Yerizal Karani

The Rationale of Fixed Combination in

the Management of Hypertension Focus on ACE-I and CCB

Current Status of

Hypertension

Measure n (95% CI)

Total number worldwide in 2000

972 million (957-987)

Total number in economically

developed countries in 2000

333 million (329-336)

Total number in economically

developing countries in 2000

639 million (625-654)

Total number worldwide in 2025 1.56 billion (1.54-1.58)

Kearney PM et al. Lancet 2005; 365:217-223.

31.3

5.8 6.1

31.9

8.69

0

5

10

15

20

25

30

35

D D/O U

Men Women

Keterangan : D = Diagnosis berdasarkan tenaga kesehatan D/O = Diagnosisi berdasarkan tenaga kesehatan atau kasus minum obat U = Diagnosis berdasarkan hasil pengukuran tekanan darah

Pre

va

len

ce

%

Dasar Diagnosis

Prevalence of HT based on gender (Basic Health Research / Indonesian Health Departement 2007)

Kannel WB. JAMA. 1996;275:1571-1576.

0

10

20

30

40

50

Men 2.0

Women 2.2

Men 3.8

Women 2.6

Men 2.0

Women 3.7

Men 4.0

Women 3.0

Normotensie Hypertensive

Coronary disease

Stroke Peripheral artery disease

Heart failure

Risk ratio:

Biennial age-adjusted rate per 1000 patients

Lewington et al. Lancet 2002;360:1903–13

Cardiovascular mortality risk

0

2

4

8

115/75 135/85 155/95 175/105

6

Systolic BP/Diastolic BP (mmHg)

*Individuals aged 40–69 years

2X risk

4X risk

8X risk

1X risk

Takeda Chemical Industries, 1998

Treating hypertension reduces cardiovascular Treating hypertension reduces cardiovascular morbidity and mortalitymorbidity and mortality

‘‘Older’ patients (mean >65 years)Older’ patients (mean >65 years)

‘‘Younger’ patients (<65 years)Younger’ patients (<65 years)

* p<0.05; ** p<0.01; *** p<0.001* p<0.05; ** p<0.01; *** p<0.001

GueyffierGueyffier et al (1996)et al (1996)

––8080

––6060

––4040

––2020

00CHFCHF StrokeStroke

CV CV mortalitymortality

MajorMajorcoronarycoronaryeventevent All deathsAll deaths

******

******

******

****** ****

**

Relative risk (%)Relative risk (%)

7

HT treatment Treatment of CV risk factors / TOD

Management associated clinical conditions

AS 2011

- Awareness 70 %

11 % aware, but not treated

- Treatment 59 %

25 % treated, but not controlled

- Control 34 %

}

}

AS 2011

Monica Group Jakarta

39,9 31,1 10,0

-Adequately treated

cases

79,4 85,3 50,9 -Treated cases

12,0 11,3 43,9 -Newly discovered

88,0 88,7 56,1

-Awareness of

responders

2,5 3,2 -Borderline hypertension

17,9 16,9 14,9 -Prevalence of hypertension

Survey 2000 ‏(%)

Survey 1993

‏(%)

Survey1988

‏(%)

AS 2011

BP GOAL

Monotherapy 42-59%

Combined therapy 54-70%

ALLHAT >50%

Combined therapy

AS 2011

Lifestyle modifications

Not at goal blood pressure (<140/90 mmHg)

(<130/80 mmHg for patients with diabetes or chronic kidney disease)

Initial drug choices

Without compelling

indications

With compelling

indications

Stage 1 hypertension

(SBP 140-159 or DBP

90-99 mmHg)

Thiazide-type diuretics

for most. May consider

ACE-I, ARB, BB, CCB

or combination

Stage 2 hypertension

(SBP 160 or DBP 100 mmHg)

Two-drug combination for

most (usually thiazide-type

diuretic and ACE-I or

ARB, or BB, or CCB)

Drug(s) for the

compelling indications

Other antihypertensive

Drugs (diuretics, ACE-I,

ARB, BB, CCB) as needed

Not at blood pressure goal

Optimize dosages or add additional drugs until goal blood pressure is achieved.

