ACTION study.ppt

7/29/2019 ACTION study.ppt

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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)



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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



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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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B A E RB A E R Bayer HealthCare*Not statistically significant

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



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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



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Nifedipine GITS provides significant

protection against debilitating stroke


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



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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



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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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ACTION study.ppt

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