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Landmark clinical trials with
pravastatin
WOS
CARE
LIPID
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WOS : NEJM 1995; 333 : 1301-1307
CARE : NEJM 1996; 335 : 1001-1009
LIPID : NEJM 1998; 339: 1349-1357
4S : Lancet 1994; 344 : 1383-1389
TexCAPS: JAMA 1998; 279: 1615-1622
Major HMG Trials
CAREn=4,159
TC 5.4 mmol/l
LIPIDn=9,014
TC 5.6 mmol/l
WOSn=6,595 TC 7.0 mmol/l
4Sn=4,444TC 6.8 mmol/l
With CHD +
high cholesterol
With CHD +
normal cholesterol
Without CHD +
high cholesterol
TexCAPSn=6,605 TC 5.7 mmol/l
Without CHD +
low HDL
22.6
15.9/13.2
7.9
2.8PlaceboMIrateper100subjectsper5
years
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Pravastatin Therapy in Post-MI Patientswith Average Cholesterol
CARE: Study Design
4159 men and women post-MI
Total Cholesterol
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Sacks et al: N Engl J Med 1996;335:10011009
24%*
20%
27%*
Stroke
10
20
30
40
0
*P< 0.05 vs placebo
Pravastatin Therapy in Post-MI Patientswith Average CholesterolCARE: Results Summary
%R
iskre
duc
tion
CHD death ornonfatal MI CHD death CABG/PTCA
31%*
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0
1
2
3
4
5
0 1 2 3 4 5
Time (yr)
Placebo
Pravastatin
32%P=0.03
CARE: Pravastatin Reduces Risk of Stroke
%w
itheven
t
Plehn et al: Circulation 1999;99:216223
128 strokes in total
83% of patients on antiplatelet therapy
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LIPID: Pravastatin Reduces Risk of Stroke
Time (yr)
0
2
4
6
The LIPID Study Group: N Engl J Med 1998;339:13491357
%w
ith
even
t
0 1 2 3 4 5 6
19%P=0.048
Placebo
Pravastatin
419 strokes in total
83% of patients on antiplatelet therapy
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Fatal coronary heart disease 11
Nonfatal MI 26CABG 25
PTCA 37
38
Stroke/TIA 13
Sacks et al. NEJM. 1996;335:1001-1009
Size of the Benefit with Pravastatin
Events Prevented in CARE
Event Events prevented per 1,000patients treated for 5 years
Other cardiovascular eventsAll cardiovascular events 150
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Pravastatin Therapy in Patients with MI orUnstable Angina and Average Cholesterol
LIPID: Study Design
9014 men and women with MI or unstable angina
Total Cholesterol 4-7 mmol/l (mean 5.6 mmol/l)
Pravastatin 40 mg, follow-up 6.1 years
83% aspirin, 47% beta-blockers,41% PTCA/CABG at baseline
Prespecified end points: CHD mortality Revascularizations
Total mortality Stroke
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The LIPID Study Group: N Engl J Med 1998;339:13491357
19%20%
22%24%
35
30
25
20
15
10
5
0
CHDmortality
Totalmortality Stroke
All risk reductions are P< 0.05 vs placebo
Pravastatin Therapy in Patients With MI orUnstable Angina and Average Cholesterol
LIPID: Results Summary
PTCA/CABG
%R
iskre
duct
ion
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Deaths 30Nonfatal MI 28
CABG 23
PTCA 20
Unstable Angina Episodes 82Nonfatal Stroke 9
The LIPID Study Group. N Engl J Med 1998;339:1349-1357
Size of the Benefit with Pravastatin
Events Prevented in LIPID
EventEvents prevented per1,000 patients treated
over 6 years
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Pravastatin Therapy in a Population at Risk for CHD
WOS: Study Design
6595 men without history of CHD
Total Cholesterol 6.5 mmol/l (mean 7.0 mmol/l)
Pravastatin 40 mg, follow-up 4.9 years
3% aspirin, 7% beta-blockers, 0% PTCA/CABGat baseline
Prespecified end points: Nonfatal MI and CHD death CHD mortality Total mortality
