiovascular Disease in the US Cardiovascular Disease in the US

Estimated for 2005Estimated for 2005

American Heart Association. Heart Disease and Stroke Statistics—2005 Update.

Heart disease

Coronary heart

disease

Stroke Hypertensive disease

Congestive heart failure

Total CVD*

Bil

lio

ns

of

Do

llar

sB

illi

on

s o

f D

oll

ars

254.8

142.1

56.8 59.727.9

393.5

0

100

200

300

400

Benefit of Blood Benefit of Blood pressurepressureLoweringLowering

Meta-analysis of 10 randomized trials. He and Whelton, J

Hypertens, 1999.

12 to 13 mm Hg Drop in Systolic BP 12 to 13 mm Hg Drop in Systolic BP Reduces Reduces

4-Year Risk of CAD, Stroke, Mortality4-Year Risk of CAD, Stroke, Mortality

Red

uct

ion

in

ri

sk

(%)

0%

-20%

-30%

-10%

-40%

CHD Stroke CVD mortalityAll-causemortality

PP<0.0001<0.0001

PP=0.005=0.005

PP<0.001<0.001

-21%-21%

-37%-37%

-25%-25%

-13%-13%

PP<0.001<0.001

Effect of Long-Term Modest Effect of Long-Term Modest Reductions in CV Risk FactorsReductions in CV Risk Factors

Emberson et al. Emberson et al. Eur Heart J.Eur Heart J. 2004;25:484-491. 2004;25:484-491.

10% 10% ReductionReduction

in BPin BP

10% Reduction

in TC+45% 45%

ReductionReductionin CVDin CVD

=

Management of Management of Hypertension Hypertension

The main objective in lowering The main objective in lowering BP is toBP is to reduce the patient’s reduce the patient’s absolute risk of premature absolute risk of premature deathdeath and disease, primarily and disease, primarily by reducing their risk of by reducing their risk of cardiovascular diseases.cardiovascular diseases.

Ogden LG,et al.Ogden LG,et al. Hypertension Hypertension. 2000. 2000

Algorithm for Treatment of Algorithm for Treatment of Hypertension from JNC-7Hypertension from JNC-7

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

Initial Drug Choices

Drug(s) for the compelling indications

Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB)

as needed.

With Compelling Indications

Lifestyle Modifications

Stage 2 Hypertension (SBP >160 or DBP >100 mmHg)

2-drug combination for most (usually thiazide-type diuretic and

ACEI, or ARB, or BB, or CCB)

Stage 1 Hypertension(SBP 140–159 or DBP 90–99

mmHg) Thiazide-type diuretics for most.

May consider ACEI, ARB, BB, CCB,

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.

Classification and Classification and Management Management

of BP from JNC-7of BP from JNC-7BP BP

classificatioclassificationn

SBP* SBP* mmHgmmHg

DBP* DBP* mmHgmmHg

Lifestyle Lifestyle modificatimodificati

onon

Initial drug therapyInitial drug therapy

Without compelling Without compelling indication indication

With compelling With compelling indicationsindications

NormalNormal <120<120 and and <80<80

EncourageEncourage

PrehypertensiPrehypertensionon

120120––139139

or 80or 80––8989

YesYes No antihypertensive No antihypertensive drug indicated.drug indicated.

Drug(s) for Drug(s) for compelling compelling indications. indications. ‡‡

Stage 1 Stage 1 HypertensionHypertension

140140––159159

or 90or 90––9999

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

Drug(s) for the Drug(s) for the compelling compelling indications.indications.‡‡

Other Other antihypertensive antihypertensive drugs (diuretics, drugs (diuretics, ACEI, ARB, BB, ACEI, ARB, BB, CCB) as needed. CCB) as needed.

Stage 2 Stage 2 HypertensionHypertension

>>160160 or or >>100100

YesYes Two-drug combination Two-drug combination for mostfor most†† (usually (usually thiazide-type diuretic thiazide-type diuretic and ACEI or ARB or BB and ACEI or ARB or BB or CCB).or CCB).

