1 / 89

Prevention of CV Disease with Statins

Prevention of CV Disease with Statins. 葉宏一 MD, PhD 馬偕醫學院 醫學系 教授兼主任 台北醫學大學 醫學科學研究所 兼任教授 馬偕紀念醫院 內科部 副主任. Content. Epidemiology Pathophysiology Pharmacological Treatment Guidelines Statin clinical trials Adverse effects Real world practice. Content. Epidemiology Pathophysiology

ethan-beard
Télécharger la présentation

Prevention of CV Disease with Statins

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Prevention of CV Disease with Statins 葉宏一MD, PhD 馬偕醫學院 醫學系 教授兼主任 台北醫學大學 醫學科學研究所 兼任教授馬偕紀念醫院 內科部 副主任

  2. Content • Epidemiology • Pathophysiology • Pharmacological Treatment • Guidelines • Statin clinical trials • Adverse effects • Real world practice

  3. Content • Epidemiology • Pathophysiology • Pharmacological Treatment • Guidelines • Statin clinical trials • Adverse effects • Real world practice

  4. Framingham: HDL-C vs LDL-C as a predictor of CHD risk CHD RR 3 2.5 2 Risk of CAD over 4 years of follow-up* 1.5 25 mg/dL 45 mg/dL 1 65 mg/dL 0.5 HDL-C 85 mg/dL 0 100 mg/dL 160 mg/dL 220 mg/dL LDL-C *Men aged 50–70 Gordon, Castelli et al. Am J Med 1977;62:707–714

  5. 3.62 (140) 4.14 (160) 4.65 (180) 5.17 (200) 5.69 (220) 6.21 (240) 6.72 (260) 7.24 (280) 7.75 (300) Elevated Cholesterol Levels are Associated with an Increased Risk of CHD Death n=12866, follow-up mean 7 years Data from MRFIT study. Martin MJ et al. Lancet 1986;ii:933–936.

  6. Correlation Between Total-C and CHD Mortality in Men from Seven Countries 2.60 (100) 3.25 (125) 3.90 (150) 4.50 (175) 5.15 (200) 5.80 (225) 6.45 (250) 7.10 (275) 7.75 (300) 8.40 (325) 9.05 (350) Data are from the Seven Countries Study of 12,467 men from Southern European Countries, the USA and Japan. Verschuren WM et al. JAMA 1995;274:131–136.

  7. INTERHEARTPopulation Attributable Risk for 1st MI by Region and Overall NON-LIFESTYLE RISK FACTORS Region HTN % Diab % Abd Obes % All PS% Lipids % All 9 RF W. Europe 22.0 14.9 63.6 38.9 44.6 94.0 E/C Europe 24.5 9.1 28.0 4.9 35.0 72.5 Middle East 9.7 15.5 26.7 41.6 70.5 95.0 Africa 29.9 17.1 58.3 40.0 74.1 97.4 S. Asia 19.4 12.1 37.0 15.9 58.7 89.4 China 22.1 10.0 5.5 35.6 43.8 89.9 S.E. Asia 38.4 21.0 58.0 26.7 67.7 93.7 Australia/NZ 22.8 7.2 61.6 28.9 43.4 89.5 S. America 32.8 12.8 45.4 35.6 47.6 89.4 N. America 18.9 7.9 59.6 51.4 50.5 98.7 Overall 1 23.4 12.4 33.7 28.8 53.8 90.4 Overall 2 17.9 9.9 20.1 32.5 49.2 90.4 Yusuf et al. Lancet, 2004

  8. Prevalence of Hypercholesterolemia in Taiwan 高總膽固醇比例 Age Data from Taiwan 3H survey Definition: total cholesterol > 240 mg/dl or taking lipid-lpwering drugs

  9. Content • Epidemiology • Pathophysiology • Pharmacological Treatment • Guidelines • Statin clinical trials • Adverse effects • Real world practice