Revascularizations
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Shepherd et al: N Engl J Med 1995;333:13011307
31% 33%
37%
22%
10
20
30
40
0
All risk reductions are P 0.05 vs placebo
Pravastatin Therapy in a Population at Risk for CHDWOS: Results Summary
%R
iskre
duc
tion
Nonfatal MI /CHD death CHDmortality Totalmortality CABG/PTCA
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Deaths 9Nonfatal MI 20
PTCA/CABG 8
Coronary Angiograms 14
Shepherd et al: N Engl J Med 1995;333:13011307
Size of the Benefit with Pravastatin
Events Prevented in WOS
EventEvents prevented per1,000 patients treated
over 5 years
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Shepherd et al: N Engl J Med 1995;333:13011307; The LIPID Study Group: N Engl J Med 1998;339:13491357;
Sacks et al: N Engl J Med 1996;335:10011009
Clinical Benefit of PravastatinEvidence of Protection
31%In post-MI patients
with averagecholesterol
Stroke
31%In patientswith high
cholesterol
24%In post-MI
patients withaverage
cholesterol
10
20
30
40
0
%R
iskre
duc
tion
22%In patientswith MI orunstable
angina27%
In post-MIpatients with
averagecholesterol
First MI Recurrent
MI
Total
mortality
PTCA/
CABGCAREWOS CARELIPID CARE
All risk reductions are P< 0.05 vs placebo
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Lewis et al: J Am Coll Cardiol 1998;32:140146; Lewis et al: Ann Intern Med 1998; 129:681-689
Goldberg et al: Circulation 1998;98:25132519 The LIPID Study Group: N Engl J Med 1998;339:13491357
50
40
30
20
10
0
29%25%*
32%*
46%*
Women Elderly(65 yr)
Unstable
anginapatients
* CHD death, nonfatal MI, CABG, or PTCA CHD death and nonfatal MI
24%
Mixed
hyper-lipidemia
CARE CARE LIPIDCARE LIPID
%R
iskre
duc
tion
Diabetics
Clinical Benefit of PravastatinBroad Range of Patients
All risk reductions are P< 0.05 vs placebo
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* No long-term clinical trials published
Weight of Clinical Evidence
0
2,000
4,000
6,000
8,000
10,000
12,000
14,000
16,000
18,000
20,000
No.pa
tien
tsinc
lin
ica
leven
ttrials
Pravastatin Simvastatin Lovastatin Atorvastatin,
cerivastatin, and
fluvastatin
*
LIPID
9014
WOS
6595
CARE4159
4S
4444
TexCAPS
6605
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Analysis of Coronary Heart Disease
Event Reduction and Cholesterol
Reduction with Pravastatin
Observations from
Landmark Clinical Trials
MRFIT
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Martin et al: Lancet 1986;2:933936
MRFITAge-Adjusted CHD Death Rate
and Serum Cholesterol in 361,662 US Men
Serum cho lesterol (mmo l/l )
6-yr
CHDd
ea
thra
teper
1,00
0men
18
16
14
12
10
8
6
4
2
0
4 5 6 7
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Pravastatin Event Reduction Analysis
To determine the relationship between reduction in
CHD events and change in LDL-C with pravastatin
To evaluate whether LDL-C reduction aloneadequately explains the observed reduction in CHD
events
Overall Objectives
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Influence of Pravastatin and Plasma Lipids
on Clinical Events in the West of Scotland
Coronary Prevention Study (WOS)
West of Scotland
Coronary Prevention Study Group
Circulation, 1998;97:1440-1445
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WOS Results Summary
Shepherd et al: N Engl J Med. 1995;333:1301-1307
% Risk
Reduct ion
-31 -32
-37
-32
-22
-40
-30
-20
-10
0
NFMI
CABG/PTCA
Totalmortality
NFMIor
CHD Death
CVmortality
Are these impressive results seen in WOS
entirely explained by the change in LDL-C ?
