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The Pyramid of Recent TrialsThe Pyramid of Recent TrialsRelative Size of the Various Segments of the PopulationRelative Size of the Various Segments of the Population4SCAREWOSCOPSAFCAPS/TexCAPSLIPIDVery high cholesterol with CHD or MIModerately high cholesterol in high risk CHD or MINormal cholesterol with CHD or MIHigh cholesterol without CHD or MINo history of CHD or MIThe Pyramid of Recent TrialsRAir Force/Texas Coronary Atherosclerosis Air Force/Texas Coronary Atherosclerosis Prevention Study(AFCAPS/TexCAPS)(1998)Prevention Study(AFCAPS/TexCAPS)(1998)nEvaluated the effects of lovastatin on first acute major coronary event in 6605 men and women without any coronary or vascular disease and withnTC 180-254 mg/dlnHDL-C 45 mg/dl in men and 47 mg/dl in womennLDL-C 130-190 mg/dl,or nLDL-C 125-129 mg/dl with TC/HDL-C ratio 6nRandomized to lovastatin 20 mg vs.placebo with titration to 40 mg with goal of LDL-C 110 mg/dlnMean follow-up 5 yearsDowns JR et al.JAMA 1998;279:1615-1622.Air Force/Texas Coronary AtherAFCAPS/TexCAPS ResultsAFCAPS/TexCAPS Results37%40%1st acute major coronary eventp0.001Fatal or nonfatal MIp=0.002Risk Reduction with Rx15011525%reductionDowns JR et al.JAMA 1998;279:1615-1622.AFCAPS/TexCAPS Results37%40%AFCAPS/TexCAPS Tertiary Endpoint AFCAPS/TexCAPS Tertiary Endpoint Analysis:MortalityAnalysis:Mortality*Too few for survival analysesAFCAPS/TexCAPS Tertiary EndpoiNCEP Adult Treatment Panel II GuidelinesNCEP Adult Treatment Panel II GuidelinesNational Cholesterol Education Program Circulation 1994;89:13291445.NCEP Adult Treatment Panel II PravastatinPravastatinPravastatinPlaceboPlaceboPlaceboCARE:Is There a Lower Threshold?CARE:Is There a Lower Threshold?Sacks FM et al.N Engl J Med.1996;335:1001-1009.Copyright 1996 Massachusetts Medical Society.All rights reserved.LDL-C 150 mg/dlChange in risk+3%p=0.85Change in risk 35%p=0.008Change in risk 26%p0.001Incidence(%)YearsYearsYears201553035251002015530352510020155303525100132450132450132450PravastatinPravastatinPravastaOn-Treatment LDL Levels and Correlation On-Treatment LDL Levels and Correlation with Major Coronary Events in 4Swith Major Coronary Events in 4SAbsolute difference in event rate:2.3%5.6%Circulation 1997;96:I-717On-Treatment LDL Levels and CoPitt B et al.N Engl J Med 1999;341:70-76.CAD 1 lesion 50%stenosisLDL-C 115 mg/dL(3.0 mmol/L)LVEF 40%Bruce protocol treadmill test or 20-W/minbicycle exercise test 4 minAtorvastatin 80 mg/d+usual medical therapyn=164*Angioplasty+usual care,including lipid loweringn=17718 monthsOccurrence of ischemic events(death from cardiac causes,resuscitation after cardiac arrest,nonfatal MI,CVA,CABG,angioplasty,worsening angina verified by objective evidence resulting in hospitalization)Time to first ischemic eventSafety*1 patient did not receive atorvastatin.11 patients did not have baseline revascularization.AVERT:Study DesignAVERT:Study DesignPitt B et al.N Engl J Med 1990510152025AtorvastatinAngioplasty/UC%of patientswith anischemic event13%21%36%difference*(p=0.048)2237*p=0.048 vs an adjusted significance level of p=0.045.Pitt B et al.N Engl J Med 1999;341:70-76.Results-Intent to TreatResults-Intent to