高血脂症治療之新趨勢 成大醫院 心臟內科 李貽恆

N Engl J Med. 1997;337:408–416. N Engl J Med. 1997;337:408–416. Importance of Cholesterol in Atherosclerosis Importance of Cholesterol in Atherosclerosis

Prospective Cardiovascular M ü nster Study CHD Risk According to LDL Cholesterol Incidence (per 1,000 in 6 years) LDL cholesterol 177 events, 4263 men aged years Taken from Lipid Metabolism Disorders and Coronary Heart Disease, G. Assmann, Editor, MMV Medizin Verlag, Munich 1993 <135 < >195 >5.0 (mg/dl) (mmol/L)

Steps for Evaluation of Hypercholesterolemia National Cholesterol Education Program (NCEP): The Third Report in Adult Treatment Panel (ATP III)

Step 1 Determine Lipoprotein Levels Obtain complete lipoprotein profile (total cholesterol, LDL, HDL, triglyceride) after 9- to 12-hour fast In all adults aged 20 years or older, a fasting lipid profile should be obtained once every 5 years

Step 2 Identify Presence of CHD or CHD Risk Equivalent Clinical Coronary heart disease (CHD) Symptomatic carotid artery disease Peripheral arterial disease Abdominal aortic aneurysm Diabetes Diabetes

Step 3 Determine Presence of Major Risk Factors Cigarette smoking Hypertension Low HDL (<40 mg/dl) Family history of premature CHD CHD in male first degree relative <55 years CHD in female first degree relative <65 years Age (men  45 years; women  55 years) HDL  60 mg/dl counts as a negative factor

100 to  130 risk equivalent † 130 to  to  190 NCEP ATP III LDL Cholesterol Goals and Therapy Recommendations *Authorities disagree on when to initiate drug therapy. † This category refers to patients without clinically evident CHD, but who have a similar risk for CHD events (eg, patients with diabetes, multiple risk factors, or other forms of atherosclerotic disease, such as peripheral artery disease). NCEP ATP III guidelines. JAMA. 2001;285: Initiate therapeutic lifestyle changes Goal Initiate drug therapy* LDL cholesterol level (mg/dL)

Current treatment guideline in Taiwan CHD or DM CHD or DM TC  200mg/dL or LDL-C  130mg/dL Goal  TC < 160mg/dL or LDL-C < 100mg/dL 2+ Risk Factor: TC  200mg/dL or LDL-C  130mg/dL Goal  TC < 200mg/dL or LDL-C < 130mg/dL 0-1+ Risk Factor: TC  240mg/dL or LDL-C  160mg/dL Goal  TC < 240mg/dL or LDL-C < 160mg/dL Risk Factors: (adapted from BNHI lipid treatment guideline) – Hypertension – Family history of premature CHD – Male  45 yrs – Female  55 yrs or postmenopausal women without treating by ERT – Smoking

Selection of Lipid-Lowing Drugs Effective Safe Evidence Effects beyond lipid-lowering

Patients with CHD event (%) S=statin treated P=placebo treated *Extrapolated to 5 years 4S-P CARE-P LIPID-P 4S-S WOSCOPS-S -P AFCAPS-P -S LIPID-S CARE-S Primary Prevention Simvastatin Pravastatin Lovastatin Atherosclerosis. 1999;143(Suppl 1): S17-S21. HPS-S -P Atorvastatin ASCOT-S * -P * Secondary Prevention LDL-C (mg/dL) Effects of lipid-lowering therapy on CHD events in statin trials

Beyond Cholesterol Lowering Effects of Statins Improved Endothelial Function Plaque stabilization Anti-inflammation Decreased lipoprotein oxidation Decreased blood coagulation

250 mmHg Baseline sec after hyperemia Celermajer et al Lancet mm 5.0 mm, FMD=11% After sublingual nitroglycerin 5.3 mm, 18 % Brachial Artery Test – flow-mediated dilatation

Time (weeks) *60 patients admitted for acute MI or unstable angina, enrolled before hospital discharge Flow-mediated dilatation (%)* Pravastatin 40 mg/day Placebo p<0.05 The RECIFE study: Pravastatin rapidly improves endothelial function after ACS Dupuis et al. Circulation 1999;99:3227–3233.

Beyond Cholesterol Lowering Effects of Statins Improved Endothelial Function Plaque stabilization Anti-inflammation Decreased lipoprotein oxidation Decreased blood coagulation

Importance of Cholesterol in Pathogenesis of Plaque Rupture Circulation 1995;91:2844

Potential Mechanisms of Benefit of Statins in Plaque Stabilization Statins LDL-C reduction Reduction in chylomicron and VLDL remnants, IDL, LDL-C Restore endothelial function Modulate SMC function Anti-inflammatory effects Decreased thrombosis Lumen Lipid Core Macrophages Smooth Muscle Cells

AVERT Study Design: Atorvastatin Versus Revascularisation Treatments 18 months atorvastatin 80 mg 341 Patients PTCA + usual care Stable CAD; ETT >4 min w/o ischemia Asymptomatic to mildly symptomatic (Class I-II angina) 1-2 vessel disease Target stenosis 50-90% LDL >115 mg/dl TG <500 mg/dl Patient Population Primary Endpoint Incidence of ischemic events (CHD death, non-fatal MI, revascularization, CVA, documented angina)

