Second Australian National Blood Pressure Study

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Second Australian National Blood Pressure Study
ANBP2
Conducted by the High Blood Pressure Research
Council of Australia in conjunction with
Australias General Practitioners
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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

ANBP2
New Engl J Med, 2003348583-92.
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Antihypertensive Drug Use in Australia
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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?

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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

ANBP2
New Engl J Med, 2003348583-92.
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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

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New Engl J Med, 2003348583-92.
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Study Organisation
ANBP2
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Study Subjects

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

• Exclusion Criteria
• Any cardiovascular end-point in the past 6 months
• Dementia
• Plasma creatinine gt 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

ANBP2
New Engl J Med, 2003348583-92.
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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 (gt 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

New Engl J Med, 2003348583-92.
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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

New Engl J Med, 2003348583-92.
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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

• 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

ANBP2
New Engl J Med, 2003348583-92.
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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

ANBP2
New Engl J Med, 2003348583-92.
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Data Analysis

• 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

ANBP2
New Engl J Med, 2003348583-92.
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GP Involvement in ANBP2
2681 - GPs 1594 - Practices
500 299
472 224
361 200
390 270
958 601
New Engl J Med, 2003348583-92.
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ANBP2 Subject Recruitment
Screened - 54288 Randomised - 6083 Rate
- 11
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Study profile
54288 screened
25805 ineligible 16899 unwilling to
participate 5501 did not meet inclusion criteria
3 yrs
6083 randomised
ACE 3044
Diuretic 3039
ITT analysis
Observation Time Median 4.1
yrs Patient yrs 24702
0 No Vital Status
2
ACE 3044
Diuretic 3037
ANBP2
Intention to treat
New Engl J Med, 2003348583-92.
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Baseline data
ACE Diuretic (3044) (3039) Male
Female 5050 4852 Age (yr) 72.0 71.9 B
lood Pressure (mmHg) 167 13 168 13
91 8 91 8 Previously Treated 62 62 B
ody Mass Index (kg/m2) 27 4 27 4 Current
Smokers 7 7 Physically Active 78 76
ANBP2
New Engl J Med, 2003348583-92.
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Baseline data
ACE Diuretic (3044) (3039) Coronary
Heart Disease 8 8 Cerebrovascular
Disease 5 5 Diabetes Mellitus 8 7 Hyper
cholesterolaemia 38 36 - lipid lowering
drugs 13 13
ANBP2
New Engl J Med, 2003348583-92.
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Drug treatments
At Randomisation At Study End ACE
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
ANBP2
New Engl J Med, 2003348583-92.
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Antihypertensive Medication Use at Study End

• 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
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New Engl J Med, 2003348583-92.
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In-study blood pressure
-26 mmHg
-12 mmHg
ANBP2
New Engl J Med, 2003348583-92.
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Primary Result
ACE Diuretic Event n
Rate n Rate HR (95CI) 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
ANBP2
New Engl J Med, 2003348583-92.
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Primary Result
Rate per 1000 patient years Adjusted for age,
gender
ANBP2
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Cause-specific first events
All subjects - first any events
ANBP2
New Engl J Med, 2003348583-92.
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Cause-specific fatal events
All subjects - fatal events
ANBP2
New Engl J Med, 2003348583-92.
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Cause-specific non-fatal events
All subjects - first non-fatal events
ANBP2
New Engl J Med, 2003348583-92.
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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

ANBP2
New Engl J Med, 2003348583-92.
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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, 2003348583-92.
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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

ANBP2
New Engl J Med, 2003348583-92.
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Acknowledgments

• Australian Commonwealth Department of Health and
  Ageing
• National Health and Medical Research Council of
  Australia
• Study staff
• Australias General Practitioners
• Merck Sharp Dohme (Australia) Pty Ltd

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Acknowledgments

• 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)

ANBP2 Management Committee
ANBP2
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Acknowledgments

• 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

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Acknowledgments

• 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)

ANBP2