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1、Primary and Secondary Prevention of Dyslipidemia: Established Therapies and Emerging Paradigms,Sidney C. Smith, Jr. MD Professor of Medicine Director, Center for Cardiovascular Science and Medicine University of North Carolina at Chapel Hill,,,,Most MIs Arise From Smaller, Non flow-limiting Stenoses

2、,,,,,68%,18%,14%,0,20,40,60,80,<50%,50%70%,70%,% Stenosis,Percent of MI Patients,Adapted from Falk et al. Circulation 1995; 92:657671.,,PCI CABG,Effects of Statins on Coronary Disease: Primary 278:313-321.,Impact of Lowering LDL-C on CVD Events and Total Mortality,Nonfatal/fatal CHD,CVDmortality,4S:

3、Major CHD Event Reduction in a Subgroup of Patients With Diabetes,Pyrl K et al. Diabetes Care. 1997;20:614-620.,Proportionwithoutmajor CHD event,Yr since randomization,,,,,,- P=0.002,,- P=0.0001,,Diabetic, simvastatin,,Diabetic, placebo,Nondiabetic, simvastatin,Nondiabetic, placebo,,,,,32%,55%,4S: T

4、reatment Benefit in Subgroup With Impaired Fasting Glucose (FG 110-125mg/dL),Haffner SM et al. Diabetes. 1998;(suppl 1):A54. Abstract.,Totalmortality,Coronarymortality,Majorcoronaryevents,Revas-culari-zations, inevents(%),P=0.005,P=0.001,P=0.010,Clinical Trial Findings: The Statins,Statins LDL-C by

5、25%-35% Benefits at various LDL-C levels; evident soon after therapy in LDL-C required for in CHD morbidity/mortality in all-cause mortality in 2 prevention and in cardiovascular mortality in 1 prevention Studies support treatment in various patient groups women elderly diabetics,,Lipid Lowering The

6、rapy for the Prevention of Vascular Disease,When Should Lipid Lowering Therapy be started? What should be the Treatment Goal? Findings of the HPS Study. Should HDL Cholesterol be a Target?,,When to Start Cholesterol Lowering Therapy in Patients with Coronary Heart Disease,“ The cardiovascular specia

7、list or attending physician should be responsible for starting some form of cholesterol lowering therapy in patients upon discharge from the hospital after acute coronary events.The cardiovascular specialist thus should insure that appropriate therapy is initiated and maintained.” AHA

8、Science Advisory Circ. 1997;95: 1683,,,,,ACS: A Treatment Gap,,,,Acute coronary event,4S3,AFCAPS / TexCAPS/WOSCOPS,CARE1 LIPID2,,,,No history of CAD,Acute Coronary Syndromes,3 mo,t=0,6 mo,Randomization:CARE - 320 moLIPID - 336 mo,Randomization:6 mo,Stable CAD,,Primary prevention,Secondary prevention

9、,,,,Duration of follow-up: 15.0 years; 26.1 years; 35.4 years. Schwartz GG et al. Am J Cardiol 1998;81:578581.,,Time of High Mortality,,,,,,,,,,,,,,,,,,,,,,,,7,12,4,9,-27,-40,5,-16,-50,-40,-30,-20,-10,0,10,20,TC,LDL-C,HDL-C,TG,,Placebo,,Atorvastatin 80 mg,% ,MIRACL: Change in Lipid Levels,Data from

10、Schwartz GG et al. JAMA. 2001;285:1711-1718.Additional data courtesy of GG Schwartz.,unstable anginaor nonQ-wave MI,3,086randomized 2496 h after admission Followed 16 weeks,,0,5,10,15,0,4,8,12,16,Time since randomization (wk),Cumulativeincidence(%),,,,,,,,,,,,,RR = 0.84(95% CI, 0.70-1.00) P = 0.048,

11、Atorvastatin,Placebo,17.4,14.8,,,*Death (any cause), nonfatal MI, resuscitated cardiac arrest, recurrent symptomatic myocardial ischemia with objective evidence requiring emergency rehospitalization.Schwartz GG et al. JAMA. 2001;285:1711-1718.,MIRACL: Time to First Ischemic Event*,MIRACL: Occurrence

