preventing the clinical manifestations of cv disease in asia: opportunities for lipid management...
TRANSCRIPT
Preventing the Clinical Manifestations of CV Disease in Asia:Opportunities for Lipid Management
Prof John JP Kastelein
Academic Medical Centre
Amsterdam, The Netherlands
Slides prepared and presented by
WHO CVD Atlas. 2002. WHO Stroke Atlas. 2002.
The Burden of CVD in Asia: CHD Deaths by Country, 2002
2
WHO CVD Atlas. 2002. WHO Stroke Atlas. 2002.
The Burden of CVD in Asia: Stroke Deaths by Country, 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 MeanTotal Cholesterol Levels in Asia 1980-2008
Farzadfar et al. Lancet. 2011;377:578-586.
Southeast Asia: Cambodia, Indonesia, Lao People’s Democratic Republic, Malaysia, Maldives, Myanmar, Philippines, Sri Lanka, Thailand, Timor-Leste, VietnamEast Asia: China, Hong Kong (China), Macau (China), Democratic People’s Republic of Korea, Taiwan,Brunei, Darussalam, Japan, Republic of Korea, Singapore, islands of Oceania
6
Men Women
Discoveryof statins
Discoveryof LDLreceptors
Endo, 1976Brown andGoldstein,1974
Statins raise LDLreceptors in the liver
Plasma LDL is reduced
Primary prevention trialsSecondary prevention trials
50 70 110 130 150 170 19090 210 % P
ati
ents
wit
h C
HD
Eve
nt
LDL cholesterol
CARE-Rx
4S-Rx
LIPID-PL
4S-PL
CARE-PL
LIPID-Rx
AFCAPS-Rx
WOSCOPS-Rx
WOSCOPS-PL
AFCAPS-PL
25
20
15
10
5
0
ASCOT-PL
ASCOT-Rx
HPS-Rx
HPS-PL
HPS
LRC-PLLRC-Rx
POSCH-PL
POSCH-Rx
non statin trials
Statin trials
(mg/dL)
1.3 1.8 2.3 2.8 3.4 3.9 4.4 4.9 5.4 (mmol/L)
TNT-80A
TNT-10A
Clear Cardiovascular Benefits of Intensive Lipid-Lowering 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
Second CTT cycle:
More vs less intensive statin therapy
Less statin
Proportional effects on MAJOR VASCULAR EVENTS per mmol/L reduction in LDL cholesterol
0.4 0.6 0.8 1 1.2 1.4
No. of events (% pa)Statin/
More statinContr ol/ Relative risk (CI)
Statin/morestatin better
Control/lessstatin better
Nonfatal MICHD death
Any major coronary event
CABGPTCAUnspecified
Any coronary revascularisation
Ischaemic strokeHaemorrhagic stroke
Unknown strokeAny stroke
Any major vascular event
3485 (1.0)1887 (0.5)5105 (1.4)
1453 (0.4)1767 (0.5)2133 (0.6)5353 (1.5)
1427 (0.4)257 (0.1)618 (0.2)
2302 (0.6)
10973 (3.2)
4593 (1.3)2281 (0.6)6512 (1.9)
1857 (0.5)2283 (0.7)2667 (0.8)6807 (2.0)
1751 (0.5)220 (0.1)709 (0.2)
2680 (0.8)
13350 (4.0)
0.73 (0.69 - 0.78)0.80 (0.74 - 0.87)0.76 (0.73 - 0.78)
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)
0.78 (0.76 - 0.80)
99% or 95% CI
Absolute effect of statin therapy onMAJOR VASCULAR EVENTS
0 1 2 3 4 5
05
1015
20
LDL cholesterol, mmol/L
Fiv
e ye
ar r
isk
of a
maj
orva
scul
ar e
vent
, %
Control
21% relative riskreduction per mmol/LStatin
15% relative riskreduction per 0.5 mmol/LMore statin
Combined evidence:~33% relative risk reductionper 1.5 mmol/L
ASAP: Atorvastatin Reduced CRP to a Greater Extent Than Simvastatin
van Wissen S et al. Atherosclerosis. 2002;165:361-366.
2 years
P<.001
1 yearBaseline
P<.022
Atorvastatin 80 mg Simvastatin 40 mg
-50
-40
-30
-20
-10
0
Ch
ang
e (%
)
44.9
40.1
19.7
14.0
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
• Nonfatal MI, including silent MI, and fatal CHD
Primary efficacy end point
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.
• Men and women aged 40-79 years
• Untreated HTN (SBP 160 mm Hg, DBP 100 mm Hg, or both)
• Treated HTN (SBP 140 mm Hg, DBP 90 mm Hg, or both)
• TC 251.4 mg/dL
• At least 3 additional CVD risk factors
Atorvastatin 10 mg(n=5168)
Placebo(n=5137)
Patient population
5 years
19,342 patientswith HTN
10,305patients with TC 251.4 mg/dL
•Trial stopped at 3.3 years, 2 years earlier than expected
RRR=relative risk reduction.
Adapted from Sever PS et al. Lancet. 2003;361:1149-1158.
ASCOT-LLA: Atorvastatin Reduced the Occurrence of First Major CV Events
4
0
1
2
3
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5Years
36% RRR innonfatal MI and fatal CHDP=.0005
Atorvastatin (10 mg)
Placebo
Pat
ien
ts w
ith
no
nfa
tal
MI
and
fat
al C
HD
(%
)
4162 patients
• Men and women aged 18 years
• Hospitalized within 10 days of acute MI or high-risk unstable angina (UA)
• TC 240 mg/dL
• Stable condition, enrolled after percutaneous coronary intervention (PCI), if planned
Atorvastatin 80 mg(n=2099)
Pravastatin 40 mg(n=2063)
18 to 36 months
PROVE IT: Study Design
Patient population
• Composite of death from any cause, MI, documented UA requiring rehospitalization, revascularization, and stroke
Primary efficacy end point
Cannon CP et al. N Engl J Med. 2004;350:1495-1504.
