The Rationale of Fixed Combination in the Management of Hypertension

Focus on ACE-I and CCB

Yerizal Karani

Current Status of Hypertension

Measure

n (95% CI)

Total number worldwide in 2000 Total number in economically developed countries in 2000 Total number in economically developing countries in 2000

972 million (957-987) 333 million (329-336) 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.

Prevalence of HT based on gender

(Basic Health Research / Indonesian Health Departement 2007)
Men Women

35

31.3 31.9

Prevalence %

30 25 20 15 10 5 0 D D/O Dasar Diagnosis U 5.8 8.6 9 6.1

Keterangan :

D D/O U

= Diagnosis berdasarkan tenaga kesehatan = Diagnosisi berdasarkan tenaga kesehatan atau kasus minum obat = Diagnosis berdasarkan hasil pengukuran tekanan darah

50
Biennial ageadjusted rate per 1000 patients

Coronary disease

Stroke

Peripheral artery disease

Heart failure

40 30 20

Normotensie Hypertensive

10 0
Risk ratio: Men Women 2.0 2.2 Men Women 3.8 2.6 Men Women 2.0 3.7 Men Women 4.0 3.0

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

Cardiovascular mortality risk 8 6

8X risk

4
2

4X risk 2X risk

1X risk

115/75

135/85

155/95

175/105

Systolic BP/Diastolic BP (mmHg)

*Individuals aged 4069 years Lewington et al. Lancet 2002;360:190313

Takeda Chemical Industries, 1998

Treating hypertension reduces cardiovascular morbidity and mortality

Relative risk (%)
0

CHF

Stroke

CV mortality

Major coronary event

All deaths

*
20

***
40

**
Older patients (mean >65 years) Younger patients (<65 years)

*** *** ***

60

* p<0.05; ** p<0.01; *** p<0.001 80 Gueyffier et al (1996)

HT treatment
Treatment of CV risk factors / TOD Management associated clinical conditions

AS 2011

Awareness
Treatment Control

70 %

} 59 % } 34 %

11 % aware, but not treated

25 % treated, but not controlled

AS 2011

Survey1988 Survey 1993 (%) (%) -Prevalence of hypertension 14,9 16,9

Survey 2000 (%) 17,9

-Borderline hypertension
-Awareness of responders -Newly discovered -Treated cases -Adequately treated cases

3,2

2,5

56,1 43,9 50,9

88,7 11,3 85,3

88,0 12,0 79,4

10,0

31,1

39,9

Monica Group Jakarta

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 Drug(s) for the compelling indications Other antihypertensive Drugs (diuretics, ACE-I, ARB, BB, CCB) as needed

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)

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

2
ADDITIVE EFFECT LOWER DOSAGE OF EACH DRUG COMPLIMENTARY PROPERTIES ADVERSE EFFECTS OF EACH DRUGS NEUTRALIZED

- SIDE EFFECTS QUALITY OF LIFE -

COMPLIANCE - Better BP controll

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, 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

ACEI-CCB Combination: Synergy for BP Lowering

Renin
SNS

Ang I
Activation of a1R (VSMC) CCB

X
Ang II

ACEI CCB

Ca++

X
VSMC

Vasoconstriction Reduced Na+ scrtion

Vasodilatation
Increased secretion of Na+ and water

BP

A Synergy also decreasing side effects

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.

Reduces ankle edema in comparison with CCB

Amlodipine alone Perindopril-Amlodipine

Precapillary vasodilation => oedema

Venous dilation hence normalising intracapillary pressure

Messerli FH, et al. Am J Cardiol. 2000;86(11):1182-1187 Ferrari, R. Current Med. Research & Opinion, 2008, 24 (12), 3543-3557

24

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

comparison with ACE inhibitor alone
Elimination of cough

Reduction of cough

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.

Perindopril + Amlodipine decreases cough

ACEI inhibit kininase II bradykinin CCB

arachidonic acid
stim. PLAz inhibit

PGEz
stim. pulm. sensory C fibers

Ca++- dep. release of glutamate at solitary tract nucleus

coughing

inhibit

Perindopril in EUROPA study cough in 2.7% Perind + amlo in STRONG Study cough in 1.5%

n= 1 250 > 160mmHg

n= 161 > 180mmHg

Perindopril+Amlodipine
Bahl UK. Fixed dose perindopril and amlodipine in moderate-to-severe hypertension. 14th World Congress of Heart Disease 2008, Toronto, Canada.

BP Reduction Whatever the profile of hypertensive patients

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

Comparison with landmark trial

n= 1 250

n= 19 342

SBP
0

DDP
0

SBP

DDP

-10

-10

-20

-20

-23
-30 -30

-25

-40

-40

-41
BP decrease (mmHg)

-50
Amlodipine 5mg + Perindopril 5mg

-50

-44

Amlodipine 5/10mg+Perindopril 5/10mg

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.

Componentsofantihypertensiveefficacy haveindependentpredictivevalue
Brachial (clinic) BP

Central BP

Antihypertensive efficacy

BP variability

24h BP: nocturnal BP control

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. J Hypertens. 2007; 25:707712.

European Society of Cardiology:

Drugs which exert their antihypertensive effect over 24 hours with a once-a-day administration should be preferred
Perindopril1

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.

BP variability: main cause of CV events.3

Stabilizes blood pressure to avoid excessive BP variability 1,2

/Perindopril

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.

Effective in reducing central aortic BP Control

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

Similar brachial BP reductions

A central aortic SBP difference of 4.3 mmHg

ASCOT insights: recent sub studies

COVERAM offers high QUALITY of Blood Pressure Control

Fixed dose combinations: where is the evidence?

Among available combinations

fixed-dose

combinations,

which

- 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

Only ASCOT shows life saving evidence

No

No

No

No

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.

International Guidelines in Hypertension

Valsartan/amlodipine Telmisartan/amlodipine Olmesartan/amlodipine

ASCOT-BPLA
19,342 hypertensive patients atenolol bendroflumethiazide PROBE design 10,305 patients
TC 6.5 mmol/L (250 mg/dL)

ASCOT-BPLA amlodipine perindopril

ASCOT-LLA

atorvastatin 10 mg

Double-blind

placebo

Investigator-led, multinational randomised controlled trial

www.ascotstudy.org

ASCOT-BPLA: summary of all end points

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 0.50
Dahlf B, et al. Lancet. 2005;366:895-906.

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) 1.00 1.45 2.00

0.70

amlodipine perindopril better

atenolol thiazide better

Cardiovascular protection and mortality reduction stronger than classical regimen

/Perindopril

/Perindopril

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

Cardiovascular protection and mortality reduction

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

Greatest synergy of Coversyl/CCB in CAD patients

A synergistic mode of action

Perindopril Amlodipine

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.

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
o

strong BP reduction (40-63 mmHg)

Controls BP over 24 h

Decreases central BP
Decreases blood pressure variability

Saves Offers
o

life (ASCOT) excellent safety

Oedema 0.7% Cough 1.5%