*Treatment determined by highest BP category.†Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension.‡Treat patients with chronic kidney disease or diabetes to BP goal of <130/80 mmHg.

Definitions & classification of BP levels Definitions & classification of BP levels (mmHg)(mmHg)

(2007 ESC/ESH guidelines)(2007 ESC/ESH guidelines)

Category Category Systolic Systolic DiastolicDiastolicOptimal Optimal <120 <120 and and < 80 < 80Normal Normal 120–129 and/or 120–129 and/or 80–8480–84High normal High normal 130–139 and/or 130–139 and/or 85–8985–89Grade 1 Grade 1 140–159 and/or 140–159 and/or 90–9990–99Grade 2 Grade 2 160–179 and/or 160–179 and/or 100–109100–109Grade 3 ≥180 and/or Grade 3 ≥180 and/or ≥ 110≥ 110Isolated systolic Isolated systolic ≥ 140 and ≥ 140 and <90<90

hypertensionhypertension

Isolated systolic hypertension should be graded (1, 2,3) according to systolic blood pressure values in the ranges indicated, provided that diastolicvalues are ,90 mmHg. Grades 1, 2 and 3 correspond to classificationin mild, moderate and severe hypertension, respectively. These termshave been now omitted to avoid confusion with quantification of total cardiovascular risk.

Blood Pressure mmHgBlood Pressure mmHgOther risk factors,

OD

Or disease

Established CV or renal disease

No other risk factors

1-2 risk factors

≥3 risk factors, MS, or OD

Diabetes

Normal

SBP 120-129

or DBP 80-84

High Normal

SBP 130-139

or DBP 85-89

Grade 1 HT

SBP 140-159

or DBP 90-99

Grade 2 HT

SBP 160-179

or DBP 100-199

Grade 3 HT

SBP ≥180

or DBP ≥110

No BP

intervention

Lifestyle changes for several months then drug

treatment if BP uncontrolled

Lifestyle changes +

Immediate drug treatment

Low added risk

Low added risk

No BP

intervention

Lifestyle changes for several months then drug

treatment if BP uncontrolled

Lifestyle changes for several months then drug

treatment if BP uncontrolled

Lifestyle changes for several months then drug

treatment if BP uncontrolled

Lifestyle changes +

Immediate drug treatment

Lifestyle changes +

Immediate drug treatment

Lifestyle changes +

Immediate drug treatment

Lifestyle changes +

Immediate drug treatment

Lifestyle changes +

Immediate drug treatment

Lifestyle changes +

Immediate drug treatment

Lifestyle changes +

Immediate drug treatment

Lifestyle changes

Lifestyle changes

Lifestyle changes & consider drug

treatmentLifestyle changes

+

drug treatment

Lifestyle changes +

drug treatment

ESH/ESC Guidelines 2007 Eur Heart Journal 2007

Lifestyle changes + drug treatment

Initiation of Antihypertensive Initiation of Antihypertensive TreatmentTreatment

Majority of Hypertensive Patients Need Majority of Hypertensive Patients Need Multiple Medications for Effective Multiple Medications for Effective

ManagementManagement

Bakris et al. Am J Kidney Dis. 2000;36:646-661; Brenner et al. N Engl J Med. 2001;345: 861-869; Lewis et al. N Engl J Med. 2001;345:851-860; Cushman et al. J Clin Hypertens. 2002;4:393-404.

More Than 1 Agent Is Usually Required to Get to BP GoalMore Than 1 Agent Is Usually Required to Get to BP GoalMore Than 1 Agent Is Usually Required to Get to BP GoalMore Than 1 Agent Is Usually Required to Get to BP Goal

2,00

3,25

3,70

2,75

2,70

3,80

0 1 2 3 4

ALLHAT (<140/90 mm Hg)ALLHAT (<140/90 mm Hg)

HOT (<80 mm Hg–diastolic)HOT (<80 mm Hg–diastolic)

MDRD (<92 mm Hg–mean arterial pressure)MDRD (<92 mm Hg–mean arterial pressure)

