Results from ASCOT-BPLA: Anglo-Scandinavian Cardiac Outcomes Trial

1
Results from ASCOT-BPLA Anglo-Scandinavian
Cardiac Outcomes TrialBlood Pressure Lowering Arm
VBWG

2
Rationale
VBWG

• 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
ASCOT Anglo-Scandinavian Cardiac Outcomes Trial
VBWG
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. 20033611149-58. Dahlöf
B et al ASCOT Investigators. Lancet.
2005366895-906.
4
ASCOT-BPLA Study design
VBWG

• Design Double-blind, placebo controlled,
  randomized
• Population N 19,257 with hypertension and 3
  other CV risk factors
• Treatment Amlodipine 510 mg perindopril 48
  mg prn (n 9639)
• Atenolol 50100 mg bendroflumethiazide
  1.252.5 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

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ASCOT-BPLA Trial profile
VBWG
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.
2005366895-906.
6
ASCOT-BPLA Treatment algorithm for BP targets
VBWG
Amlo 10 mg peri 8 mg(2 x 4 mg) doxa 8 mg
BP medication titrated to achieve target No
diabetes lt140/90 mm Hg Diabetes lt130/80 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 4079 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. 2001191139-47.
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ASCOT-BPLA Reduction in primary outcome
(nonfatal MI and fatal CHD)
VBWG
10
8
HR 0.90 (95 CI, 0.791.02) RRR 10 P
0.1052
6
Proportionof events ()
4
Atenolol-based regimen
2
Amlodipine-based regimen
0
1
2
3
4
5
6
0
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 50100 mg bendroflumethiazide
1.252.5 mg/potassium prnAmlodipine 510 mg
perindopril 48 mg prn
Dahlöf B et al ASCOT Investigators. Lancet.
2005366895-906.
8
ASCOT-BPLA Reduction in fatal and nonfatal
stroke
VBWG
10
8
HR 0.77 (95 CI, 0.660.89) RRR 23 P
0.0003
6
Proportionof events ()
4
Atenolol-based regimen
2
Amlodipine-based regimen
0
1
2
3
4
5
0
6
Time (years)
Number at risk Amlodipine-based
regimen 9639 9483 9331 9156 8972 7863 (327
events) Atenolol-based regimen 9618 9461 9274 905
9 8843 7720 (422 events)
Atenolol 50100 mg bendroflumethiazide
1.252.5 mg/potassium prnAmlodipine 510 mg
perindopril 48 mg prn
Dahlöf B et al ASCOT Investigators. Lancet.
2005366895-906.
9
ASCOT-BPLA Additional reductions in group
receiving the amlodipine-based regimen
VBWG
Amlodipine-based(n 9639)
Atenolol-based (n 9618)
Rate/1000patient years
Rate/1000patient years
lt0.05 lt0.01 lt0.0001 lt0.05 0.001
lt0.001 NS lt0.0001 lt0.05
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 510 mg perindopril 48 mg
prn Atenolol 50100 mg bendroflumethiazide
1.252.5 mg/potassium prn
Unadjusted risk reduction
Dahlöf B et al ASCOT Investigators. Lancet.
2005366895-906.
10
ASCOT-BPLA Reductions in BP over time
VBWG
180
Systolic BP
160
BP
137.7 136.1
140
Mean difference 2.7, P lt 0.0001
Blood pressure(mm Hg)
120
100
Diastolic BP
79.2 77.4
80
Mean difference 1.9, P lt 0.0001
60
0
Final visit (mean 5.7 SD 0.6, range 4.67.3)
2.0
4.0
0.5
1.5
2.5
3.5
4.5
1.0
3.0
5.0
0
5.5
Time (years)
Atenolol 50100 mg bendroflumethiazide
1.252.5 mg/potassium prnAmlodipine 510 mg
perindopril 48 mg prn
Dahlöf B et al ASCOT Investigators. Lancet.
2005366895-906.
11
ASCOT-BPLA Overall results
VBWG

• 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.
2005366895-906.
12
ASCOT-BPLA Summary
VBWG

• 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. 2005366895-906. Poulter
NR et al. Lancet. 2005366907-13.
mean in-trial systolic BP difference 2.7 mm Hg