P Sever (Co-chair), B DahIf (Co-chair), N PouIter (Secretary), H WedeI

(Statistician), G Beevers, M CauIfieId, R CoIIins, SE KjeIdsen, A Kristinsson,

J MehIsen, G McInnes, M Nieminen, E O'Brien, J stergren
On behaIf of the ASCOT Investigators
P0TENT|AL 8YNERCY ETwEEN L|P|0 L0wER|NC AN0 L000 PRE88URE
L0wER|NC |N ThE ANCL0-86AN0|NAV|AN 6AR0|A6 0UT60HE8 TR|AL-L|P|0-
L0wER|NC ARH
PREL!N!NARY DATA PREL!N!NARY DATA
A randomised controIIed triaI of the prevention of
coronary heart disease events and other vascuIar events
by bIood pressure Iowering and by choIesteroI Iowering in
a factoriaI study design
ASCOT-BPLA and LLA
To compare the effect on non-fatal myocardial infarction
(M) 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)
Primary Objectives
Study design
atenolol
bendroflumethiazide
amlodipine
perindopril
19,257
hypertensive
patients
PROBE
design
ASCOT-BPLA
Investigator-Ied, muItinationaI
randomised controIIed triaI
placebo
atorvastatin 10 mg
Double-blind
ASCOT-LLA
10,305 patients
TC > 6.5 mmol/L (250 mg/dL)
Reductions in Total and LDL
Cholesterol
2
4
6
0 1 2 3
Atorvastatin 10 mg PIacebo
1
2
3
4
0 1 2 3
200
150
150
75
125
100
100
(
m
g
/
d
L
)
(
m
g
/
d
L
)
T
o
t
a
I

c
h
o
I
e
s
t
e
r
o
I

(
m
m
o
I
/
L
)
L
D
L

c
h
o
I
e
s
t
e
r
o
I

(
m
m
o
I
/
L
)
Years
mmo||L mmo||L
mmo||L mmo||L
Sever PS, Dahlf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
6|ose-out
0
1
2
3
4
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Years
C
u
m
u
I
a
t
i
v
e

I
n
c
i
d
e
n
c
e

(
%
)

36%
reduction
Primary End Point: Nonfatal M
and Fatal CHD
HR = 0.64 (0.50-0.83)
Atorvastatin 10 mg Number of events 100
PIacebo Number of events 154
p=0.0005
Sever PS, Dahlf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
$econdary End Point: Fatal
and Nonfatal $troke
27%
reduction
HR = 0.73 (0.56-0.96) p=0.0236
Atorvastatin 10 mg Number of events 89
PIacebo Number of events 121
0
1
2
3
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Years
C
u
m
u
I
a
t
i
v
e

I
n
c
i
d
e
n
c
e

(
%
)

