1. Insights from the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)
Magnitude of cardiovascular benefits from blood pressure lowering and lipid lowering
Insights from the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)
Peter Sever, Neil Poulter, Bjorn Dahlof, Hans Wedel
on behalf of the ASCOT Investigators
PRELIMINARY DATA

2. Investigator-led, multinational randomised controlled trial
ASCOT: Study design
19,257 hypertensive patients
ASCOT-BPLA stopped after 5.5 yrs
atenolol ± bendroflumethiazide
PROBE
design
amlodipine ± perindopril
Investigator-led, multinational randomised controlled trial
placebo
atorvastatin 10 mg
Double-blind
ASCOT-LLA stopped after 3.3 yrs
10,305 patients
TC ≤ 6.5 mmol/L (250 mg/dL)

3. Patient inclusion criteria
Screening and baseline BP
 160/100 mm Hg untreated
 140/90 mm Hg following treatment with 1 or more drugs
Age years
No previous MI or current clinical CHD i.e. primary prevention
3 or more CV risk factors 2

4. Systolic and diastolic blood pressure
atenolol  thiazide
amlodipine  perindopril
180
164.1
SBP
160
163.9
Mean difference 2.7
137.7
140
136.1
mm Hg
120
DBP
100
94.8
Mean difference 1.9
94.5
79.2 80
77.4 60
Baseline
0.5 1
1.5 2
2.5 3
3.5 4
4.5 5
5.5
Last visit
Time (years)

5. ASCOT-LLA Summary of all end points
Area of squares is proportional to the amount of statistical information
0.5
1.0
1.5
Atorvastatin better
Placebo better
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
Tertiary End Points
Silent MI
Unstable angina
Chronic stable angina
Peripheral arterial disease
Development of diabetes mellitus
Development of renal impairment
Risk Ratio
Hazard Ratio
0.64 ( )
0.79 ( )
0.71 ( )
0.62 ( )
0.87 ( )
0.90 ( )
0.73 ( )
1.13 ( )
0.82 ( )
0.87 ( )
0.59 ( )
1.02 ( )
1.15 ( )
1.29 ( )
There was a significant reduction in the primary end point and also in four of the seven secondary end points, some of which were incorporated the primary end point.
Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:

6. Summary of all end points: BPLA
Unadjusted Hazard ratio (95% CI)
0.90 ( )
0.87 ( )
0.87 ( )
0.84 ( )
0.89 ( )
0.76 ( )
0.77 ( )
0.84 ( )
1.27 ( )
0.68 ( )
0.98 ( )
0.65 ( )
1.07 ( )
0.69 ( )
0.85 ( )
0.86 ( )
0.84 ( )
Primary Non-fatal MI (incl silent) + fatal CHD
Secondary Non-fatal MI (exc. Silent) +fatal CHD
Total coronary end point Total CV event and procedures All-cause mortality Cardiovascular mortality Fatal and non-fatal stroke Fatal and non-fatal heart failure
Tertiary Silent MI
Unstable angina Chronic stable angina Peripheral arterial disease Life-threatening arrhythmias New-onset diabetes mellitus New-onset renal impairment
Post hoc
Primary end point + coronary revasc procs
CV death + MI + stroke
0.50
0.70
1.00
1.45
2.00
Amlodipine  perindopril better
Atenolol  thiazide better
The area of the blue square is proportional to the amount of statistical information

7. Primary endpoint: Non-fatal MI and fatal CHD
ASCOT-LLA 2x2 analyses
Primary endpoint: Non-fatal MI and fatal CHD
Amlodipine-based treatment
Atenolol-based treatment
4.0
4.0
Atorvastatin
Placebo
Atorvastatin
Placebo
3.0
3.0
16%
53%
Cumulative incidence (%)
2.0
Cumulative incidence (%)
2.0
1.0
1.0
HR=0.47 ( ) p<0.001
HR=0.84 ( ) p=0.30
0.0
0.0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Years
Years
P for interaction = 0.02

