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 disease
Biennial ageadjusted rate per 1000 patients 50 40 30 20 10 0 Risk ratio: Stroke

Peripheral artery disease

Heart failure

Normotensive Hypertensive

Men Women 2.0 2.2

Men Women 3.8 2.6

Men Women 2.0 3.7

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Men Women 4.0 3.0

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

BP is Closely Associated with Risk of Death from CHD

6.40 5.26 Relative risk of CHD mortality 7 6 5 4 3 2 2.56 1.00
<120 < 80

SBP DBP 2.45 1.00 1.28 1.66

3.42 5.17 3.45 1.84

1
0
SBP (mm Hg) DBP (mm Hg)

1.21

1.48

120-129 130-139 140-159 160-179 180-209 80-84 85-89 90-99 100-109 110-119
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210 120

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

Cardiovascular events

Cardiovascular mortality

0 -10

Percent reduction

-20
-30 -40 -38%

-16%
-21%

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Cumulative rate of persistence with antihypertensive therapy by index drug class

100
Cumulative persistence rate (%)

90 80 70 60 50 40 30 20 10 0 0 1 -blocker

CCB ACEI

Diuretic

3 Time (yr)

From Caro CMAJ 1999; 160: 41

B A BAY ER E R

440

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Guidelines Recognize Growing Treatment Complexities and Recommend Tighter Control

For individuals with hypertension and: JNC 7 Without diabetes or renal disease With diabetes or renal disease ESH/ESC Without diabetes With diabetes WHO/ISH Without diabetes With diabetes BP goal:

<140/90 mm Hg <130/80 mm Hg

<140/90 mm Hg <130/80 mm Hg

<140/90 mm Hg <130/80 mm Hg

Chobanian AV et al. JAMA. 2003;289:2560-2572. Guidelines Committee. J Hypertens. 2003; 21: 1011-1053. B A Guidelines Subcommittee. J Hypertens. 1999; 17: 151-183. World Health Organization, International Society BAY ER Bayer E R of Hypertension Writing Group. J Hypertens. 2003; 21: 1983-1992.

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BP Control in European and Extraeuropean Countries

29% 17% 19% 19% 36%

USA
11.5%

Canada
39%

Germany
31%

England
17%

Spain
20%

Italy
5%

France
26%

Belgium
30%

Scotland
16%

Finland
5%

Egypt

Nigeria

India

Bahrain

China
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9452 M

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Factors Involved in Lack of BP Control in Hypertensive Population

Patients low compliance Doctors behaviour

Refusal to accept life-long treatment need

Side effects

Limited scientific update

Inertia Drug underdosing

Real (or perceived) treatment inefficacy Limited use of combination T

Cost / Difficulties posed by Health Care System

Patients educational level / demography/ habits

Suboptimal doctor-patient relationship Short / infrequent visits

Complexity of treatment

Limited information from / to patient

Low prescription readability Side effect minimization

9960 M

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Physicians Behaviour according to Uncontrolled Hypertension ( 140/90 mmHg) in Spanish Hospital Hypertension Units (CLUE Study)
70
%

No diabetes 60
53 52 56

No kidney disease WHO/ISH medium/low risk

50 40 30

21

20 10 0
No drug T modification

18

18

21 20

16 8 9 8

Dose increase

Add another drug

Switch to another drug

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9911 M

Banegas et al., Hypertension 2004; 43: 1338 Bayer HealthCare

International Nifedipine Study Risk Factors

Intermediate Endpoints

Clinical Outcome: CV Events

Hypertension Hyperlipidemia Diabetes

IntimaCoronary MediaCalcification Thickness

INSIGHT Side Arm Studies

INSIGHT Main Study

Effects Beyond Blood Pressure Control

CV Risk Reduction
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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 MONICA data

20

17
10

Predicted
from cardiovascular risk profiling at baseline

Observed
in all INSIGHT patients
Brown et al: Lancet 2000: 56: 366-72
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International Nifedipine Study

Impact on Intima-Media Thickness

IMT Change from baseline (mm)
0.040

Progression
0.030 0.020

HCTZ/ Amiloride

0.010
0 -0.010

Nifedipine GITS

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

100

Effect on Progression of Maximum Total Calcium Score

HCTZ/Amiloride Nifedipine GITS

Increase (%)

75
p=0.02

50

25 0 Baseline
Motro et al. Hypertension (in press, 2001)

Year 1

Year 2
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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 15

Improvement

18.8

p = 0.04

88%

10
5 0

10.0 Endothelial Function Study

Lscher: ENCORE results, American Heart Association, 2000

Placebo

Nifedipine GITS
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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 :
nitrates

Disease modifying :
anti-platelet statins ACE inhibitors

beta blockers
Ca++ channel blockers

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Nifedipine GITS has been shown to have anti-ischaemic effects

1.5 Mean number of ischaemic events
Nifedipine GITS

1.5 Mean number of ischaemic events

Nifedipine GITS + -blocker

1.2
Placebo (baseline)

1.2
Placebo (baseline)

0.9

0.9

0.6
Nifedipine GITS

0.6

0.3

0.3
Nifedipine GITS

0
0 5 10 15 20 25

0
0 5 10 15
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20

25

Time (hours)
Modified from Parmley W, et al. J Am Coll Cardiol 1992;19:13809.