Treat0510152025AtorvastatinAngiopla05101520250.00.51.01.5p=0.027Risk reduction 36%(95%CI:5%to 67%)Cumulative Incidence(%)AtorvastatinAngioplasty/UCTime since randomization(yr)Pitt B et al.N Engl J Med 1999;341:70-76.Copyright 1999 Massachusetts Medical Society.All rights reserved.Time to First Ischemic Event:Intent-to-Time to First Ischemic Event:Intent-to-Treat AnalysisTreat Analysis05101520250.00.51.01.5p=0.027C*Significantly different from angioplasty/UC(p0.05).To convert TG to mmol/L,multiply by 0.011.Note:73%of angioplasty/UC-treated patients were on lipid-lowering medication.18%31%*46%*10%10%11%*8%11%250(6.5)200(5.2)150(3.9)100(2.6)50(1.3)0LDL-CTCTGHDL-Cmg/dL(mmol/L)Atorvastatin baselineAtorvastatin end of studyAngioplasty/UC baselineAngioplasty/UC end of studyPitt B et al.N Engl J Med 1999;341:70-76.Copyright 1999 Massachusetts Medical Society.All rights reserved.Summary of Lipid ParametersSummary of Lipid Parameters*Significantly different from Ballantyne CM.Am J Cardiol.1998;82:3Q-12Q.Reprinted with permission from Excerpta Medica Inc.2 prevention placebo2 prevention statin1 prevention placebo1 prevention statinAFCAPSAFCAPSWOSCOPSWOSCOPSCARECARELIPIDLIPID4S4SEvent Rate(%)Clinical Event Rates by LDL-C Achieved in Clinical Event Rates by LDL-C Achieved in Statin TrialsStatin TrialsBallantyne CM.Am J Cardiol.1How Low Should You Go?How Low Should You Go?nSEARCH:Study of the Effectiveness of Additional Reductions of Cholesterol and HomocysteinenSimvastatin 20 mg vs.80 mgnTNT:Treating to New TargetsnAtorvastatin 10 mg vs.80 mgHow Low Should You Go?SEARCH:Clinical JudgmentClinical JudgmentnThe NCEP ATP II guidelines recommend the use of clinical judgment in deciding whether to initiate drug therapy innPatients with CHD and LDL-C 100129 mg/dlnPatients without CHD who have 2 risk factors and LDL-C 130159 mg/dlnMiddle-aged and older patients without CHD who have 2 risk factors and LDL-C 160189 mg/dlNational Cholesterol Education Program Circulation 1994;89:13291445.Clinical JudgmentThe NCEP ATP 2 RF2 RFCHDNumber of US Adults(millions)107.138.59.4NHANES III Adult Population EstimatesNHANES III Adult Population Estimatesby ATP II Risk Categoryby ATP II Risk CategoryJacobson TA et al.Arch Intern Med.2000;160(9):1361-9.2 RF2 RFCHDNumber of US AdulLDL-C(mg/dl)Number of US Adults(millions)without CHD and with 2 RF606069707980899099100109110119120129130139140149150159160169170179180189190199200209210219220229230239240249250259260269270279280289290299300309310319320329330339340349 350with CHDLDL-C Distribution in U.S.AdultsLDL-C Distribution in U.S.Adults Data from NHANES III,19881994Data from NHANES III,19881994Jacobson TA et al.Arch Intern Med.2000;160(9):1361-9.LDL-C(mg/dl)Number of US AdulUS Adults Requiring Drug Therapy US Adults Requiring Drug Therapy Assuming 10%LDL-C Reduction with DietAssuming 10%LDL-C Reduction with Diet2 RF2 RFCHDTotalNumber of US Adults(millions)1.64.15.517.53.36.810.428.4Jacobson TA et al.Arch Intern Med.2000;160(9):1361-9.US Adults Requiring Drug TheraEffect of Statin Therapy on CHD:Clinical Effect of Statin Therapy on CHD:Clinical Events TrialsEvents TrialsJacobson TA et al.Arch Intern Med 1998;158:19771989.