Ascot Trial

P Sever (Co-chair), B Dahlf (Co-chair), N Poulter (Secretary),
H Wedel (Statistician), G Beevers, M Caulfield, R Collins,

SE Kjeldsen, A Kristinsson, J Mehlsen, G McInnes, M Nieminen,
E OBrien, J stergren
On behalf of the ASCOT Investigators
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
Sever PS, et al, for the ASCOT Investigators. J Hypertens. 2001;19:1139-1147

Sever PS, Dahlf B, Poulter N, Wedel H et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
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])
Lipid-Lowering Arm (LLA)

Primary Objective
To compare the effects on the combined outcome of

nonfatal MI (including silent MI) and fatal CHD of
atorvastatin 10 mg with those of placebo in
hypertensive patients with TC levels of 6.5 mmol/L
(250 mg/dL)
Sever PS, Dahlf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
Secondary and Tertiary End Points

Secondary
Tertiary
Primary outcome without silent MI

All-cause mortality
CV mortality
Fatal + nonfatal stroke
Fatal + nonfatal heart failure
Total coronary end points
All CV events and procedures
Silent MI
Unstable angina
Chronic stable angina
Peripheral vascular disease
Development of diabetes
Development of renal
impairment
Major study end points in
specific subpopulations
Sample Size and Statistical Power (LLA)

Primary End Point: Nonfatal MI and Fatal CHD
Cholesterol reduction with statin
30%
Relative effect on end point of statin vs placebo
30%
Cumulative end point rate on placebo for 5 years
6.35%
Significance level
1%
Power
90%
Total sample size
9000
Patient Population: LLA

Eligibility criteria
SBP 160 mm Hg and/or DBP 100 mm Hg
(untreated) or SBP 140 mm Hg and/or
DBP 90 mm Hg (treated)
TC 6.5 mmol/L (250 mg/dL) and TGs 4.5 mmol/L
(400 mg/dL)
40-79 years of age
3+ CVD risk factors
No history of CHD
ASCOT Study Design

R = Randomized
18,000 patients
R
9000 -blocker
diuretic
5000 TC 6.5 mmol/L
(250 mg/dL)
500
open lipid
lowering
2250
statin
9000 CCB ACEI
4000 TC >6.5 mmol/L

(>250 mg/dL)
4000 TC >6.5 mmol/L

(>250 mg/dL)
5000 TC 6.5 mmol/L

(250 mg/dL)
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
Recruitment: February 1998 May

718 centers, including 686 general2000
practices in Denmark, Finland, Iceland,
Norway, and Sweden and 32 regional centres in Ireland and the UK
2229
876
1314
1031
4855
Total = 10,305
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
SBP* (mm Hg)
164.2 17.7
164.2 18.0
DBP* (mm Hg)
95.0 10.3
95.0 10.3
TC* (mmol/L [mg/dL])
5.5 0.8 (213 31)
5.5 0.8 (213 31)
LDL-C* (mmol/L [mg/dL])
3.4 0.7 (131 27)
3.4 0.7 (131 27)
TG* (mmol/L [mg/dL])
1.7 0.9 (150 80)
1.6 0.9 (142 80)
HDL-C* (mmol/L [mg/dL])
1.3 0.4 (50 27)
1.3 0.4 (50 27)
Number of risk factors*
3.7 0.9
3.7 0.9
*Mean SD
ASCOT LLA: Patient Population

Risk Factor Profile
All patients in ASCOT have hypertension plus 3 risk factors for CHD
Patients with risk factor (%)

Lipid arm closure

The DSMB in September 2002 reported that in the
lipid arm of ASCOT there was a highly significant
reduction in the primary end point as well as a
significant reduction in stroke
The DSMB recommended that the double-blind
cholesterol lowering study treatment arm be
terminated since the results were outside of
the stopping rules of the trial
The Steering Committee endorsed the
recommendation of the DSMB, and the lipid arm
was closed after a median follow-up period of
3.3 years
ASCOT LLA: Patient

Inclusion and Follow-Up Status
19,342 patients randomized to
antihypertensive treatment
10,305 randomized in
lipid-lowering arm
5168 atorvastatin
4928 alive with

complete information
185 dead with

5137 placebo
4861 alive with

Incomplete information:
39 alive after 1st Oct 2002
4 alive before 1st Oct 2002
5 withdrew consent
7 lost to follow-up
212 dead with

Incomplete information:
42 alive after 1st Oct 2002
3 alive before 1st Oct 2002
9 withdrew consent
10 lost to follow-up
Complete information obtained on 98.8% of patients

ASCOT Statistical Methods

Based on an Intention-to-Treat Analysis
Time to first primary event
Log-Rank Procedure and Coxs Proportional Hazards
were used to calculate confidence intervals
Cumulative Incidence Curves generated by using the
Kaplan-Meier method
Blood Pressure Changes

Atorvastatin 10 mg
SBP (mm Hg)
170
Placebo
Baseline 164/95
Treated 138/80
160
150
140
130
Close-out
3 Close-out
DBP (mm Hg)
100
95
90
85
80
75
Years
Reductions in Total and LDL Cholesterol

