the rationale of fixed combination in the … rationale of fixed combination in the management of...
TRANSCRIPT
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Yerizal Karani
The Rationale of Fixed Combination in
the Management of Hypertension Focus on ACE-I and CCB
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Current Status of
Hypertension
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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.
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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)
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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
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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
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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
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HT treatment Treatment of CV risk factors / TOD
Management associated clinical conditions
AS 2011
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- Awareness 70 %
11 % aware, but not treated
- Treatment 59 %
25 % treated, but not controlled
- Control 34 %
}
}
AS 2011
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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
(%)
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AS 2011
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BP GOAL
Monotherapy 42-59%
Combined therapy 54-70%
ALLHAT >50%
Combined therapy
AS 2011
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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
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HYPERTENSION
- COMPLEX DISORDERS
- MULTIPLE PATHOGENETIC FACTORS
( INCREASED BLOOD VOLUME,
VASOCONSTRICTION,
OVERACTIVITY SNS AND RAAS )
AS 2011
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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
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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
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Can we improve BP control rates ?
Gupta A, et al. Hypertension 2010; 55:399-407
Systolic and Diastolic BP normalization ratios
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Can we improve compliance rates ?
Gupta A, et al. Hypertension 2010; 55:399-407
FDC and Compliance or Persistence with therapy
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Primary Target RAAS
( ACEI/ARB, ß Blockers )
Low Renin States
( CCB, Diuretic )
AS 2011
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COMBINATION THERAPY
SHOULD BE
EFFECTIVE
WELL TOLERATED
POSITIVE / NEUTRAL EFFECTS
on metabolic parameters
and concomitant
diseases / risk factors
AS 2011
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The synergistic action of Perindopril - Amlodipine
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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
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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
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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
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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
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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
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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%
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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
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Whatever the profile of hypertensive patients
Bahl VK et al. Am J Cardiovasc Drugs. 2009;9:135-142.
BP Reduction
Perindopril+Amlodipine
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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
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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.
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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
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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
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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…
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ASCOT insights: recent sub studies
COVERAM offers high QUALITY of Blood Pressure Control
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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?
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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
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Valsartan/amlodipine
Telmisartan/amlodipine
Olmesartan/amlodipine
International Guidelines in Hypertension
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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
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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)
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Cardiovascular protection and mortality reduction stronger than classical regimen
Dahlöf B et al. Lancet. 2005:366;895-906.
/Perindopril /Perindopril
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Cardiovascular protection and mortality reduction
Dahlöf B et al. Lancet. 2005:366;895-906.
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Greatest synergy of Coversyl/CCB in CAD patients
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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
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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.
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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%
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