PROVE IT: Significant Clinical Benefit With Atorvastatin Occurred as Early as 30 Days
Adapted from Cannon CP et al. Circulation. 2004;110(suppl III);III-499.
100 5 15 20 3025Time after entry to trial (days)
Pravastatin (40 mg)
Atorvastatin (80 mg)
4
0
2
1
3
Dea
th,
MI,
urg
ent
reva
scu
lari
zati
on
(%
)
33% RRRP=.043
Composite end point of death, MI, or urgent revascularization
Atorvastatin Is the Only Statin With an Active HMG CoA Reductase Inhibitor Metabolite
CHCH3CH3O
F
NHC N
Atorvastatin parent molecule
ON
H3CCH3
F
OH
OOHOH..
H
O
HSite*
70% of the activity of atorvastatin is attributed to active metabolites
N
O
H
Active ortho-hydroxy-atorvastatin metabolite
*Unique to ortho-hydroxy metabolite.
Data on file (RP Mason). Pfizer Inc., New York, NY.
..O
OOHOH
-
What Accounts for the Added Benefits of Atorvastatin?
Reduction of lipids +
• Endothelial effects
• Anti-inflammatory effects
• Antioxidant effects
• Reduction in plaque progression
• Plaque stabilization
Wassmann S, Nickenig G. Endothelium. 2003;10:23-33.
Number needed to treat for 1 year to:
Cause a GI Bleed1 Cause a Fatal GI Bleed1
Aspirin
Cause Severe Myositis2 Cause Fatal Myositis2
Statins
1Derry S, Loke YK. 20002Thompson PD, et al. 2003
Statin Safety in Perspective
248 2066
100,000 1,000,000
Safety of Atorvastatin 80 mg in Clinical Trials
Follow-up PatientsALT/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%)
Total variable 18,696 267 (1.43%) 4 (0.021%)
20
*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.
Is Current LDL Reduction Enough?C
V e
ven
ts
placebo
treated
700
600
500
400
300
200
100
04S2º prevention trialwith simvastatin
WOSCOPS1º prevention trialwith pravastatin
31.0%reduction
30.6%reduction
The Future of Best Practice“Normal” plasma cholesterol
-
-
-
-
-
- 700(18.0)
300(7.7)
200(5.2)
150(3.9)
100(2.6)
50(1.3)
0
Pla
sma
c ho
les t
e ro
l l e
v el
mg
/dL
(m
mo
l/L
)
Rat
Guinea pig
Sheep
Rabbit
Pig
Newborns
Normal adults
FH homozygotes
FH heterozygotes
Physiologic level forplasma LDL-cholesterolas predicted from receptorstudies25 mg/dL (0.65 mmol/L)
Cow
Camel
REVERSAL: Benefit of Intensive LDL-C Lowering on Plaque Progression
Per
cen
t ch
ang
e in
at
her
om
a vo
lum
e
Progression (P=0.001)
No change (P=0.98)
P=0.02 between treatment groups
pravastatin 40 mg
atorvastatin 80 mg
Nissen SE et al. JAMA 2004;291:1071–1080
3
2
1
0
-1
REVERSALComparison of % LDL Cholesterol Reduction and Change in Atheroma Volume
% Change in LDL Cholesterol
Ch
ang
e in
Ath
ero
ma
Vo
lum
e, m
m3
50% LDL-C reduction
-15
-10
-5
0
5
10
15
20
-80 -70 -60 -50 -40 -30 -20 -10 0 10 20
For any degree reduction in LDL-C, the progression rate was lower with atorvastatin than with pravastatin
REVERSAL: Intensive Lipid Lowering With Atorvastatin Halted Plaque Progression After 18 Months
Nissen SE et al. JAMA. 2004;291:1071-1080.
20
15
10
5
0
-5
-10
-15
Change in LDL-C (%)
Ch
ang
e in
ath
ero
ma
volu
me
(mm
3 )
-80 -70 -60 -50 -40 -30 -20 -10 0 10 20
Pravastatin (40 mg)
Atorvastatin (80 mg)
26
0
2
4
6
8
10
12
14
16
≥60 45–59 30–44 15–29 <15
0
5
10
15
20
25
30
35
40
≥60 45–59 30–44 15–29 <15
0
20
40
60
80
100
120
140
160
≥60 45–59 30–44 15–29 <15
Relationship Between Estimated GFR (eGFR) and Clinical Outcomes
Go AS, et al. N Engl J Med. 2004;351:1296-305.
Death from Any CauseTotal Events = 51,424
Cardiovascular EventsTotal Events = 139,011
Any HospitalizationTotal Events = 554,651
Ag
e-S
tan
da
rdiz
ed
Ev
en
t R
ate
(pe
r 1
00
Pe
rso
n-Y
r)
eGFR (mL/min/1.73 m2)
Proportion of Patients With Decline or Improvement From Baseline eGFR
0
10
20
30
40
50
% o
f pat
ient
s w
ith c
hang
e in
eG
FR Atorvastatin 10 mg
Atorvastatin 80 mg
P<0.0001
P<0.0001
(n=3324) (n=3225) (n=1505) (n=1602)
eGFR decline from eGFR improvement from≥60 mL/min/1.73 m2 <60 mL/min/1.73 m2
9.2%6.6%
37.8%
45.6%