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ACTION Study
ACTION Study
Wahyu Widjanarko MD
B A BAY ER E R
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Heart failure
Normotensive Hypertensive
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
B A BAY ER E R
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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Cerebrovascular events
Cardiovascular events
Cardiovascular mortality
0 -10
Percent reduction
-20
-30 -40 -38%
-16%
-21%
B A BAY ER E R
90 80 70 60 50 40 30 20 10 0 0 1 -blocker
CCB ACEI
Diuretic
3 Time (yr)
440
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<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.
HealthCare
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
B A BAY ER E R
9452 M
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Complexity of treatment
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
50 40 30
21
20 10 0
No drug T modification
18
18
21 20
16 8 9 8
Dose increase
9911 M
Intermediate Endpoints
CV Risk Reduction
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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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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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100
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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Coronary Arteries:
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20 15
Improvement
18.8
p = 0.04
88%
10
5 0
Placebo
Nifedipine GITS
B A BAY ER E R
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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Angina is disabling
quality of life can be poor
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Disease modifying :
anti-platelet statins ACE inhibitors
beta blockers
Ca++ channel blockers
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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
B A BAY ER E R
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 :
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ACTION : rationale
Nifedipine GITS is widely used to treat angina
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Study design
Nifedipine GITS 30-60mg once daily on top of best practice CV therapy n = 3,825
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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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
Acute MI
New overt heart failure Debilitating stroke Refractory angina Peripheral revascularisation
Debilitating stroke
Acute MI
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Lipid-lowering
ACE inhibitors Aspirin -blockers
68
20 86 80
B A BAY ER E R
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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
Primary endpoint for efficacy (death, MI, RA, HF, CVA, PREV) p=0.5
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
Individual endpoints
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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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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
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188
112 146 70 47 50 123 82
178
114 149 91 76 75 171 76
38
33 28 8 16 6 10
0.4 1 1.6 2.2
464
190 163
545
203 182
38%
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Debilitating stroke significantly reduced Greater reduction in hypertensive subgroup Stringent diagnostic criteria
22%
33%
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13%
additional risk reduction
SBP > 140mmHg or DBP > 90mmHg Primary endpoint met in large hypertensive population (p=0.015)
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0.5
1.5
2.5
3.5
4.5
5.5
B A BAY ER E R
Follow-up (years)
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Background slide
38% reduction in
new overt heart failure
33% reduction in
debilitating stroke
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
4% placebo
1% peripheral oedema 0.5% headache
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Hypotension
Dizziness Peripheral oedema
46
766 1446
41
762 546
B A BAY ER E R
NS
NS
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4. Protects myocardium
Increase in peripheral procedures probably because of relief of angina
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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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Selama pemberian
Nifedipine dikeluarkan Melalui lubang
Membran semipermeabel
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TP Ratio
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