Rationale

1. P Sever (Co-chair), B Dahlöf (Co-chair), N Poulter (Secretary), H Wedel (Statistician), G Beevers, M Caulfield, R Collins, SE Kjeldsen, A Kristinsson, J Mehlsen, G McInnes, M Nieminen, E O’Brien, J Östergren On behalf of the ASCOT Investigators

2. Rationale • CHD incidence remains a major unresolved problem in BP management • High prevalence of dyslipidaemia in hypertensive patients • Combinations of risk factors synergistic for CHD • No trial has specifically addressed benefits of lipid lowering in primary prevention of CHD in hypertensive patients not conventionally deemed dyslipidaemic Sever PS, et al, for the ASCOT Investigators. J Hypertens. 2001;19:1139-1147 Sever PS, Dahlöf B, Poulter N, Wedel H et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

3. Rationale • The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) is a multicentre, international trial, which involves 2 treatment comparisons in a factorial design • A prospective, randomized, open, blinded end point (PROBE) design comparing 2 antihypertensive regimens • A double-blind, placebo-controlled trial of a lipid-lowering agent in a subsample of those hypertensive patients studied (lipid-lowering arm [LLA]) Sever PS, et al, for the ASCOT Investigators. J Hypertens. 2001;19:1139-1147

4. Lipid-Lowering Arm (LLA)Primary Objective To compare the effects on the combined outcome of nonfatal MI (including silent MI) and fatal CHD of atorvastatin 10 mg with those of placebo in hypertensive patients with TC levels of 6.5 mmol/L (250 mg/dL) Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

5. Secondary • Primary outcome without silent MI • All-cause mortality • CV mortality • Fatal + nonfatal stroke • Fatal + nonfatal heart failure • Total coronary end points • All CV events and procedures Tertiary • Silent MI • Unstable angina • Chronic stable angina • Peripheral vascular disease • Development of diabetes • Development of renal impairment • Major study end points in specific subpopulations Secondary and Tertiary End Points Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

6. Cholesterol reduction with statin 30% Relative effect on end point of statin vs placebo 30% Cumulative end point rate on placebo for 5 years 6.35% Significance level 1 % Power 90% Total sample size 9000 Sample Size and Statistical Power (LLA) Primary End Point: Nonfatal MI and Fatal CHD Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

7. Patient Population: LLA Eligibility criteria • SBP 160 mm Hg and/or DBP 100 mm Hg (untreated) or SBP 140 mm Hg and/or DBP 90 mm Hg (treated) • TC 6.5 mmol/L (250 mg/dL) and TGs 4.5 mmol/L (400 mg/dL) • 40-79 years of age • 3+ CVD risk factors • No history of CHD Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

8. ASCOT Study Design R = Randomized 18,000 patients R 9000 -blocker ± diuretic 9000 CCB ±ACEI + 5000 TC 6.5 mmol/L (250 mg/dL) 4000 TC >6.5 mmol/L (>250 mg/dL) 4000 TC >6.5 mmol/L (>250 mg/dL) 5000 TC 6.5 mmol/L (250 mg/dL) 500 open lipid lowering 4500 4500 500 open lipid lowering R R 2250 statin 2250 placebo 8000 open lipid lowering 2250 placebo 2250 statin Sever PS, et al, for the ASCOT Investigators. J Hypertens. 2001;19:1139-1147

9. Therapeutic Interventions and Targets (LLA) Atorvastatin 10 mg vs placebo No fixed lipid-lowering target Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

10. 1314 2229 1031 876 4855 Total = 10,305 Recruitment: February 1998 – May 2000 718 centers, including 686 general practices in Denmark, Finland, Iceland, Norway, and Sweden and 32 regional centres in Ireland and the UK Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

11. Baseline Characteristics Atorvastatin (n=5168) Placebo (n=5137) Characteristic Age* (years) Male (%) Caucasian (%) SBP* (mm Hg) DBP* (mm Hg) TC* (mmol/L [mg/dL]) LDL-C* (mmol/L [mg/dL]) TG* (mmol/L [mg/dL]) HDL-C* (mmol/L [mg/dL]) Number of risk factors* 63.1 ± 8.5 81.1 94.6 164.2 ± 17.7 95.0 ± 10.3 5.5 ± 0.8 (213 ± 31) 3.4 ± 0.7 (131 ± 27) 1.7 ± 0.9 (150 ± 80) 1.3 ± 0.4 (50 ± 27) 3.7 ± 0.9 63.2 ± 8.6 81.3 94.7 164.2 ± 18.0 95.0 ± 10.3 5.5 ± 0.8 (213 ± 31) 3.4 ± 0.7 (131 ± 27) 1.6 ± 0.9 (142 ± 80) 1.3 ± 0.4 (50 ± 27) 3.7 ± 0.9 *Mean ± SD Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

12. ASCOT LLA: Patient Population Risk Factor Profile All patients in ASCOT have hypertension plus 3 risk factors for CHD Patients with risk factor (%) Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

13. Lipid arm closure • The DSMB in September 2002 reported that in the lipid arm of ASCOT there was a highly significant reduction in the primary end pointas well as a significant reduction in stroke • The DSMB recommended that the double-blind cholesterol lowering study treatment arm be terminated since the results were outside of the stopping rules of the trial • The Steering Committee endorsed the recommendation of the DSMB, and the lipid arm was closed after a median follow-up period of 3.3 years Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

