1. Results from ASCOT-BPLA: Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm VBWG

2. Rationale Cardiovascular (CV) disease continues to be the chief cause of mortality and morbidity worldwide –Most of this is due to coronary heart disease (CHD) Multiple risk factors have synergistic effects in the pathogenesis of CV disease Combination treatment regimens using  2 agents are recommended to reach target BP goals Limited outcome data have led to an investigation comparing standard vs newer antihypertensive treatment options VBWG

3. ASCOT: Anglo-Scandinavian Cardiac Outcomes Trial These slides present results from the newly released ASCOT-BPLA arm Sever PS et al. Lancet. 2003;361:1149-58. Dahlöf B et al; ASCOT Investigators. Lancet. 2005;366:895-906. ASCOT — multicenter, international trial comparing treatment regimens Study 1: ASCOT-LLA Double-blind, randomized, placebo-controlled trial of a lipid- lowering agent in a sample of the total ASCOT patient population Study 2: ASCOT-BPLA Prospective, randomized, open, blinded endpoint (PROBE) design comparing two antihypertensive regimens in the total ASCOT patient population VBWG

4. ASCOT-BPLA: Study design Design:Double-blind, placebo controlled, randomized Population:N = 19,257 with hypertension and ≥3 other CV risk factors Treatment:Amlodipine 5–10 mg ± perindopril 4–8 mg prn (n = 9639) Atenolol 50–100 mg ± bendroflumethiazide 1.25–2.5 mg/potassium prn (n = 9618) Primary outcome:Nonfatal MI (including silent MI) and fatal CHD Secondary outcome:All-cause mortality, stroke, nonfatal MI (excluding silent MI), all coronary events, CV events/procedures, CV mortality, fatal/nonfatal HF VBWG

5. ASCOT-BPLA: Trial profile 19,342 Randomized 19,257 Evaluable 85Excluded because of BP measurement irregularities 9639 Assigned amlodipine- based regimen 9618 Assigned atenolol- based regimen 171 Incomplete information 102 Alive at last visit 36 Withdrew consent 33 Lost to follow-up 121 Incomplete information 81 Alive at last visit 24 Withdrew consent 16 Lost to follow-up 9639 Assessed for primary outcome intention-to-treat basis 9518 Complete information (8780 alive, 738 dead) 9618 Assessed for primary outcome intention-to-treat basis 9447 Complete information (8627 alive, 820 dead) Dahlöf B et al; ASCOT Investigators. Lancet. 2005;366:895-906. VBWG

6. ASCOT-BPLA: Treatment algorithm for BP targets 19,342 patients 40–79 y with U N T R E A T E D SBP ≥160 mmHg and/or DBP ≥100 mmHg OR T R E A T E D SBP ≥140 mmHg and/or DBP ≥90 mmHg In each arm, pts with total cholesterol ≤6.5 mmol/L randomized to atorvastatin (10 mg) or placebo daily (n = 10,297) RANDOMIZATION Atenolol 50 mg Amlo 5 mg Amlo 10 mg Atenolol 100 mg Amlo 10 mg + peri 4 mg Amlo 10 mg + peri 8 mg (2 x 4 mg) Amlo 10 mg + peri 8 mg (2 x 4 mg) + doxa 4 mg Amlo 10 mg + peri 8 mg (2 x 4 mg) + doxa 8 mg Atenolol 100 mg + BFZ 2.5 mg + K + Atenolol 100 mg + BFZ 2.5 mg + K + + doxa 4 mg Atenolol 100 mg + BFZ 1.25 mg + K + Atenolol 100 mg + BFZ 2.5 mg + K + + doxa 8 mg 5 Years or 1150 primary events BP medication titrated to achieve target: No diabetes: <140/90 mm Hg Diabetes: <130/80 mm Hg Sever PS et al. J Hypertens. 2001;19:1139-47. Amlo = amlodipine; Peri = perindopril; Doxa = doxazosin GITS (Gastrointestinal Transport System); BFZ = bendroflumethiazide VBWG

7. ASCOT-BPLA: Reduction in primary outcome (nonfatal MI and fatal CHD) Number at risk Amlodipine-based regimen963994759337916889667863 (429 events) Atenolol-based regimen961894709290908388587743 (474 events) Proportion of events (%) 6 2 4 0 1234 8 10 560 Time since randomization (years) HR = 0.90 (95% CI, 0.79–1.02) RRR = 10% P = 0.1052 Atenolol-based regimen* Amlodipine-based regimen † Dahlöf B et al; ASCOT Investigators. Lancet. 2005;366:895-906. VBWG *Atenolol 50–100 mg ± bendroflumethiazide 1.25–2.5 mg/potassium prn † Amlodipine 5–10 mg ± perindopril 4–8 mg prn

