Preventing the Clinical Manifestations of
CV Disease in Asia:
Opportunities for Lipid Management
Slides prepared and presented by
Prof John JP Kastelein
Academic Medical Centre
Amsterdam, The Netherlands
The Burden of CVD in Asia: CHD
Deaths by Country, 2002
WHO CVD Atlas. 2002. WHO Stroke Atlas. 2002.
2
The Burden of CVD in Asia: Stroke
Deaths by Country, 2002
WHO CVD Atlas. 2002. WHO Stroke Atlas. 2002.
3
Age-Standardized Stroke and CHD
Death Rates by Country, 2002
Ueshima H et al. Circulation. 2008;118:2702-2709.
4
Projected Stroke and CHD Increase to
2030 in China
Moran et al. Circ Cardiovasc Qual Outcomes. 2010;3;243-252.
5
Increase in Age-Standardized Mean
Total Cholesterol Levels in
Asia 1980-2008
Men
Women
Southeast Asia: Cambodia, Indonesia, Lao People’s Democratic Republic, Malaysia, Maldives, Myanmar, Philippines,
Sri Lanka, Thailand, Timor-Leste, Vietnam
East Asia: China, Hong Kong (China), Macau (China), Democratic People’s Republic of Korea, Taiwan,
Brunei, Darussalam, Japan, Republic of Korea, Singapore, islands of Oceania
Farzadfar et al. Lancet. 2011;377:578-586.
6
Discovery
of statins
Discovery
of LDL
receptors
Brown and
Goldstein,
1974
Endo, 1976
Statins raise LDL
receptors in the liver
Plasma LDL is reduced
Clear Cardiovascular Benefits of
Intensive Lipid-Lowering Therapy
POSCH-PL
% Patients with CHD Event
4S-PL
Primary
prevention
trials
Secondary
prevention
trials
HPS
25
POSCH-Rx
CARE-PL
20
4S-Rx
15
10
LIPID-PL
TNT-10A
CARE-Rx
WOSCOPS-PL
LIPID-Rx
TNT-80A
WOSCOPS-Rx
HPS-Rx
LRC-PL
5
ASCOT-PL
ASCOT-Rx
0
Statin trials
HPS-PL
non statin
trials
LRC-Rx
AFCAPS-PL
AFCAPS-Rx
50
70
90
110
1.3
1.8
2.3
5.4 (mmol/L)
130
2.8
150 170 190 210 (mg/dL)
3.4
3.9
4.4
4.9
LDL cholesterol
Second CTT cycle:
More vs less intensive statin therapy
Study
Treatment
comparison
N
Target
population
Entry lipid criteria
PROVE-IT
A 80 vs. P 40
4162
ACS
TC ≤240 mg/dL
A to Z
S 40 then S 80 vs.
placebo then S 20
4497
ACS
TC ≤250 mg/dL
TNT
A 80 vs. A 10
10,001
Prior CHD
LDL-C 130-250 mg/dL
TG ≤600 mg/dL
IDEAL
A 80 vs. S 20-40
8888
Prior CHD
TG ≤600 mg/dL
SEARCH
S 80 vs. S 20
12,064
Prior CHD
TC ≥4.5 mmol/L or ≥3.5 if on
statins
Proportional effects on MAJOR VASCULAR EVENTS
of events
(% pa)
per mmol/L reduction inNo.
LDL
cholesterol
Statin/
Control/
More statin Less statin
Relative risk (CI)
3485 (1.0)
1887 (0.5)
5105 (1.4)
4593 (1.3)
2281 (0.6)
6512 (1.9)
0.73 (0.69 - 0.78)
0.80 (0.74 - 0.87)
0.76 (0.73 - 0.78)
1453 (0.4)
CABG
1767 (0.5)
PTCA
Unspecified
2133 (0.6)
Any coronary revascularisation
5353 (1.5)
1427 (0.4)
Ischaemic stroke
Haemorrhagic stroke
257 (0.1)
618 (0.2)
Unknown stroke
Any stroke
2302 (0.6)
1857 (0.5)
2283 (0.7)
2667 (0.8)
6807 (2.0)
1751 (0.5)
220 (0.1)
709 (0.2)
2680 (0.8)
0.75 (0.69 - 0.82)
0.72 (0.65 - 0.80)
0.76 (0.70 - 0.82)
0.75 (0.72 - 0.78)
0.79 (0.72 - 0.87)
1.12 (0.88 - 1.43)
0.88 (0.76 - 1.01)
0.84 (0.79 - 0.89)
Any major vascular event 10973 (3.2) 13350 (4.0)
0.78 (0.76 - 0.80)
Nonfatal MI
CHD death
Any major coronary event
99% or
95% CI
0.4 0.6 0.8
Statin/more
statin better
1
1.2 1.4
Control/less
statin better
Absolute effect of statin therapy on
MAJOR VASCULAR EVENTS
15
Statin
15% relative risk
reduction per 0.5 mmol/L
10
More statin
21% relative risk
reduction per mmol/L
5
Combined evidence:
~33% relative risk reduction
per 1.5 mmol/L
0
Five year risk of a major
vascular event, %
20
Control
0
1
2
3
LDL cholesterol, mmol/L
4
5
ASAP: Atorvastatin Reduced CRP to a Greater
Extent Than Simvastatin
Baseline
0
Change (%)
-10
1 year
2 years
14.0
19.7
-20
P<.001
-30
P<.022
-40
40.1
-50
44.9
Atorvastatin 80 mg
Simvastatin 40 mg
van Wissen S et al. Atherosclerosis. 2002;165:361-366.
