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

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

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

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

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

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

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

Sample Size and Statistical Power: Blood Pressure Lowering Primary Endpoint: Non fatal MI and fatal CHD Yearly rate of primary endpoint 1.4% Relative additional benefit of ‘new’ drug regimen 20% Significance level 5% Power for primary endpoint 80 %* Total sample size 18,000 Total number of endpoints 1,150 * adjusted for withdrawals, non-compliance 1

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

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 1 % Power 90% Total sample size 9,000 1

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

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 1.25mg Step 4 amlodipine 10mg atenolol 100mg perindopril 8mg BFZ +K 2.5mg Step 5 amlodipine 10mg atenolol 100mg perindopril 8mg BFZ +K 2.5mg doxazosin GITS 4mg doxazosin GITS 4mg Step 6 amlodipine 10mg atenolol 100mg perindopril 8mg BFZ +K 2.5mg doxazosin GITS 8mg doxazosin GITS 8mg 3

Cholesterol Lowering Regimen atorvastatin 10mg vs. placebo 1

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 40-79 years Patient has 3 or more risk factors for a future cardiovascular event 2

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

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

International Trial Structure Gothenburg • • London 3