wos care lipid

7/28/2019 Wos Care Lipid

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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


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


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



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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



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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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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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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



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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



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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

wos care lipid

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