The Effects of Calcium Channel Blockers on

Cardiovascular Outcomes

Wahyu Widjanarko MD

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 Hypertension is a Major Risk Factor
for CV Disease
Coronary Peripheral artery Heart
disease Stroke disease failure
Biennial 50
age-
adjusted
rate 40
Normotensive
per 1000
Hypertensive
patients 30

20

10

0
Men Women Men Women Men Women Men Women
Risk ratio: 2.0 2.2 3.8 2.6 2.0 3.7 4.0 3.0
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Kannel WB. JAMA. 1996;275:1571-1576.

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 BP is Closely Associated with
Risk of Death from CHD
6.40

5.26

Relative 7 SBP
risk of 3.42
6 DBP
CHD
mortality 5 2.45 5.17
1.66
4 1.00 1.28
3.45
3
2.56
2 1.84
1.21 1.48
1 1.00
0
SBP (mm Hg) <120 120-129 130-139 140-159 160-179 180-209 ≥ 210
DBP (mm Hg) < 80 80-84 85-89 90-99 100-109 110-119 ≥ 120

N=347,978 men without previous myocardial infarction. B

Neaton JD et al. In: Hypertension: Pathophysiology, Diagnosis, and Management. 1995:127-144.

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 Coincidence of Diseases

Renal
disease

Hypertension Diabetes
Dyslipidemia

CHF MI CAD

6081 M
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 Reduction in morbidity and mortality by antihypertensive treatment

Cerebrovascular Cardiovascular Cardiovascular

events events mortality
0

-10
Percent reduction

-20 -16%
-21%
-30

-40 -38%

Collins R. et al., Lancet 1990; 335:

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 Cumulative rate of persistence with antihypertensive therapy
by index drug class
100
90 CCB
Cumulative persistence rate (%)

80 ACEI
70
60
50 ß-blocker
40 Diuretic
30
20
10
0
0 1 2 3 4 5
Time (yr)
From Caro CMAJ 1999; 160: 41

440 B
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 Guidelines Recognize Growing Treatment
Complexities and Recommend Tighter Control
For individuals with hypertension and: BP goal:

JNC 7
• Without diabetes or renal disease <140/90 mm Hg
• With diabetes or renal disease <130/80 mm Hg

ESH/ESC
• Without diabetes <140/90 mm Hg
• With diabetes <130/80 mm Hg

WHO/ISH
• Without diabetes <140/90 mm Hg
• With diabetes <130/80 mm Hg

Chobanian AV et al. JAMA. 2003;289:2560-2572. Guidelines Committee. J Hypertens. 2003; 21: 1011-1053.
Guidelines Subcommittee. J Hypertens. 1999; 17: 151-183. World Health Organization, International Society
B

of Hypertension Writing Group. J Hypertens. 2003; 21: 1983-1992.

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 BP
BP Control
Control in
in European
European and
and Extraeuropean
Extraeuropean Countries
Countries
29% 17% 19% 19% 36%

USA Canada Germany England Spain

11.5% 39% 31% 17% 20%

Italy France Belgium Scotland Finland

5% 26% 30% 16% 5%

Egypt Nigeria India Bahrain China

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 Factors
Factors Involved
Involved in
in Lack
Lack of
of BP
BP Control
Control
in
in Hypertensive
Hypertensive Population
Population
Patient’s low compliance Doctor’s behaviour

Refusal to accept life-long treatment Limited scientific update

need
Inertia
Side effects
Drug underdosing
Real (or perceived) treatment inefficacy
Limited use of combination T
Cost / Difficulties posed by Health Care
System Suboptimal doctor-patient
relationship
Patient’s educational level /
demography/ habits Short / infrequent visits

Complexity of treatment Limited information from / to patient

Low prescription readability
Side effect minimization
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 Physician’s
Physician’sBehaviour
Behaviouraccording
accordingto
toUncontrolled
UncontrolledHypertension
Hypertension
(≥
(≥140/90
140/90mmHg)
mmHg)in inSpanish
SpanishHospital
HospitalHypertension
HypertensionUnits
Units(CLUE
(CLUEStudy)
Study)
70
% No diabetes
60 56 No kidney disease
53 52
50 WHO/ISH medium/low risk

