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โรคหวใจขาดเลอดและภาวะไขมนผดปกต

Assist Prof. Surarong Chinwong, Ph.D.Department of Pharmaceutical Care

Faculty of Pharmacy. Chiang Mai University.

462505 -2553/1

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Ischaemic heart disease (IHD) is also called coronary heart disease (CHD) or coronary artery disease (CAD)Ischaemic refers to a decreased supply of oxygenated blood, in this case to the heart muscle. Cause by the narrowing of one or more of the major coronary arteries that supply blood to the heart, most commonly by atherosclerotic plaques.

What is ischaemic heart disease?

Cavallari LH, DiDomenico RJ. Ischemic Heart Disease. In: CHISHOLM-BURNS MA, G.WELLS B, SCHWINGHAMMER TL, MALONE PM, KOLESAR JM, ROTSCHAFER JC, et al., editors. Pharmacotherapy: Principles & Practice. New York: The McGraw-Hill Companies, Inc.; 2008. p. 63-82

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Result from an imbalance between myocardial oxygen supply and oxygen demand.Common clinical manifestations of IHD include

chronic stable angina acute coronary syndromes (ACS)

unstable anginanon–ST-segment elevation myocardial

infarction (MI)ST-segment elevation MI.

Ischaemic heart disease


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Prinzmetal’s angina:vasospasm in coronary arteries with no or minimal atherosclerotic disease can produce angina and even precipitate ACSless common

Ischaemic heart disease


6Cavallari LH, DiDomenico RJ. Ischemic Heart Disease. In: CHISHOLM-BURNS MA, G.WELLS B, SCHWINGHAMMER TL, MALONE PM, KOLESAR JM, ROTSCHAFER JC, et al., editors. Pharmacotherapy: Principles & Practice. New York: The McGraw-Hill Companies, Inc.; 2008. p. 63-82

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Atherosclerosis

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What is atherosclerosis?Comes from the Greek words athero

(meaning gruel or paste) and sclerosis (hardness)Condition where vascular smooth

muscle cells, inflammatory cells, lipids, cholesterol and cellular waste accumulate in the inner lining of an arteryProducing a fibro-fatty plaqueThickening of the arterial wall

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Tunica adventitiaTunica mediaTunica intima

Endothelium

Subendothelial connectivetissue

Smooth muscle cell

Internal elastic membrane

Elastic/collagen fibres

External elastic membrane

Adapted from Weissberg PL. Eur Heart J Supplements 1999:1:T13–18

Normal Arterial Wall

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Adhesion molecules

oxLDL

VCAM-1ICAM-1

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TNFα, TNFß, γ interferon,

IL-1, CRP

fibrogenicmediator, GF

Matrix metalloproteinase (MMP)

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migration and proliferation of SMC

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15 16

Acute Coronary SyndromeIschaemic DiscomfortUnstable Symptoms

No ST-segmentelevation

ST-segmentelevation

Unstable angina Non-Q AMI Q-Wave AMI

Abnormal ECG and myocardial infarction

Myocardial ischaemiaT wave inversion, ST segment

depressionMyocardial injury

ST segment elevationMyocardial infarction (necrosis)

abnormal Q-wave (broad (>1mm) and deep (>2mm or more than 25% of the amplitude of the following R wave)

http://www.publicsafety.net/12lead_dx.htm

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Coronary Syndrome (ACS)