Consider consultation with hypertension specialist.

SBP, systolic blood pressure; DBP, diastolic blood pressure; ACE-I,

angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor

blocker; BB, beta-blocker; CCB, calcium-channel blocker

HYPERTENSION

- COMPLEX DISORDERS

- MULTIPLE PATHOGENETIC FACTORS

( INCREASED BLOOD VOLUME,

VASOCONSTRICTION,

OVERACTIVITY SNS AND RAAS )‏

AS 2011

ADDITIVE COMPLIMENTARY

EFFECT PROPERTIES

ADVERSE EFFECTS

LOWER DOSAGE OF EACH DRUGS

OF EACH DRUG NEUTRALIZED

- SIDE EFFECTS

QUALITY OF LIFE -

COMPLIANCE - Better BP controll

2

AS 2011

RESPONSE RATE TO THERAPY

FROM 40 %-50 % TO 70%-80%

RACIAL AND AGE DIFFERENCES

IN RESPONSE TO INDIVIDUAL

THERAPY ELIMINATED

OFFICE VISITS COST

SIDE EFFECTS

COMPLIANCE

AS 2011

Can we improve BP control rates ?

Gupta A, et al. Hypertension 2010; 55:399-407

Systolic and Diastolic BP normalization ratios

Can we improve compliance rates ?

Gupta A, et al. Hypertension 2010; 55:399-407

FDC and Compliance or Persistence with therapy

Primary Target RAAS

( ACEI/ARB, ß Blockers )‏

Low Renin States

( CCB, Diuretic )‏

AS 2011

COMBINATION THERAPY

SHOULD BE

EFFECTIVE

WELL TOLERATED

POSITIVE / NEUTRAL EFFECTS

on metabolic parameters

and concomitant

diseases / risk factors

AS 2011

The synergistic action of Perindopril - Amlodipine

CCB

Vasodilatation

ACEI

Increased secretion of

Na+ and water

ACEI-CCB Combination: Synergy for BP Lowering

VSMC

Ca++

X

Renin

SNS

Ang II

Ang I

BP

Activation of

a1R

(VSMC)

Vasoconstriction

Reduced Na+

sécrétion

CCB X X

X

Ferrari R. Optimizing the treatment of hypertension and stable coronary artery disease:

clinical evidence for fixed-combination perindopril/amlodipine. Curr Med Res Opin. 2008;24:3543-3557.

A Synergy also decreasing side effects

24

Reduces ankle edema in comparison with CCB

Messerli FH, et al. Am J Cardiol. 2000;86(11):1182-1187

Ferrari, R. Current Med. Research & Opinion, 2008, 24 (12), 3543-3557

Amlodipine alone

Precapillary vasodilation => oedema

Venous dilation hence normalising intracapillary pressure

Perindopril-Amlodipine

Less peripheral oedema with a CCB/RAS combination

than with a CCB monotherapy

Makani H, Bangalore S, Romero J et al. Am J Med. 2011. 124, 128-135

Number and percentage of patients with elimination or reduction of ACE inhibitor-induced cough when treated with placebo or amlodipine. *P<0.05

Fogari R, et al. Curr Ther Res. 1999;60:121-128.

ACE inhibitor/CCB combination reduces cough in

comparison with ACE inhibitor alone

Elimination of cough Reduction of cough

Perindopril + Amlodipine decreases cough

ACEI CCB

inhibit kininase II

bradykinin

stim. PLAz inhibit

stim. pulm. sensory C fibers

coughing inhibit

arachidonic acid

PGEz

Ca++- dep. release

of glutamate at

solitary tract

nucleus

Perindopril in EUROPA study cough in 2.7%

Perind + amlo in STRONG Study cough in 1.5%

Bahl UK. Fixed dose perindopril and amlodipine in moderate-to-severe hypertension.