40

30
21 21 20
20 18 18
16

8 9 8
10

0
No drug T Dose increase Add Switch to
modification another drug another drug

Banegas et al., Hypertension Bayer

2004; HealthCare
43: 1338
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 International Nifedipine Study

Risk Intermediate Clinical Outcome:

Factors Endpoints CV Events

Hyper- Intima- Coronary

tension Media- Calcification
Hyper- Thickness
lipidemia
INSIGHT INSIGHT
Diabetes Side Arm Studies Main Study
Effects Beyond CV Risk
Blood Pressure Reduction
Control
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 International Nifedipine Study

Benefit Achieved by INSIGHT Treatment

(Risk reduction estimated from Framingham data)
Cardiovascular Endpoints
per 1,000 Patient Years

30 34
50%* * > 35%
risk reduction
estimated from
20
MONICA data
17
10

0
Predicted Observed
from cardiovascular in all INSIGHT
risk profiling at baseline patients
Brown et al: Lancet 2000: 56: 366-72
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 International Nifedipine Study

Impact on Intima-Media Thickness

0.040
HCTZ/
IMT Change from baseline (mm)

Progression Amiloride
0.030

0.020

0.010

0
Nifedipine
-0.010 GITS
Regression
0 1 2 3 4
Follow-up (years)
Simon et al. Circulation (in press, 2001)
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 International Nifedipine Study

INSIGHT Coronary Calcification Study

Effect on Progression
100
of Maximum Total Calcium Score
HCTZ/Amiloride
Nifedipine GITS
75
Increase (%)

p=0.02
50

25

Motro et al. Hypertension (in press, 2001)

0
Baseline Year 1 Year 2 Year 3
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Antiatherosclerotic Effects of Nifedipine

Coronary Arteries:
Endothelial
Function
Study

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 Antiatherosclerotic Effects of Nifedipine
All Patients Evaluable per Protocol, Index Artery Segment

Angiographic Changes in Coronary Vessel Diameter after Acetylcholine Administration

Placebo vs Nifedipine GITS (Secondary Comparison)
Change vs Baseline (%)

20
p = 0.04
18.8
Improvement
15 88%
10
10.0
5
Endothelial Function Study
Lüscher: ENCORE
results, American
Heart Association,
2000
0
Placebo Nifedipine GITS
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
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A Coronary disease Trial Investigating
Outcome with Nifedipine GITS
(Gastro Intestinal Therapeutic System)

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 Coronary Artery Disease Facts
 Angina 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 : Disease modifying :

– nitrates – anti-platelet
– beta blockers – statins
– Ca++ channel blockers – ACE inhibitors

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 Nifedipine GITS has been shown
to have anti-ischaemic effects
1.5 Nifedipine GITS 1.5 Nifedipine GITS + -blocker
Mean number of ischaemic events

Mean number of ischaemic events

1.2 1.2
Placebo Placebo
(baseline) (baseline)
0.9 0.9

0.6 0.6
Nifedipine GITS

0.3 0.3
Nifedipine GITS

0 0
0 5 10 15 20 25 0 5 10 15 20 25
Time (hours) Time (hours)
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Modified from Parmley W, et al. J Am Coll Cardiol 1992;19:1380–9.

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But……… in the mid 1990’s case control
and cohort studies suggested that in
hypertensive patients calcium channel
blockers were :

 Associated with an increased

rate of myocardial infarction
 Gastrointestinal haemorrhage
 Cancer

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ACTION

Philipp Poole-Wilson

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 ACTION : rationale
 Nifedipine GITS is widely used to treat angina
and hypertension
 Controversy circa 1995 on safety based on :
– Data from unapproved indications
– Observational studies
– Meta-analyses (Furberg, 1995)
 Short-acting formulations of nifedipine possibly
harmful
 No evidence from outcome trials in patients with
stable angina
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Study design