Non-ST-segment elevation ACS

ST-segment elevation MI

ST-segment Elevation

Time Dependent: Emergency Evaluation of ACS

Chest pain or Short of Breath

Unstable Angina

ST-segment Depression

– + +

Presentation

ECG

Diagnosis

Braunwald E,2002 http://www.acc.org/clinical/guidelines/unstable/unstable

Normal

Markers

Acute MI

–+

Rule-Out

No ST Elevation ST Elevation

Acute Coronary Syndrome

Unstable Angina NQMI Qw MI

NSTEMI

Myocardial Infarction

Davies MJ Heart 83:361, 2000

Ischemic DiscomfortPresentation

Working Dx

ECG

Biochem. Marker

Final Dx

Hamm Lancet 358:1533,2001

No ST Elevation ST Elevation

Acute Coronary Syndrome

Uns Angina NQMI Qw MI

NSTEMI

Myocardial Infarction

Fibrinolytics

Antiplatelet Rx

Antithrombin Rx 25

1. ปองกนการเกด acute coronary syndrome และการเสยชวต

2. บรรเทาอาการเฉยบพลนของกลามเนอหวใจขาดเลอด3. ปองกนอาการของกลามเนอหวใจขาดเลอดทจะ

กลบมาเปนซา และ4. หลกเลยงหรอลดอาการขางเคยงของการรกษาลงให

นอยทสด

เปาหมายของการรกษาโรคหวใจขาดเลอด

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1. ปรบเปลยนปจจยเสยงของการเกดโรคหวใจและหลอดเลอด โดยมงเนนไปทปจจยเสยงทปรบเปลยนได (modifiable risk factors)

2. ชะลอการดาเนนไปของการเกด atherosclerosis3. ทาให atherosclerosis plaques มเสถยรภาพ เพอไมใหเกด

plague rupture ซงจะตามมาดวย การเกด thrombus หรอ embolus อนเปนสามเหตของการเกด acute coronary syndrome

วธในการการปองกนการเกด ASC และการเสยชวต

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A: Aspirin, Antiplatelet and Antianginal therapy

B: Beta blocker and Blood pressureC: Cigarette smoking and

CholesterolD: Diet and DiabetesE: Education and Exercise

Initial treatment of patients with chronic stable angina

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แพทย

สภา, ชม

รมชางไฟฟ

าหวใจ, กรมก

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ข, สมาคม

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ศไทย

, ราชวท

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, สมาคม

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ดงแห


และคณะ

. แนว

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าดเลอ

ด;20

07.

มไมม

30

*ไมควรใช short acting dihydropyridine CCB

แพทย

สภา, ชม



ารแพ

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ไมม ม

31

แพทย

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ารแพ

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Indicationผปวยภาวะหวใจขาดเลอดเฉยบพลนผปวยโรคหวใจขาดเลอดทกรายทไมมขอหามใชเพอปองกนการเสยชวต และการเกดภาวะแทรกซอน (secondary prevention)

Dosage and administration160-325 mg. เคยวกลนทนทตามดวย 75-325 mg/วน

Caution/precautionมประวตแพยาแอสไพรนเชน เกด bronchospasm, angio-edema, หรอanaphylaxisกาลงมภาวะเลอดออกอยางรนแรง (active bleeding)

Aspirin

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Indicationผปวยโรคหวใจขาดเลอดทไม สามารถใหยา ASA ได (ใชแทน ASA)ผปวยทได รบการใสขดลวดถางหลอดเลอดหวใจ (coronary stents) โดยใหรวมกบ ASA นาน 1 เดอน (Thai)ผปวยภาวะหวใจขาดเลอดเฉยบพลน กลมความเสยงสง และปานกลาง โดยใหรวมกบ ASA นาน 1-9 เดอน (Thai)

Dosage and administrationClopidogrel 300 mg. ทนท ตามดวย 75 mg/วนTiclopidine 500 mg. ทนท ตามดวย 250 mg.วนละ 2 ครง

Clopidogrel, ticlopidine

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Dosage and administrationให clopidogrel 75mg/วน รวมกบ aspirin เปนเวลา 12 เดอนในผปวยหลงเปน acute coronary syndrome (AHA/ACC 2006 – I (B)ให clopidogrel 75mg/วน รวมกบ aspirin ในผปวยทาบอลลนทมการใสขดลวด เปนเวลาอยางนอย 1 เดอนสาหรบ bare metal stent, อยางนอย 3 เดอนสาหรบ sirolimus-eluting stent และอยางนอย 6 เดอนสาหรบ paclitaxel-eluting stent (AHA/ACC 2006 – I (B)

Caution/precautionมโอกาสเกด rash, severe neutropenia, thrombotic, thrombocytopenic purpura (TTP) ซงพบใน ticlopideine มากกวา clopidogrel