Sever PS, Dahlf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
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)
Rates and Hazard Ratios at Various Timepoints for Non-
fatal M (incl silent) + Fatal CHD in A$COT-LLA
Area of squares is proportional to the amount of statistical information
0.5 1.0 1.5
Alorvaslal|r oeller P|aceoo oeller
Primary End Points
Nonfatal M (incl silent) + fatal CHD
Secondary End Points
Total CV events and procedures
Total coronary events
Nonfatal M (excl silent) + fatal CHD
All-cause mortality
Cardiovascular mortality
Fatal and nonfatal stroke
Fatal and nonfatal heart failure
Tertiary End Points
$ilent M
Unstable angina
Chronic stable angina
Peripheral arterial disease
Development of diabetes mellitus
Development of renal impairment
Risk Ratio
Sever PS, Dahlf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
$tudy Design
atenolol
bendroflumethiazide
amlodipine
perindopril
19,257
hypertensive
patients
PROBE
design
ASCOT-BPLA
placebo
atorvastatin 10 mg
Double-blind
ASCOT-LLA
10,305 patients
TC > 6.5 mmol/L (250 mg/dL)
A$COT-BPLA: $ummary of all End Points
The area of the blue square is proportional to the amount of statistical information
AmIodipine I perindopriI better AtenoIoI I thiazide better
0.50 0.70 1.00 1.45
Primary
Non-fatal M (incl silent) + fatal CHD
Secondary
Non-fatal M (exc. $ilent) +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
$ilent M
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 + M + stroke
2.00
Unadjusted Hazard
ratio (95% CI)
0.90 (0.79-1.02)
0.87 (0.76-1.00)
0.87 (0.79-0.96)
0.84 (0.78-0.90)
0.89 (0.81-0.99)
0.76 (0.65-0.90)
0.77 (0.66-0.89)
0.84 (0.66-1.05)
1.27 (0.80-2.00)
0.68 (0.51-0.92)
0.98 (0.81-1.19)
0.65 (0.52-0.81)
1.07 (0.62-1.85)
0.69 (0.63-0.77)
0.85 (0.75-0.97)
0.86 (0.77-0.96)
0.84 (0.76-0.92)
Additional objectives include:
Secondary end points
TotaI stroke
AII coronary events
Primary end point minus
siIent MI
TotaI cardiovascuIar (CV)
events and procedures
CV mortaIity
AII-cause mortaIity
Heart faiIure
Tertiary end points
DeveIopment of diabetes
Impairment of renaI 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 totaI
CV events and procedures
HeaIth economic anaIyses
A860T-LLA
Pr|rary erdpo|rl: Nor-lala| Vl ard lala| Cl0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
0.0
1.0
2.0
3.0
4.0
Years
C
u
m
u
l
a
t
i
v
e

i
n
c
i
d
e
n
c
e

(
%
)
Atorvastatin
Placebo
53%
Amlodipine-based treatment
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
0.0
1.0
2.0
3.0
4.0
Years
C
u
m
u
l
a
t
i
v
e

i
n
c
i
d
e
n
c
e

(
%
)
Atorvastatin
Placebo
16%
Atenolol-based treatment
HR=0.84 (0.60 - 1.17) p=0.30
HR=0.47 (0.32 - 0.69) p<0.001
A860T-LLA
ala| ard ror-lala| slro|e
0.0
0.5 1.0 1.5 2.0 2.5 3.0 3.5
0.0
1.0
2.0
3.0
Years
C
u
m
u
l
a
t
i
v
e

i
n
c
i
d
e
n
c
e

(
%
)
Atorvastatin
Placebo
31%
Amlodipine-based treatment Atenolol-based treatment
HR=0.76 (0.63 - 1.08) p=0.013 HR=0.69 (0.45 - 1.06) p=0.09
0.0
0.5 1.0 1.5 2.0 2.5 3.0 3.5
0.0
1.0
2.0
3.0
Years
C
u
m
u
l
a
t
i
v
e

