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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