Time (hours)

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But in the mid 1990s 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 : 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 n = 3,825

Patients with stable angina aged 35 years n=7,665

Placebo on top of best practice CV therapy n = 3,840 0 1 2 3

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 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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Ejection fraction >40%

Receiving lipid-lowering therapy Able to attend out-patient clinic

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Endpoints combined clinically important outcomes

Combined primary endpoint for efficacy
All-cause mortality

Combined secondary endpoints for efficacy 1) Death, any CV event or procedure (primary efficacy endpoint plus coronary angiography, PCI, CABG) 2) Any vascular event or procedure:
CV death Acute MI Refractory angina Peripheral revascularisation Debilitating stroke PCI CABG

Combined primary endpoint for safety

All-cause mortality

Acute MI
New overt heart failure Debilitating stroke Refractory angina Peripheral revascularisation

Debilitating stroke
Acute MI

3) Any CV event (primary efficacy endpoint minus non-CV death)

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Patient pre-treatment met best practice criteria at baseline

Baseline medication Anti-anginal Patients (%) 99

Lipid-lowering
ACE inhibitors Aspirin -blockers

68
20 86 80

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ACTION : heart rate and blood pressure

Heart rate (bpm) Systolic blood pr. (mm Hg) 68 66 64 140 135 130 125 Diastolic blood pr. (mm Hg) years 80 p<0.0001 Mean reduction 6/3 mm Hg nifedipine p<0.0001 p<0.0001

placebo

74
0 1 2 3 4 5
B A BAY ER E R

6
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ACTION : outcome
Proportion event-free
1.0 0.8 0.6 0.4

All-cause death (p=0.4)

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

Primary endpoint for safety (death, MI, CVA, p=0.9)

nifedipine

0.2
RA PREV = refractory angina = peripheral revascularisation

placebo
4 6
B A BAY ER E R

0.0 0 2

years

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Summary of Outcomes
Primary endpoint
Proven safety of nifedipine GITS vs placebo Neutral efficacy in addition to best practice therapy

Primary plus interventions: Coronary angiography CABG PTCA

11% reduction in events 9% reduction in vascular events

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

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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 GITS Total patient population Hypertension at baseline 3825 (0.0) Placebo 3840 (0.0) Total n (%) 7665 (100.0)

1975

2002

3977

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Hypertensive subgroup analysis

Summary of key outcomes

Primary endpoints
13% reduction in primary efficacy endpoint Proven safety of nifedipine GITS

Secondary endpoints

17% reduction in any CV event 10% reduction in death, any CV event or procedure 11% reduction in any vascular event or procedure

Individual endpoints

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* *Not statistically significant
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Nifedipine GITS dual mode of action provides additional benefits

Dual mode of action
BP lowering Vascular protection

Heart failure Stroke/TIA

Coronary interventions (coronary angiography, CABG) 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 All-cause mortality CV death Acute MI Refractory angina Patients with events (n) Nifedipine GITS Placebo Change (%) 6 2 2 23 Hazard ratio (95% CI)

188
112 146 70 47 50 123 82

178
114 149 91 76 75 171 76

New overt heart failure

Debilitating stroke Any stroke or TIA Peripheral revascularisation Coronary angiography PCI CABG

38
33 28 8 16 6 10
0.4 1 1.6 2.2

464
190 163

545
203 182

B A Favours BAY ER BayerFavours HealthCare E R nifedipine GITS placebo

Hypertensive subgroup analysis

Nifedipine GITS prevents more cases of new overt heart failure

Heart failure significantly reduced in hypertensive patients

Greater reduction in hypertensive subgroup Nifedipine GITS is the only CCB proven to prevent heart failure
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38%

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Hypertensive subgroup analysis

Nifedipine GITS provides significant protection against debilitating stroke

Overall population Hypertensive subgroup

Debilitating stroke significantly reduced Greater reduction in hypertensive subgroup Stringent diagnostic criteria

22%

33%

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Primary endpoint significant in hypertensive subgroup (2)

3,977 patientsa very large group

13%
additional risk reduction

SBP > 140mmHg or DBP > 90mmHg Primary endpoint met in large hypertensive population (p=0.015)
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Nifedipine GITS provides additional BP control on top of best practice therapy

155

Mean SBP (mmHg)

150 145 140 135 130 125 120

Nifedipine GITS Placebo

Hypertensive at baseline Normotensive at baseline

Mean DBP (mmHg)

Hypertensive at baseline Normotensive at baseline

0.5

1.5

2.5

3.5

4.5

5.5
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Follow-up (years)

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Background slide

Hypertensive subgroup analysis

Key benefits of nifedipine GITS in CAD patients with hypertension

38% reduction in
new overt heart failure

33% reduction in
debilitating stroke

Nifedipine GITS adds more benefit in hypertensive patients 16% reduction in

coronary angiography

28% reduction in
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 Cancer GI bleeds 358 58 Placebo 311 62 NS NS

Hypotension
Dizziness Peripheral oedema

46
766 1446

41
762 546
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NS
NS

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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
Lapisan nifedipine

Selama pemberian
Nifedipine dikeluarkan Melalui lubang

Sistem pengeluaran pompa osmotik (lapisan pendorong polymeric)

Membran semipermeabel

Lapisan pendorong mengembang

Air masuk dgn osmosis

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TP Ratio

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

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