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

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