ABCD (<75 mm Hg–diastolic)ABCD (<75 mm Hg–diastolic)

UUKKPDS 83 (< 85 mm Hg–diastolic)PDS 83 (< 85 mm Hg–diastolic)

IDNT (135/85 mm Hg)IDNT (135/85 mm Hg)

Number of Agents

Multiple medications can increase the complexity of treatmentMultiple medications can increase the complexity of treatmentMultiple medications can increase the complexity of treatmentMultiple medications can increase the complexity of treatment

Anti Hypertension Combination (2007 ESC/ESH

guidelines)Diuretic

ACE inhibitors

ARBs

CCBs=CA Antagonist

-blockers

-blockers

Unmet NeedsUnmet Needs

Trends in awareness,treatment, Trends in awareness,treatment, and control of High BP in adults and control of High BP in adults

ages 18-74ages 18-74National Health Ans Nutrition Examination National Health Ans Nutrition Examination Survey, PercentSurvey, Percent

IIII

(1976-(1976-1980)1980)

III(Phase III(Phase 11

1988-91)1988-91)

III(Phase III(Phase 22

1991-94)1991-94)1999-1999-20002000

AwarenesAwarenesss

5151 7373 6868 7070

TreatmentTreatment 3131 5555 5454 5959

ControlControl 1010 2929 2727 3434

Sources: Unpublished data for 1999-2000 computed by M.Wolz,NHLBI

Hypertension control rates around the Hypertension control rates around the worldworld

<140/90 mmHg (%)<140/90 mmHg (%)

United StatesUnited States 27 27

FranceFrance 24 24

CanadaCanada 2222

ItalyItaly 99

EgyptEgypt 88

EnglandEngland 66

KoreaKorea 55

ChinaChina 33

PolandPoland 2 2

<160/95 mmHg (%)

Germany 23

Finland 21

Spain 20

Australia 19

Scotland 18

India 9

Zaire 3

JNC VI. Arch Intern Med 1997;157:2413-2446; Joffres MR, et al. Am J Hypertens 1997;10:1097-1102; Colhoun HM, et al. J Hypertens 1998;16:747-752; Chamotin B, et al. Am J Hypertens 1998;11:759-762; Marques-Vidal P, et al. J Hum Hypertens 1997;11:213-220

Indonesia?

What’s the Importance in What’s the Importance in Hypertension Hypertension management:management:

REACH THE TARGET REACH THE TARGET IMMEDIATELYIMMEDIATELY

How to initiate pharmacological How to initiate pharmacological therapy : Which monotherapy therapy : Which monotherapy

andandWhen to use combination When to use combination

therapytherapy The mono therapy :The mono therapy :

– Inadequate, because the percentage of patient Inadequate, because the percentage of patient requiring combination therapy to obtain requiring combination therapy to obtain adequate BP control is elevated (only 22-24% adequate BP control is elevated (only 22-24% actually achieve BP goals with mono therapy in actually achieve BP goals with mono therapy in clinical trials) clinical trials)

– In fact, unwanted metabolic effects of some In fact, unwanted metabolic effects of some AHDs are attenuated when used in combination, AHDs are attenuated when used in combination, in particular with drugs that suppress the RASin particular with drugs that suppress the RAS

Rationale of combination Rationale of combination therapytherapy

There is a value to the use of drug There is a value to the use of drug combination, not only to improve overall combination, not only to improve overall efficacy within and between individuals but efficacy within and between individuals but also to reduce dose-dependent side effectsalso to reduce dose-dependent side effects

Multiple physiologic system contribute to BP Multiple physiologic system contribute to BP elevation, multiple drugs will be needed to elevation, multiple drugs will be needed to maintain BP controlmaintain BP control

Fixed-dose combinations are more acceptable Fixed-dose combinations are more acceptable because the efficacy and tolerability because the efficacy and tolerability

fixed-dose products should be considered fixed-dose products should be considered for first-line therapyfor first-line therapy

How to initiate pharmacological therapy : How to initiate pharmacological therapy : Which monotherapy andWhich monotherapy and

