the prospective pravastatin pooling project

The Prospective Pravastatin Pooling Project

L I PL I P I DI DL I PL I P I DI D

CARECARECARECARE

PPP Project Investigators Am J Cardiol 1995; 76:899–905

WOSCOPS Study Design

Males aged 45–64 years with total-C 252 mg/dland no prior MI

Diet therapy x 4 weeks

LDL-C 155 mg/dl on visits 2 and 3and 174 232 mg/dl on 1 of these visits

5 years

Placebo(n = 3293)

Pravastatin 40 mg QD(n = 3302)

Shepherd et al. N Engl J Med. 1995;333:1301–07.

WOSCOPS: Baseline Characteristics

Age at visit 1 (years) 55 55

History of MI (%) 0 0

Mean LDL-C at baseline (mg/dl) 192 192

History of hypertension (%) 15 16

Current cigarette smoker (%) 35 35


PlaceboPlacebo Pravastatin Pravastatin(n = 3293)(n = 3293) (n = 3302) (n = 3302)

Early Benefit with Pravastatin in WOSCOPS: Myocardial Infarction*


00

11

22

44

66Percent

withEvent

88

1010

1212

22 3 3

Years44 55 66

Pravastatin (n = 3302)

Placebo (n = 3293)

31% risk reduction P < 0.001

* Primary endpoint: Non-fatal MI and CHD death

Early Benefit with Pravastatin in WOSCOPS: Cardiovascular Mortality


0.00.000 11 22 33

Years

44 55 66

0.50.5

1.01.0

1.51.5

2.02.0Percent with Event

2.52.5

3.03.0

3.53.5

32% risk reduction P = 0.033


Placebo (n = 3293)

Benefit with Pravastatin in WOSCOPS: Total Mortality

Shepherd et al. N Engl J Med. 1995;333:1301-7.

00

11

11

22

33

Percentwith

Event

44

55

66

22 3 3

Years44 55 66

22% riskreductionP = 0.051


Placebo (n = 3293)

CARE: Study Design

Sacks et al. N Engl J Med. 1996;335:1001–9.

4159 Males and Females, 21–75 years of age4159 Males and Females, 21–75 years of age

Post-MI 3–20 months, LVEF >25%Post-MI 3–20 months, LVEF >25%

Total-C < 240 mg/dL, LDL-C 115-174 mg/dLTotal-C < 240 mg/dL, LDL-C 115-174 mg/dLand TG < 350 mg/dLand TG < 350 mg/dL

Step II diet if LDL-C > 174 mg/dLStep II diet if LDL-C > 174 mg/dL

5 years5 years

Placebo(n = 2078)


Primary Endpoint: Fatal CHD or confirmed non-fatal MIPrimary Endpoint: Fatal CHD or confirmed non-fatal MISecondary endpoints: Revascularizations, combined coronary Secondary endpoints: Revascularizations, combined coronary

events, stroke events, stroke

CARE: Baseline Characteristics


PlaceboPlacebo PravastatinPravastatinCharacteristicCharacteristic n = 2078n = 2078 n = 2081n = 2081

Other MedicationsOther Medications

Age (years)Age (years)

Women/Men (%)Women/Men (%)

History of HTN (%)History of HTN (%)

Diabetes (%)Diabetes (%)

Total Chol. mg/dL (mean)Total Chol. mg/dL (mean)

LDL mg/dL (mean)LDL mg/dL (mean)

Aspirin (%)Aspirin (%)

4343

1515

14/8614/86

5959

209209

139139

8383 8383

139139

209209

1414

4242

14/8614/86

5959

Antihypertensives (%)Antihypertensives (%) 8282 8282

Current Cig. Smoker (%) 21 21

CARE: Cardiovascular Events: Reduction of Relative Risk


% Risk% RiskReductionReduction

CHDDeath

orNon-fatal

MI*

CHDDeath

Fatal MI

Non-fatalMI*

CABG*

PTCA*

UnstableAngina

Stroke*

-10

-20

-30

-40

0

* p < 0.05* p < 0.05

-24%

-20%

-37%

-23%-26%

-23%

-13%

-31%

CARE: Stroke and Stroke/TIA

-40

-30

-20

-10

0StrokeStroke Stroke/TIAStroke/TIA

RelativeRelative Risk Risk

ReductionReduction

p = 0.029

p = 0.03

-31%-26%

Sacks et al. N Engl J Med. 1996;335:1001–09.Revised Pravastatin Package Insert. Indications and Usage. March 1998.