14. ASCOT LLA: Patient Inclusion and Follow-Up Status 10,305 randomized in lipid-lowering arm 19,342 patients randomized to antihypertensive treatment 5168 atorvastatin 5137 placebo 4928 alive with complete information 185 dead with complete information 4861 alive with complete information 212 dead with complete information Incomplete information: 39 alive after 1st Oct 2002 4 alive before 1st Oct 2002 5 withdrew consent 7 lost to follow-up Incomplete information: 42 alive after 1st Oct 2002 3 alive before 1st Oct 2002 9 withdrew consent 10 lost to follow-up Complete information obtained on 98.8% of patients Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

15. ASCOT Statistical Methods • Based on an Intention-to-Treat Analysis • Time to first primary event • Log-Rank Procedure and Cox’s Proportional Hazards were used to calculate confidence intervals • Cumulative Incidence Curves generated by using the Kaplan-Meier method Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

16. Blood Pressure Changes Baseline 164/95 Treated 138/80 SBP (mm Hg) Close-out DBP (mm Hg) Close-out Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

17. 200 (mg/dL) Total cholesterol (mmol/L) 150 100 150 125 (mg/dL) LDL cholesterol (mmol/L) 100 75 Years Reductions in Total and LDL Cholesterol 1.3 mmol/L 1.0 mmol/L 1.2 mmol/L 1.0 mmol/L Close-out Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

18. Primary End Point: Nonfatal MI and Fatal CHD Atorvastatin 10 mg Number of events 100 Placebo Number of events 154 36% reduction HR = 0.64 (0.50-0.83) p=0.0005 Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

19. Secondary End Point: Fatal and Nonfatal Stroke Atorvastatin 10 mg Number of events 89 Placebo Number of events 121 27% reduction HR = 0.73 (0.56-0.96) p=0.0236 Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

20. Secondary End Point: All CV Events and Procedures Atorvastatin 10 mg Number of events 389 Placebo Number of events 486 21% reduction HR= 0.79 (0.69-0.90) p=0.0005 Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

21. Secondary Endpoint: All Coronary Events Atorvastatin 10 mg Number of events 178 Placebo Number of events 247 29% reduction HR=0.71 (0.59-0.86) p=0.0005 Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

22. Risk Ratio • Primary End Points • Nonfatal MI (incl silent) + fatal CHD • Secondary End Points • Total CV events and procedures • Total coronary events • Nonfatal MI (excl silent) + fatal CHD • All-cause mortality • Cardiovascular mortality • Fatal and nonfatal stroke • Fatal and nonfatal heart failure • Tertiary End Points • Silent MI • Unstable angina • Chronic stable angina • Peripheral arterial disease • Development of diabetes mellitus • Development of renal impairment Atorvastatin better Placebo better 0.5 1.0 1.5 Area of squares is proportional to the amount of statistical information End Points • Hazard Ratio • 0.64 (0.50-0.83) • 0.79 (0.69-0.90) • 0.71 (0.59-0.86) • 0.62 (0.47-0.81) • 0.87 (0.71-1.06) • 0.90 (0.66-1.23) • 0.73 (0.56-0.96) • 1.13 (0.73-1.78) • 0.82 (0.40-1.66) • 0.87 (0.49-1.57) • 0.59 (0.38-0.90) • 1.02 (0.66-1.57) • 1.15 (0.91-1.44) • 1.29 (0.76-2.19) Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

23. Risk Ratio Diabetes Nondiabetes Current smoker Noncurrent smoker Obese Nonobese LVH No LVH Older (>60 years) Younger (≤60 years) Female Male Previous vascular disease No previous vascular disease Renal dysfunction No renal dysfunction With metabolic syndrome Without metabolic syndrome All patients Atorvastatin better Placebo better 0.5 1.0 1.5 Pre-specified Subgroups: Primary End Point Hazard Ratio 0.84 (0.55-1.29) 0.56 (0.41-0.77) 0.56 (0.37-0.85) 0.70 (0.51-0.96) 0.59 (0.39-0.90) 0.67 (0.49-0.92) 0.67 (0.35-1.29) 0.64 (0.49-0.84) 0.64 (0.47-0.86) 0.66 (0.41-1.06) 1.10 (0.57-2.12) 0.59 (0.44-0.77) 0.80 (0.45-1.42) 0.61 (0.46-0.81) 0.61 (0.44-0.84) 0.70 (0.47-1.04) 0.77 (0.52-1.12) 0.56 (0.40-0.79) 0.64 (0.50-0.83) Area of squares is proportional to the amount of statistical information Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

24. Safety Evaluations • Numbers of non-CV deaths were similar (111 atorvastatin, 130 placebo) • No significant difference between atorvastatin and placebo in: • Incidence of fatal cancers • Incidence of serious adverse events • Incidence of liver enzyme abnormalities • 1 nonfatal case of rhabdomyolysis in a patient receiving atorvastatin (causation confounded by alcohol abuse and recent febrile illness) Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

25. Summary and Conclusions • In hypertensive patients at modest risk of CHD, atorvastatin is associated with a highly significant reduction in the primary end point of CHD, together with significant reductions in the secondary end points of stroke, all cardiovascular events and procedures, and total coronary events • These reductions in major cardiovascular events are large given the short follow-up time and occurred earlier than in many other statin trials • There was no significant heterogeneity among pre-specified subgroups Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

26. Summary and Conclusions (continued) • Risk reductions in CHD events were unrelated to baseline cholesterol levels and were consistent across the whole range of cholesterol • Were the trial to have continue to its planned duration of 5 years, it is estimated that atorvastatin would have reduced CHD incidence by approximately 50% • Benefits occurred in the absence of any increased risk of non-cardiovascular disease, including fatal cancer • These findings have implications for future lipid-lowering guidelines, particularly with reference to hypertensive patients Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58