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The Effects of Calcium Channel Blockers on
Cardiovascular Outcomes
Wahyu Widjanarko MD
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B A E RB A E R Bayer HealthCareKannel 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
Normotensive
Hypertensive
Coronarydisease Stroke
Peripheral arterydisease
Heartfailure
Risk ratio:
Biennialage-adjustedrate
per 1000patients
Hypertension is a Major Risk Factor for CV Disease
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B A E RB A E R Bayer HealthCareN=347,978 men without previous myocardial infarction.Neaton JD et al. In: Hypertension: Pathophysiology, Diagnosis, and Management . 1995:127-144.
SBP (mm Hg)
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B A E RB A E R Bayer HealthCare6081 M
Coincidence of Diseases
Hypertension
Renaldisease
CHF MI
Diabetes
Dyslipidemia
CAD
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-38%
-16%
-21%
-40
-30
-20
-10
0
P e r c e n
t r e
d u c
t i o n
Reduction in morbidity and mortality by antihypertensive treatment
Cerebrovascularevents
Cardiovascularevents
Cardiovascularmortality
Collins R. et al., Lancet 1990; 335: 827-839
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From Caro CMAJ 1999; 160: 41
Cumulative rate of persistence with antihypertensive therapyby index drug class
From Caro CMAJ 1999; 160: 41
Cumulative rate of persistence with antihypertensive therapyby index drug class
0 1 2 3 4 5Time (yr)
0
10
20
30
40
50
60
70
80
90
100
C u m
u l a t
i v e p e r s
i s t e n c e r a
t e ( % )
CCB
-blocker
Diuretic
ACEI
440
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For individuals with hypertension and: BP goal:
JNC 7 Without diabetes or renal disease With diabetes or renal disease
ESH/ESC Without diabetes With diabetes
WHO/ISH Without diabetes With diabetes
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BP Control in European and Extraeuropean Countries
9452 M
USA Canada Germany England Spain
Italy France Belgium Scotland Finland
Egypt Nigeria India Bahrain China
29% 17% 19% 19% 36%
11.5% 39% 31% 17% 20%
5% 26% 30% 16% 5%
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Factors Involved in Lack of BP Controlin Hypertensive Population
9960 M
Patients low compliance
Refusal to accept life-long treatmentneed
Side effects
Real (or perceived) treatment inefficacy
Cost / Difficulties posed by Health CareSystem
Patients educational level /demography/ habits
Complexity of treatment
Doctors behaviour
Limited scientific update
Inertia
Drug underdosing
Limited use of combination T
Suboptimal doctor-patientrelationship
Short / infrequent visits
Limited information from / to patient
Low prescription readability
Side effect minimization
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53 5256
18 1816
21 21 20
8 9 8
0
10
20
30
40
50
60
70No diabetes
No kidney disease
WHO/ISH medium/low risk
9911 M
Physicians Behaviour according to Uncontrolled Hypertension( 140/90 mmHg) in Spanish Hospital Hypertension Units (CLUE Study)
Banegas et al., Hypertension 2004; 43: 1338
%
No drug Tmodification
Dose increase Addanother drug
Switch toanother drug
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Benefit Achieved by INSIGHT Treatment(Risk reduction estimated from Framingham data)
C a r d
i o v a s c u
l a r E n
d p o
i n t s
p e r
1 , 0
0 0 P a t i e n
t Y e a r s 34
17
0
10
20
30
Predictedfrom cardiovascular
risk profiling at baseline
Observedin all INSIGHT
patients
50%* * > 35%risk reduction
estimated fromMONICA data
Brown et al: Lancet 2000: 56: 366-72
International Nifedipine Study
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Impact on Intima-Media Thickness
Follow-up (years)
I M T C h a n g e
f r o m b a s e
l i n e
( m m )
0
-0.010
0
0.010
0.020
0.030
0.040
1 2 3 4
HCTZ/Amiloride
Nifedipine
GITS
Progression
Regression
Simon et al. Circulation (in press, 2001)
International Nifedipine Study
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100
0
25
50
75
Baseline Year 1
I n c r e a s e
( % )
HCTZ/AmilorideNifedipine GITS
Year 2 Year 3
p=0.02
Motro et al. Hypertension (in press, 2001)
INSIGHT Coronary Calcification Study
Effect on Progressionof Maximum Total Calcium Score
International Nifedipine Study
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All Patients Evaluable per Protocol, Index Artery Segment
Angiographic Changes in Coronary Vessel Diameter after Acetylcholine Administration
Placebo vs Nifedipine GITS (Secondary Comparison)
Nifedipine GITS Placebo
C h a n g e v s
B a s e l i n
e ( % )
20 p = 0.04
15
10
5
0
10.0
18.8
Difference between % change at baseline and % change at month 6; Highest dose of acetylcholine administered at baseline and at month 6; p-value vs placebo
88%Improvement
Lscher: ENCOREresults, AmericanHeart Association,2000
Endothelial Function Study
Antiatherosclerotic Effects of Nifedipine
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Coronary Artery Disease FactsAngina is common
affects over 10% of men and women over 60
Angina is disabling quality of life can be poor
Angina affects outcome variably 3% to 20% annual rate of cardiac events
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Current Medical Treatment of Angina
Anti anginal :
nitrates beta blockers Ca ++ channel blockers
Disease modifying :
anti-platelet statins ACE inhibitors
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Nifedipine GITS has been shown
to have anti-ischaemic effects
Modified from Parmley W, et al. J Am Coll Cardiol 1992;19:1380 9.