All risk reductions are P 0.05 vs place
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Pravastatin Event Reduction AnalysisComponents of the WOS Analysis
Quintile Analysis
Objective: To examine the relationship between reduction in
CHD events and reduction in LDL-C levels
Overlap Analysis
Framingham Analysis
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Quintile Analysis Methods1. Rank all pravastatin subjects on the basis of percent change in LDL-C
2. Divide group into quintiles of equal subject numbers (n 500/quintile)
3. Derive Kaplan-Meier risk of cardiac event for each quintile
1 2 3 4 5Quintile
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Baseline LDL-C
On-treatment LDL-C
4.4 Yr
CHD Event
Rate (%)
Mean % LDL-C Reduct io n
4.9 4.9 5.0 5.0 5.1
4.9 4.3 3.7 3.4 3.0
Circulation, 1998; 97:1440-1445
Quintile AnalysisResults
0
2.5
5.0
7.5
10.0
0% 12% 24% 31% 39%
n 500/quintile
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Quintile AnalysisResults
LDL-C lowering was an important contributor to CHD
event reduction with pravastatin in WOS
Maximum risk reduction (~45%) occurred inpravastatin-treated subjects whether the LDL-C was
decreased by 25% or by 40% or more
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Pravastatin Event Reduction Analysis
Components of the WOS Analysis
Quintile Analysis
Overlap Analysis
Objective:To determine whether subjects on
placebo or pravastatin therapy who had similar
LDL-C levels had similar CHD risk
Framingham Analysis
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On-treatment LDL -C (mmo l/l)
Overlap Analysis: Methods
2
4
6
8
10
12
14
0
Pravastatin
Placebo
Percen
tage
ofpa
tien
ts
65432
Adapted from WOS Group: Circulation 1998;97:14401445
Overlap
(3.6 - 4.6 mmol/l)
Overlap Analysis Results
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9.6%
6.3%
0
2
4
6
8
10
12
PlaceboMean LDL-C, 4.38 mmol/l
PravastatinMean LDL-C, 4.10 mmol/l
36% lower risk(P=0.014)*
*Adjusted for risk factors
4.4-yre
ven
tra
tes
(%)
WOS Group: Circulation 1998;97:14401445
Overlap AnalysisResultsPravastatin subjects with similar LDL-C levels had lower ris
LDL-C range, 3.64.6 mmol/l
(n=2191)
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Overlap AnalysisResults
Pravastatin subjects had a 36% lower event rate
compared to placebo subjects with similar LDL-C
levels(P=0.014)
Analysis of different LDL-C ranges of overlapsupported the same conclusion
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Pravastatin Event Reduction Analysis
Components of the WOS Analysis
Quintile Analysis
Overlap Analysis
Framingham Analysis Objective:To compare on-treatment event rates
for WOS to the event rates predicted by the
Framingham model
Framingham Analysis Results
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Framingham AnalysisResultsPredicted vs Actual CHD Event Rate in WOS
Circulation, 1998; 97:1440-1445
0
2
4
6
8
10
12
14
Quintiles of Predicted Framingham Risk
P= 0.58
1 2 3 4 5
Observed
Predicted
P= 0.026
1 2 3 4 5
Observed
Predicted
Even
tRa
te(%)
Even
tRa
te(%)
0
2
4
6
8
10
12
14
Placebo Group Pravastatin Group
Framingham Analysis Results
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WOS Group: Circulation 1998;97:14401445
*Based on lipid changes achieved by pravastatinNonfatal MI, CHD death, CABG, PTCA
%R
iskre
duct
ion
Predicted* Actual
40
30
20
10
0
24%
35%
Framingham AnalysisResultsRisk reduction with pravastatin was greater than predicted
P= 0.026
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Framingham AnalysisResults
When event rates in WOS were compared to those
predicted by Framingham, subjects on pravastatin
therapy had greater risk reduction than predictedfrom lipid changes
Circulation, 1998; 97:1440-1445
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Relationship Between Plasma LDL
Concentrations During Treatment withPravastatin and Recurrent Coronary Events in
the CARE Trial
Frank M. Sacks, Lemuel A. Moye, Barry R. Davis,
Thomas G. Cole, Jean L. Rouleau, David Nash,Marc A. Pfeffer, Eugene Braunwald
for the CARE Investigators
Circulation, 1998;97:1446-1452
CARE R lt S
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CARE Results SummaryRisk Reduction with Pravastatin Therapy
Sacks et al: N Engl J Med 1996;335.
