second australian national blood pressure study conducted by the high blood pressure research...

Second Australian National Blood Pressure Study

Conducted by the High Blood Pressure Research Council of Australia in conjunction

with Australia’s General Practitioners

ANBP2

Background

• Treatment of hypertension based on diuretics and/or beta blockers provides a definite outcome benefit

• Additional benefit beyond that resulting from blood pressure reduction may result with therapy based on agents inhibiting the renin-angiotensin system

ANBP2New Engl J Med, 2003;348:583-92.

Antihypertensive Drug Use in Australia

Hypertension Patient Numbers 1993-98

0

100000

200000

300000

400000

500000

600000

70000019

93

1994

1995

1996

1997

1998

Patie

nt n

umbe

rs (

Hyp

erte

nsio

n)

Diuretics

Beta Blockers

Calcium ChannelBlockers

ACE Inhibitors

Angiotensin IIAntagonists

Background

• No outcome data with ACE inhibitor based regimens• Potential benefits include

– Reduction in LVH– Improved survival with cardiac failure– Enhanced insulin sensitivity– Lipid “neutrality”

Will outcome be the same better or worse than those of published studies?

ANBP2

Main Aim

To determine in hypertensive patients aged 65-

84 years whether there is any difference in

total cardiovascular events (fatal and non-

fatal) over a 5 year treatment period between

treatment with either a diuretic-based

regimen or an ACE inhibitor-based regimen


Study Design

P prospective

R randomised

O open label

B blinded

E endpoints

Features• Intention to treat• General practice based• 600 practices• 6000 patients• Recruitment: 2.5 years


ANBP2

National Centre (BMRI)

ManagementCommittee(HBPRCA) Sub Committees

General PracticeData monitoringEnd - pointAuditSubstudies: ABPM, LVH,Genetic, Health Econ

Regional Centers

SA QLDVIC NSW

WA

Data ManagementCentre

(Uni of Adelaide)

Study Organisation

Study SubjectsInclusion Criteria

• Men and women 65 - 84 years• Previously treated or newly diagnosed hypertensives • Untreated sitting SBP > 160 and/or DBP > 90 mmHg• Able to give consent and to attend GP practice• No recent cardiovascular morbidity

ANBP2

Exclusion Criteria• Any cardiovascular end-point in the past 6 months• Dementia• Plasma creatinine > 0.2 mmol/L• Any life threatening illness (unlikely to survive 5 years)• Unwillingness of GP to enter subject into study• Unable to attend GP practice• Absolute contraindication to ACE or diuretic

New Engl J Med, 2003;348:583-92.

Study Protocol• Blood Pressure Screening

• 3 visits conducted by Study Nurses• 3 measurements (average of 2nd and 3rd)• Mercury sphygmomanometer• Entry BP - average of 2nd and 3rd visit readings

• Randomisation• Central - Data Management Centre (Adelaide)• Stratified for age (> or 75)

• Follow-Up• GP manages patient according to usual practice• Conform (where possible) to randomisation arm• Achieve subject goal BP• At least 2 visits per year


Study Drug Treatments

• ACE Inhibitor Group• Step 1. ACE Inhibitor (enalapril recommended)• Step 2. Beta or alpha blocker or calcium antagonist• Step 3. Drug from class not used in Step 2 or diuretic• Step 4. Drug from class not used in step 2 or 3

• Diuretic Group• Step 1. Thiazide type diuretic (low dose)• Step 2. Beta or alpha blocker or calcium antagonist• Step 3. Drug from class not used in Step 2• Step 4. Drug from class not used in step 2 or 3


Study End-points

• Obtained by study nurses from GP case notes, hospital case records and death certificates

• End-point Committee (blinded to treatment allocation) evaluated all data relating to potential study end-points

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• Primary Outcome: All cardiovascular events (initial and subsequent) or death from any cause – ‘total burden of cardiovascular disease’

• Any first event or death – ‘event-free survival’• Cause-specific first events

New Engl J Med, 2003;348:583-92.

End-points

• myocardial infarction (fatal and non-fatal)• sudden or rapid or ‘other’ cardiac death• coronary events resulting in coronary therapeutic

procedures• cardiac failure (fatal or non-fatal)• stroke (fatal or non-fatal)• transient cerebral ischaemic attacks• acute non-coronary or non-cerebral vascular

occlusion • other vascular deaths• dissecting or ruptured aortic aneurysm


Data Analysis

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• Multivariate proportional hazards (Cox) models incorporating:– Wei-Lin-Weissfeld method for multiple failure time data– Li-Lagakos application of WLW method to analyse recurrent

event data with a terminating event– Robust variance estimation– Validation by simulation

• Proportional hazards (Cox) models for cause-specific first events

New Engl J Med, 2003;348:583-92.