Total cholesterol
(mmol/L)
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
(mg/dL)
LDL cholesterol
(mmol/L)
4 0
Primary End Point: Nonfatal MI

and Fatal CHD
Cumulative Incidence (%)
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
p=0.0005
Secondary End Point: Fatal

and Nonfatal Stroke
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
p=0.0236
Secondary End Point:

All CV Events and Procedures
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
p=0.0005
Secondary Endpoint: All Coronary Events
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
p=0.0005
End Points
Risk Ratio
Primary End Points

Nonfatal MI (incl silent) + fatal CHD
Secondary End Points
Total CV events and procedures
Total coronary events
Nonfatal MI (excl silent) + fatal CHD
All-cause mortality
Cardiovascular mortality
Fatal and nonfatal stroke
Fatal and nonfatal heart failure
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)
Tertiary End Points

Silent MI
Unstable angina
Chronic stable angina
Peripheral arterial disease
Development of diabetes mellitus
Development of renal impairment
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
Area of squares is proportional to the amount of statistical information

Pre-specified Subgroups: Primary End Point

Risk Ratio
Diabetes
Nondiabetes
Current smoker
Noncurrent smoker
Obese
Nonobese
LVH
No LVH
Older (>60 years)
Younger (60 years)
Female
Male
Previous vascular disease
No previous vascular disease
Renal dysfunction
No renal dysfunction
With metabolic syndrome
Without metabolic syndrome
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
Area of squares is proportional to the amount of statistical information

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
1 nonfatal case of rhabdomyolysis in a patient

receiving atorvastatin (causation confounded by
alcohol abuse and recent febrile illness)
Summary and Conclusions

In hypertensive patients at modest risk of CHD,
atorvastatin is associated with a highly significant
reduction in the primary end point of CHD,
together with significant reductions in the
secondary end points of stroke, all cardiovascular
events and procedures, and total coronary events
These reductions in major cardiovascular events
are large given the short follow-up time and
occurred earlier than in many other statin trials
There was no significant heterogeneity among
pre-specified subgroups
Summary and Conclusions (continued)

Risk reductions in CHD events were unrelated to
baseline cholesterol levels and were consistent across
the whole range of cholesterol
Were the trial to have continue to its planned duration
of 5 years, it is estimated that atorvastatin would have
reduced CHD incidence by approximately 50%
Benefits occurred in the absence of any increased risk
of non-cardiovascular disease, including fatal cancer
These findings have implications for future lipid-lowering
guidelines, particularly with reference to hypertensive
patients

Ascot Trial

Transféré par

Informations du document

Copyright

Formats disponibles

Partager ce document

Partager ou intégrer le document

Options de partage

Avez-vous trouvé ce document utile ?

Ce contenu est-il inapproprié ?

Droits d'auteur :

Formats disponibles

Ascot Trial

Transféré par

Droits d'auteur :

Formats disponibles

P Sever (Co-chair), B Dahlf (Co-chair), N Poulter (Secretary),

H Wedel (Statistician), G Beevers, M Caulfield, R Collins,

Sever PS, et al, for the ASCOT Investigators. J Hypertens. 2001;19:1139-1147

Sever PS, et al, for the ASCOT Investigators. J Hypertens. 2001;19:1139-1147

Lipid-Lowering Arm (LLA)

To compare the effects on the combined outcome of

Secondary and Tertiary End Points

Primary outcome without silent MI

Sample Size and Statistical Power (LLA)

Relative effect on end point of statin vs placebo

Cumulative end point rate on placebo for 5 years

Total sample size

Patient Population: LLA

ASCOT Study Design

9000 CCB ACEI

4000 TC >6.5 mmol/L

4000 TC >6.5 mmol/L

5000 TC 6.5 mmol/L

Sever PS, et al, for the ASCOT Investigators. J Hypertens. 2001;19:1139-1147

Recruitment: February 1998 May

SBP* (mm Hg)

DBP* (mm Hg)

TC* (mmol/L [mg/dL])

5.5 0.8 (213 31)

5.5 0.8 (213 31)

LDL-C* (mmol/L [mg/dL])

3.4 0.7 (131 27)

3.4 0.7 (131 27)

TG* (mmol/L [mg/dL])

1.7 0.9 (150 80)

1.6 0.9 (142 80)

HDL-C* (mmol/L [mg/dL])

1.3 0.4 (50 27)

1.3 0.4 (50 27)

Number of risk factors*

ASCOT LLA: Patient Population

Patients with risk factor (%)

Lipid arm closure

ASCOT LLA: Patient

4928 alive with

185 dead with

4861 alive with

212 dead with

Complete information obtained on 98.8% of patients

ASCOT Statistical Methods

Blood Pressure Changes

SBP (mm Hg)

DBP (mm Hg)

Reductions in Total and LDL Cholesterol

Primary End Point: Nonfatal MI

Secondary End Point: Fatal

Secondary End Point:

Cumulative Incidence (%)

Secondary Endpoint: All Coronary Events

Cumulative Incidence (%)

Primary End Points

Tertiary End Points

Area of squares is proportional to the amount of statistical information

Pre-specified Subgroups: Primary End Point

Area of squares is proportional to the amount of statistical information

1 nonfatal case of rhabdomyolysis in a patient

Summary and Conclusions

Summary and Conclusions (continued)

Vous aimerez peut-être aussi