12、 of Primary Combined End Point,Adapted from Schwartz GG et al. JAMA. 2001;285:1711-1718.,,,,,,,,,,,,,,,0.0,0.5,1.0,1.5,2.0,0,4,8,12,16,Time since randomization (wk),RR = 0.50(95% CI, 0.26-0.99) P = 0.045,Atorvastatin,Placebo,,,,1.6,0.8,MIRACL: Fatal or Nonfatal Stroke,Cumulativeincidence(%),Data fro

13、m Schwartz GG et al. JAMA. 2001;285:1711-1718.,,,19,599 men and women < 80 yo discharged post AMI, 58 Swedish Hospitals, 1995-1998 5528 (28%) statin rx vs 14071 (72%) no statin rx, highest hospital rates of use 48%; lowest 12% Stenestrand JAMA 2001;285;430-436,Early Statin Treatment and Survival in

14、AMI,RR 0.75 (0.63-0.89) P=0.001,25% Risk Reduction,PRISM: Event Rate Cur ves,Heeschen C et al. Circulation. 2002;105:1446-1452.,051015202530,18 16 14 12 10 8 6 4 2 0,Follow-up (day),Event rates (%),,,,Statins discontinued,No statins,Statins continued,Events = mortality, MI,Statin Trials and Goals of

15、 Cholesterol-Lowering Therapy,Grundy. Circulation. 1998;97:1436-1439.,The quantitative relation between the magnitude of cholesterol lowering and CHD reduction has not been precisely defined 3 models,,,,,,,,a) Linear,b) Threshold,c) Curvilinear,,,,,,,,,,,,,,,,,25,20,15,10,5,0,50,70,90,110,130,150,17

16、0,190,210,TNT 80mg,TNT 10 mg,CARE-S,LIPID-S,4S-S,CARE-P,LIPID-P,TNT Entry,4S-P,CHD Event (%),LDL-C (mg/dL),Correlation Between CHD Events and LDL-C Levels,S=Statin treated; P=Placebo treated,,AVERT 80mg: LDL=77 mg/dL 13.4% Event Rate,,,,,,,,,,,I - Intervention is useful and effective IIa -Weight of

17、evidence/opinion is in favor of usefulness/efficacy IIb - Usefulness/efficacy is less well established by evidence/opinion III - Intervention is not useful/effective and may be harmful,,,,Data from many large, RCTs Data from fewer, smaller RCTS, careful analyses of nonrandomized studies, observation

18、al registries Expert consensus,=,Level of evidence,Classification of Recommendations,ACC/AHA Practice Guidelines,LIPID LOWERING AT HOSPITAL DISCHARGE,Lipid-lowering agent and diet in patients with LDL cholesterol 130 mg/dL,Lipid-lowering agent if LDL cholesterol level is 100 mg/dL,,,IIb,A,A,I,ACC/

19、AHA UA/ NSTEMI Guidelines 2002,MRC/BHF Heart Protection Study: ELIGIBILITY,Increased risk of CHD death due to prior disease: -Myocardial infarction or other coronary heart disease -Occlusive disease of non-coronary arteries -Diabetes mellitus, Type I or II -Treated Hypertension Age 40-80 years 20,

20、536 participants (men=15,454, women=5,082) Total cholesterol 3.5 mmol/l (135mg/dl) Statin or vitamins not considered clearly indicated or contraindicated by patients own doctors,,HEART PROTECTION STUDY (HPS) MAJOR VASCULAR EVENTS,Risk ratio and 95% CI,STATIN,PLACEBO,Vascular,event,(10269),(10267),ST

21、ATIN better,STATIN worse,Total CHD,914,1234,,,Total stroke,456,613,,,Revascularization,926,1185,,,ANY OF ABOVE,2042,2606,(19.9%),(25.4%),24%,SE 2.6,reduction,(2P<0.00001),,,,,,0.4,,,0.6,,,0.8,,,1.0,,,1.2,,,1.4,,,HEART PROTECTION STUDY (HPS) VASCULAR EVENT by PRIOR DISEASE,Risk ratio and 95% CI,STATI

22、N,PLACEBO,Baseline,feature,(10269),(10267),STATIN better,STATIN worse,STATIN worse,,,Previous MI,1007,1255,,,,Other CHD (not MI),452,597,,,,No prior CHD,,,,CVD,182,215,,,,PVD,332,427,,,,Diabetes,279,369,,,,ALL PATIENTS,2042,2606,(19.9%),(25.4%),24%,SE 2.6,reduction,(2P<0.00001),,,,,,0.4,,,0.6,,,0.8,

23、,,1.0,,,1.2,,,1.4,,,HPS: Effects of Simvastatin on Vascular Events by Year,,0,10,20,30,0,1,2,3,4,5,6,Proportion withevent (%),Years of follow-up,Benefit/1,000 (SE)5 (3)20 (4)35 (5)46 (5)54 (7)60 (18),Logrank P <0.0001,Placebo,Simvastatin,,,,,,,,,,,,,,,,HPS Collaborative Group. Lancet. 2002;360:7-22.