Clopidogrel, ticlopidine

CURE Study

Clinical Efficacy of Clopidogrel

Trial Patients Design Maximumfollow-up

Number ofpatients

CAPRIE1 Myocardial infarction, stroke, peripheralarterial disease

Clopidogrelvs ASA

3 years 19,185

CURE3 Acute coronarysyndrome†

Clopidogrel*vs placebo*

1 year 12,562

CLASSICS2 Coronary stenting Clopidogrel*vs ticlopidine*

4 weeks 1,020

1. CAPRIE Steering Committee. Lancet 1996; 348: 1329–39. 2. Bertrand NE et al. Circulation2000; 102: 624–9 3. The CURE Trial Investigators. N Engl J Med 2001; 345: 494–502.

Clinical Benefit of Clopidogrel in more than 30,000 Patients – from CAPRIE to CURE

*On top of standard therapy (including ASA)†Without ST segment elevation

CAPRIE: Long-Term Benefit ofClopidogrel (75) vs. ASA (325)

Cumulative Event Rate(Myocardial Infarction, Ischemic Stroke or Vascular Death)

*ITT analysis

CAPRIE Steering Committee. Lancet 1996; 348: 1329–39.

Months of follow-up

8.7%*

Overallrelative

riskreduction

0

4

8

12

16

0 3 6 9 12 15 18 21 24 27 30 33 36

Cum

ulat

ive

even

t rat

e (%

)

ASA

p = 0.043, n = 19,185

Clopidogrel

CAPRIE: Benefit of Clopidogrel over ASA in the Reduction of Myocardial Infarction1

1. Gent M. Circulation 1997; 96(suppl 8): I-467.

Months of follow-up

0

1

2

3

4

5

0 3 6 9 12 15 18 21 24 27 30 33 36

Cum

ulat

ive

even

t rat

e (%

)

p = 0.008, n = 19,185

ASA 3.6%

Clopidogrel 2.9%

Clopidogrel

ASA 19.2%*

Relativerisk

reduction

*ITT analysis

1. The CURE Study Investigators. Eur Heart J 2000; 21: 2033–41.

CURE: Design1

Double-blind treatment up to 12 months

ASA 75–325 mg o.d.

Clopidogrel75mg o.d.(n = 6,259)

Placebo1 tab o.d.(n = 6,303)

ASA 75–325 mg o.d.

Day 1

6 mon

th vi

sit

9 mon

th vi

sit

12 m

onth

or fi

nal v

isit

Clopidogrel

300m

g load

ing

dose

3 mon

th vi

sit

Disc

harg

e vis

it1 m

onth

visi

t

Patients withacute coronary

syndrome

(unstable angina or non-Q-wave

myocardialinfarction)

Plac

ebo

load

ing

dose

R = Randomization

n = 12,562

28 countries

R

CURE: Early and Long-Term Benefits of Clopidogrel1,2

1. The CURE Trial Investigators. N Engl J Med 2001; 345: 494–502. 2. Data on file, 2002, p73 internal CSR-EFC 3307.

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0 3 6 9 12

Months of follow-up

Cum

mul

ativ

eha

zard

rate Placebo*

(n = 6,303)

Clopidogrel*(n = 6,259)

20% Relativerisk reduction

p = 0.00009

Cumulative Events(Myocardial Infarction, Stroke, or Cardiovascular Death)

*On top of standard therapy (including ASA)

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Indicationผปวยหลงเกดกลามเนอหวใจตายเฉยบพลน ในทมความเสยงสงตอการเกด systemic emboli โดยใหรวมกบ ASA

Dosage and administrationให warfarin โดยใหมคา INR 2 – 3 ในผปวยทม paroxymal หรอ chronic atrial fibrillation หรอ flutter และในผปวยหลงกลามเนอหวใจขาดเลอดทมขอบงใช (เชน atrial fibrillation, left ventricular thrombus)