% Risk
Reduct ion
CHDDeath
orNonfatal
MI
*
-24 CHDDeath
-20
Fatal MI
-37
NonfatalMI*
-23CABG
*
-26 PTCA*
-23UnstableAngina
-13
Stroke*
-31
-10
-20
-30
-40
0
* p < 0.05 vs. placebo
P t ti T t t A l i R lt
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*CHD death, nonfatal MI, CABG / PTCA
Pravastatin Treatment AnalysisResultsPravastatin Treatment Group CARE
Circulation, 1998;97:1446-1452
0.0
0.2
0.4
0.6
0.8
1.0
1.2
Fol low-up LDL-C (mm ol/ l)
Relative
Risk
of an
Event*
( )
2 2.5 3 3.5
Decile #
Median follow-up LDL-C
% LDL-C decrease
1
1.8
43
2
2.0
38
3
2.2
35
4
2.3
33
5
2.4
31
6
2.5
30
7
2.7
26
8
2.8
25
9
3.0
21
10
3.5
9
P i T A l i R l
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Pravastatin Treatment AnalysisResultsCARE: CHD Events and Achieved LDL-C
The relationship between follow-up LDL-C levels andcoronary events was not linear
Maximal benefit was observed when LDL-C was loweredto the range of 1.8 - 3.2 mmol/l
90% of subjects in the pravastatin group achieved this
maximal benefit
Pravastatin Event Reduction Analysis
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y
Consistent Results from Two Independent trials,
WOS and CARE:
The relationship between CHD risk and LDL-Cconcentration was found to be nonlinear
The absolute or the percent LDL-C reduction did notpredict the event rate
Maximum risk reduction (~45%) occurred in pravastatinsubjects whether the LDL-C was decreased by 25% or by40% or more
Pravastatin Event Reduction Analysis
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Pravastatin Event Reduction AnalysisImplications
Epidemiology does not fully explain the results oftreatment
Extreme LDL-C reductions may not be necessary
with pravastatin treatment
Additional mechanisms beyond LDL-C lowering may
account for some of the benefit with pravastatin
LDL-C changes alone do not explain the full benefit
of pravastatin therapy
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Additional Mechanisms for Coronary
Event Reduction
Plaque stabilisation
Reduced thrombus formation Anti-inflammatory effects
A h l i I l M Th J Li id
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Atherosclerosis Involves More Than Just Lipids
Thrombus
FibrousCap
Lipid
Core
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Thin
Fibrous Cap
InflammatoryCells
Few
SMCs
Unstable plaque
Eroded
Endothelium
Activated
Macrophages
Thick
Fibrous Cap
Lack of
InflammatoryCells
Foam Cells
Intact
Endothelium
More
SMCs
Stable plaqueAdapted from Libby: Circulation. 1995;91:2844-2850.
Atherosclerosis Involves More Than Just Lipids
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Most MIs Arise From Smaller Stenoses
68%
18%14%
0
10
30
50
70
70%
% Stenosis
MIpa
tien
ts(%)
Falk et al: Circulation 1995;92:657671
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Rosenson et al: JAMA 1998;279:16431650
Atherosclerosis Involves More Than Just Lipids:
Effects of Statins
Common to all statins
Lipid modification
Lipoprotein oxidation
Endothelial function
Differences among statins
Effect on smooth muscle cells
Effect on inflammation?
Effect on platelet thrombus
formation?