24、,HPS: Absolute Risk Reductions,,ARR=absolute risk reduction; NNT=number needed to treat.,HPS Collaborative Group. Lancet. 2002;360:7-22.,HPS enrolled high-risk primary- and secondary-prevention patients. HPS. Lancet. 2002;360:7. Downs. JAMA. 1998;279:1615. LIPID. N Engl J Med. 1998;339:1349. Sacks.

25、N Engl J Med. 1996;335:1001. 4S. Lancet. 1995;345:1274. Shepherd. N Engl J Med. 1995;333:1301.,Relation Between CHD Events and LDL-C Outcomes in Statin Trials,% with CHD event,Mean LDL-C level at follow-up (mg/dL),,,,,,,,,,,,,,,,,,,,,,,,,,,,,0,5,10,15,20,25,30,90,110,130,150,170,190,210,CARE-Rx,LIPI

26、D-Rx,4S-Rx,CARE-PI,LIPID-PI,4S-PI,2 Prevention,1 Prevention,WOSCOPS-PI,WOSCOPS-Rx,AFCAPS-Rx,AFCAPS-PI,,,HPS-Pl,HPS-Rx,,,HPS-Rx,HPS-Pl,,,w/revasc+stroke CHD only,,PI=placebo Rx=treatment,,70,AFCAPS/TexCAPS: Lovastatin in Primary PreventionRisk Reductions Across Baseline HDL-C Tertiles,Downs JR, et a

27、l. JAMA. 1998;279:1615.,,,,,,,,,,,,,0,1,2,3,4,5,6,7,8,,Lovastatin,Placebo,34,40,3539,HDL-C Tertile (mg/dL),Events, %,,,VAHIT: Favorable Effects of Fibrate on CVD Events in CHD Patients With Isolated Low HDL-C,*P<0.01; P=0.006; P=0.05P=placebo group; Rx=treated group. Presented by HB Rubins at the 71

28、st annual AHA Scientific Sessions; Dallas, Texas.,Subjects: 2,531 men Age: 74 (avg 64) yr Mean baseline LDL-C: 111 mg/dL Mean baseline HDL-C: 32 mg/dL Mean baseline TG: 161 mg/dL Duration: 7 yr Intervention: Gemfibrozil 600 mg bid,%+,P/Rx111/11532/34161/122274/219118/9388/64219/197,*,*,,,LDL-C,HDL-C

29、,TG,Nonfatal MI/CHD death,CHDdeath,All-causemortality,Stroke,HATS: Clinical Endpoints,Brown BG, et al. N Engl J Med. 2001;345:1583.,,,,,,,,,,,,,,,23.7,2.6,21.4,14.3,0,5,10,15,20,25,Coronary Death, MI, Stroke, or Revascularization,Composite Event Rate, %,89%Reduction,*,*P <.05 vs placebo,L-TAP: Patie

30、nts Achieving NCEP ATP II Goals,Pearson TA, et al. Arch Intern Med. 2000;160:459.,,,,,0,40,80,Percent of Patients by Risk Group,Patients on Nondrug and Drug Therapies,,37%,n = 2285,High-risk Patients,,18%,n = 1460,CHDPatients,,38%,N = 4888,All Patients,,68%,n = 1143,Low-risk Patients,,% of Patient

31、s on Lipid Lowering Therapy: Based on Gender n = 17,639 Male; n = 38,317,,,%,Lipid Trials and Their Implications:,Efficacy of LDL reduction for Primary and Secondary Prevention is Established Target LDL requires further investigation Further investigation needed regarding therapeutic benefits of increasing HDL Benefits of early statin therapy may be secondary to anti - inflammatory effects Statin profile safe for majority, new medications require clinical trials. Emphasis should be placed on increasing physician compliance with guidelines and patient adherence to therapies,,