  10. Atherosclerosis and Thrombosis PHASE I: Initiation PHASE II: Progression PHASE III: Complication Disease progression

  11. LDL, β-VLDL, Lp(a) Lumen AdhesionVCAM-1ICAM-1 P-selectin E-selectin Monocyte MigrationMCP-1CCR-2 oxLDL Endothelialcells CytokinesMMPsEndothelin-1 Induction of adhesionmolecules and chemotaxis oxidation T lymphocyte Differentiation(GM-CSF) Intima CD36SR-A CD40 IFN-gamma Foam cell Macrophage Internal elastic lamina Smooth muscle cells Development of an Atheroma lipid + inflammation Adapted from Fan J, Watanabe T. J Atheroscler Thromb. 2003;10:63–71.

  12. Content • Epidemiology • Pathophysiology • Pharmacological Treatment • Guidelines • Statin clinical trials • Adverse effects • Real world practice

  13. Nicotinic acid1 ↓ 5–25% ↓ 20–50% ↑ 15–35% ↑ 10–20% Fibric acids1 ↓ 5–20% ↓ 20–50% ↓ up to 40% ↑ 5–15% Probucol3 Statins1 ↓ 18–55% ↓ 10–17% No change ↓ 7–30% ↑ 3–5% Bile acid sequestrants1 ↓ 15–30% No change or increase Ezetimibe*2 ↓ 18% ↓ 8% ↑ 1% Impact of Existing Drug Therapies on Lipid Parameters HDL-C effect Drug class/agents LDL-C effect Triglyceride effect *Selective inhibitor of intestinal cholesterol absorption Adapted from 1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486–2497. 2. Ezetrol (ezetimibe) product information. WPC 072005. Merck Sharp and Dohme. NSW, Australia. 2006. 3. Nippon Rinsho. 1994 Dec;52(12):3279-84.

  14. Cholesterol Biosynthesis Pathway HMG-CoA reductase Dolichol Acetyl CoA HMG- CoA Farnesyl pyrophosphate Cholesterol Mevalonate Squalene Ras protein Farnesyl- transferase E,E,E-Geranylgeranyl pyrophosphate Farnesylated proteins Geranylgeranylated proteins Ubiquinones

  15. Platelet activatin Thrombotic effect Plaque stability Endothelial dysfunction SMC proliferation SMC hypertrophy Vasoconstriction Vascular inflammation HMG-CoA Reductase inhibitirors RhoA ET-1 t-PA PAI-1 Rac1 RhoA AT1 receptor TXA2 Macrophage growth MMPs hs-CRP ROS N0 TF Adhesion molecule + Atherosclerosis Hypertension Cardiovascular Diseases Takemoto and Liao, 2001

  16. Double dose of statins results in ~6% reduction of LDL The STELLAR Trial Change in LDL-C From Baseline (%) 0 -5 -10 -15 -20 -30 -35 -40 -45 -50 -55 -60 -25 10 mg * 20 mg ** 40 mg † 10 mg 20 mg 40 mg 80 mg Rosuvastatin Atorvastatin Simvastatin 10 mg 20 mg 40 mg 80 mg Pravastatin 40 mg 10 mg 20 mg STELLAR = Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin. *P<.002 vs atorvastatin 10 mg; simvastatin 10, 20, 40 mg; pravastatin 10, 20, 40 mg. **P<.002 vs atorvastatin 20, 40 mg; simvastatin 20, 40, 80 mg; pravastatin 20, 40 mg. †P<.002 vs atorvastatin 40 mg; simvastatin 40, 80 mg; pravastatin 40 mg. Adapted from Jones et al. Am J Cardiol 2003;92:152–160.