Nifedipine GITS
M e a n n u m
b e r o
f i s c
h a e m
i c e v e n
t s
Placebo
(baseline)
Nifedipine GITS
Time (hours)
1.5
1.2
0.9
0.6
0.3
00 5 10 15 20 25
Placebo
(baseline)
Nifedipine GITS
1.5
1.2
0.9
0.6
0.3
0 M e a n n u m
b e r o
f i s c
h a e m
i c e v e n
t s
Time (hours)0 5 10 15 20 25
Nifedipine GITS + -blocker
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As so cia ted w i th an inc reased rate o f m yo card ial in farc t ion
Gast ro in tes t ina l haem orrh age
Cancer
But in the mid 1990 s case controland cohort studies suggested that inhypertensive patients calcium channelblockers were :
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ACTION : rationale
Nifedipine GITS is widely used to treat anginaand hypertensionControversy circa 1995 on safety based on : Data from unapproved indications Observational studies Meta-analyses (Furberg, 1995)
Short-acting formulations of nifedipine possiblyharmfulNo evidence from outcome trials in patients withstable angina
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Study design
Placebo on top of bestpractice CV therapy
n = 3,840
0 1 2 3 4 5 6
Years
Study end
Patients with
stable anginaaged
35 yearsn=7,665
Nifedipine GITS 30-60mg once dailyon top of best practice CV therapy
n = 3,825
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Patient selection
Key inclusion criteria Key exclusion criteria
35 years of age
Confirmed CAD
Stable clinical conditionfor 1 month
Current angina treatment notto include CCBs 2 weeks prior
to study start Ejection fraction >40%
Receiving lipid-lowering therapy
Able to attend out-patient clinic
Major CV events or interventions3 months prior to study start
Planned coronaryangiography/intervention
Clinically significant heart failure
Intolerance to CCBs
Diseases including valvular, pulmonary,unstable insulin-dependent diabetes andgastrointestinal conditions (GITS tablet)
Orthostatic hypotension or very high BP
Pregnancy
Background slide
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Patient pre-treatment met bestpractice criteria at baseline
80 -blockers 86 Aspirin
20 ACE inhibitors
68 Lipid-lowering99 Anti-anginal
Patients (%) Baseline medication
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ACTION : heart rate and blood pressure
p
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ACTION : outcomeAll-cause death (p=0.4)
RA = refractory anginaPREV = peripheral revascularisation
Primary endpoint for
efficacy (death, MI, RA, HF, CVA,PREV)p=0.5
Primary endpoint for safety (death, MI, CVA,p=0.9)
0.0
0.2
0.4
0.6
0.8
1.0
0 2 4 6years
Proportion event-free
nifedipineplacebo
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Individual endpoints
Proven safety of nifedipine GITS vs placebo
Neutral efficacy in addition to best practice therapy
11% reduction in events
9% reduction in vascular events
Additional BP reduction of 6/3mmHg
22% reduction in stroke*
29% reduction in new heart failure
18% reduction in coronary angiography
21% reduction in CABG
14% reduction in refractory angina*
Summary of Outcomes
*Not statistically significant
Primary plus interventions: Coronary angiography CABG PTCA
Primary endpoint
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A Coronary disease Trial InvestigatingOutcome with Nifedipine GITS
Nifedipine GITS adds more benefit inhigh-risk CAD patients with hypertension
Hyper tens ive subg roup analys is
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Disposition of patients
ITT analysis in grade 1-3 hypertension at baseline
Total patientpopulation
Hypertension
at baseline
Nifedipine
GITS
Placebo Total
n (%)
3825 (0.0)
1975
3840 (0.0)
2002
7665 (100.0)
3977
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Individualendpoints
13% reduction in primary efficacy endpoint
Proven safety of nifedipine GITS
17% reduction in any CV event10% reduction in death, any CV event or procedure
11% reduction in any vascular event or procedure
BP reduction of 14.5/7.0mmHg
38% reduction in new overt heart failure
33% reduction in debilitating stroke
28% reduction in any stroke or transient ischaemic attack
16% reduction in coronary angiography
23% reduction in refractory angina*
Secondaryendpoints
Primaryendpoints
Summary of key outcomes
Hyper tens ive subg roup analys is
