coveram-symcard-dr-yerizal.pdf

8/14/2019 coveram-symcard-dr-yerizal.pdf

1/47

Yerizal Karani

The Rationale of Fixed Combination in

the Management of HypertensionFocus on ACE-I and CCB


2/47


3/47

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.


4/47

31.3

5.8 6.1

31.9

8.6 9

0

5

10

15

20

25

30

35

D D/O U

Men Women

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

Prevalence%

Dasar Diagnosis

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


5/47

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

0

10

20

30

40

50

Men2.0

Women2.2

Men3.8

Women2.6

Men2.0

Women3.7

Men4.0

Women3.0

Normotensie

Hypertensive

Coronarydisease

Stroke Peripheral arterydisease

Heartfailure

Risk ratio:

Biennial age-adjusted rateper 1000patients


6/47

Lewington et al. Lancet 2002;360:190313

Cardiovascular mortality risk

0

2

4

8

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

6

Systolic BP/Diastolic BP (mmHg)

*Individuals aged 4069 years

2Xrisk

4Xrisk

8Xrisk

1X risk


7/47

Takeda Chemical Industries, 1998

Treating hypertension reduces cardiovascularTreating hypertension reduces cardiovascular

morbidity and mortalitymorbidity and mortality

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

Younger patients (


8/47

HT treatment

Treatment of CV risk factors / TODManagement associated clinical conditions

AS 2011


9/47

- Awareness 70 %

11 % aware, but not treated

- Treatment 59 %

25 % treated, but notcontrolled

- Control 34 %

}}

AS 2011


10/47

Monica Group Jakarta

39,931,110,0

-Adequately treated

cases

79,485,350,9-Treated cases

12,011,343,9-Newly discovered

88,088,756,1

-Awareness of

responders

2,53,2-Borderline hypertension

17,916,914,9-Prevalence ofhypertension

Survey 2000(%)

Survey 1993

(%)Survey1988

(%)


11/47AS 2011


12/47

BP GOAL

Monotherapy

42-59%

Combined therapy

54-70%

ALLHAT>50% Combined therapy

AS 2011


13/47

Lifestyle modifications

Not at goal blood pressure (


14/47

HYPERTENSION

- COMPLEX DISORDERS

- MULTIPLE PATHOGENETIC FACTORS

( INCREASED BLOOD VOLUME,

VASOCONSTRICTION,

OVERACTIVITY SNS AND RAAS )

AS 2011


15/47

ADDITIVE COMPLIMENTARY

EFFECT PROPERTIES

ADVERSE EFFECTS

LOWER DOSAGE OF EACH DRUGSOF EACH DRUG NEUTRALIZED

- SIDE EFFECTSQUALITY OF LIFE -

COMPLIANCE - Better BP controll

2

AS 2011


16/47

RESPONSE RATE TO THERAPY

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

RACIAL AND AGE DIFFERENCESIN RESPONSE TO INDIVIDUAL

THERAPY ELIMINATED

OFFICE VISITS COST SIDE EFFECTS COMPLIANCE

AS 2011


17/47

Can we improve BP control rates ?

Gupta A, et al. Hypertension2010; 55:399-407

Systolic and Diastolic BP normalization ratios


18/47

Can we improve compliance rates ?

Gupta A, et al. Hypertension2010; 55:399-407

FDC and Compliance or Persistence with therapy


19/47

Primary Target RAAS(ACEI/ARB, Blockers)

Low Renin States

( CCB, Diuretic )

AS 2011


20/47

COMBINATION THERAPY

SHOULD BE

EFFECTIVE

WELL TOLERATED

POSITIVE / NEUTRAL EFFECTS

on metabolic parameters

and concomitant

diseases / risk factors

AS 2011


21/47

The synergistic action of Perindopril -Amlodipine

ACEI CCB C bi ti S f BP L i


22/47

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

a

1R(VSMC)