N Engl J Med 1999;341:  36% difference * (P=0.048) n=22 of 164n=37 of 177 Ischemic Events

P=0.027 Time since randomization (months) N Engl J Med 1999;341:70 Atorvastatin (n=164) Angioplasty/UC (n=177) Time to First Ischemic Event

MIRACL study design Prospective, randomised, multicentre, double-blind 3,086 patients 80 mg atorvastatin, commenced within 24–96 h of event Follow up at 2, 6 and 16 weeks for endpoints, ECG, labs and AEs Inclusion criteria UA or non-Q-wave MI in previous 1–4 days Primary Time from randomisation to first occurrence of any of the following: nDeath (any cause) nNon-fatal MI nResuscitated cardiac arrest nWorsening angina pectoris with new objective evidence of myocardial ischaemia, requiring urgent rehospitalisation Placebo, commenced within 24–96 h of event Secondary Time to occurrence and incidence of each of the primary outcome components, plus: nStroke nMyocardial revascularisation (CABG or PTCA) nWorsening congestive heart failure nWorsening angina without new objective evidence of ischaemia Schwartz et al JAMA 1998;285 :

Cumulative incidence (%) Time since randomisation (weeks) Atorvastatin Placebo 17.4% 14.8% Risk reduction = 16% p=0.048 Time to first occurrence of composite endpoint of: Primary efficacy measure 95% CI = 0.701–0.999 n Death (any cause) n Non-fatal MI n Resuscitated cardiac arrest n Worsening angina with new objective evidence and urgent rehospitalisation Schwartz et al JAMA 1998;285 :

LIPID-Rx 4S-Pl CARE-Rx % reduction CAD morbidity LDL cholesterol mg/dl WOS-Rx WOS-Pl -RX AFCAPS-RX AFCAPS-Pl S-Rx LIPID-Pl CARE-Pl Secondary CAD prevention Primary CAD prevention ? How low do we have to go ? ?

4,162 patients with an Acute Coronary Syndrome < 10 days ASA + Standard Medical Therapy “Standard Therapy” Pravastatin 40 mg “Intensive Therapy” Atorvastatin 80 mg Duration: Mean 2 year follow-up (>925 events) Primary Endpoint: Death, MI, Documented UA requiring hospitalization, revascularization (> 30 days after randomization), or Stroke PROVE IT - TIMI 22 Study Design 2x2 Factorial: Gatifloxacin vs. placebo Double-blind

Changes from Baseline in Median LDL-C Note: Changes in LDL-C may differ from prior trials: 25% of patients on statins prior to ACS event 25% of patients on statins prior to ACS event ACS response lowers LDL-C from true baseline ACS response lowers LDL-C from true baseline LDL-C (mg/dL) Rand.30 Days4 Mos.8 Mos.16 Mos.Final Pravastatin 40mg Atorvastatin 80mg 49%  21%  P<0.001 Median LDL-C (Q1, Q3) 95 (79, 113) 62 (50, 79) <24h

All-Cause Death or Major CV Events in All Randomized Subjects % with Event Months of Follow-up Pravastatin 40mg (26.3%) Atorvastatin 80mg (22.4%) 16% RR (P = 0.005)

Our findings indicate that patients recently hospitalized for an acute coronary syndrome benefit from early and continued lowering of LDL-C to levels substantially below current target levels. Cannon CP, Braunwald E, McCabe CH, et al. N Engl J Med 2004;350:15

Monitoring statin use Headache, dyspepsia Muscle soreness, tenderness and pain Evaluate muscle symptoms and CK before starting therapy, at 6-12 wks after therapy and at each visit. GOT, GPT Evaluate GOT/GPT initially, 12 weeks after therapy and annually or more frequently if necessary. JACC 2002;40:567

Current treatment guideline in Taiwan CHD or DM CHD or DM TC  200mg/dL or LDL-C  130mg/dL Goal  TC < 160mg/dL or LDL-C < 100mg/dL 2+ Risk Factor: TC  200mg/dL or LDL-C  130mg/dL Goal  TC < 200mg/dL or LDL-C < 130mg/dL 0-1+ Risk Factor: TC  240mg/dL or LDL-C  160mg/dL Goal  TC < 240mg/dL or LDL-C < 160mg/dL Risk Factors: (adapted from BNHI lipid treatment guideline) – Hypertension – Family history of premature CHD – Male  45 yrs – Female  55 yrs or postmenopausal women without treating by ERT – Smoking

Summary Well control of hyperlipidemia can reduced CAD LDL level is the first target to treat HMGCoA reductase inhibitors are effective lipid- lowering drugs with clinical evidence Early administration of statin in acute coronary syndrome can reduce ischemic events

Classification of Serum Triglycerides Normal <150 mg/dL Borderline high150–199 mg/dL High200–499 mg/dL Very high  500 mg/dL ATP III Lipid and Lipoprotein Classification

New Features of ATP III Non-HDL Cholesterol: Secondary Target Non-HDL cholesterol = VLDL + LDL cholesterol = (Total Cholesterol – HDL cholesterol) Non-HDL cholesterol: secondary target of therapy when serum triglycerides are  200 mg/dL (esp. 200 – 499 mg/dL) Non-HDL cholesterol goal: LDL-cholesterol goal + 30 mg/dL