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The Prospective Pravastatin Pooling Project

CARE. L I P I D. The Prospective Pravastatin Pooling Project. 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.

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The Prospective Pravastatin Pooling Project

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

  2. 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 Placebo(n = 3293) Pravastatin 40 mg QD(n = 3302) 5 years Shepherd et al. N Engl J Med. 1995;333:1301–07.

  3. 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 Placebo Pravastatin (n = 3293) (n = 3302) Shepherd et al. N Engl J Med. 1995;333:1301–07.

  4. Early Benefit with Pravastatin in WOSCOPS: Myocardial Infarction* 12 10 31% risk reduction 8 Placebo (n = 3293) Percent P < 0.001 with 6 Event 4 Pravastatin (n = 3302) 2 0 1 2 3 4 5 6 Years * Primary endpoint: Non-fatal MI and CHD death Shepherd et al. N Engl J Med. 1995;333:1301–07.

  5. Early Benefit with Pravastatin in WOSCOPS: Cardiovascular Mortality 3.5 3.0 32% risk reduction 2.5 P = 0.033 Percent Placebo (n = 3293) 2.0 with 1.5 Event 1.0 Pravastatin (n = 3302) 0.5 0.0 0 1 2 3 4 5 6 Years Shepherd et al. N Engl J Med. 1995;333:1301–07.

  6. Benefit with Pravastatin in WOSCOPS: Total Mortality 6 22% risk reduction P = 0.051 5 4 Placebo (n = 3293) Percent with 3 Event 2 Pravastatin (n = 3302) 1 0 1 2 3 4 5 6 Years Shepherd et al. N Engl J Med. 1995;333:1301-7.

  7. CARE: Study Design 4159 Males and Females, 21–75 years of age Post-MI 3–20 months, LVEF >25% Total-C < 240 mg/dL, LDL-C 115-174 mg/dLand TG < 350 mg/dL Placebo(n = 2078) Pravastatin 40 mg QD(n = 2081) Step II diet if LDL-C > 174 mg/dL 5 years Primary Endpoint: Fatal CHD or confirmed non-fatal MI Secondary endpoints: Revascularizations, combined coronary events, stroke Sacks et al. N Engl J Med. 1996;335:1001–9.

  8. CARE: Baseline Characteristics Placebo Pravastatin Characteristic n = 2078 n = 2081 Age (years) 59 59 14/86 14/86 Women/Men (%) 43 42 History of HTN (%) Current Cig. Smoker (%) 21 21 15 14 Diabetes (%) 209 209 Total Chol. mg/dL (mean) LDL mg/dL (mean) 139 139 Other Medications 83 83 Aspirin (%) Antihypertensives (%) 82 82 Sacks et al. N Engl J Med. 1996;335:1001–09.

  9. 0 -10 -20 -30 -40 CARE: Cardiovascular Events: Reduction of Relative Risk -13% UnstableAngina % RiskReduction -20% -23% -23% -24% CHDDeath -26% Non-fatalMI* PTCA* CHDDeathorNon-fatalMI* -31% CABG* Stroke* -37% Fatal MI * p < 0.05 Sacks et al. N Engl J Med. 1996;335:1001–09.

  10. CARE: Stroke and Stroke/TIA Stroke Stroke/TIA 0 -10 Relative Risk Reduction -20 -26% -31% p = 0.029 -30 • 83% Aspirin Use • 82% Use of Antihypertensives p = 0.03 -40 Sacks et al. N Engl J Med. 1996;335:1001–09. Revised Pravastatin Package Insert. Indications and Usage. March 1998.

  11. 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 Placebo(n = 4502) Pravastatin 40 mg QD(n = 4512) 6.0 years Primary endpoint: Coronary mortality Secondary endpoints: Total mortality, nonfatal MI & CHD death, stroke etc. The LIPID Study Group. Am J Cardiol. 1995;76:474–79.