14th World Congress of Heart Disease 2008, Toronto, Canada.

Perindopril+Amlodipine

n= 1 250 > 160mmHg

n= 161 > 180mmHg

Whatever the profile of hypertensive patients

Bahl VK et al. Am J Cardiovasc Drugs. 2009;9:135-142.

BP Reduction

Perindopril+Amlodipine

Bahl UK. Fixed dose perindopril and amlodipine in moderate-to-severe hypertension. 14th World Congress of Heart Disease 2008, Toronto, Canada. Poulter NR, Chang CL, Dahlof B, Gupta AK, Sever PS, Wedel H, on behalf of the ASCOT investigators. Evaluating the efficacy of the stepped-care anti-hypertensive strategies used in the Anglo-Scandinavian Cardiac Outcomes Trial BP Lowering Arm (ASCOT-BPLA).

Hypertension. 2008. OS11/1.

Comparison with landmark trial

-44

-25

-50

-40

-30

-20

-10

0

SBP DDP

-41

-23

-50

-40

-30

-20

-10

0

SBP DDP

BP decrease (mmHg)

n= 1 250 n= 19 342

Amlodipine 5mg + Perindopril 5mg Amlodipine 5/10mg+Perindopril 5/10mg

24h BP: nocturnal

BP control

BP variability

Brachial

(clinic) BP

Central BP Antihypertensive

efficacy

Components‏of‏antihypertensive‏efficacy…

value‏predictive‏independent‏have‏…

1. Ohkubo DT, et al. The Ohasama study. J Hypertens. 2000;18:847–854. 2. Yamamoto Y, et al. Stroke. 1998; 29:570–576.

3. Ohkubo T et al. J Hypertens. 2002;20:2183–2189. 4. Stanton A, et al. Blood Press. 1993;2:289–295. 5. Pedersen OL, et al. VALUE trial group. J

Hypertens. 2007; 25:707–712.

European Society of Cardiology:

1.Hurst M el al. Drugs. 2001;61(6):867-896. 2. Hernandez RH et al. Blood Press Monit. 2001;6(1):47-57.

3. McClellan KJ et al. Drugs. 2000;60(5):1123-1140. 4. Diamant M et al. J Hum Hypertens. 1999;13(6):405-412.

5. Zannad F et al. Am J Hypertens. 1996;9(7):633-643. 6. Gradman AH, et al. Circulation. 2005;111:1012-1018.

7. Neutel JM et al. J Clin Hypertens. (Greenwich). 2002;4(5):325-331. 8. Hermida RC et al. Hypertens. 2003;42(3):283-290.

“ Drugs which exert their antihypertensive effect over 24 hours

with a once-a-day administration should be preferred ”

Perindopril1

Stabilizes blood pressure to avoid excessive BP variability 1,2

BP variability: main cause of CV events.3

1.Rothwell PM et al. Lancet Neurol. 2010;9(5):469-480 2. Rothwell PM et al. Lancet. 2010;375:938-948.

3. Rothwell PM et al. Lancet. 2010;375:895–905.

/Perindopril

A central aortic SBP difference of 4.3 mmHg

Similar brachial BP reductions

Central Aortic BP reduction is linked to a reduction in CV events

Effective in reducing central aortic BP Control…

ASCOT insights: recent sub studies

COVERAM offers high QUALITY of Blood Pressure Control

Fixed dose combinations: where is the evidence?

Among available fixed-dose combinations, which

combinations

- have been evaluated in morbidity-mortality trials?

- have been compared with other combinations?

- have proved clear superiority over comparators for

preventing CV events and mortality?

Only ASCOT shows life saving evidence

No: Nonsignificant

1. Dahlöf B et al. Lancet. 2005:366;895-906. 2. Pepite CJ. JAMA. 2003;290:2805-2816. 3. Jamerson K et al. N Engl J Med. 2008;359:2417-2428.