Caution/precautionควรระวง drug-drug และ food – drug interaction

Warfarin

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Indicationผปวยภาวะหวใจขาดเลอดเฉยบพลนทกรายทไมมขอหามใชผปวยภาวะเจบเคนอกเพอควบคมอาการเจบเคนอกผปวยภาวะหวใจลมเหลวผปวยโรคหวใจขาดเลอดทมความดนโลหตสง (เพอควบคมความดนโลหต)ผปวยทมอาการเจบเคนอกหลงกลามเนอหวใจตายเฉยบพลนผปวย AF ทตองการควบคม ventricular rate

Beta-adrenergic blockers

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Indication (AHA/ACC 2006)Start and continue indefinitely in all patients who have had myocardial infarction, acute coronary syndrome, or left ventricular dysfunction with or without heart failure symptoms, unless contraindicated. I (A)Consider chronic therapy for all other patients with coronary or other vascular disease or diabetes unless contraindicated. IIa (C)


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Dosage and administrationAtenolol 50-200 mg/วนMetoprolol 50-200 mg/วน Propranolol 20-80 mg.วนละ 2ครงBisoprolol 5-10 mg/วน


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Caution/precautionมประวตแพยากลม ß-blockersมหวใจเตนชาผดปกต (อตราการเตนของหวใจ<60 ครงตอนาท)มภาวะหวใจลมเหลวเฉยบพลนม SBP <100 mmHgมคา PR interval >0.24 secม second และ third degree AV block หรอ bifascicular blockเปนหอบหดหรอภาวะปอดอดกนเรอรงภาวะหวใจลมเหลวทยงมนาเกนอย


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Indicationผปวยภาวะหวใจขาดเลอดเฉยบพลน ทมขอหามตอยา ß -blockersผปวยโรคหวใจขาดเลอดทไมสามารถควบคมอาการไดดวยยา ß-blockers และ nitratesผปวยทมอาการเจบเคนอกหลงกลามเนอหวใจตายเฉยบพลน ทไมสามารถคมอาการไดดวย ß -blockersผปวย AF ทตองการควบคม ventricular rate ในรายทมขอหามตอยา ß -blockers (ใหใช verapamil หรอ diltiazem)ใชควบคมความดนเลอด เมอใชยากลมอนไมไดผล

Calcium channel blockers

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Indication (ACC/AHA 2007 UA/NSTEMI)Calcium channel blockers are recommended for ischemic symptoms when beta blockers are not successful –I(B)Calcium channel blockers are recommended for ischemic symptoms when beta blockers are contraindicated or cause unacceptable side effects – I(C)


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Dosage and administrationDiltiazem 120-320 mg/วนVerapamil 120-480 mg/วนAmlodipine 5-10 mg/วนFelodipine 5-10 mg/วน


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Caution/precautionผปวยทม LVEF<0.40ผปวยทมอาการ และอาการแสดงของนาทวมปอด(pulmonary congestion)ม 2nd และ 3rd degree AV block หรอ bifascicular block


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Indicationผปวยโรคหวใจขาดเลอดทกรายเพอปองกนการเสยชวต และการเกดภาวะแทรกซอน (secondary prevention)ผปวยภายหลงกลามเนอหวใจตายทกรายทไมมขอหามใช โดยเฉพาะผทม LVEF<0.40, ม large anterior wall MI, มอาการของหวใจลมเหลวผปวยภาวะหวใจขาดเลอดเฉยบพลนทม LVEF<0.40 และ/หรอมอาการของหวใจลมเหลวผปวย ภาวะหวใจขาดเลอดเฉยบพลน ทไมสามารถควบคมความดนเลอดไดดวย ß -blockers และ nitrates

ACE inhibitors

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Indication (AHA/ACC 2006)Start and continue indefinitely in all patients with left ventricular ejection fraction ≤40% and in those with hypertension, diabetes, or chronic kidney disease, unless contraindicated – I (A)Consider for all other patients – I (B)

ACE inhibitors

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Dosage and administration ขนาดสงสดจากผลการศกษา

Captopril 150 mg/วนEnalapril 40 mg/วนLisinopril 40 mg/วนFosinopril 40 mg/วนRamipril 10 mg/วนQuinapril 40 mg/วน

