Results from ASCOT-BPLA: A nglo- S candinavian C ardiac O utcomes T rial– B lood P ressure L owering A rm

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

2. VBWG 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

3. VBWG ASCOT: Anglo-Scandinavian Cardiac Outcomes Trial 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 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.

4. VBWG 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

5. VBWG ASCOT-BPLA: Trial profile 19,342 Randomized 85 Excluded because of BP measurement irregularities 19,257 Evaluable 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.

6. VBWG ASCOT-BPLA: Treatment algorithm for BP targets Amlo 10 mg +peri 8 mg(2 x 4 mg) +doxa 8 mg BP medication titrated to achieve target: No diabetes: <140/90 mm Hg Diabetes: <130/80 mm Hg Amlo 10 mg +peri 8 mg(2 x 4 mg) +doxa 4 mg Amlo 10 mg +peri 8 mg(2 x 4 mg) Amlo 10 mg +peri 4 mg Amlo10 mg Amlo 5 mg In each arm, pts with total cholesterol ≤6.5 mmol/L randomized to atorvastatin (10 mg) or placebo daily(n = 10,297) 19,342 patients 40–79 ywithU N T R E A T E D SBP ≥160 mmHg and/orDBP ≥100 mmHg ORT R E A T E D SBP ≥140 mmHg and/or DBP ≥90 mmHg Atenolol100 mg +BFZ 2.5 mg + K+ + doxa 8 mg Atenolol100 mg +BFZ 2.5 mg + K+ + doxa 4 mg Atenolol100 mg +BFZ 2.5 mg + K+ Atenolol100 mg +BFZ 1.25 mg + K+ RANDOMIZATION Atenolol100 mg Atenolol50 mg 5 Years or 1150 primary events Amlo = amlodipine; Peri = perindopril; Doxa = doxazosin GITS (Gastrointestinal Transport System); BFZ = bendroflumethiazide Sever PS et al. J Hypertens. 2001;19:1139-47.

7. VBWG ASCOT-BPLA: Reduction in primary outcome (nonfatal MI and fatal CHD) 10 8 HR = 0.90 (95% CI, 0.79–1.02) RRR = 10% P = 0.1052 6 Proportionof events (%) 4 Atenolol-based regimen* 2 Amlodipine-based regimen† 0 0 1 2 3 4 5 6 Time since randomization (years) Number at risk Amlodipine-based regimen 9639 9475 9337 9168 8966 7863 (429 events) Atenolol-based regimen 9618 9470 9290 9083 8858 7743 (474 events) *Atenolol 50–100 mg ± bendroflumethiazide 1.25–2.5 mg/potassium prn†Amlodipine 5–10 mg ± perindopril 4–8 mg prn Dahlöf B et al; ASCOT Investigators. Lancet. 2005;366:895-906.

8. VBWG ASCOT-BPLA: Reduction in fatal and nonfatal stroke 10 8 HR = 0.77 (95% CI, 0.66–0.89) RRR = 23% P = 0.0003 6 Proportionof events (%) 4 Atenolol-based regimen* 2 Amlodipine-based regimen† 0 6 0 1 2 3 4 5 Time (years) Number at risk Amlodipine-based regimen 9639 9483 9331 9156 8972 7863 (327 events) Atenolol-based regimen 9618 9461 9274 9059 8843 7720 (422 events) *Atenolol 50–100 mg ± bendroflumethiazide 1.25–2.5 mg/potassium prn†Amlodipine 5–10 mg ± perindopril 4–8 mg prn Dahlöf B et al; ASCOT Investigators. Lancet. 2005;366:895-906.

9. VBWG ASCOT-BPLA: Additional reductions in group receiving the amlodipine-based regimen Amlodipine-based*(n = 9639) Atenolol-based † (n = 9618) Rate/1000patient years Rate/1000patient years <0.05 <0.01 <0.0001 <0.05 0.001 <0.001 NS <0.0001 <0.05 Secondary endpoints Nonfatal MI (excluding silent) 7.4 8.5 + fatal CHD Total coronary endpoint 14.6 16.8 Total CV events and procedures 27.4 32.8 All-cause mortality 13.9 15.5 CV mortality 4.9 6.5 Fatal/nonfatal stroke 6.2 8.1 Fatal/nonfatal HF 2.5 3.0 Tertiary endpoints Development of diabetes 11.0 15.9 Development of renal impairment 7.7 9.1 Amlodipine-based better Atenolol-based better P 0.50 0.70 1.00 1.45 2.00 *Amlodipine 5–10 mg ± perindopril 4–8 mg prn †Atenolol 50–100 mg ± bendroflumethiazide 1.25–2.5 mg/potassium prn Unadjusted risk reduction Dahlöf B et al; ASCOT Investigators. Lancet. 2005;366:895-906.

10. Atenolol-based regimen* Amlodipine-based regimen† VBWG ASCOT-BPLA: Reductions in BP over time 180 Systolic BP 160 BP 137.7 136.1 140 Mean difference = 2.7, P < 0.0001 Blood pressure(mm Hg) 120 Diastolic BP 100 79.2 77.4 80 Mean difference = 1.9, P < 0.0001 60 0 Final visit (mean 5.7 [SD 0.6], range 4.6–7.3) 4.0 0.5 1.5 2.0 3.5 4.5 2.5 0 1.0 3.0 5.0 5.5 Time (years) *Atenolol 50–100 mg ± bendroflumethiazide 1.25–2.5 mg/potassium prn†Amlodipine 5–10 mg ± perindopril 4–8 mg prn Dahlöf B et al; ASCOT Investigators. Lancet. 2005;366:895-906.

11. VBWG 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.

12. VBWG ASCOT-BPLA: Summary • 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 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