ANBP2

GP Involvement in ANBP2

390270

500299

472224

958601

361200

2681 - GPs 1594 - Practices

New Engl J Med, 2003;348:583-92.

146691310 9%

7530 84911%

7607 672 9%

744876310%

17145248915% ANBP2

ANBP2 Subject Recruitment

Screened - 54288Randomised - 6083Rate - 11%

Study profile54288

screened25805 ineligible16899 unwilling to participate5501 did not meet inclusion criteria

6083randomised

ACE3044

Diuretic3039

0 No Vital Status 2

ACE3044

Diuretic3037

ITT* analysis

ANBP2* Intention to treat

Observation Time

Median 4.1 yrs

Patient yrs 24702

~ 3 yrs

New Engl J Med, 2003;348:583-92.

Baseline data

ANBP2

ACE Diuretic(3044) (3039)

Male: Female 50:50 48:52

Age (yr) 72.0 71.9

Blood Pressure (mmHg) 167 ± 13 168 ± 13 91 ± 8 91 ± 8

Previously Treated 62% 62%

Body Mass Index (kg/m2) 27 ± 4 27 ± 4

Current Smokers 7% 7%Physically Active 78% 76%

New Engl J Med, 2003;348:583-92.

Baseline data

ANBP2

ACE Diuretic(3044) (3039)

Coronary Heart Disease 8% 8%

Cerebrovascular Disease 5% 5%

Diabetes Mellitus 8% 7%

Hypercholesterolaemia 38% 36% - lipid lowering drugs 13% 13%

New Engl J Med, 2003;348:583-92.

Drug treatments

ANBP2

At Randomisation At Study EndACE Diuretic ACE Diuretic(3044) (3039) (3044) (3039)

Allocated Therapy 83% 83% 58% 62%

Monotherapy 82% 82% 65% 67%

3 agents 6% 5%

No drugs 16% 15% 4% 3%

New Engl J Med, 2003;348:583-92.

Antihypertensive Medication Use at Study End

ANBP2

ACE Diuretic

ACE 58 18

Beta Blocker 11 14

Ca Blocker 23 25

Diuretic 24 62

Single Drug 65 67

2 Drugs 25 25

3 + Drugs 6 5

Data represent %

New Engl J Med, 2003;348:583-92.

Blo

od P

ress

ure

(mm

Hg)

75

80

85

90

95

130

140

150

160

170

Years Since Randomization

0 1 2 3 4 5

ACEDiuretic

Systolic

Diastolic6083

6035 5583 5487 4320 1183

6083

6035 5585 5487 4323 1183

In-study blood pressure

ANBP2

-26 mmHg

-12 mmHg

New Engl J Med, 2003;348:583-92.

Primary Result

ANBP2

ACE Diuretic Event n Rate n Rate HR (95%CI) p

All cardiovascular 692 55.8 732 59.5 0.89 (0.79,1.00) 0.05 events or any death

First cardiovascular 490 41.9 529 45.7 0.89 (0.79,1.01) 0.06 event or death

Death 195 15.7 210 17.1 0.90 (0.75,1.09) 0.27

Rate per 1000 patient years

Adjusted for age, gender

New Engl J Med, 2003;348:583-92.

Primary Result

ANBP2Rate per 1000 patient years

Adjusted for age, gender

Hazard Ratio (95% CI) p ACE better Diuretic better0.2 1.0 5.0

Cardiovascular 0.88 (0.77,1.01) 0.07

Non-Fatal Cardiovascular 0.86 (0.74,0.99) 0.03

Cerebrovascular 0.90 (0.73,1.12) 0.35

Stroke 1.02 (0.78,1.33) 0.91

Coronary 0.86 (0.70,1.06) 0.16

Myocardial Infarction 0.68 (0.47,0.98) 0.04

Other Cardiovascular 0.90 (0.71,1.14) 0.36

Heart Failure 0.85 (0.62,1.18) 0.33

Cause-specific first events

ANBP2All subjects - first any events

New Engl J Med, 2003;348:583-92.