Vasoconstriction

Reduced Na+scrtion

CCB X X

X


23/47

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


24/47

24

Reduces ankle edema incomparison 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 normalisingintracapillary pressure

Perindopril-Amlodipine


25/47

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

ACE inhibitor/CCB combination reduces cough in


26/47

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


27/47

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. releas

of glutamate atsolitary tract

nucleus

Perindopril in EUROPA study

cough in 2.7%Perind + amlo in STRONG Study cough in 1.5%


28/47

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

BP R d ti


29/47

Whatever the profile ofhypertensive patients

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

BP Reduction

Perindopril+Amlodipine

C i ith l d k t i l


30/47

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

Amlodipine5mg +Perindopril5mg Amlodipine5/10mg+Perindopril5/10mg

C t f tih t i ffi


31/47

24h BP: nocturnal

BP control

BP variability

Brachial

(clinic) BP

Central BP Antihypertensive

efficacy

Components of antihypertensive efficacy

have independent predictive value

1. Ohkubo DT, et al. The Ohasama study. J Hypertens. 2000;18:847854. 2. Yamamoto Y, et al. Stroke.1998; 29:570576.

3. Ohkubo T et al. J Hypertens. 2002;20:21832189. 4. Stanton A, et al. Blood Press.1993;2:289295. 5. Pedersen OL, et al. VALUE trial group. JHypertens. 2007; 25:707712.

E opean Societ of Ca diolog


32/47

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

BP variability: main cause of CV events 3


33/47

Stabilizes blood pressure to avoidexcessive 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;375:895905.

/Perindopril

Effective in reducing central aortic BP Control


34/47

A central aorticSBP difference

of 4.3 mmHg

Similar brachial BP

reductions

Central Aortic BP reduction is linked to areduction in CV events

Effective in reducing central aortic BP Control

ASCOT insights: recent sub studies


35/47

ASCOT insights: recent sub studies

COVERAM offers high QUALITY of Blood Pressure Control


36/47

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?

Among ACEi + CCB combinations


37/47

Only ASCOT shows life saving evidence

No: Nonsignificant

1. Dahlf 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


38/47

Valsartan/amlodipineTelmisartan/amlodipine

Olmesartan/amlodipine

International Guidelines in Hypertension

ASCOT BPLA


39/47

ASCOT-BPLA

www.ascotstudy.org

atenolol

bendroflumethiazideamlodipine

perindopril

19,342

hypertensivepatients

PROBE

design

ASCOT-BPLA

placeboatorvastatin10 mg Double-blind

ASCOT-LLA10,305 patients

TC 6.5 mmol/L (250 mg/dL)

Investigator-led, multinational

randomised controlled trial

ASCOT-BPLA: summary of all end points


40/47

ASCOT BPLA: summary of all end points

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

amlodipine perindopril better atenolol thiazide better0.50 0.70 1.00 1.45

PrimaryNon-fatal MI (incl silent) + fatal CHD

Secondary

Non-fatal MI (exc. Silent) + fatal CHDTotal coronary end pointTotal CV event and procedures

All-cause mortalityCardiovascular mortalityFatal and non-fatal strokeFatal and non-fatal heart failure

TertiarySilent MIUnstable anginaChronic stable anginaPeripheral arterial diseaseLife-threatening arrhythmiasNew-onset diabetes mellitus

New-onset renal impairment

Post hocPrimary end point + coronary revasc procsCV 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)

C di l t ti d t lit


41/47

Cardiovascular protection and mortalityreduction stronger than classical regimen

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

/Perindopril/Perindopril


42/47

Cardiovascular protection andmortality reduction

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


43/47

Greatest synergy of Coversyl/CCB in CAD patients

A synergistic mode of action


44/47

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


45/47

Only 3 clinical trials in hypertensiondecrease 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.


46/47

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%


47/47

Documents

coveram-symcard-dr-yerizal.pdf