Nifedipine GITS 30-60mg once daily

on top of best practice CV therapy
Patients with
n = 3,825
stable angina
aged
35 years Placebo on top of best
n=7,665 practice CV therapy
n = 3,840
0 1 2 3 4 5 6
Years
Study end
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Background slide
Patient selection
Key inclusion criteria
 35 years of age
 Confirmed CAD
 Stable clinical condition
for 1 month
 Current angina treatment not
to include CCBs 2 weeks prior
to study start
 Ejection fraction >40%
 Receiving lipid-lowering therapy
 Able to attend out-patient clinic
Key exclusion criteria
 Major CV events or interventions
3 months prior to study start
 Planned coronary
angiography/intervention
 Clinically significant heart failure
 Intolerance to CCBs
 Diseases including valvular, pulmonary,
unstable insulin-dependent diabetes and
gastrointestinal conditions (GITS tablet)
 Orthostatic hypotension or very high BP
 Pregnancy
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 Endpoints combined clinically important
outcomes
Combined primary
endpoint for efficacy
• All-cause mortality
• Acute MI
• New overt heart failure
• Debilitating stroke
• Refractory angina
• Peripheral revascularisation
Combined secondary Combined primary
endpoints for efficacy endpoint for safety
1) Death, any CV event or • All-cause mortality
procedure (primary efficacy • Debilitating stroke
endpoint plus coronary • Acute MI
angiography, PCI, CABG)
2) Any vascular event or
procedure:
– CV death
– Acute MI
– Refractory angina
– Peripheral revascularisation
– Debilitating stroke
– PCI
– CABG
3) Any CV event (primary efficacy B
endpoint minus non-CV death)
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Patient pre-treatment met best
practice criteria at baseline
Baseline medication Patients (%)
Anti-anginal 99
Lipid-lowering 68
ACE inhibitors 20
Aspirin 86
-blockers 80

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ACTION : heart rate and blood pressure
Heart 68
p<0.0001
rate 66
(bpm) 64
140
Systolic 135
blood pr. p<0.0001
130
(mm Hg)
125 nifedipine
Mean reduction 6/3 mm Hg
80 placebo
Diastolic
blood pr. p<0.0001
(mm Hg)
74
years 0 1 2 3 4 5 6
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 ACTION : outcome
Proportion event-free
All-cause death (p=0.4)
1.0

0.8 Primary endpoint for

efficacy
(death, MI, RA, HF, CVA, Primary endpoint for
0.6
PREV) safety (death, MI, CVA,
p=0.5 p=0.9)
0.4

nifedipine
0.2
RA = refractory angina placebo
PREV = peripheral revascularisation
0.0
0 2 4 6
years B
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 Summary of Outcomes
Proven safety of nifedipine GITS vs placebo
Primary endpoint
Neutral efficacy in addition to best practice therapy

Primary plus interventions:

Coronary angiography 11% reduction in events
CABG 9% reduction in vascular events
PTCA

Additional BP reduction of 6/3mmHg

Individual endpoints
22% reduction in stroke*
29% reduction in new heart failure
18% reduction in coronary angiography
21% reduction in CABG
14% reduction in refractory angina*

*Not statistically significant Bayer HealthCare

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 Hypertensive subgroup analysis

A Coronary disease Trial Investigating

Outcome with Nifedipine GITS

Nifedipine GITS adds more benefit in

high-risk CAD patients with hypertension

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 Disposition of patients
ITT analysis in grade 1-3 hypertension at baseline

Nifedipine Placebo Total

GITS n (%)

Total patient
3825 (0.0) 3840 (0.0) 7665 (100.0)
population

Hypertension
1975 2002 3977
at baseline

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 Hypertensive subgroup analysis

Summary of key outcomes

Primary 13% reduction in primary efficacy endpoint

endpoints Proven safety of nifedipine GITS

17% reduction in any CV event

Secondary
10% reduction in death, any CV event or procedure
endpoints
11% reduction in any vascular event or procedure

