Results from ASCOT-BPLA:Results from ASCOT-BPLA: AAnglo-nglo-SScandinavian candinavian CCardiac ardiac

OOutcomes utcomes TTrial–rial–BBlood lood PPressure ressure LLowering owering AArmrm

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

VBWG

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

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

ASCOT-BPLA: Trial profile19,342 Randomized

19,257 Evaluable

85 Excluded because of BP measurement irregularities

9639 Assigned amlodipine-based regimen

9618 Assigned atenolol-based regimen

171 Incomplete information

102 Alive at last visit36 Withdrew consent33 Lost to follow-up

121 Incomplete information

81 Alive at last visit24 Withdrew consent16 Lost to follow-up

9639 Assessed for primaryoutcome intention-to-treat basis

9518 Complete information(8780 alive, 738 dead)

9618 Assessed for primaryoutcome intention-to-treat basis

9447 Complete information(8627 alive, 820 dead)

Dahlöf B et al; ASCOT Investigators. Lancet. 2005;366:895-906.

VBWG

ASCOT-BPLA: Treatment algorithm for BP targets

19,342 patients40–79 y

withU N T R E A T E DSBP ≥160 mmHg

and/orDBP ≥100 mmHg

ORT 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)R

ANDOMIZATIO

RANDOMIZATIO

NN

Atenolol50 mg

Amlo5 mg

Amlo10 mg

Atenolol100 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

Atenolol100 mg +BFZ 2.5 mg + K+

Atenolol100 mg +BFZ 2.5

mg + K+ + doxa 4 mg

Atenolol100 mg +BFZ 1.25 mg + K+

Atenolol100 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

ASCOT-BPLA: Reduction in primary outcome (nonfatal MI and fatal CHD)

Number at riskAmlodipine-based regimen 9639 9475 9337 9168 8966 7863(429 events)Atenolol-based regimen 9618 9470 9290 9083 8858 7743(474 events)

Proportionof events

(%)

6

2

4

01 2 3 4

8

10

5 60Time 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

ASCOT-BPLA: Reduction in fatal and nonfatal stroke

Number at riskAmlodipine-based regimen 9639 9483 9331 9156 8972 7863(327 events)Atenolol-based regimen 9618 9461 9274 9059 8843 7720(422 events)

Proportionof events

(%)

6

2

4

01 2 3 4

8

10

50Time (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

Secondary endpointsNonfatal MI (excluding silent) 7.4 8.5+ fatal CHDTotal coronary endpoint 14.6 16.8Total 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 endpointsDevelopment of diabetes 11.0 15.9 Development of renal impairment 7.7 9.1

Rate/1000patient 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

PAmlodipine-based

betterAtenolol-based

better

0.50 0.70 1.00 1.45 2.00

ASCOT-BPLA: Additional reductions in group receiving the amlodipine-based regimen

Unadjusted risk reduction

Rate/1000patient 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

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 0.5 1.5 2.5 3.5 4.5 5.5

80

120

140

160

180

Mean difference = 2.7, P < 0.0001

Systolic BP

Diastolic BP

137.7136.1

79.277.4

BP

*Atenolol 50–100 mg ± bendroflumethiazide 1.25–2.5 mg/potassium prn†Amlodipine 5–10 mg ± perindopril 4–8 mg prn

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

ASCOT-BPLA: SummaryVBWG

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