ACE inhibitors

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Caution/precaution มประวตแพยากลม ACEIs หรอทนผลขางเคยง (เชน ไอ) ไมได มลนหวใจเอออรตกตบปานกลางถงรนแรง มหลอดเลอดแดงทไตตบทง 2 ขาง (bilateral renal artery stenosis) มประวตเกด angioedema ลมพษหรอผน เมอไดยากลม ACEIs มภาวะโปแตสเซยมในเลอดสง มการทางานของไตเสอมลงอยางรนแรง

ACE inhibitors

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Indication (ACC/AHA 2006)ใชในผปวยทไมสามารถทนตอ ACEI และมภาวะหวใจลมเหลว หรอมกลามเนอหวใจตายรวมกบม left ventricular ejection fraction ≤40% - I (A)อาจพจารณาใหในผปวยทกคนทไมสามารถทนตอ ACEI และไมมขอหามใช I (B)

Caution/precautionมลนหวใจเอออรตกตบปานกลางถงรนแรงมหลอดเลอดแดงทไตตบทง 2 ขาง (bilateral renal artery stenosis)มภาวะโปแตสเซยมในเลอดสงมการทางานของไตเสอมลงอยางรนแรง

Angiotensin receptor blockers

58

Indication

ใหในผปวยหลงกลามเนอหวใจตายทกาลงไดรบ ACEI และ ß -blocker, ม left ventricular ejection fraction ≤40% และเปนเบาหวานหรอหวใจลมเหลวและตองไมมการทางานของไตบกพรองอยางมนยสาคญหรอมภาวะโปแตสเซยมสงในเลอด - I (A)

Aldosterone antagonist

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Indication ผปวยโรคหวใจขาดเลอด ทยงมอาการเจบเคนอก (ใชบรรเทาอาการเจบหนาอก) ผปวยภาวะหวใจขาดเลอด ทตองการควบคมลดความดนเลอดและรกษาภาวะหวใจลมเหลว

Dosage and administrationNTG ชนดอมใตลน 1 เมด หรอสเปรย 1 ครงซาไดทก 5 นาท

ชนดหยดทางหลอดเลอดดาเรม NTG ท 10 μg/min เพมไดทก 5 นาท ขนาดสงสดของ IV NTG 200 μg/min ควรเปลยนเปน long-acting nitrates ภายใน 24 ชวโมง เมออาการคงตวแลว

Nitrates

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Treatment & prophylaxis of angina pectorisOral tablet: 5 – 20mg daily วนละ 4 ครง ขนาด maintenance 10 – 40mg วนละ 4 ครง รบประทาน กอนอาหาร 30 นาทSublingual: 1 – 2 tab ทก 2 – 3 ชวโมง

Acute anginaSublingual: 1 tab คอยๆเพมขนาดจนกวาอาการจะดขนหรอมอาการขางเคยง (ปกตจะใชเวลาประมาณ 15 นาทจงจะเหนผล)

Isosorbide dinitrate

61

Prophylaxis of angina pectorisImmediate release 5 -20mg

ควรเรมตนจากขนาด 5mg ในผปวยทตวเลก แตควรเพมเปน 10mg ในวนท 2-3 ขนาดใชทวไป 20mg twice/day โดยรบประทานยาครงแรกหลงตนนอนและครงทสองอก 7 ชวโมงตอมา

Sustained release1 tab วนละครง ในตอนเชา อาจเพมเปน 2 tab ในตอนเชา ถามอาการปวดศรษะ อาจลดลงเหลอ ½ tab daily ไมแนะนาใหใชสาหรบอาการเฉยบพลน

Isosorbide mononitrate

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Caution/precaution ผปวยท SBP <90 mmHg ผปวยทมชพจร <50 ครงตอนาท ผปวยทสงสยวาม right ventricular MI หลกเลยงการใชรวมกบ sildenafil, tadalafil, vardenafil

Nitrates

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Antidyslipidaemicagents

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ชนด ระดบ lipoprotein ทสง I Chylomicrons

IIa Low-density lipoprotein cholesterol (LDL-C)

IIb Low-density lipoprotein cholesterol (LDL-C) and Very-low-density lipoprotein cholesterol (VLDL-C)

