The Prospective Pravastatin Pooling Project L I P I D CARECARE PPP Project Investigators Am J Cardiol 1995; 76:899–905.

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Presentation transcript:

The Prospective Pravastatin Pooling Project L I P I D CARECARE PPP Project Investigators Am J Cardiol 1995; 76:899–905

WOSCOPS Study Design Males aged 45–64 years with total-C  252 mg/dl and no prior MI Diet therapy x 4 weeks LDL-C  155 mg/dl on visits 2 and 3 and  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) History of hypertension (%)15 16 Current cigarette smoker (%)35 35 Shepherd et al. N Engl J Med. 1995;333:1301–07. Placebo Pravastatin (n = 3293) (n = 3302)

Early Benefit with Pravastatin in WOSCOPS: Myocardial Infarction* Shepherd et al. N Engl J Med. 1995;333:1301– Percent with Event Years 456 Pravastatin (n = 3302) Placebo (n = 3293) 31% risk reduction P < * Primary endpoint: Non-fatal MI and CHD death

Early Benefit with Pravastatin in WOSCOPS: Cardiovascular Mortality Shepherd et al. N Engl J Med. 1995;333:1301– Years Percent with Event % risk reduction P = Pravastatin (n = 3302) Placebo (n = 3293)

Benefit with Pravastatin in WOSCOPS: Total Mortality Shepherd et al. N Engl J Med. 1995;333: Percent with Event Years % risk reduction P = Pravastatin (n = 3302) Placebo (n = 3293)

CARE: Study Design Sacks et al. N Engl J Med. 1996;335:1001– Males and Females, 21–75 years of age Post-MI 3–20 months, LVEF >25% Total-C < 240 mg/dL, LDL-C mg/dL and TG < 350 mg/dL Step II diet if LDL-C > 174 mg/dL 5 years Placebo (n = 2078) Pravastatin 40 mg QD (n = 2081) Primary Endpoint: Fatal CHD or confirmed non-fatal MI Secondary endpoints: Revascularizations, combined coronary events, stroke

CARE: Baseline Characteristics Sacks et al. N Engl J Med. 1996;335:1001–09. Placebo Pravastatin Characteristic n = 2078 n = 2081 Other Medications Age (years) Women/Men (%) History of HTN (%) Diabetes (%) Total Chol. mg/dL (mean) LDL mg/dL (mean) Aspirin (%) / /86 59 Antihypertensives (%) 8282 Current Cig. Smoker (%) 21

CARE: Cardiovascular Events: Reduction of Relative Risk Sacks et al. N Engl J Med. 1996;335:1001–09. % Risk Reduction CHD Death or Non-fatal MI * CHD Death Fatal MI Non-fatal MI * CABG * PTCA * Unstable Angina Stroke * * p < % -20% -37% -23% -26% -23% -13% -31%

CARE: Stroke and Stroke/TIA StrokeStroke/TIA Relative Risk RiskReduction p = p = % -26% Sacks et al. N Engl J Med. 1996;335:1001–09. Revised Pravastatin Package Insert. Indications and Usage. March % Aspirin Use 82% Use of Antihypertensives

Long-term Intervention with Pravastatin Ischemic Disease (LIPID) Trial Design Males & females aged 31–75 years with average cholesterol and 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) Pravastatin 40 mg QD (n = 4512) The LIPID Study Group. Am J Cardiol. 1995;76:474–79. Primary : Coronary mortality Primary endpoint: Coronary mortality Secondary endpoints: Total mortality, nonfatal MI & CHD death, stroke etc.

LIPID: Baseline Characteristics The LIPID Study Group. Am J Cardiol. 1995;76:474–79. PlaceboPravastatin Characteristic n = 4502 n = 4512 Other Medication Use Age (years) Women/Men (%) History of HTN (%) Current Cig. Smoker (%) Diabetes (%) Total Chol. mg/dL (mean) LDL mg/dL (mean) Aspirin (%) / /83 62

Years Since Randomization % 5% 10% Cumulative Risk p = Placebo Pravastatin 24% reduction CHD Mortality LIPID: Total & CHD LIPID: Total & CHD Mortality Total Mortality Years Since Randomization % 5% 15% Cumulative Risk p = Placebo Pravastatin 23% reduction 10% The LIPID Study Group. N Engl J Med. 1998;339:1349–57.