  17. Content • Epidemiology • Pathophysiology • Pharmacological Treatment • Guidelines • Statin clinical trials • Adverse effects • Real world practice

  18. ATP III: Lipid-Lowering Treatment Guidelines Risk factors: FHx, HTN, smoking, male ≥45, female ≥55, HDL-C <40 mg/dL

  19. TC ≧200mg/dl × × <160mg/dl (87/7/1) LDL-C ≧130mg/dl × × ≦100mg/dl (87/7/1) TG ≧200mg/dl (需同時合併有TC/HDL-C>5或是HDL-C <40mg/dl) × ˇ < 150mg/dl (87/7/1) Reimbursement guidelines from BNHI, Taiwan 血脂異常之 起步治療準則 ≧2個危險因子 (如附註二) TC/HDL-C>5或 HDL-C<40mg/dl 血脂濃度 治療目標 * 有 心 血 管 疾 病 患 者 同時予以非藥物治療 或 糖 尿 病 * 冠狀動脈粥狀硬化, 腦血管病變, 周邊血管粥狀硬化 (ˇ)需符合此項條件 (×)不需符合此項條件 周邊血管粥狀硬化有缺血性症狀且經血管都卜勒超音波或血管攝影證實者

  20. × ˇ × <200mg/dl ≧200mg/dl ˇ × × <240 mg/dl ≧240mg/dl ˇ × <130mg/dl ≧130mg/dl × <160mg/dl × ≧160mg/dl 全民健保降血脂藥物給付規定（畫線部分為91/9/1後適用） * 血脂異常之 起步治療準則 ≧2個危險因子 (如附註二) TC/HDL-C>5或 HDL-C<40mg/dl 血脂濃度 治療目標 TC 有下列情況之一時 ，應給予 無 心 血 管 疾 病 患 者 三至六個月非藥物治療 ︵ 如 附 註 一 ︶ LDL-C TG ≧200mg/dl (需同時合併有TC/HDL-C>5或是HDL-C<40mg/dl) <200mg/dl(87/4/1) * 高血壓, 糖尿病, 男≧45歲, 有早發性冠心病家族史, 女≧55歲或停經沒有雌激素療法, 吸菸

  21. Content • Epidemiology • Pathophysiology • Pharmacological Treatment • Guidelines • Statin clinical trials • Adverse effects • Real world practice

  22. Statin Clinical Trials Comparators Statin vs placebo - statin alone - combined with non-statin Statin vs statin - different statins - same statin, different dose - combined with non-statin End points • Disease outcome • Surrogate marker

  23. Statin Clinical Trials Comparators Statin vs placebo - statin alone - combined with non-statin Statin vs statin - different statin - same statin, different dose - combined with non-statin End points • Disease outcome • Surrogate marker

  24. 30 NCEP2004 NCEP 2001 Eur Joint 2003 4S - PBO Secondary Prevention 4S - Rx 20 LIPID - PBO Event rate (%) CARE - PBO LIPID - Rx HPS - PBO Primary Prevention CARE - Rx 10 TNT - ATV10 WOSCOPS - PBO TNT - ATV80 HPS - Rx HPS - Rx AFCAPS - PBO PROVE-IT - PRA PROVE-IT - ATV80 WOSCOPS - Rx ASCOT - PBO AFCAPS - Rx AFCAPS - Rx ASCOT - Rx 0 40 (1.0) 60 (1.6) 80 (2.1) 100 (2.6) 120 (3.1) 140 (3.6) 160 (4.1) 180 (4.7) 200 (5.2) LDL-C achieved mg/dL (mmol/L) On-treatment LDL-C & CHD Events in Statin Trials Adapted from Rosensen, Exp Opin Emerg Drugs 2004;9:269; LaRosa J et al, N Engl J Med, 2005;352:1425

  25. Cholesterol Treatment Trialists’Collaboration • randomised trials involving at least 1000 participants and at least 2 years’ treatment duration • more versus less intensive statin regimens (5 trials; 39612 individuals; median follow-up 5.1 years) • statin versus control (21 trials; 129526 individuals; median follow-up 4.8 years). Lancet Vol 376 November 13, 2010