• 83% Aspirin Use

• 82% Use of Antihypertensives

Long-term Intervention with Pravastatin Ischemic Disease (LIPID) Trial Design

Males & females aged 31–75 years with average cholesteroland a prior history of acute MI or unstable angina

Diet therapy x 8 weeks

Total cholesterol between 155–271 mg/dl,Triglycerides

< 445 mg/dl, stratified by Diagnosis

6.0 years

Placebo(n = 4502)


The LIPID Study Group. Am J Cardiol. 1995;76:474–79.

Primary Primary endpoint: Coronary mortality : Coronary mortality

Secondary endpoints: Total mortality, nonfatal MI & CHD death, stroke etc.Secondary endpoints: Total mortality, nonfatal MI & CHD death, stroke etc.

LIPID: Baseline Characteristics

The LIPID Study Group. Am J Cardiol. 1995;76:474–79.

PlaceboPlacebo PravastatinPravastatinCharacteristicCharacteristic n = 4502n = 4502 n = 4512n = 4512

Other Medication UseOther Medication Use

Age (years)Age (years)

Women/Men (%)Women/Men (%)

History of HTN (%)History of HTN (%)

Current Cig. Smoker (%)Current Cig. Smoker (%)

Diabetes (%)Diabetes (%)

Total Chol. mg/dL Total Chol. mg/dL (mean)(mean)

LDL mg/dL LDL mg/dL (mean)(mean)

Aspirin (%)Aspirin (%)

4242

991010

17/8317/836262

218218150150

8282 8383

150150218218

99994141

17/8317/836262

Years Since Randomization0 1 2 3 4 5 6 7

0%

5%

10%

Cu

mu

lati

ve R

isk

p = 0.0004 Placebo

Pravastatin

24% reduction

CHD MortalityCHD Mortality

LIPID: Total & CHD LIPID: Total & CHD Mortality

Total MortalityTotal Mortality

Years Since Randomization0 1 2 3 4 5 6 7

0%

5%

15%

Cu

mu

lati

ve R

isk

p = 0.00002

Placebo

Pravastatin

23% reduction

10%

The LIPID Study Group. N Engl J Med. 1998;339:1349–57.

LIPID: Total Stroke

0 1 2 3 4 5 6 7

Years since randomization

0%

2%

4%

6%

Cumulative Risk

Placebo (n = 4502)


19% riskreductionp = 0.048

The LIPID Study Group. N Engl J Med. 1998;339:1349–57.

Benefit of Pravastatin in Reducing Stroke

-40

-30

-20

-10

0 CARECARE LIPIDLIPID

RelativeRelative Risk Risk

ReductionReduction p = 0.048

p = 0.03

In both trials, stroke was a pre-specified endpoint and 83% of all pravastatin patients received aspirin.

-31%

-19%


Tonkin et al. ACC, March 1998.

CARECARE(U.S./Canada)(U.S./Canada)

4159 M&F4159 M&FAge: 21–75Age: 21–75

100% MI100% MI

WOSCOPSWOSCOPS(Scotland)(Scotland)6595 Males6595 MalesAge: 45–64Age: 45–645% Angina5% Angina

0% MI0% MI

LIPIDLIPID(Australia /N. Zealand)(Australia /N. Zealand)

9014 M&F9014 M&FAge: 31–75Age: 31–75

64% MI64% MI36% Unstable 36% Unstable

Angina PectorisAngina Pectoris

The PPP Investigators. Am J Cardiol. 1995;76:899–905.

Pravastatin Pooling Project (PPP)

Over 110,000 patient-years of follow-up

Prospective Pravastatin Pooling Project: Baseline Characteristics

CHD status No CHD MI

WOSCOPS(n = 6595)

CARE(n = 4159)

MI, unstable angina

LIPID(N=9014)

LIPID(n = 9014)

Age (years)MeanUpper limit

5564

5975

6175

Men 100% 86% 83%

Diabetes 1% 14% 9%

Hypertension 16% 43% 42%

Smokers 35% 16% 10%

Prospective Pravastatin PoolingProject: Baseline Lipids

Lipids(mg/dL)

WOSCOPS(n = 6595)

CARE(n = 4159)

LIPID(N=9014)

LIPID(n = 9014)

Total cholesterolLimitsMean

> 252272

< 240209

155–271219

LDL cholesterolLimitsMean

174–232192

115–174139

None150

HDL cholesterolMean 44 39 37

Triglycerides Limits

Mean< 533 162

< 350 156

< 445 159

0

10

20

30

24%(P<0.001)

12%(P=0.1)17%

(P=0.25)

RelativeRisk

Reduction(%)

CHD Mortality

OtherVascularMortality

Non-CVDMortality

Prospective Pravastatin PoolingProject: Mortality

Simes et al. Eur Heart J. 2002;23:207–15.

