1. Presenter Disclosure Information
The ASCOT Trial: Morbidity and Mortality Outcomes From Lipid Lowering in a Hypertensive Patient Population. The following relationships exist related to this presentation:
Name
Research Grants
Consultancies
Peter S. Sever
Pfizer, Servier, AstraZeneca
Björn Dahlöf
Pfizer, Merck, AstraZeneca, Servier
Pfizer, Merck, Boehringer
Neil R. Poulter
Pfizer, Servier
Pfizer, AstraZeneca, Merck/Schering Plough
Hans Wedel
Pfizer, AstraZeneca
Pfizer, AstraZeneca, Merck, Medtronic Inc
Gareth Beevers
Merck
Mark Caulfield
AstraZeneca
Rory Collins
Merck, AstraZeneca
Sverre E. Kjeldsen
Merck, AstraZeneca, Pfizer
Arni Kristinsson
Gordon T. McInnes
Pfizer, Merck, Aventis, AstraZeneca
AstraZeneca, Boehringer, Merck, Servier, Merck/Schering Plough
Jesper Mehlsen
Pfizer
Markku Nieminen
Pfizer, Merck
Pfizer, Merck, AstraZeneca
Eoin O’Brien
Jan Östergren
Aventis, Merck, AstraZeneca

2. On behalf of the ASCOT Investigators
ASCOT-LLA REVISITED: INTERACTION OF ANTIHYPERTENSIVE AND LIPID-LOWERING THERAPY
P Sever (Co-chair), B Dahlöf (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 O’Brien, J Östergren
On behalf of the ASCOT Investigators

3. ASCOT-BPLA and LLA Primary Objectives
To compare the effect on non-fatal myocardial infarction (MI) and fatal CHD of :
a standard antihypertensive regimen (-blocker +/- diuretic) with a more contemporary regimen (CCB +/- ACE inhibitor)
and
atorvastatin with placebo in those with total cholesterol < 6.5 mmol/L(250mg/dl)

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

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. Study design 19,257 hypertensive patients ASCOT-BPLA
atenolol ± bendroflumethiazide
PROBE
design
amlodipine ± perindopril
placebo
atorvastatin 10 mg
Double-blind
ASCOT-LLA
10,305 patients
TC ≤ 6.5 mmol/L (250 mg/dL)

7. ASCOT-BPLA :summary of all end points
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 ( )
0.70 ( )
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

8. Additional objectives include:
Secondary end points
Total stroke
All coronary events
Primary end point minus silent MI
Total cardiovascular (CV) events and procedures
CV mortality
All-cause mortality
Heart failure
Tertiary end points
Development of diabetes
Impairment of renal function
Pre-specified end points in pre-specified subgroups
Life-threatening arrhythmias
Other objectives
Interaction between statins and antihypertensive treatment on the primary endpoint and total CV events and procedures
Health economic analyses

9. Primary endpoint: Non-fatal MI and fatal CHD
ASCOT-LLA
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

10. Primary endpoint: Non-fatal MI and fatal CHD
ASCOT-LLA
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

11. Amlodipine-based treatment Atenolol-based treatment
4.0
4.0
Atorvastatin
Placebo
Atorvastatin
Placebo
3.0
3.0
16%
53%
2.0
Cumulative incidence (%)
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

12. Total cardiovascular events and procedures
ASCOT-LLA
Total cardiovascular events and procedures
Amlodipine-based treatment
Atenolol-based treatment
12.0
12.0
10.0
Atorvastatin
Placebo
10.0
Atorvastatin
Placebo
15%
27%
8.0
8.0
Cumulative incidence (%)
6.0
Cumulative incidence (%)
6.0
4.0
4.0
2.0
2.0
HR=0.73 ( ) p=0.001
HR=0.85 ( ) p=0.08
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