LIPID: Total Stroke Years since randomization 0% 2% 4% 6% Cumulative Risk Placebo (n = 4502) Pravastatin (n = 4512) 19% risk reduction p = The LIPID Study Group. N Engl J Med. 1998;339:1349–57.

Benefit of Pravastatin in Reducing Stroke CARELIPIDRelative Risk RiskReduction p = p = 0.03 In both trials, stroke was a pre-specified endpoint and 83% of all pravastatin patients received aspirin. -31% -19% Sacks et al. N Engl J Med. 1996;335:1001–09. Tonkin et al. ACC, March 1998.

CARE(U.S./Canada) 4159 M&F Age: 21–75 100% MI WOSCOPS(Scotland) 6595 Males Age: 45–64 5% Angina 0% MI LIPID (Australia /N. Zealand) 9014 M&F Age: 31–75 64% MI 36% Unstable Angina 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 statusNo CHDMI WOSCOPS (n = 6595) CARE (n = 4159) MI, unstable angina LIPID (N=9014) LIPID (n = 9014) Age (years) Mean Upper limit Men100%86%83% Diabetes1%14%9% Hypertension16%43%42% Smokers35%16%10%

Prospective Pravastatin Pooling Project: Baseline Lipids Lipids (mg/dL) WOSCOPS (n = 6595) CARE (n = 4159) LIPID (N=9014) LIPID (n = 9014) Total cholesterol Limits Mean > < – LDL cholesterol Limits Mean 174– – None 150 HDL cholesterol Mean Triglycerides Limits Mean < < <

% (P<0.001) 12% (P=0.1) 17% (P=0.25) Relative Risk Reduction (%) CHD Mortality Other Vascular Mortality Non-CVD Mortality Prospective Pravastatin Pooling Project: Mortality Simes et al. Eur Heart J. 2002;23:207–15. 20% (P<0.001) Total Mortality 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) % (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) EventRate (%) * (%) * * 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 Project Extent of Exposure to Study Medication Number of subjects receiving at least 1 dose of study medication Pravastatin 40 mg n = 9809 Placebo n = 9783 Extent of Exposure to Study Medication (Years) Mean + SD Median Min (days) Max Mean + SD Median Min (days) Max

Number of Subjects Years of Exposure The Prospective Pravastatin Pooling Project Extent of Exposure to Study Medication Pfeffer MA et al. European Heart J 2001;22:271. PravastatinPlacebo

The Prospective Pravastatin Pooling Project Common Serious Adverse Events (Non-CV) Modified from Pfeffer et al. Circulation 2002;105:r95–r100. 5% 10% 15%20%UrologicProc. MuscularPain Inv. GI Proc. Ortho.SurgProstateDisorderAbd.Surg Hernia DermNeopl.DermProc.PulmInfect. Gall Bl Disorder EyeSurgLensOpacity Musculo- Skel Abn. PUD Reprod.NeoplasmBoneFx Gall Bl. SurgPlaceboPravastatin

The Prospective Pravastatin Pooling Project Incidence of Cancer by Treatment Group Pfeffer MA Data on File Treatment Group PlaceboPravastatinTotal Fatal Cancer 221 (2.3%) 234 (2.4%) 455 (2.3%) Any Cancer 946 (9.6%) 946 (9.6%) 914 (9.3%) 914 (9.3%) 1860 (9.5%)

The Prospective Pravastatin Pooling Project Site Specific Incidence of Primary Cancer Pfeffer MA et al. European Heart J 2001;22:271. PlaceboPravastatin HematDermGIEndoHep Musc - Skel RenalResp General Neuro Special Senses Any Ca Pravastatin 9.3% Placebo 9.6% 0 5% 3% 4% 2% 1%

The Prospective Pravastatin Pooling Project Total Number of AST and ALT Measurements Taken at Baseline and Post Baseline Total Number of Measurements Number of Subjects with Laboratory Measurements Mean Number of Measurements per Subject AST 154,431 Overall 11, ,685 Pravastatin ,746 Placebo ALT 243,506 Overall 18, ,193 Pravastatin ,313 Placebo Pfeffer MA et al. European Heart J 2001;22:271.

