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Rationale
CHD incidence remains a major unresolved problem
in BP management
High prevalence of dyslipidaemia in hypertensive
patients
Combinations of risk factors synergistic for CHD
No trial has specifically addressed benefits
of lipid lowering in primary prevention of CHD in
hypertensive patients not conventionally deemed
dyslipidaemic
Rationale
The Anglo-Scandinavian Cardiac Outcomes
Trial (ASCOT) is a multicentre, international trial,
which involves 2 treatment comparisons in a
factorial design
A prospective, randomized, open, blinded
end point (PROBE) design comparing
2 antihypertensive regimens
A double-blind, placebo-controlled trial of a
lipid-lowering agent in a subsample of those hypertensive
patients studied (lipid-lowering
arm [LLA])
Sever PS, Dahlf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
Tertiary
Silent MI
Unstable angina
Chronic stable angina
Peripheral vascular disease
Development of diabetes
Development of renal
impairment
Major study end points in
specific subpopulations
Sever PS, Dahlf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
30%
30%
6.35%
Significance level
1%
Power
90%
9000
Sever PS, Dahlf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
Sever PS, Dahlf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
18,000 patients
R
9000 -blocker
diuretic
5000 TC 6.5 mmol/L
(250 mg/dL)
500
open lipid
lowering
2250
statin
4500
4500
R
2250
placebo
8000
open lipid lowering
2250
placebo
500
open lipid
lowering
2250
statin
Therapeutic Interventions
and Targets (LLA)
Atorvastatin 10 mg vs placebo
No fixed lipid-lowering target
Sever PS, Dahlf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
2229
876
1314
1031
4855
Total = 10,305
Sever PS, Dahlf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
Baseline Characteristics
Characteristic
Atorvastatin (n=5168)
Placebo (n=5137)
Age* (years)
63.1 8.5
63.2 8.6
Male (%)
81.1
81.3
Caucasian (%)
94.6
94.7
164.2 17.7
164.2 18.0
95.0 10.3
95.0 10.3
3.7 0.9
3.7 0.9
*Mean SD
Sever PS, Dahlf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
10,305 randomized in
lipid-lowering arm
5168 atorvastatin
5137 placebo
Incomplete information:
39 alive after 1st Oct 2002
4 alive before 1st Oct 2002
5 withdrew consent
7 lost to follow-up
Incomplete information:
42 alive after 1st Oct 2002
3 alive before 1st Oct 2002
9 withdrew consent
10 lost to follow-up
Sever PS, Dahlf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
170
Placebo
Baseline 164/95
Treated 138/80
160
150
140
130
Close-out
3 Close-out
100
95
90
85
80
75
Years
Sever PS, Dahlf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
1.3 mmol/L
Placebo
200
1.0 mmol/L
150
(mg/dL)
Atorvastatin 10 mg
100
2
1
150
125
1.2 mmol/L
1.0 mmol/L
100
75
1
0
Years
Close-out
Sever PS, Dahlf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
(mg/dL)
LDL cholesterol
(mmol/L)
4 0
Atorvastatin 10 mg
Number of events
100
Placebo
Number of events
154
36%
reduction
HR = 0.64 (0.50-0.83)
0
0,0
0,5
1,0
1,5
2,0
2,5
3,0
3,5
Years
Sever PS, Dahlf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
p=0.0005
Atorvastatin 10 mg
Number of events
89
Placebo
Number of events
121
27%
reduction
HR = 0.73 (0.56-0.96)
0
0,0
0,5
1,0
1,5
2,0
2,5
3,0
3,5
Years
Sever PS, Dahlf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
p=0.0236
12
Atorvastatin 10 mg
Number of events
389
Placebo
Number of events
486
10
21%
reduction
8
6
4
HR= 0.79 (0.69-0.90)
2
0
0,0
0,5
1,0
1,5
2,0
2,5
3,0
3,5
Years
Sever PS, Dahlf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
p=0.0005
Atorvastatin 10 mg
Number of events
178
Placebo
Number of events
247
29%
reduction
5
4
3
2
HR=0.71 (0.59-0.86)
1
0
0,0
0,5
1,0
1,5
2,0
2,5
3,0
3,5
Years
Sever PS, Dahlf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
p=0.0005
End Points
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)
Atorvastatin better
0.5
Placebo better
1.0
1.5
Hazard Ratio
0.84 (0.55-1.29)
0.56 (0.41-0.77)
0.56 (0.37-0.85)
0.70 (0.51-0.96)
0.59 (0.39-0.90)
0.67 (0.49-0.92)
0.67 (0.35-1.29)
0.64 (0.49-0.84)
0.64 (0.47-0.86)
0.66 (0.41-1.06)
1.10 (0.57-2.12)
0.59 (0.44-0.77)
0.80 (0.45-1.42)
0.61 (0.46-0.81)
0.61 (0.44-0.84)
0.70 (0.47-1.04)
0.77 (0.52-1.12)
0.56 (0.40-0.79)
All patients
0.64 (0.50-0.83)
Atorvastatin better
0.5
Placebo better
1.0
1.5
Safety Evaluations
Numbers of non-CV deaths were similar
(111 atorvastatin, 130 placebo)
No significant difference between atorvastatin
and placebo in:
Incidence of fatal cancers
Incidence of serious adverse events
Incidence of liver enzyme abnormalities
Sever PS, Dahlf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
Sever PS, Dahlf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
Sever PS, Dahlf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58