13. 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

14. Fatal CHD + non-fatal MI
n.s.
n.s.
p<0.0001
p=0.015
Events/1000 patient years
Interaction p=0.025

15. Total CV events and procedures
n.s.
p=0.08
p=0.001
p=0.021
Events/1000 patient years
Interaction p=0.25

16. Stroke n.s. p=0.06 p=0.09 p=0.04 Interaction p=0.73
Events/1000 patient years
Interaction p=0.73

17. Fatal CHD + Non-fatal MI Fatal CHD + non-fatal MI
On-treatment
Fatal CHD + Non-fatal MI
Fatal CHD + non-fatal MI
Primary + Revascularisation
n.s.
n.s.
n.s.
p<0.0001
n.s.
n.s.
n.s.
p<0.0001
p=0.003
p=0.015
p=0.015
p=0.019
Events/1000 patient years
Interaction p=0.025
Interaction p=0.043
Interaction p=0.043

18. CHD events * Per 1000 patient years Events ( Rate)* Censoring Time
HR Atorva Placebo
Censoring Time
Hazard Ratios (95% CI)
30 days
90 days
180 days
1 Year
2 Years
End of Study
0.17( ) 1 (2.4) 6 (14.2)
0.33( (5.5) (16.6)
0.52( ) 19 (7.5) 36 (14.3)
0.55( ) 34 (6.6) 61 (12.0)
0.62( ) 60 (5.9) 96 (9.5)
0.64( ) (6.0) 154 (9.4)
* Per 1000 patient years
Atorvastatin better
Placebo better

19. Rates and hazard ratios at various timepoints for non-fatal MI (incl silent) + fatal CHD amongst patients in the Amlodipine arm
CHD Event (Rate*)
HR (95% CI) Atorvastatin Placebo
0.33 ( ) 1 (4.9) 3 (14.8)
0.27 ( ) 3 (4.8) 11 (17.7)
0.40 ( ) 9 (7.1) 22 (17.7)
0.46 ( ) 16 (6.2) 34 (13.5)
0.39 ( ) 20 (3.9) 51 (10.2)
0.47 ( ) 38 (4.6) 80 (9.8)
Censoring Time
Hazard Ratios (95% CI)
3.17
30 days
90 days
180 days
1 year
2 years
End of study //
0.0
0.5
1.0
1.5
Atorvastatin better
Placebo better
* Per 1000 patient years

20. Summary
Benefits of atorvastatin on coronary end points greater in those allocated amlodipine compared with atenolol-based treatment.
A formal test for interaction between lipid-lowering and blood pressure-lowering treatment was of borderline significance for this endpoint.
No significant interaction was evident for two other endpoints (total CV events and procedures and fatal and non-fatal stroke)
Whilst these observations could be a chance finding, there is a plausible biological explanation for a synergistic effect of atorvastatin and amlodipine-based treatment on acute coronary events.

21. LDL Monocytes Vascular endothelium Smooth muscle cells Expression
of adhesion
molecules
Vascular endothelium
Uptake
of LDL
Foam cell
Monocyte
Macrophage
Oxidised LDL
Smooth muscle cells

22. SMC dedifferentiation
To synthetic phenotype
Macrophage
Foam cells
Cytokine release
SMC
migration
and
proliferation

23. Formation of fibrous cap

24. Apoptosis
MMPs
Destruction
of inter-cellular
matrix
Lipid-laden
macrophage

25. Plaque rupture

26. SMC DEDIFFERENTIATION
Contractile phenotype Synthetic phenotype
Loss of
Functionality
of L-type VOC
• CCBs ineffective
CCB
Ca2+
Presence of statins leads to growth arrest and re-expression of functioning L-type VOCs
L-type VOC
• CCBs effective

27. An additional mechanism?

28. SMC: reversion to a more differentiated phenotype

29. Hypothesis
Electrochemical bonding of atorvastatin and amlodipine in the lipid bilayer of vascular smooth muscle cell membranes (Mason)
Restoration of functionality of L-type calcium channels in vsm cells which is lost during migration and proliferation( de-differentiation) due to an action of atorvastatin inducing growth arrest of cells ,and restoration of responsiveness of vsm to CCBs
Return of vsm cells to more differentiated phenotype
Stabilisation of plaque possibly due to reduced destruction and apoptosis of vsm cells, a reduction in release of MMPs and preservation of intercellular matrix.