  26. Cholesterol Treatment Trialists’Collaboration

  27. MVE per 1.0 mmol/L reduction in LDL-C, by baselineprognostic factor

  28. Cause-specific mortality per 1.0 mmol/L reduction in LDL-C

  29. Site-specific cancer incidence per 1.0 mmol/L reduction in LDL-C

  30. 30 NCEP2004 NCEP 2001 Eur Joint 2003 4S - PBO Secondary Prevention 4S - Rx 20 LIPID - PBO Event rate (%) CARE - PBO LIPID - Rx HPS - PBO Primary Prevention CARE - Rx 10 TNT - ATV10 WOSCOPS - PBO TNT - ATV80 HPS - Rx HPS - Rx AFCAPS - PBO PROVE-IT - PRA PROVE-IT - ATV80 WOSCOPS - Rx ASCOT - PBO AFCAPS - Rx AFCAPS - Rx ASCOT - Rx 0 40 (1.0) 60 (1.6) 80 (2.1) 100 (2.6) 120 (3.1) 140 (3.6) 160 (4.1) 180 (4.7) 200 (5.2) LDL-C achieved mg/dL (mmol/L) On-treatment LDL-C & CHD Events in Statin Trials Adapted from Rosensen, Exp Opin Emerg Drugs 2004;9:269; LaRosa J et al, N Engl J Med, 2005;352:1425

  31. Tx based on hsCRP level

  32. JUPITER Comparators Statin vs placebo - statin alone - combined with non-statin Statin vs statin - different statin - same statin, different dose - combined with non-statin End points • Disease outcome • Surrogate marker

  33. JUPITER Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin • a randomized, double-blind, placebo-controlled primary prevention trial (26 countries) • studied over 17,802 patients (men>= 50 yrs; women>= 60 yrs; 6,801 women; 5,577 with metabolic syndrome) without evidence of cardiovascular disease and low to normal LDL-C (<130 mg/dl, median 108 mg/dl), but elevated C-reactive protein (hs-CRP ≧2 mg/L). • rosuvastatin (20 mg) vs placebo ACC 2008

  34. JUPITER Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death Ridker et al NEJM 2008 HR 0.56, 95% CI 0.46-0.69 P < 0.00001 Placebo 251 / 8901 0.08 Number Needed to Treat (NNT5) = 25 - 44 % 0.06 Cumulative Incidence 0.04 Rosuvastatin 142 / 8901 0.02 0.00 0 1 2 3 4 Follow-up (years) Number at Risk Rosuvastatin 8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157 Placebo 8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174

  35. JUPITER Dual Target Analysis: LDLC<70 mg/dL, hsCRP<2 mg/L 0.08 Placebo HR 1.0 (referent) 0.06 LDL > 70 mg/dL and / or hsCRP > 2 mg/L HR 0.64 (0.49-0.84) Cumulative Incidence 0.04 LDL < 70 mg/dL and hsCRP < 2 mg/L HR 0.35 (0.23-0.54) 0.02 0.00 0 1 2 3 4 Follow-up (years) Number at Risk P < 0.0001 Rosuvastatin 7,716 7,699 7,678 6,040 3,608 1,812 1,254 913 508 145 Placebo 7,832 7,806 7,777 6,114 3,656 1,863 1,263 905 507 168

  36. Anti-inflammatory effects of LDL-C reducion on hsCRP • >90% of the reduction in CRP was directly associated with the magnitude of LDL cholesterol reduction, with no difference between high-dose statins or statin-ezetimibe combinations Kinlay S. JACC 2007