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Nifedipine GITS dual mode of action
provides additional benefits
Dual mode of action
BP lowering Vascular protection
Heart failureStroke/TIA
Coronary interventions
(coronary angiography, CABG)Refractory angina
Significant reduction in CV morbidity and mortality
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Nifedipine GITS prevents more cases of
new overt heart failure
38%
Heart failure significantly
reduced in hypertensivepatients
Greater reduction inhypertensive subgroup
Nifedipine GITS is theonly CCB proven toprevent heart failure
Hyper tens ive subg roup analys is
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Nifedipine GITS provides significant
protection against debilitating stroke
Hyper tens ive subg roup analys is
Debilitating strokesignificantly reduced
Greater reductionin hypertensivesubgroup
Stringent diagnosticcriteria
33%
Hypertensive subgroupOverall population
22%
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3,977 patients-a very large group
SBP > 140mmHgor DBP > 90mmHg
Primary endpoint metin large hypertensivepopulation (p=0.015)
13%
additionalrisk reduction
Primary endpoint significant
in hypertensive subgroup (2)
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M e a n
D B P ( m m
H g
)
M e a n
S B P ( m m
H g
)155
150
145
140
135
130
125
120
Follow-up (years)
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5
Nifedipine GITSPlacebo
Hypertensive atbaseline
Hypertensive atbaseline
Normotensive atbaseline
Normotensive atbaseline
Nifedipine GITS provides additional BP control on
top of best practice therapy
H t i b l iB k d lid
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Key benefits of nifedipine GITS
in CAD patients with hypertension
38% reduction innew overt heart failure
28% reduction inany stroke/TIA
33% reduction indebilitating stroke
16% reduction incoronary angiography
Nifedipine GITS addsmore benefit in
hypertensive patients
Hyper tens ive subg roup analys is Background slide
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ACTION : tolerance
% follow-up time on study medication :
79% for nifedipine arm82% for placebo arm
Withdrawal because of adverse event :
10% nifedipine 4% peripheral oedema 1% headache
4% placebo 1% peripheral oedema 0.5% headache
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ACTION: selected adverse events
Numbers of patients with first event :
Nifedipine Placebo
Cancer 358 311 NS
GI bleeds 58 62 NS
Hypotension 46 41 NS
Dizziness 766 762 NS
Peripheral oedema 1446 546
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ACTION :mechanisms for reduction of procedures
1. Anti-anginal effect
2. Modification of endothelial dysfunction or damage3. Inhibits progression of atheroma
4. Protects myocardium
Increase in peripheral procedures probably because of relief of angina
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ACTION : mechanisms for reduction of CHFPossible mechanisms by which nifedipine GITSreduced the incidence of heart failure :
Antihypertensive effect Reduction in ischemia
Reduction in myocardial infarction size
Hyper tens ive subg roup analys is
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Safety and efficacy of nifedipine GITS provedin CAD patients with hypertension who werealready receiving best practice therapy
13% reduction in primary endpoint38% reduction in new overt heart failure33% reduction in debilitating stroke
Nifedipine GITS provides even greater benefitsin CAD patients with hypertension
Summary
Hyper tens ive subg roup analys is
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Why should beAdalat OROS?
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Chronobiology and Chronotherapeutics
Biologic functions are preciselyorganized in space and time
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OROS ( Or al Osmotic Delivery S ystem)
Sebelum pemberian Selama pemberian
Lapisan nifedipine Nifedipine dikeluarkan Melalui lubang
Sistem pengeluaran
pompa osmotik(lapisan pendorong
polymeric )
Membran
semipermeabel
Lapisan
pendorongmengembang Air masuk dgn osmosis
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TP Ratio
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TP Ratio
Journal of Hypertension 1994, 12 (suppl 5): S29-S33
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