8. Fatal and non-fatal stroke
ASCOT-LLA
Fatal and non-fatal stroke
Amlodipine-based treatment
Atenolol-based treatment
3.0
3.0
24%
Atorvastatin
Placebo
Atorvastatin
Placebo
2.0
2.0
31%
Cumulative incidence (%)
Cumulative incidence (%)
1.0
1.0
HR=0.69 ( ) p=0.09
HR=0.76 ( ) p=0.013
0.0
0.0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Years
Years

9. ASCOT: BPLA and LLA combined: Insight into optimal CV prevention
Rates* / 1000 patient years at end of LLA
Endpoint
Amlodipine  perindopril + atorvastatin
Atenolol 
thiazide +
placebo
Relative risk reduction
Fatal MI and non-fatal CHD
4.8
9.0
47%
Fatal and non-fatal stroke
5.7
9.4
40%
* Updated figures with late reported events now included

10. These risk reductions do not take into account the benefits from blood pressure lowering per se

11. Systolic Blood Pressure
atenolol  thiazide
amlodipine  perindopril
180
164.1
mm Hg
163.9
Mean difference 2.7
160
137.7
140
136.1 18
CHD 15 12
Stroke 9
Event Rate*
*per 1000 patient years
Not randomised to statin 6 3
Baseline
0.5 1
1.5 2
2.5 3
3.5 4
4.5 5
5.5
Last visit
Time (years)
. Sever P, Poulter N et al. Am J Cardiol. 2005;96 [suppl]:39F-44F

12. Event rates during the first 6 months of LLA in those not assigned atorvastatin, and rates at the end of LLA in those assigned Amlodipine/Perindopril based treatment and atorvastatin
Early in-trial event rates
(per 1000 patient years)
Amlodipine/Atorvastatin
RRR
Fatal MI and
Non-fatal CHD
14.3
4.8
66%
Fatal and non-fatal stroke
11.5
5.7
50%

13. Blood Pressure Lowering Combined Blood Pressure & Lipid Lowering
Estimated benefits of combined blood pressure and lipid lowering from meta-analyses of placebo controlled trials
Blood Pressure Lowering
(15/10mmHg)
Lipid Lowering
(1mmol/L)
Combined Blood Pressure & Lipid Lowering
CHD
30%
25-35%
About 50%
Stroke
45%
15-20%
About 55%

14. Early in-trial event rates based on small numbers of events.
Early event rates may underestimate rapid onset of benefits from blood pressure and lipid-lowering.
Using Framingham model (validated for CHD estimates in Northern European Populations*) risk reductions from baseline for CHD are greater.
* Haq et al. Heart. 1999;81:40-6

15. Reduction in risk of non-fatal MI and fatal CHD using Framingham model for baseline estimates **
Framingham risk estimate from baseline data ( n=10,305)
Final risk in those assigned amlodipine/perindopril and atorvastatin
Relative risk reduction
22.8*
4.8*
79%
*per 1000 patient years
**Variables include SBP, smoking status, total and HDL-cholesterol, presence or absence of LVH,
age, gender, presence or absence of diabetes. No correction for on- treatment blood pressure

16. ASCOT- a multiple risk intervention trial
Identified hypertensive patients most of whom were poorly controlled.
Controlled BP with two intervention strategies.
Intervention 1
Compared beta-blocker/diuretic with calcium blocker/ACEI regimens Intervention 2
Investigated benefit of statin in hypertensives with “normal” or modestly raised cholesterol levels. Intervention 3
Allowed estimate of total benefit from 3 interventions.

17. Conclusions
Combined benefits from blood pressure reduction, assignment to an amlodipine/perindopril regimen with atorvastatin were substantial.
For CHD events these benefits were greater than predicted and could indicate synergy between atorvastatin and the amlodipine/perindopril regimen.
We estimate treating about 55 patients for one year with an amlodipine – based regimen and atorvastatin compared with former treatment (without a statin ) would prevent one major CHD event.