Insights from the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Magnitude of cardiovascular benefits from blood pressure lowering and lipid lowering Insights from the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Peter Sever, Neil Poulter, Bjorn Dahlof, Hans Wedel on behalf of the ASCOT Investigators PRELIMINARY DATA

Investigator-led, multinational randomised controlled trial ASCOT: Study design 19,257 hypertensive patients ASCOT-BPLA stopped after 5.5 yrs atenolol ± bendroflumethiazide PROBE design amlodipine ± perindopril Investigator-led, multinational randomised controlled trial placebo atorvastatin 10 mg Double-blind ASCOT-LLA stopped after 3.3 yrs 10,305 patients TC ≤ 6.5 mmol/L (250 mg/dL)

Patient inclusion criteria Screening and baseline BP  160/100 mm Hg untreated  140/90 mm Hg following treatment with 1 or more drugs Age 40-79 years No previous MI or current clinical CHD i.e. primary prevention 3 or more CV risk factors 2

Systolic and diastolic blood pressure atenolol  thiazide amlodipine  perindopril 180 164.1 SBP 160 163.9 Mean difference 2.7 137.7 140 136.1 mm Hg 120 DBP 100 94.8 Mean difference 1.9 94.5 79.2 80 77.4 60 Baseline 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 Last visit Time (years)

ASCOT-LLA Summary of all end points Area of squares is proportional to the amount of statistical information 0.5 1.0 1.5 Atorvastatin better Placebo better 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 Risk Ratio 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) There was a significant reduction in the primary end point and also in four of the seven secondary end points, some of which were incorporated the primary end point. Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

Summary of all end points: BPLA Unadjusted Hazard ratio (95% CI) 0.90 (0.79-1.02) 0.87 (0.76-1.00) 0.87 (0.79-0.96) 0.84 (0.78-0.90) 0.89 (0.81-0.99) 0.76 (0.65-0.90) 0.77 (0.66-0.89) 0.84 (0.66-1.05) 1.27 (0.80-2.00) 0.68 (0.51-0.92) 0.98 (0.81-1.19) 0.65 (0.52-0.81) 1.07 (0.62-1.85) 0.69 (0.63-.077) 0.85 (0.75-0.97) 0.86 (0.77-0.96) 0.84 (0.76-0.92) Primary Non-fatal MI (incl silent) + fatal CHD Secondary Non-fatal MI (exc. Silent) +fatal CHD Total coronary end point Total CV event and procedures All-cause mortality Cardiovascular mortality Fatal and non-fatal stroke Fatal and non-fatal heart failure Tertiary Silent MI Unstable angina Chronic stable angina Peripheral arterial disease Life-threatening arrhythmias New-onset diabetes mellitus New-onset renal impairment Post hoc Primary end point + coronary revasc procs CV death + MI + stroke 0.50 0.70 1.00 1.45 2.00 Amlodipine  perindopril better Atenolol  thiazide better The area of the blue square is proportional to the amount of statistical information

Primary endpoint: Non-fatal MI and fatal CHD ASCOT-LLA 2x2 analyses Primary endpoint: Non-fatal MI and fatal CHD Amlodipine-based treatment Atenolol-based treatment 4.0 4.0 Atorvastatin Placebo Atorvastatin Placebo 3.0 3.0 16% 53% Cumulative incidence (%) 2.0 Cumulative incidence (%) 2.0 1.0 1.0 HR=0.47 (0.32 - 0.69) p<0.001 HR=0.84 (0.60 - 1.17) p=0.30 0.0 0.0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years Years P for interaction = 0.02

Fatal and non-fatal stroke ASCOT-LLA Fatal and non-fatal stroke Amlodipine-based treatment Atenolol-based treatment 3.0 3.0 24% Atorvastatin Placebo Atorvastatin Placebo 2.0 2.0 31% Cumulative incidence (%) Cumulative incidence (%) 1.0 1.0 HR=0.69 (0.45 - 1.06) p=0.09 HR=0.76 (0.63 - 1.08) p=0.013 0.0 0.0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years Years

ASCOT: BPLA and LLA combined: Insight into optimal CV prevention Rates* / 1000 patient years at end of LLA Endpoint Amlodipine  perindopril + atorvastatin Atenolol  thiazide + placebo Relative risk reduction Fatal MI and non-fatal CHD 4.8 9.0 47% Fatal and non-fatal stroke 5.7 9.4 40% * Updated figures with late reported events now included

These risk reductions do not take into account the benefits from blood pressure lowering per se

Systolic Blood Pressure atenolol  thiazide amlodipine  perindopril 180 164.1 mm Hg 163.9 Mean difference 2.7 160 137.7 140 136.1 18 CHD 15 12 Stroke 9 Event Rate* *per 1000 patient years Not randomised to statin 6 3 Baseline 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 Last visit Time (years) . Sever P, Poulter N et al. Am J Cardiol. 2005;96 [suppl]:39F-44F

Event rates during the first 6 months of LLA in those not assigned atorvastatin, and rates at the end of LLA in those assigned Amlodipine/Perindopril based treatment and atorvastatin Early in-trial event rates (per 1000 patient years) Amlodipine/Atorvastatin RRR Fatal MI and Non-fatal CHD 14.3 4.8 66% Fatal and non-fatal stroke 11.5 5.7 50%

Blood Pressure Lowering Combined Blood Pressure & Lipid Lowering Estimated benefits of combined blood pressure and lipid lowering from meta-analyses of placebo controlled trials Blood Pressure Lowering (15/10mmHg) Lipid Lowering (1mmol/L) Combined Blood Pressure & Lipid Lowering CHD 30% 25-35% About 50% Stroke 45% 15-20% About 55%

Early in-trial event rates based on small numbers of events. Early event rates may underestimate rapid onset of benefits from blood pressure and lipid-lowering. Using Framingham model (validated for CHD estimates in Northern European Populations*) risk reductions from baseline for CHD are greater. * Haq et al. Heart. 1999;81:40-6

Reduction in risk of non-fatal MI and fatal CHD using Framingham model for baseline estimates ** Framingham risk estimate from baseline data ( n=10,305) Final risk in those assigned amlodipine/perindopril and atorvastatin Relative risk reduction 22.8* 4.8* 79% *per 1000 patient years **Variables include SBP, smoking status, total and HDL-cholesterol, presence or absence of LVH, age, gender, presence or absence of diabetes. No correction for on- treatment blood pressure

ASCOT- a multiple risk intervention trial Identified hypertensive patients most of whom were poorly controlled. Controlled BP with two intervention strategies. Intervention 1 Compared beta-blocker/diuretic with calcium blocker/ACEI regimens. Intervention 2 Investigated benefit of statin in hypertensives with “normal” or modestly raised cholesterol levels. Intervention 3 Allowed estimate of total benefit from 3 interventions.

Conclusions Combined benefits from blood pressure reduction, assignment to an amlodipine/perindopril regimen with atorvastatin were substantial. For CHD events these benefits were greater than predicted and could indicate synergy between atorvastatin and the amlodipine/perindopril regimen. We estimate treating about 55 patients for one year with an amlodipine – based regimen and atorvastatin compared with former treatment (without a statin ) would prevent one major CHD event.