Pravastatin Placebo 95% CI Pravastatin Placebo 95% CI Any Elevated ALT 804 / 9185 (8.8%) 746 / 9152 (8.2%) -0.21, 1.42 > < 3 X ULN 676 (7.4%) 615 (6.7%) -0.11, 1.39 > < 5 X ULN 84 (0.9%)90 (1.0%) -0.36, 1.39 > < 7 X ULN 24 (0.3%)19 (0.2%) -0.10, 0.21 > < 9 X ULN6 (<0.1) 9 (<0.1%) -0.13, 0.06 > 9 X ULN 14 (0.2%)13 (0.1%) -0.11, 0.13 Any Elevated ALT 804 / 9185 (8.8%) 746 / 9152 (8.2%) -0.21, 1.42 > < 3 X ULN 676 (7.4%) 615 (6.7%) -0.11, 1.39 > < 5 X ULN 84 (0.9%)90 (1.0%) -0.36, 1.39 > < 7 X ULN 24 (0.3%)19 (0.2%) -0.10, 0.21 > < 9 X ULN6 (<0.1) 9 (<0.1%) -0.13, 0.06 > 9 X ULN 14 (0.2%)13 (0.1%) -0.11, 0.13 The Prospective Pravastatin Pooling Project Post Baseline Elevations in ALT Pfeffer MA et al. European Heart J 2001;22:271.

The Prospective Pravastatin Pooling Project: Incidence of Post-baseline ALT Abnormalities In 579 Subjects With Abnormal Baseline ALTALT > 1.5 X ULN > 3 X ULN Pravastatin 127 / 317 (40.1%) 16 / 317 (5.0%) Placebo 101 / 262 (38.5%) 19 / 262 (7.3%) Pfeffer MA et al. European Heart J ;22:271. Pfeffer MA et al. European Heart J 2001;22:271.

The Prospective Pravastatin Pooling Project: Total Number of CPK Measurements Taken at Baseline and Post Baseline Total Number of Measurements Number of Subjects with Laboratory Measurements Mean Number of Measurements per Subject CPK 1 126,370Overall10, ,452Pravastatin ,918Placebo LIPID does not include CORE Lab CPK Pfeffer MA et al. European Heart J 2001;22:271.

Pravastatin Placebo 95% CI Pravastatin Placebo 95% CI Any Elevated CPK 587 / 5245 (11.2%) 563 / 5233 (10.8%)-0.78, 1.65 > < 3 X ULN 480 (9.2%) 460 (8.8%)-0.75, 1.48 > < 5 X ULN 84 (1.6%) 79 (1.5%)-0.40, 0.59 > < 7 X ULN 8 (0.2%) 16 (0.3%)-0.36, 0.05 > < 9 X ULN 6 (0.1) 6 (0.1%)-0.15, 0.15 > 9 X ULN 9 (0.2%)2 ( 9 X ULN 9 (0.2%)2 (<0.1%)-0.02, 0.28 Any Elevated CPK 587 / 5245 (11.2%) 563 / 5233 (10.8%)-0.78, 1.65 > < 3 X ULN 480 (9.2%) 460 (8.8%)-0.75, 1.48 > < 5 X ULN 84 (1.6%) 79 (1.5%)-0.40, 0.59 > < 7 X ULN 8 (0.2%) 16 (0.3%)-0.36, 0.05 > < 9 X ULN 6 (0.1) 6 (0.1%)-0.15, 0.15 > 9 X ULN 9 (0.2%)2 ( 9 X ULN 9 (0.2%)2 (<0.1%)-0.02, 0.28 The Prospective Pravastatin Pooling Project: Post Baseline Elevations in CPK Pfeffer MA et al. European Heart J 2001;22:271.

Myotoxicity In Major Statin Trials Trial Pravastatin Pooling Project [CARE, LIPID, WOSCOPS] (n = 19,592) 4S (n = 4444) AFCAPS/TexCAPS (n = 5605) Total (n = 30,641) Farmer JA Lancet. 2001;358:1383–85. Myositis Myositis Statin Control Rhabdomyolysis Statin Control

Proportion of Subjects Still On Meds Years of Follow-up Time to Discontinuation of Study Medication Excluding Discontinuation Due to CV AEs Pravastatin ( n = 9809) Placebo (n = 9783) Pfeffer MA et al. European Heart J 2001;22:271. Placebo Pravastatin Number of Subjects < 1 Yr 1 - <2 yr 2 - <3 yr 3 - <4 yr 4 - <5 yr > 6 yr

The Prospective Pravastatin Pooling Project: Predicting Medication Discontinuation A Multivariate Cox Model Parameter Hazard Ratio p-value Treatment Group (Pravastatin) History of Diabetes Presence of CV SAE Current Smoker Gender (males) Primary/Secondary Prevention Age Pfeffer MA et al. European Heart J 2001;22:271.