Cardiovascular 0.99 (0.72,1.35) 0.94

Non-Cardiovascular 0.84 (0.66,1.08) 0.18

Cancer 0.98 (0.73,1.32) 0.89

Trauma 2.87 (0.31,26.9) 0.36

Other Non-Cardiovascular 0.57 (0.37,0.90) 0.01

Stroke 1.91 (1.04,3.50) 0.04

Coronary 0.74 (0.49,1.11) 0.14



Heart Failure 0.24 (0.03,1.94) 0.18

Cause-specific fatal events

ANBP2All subjects - fatal events

New Engl J Med, 2003;348:583-92.


Stroke 0.93 (0.70,1.26) 0.65

Coronary 0.92 (0.73,1.16) 0.49



Heart Failure 0.85 (0.62,1.17) 0.32

Cause-specific non-fatal events

ANBP2

All subjects - first non-fatal events

New Engl J Med, 2003;348:583-92.

Summary

• 11% reduction in total cardiovascular events (or death from any cause) with ACE inhibitor treatment

• 11% reduction in first events with ACE inhibitor treatment

• 17% reduction in total events in males and no effect in females


Summary

• No difference between treatments– total or cardiovascular mortality– all cerebrovascular events– all coronary events

• With ACE inhibitor treatment– reduction in first non-fatal cardiovascular events

(HR 0.86)– reduction in non-fatal myocardial infarctions (HR

0.68)– increase in fatal strokes (HR 1.91)– cause-specific effects only in males ANBP2

New Engl J Med, 2003;348:583-92.

Conclusion

Initiation of antihypertensive treatment in older patients with an ACE inhibitor particularly in males has a modest but definite outcome advantage over a diuretic despite a similar

reduction in blood pressure


Acknowledgments

• Australian Commonwealth Department of Health and Ageing

• National Health and Medical Research Council of Australia

• Study staff• Australia’s General Practitioners• Merck Sharp & Dohme (Australia) Pty Ltd

ANBP2

Acknowledgments

ANBP2

Prof L. Wing (SA - Chairperson)

Dr C. Reid (Vic - Study Director)

Dr P. Ryan (SA - Statistician)

Prof G. Jennings (Vic)

Prof J. McNeil (Vic)

Prof M. Brown (NSW)

Prof C. Johnston (Vic)

Prof T. Morgan ( Vic)

Prof J. Marley (SA)

Prof L. Beilin (WA)

Prof M. West (Qld)

Prof G. MacDonald (NSW)

ANBP2Management

Committee

Acknowledgments

ANBP2

Regional Co-ordinating Centres:

Mark Nelson, Anne Bruce, Paul Beckinsale, Jill Thompson, Marilyn McMurchie,

Glenda Fraser, David Gleave, Vicki Cope, Fred DeLooze, Sue Moore,

Cathy Dibben, Jonathon Newbury

Data Management and National Coordinating Centres:

Helen Miles, Brian McDermott, Kristyn Willson, Carol Bear

Genetic Sub-Committee:

Malcolm West, Stephen Harrap, Colin Johnston, Lawrie Beilin, Philip Ryan,

Lindon Wing, Christopher Reid

Ambulatory Blood Pressure Monitoring Sub-Committee:

Lawrie Beilin, Mark Brown, Philip Ryan, Lindon Wing, Christopher Reid

LVH Sub-Committee:

Garry Jennings, Peter Fletcher, Michael Feneley, Elizabeth Dewar, Lindon Wing,

Christopher Reid

Acknowledgments

ANBP2

Data Audit Sub-Committee:

John McNeil, Lindon Wing, John Marley, Christopher Reid

Finance Sub-Committee:

Colin Johnston, Garry Jennings, Lindon Wing, Christopher Reid

Health Economic/Quality of Life Sub-Committee:

John Marley, John Moss, Penny Webb, Paul Glasziou, Fran Boyle, John Primrose,

Lindon Wing, Christopher Reid

GP Advisory Committee: Ian Steven, Leon Piterman, Fred De Looze,

Jim Dickinson, John Gambrill, Peter Joseph, Christopher Reid

End-point Committee: David Hunt, Geoff Donnan, Lindon Wing, Trefor Morgan

Independent Data Audit Sub-Committee: John Chalmers,

Judith Whitworth, Stephen MacMahon, Chris Silagy (Decd)

second australian national blood pressure study conducted by the high blood pressure research...

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