*Nonfatal MI or CHD death in WOSCOPS,CARE,LIPID;nonfatal or fatal MI,unstable angina,or sudden cardiac death as first event in AFCAPS;nonfatal MI,coronary death,or resuscitated cardiac arrest in 4S.vs.placeboEffect of Statin Therapy on CHLDL and HDL Impact on CHD RiskLDL and HDL Impact on CHD RiskA Compounded Rather Than Additive Impact A Compounded Rather Than Additive Impact 010020030040055195HDL-cholesterol(mg/dL)LDL-cholesterol(mg/dL)Incidence per1000(in 6 years)Assmann G,et al.Atherosclerosis 1996;124(suppl):S11-S20.Reprinted with permission from Elsevier Science.LDL and HDL Impact on CHD RiskHDL is a major factor in predicting CADHDL is a major factor in predicting CAD02040608010012055HDL-cholesterol(mg/dL)Incidence of CHD(per 1000 in 6 years)n=4,407Assmann G,et al.Atherosclerosis 1996;124(suppl):S11-S20.Reprinted with permission from Elsevier Science.HDL is a major factor in prediHDL-C Distribution in US AdultsHDL-C Distribution in US AdultsData from NHANES III,19881994.Number of US Adults(millions)HDL-C(mg/dl)HDL-C Distribution in US AdultHDL-C in Clinical PracticeHDL-C in Clinical PracticenRisk assessmentnRoutinely measured in all adult patientsnHDL-C 35 mg/dL is a major positive risk factornHDL-C 60 mg/dL is a negative risk factor;subtract 1 risk factor from totalnRisk reductionnNonpharmacologic therapy(exercise,weight loss,smoking cessation)nPharmacologic therapynClinical trial data show decreased CAD progression and decreased CAD events with increased HDL-CHDL-C in Clinical PracticeRiskProgression(MLD decrease),mmHDL-C 35 mg/dl(p=0.0004)n=43n=25HDL-C 35 mg/dl(p=0.09)n=128n=1430.0650.2740.0360.083p=0.01Ballantyne CM et al.Circulation 1999;99:736-743.Reduction in CAD Progression with Reduction in CAD Progression with Fluvastatin in Low vs.High HDL-C PatientsFluvastatin in Low vs.High HDL-C PatientsProgression(MLD decrease),mmBallantyne CM et al.Circulation 1999;99:736-743.FluvastatinPlaceboHDL-C 35 mg/dlp=0.002FluvastatinHDL-C 35 mg/dlp=0.232122.501.000.750.500.250.001.000.750.500.250.00Probability of event-free survivalYearsPlaceboReduced CAD Events with Fluvastatin in Reduced CAD Events with Fluvastatin in Low HDL-C PatientsLow HDL-C Patients122.50Ballantyne CM et al.CirculatiAngiographic Trials in LowHDL-C PatientsAngiographic Trials in LowHDL-C PatientsBallantyne CM et al.Circulation 1999;99:736-743.Baseline(mg/dl)%MLDPL MLDDR(mm)TrialDrugLDL-CHDL-CLDL-CHDL-CLCASfluvastatin 40 mg/d1464325+90.07LCAS HDL-C 35 mg/dlfluvastatin 40 mg/d1433225+160.21BECAITbezafibrate 600 mg/d180343.5+90.11LOCATgemfibrozil 1200 mg/d138314.5+210.04Angiographic Trials in LowHDLAtherosclerosis Progression and Baseline Atherosclerosis Progression and Baseline HDL-C:HDL-C:Results from Post-CABGResults from Post-CABGProgression rate(%)HDL-C(mg/dl)Moderatetherapy(LDL-C 134)Aggressivetherapy(LDL-C 95)Relative risk 95%CI3547300.480.350.67353940280.580.390.85404437250.560.350.894530270.870.571.33Hunninghake D et al.Circulation 1997;96:I-413.Atherosclerosis Progression anAdapted from Ballantyne CM et al.Circulation 1999;99:736-743.4SWOSCOPSAFCAPSCoronary Events(%)403452 38 4343LIPID 39 130 mg/dL(mean 156)-Triglycerides 300-700 mg/dL(median 389)nTreatment:placebo,simvastatin 40 and 80 mg/day(6 weeks each)nMain