  12. LIPID: Baseline Characteristics Placebo Pravastatin Characteristic n = 4502 n = 4512 62 62 Age (years) 17/83 17/83 Women/Men (%) 42 41 History of HTN (%) 10 9 Current Cig. Smoker (%) 9 9 Diabetes (%) 218 218 Total Chol. mg/dL (mean) 150 150 LDL mg/dL (mean) Other Medication Use 82 83 Aspirin (%) The LIPID Study Group. Am J Cardiol. 1995;76:474–79.

  13. LIPID: Total & CHD Mortality Total Mortality CHD Mortality 15% 23% reduction 24% reduction 10% p = 0.00002 p = 0.0004 Placebo 10% Placebo Cumulative Risk Cumulative Risk 5% 5% Pravastatin Pravastatin 0% 0% 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 Years Since Randomization Years Since Randomization The LIPID Study Group. N Engl J Med. 1998;339:1349–57.

  14. LIPID: Total Stroke 6% 19% risk reduction p = 0.048 Placebo (n = 4502) 4% Cumulative Risk 2% Pravastatin (n = 4512) 0% 0 1 2 3 4 5 6 7 Years since randomization The LIPID Study Group. N Engl J Med. 1998;339:1349–57.

  15. CARE LIPID Benefit of Pravastatin inReducing Stroke 0 -10 Relative Risk Reduction -19% -20 p = 0.048 -31% -30 p = 0.03 -40 In both trials, stroke was a pre-specified endpoint and 83% of all pravastatin patients received aspirin. Tonkin et al. ACC, March 1998. Sacks et al. N Engl J Med. 1996;335:1001–09.

  16. Pravastatin Pooling Project (PPP) 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 Over 110,000 patient-years of follow-up The PPP Investigators. Am J Cardiol. 1995;76:899–905.

  17. Prospective Pravastatin Pooling Project: Baseline Characteristics WOSCOPS (n = 6595) CARE (n = 4159) LIPID (N=9014) LIPID (n = 9014) CHD status No CHD MI MI, unstable angina Age (years) Mean Upper limit 55 64 59 75 61 75 Men 100% 86% 83% Diabetes 1% 14% 9% Hypertension 16% 43% 42% Smokers 35% 16% 10%

  18. Lipids (mg/dL) WOSCOPS (n = 6595) CARE (n = 4159) LIPID (N=9014) LIPID (n = 9014) Total cholesterol Limits Mean >252 272 <240 209 155–271 219 LDL cholesterol Limits Mean 174–232 192 115–174 139 None 150 HDL cholesterol Mean 44 39 37 Triglycerides Limits Mean <533 162 <350 156 <445 159 Prospective Pravastatin PoolingProject: Baseline Lipids

  19. Prospective Pravastatin PoolingProject: Mortality Other Vascular Mortality CHD Mortality Non-CVD Mortality Total Mortality 0 12% (P=0.1) Relative Risk Reduction (%) 17% (P=0.25) 10 20% (P<0.001) 24% (P<0.001) 20 30 CARE, LIPID, & WOSCOPS (n = 19,768) Simes et al. Eur Heart J. 2002;23:207–15.

  20. 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) 0 -5 Event Rate (%) * -10 -15 22% (P<0.001) 22% (P<0.001) 23% (P<0.001) 23% (P<0.001) 26% (P<0.002) 26% (P<0.001) -20 27% (P<0.001) -25 -30 * CHD death and non-fatal MI, PTCA, CABG, stroke; 4131 patients with events Sacks et al. Circulation. 1999;100:I–238.

  21. The Prospective Pravastatin Pooling ProjectExtent of Exposure to Study Medication Pravastatin 40 mg n = 9809 Placebo n = 9783 Number of subjects receiving at least 1 dose of study medication Extent of Exposure to Study Medication (Years) Mean + SD Median Min (days) Max 4.6 + 1.7 5.0 1 7.1 4.5 + 1.8 5.0 1 7.1

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

  23. 20% Pravastatin Placebo 15% 10% 5% The Prospective Pravastatin Pooling ProjectCommon Serious Adverse Events (Non-CV) Urologic Proc. Ortho. Surg Prostate Disorder Abd. Surg Eye Surg Lens Opacity Reprod. Neoplasm Bone Fx Gall Bl. Surg Inv. GI Proc. Hernia Derm Neopl. Derm Proc. Pulm Infect. Gall Bl Disorder Musculo- Skel Abn. PUD Muscular Pain Modified from Pfeffer et al. Circulation 2002;105:r95–r100.