Additional Findings
• No correlation between
CRP and LDL-C reduction
• Significant correlation
between decrease in
CRP and reduction in
IMT (r =.13; P=.03)
• Patients in the highest
tertile of change in CRP
had the greatest mean
reduction in IMT
Anglo-Scandinavian Cardiac Outcomes Trial—
Lipid Lowering Arm (ASCOT-LLA): Study Design
•
•
•
•
•
Patient population
Men and women aged
40-79 years
Untreated HTN
(SBP 160 mm Hg,
DBP 100 mm Hg, or
both)
19,342
10,305
patients patients with
with HTN TC 251.4 mg/dL
Treated HTN
(SBP 140 mm Hg,
DBP 90 mm Hg, or
both)
TC 251.4 mg/dL
Atorvastatin 10
mg
(n=5168)
Placebo
(n=5137)
5 years
•Trial stopped at 3.3 years,
2 years earlier than expected
At least 3 additional
Primary
CVD risk
factors efficacy end point
•
Nonfatal MI, including silent MI, and fatal CHD
HTN=hypertension; SBP=systolic blood pressure; DBP=diastolic blood pressure; TC=total cholesterol;
CVD=cardiovascular disease.
Sever PS et al. Lancet. 2003;361:1149-1158.
ASCOT-LLA: Atorvastatin Reduced the
Occurrence of First Major CV Events
Patients with nonfatal MI
and fatal CHD (%)
4
36% RRR in
nonfatal MI
and fatal CHD
P=.0005
3
Placebo
2
Atorvastatin
(10 mg)
1
0
0.0
0.5
1.0
1.5 2.0
Years
RRR=relative risk reduction.
Adapted from Sever PS et al. Lancet. 2003;361:1149-1158.
2.5
3.0
3.5
PROVE IT: Study Design
Patient population
• Men and women aged
18 years
•
•
•
Hospitalized within 10
days of acute MI or highrisk unstable angina (UA)
TC 240 mg/dL
Atorvastatin 80 mg
(n=2099)
4162 patients
Stable condition, enrolled
after percutaneous
coronary intervention
(PCI), if planned
Pravastatin 40 mg
(n=2063)
18 to 36 months
Primary efficacy end point
•
Composite of death from any cause, MI, documented UA requiring
rehospitalization, revascularization, and stroke
Cannon CP et al. N Engl J Med. 2004;350:1495-1504.
Death, MI, urgent revascularization (%)
PROVE IT: Significant Clinical Benefit With
Atorvastatin Occurred as Early as 30 Days
Composite end point of death, MI, or urgent revascularization
4
Pravastatin
(40 mg)
3
33% RRR
P=.043
2
Atorvastatin
(80 mg)
1
0
0
5
10
15
20
25
Time after entry to trial (days)
Adapted from Cannon CP et al. Circulation. 2004;110(suppl III);III-499.
30
Atorvastatin Is the Only Statin With an Active
HMG CoA Reductase Inhibitor Metabolite
Atorvastatin parent molecule
CH3
CH3
CH
O
..
NHC
N
OH OH
O
O
F
Active ortho-hydroxy-atorvastatin
metabolite
70% of the activity
of atorvastatin is
attributed to active
metabolites
Site*
H
O O
N O
H3C H
CH3 OH OH
..
N
H
*Unique to ortho-hydroxy metabolite.
Data on file (RP Mason). Pfizer Inc., New York, NY.
F
O
OH
What Accounts for the Added Benefits
of Atorvastatin?
• Endothelial effects
• Anti-inflammatory effects
Reduction of
lipids
+
• Antioxidant effects
• Reduction in plaque
progression
• Plaque stabilization
Wassmann S, Nickenig G. Endothelium. 2003;10:23-33.