20%(P<0.001)

TotalMortality

CARE, LIPID, & WOSCOPS (n = 19,768)

Prospective Pravastatin Pooling Project: Population Subgroups (Expanded End Points)

Age <55(6637)

Age 55–64(8288)

Age 65–75(4843)

Men(17,676)

Women(2092)

Diabetic(1444)

Non-diabetic(18,324)

-30

-25

-20

-15

-10

-5

0

22%(P<0.001)

22%(P<0.001) 26%

(P<0.001)

23%(P<0.001) 27%

(P<0.001)

26%(P<0.002)

23%(P<0.001)

Event Event RateRate

(%) (%) **

* CHD death and non-fatal MI, PTCA, CABG, stroke; 4131 patients with events

Sacks et al. Circulation. 1999;100:I–238.

The Prospective Pravastatin Pooling ProjectExtent of Exposure to Study Medication

Number of subjects receiving atNumber of subjects receiving atleast 1 dose of study medicationleast 1 dose of study medicationNumber of subjects receiving atNumber of subjects receiving atleast 1 dose of study medicationleast 1 dose of study medication

PravastatinPravastatin40 mg40 mg

n = 9809n = 9809

PlaceboPlacebo

n = 9783n = 9783

Extent of Exposure to Study Medication Extent of Exposure to Study Medication (Years)(Years)

Mean Mean ++ SD SD

MedianMedian

Min (days)Min (days)

MaxMax

Mean Mean ++ SD SD

MedianMedian

Min (days)Min (days)

MaxMax

4.6 4.6 ++ 1.7 1.7

5.0

11

7.17.1

4.6 4.6 ++ 1.7 1.7

5.0

11

7.17.1

4.5 4.5 ++ 1.8 1.8

5.05.0

11

7.17.1

4.5 4.5 ++ 1.8 1.8

5.05.0

11

7.17.1

755

431 339579

2227

3488

1690

826

538 449710

2465

3322

1473

0

1000

2000

3000

4000

< 1 1 - < 2 2 - < 3 3 - < 4 4 - < 5 5 - < 6 > 6

Num

ber

of S

ubje

cts

Num

ber

of S

ubje

cts

Years of ExposureYears of Exposure

The Prospective Pravastatin Pooling Project Extent of Exposure to Study Medication

Pfeffer MA et al. Pfeffer MA et al. European Heart JEuropean Heart J 2001;22:271. 2001;22:271.

PravastatinPravastatin PlaceboPlacebo

The Prospective Pravastatin Pooling ProjectCommon Serious Adverse Events (Non-CV)

Modified from Pfeffer et al. Modified from Pfeffer et al. Circulation Circulation 2002;105:r95–r100. 2002;105:r95–r100.

5%5%

10%10%

15%15%

20%20%

UrologicUrologicProc.Proc.

UrologicUrologicProc.Proc.

MuscularMuscularPainPain

MuscularMuscularPainPain

Inv. GIInv. GIProc.Proc.

Inv. GIInv. GIProc.Proc.

Ortho.Ortho.SurgSurg

Ortho.Ortho.SurgSurg

ProstateProstateDisorderDisorderProstateProstateDisorderDisorder

Abd.Abd.SurgSurgAbd.Abd.SurgSurg

HerniaHerniaHerniaHernia DermDermNeopl.Neopl.DermDermNeopl.Neopl.

DermDermProc.Proc.DermDermProc.Proc.

PulmPulmInfect.Infect.PulmPulmInfect.Infect.

Gall BlGall BlDisorderDisorderGall BlGall Bl

DisorderDisorder

EyeEyeSurgSurgEyeEyeSurgSurg

LensLensOpacityOpacity

LensLensOpacityOpacity

Musculo-Musculo-Skel Abn.Skel Abn.Musculo-Musculo-Skel Abn.Skel Abn.

PUDPUDPUDPUD

Reprod.Reprod.NeoplasmNeoplasmReprod.Reprod.

NeoplasmNeoplasmBoneBone

FxFxBoneBone

FxFxGall Bl.Gall Bl.

SurgSurgGall Bl.Gall Bl.