endpoints:-TC,TG,apo B,LDL-C,VLDL-C,apo A-I,HDL-CHunninghake DB et al.J Am Coll Cardiol 1999;33:244ASimvastatin Combined HyperlipiChanges in LipidsChanges in LipidsHunninghake DB et al.J Am Coll Cardiol 1999;33:244A-29-2813-36-3316-40-30-20-1001020Simvastatin 40 mg/dSimvastatin 80 mg/dLDL-CTGMean%ChangeHDL-Cp0.001p0.001p0.001Changes in LipidsHunninghake DComparison of Simvastatin and AtorvastatinComparison of Simvastatin and AtorvastatinStudy Objective:nTo compare relative efficacy of simvastatin and atorvastatinStudy Design:n12-week,open-label,randomized,parallel-group,multicenter study n842 patients,men and women,ages 21-70nFollowing a 4-week diet run-in period,patients were randomized into 4 treatment groups(simvastatin 40 mg,simvastatin 80 mg,atorvastatin 20 mg,atorvastatin 40 mg)for 12 weeksCrouse JR III et al.Am J Cardiol 1999;83:1476-1477.Comparison of Simvastatin and Lipid ChangesLipid ChangesCrouse JR III et al.Am J Cardiol 1999;83:1476-1477.-60-50-40-30-20-10010Simvastatin 40 mg/dAtorvastatin 20 mg/dSimvastatin 80 mg/dAtorvastatin 40 mg/dLDL-CHDL-CTGapo A-I-43-45-49-51-23-23-25-30+7+4+7+3+5+6+60Mean%Changep0.05p0.05p0.05p0.01p0.01p0.001Lipid ChangesCrouse JR III et Subgroup Analysis for HDL-C Subgroup Analysis for HDL-C above or below 35 mg/dlabove or below 35 mg/dlMean%change in HDL-C13121776353p0.005p0.05Crouse JR III et al.Am J Cardiol 1999;83:1476-1477.Reprinted with permission from Excerpta Medica,Inc.Subgroup Analysis for HDL-C aCombination Therapy:Statin+Nicotinic AcidCombination Therapy:Statin+Nicotinic AcidnSimvastatin 10 mg/day+nicotinic acid titrated up to 1.5 g/day1nLDL-C by 29%nHDL-C by 31%nTG by 31%nFluvastatin 20 mg/day+nicotinic acid titrated up to 3 g/day2nLDL-C by 40%nHDL-C by 28%nTG by 30%1Stein EA et al.J Cardiovasc Pharmacol Ther 1996;1:107-116.2Jacobson TA et al.Am J Cardiol 1994;74:149-154.Combination Therapy:Statin+Combination Therapy:Statin+FibrateCombination Therapy:Statin+FibratenLovastatin 2040 mg/day+gemfibrozil 1200 mg/day1nLDL-C by 26%nHDL-C by 3%nTG by 35%nPravastatin 40 mg/day+gemfibrozil 1200 mg/day2nLDL-C by 37%nHDL-C by 17%nTG by 42%1Glueck CJ et al.Am J Cardiol 1992;70:1-92Wiklund O et al.Am J Med 1993;94:13-20Combination Therapy:Statin+Combination Therapy:Pros and ConsCombination Therapy:Pros and ConsnLDL-C,TG,HDL-CnMay Lp(a)(niacin)nLDL particle sizenFibrinogen(fibrate)nAngiographic datanIncreased adverse effects(rhabdomyolysis)nDrug interactionsnIncreased costsnLack of outcome studiesProsConsCombination Therapy:Pros and SummarySummarynRecent clinical trials have shown a consistent benefit on reducing CHD in both primary and secondary prevention,in patients with LDL-C elevations ranging from mild to severe.nPatients with low HDL-C are at increased risk for CHD events.nStatins have been effective in patients with low HDL-C for slowing CAD progression and reducing CAD events.SummaryRecent clinical trials Summary(continued)Summary(continued)nSome but not all trials with fibrates have shown benefit for patients with low HDL-C.nCombination therapy with statins and other agents is very effective for comprehensive modification of the lipid profile,but drug side effects may be 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