BP reduction of 14.5/7.0mmHg
Individual
38% reduction in new overt heart failure
endpoints
33% reduction in debilitating stroke
28% reduction in any stroke or transient ischaemic
attack
16% reduction in coronary angiography
23% reduction in refractory angina*
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*Not statistically significant

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 Nifedipine GITS’ dual mode of action
provides additional benefits

Dual mode of action

BP lowering Vascular protection

 Coronary interventions
 Heart failure
(coronary angiography, CABG)
 Stroke/TIA  Refractory angina

Significant reduction in CV morbidity and mortality

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 Hypertensive subgroup analysis

Nifedipine GITS significantly reduces

important individual endpoints
Individual endpoints Patients with events (n)
Hazard ratio
Change (%)
Nifedipine GITS Placebo (95% CI)
All-cause mortality 188 178  6
CV death 112 114  2
Acute MI 146 149  2
Refractory angina 70 91  23
New overt heart failure 47 76  38
Debilitating stroke 50 75  33
Any stroke or TIA 123 171  28
Peripheral
82 76  8
revascularisation
Coronary angiography 464 545  16
PCI 190 203  6
CABG 163 182  10

0.4 1 1.6 2.2

Favours
BayerFavours
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GITS placebo
 Hypertensive subgroup analysis

Nifedipine GITS prevents more cases of

new overt heart failure

 Heart failure significantly

reduced in hypertensive
patients
38%
38%  Greater reduction in
hypertensive subgroup

 Nifedipine GITS is the

only CCB proven to
prevent heart failure
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 Hypertensive subgroup analysis

Nifedipine GITS provides significant

protection against debilitating stroke
Overall population Hypertensive subgroup
 Debilitating stroke
significantly reduced
22%
 Greater reduction

33% in hypertensive
subgroup

 Stringent diagnostic
criteria

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 Primary endpoint significant
in hypertensive subgroup (2)
 3,977 patients-
a very large group
13%  SBP > 140mmHg
or DBP > 90mmHg

 Primary endpoint met

additional in large hypertensive
risk reduction population (p=0.015)
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 Nifedipine GITS provides additional BP control on
top of best practice therapy
155 Nifedipine GITS
150 Placebo
Mean SBP (mmHg)

145

140 Hypertensive at
135 baseline
130
Normotensive at
125 baseline
120
Mean DBP (mmHg)

Hypertensive at
baseline
Normotensive at
baseline

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5

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Follow-up (years) Bayer HealthCare

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Background slide Hypertensive subgroup analysis

Key benefits of nifedipine GITS

in CAD patients with hypertension

38% reduction in 33% reduction in

new overt heart failure debilitating stroke

Nifedipine GITS adds

more benefit in
hypertensive patients
16% reduction in 28% reduction in
coronary angiography any stroke/TIA

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 ACTION : tolerance
% follow-up time on study medication :
79% for nifedipine arm
82% 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 damage
3. 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 CHF

Possible mechanisms by which nifedipine GITS

reduced the incidence of heart failure :

• Antihypertensive effect
• Reduction in ischemia
• Reduction in myocardial infarction size

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 Hypertensive subgroup analysis

Summary
 Safety and efficacy of nifedipine GITS proved
in CAD patients with hypertension who were
already receiving best practice therapy
 13% reduction in primary endpoint
 38% reduction in new overt heart failure
 33% reduction in debilitating stroke

 Nifedipine GITS provides even greater benefits

in CAD patients with hypertension
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Why should be
Adalat® OROS?

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Chronobiology and Chronotherapeutics

Biologic functions are precisely

organized in space and time

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 OROS (Oral Osmotic Delivery System)

Sebelum pemberian Selama pemberian

Nifedipine dikeluarkan
Lapisan nifedipine Melalui lubang

Sistem pengeluaran Membran Lapisan

pompa osmotik semipermeabel pendorong
(lapisan pendorong mengembang Air masuk dgn osmosis
polymeric)

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 B
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 B
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 TP Ratio

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Journal of Hypertension 1994, 12 (suppl 5): S29-S33 A
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 B
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 B
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