  24. Treatment Group Placebo Pravastatin Total Fatal Cancer 221 (2.3%) 234 (2.4%) 455 (2.3%) Any Cancer 946 (9.6%) 914 (9.3%) 1860 (9.5%) The Prospective Pravastatin Pooling ProjectIncidence of Cancer by Treatment Group Pfeffer MA Data on File

  25. 5% Pravastatin Placebo 4% 3% 2% 1% 0 GI Endo Derm Hep Musc - Skel Hemat Renal Special Senses General Resp Neuro The Prospective Pravastatin Pooling ProjectSite Specific Incidence of Primary Cancer Any Ca Pravastatin 9.3% Placebo 9.6% Pfeffer MA et al. European Heart J 2001;22:271.

  26. Number of Subjects with Laboratory Measurements Mean Number of Measurements per Subject Total Number of Measurements AST Overall 11,704 13.2 154,431 Pravastatin 5852 13.3 77,685 Placebo 5852 13.1 76,746 ALT Overall 18,637 13.1 243,506 Pravastatin 9338 13.2 123,193 Placebo 9299 12.9 120,313 The Prospective Pravastatin Pooling ProjectTotal Number of AST and ALT Measurements Taken at Baseline and Post Baseline Pfeffer MA et al. European Heart J 2001;22:271.

  27. The Prospective Pravastatin Pooling ProjectPost Baseline Elevations in ALT Pravastatin Placebo 95% CI Any Elevated ALT 804 / 9185 (8.8%) 746 / 9152 (8.2%) -0.21, 1.42 > 1.5 - < 3 X ULN 676 (7.4%) 615 (6.7%) -0.11, 1.39 > 3 - < 5 X ULN 84 (0.9%) 90 (1.0%) -0.36, 1.39 > 5 - < 7 X ULN 24 (0.3%) 19 (0.2%) -0.10, 0.21 > 7 - < 9 X ULN 6 (<0.1) 9 (<0.1%) -0.13, 0.06 > 9 X ULN 14 (0.2%) 13 (0.1%) -0.11, 0.13 Pfeffer MA et al. European Heart J 2001;22:271.

  28. CPK1 Overall 10,576 11.9 126,370 Pravastatin 5295 12.0 63,452 Placebo 5281 11.9 62,918 The Prospective Pravastatin Pooling Project:Total Number of CPK MeasurementsTaken at Baseline and Post Baseline Number of Subjects with Laboratory Measurements Mean Number of Measurements per Subject Total Number of Measurements LIPID does not include CORE Lab CPK Pfeffer MA et al. European Heart J 2001;22:271.

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

  30. 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) Myositis StatinControl 3 7 6 1 21 21 30 39 Rhabdomyolysis StatinControl 0 0 1 0 1 2 2 2 Farmer JA Lancet. 2001;358:1383–85.

  31. Time to Discontinuation of Study Medication Excluding Discontinuation Due to CV AEs Number of Subjects < 1 Yr 1 - <2 yr 2 - <3 yr 3 - <4 yr 4 - <5 yr 4 - <5 yr > 6 yr Pravastatin 826 431 339 579 2527 3488 1690 Placebo 755 538 439 710 2465 3322 1473 Pravastatin ( n = 9809) Proportion of Subjects Still On Meds Placebo (n = 9783) 1 2 3 4 5 6 7 Years of Follow-up Pfeffer MA et al. European Heart J 2001;22:271.

  32. The Prospective Pravastatin Pooling Project: Predicting Medication Discontinuation A Multivariate Cox Model Parameter Hazard Ratio p-value Treatment Group (Pravastatin) 0.69 0.0001 History of Diabetes 1.34 0.0001 Presence of CV SAE 0.76 0.0001 Current Smoker 1.25 0.0001 Gender (males) 0.83 0.0001 Primary/Secondary Prevention 1.15 0.0042 Age 1.00 0.4718 Pfeffer MA et al. European Heart J 2001;22:271.

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