SurgSurg

PlaceboPlaceboPravastatinPravastatin

The Prospective Pravastatin Pooling ProjectIncidence of Cancer by Treatment Group

Pfeffer MA Data on FilePfeffer MA Data on File

Treatment GroupTreatment Group

PlaceboPlacebo

PravastatinPravastatin

TotalTotal

Fatal CancerFatal Cancer

221 (2.3%)221 (2.3%)

234 (2.4%)234 (2.4%)

455 (2.3%)455 (2.3%)

Any CancerAny Cancer

946 (9.6%)946 (9.6%)

914 (9.3%)914 (9.3%)

1860 (9.5%)1860 (9.5%)

The Prospective Pravastatin Pooling ProjectSite Specific Incidence of Primary Cancer


PlaceboPravastatin

HematDerm GI Endo Hep Musc- Skel

Renal Resp General Neuro SpecialSenses

Any CaPravastatin 9.3%

Placebo 9.6%

0

5%

3%

4%

2%

1%

The Prospective Pravastatin Pooling ProjectTotal Number of AST and ALT Measurements Taken at

Baseline and Post Baseline

Total Numberof Measurements

Number of Subjects with Laboratory Measurements

Mean Number ofMeasurements

per Subject

AST

154,431Overall 11,704 13.2

77,685Pravastatin 5852 13.3

76,746Placebo 5852 13.1

ALT

243,506Overall 18,637 13.1

123,193Pravastatin 9338 13.2

120,313Placebo 9299 12.9


PravastatinPravastatin Placebo Placebo 95% 95% CICIAny Elevated ALT 804 / 9185 Any Elevated ALT 804 / 9185 (8.8%) (8.8%) 746 / 9152 746 / 9152 (8.2%)(8.2%) -0.21, 1.42 -0.21, 1.42

> 1.5 - > 1.5 - << 3 X ULN 3 X ULN 676 676 (7.4%)(7.4%) 615 615 (6.7%)(6.7%) -0.11, 1.39 -0.11, 1.39

> 3 - > 3 - < < 5 X ULN 5 X ULN 84 84 (0.9%)(0.9%) 90 90 (1.0%)(1.0%) -0.36, 1.39 -0.36, 1.39

> 5 - > 5 - < < 7 X ULN 7 X ULN 24 24 (0.3%)(0.3%) 19 19 (0.2%)(0.2%) -0.10, 0.21 -0.10, 0.21

> 7 - > 7 - < < 9 X ULN9 X ULN 6 6 (<0.1) (<0.1) 9 9 (<0.1%)(<0.1%) -0.13, 0.06 -0.13, 0.06

> 9 X ULN > 9 X ULN 14 14 (0.2%)(0.2%) 13 13 (0.1%)(0.1%) -0.11, 0.13 -0.11, 0.13

Any Elevated ALT 804 / 9185 Any Elevated ALT 804 / 9185 (8.8%) (8.8%) 746 / 9152 746 / 9152 (8.2%)(8.2%) -0.21, 1.42 -0.21, 1.42

> 1.5 - > 1.5 - << 3 X ULN 3 X ULN 676 676 (7.4%)(7.4%) 615 615 (6.7%)(6.7%) -0.11, 1.39 -0.11, 1.39

> 3 - > 3 - < < 5 X ULN 5 X ULN 84 84 (0.9%)(0.9%) 90 90 (1.0%)(1.0%) -0.36, 1.39 -0.36, 1.39

> 5 - > 5 - < < 7 X ULN 7 X ULN 24 24 (0.3%)(0.3%) 19 19 (0.2%)(0.2%) -0.10, 0.21 -0.10, 0.21

> 7 - > 7 - < < 9 X ULN9 X ULN 6 6 (<0.1) (<0.1) 9 9 (<0.1%)(<0.1%) -0.13, 0.06 -0.13, 0.06

> 9 X ULN > 9 X ULN 14 14 (0.2%)(0.2%) 13 13 (0.1%)(0.1%) -0.11, 0.13 -0.11, 0.13

The Prospective Pravastatin Pooling ProjectPost Baseline Elevations in ALT


The Prospective Pravastatin Pooling Project: Total Number of CPK MeasurementsTaken at Baseline and Post Baseline

Total Numberof Measurements

Number of Subjects with Laboratory Measurements

Mean Numberof Measurements

per Subject

CPK1

126,370Overall 10,576 11.9

63,452Pravastatin 5295 12.0

62,918Placebo 5281 11.9

LIPID does not include CORE Lab CPK Pfeffer MA et al. Pfeffer MA et al. European Heart JEuropean Heart J 2001;22:271. 2001;22:271.

