1. The Anglo Scandinavian Cardiac Outcomes Trial
Randomised controlled trial of prevention of CHD and other vascular events by blood pressure lowering and by cholesterol lowering (factorial design) 1

2. Rationale Insufficient outcome data on newer types of blood pressure
lowering agents
No data on the evaluation of specific combination treatment
regimens
Shortfall of CHD prevention using standard therapy
Need to evaluate multiple risk factors in the prevention of
CHD
No data on the benefits of lipid lowering among hypertensives

3. Primary Objectives
To assess non fatal MI and fatal CHD of the standard anti-hypertensive regimen (b-blocker +/- diuretic) with a more contemporary regimen (Ca channel blocker +/- ACE inhibitor)
To compare the effect on non fatal MI and fatal CHD of a statin vs. placebo among patients with a total cholesterol < 6.5 mmol/l 2

4. Secondary Objectives Antihypertensives Lipid lowering
To compare the effects To compare the effects
of the 2 regimens on: of statin vs. placebo on:
total stroke • total stroke
all cause mortality • all cause mortality
total heart failure • total CV mortality
total CV mortality • all CV events and
all CV events and procedures
procedures 3

5. Tertiary Objectives (i)
Antihypertensives Lipid lowering
To compare the effects To compare the effects
of the 2 regimens on: of the 2 regimens on:
total coronary events • total coronary events
including silent MI including silent MI
development of diabetes • all major study end-
mellitus or renal impairment points among specific subgroups of patients
all major study endpoints
among specific subgroups
of patients 1

6. Tertiary Objectives (ii)
To evaluate whether synergistic effects on total coronary or CV events are observed in association with the combined use of atorvastatin and amlodipine
To compare the effects of the different anti-hypertensive and lipid lowering regimens on health care costs 2

7. Design Prospective randomised open blinded endpoints (PROBE)
2x2 factorial trial
antihypertensive first line regimens:
ß-blocker vs. Ca channel blocker
cholesterol lowering: statin vs. placebo
18,000 patients
Duration: 1,150 primary events or 5 years follow-up 3

8. Sample Size and Statistical Power: Blood Pressure Lowering Primary Endpoint: Non fatal MI and fatal CHD
Yearly rate of primary endpoint %
Relative additional benefit of ‘new’ drug regimen 20%
Significance level %
Power for primary endpoint %*
Total sample size ,000
Total number of endpoints ,150
* adjusted for withdrawals, non-compliance 1

9. Study Treatments ® ® ® ® = randomised 18,000 patients 9,000
ß-blocker +/-
diuretic
9,000
Ca channel blocker +/-
ACE inhibitor
5,000
total cholesterol
< 6.5 mmol/l
5,000
total cholesterol
< 6.5 mmol/l
(4,000+4,000)
total cholesterol
>6.5 mmol/l
4,500
4,500
500
open lipid
lowering
500
open lipid
lowering
8,000
open lipid
lowering
2,250
statin
2,250
placebo
2,250
statin
2,250
placebo
® = randomised 3

10. Sample Size and Statistical Power: Lipid Lowering Primary Endpoint: Non fatal MI and fatal CHD
Cholesterol reduction with statin 30%
Relative effect on endpoint of statin vs. placebo 30%
Cumulative endpoint rate on placebo for 5 years 6.35
Significance level %
Power %
Total sample size ,000 1

11. Antihypertensive Regimens (i)
‘New’ ‘Standard’
Amlodipine Atenolol
+/- +/-
Perindopril Bendroflumethiazide + K
Doxazosin Doxazosin 2

12. Antihypertensive Regimens (ii)
‘New’ ‘Standard’
Step 1 amlodipine 5mg atenolol 50mg
Step 2 amlodipine 10mg atenolol 100mg
Step 3 amlodipine 10mg atenolol 100mg
perindopril 4mg BFZ +K mg
Step 4 amlodipine 10mg atenolol 100mg
perindopril mg BFZ +K 2.5mg
Step 5 amlodipine 10mg atenolol 100mg
perindopril 8mg BFZ +K 2.5mg
doxazosin GITS mg doxazosin GITS 4mg
Step 6 amlodipine 10mg atenolol 100mg
perindopril 8mg BFZ +K 2.5mg
doxazosin GITS mg doxazosin GITS 8mg 3

13. Cholesterol Lowering Regimen
atorvastatin 10mg
vs.
placebo 1

14. Patient Inclusion Criteria Hypertension
No clear indications/ contraindications for any one of the trial treatments
Patient willing and able to attend clinic regularly for 5 years
At screening and baseline BP > 160/100 mmHg untreated or at baseline > 140/90 mmHg treated with one or more drugs
Patient aged years
Patient has 3 or more risk factors for a future cardiovascular event 2

15. Patient Eligibility Criteria Any 3 of these risk factors for a CV event required:
Smoking • NIDDM
LVH • Peripheral vascular
ECG abnormalities disease
History of early CHD • History of
in first degree relative cerebrovascular event
Age > 55 years • Male sex
Microalbuminuria/ • Plasma TC/ HDL ratio > 6
proteinuria 3

16. Therapeutic Target Blood Pressure <140/90 mmHg: non diabetic
< 130/80 mmHg: diabetic
Lipid Lowering
no fixed target 1

17. International Trial Structure
Gothenburg • •
London 3