Eff t f P t ti
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Effects of Pravastatin
Effects on lipids Additional mechanisms
Pravastatin 40 mg*:
TC-25%, LDL -34%
TG-24%, HDL+12%
Effects on atherosclerosis
Reduction cardiovascular morbidity/mortality
(including MI and stroke)
No inhibition SMCs
Reduced thrombus formation
Anti-inflammatory effects
*Jones: Clin Cardiol 1991;14:146-151
Effects of Pravastatin On Plaque
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Crisby et al: The Lancet Conference. The Challenge of Stroke, October 1998.
Parameter
Lipid Content
Oxidized LDL
Macrophages #
T-cells #Cell Death
Smooth Muscle Cells #
* Carotid endarterectomy samples
following 3 months pravastatin therapy
P value
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Smooth Muscle Cells Foster Plaque Stability
Smooth Muscle Cells:
Strengthen the fibrous cap
Regulate synthesis of interstitial collagen
Are involved in the healing process after plaque rupture
Lafont A., Libby P.: J Am Coll Cardiol 1998;32:283-285
Eff t f St ti S th M l C ll
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37.6
Drug concentration required to inhibit 25% of
human smooth muscle cell proliferation in vitro40
0
1
2
3
4
Cerivastatin Fluvastatin LovastatinSimvastatin Atorvastatin
1.0
0.20.4
0.02
0.8IC25
(mo
l/L)
Adapted from Negre-Aminou et al: Biochim Biophys Acta 1997;1345:259268
Pravastatin
Effects of Statins on Smooth Muscle Cells
Pravastatin Reduces Platelet Thrombus Formation
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Adapted from Lacoste et al: Circulation 1995;92:31723177 *P< 0.05 vs baseline
Plateletthr
om
bus
forma
tion
(
m2/mm
)
Hypercholesterolemic patients (n=16)
Baseline After Pravastatin
Pravastatin Reduces Platelet Thrombus Formation
0
1
2
3
4
5
2.0*
4.8
Reduced Thrombus Formation With Pravastatin
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Lacoste et al: J Am Coll Cardiol 1996 ;27:413A
Includes ASA 325 mg/d
*P< 0.05 vs baselineP< 0.05 vs simvastatin
Plateletthrom
bus
forma
tion
(
m2/mm
)
2.0
1.0*
2.12.0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Pravastatin Simvastatin
Baseline Treatment Baseline Treatment
educed o bus o o W v sbut not with Simvastatin
(n=16) (n=16)
Effects of Statins on Inflammation
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Ridker et al: Circulation. 1998;98:839-844.
Effects of Statins on Inflammation
Inflammation is associated with initiation and
progression of atherosclerosis
Markers of inflammation have been shown to
predict risk of vascular events
Preventive agents may have differential effects
on inflammation
CARE: Pravastatin Reduces Risk Posed by Inflammati
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0
1
2
3
Re
lativeris
ko
faneven
t
Inflammation Absent Inflammation Present
( CRP and SAA)
Ptrend = 0.005
Ridker et al: Circulation 1998;98:839844
P= 0.007
CARE: Pravastatin Reduces Risk Posed by Inflammati
Pravastatin Placebo Pravastatin Placebo
Inflammation, Pravastatin and Events
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Ridker et al: Circulation. 1998;98:839-844.
,
Conclusion
Evidence of inflammation after MI is
associated with increased risk of recurrent
coronary events
The effect of inflammation on coronary risk may belowered by pravastatin therapy
. . . the efficacy of pravastatin may result in part from
anti-inflammatory as well as lipid-lowering properties . . .
The Complexity of Atherosclerosis:Beyond Cholesterol Lowering
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Beyond Cholesterol LoweringConclusions
Apart from lipid modification, other mechanisms
may play a role in the net benefits of statin therapy
Statins may differ in their effect on:
Smooth muscle cells Platelet thrombus formation
Inflammation
Others
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Since the nonlipid properties of statins differdespite comparable LDL cholesterol level
lowering, the net clinical eff icacy of these
agents requires validation by randomised
clinical trials.
Rosenson: JAMA 1998; 279 : 1643-1650