i
n
c
i
d
e
n
c
e

(
%
)
Atorvastatin
Placebo
24%

AtenoIoI
AmIodipine
+ Atorva
- Atorva
8.0
8.6
7.7
4.6

AtenoIoI
AmIodipine
+ Atorva
- Atorva
12.1
12.5
9.9
6.5

AtenoIoI
AmIodipine
+ Atorva
- Atorva
9.0
9.8
7.5
4.6
E
v
e
n
t
s
/
1
0
0
0

p
a
t
i
e
n
t

y
e
a
r
s
ataI CHD +
non-fataI MI
Primary +
RevascuIarisation
On-treatment
ataI CHD +
Non-fataI MI
nteraction p=0.025
nteraction p=0.043
n.s
n.s
n.s.
p<0.0001
p=0.015
n.s.
n.s.
p=0.015
p<0.0001
n.s.
p=0.003
p=0.019
nteraction p=0.043
Censoring Time
Events ( Rate)*
HR Atorva PIacebo
Hazard Ratios (95% CI)
Atorvastatin better PIacebo better
30 days
90 days
180 days
1 Year
2 Years
End of $tudy
CHD events
0.17(0.02-1.38) 1 (2.4) 6 (14.2)
0.33(0.14-0.78 7 (5.5) 21 (16.6)
0.52(0.30-0.91) 19 (7.5) 36 (14.3)
0.55(0.36-0.84) 34 (6.6) 61 (12.0)
0.62(0.45-0.85) 60 (5.9) 96 (9.5)
0.64(0.50-0.83) 100 (6.0) 154 (9.4)
* Per 1000 patient years
//
3.17
1.0 1.5 0.5 0.0
30 days
90 days
180 days
1 year
2 years
End of study
Censoring Time Hazard Ratios (95% CI)
Rates and hazard ratios at various timepoints for non-fatal
M (incl silent) + fatal CHD amongst patients in the
Amlodipine arm
HR (95% CI) Atorvastatin PIacebo
0.33 (0.03-3.17) 1 (4.9) 3 (14.8)
0.27 (0.08-0.97) 3 (4.8) 11 (17.7)
0.40 (0.19-0.88) 9 (7.1) 22 (17.7)
0.46 (0.26-0.84) 16 (6.2) 34 (13.5)
0.39 (0.23-0.65) 20 (3.9) 51 (10.2)
0.47 (0.32-0.69) 38 (4.6) 80 (9.8)
* Per 1000 patient years
CHD Event (Rate*)
Atorvastatin better PIacebo better
Summary
Benefits of atorvastatin on coronary end points greater in those
allocated amlodipine compared with atenolol-based treatment.
A formal test for interaction between lipid-lowering and blood
pressure-lowering treatment was of borderline significance for
this endpoint.
No significant interaction was evident for two other endpoints
(total CV events and procedures and fatal and non-fatal stroke).
Whilst these observations could be a chance finding, there is a
plausible biological explanation for a synergistic effect of
atorvastatin and amlodipine-based treatment on acute coronary
events, which requires further analysis in future studies.
No new, unexpected adverse events were observed beyond
those seen in previously published A$COT results.
LDL
Oxidised LDL
Expression
of adhesion
molecules
Monocytes
Monocyte Macrophage
Vascular endothelium
Uptake
of LDL
Foam cell
$mooth muscle cells
Macrophage
Cytokine release
Foam cells
$MC dedifferentiation
To synthetic phenotype
$MC
migration
and
proliferation
Formation of fibrous cap
Destruction
of inter-cellular
matrix
Apoptosis
Lipid-laden
macrophage
MMPs
Plaque rupture
$MC DEDFFERENTATON
Contractile phenotype $ynthetic phenotype
L-type VOC
CCBs effective
Loss of
Functionality
of L-type VOC
CCBs ineffective
Presence of statins
leads to growth arrest
and re-expression
of functioning
L-type VOCs
Ca
2+
CCB
Acetyl-CoA + Acetoacetyl-CoA
HMG-CoA
HMG-CoA
Reductase
$tatins
Mevalonate
P13-Kinase/Protein Kinase Aid eNO$
BMP-2/Bone formation
Angiogenesis
Cellular growth
Proliferation
Dolichol
Haam
Ubiquinone
Ras
+ sopenteryl-PP
Geranylgeranyl-PP
Lipoprotein
Vitamin D
Bile acids
$teroid hormones
Cholesterol
$qualene
Farnesyl-PP
Actin
Cytoskeleton
Oxidase Abrass
NAD(P)H Oxidase
Proliferation
and migration
OPP
Cd642 Rac1
RhoA
-PA
ET-1,
PA-1,
e-NO$,
An additional mechanism?
$MC: reversion to a more differentiated phenotype
Hypothesis
Electrochemical bonding of atorvastatin and
amlodipine in the lipid bilayer of vascular smooth
muscle (V$M) cell membranes (Mason)
Restoration of functionality of L-type calcium
channels in V$M cells, which has been lost during
migration and proliferation (de-differentiation). This is
due to an action of atorvastatin in inducing growth
arrest of cells, as well as restoration of
responsiveness of V$M to CCBs
Return of V$M cells to more differentiated phenotype
$tabilisation of plaque possibly due to reduced
destruction and apoptosis of V$M cells, a reduction in
release of MMPs and preservation of intercellular
matrix