  37. ANDROMEDA – reduction in hsCRP in patients with baseline CRP ≥2 mg/L * ‡ 8 weeks 16 weeks RSV 10 mg ATV 10 mg RSV 20 mg ATV 20 mg 0 n=120 n=121 n=115 n=112 –20 Median changefrom baseline(%) –32 –40 ‡ –43 –44 ‡ –52 –60 ‡ ANDROMEDA=A raNdomised, Double-blind, double-dummy, multicentre, phase IIIb, parallel-group study to compare the efficacy and safety of Rosuvastatin (10 mg and 20 mg) and atOrvastatin (10 Mg and 20 mg) in patiEnts with type II DiAbetes mellitus; hsCRP=high-sensitivity C-reactive protein; RSV=rosuvastatin; ATV=atorvastatin*p<0.05 vs ATV at same time point; ‡p<0.001 vs baseline Betteridge DJ et al. Am J Cardiol 2007 in press ;Betteridge DJ et al. Atheroscler Suppl 2005; 6: 102 Abs W16-P-007Betteridge DJ et al. EAS April 2005. Poster presentation

  38. The history of JUPITER 2008 Nov, AHA: JUPITER (paper in NEJM) 2009 Feb, ISC : Stroke (09 Dec. paper in circulation) 2009 Mar, ACC: VTE / Dual treatment target 2009 Sep, ESC: Elderly 2009 Sep: NNT (Circulation Cardiovascular Quality and Outcomes. 2009) 2009 Nov, AHA: Women / IFG / Very low LDL-C 2009 Dec, news: FDA voted

  39. Venous thromboembolism

  40. JUPITER Total Venous Thromboembolism Glynn et al NEJM 2009 HR 0.57, 95%CI 0.37-0.86 P= 0.007 0.025 0.020 Placebo 60/ 8901 0.015 - 43 % Cumulative Incidence 0.010 Rosuvastatin34 / 8901 0.005 0.000 0 1 2 3 4 Follow-up (years) Number at Risk Rosuvastatin 8,901 8,648 8,447 6,575 3,927 1,986 1,376 1,003 548 161 Placebo 8,901 8,652 8,417 6,574 3,943 2,012 1,381 993 556 182 Ridker PM et al on behalf of the JUPITER Trial Study Group N Engl J Med 2009;360

  41. Systolic Heart Failure

  42. CORONA and GISSI-HF Comparators Statin vs placebo - statin alone - combined with non-statin Statin vs statin - different statin - same statin, different dose - combined with non-statin End points • Disease outcome • Surrogate marker

  43. CORONA Rosuvastatin in older patients with systolic heart failure • Patients (≥ 60 yr; n=5011) with systolic heart failure of ischemic cause (EF < 0.4, NYHA II-IV) • 10 mg rosuvastatin daily • LDL-C  45%; hsCRP  37% • Median follow-up of 32.8 months • Primary outcome: death from CV causes, non-fatal MI, and nonfatal stroke NEJM 2007

  44. GISSI-HF / Statin Rosuvastatin in patients with chronic heart failure • Patients (68±11 yr; n=4631) with heart failure (NYHA II-IV) • 10 mg rosuvastatin daily • LDL-C  32% (1st yr), 27% (2nd yr); hsCRP  16% • Median follow-up of 3.9 yrs, average EF < 0.4, • Primary outcome: death • Secondary outcome: death + CV hospitalization Death Death + CV Hospitalization LANCET 2008

  45. Stroke / TIA

  46. SPARCL Comparators Statin vs placebo - statin alone - combined with non-statin Statin vs statin - different statin - same statin, different dose - combined with non-statin End points • Disease outcome • Surrogate marker

  47. SPARCL The Stroke Prevention by Aggressive Reduction in Cholesterol Levels • 4731 patients who with a stroke or TIA within 1-6 months before study entry • LDL-C 100 to 190 mg/dl • No known coronary heart disease • 80 mg of atorvastatin per day or placebo NEJM. 2006

  48. High-Dose Atorvastatin after Strokeor Transient Ischemic Attack (SPARCL) 129 mg/dl 73 mg/dl NJEM. 2006

  49. Chronic Kidney Disease

More Related