No No

No No

Among ACEi + CCB combinations

Valsartan/amlodipine

Telmisartan/amlodipine

Olmesartan/amlodipine

International Guidelines in Hypertension

ASCOT-BPLA

www.ascotstudy.org

atenolol ±

bendroflumethiazide

amlodipine ±

perindopril

19,342

hypertensive

patients

PROBE

design

ASCOT-BPLA

placebo atorvastatin 10 mg Double-blind

ASCOT-LLA 10,305 patients

TC ≤ 6.5 mmol/L (250 mg/dL)

Investigator-led, multinational

randomised controlled trial

ASCOT-BPLA: summary of all end points

Dahlöf B, et al. Lancet. 2005;366:895-906.

amlodipine perindopril better atenolol thiazide better

0.50 0.70 1.00 1.45

Primary Non-fatal MI (incl silent) + fatal CHD

Secondary Non-fatal MI (exc. Silent) + fatal CHD Total coronary end point Total CV event and procedures All-cause mortality Cardiovascular mortality Fatal and non-fatal stroke Fatal and non-fatal heart failure

Tertiary Silent MI Unstable angina Chronic stable angina Peripheral arterial disease Life-threatening arrhythmias New-onset diabetes mellitus New-onset renal impairment Post hoc Primary end point + coronary revasc procs CV death + MI + stroke

2.00

Unadjusted HR (95% CI)

0.90 (0.79-1.02)

0.87 (0.76-1.00) 0.87 (0.79-0.96) 0.84 (0.78-0.90) 0.89 (0.81-0.99) 0.76 (0.65-0.90) 0.77 (0.66-0.89) 0.84 (0.66-1.05)

1.27 (0.80-2.00) 0.68 (0.51-0.92) 0.98 (0.81-1.19) 0.65 (0.52-0.81) 1.07 (0.62-1.85) 0.70 (0.63-.078) 0.85 (0.75-0.97)

0.86 (0.77-0.96) 0.84 (0.76-0.92)

Cardiovascular protection and mortality reduction stronger than classical regimen

Dahlöf B et al. Lancet. 2005:366;895-906.

/Perindopril /Perindopril

Cardiovascular protection and mortality reduction

Dahlöf B et al. Lancet. 2005:366;895-906.

Greatest synergy of Coversyl/CCB in CAD patients

A synergistic mode of action

Ferrari R. Optimizing the treatment of hypertension and stable coronary artery disease:

clinical evidence for fixed-combination perindopril/amlodipine. Curr Med Res Opin. 2008;24:3543-3557.

Perindopril Amlodipine

Only 3 clinical trials in hypertension decrease mortality1

1.RR: relative risk. NS: not significant. HCTZ: hydrochlorothiazide. ARB: angiotensin receptor blocker. ACEi: angiotensin-converting enzyme inhibitors. BFTZ: bendroflumethiazide

Mourad JJ et al. J Hypertens. 2010;28:e98-e99. 2. Lithell H et al. J Hypertens. 2003;21:875-886. 3. Yui Y et al. Hypertens Res. 2004;27:181-191.

4. Schrader J et al. Stroke. 2005;36:1218-1226. 5. Kasanuki H et al. Eur Heart J. 2009;30:1203-1212. Principal reports of the morbidity-mortality trials using ARB or ACE-inhibitor as active treatment

or as a comparison, since 01.01.2000. More than 66% of hypertensive patients identified in those trials. All-cause mortality: a prespecified end point (EP) or a composite of the primary or secondary EP,

or reported in the principal study publication; and heart failure trials were excluded.

TAKE HOME MESSAGE

Provides strong BP reduction (40-63 mmHg)

o Controls BP over 24 h

o Decreases central BP

o Decreases blood pressure variability

Saves life (ASCOT)

Offers excellent safety

o Oedema 0.7%

o Cough 1.5%