Pravastatin Placebo 95% CIPravastatin Placebo 95% CI

Any Elevated CPK 587 / 5245 Any Elevated CPK 587 / 5245 (11.2%) (11.2%) 563 / 5233 563 / 5233 (10.8%)(10.8%) -0.78, 1.65-0.78, 1.65

> 1.5 - > 1.5 - << 3 X ULN 3 X ULN 480 480 (9.2%)(9.2%) 460 460 (8.8%)(8.8%) -0.75, 1.48-0.75, 1.48

> 3 - > 3 - < < 5 X ULN 5 X ULN 84 84 (1.6%)(1.6%) 79 79 (1.5%)(1.5%) -0.40, 0.59-0.40, 0.59

> 5 - > 5 - < < 7 X ULN 7 X ULN 8 8 (0.2%)(0.2%) 16 16 (0.3%)(0.3%) -0.36, 0.05-0.36, 0.05

> 7 - > 7 - < < 9 X ULN 9 X ULN 6 6 (0.1) (0.1) 6 6 (0.1%)(0.1%) -0.15, 0.15-0.15, 0.15

> 9 X ULN > 9 X ULN 9 9 (0.2%)(0.2%) 2 2 (<0.1%)(<0.1%) -0.02, 0.28-0.02, 0.28

Any Elevated CPK 587 / 5245 Any Elevated CPK 587 / 5245 (11.2%) (11.2%) 563 / 5233 563 / 5233 (10.8%)(10.8%) -0.78, 1.65-0.78, 1.65

> 1.5 - > 1.5 - << 3 X ULN 3 X ULN 480 480 (9.2%)(9.2%) 460 460 (8.8%)(8.8%) -0.75, 1.48-0.75, 1.48

> 3 - > 3 - < < 5 X ULN 5 X ULN 84 84 (1.6%)(1.6%) 79 79 (1.5%)(1.5%) -0.40, 0.59-0.40, 0.59

> 5 - > 5 - < < 7 X ULN 7 X ULN 8 8 (0.2%)(0.2%) 16 16 (0.3%)(0.3%) -0.36, 0.05-0.36, 0.05

> 7 - > 7 - < < 9 X ULN 9 X ULN 6 6 (0.1) (0.1) 6 6 (0.1%)(0.1%) -0.15, 0.15-0.15, 0.15

> 9 X ULN > 9 X ULN 9 9 (0.2%)(0.2%) 2 2 (<0.1%)(<0.1%) -0.02, 0.28-0.02, 0.28

The Prospective Pravastatin Pooling Project:Post Baseline Elevations in CPK


Myotoxicity In Major Statin Trials

TrialTrial

Pravastatin Pooling ProjectPravastatin Pooling Project[CARE, LIPID, WOSCOPS][CARE, LIPID, WOSCOPS](n = 19,592)(n = 19,592)

4S (n = 4444)4S (n = 4444)

AFCAPS/TexCAPS AFCAPS/TexCAPS (n = 5605)(n = 5605)

Total (n = 30,641)Total (n = 30,641)

Farmer JA Lancet. 2001;358:1383–85.

MyositisMyositisStatinStatin ControlControl

33 7 7

66 1 1

21 21 21 21

3030 39 39

RhabdomyolysisRhabdomyolysisStatinStatin ControlControl

00 0 0

11 0 0

1 1 2 2

22 2 2

Proportion Proportion of Subjectsof Subjects

Still On Still On MedsMeds

0.0

0.2

0.4

0.6

0.8

1.0

2 3 4 5 6 71Years of Follow-upYears of Follow-up

Time to Discontinuation of Study MedicationExcluding Discontinuation Due to CV AEs

Pravastatin( n = 9809)

Placebo(n = 9783)


PlaceboPlacebo

PravastatinPravastatin

538538

431431

439439

339339

755755

826826

710710

579579

24652465

25272527

33223322

34883488

14731473

16901690

Number of SubjectsNumber of Subjects

< 1 Yr< 1 Yr 1 - <2 yr1 - <2 yr 2 - <3 yr2 - <3 yr 3 - <4 yr3 - <4 yr 4 - <5 yr4 - <5 yr 4 - <5 yr4 - <5 yr > 6 yr> 6 yr

The Prospective Pravastatin Pooling Project:Predicting Medication Discontinuation

A Multivariate Cox Model

ParameterParameter Hazard Ratio Hazard Ratio p-value p-value

Treatment Group (Pravastatin)Treatment Group (Pravastatin) 0.690.69 0.00010.0001

History of DiabetesHistory of Diabetes 1.341.34 0.00010.0001

Presence of CV SAEPresence of CV SAE 0.760.76 0.00010.0001

Current SmokerCurrent Smoker 1.251.25 0.00010.0001

Gender (males)Gender (males) 0.830.83 0.00010.0001

Primary/Secondary PreventionPrimary/Secondary Prevention 1.151.15 0.00420.0042

AgeAge 1.001.00 0.47180.4718


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