8. ASCOT-BPLA: Reduction in fatal and nonfatal stroke Number at risk Amlodipine-based regimen963994839331915689727863 (327 events) Atenolol-based regimen 961894619274905988437720 (422 events) Proportion of events (%) 6 2 4 0 1234 8 10 50 Time (years) 6 Atenolol-based regimen* Amlodipine-based regimen † HR = 0.77 (95% CI, 0.66–0.89) RRR = 23% P = 0.0003 Dahlöf B et al; ASCOT Investigators. Lancet. 2005;366:895-906. VBWG *Atenolol 50–100 mg ± bendroflumethiazide 1.25–2.5 mg/potassium prn † Amlodipine 5–10 mg ± perindopril 4–8 mg prn

9. Secondary endpoints Nonfatal MI (excluding silent)7.4 8.5 + fatal CHD Total coronary endpoint14.6 16.8 Total CV events and procedures 27.4 32.8 All-cause mortality13.9 15.5 CV mortality4.9 6.5 Fatal/nonfatal stroke6.2 8.1 Fatal/nonfatal HF2.5 3.0 Tertiary endpoints Development of diabetes11.0 15.9 Development of renal impairment7.7 9.1 Rate/1000 patient years Amlodipine-based* (n = 9639) Atenolol-based † (n = 9618) <0.05 <0.01 <0.0001 <0.05 0.001 <0.001 NS <0.0001 <0.05 P Amlodipine-based better Atenolol-based better 0.500.701.001.452.00 ASCOT-BPLA: Additional reductions in group receiving the amlodipine-based regimen Unadjusted risk reduction Rate/1000 patient years Dahlöf B et al; ASCOT Investigators. Lancet. 2005;366:895-906. VBWG *Amlodipine 5–10 mg ± perindopril 4–8 mg prn † Atenolol 50–100 mg ± bendroflumethiazide 1.25–2.5 mg/potassium prn

10. ASCOT-BPLA: Reductions in BP over time Atenolol-based regimen*Amlodipine-based regimen † Dahlöf B et al; ASCOT Investigators. Lancet. 2005;366:895-906. VBWG Mean difference = 1.9, P < 0.0001 Time (years) Blood pressure (mm Hg) 60 100 0 1.0 2.0 3.0 4.0 5.0 Final visit (mean 5.7 [SD 0.6], range 4.6–7.3) 0 0.51.5 2.5 3.54.5 5.5 80 120 140 160 180 Mean difference = 2.7, P < 0.0001 Systolic BP Diastolic BP 137.7 136.1 79.2 77.4 BP *Atenolol 50–100 mg ± bendroflumethiazide 1.25–2.5 mg/potassium prn † Amlodipine 5–10 mg ± perindopril 4–8 mg prn

11. ASCOT-BPLA: Overall results Study stopped prematurely after 5.5-year median follow- up because of higher death rate in assigned atenolol- based-regimen group Group receiving amlodipine-based regimen had nonsignificant 10% reduction in primary outcome (nonfatal MI plus fatal CHD) and significant reductions in nearly all secondary CV endpoints and new-onset diabetes Dahlöf B et al; ASCOT Investigators. Lancet. 2005;366:895-906. VBWG

12. ASCOT-BPLA: Summary VBWG Dahlöf B et al. Lancet. 2005;366:895-906. Poulter NR et al. Lancet. 2005;366:907-13. *mean in-trial systolic BP difference 2.7 mm Hg Newer antihypertensive drug regimens should be considered in preference to older beta-blocker ± diuretic therapies Amlodipine-based regimen was beneficial in lowering BP and prevention of CV events compared to beta-blocker ± diuretic-based regimen Amlodipine ± perindopril showed reductions in: –Major CV events 16% –New-onset diabetes 30% –Stroke 23% –Mortality 11% Improved BP control* with amlodipine ± perindopril may explain some, but not all, of the benefit ASCOT results support the use of newer drugs, in multi-drug combinations, to modify risk factors and/or metabolic disturbances, especially in patients with complicated hypertension