Statin Safety in Perspective
Number needed to treat for 1 year to:
Cause a GI Bleed1
Aspirin
Cause a Fatal GI Bleed1
248
Cause Severe Myositis2
Statins
100,000
2066
Cause Fatal Myositis2
1,000,000
1Derry
S, Loke YK. 2000
2Thompson PD, et al. 2003
Safety of Atorvastatin 80 mg
in Clinical Trials
Follow-up
Patients
ALT/AST
>3x ULN*
CK >10x
ULN*
Newman et al†
variable
4798
26 (0.6%)
2 (0.06%)
PROVE-IT
2 years
2099
69 (3.3%)
NA
TNT
4.9 years
4995
60 (1.2%)
0
IDEAL
4.8 years
4439
61 (1.38%)
0
SPARCL
4.9 years
2365
51 (2.2%)
2 (0.08%)
variable
18,696
267 (1.43%)
4 (0.021%)
Total
*Consecutive measurements.
†Newman C et al. Am J Cardiol. 2006;97:61-67; Cannon CP et al. N Engl J Med. 2004;350:1495-1504; LaRosa
JC, et al. N Engl J Med. 2005;352:1425-1435; Pedersen TR et al; for the IDEAL Study Group. JAMA.
2005;294:2437-2445; Amarenco P et al. N Engl J Med. 2006;355:549-559.
20
Is Current LDL Reduction Enough?
700
600
CV events
500
placebo
treated
30.6%
reduction
400
31.0%
reduction
300
200
100
0
4S
2º prevention trial
with simvastatin
WOSCOPS
1º prevention trial
with pravastatin
The Future of Best Practice
“Normal” plasma cholesterol
700
(18.0)
300
(7.7)
-
-
Physiologic level for
plasma LDL-cholesterol
as predicted from receptor
studies
25 mg/dL (0.65 mmol/L)
FH homozygotes
FH heterozygotes
200
(5.2)
-
150
(3.9)
-
100
(2.6)
-
50
(1.3)
-
0
Guinea pig
Sheep
Rat
Rabbit
Cow
Camel
Pig
Normal adults
Newborns
REVERSAL: Benefit of Intensive
LDL-C Lowering on Plaque Progression
3
Progression (P=0.001)
pravastatin 40 mg
Percent change in
atheroma volume
2
1
atorvastatin 80 mg
P=0.02 between treatment groups
0
No change (P=0.98)
-1
Nissen SE et al. JAMA 2004;291:1071–1080
REVERSAL
Comparison of % LDL Cholesterol Reduction and
Change in Atheroma Volume
20
Change in Atheroma
Volume, mm3
15
10
5
0
50% LDL-C reduction
-5
-10
-15
-80
-70
-60
-50
-40
% Change in LDL Cholesterol
-30
-20
-10
0
10
20
REVERSAL: Intensive Lipid Lowering With
Atorvastatin Halted Plaque Progression
After 18 Months
Change in atheroma
volume (mm3)
20
15
10
Pravastatin (40 mg)
5
0
Atorvastatin (80 mg)
-5
-10
-15
-80
For any degree
reduction in LDL-C,
the progression rate
was lower with
atorvastatin than
with pravastatin
-70 -60 -50 -40 -30 -20 -10
Change in LDL-C (%)
Nissen SE et al. JAMA. 2004;291:1071-1080.
0
10
20
Age-Standardized Event Rate
(per 100 Person-Yr)
Relationship Between Estimated GFR
(eGFR) and Clinical Outcomes
Death from Any Cause
Total Events = 51,424
Cardiovascular Events
Total Events = 139,011
Any Hospitalization
Total Events = 554,651
16
40
160
14
35
140
12
30
120
10
25
100
8
20
80
6
15
60
4
10
40
2
5
20
0
0
0
≥60
45–59 30–44 15–29
<15
≥60
45–59 30–44 15–29
<15
≥60
45–59 30–44 15–29
<15
eGFR (mL/min/1.73 m2)
Go AS, et al. N Engl J Med. 2004;351:1296-305.
26
% of patients with change in eGFR
Proportion of Patients With Decline or
Improvement From Baseline eGFR
50
Atorvastatin 10 mg
P<0.0001
Atorvastatin 80 mg
45.6%
40
37.8%
30
20
10
0
P<0.0001
9.2%
6.6%
(n=3324) (n=3225)
(n=1505) (n=1602)
eGFR decline from
≥60 mL/min/1.73 m2
eGFR improvement from
<60 mL/min/1.73 m2