When to use combination therapyWhen to use combination therapy

The conclusion :The conclusion :– Using combination, either free or fixed, from Using combination, either free or fixed, from

the beginning of pharmacological therapy is the beginning of pharmacological therapy is contemplated in both guidelinescontemplated in both guidelines

– Implementing this possibility will probably Implementing this possibility will probably contribute to improvements in BP control contribute to improvements in BP control due to the ability of a combination therapy due to the ability of a combination therapy to lower BP to lower BP

Drug combinationDrug combination

In clinical trialsIn clinical trials The major challenge in the contemporary The major challenge in the contemporary

treatment of hypertension is the prompt treatment of hypertension is the prompt achievement and long-term maintenance of BP achievement and long-term maintenance of BP levels that are low enough to reduce the incidence levels that are low enough to reduce the incidence of major CV endpointsof major CV endpoints

Multidrug therapy has been necessary in Multidrug therapy has been necessary in approximately 75% of hypertensive individualsapproximately 75% of hypertensive individuals– LIFE : >90% required more than one AHDLIFE : >90% required more than one AHD– ALLHAT : only 26% of subjects were at goal with ALLHAT : only 26% of subjects were at goal with

a single agenta single agent

The goals of combinationThe goals of combination

To improve the long-term To improve the long-term efficacy and tolerability of drug efficacy and tolerability of drug treatmenttreatment

To facilitate the prompt To facilitate the prompt achievement of target BPachievement of target BP

To increase predictability of To increase predictability of responses in heterogeneous responses in heterogeneous populationpopulation

Tolerability Tolerability

Uncontrolled BPUncontrolled BP

Increased Increased dosedose

Poor Poor compliancecompliance

Increase incidence Increase incidence of adverse effectsof adverse effects

The particularly efficacious two-The particularly efficacious two-drug combinationsdrug combinations

A thiazide diuretic A thiazide diuretic oror CCB CCB

++ACEI ACEI oror ARB ARB oror Beta-blocker Beta-blocker

Fixed-dose combinationsFixed-dose combinations

The rationale :The rationale :Traditional teaching based on Traditional teaching based on

maximum flexibility of dose maximum flexibility of dose titration and that combination titration and that combination make it difficult to ascertain the make it difficult to ascertain the cause of any side effect is of little cause of any side effect is of little importanceimportance

Fixed-dose combinationsFixed-dose combinations

The rationale :The rationale : In contrast, the advantages of the In contrast, the advantages of the

combination are significant :combination are significant :– Nonadherence to multidose-multidrug, fixed-Nonadherence to multidose-multidrug, fixed-

dose simplify the treatment regimen and dose simplify the treatment regimen and promote adherencepromote adherence

– Cost lessCost less– Have been carefully studied and approved to Have been carefully studied and approved to

produce greater long-term BP reduction produce greater long-term BP reduction than monotherpythan monotherpy

Clinical use:Clinical use: Most often as the “second step”Most often as the “second step” ““Low-dose combination” is Low-dose combination” is

– an alternative strategy to the an alternative strategy to the traditional approach of increasing traditional approach of increasing the dose the dose

– Now likely that many fixed-dose Now likely that many fixed-dose combination will receive indication combination will receive indication for initial treatment of hypertension for initial treatment of hypertension

Fixed-dose combinationsFixed-dose combinations

Beta-blocker and thiazide :Beta-blocker and thiazide : 2.5 mg and 6.25 mg is a low-dose 2.5 mg and 6.25 mg is a low-dose

combinationcombination BB are effective antihypertensive BB are effective antihypertensive

agent and are preferred therapy in agent and are preferred therapy in ischemic heart diseaseischemic heart disease

BB attenuate the RAAS activation BB attenuate the RAAS activation that accompanies the use of thiazide that accompanies the use of thiazide diureticsdiuretics

Thiazide also improves the Thiazide also improves the effectiveness of BB in blacks and effectiveness of BB in blacks and others with low-renin hypertension others with low-renin hypertension

Fixed-dose combinationsFixed-dose combinations