III Intermediate-density lipoprotein cholesterol (IDL-C)

IV Very-low-density lipoprotein cholesterol (VLDL-C)

V Very-low-density lipoprotein cholesterol (VLDL-C) และ Chylomicrons

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Relationship between cholesterol

and CHD risk

66

0

Castelli WP. Am J Med 1984;76:4–12

25

50

75

100

125

150

<204 205–234 235–264 265–294 >295

CH

D in

cide

nce

per 1

000

Serum cholesterol (mg/100 mL)

The Framingham Study: Relationship Between Cholesterol and CHD Risk

67

35

Verschuren WM et al. J Am Med Assoc 1995;274(2):131–136

Serum total cholesterol (mmol/L)

30

25

20

15

10

5

0

Death

rate

fro

m C

HD

/1

00

0 m

en

2.60 3.25 3.90 4.50 5.15 5.80 6.45 7.10 7.75 8.40 9.05

Northern Europe

United States

Southern Europe, Inland

Southern Europe, Mediterranean

Japan

Serbia

Seven Countries Study: Relationship between cholesterol and mortality

68

Benefits of lipid lowering treatment

69

4S1

WOSCOPS2

CARE3

LIPID4

AFCAPS/TexCAPS5

HPS6

ASCOT-LLA7

Statin Existing CHD

Patients Cholesterol Follow-up (years)

simvastatin20 mg od

pravastatin40 mg od

pravastatin40 mg od

pravastatin40 mg od

lovastatin40 mg od

Yes

No MI,angina(5%)

Yes

Yes

No

Raised Mean LDL-C 4.87 mmol/L,

188 mg/dL

Raised Mean LDL-C 4.97 mmol/L,

192 mg/dL

Average Mean LDL-C 3.59 mmol/L,

139 mg/dL


147 mg/dL


150 mg/dL

5.4

4.9

5.0

6.1

5.2

4444 male and female, aged 35–70

6595 male, aged 45–64




Study

Yes

In some patients

simvastatin40 mg od


Low/average Mean LDL-C 3.4 mmol/L,

130 mg/dL

5.0

3.3atorvastatin10 mg od

Low/averageMean LDL-C 3.4 mmol/L,

130 mg/dL


Design of Key Statin Trials

70

4S1

LIPID2

CARE4

WOSCOPS6

AFCAPS/TexCAPS7

CHD/high cholesterol

CHD/average to high cholesterol

CHD/average cholesterol

No MI/high cholesterol

No CHD/average cholesterol

HPS3 CHD*/average to high cholesterol

*CHD or CHD risk equivalent, e.g. diabetes

Increasing absolute CHD risk

ASCOT-LLA5 Some patients with CHD/average cholesterol

Spectrum of Risk

71Adapted from Ballantyne CM et al. Am J Cardiol 1998;82:3Q–12Q.

LDL-C achieved mg/dL (mmol/L)

WOSCOPS - Pl

AFCAPS/TexCAPS - Pl

ASCOT - PlAFCAPS/TexCAPS- Rx

WOSCOPS - Rx

ASCOT - Rx

ALLHAT - RxALLHAT - Pl

0

5

10

15

20

25

30

70 (1.8) 90 (2.3) 110 (2.8) 130 (3.4) 150 (3.9) 170 (4.4) 190 (5.0) 210 (5.4)

Even

t ra

te (

%)

- Primary prevention

Rx - Statin therapy

Pl - Placebo

Before 2001



4S - Rx

HPS - Pl

LIPID - Rx

4S - Pl

CARE - Rx

LIPID - Pl

PROSPER - PlCARE - Pl

HPS - Rx

PROSPER - Rx

0

5

10

15

20

25

30

70 (1.8) 90 (2.3) 110 (2.8) 130 (3.4) 150 (3.9) 170 (4.4) 190 (5.0) 210 (5.4)

Even

t ra

te (

%)

- Secondary prevention

Rx - Statin therapy

Pl - Placebo

Before 2001



WOSCOPS - Pl

AFCAPS/TexCAPS - Pl

ASCOT - PlAFCAPS/TexCAPS- Rx

WOSCOPS - Rx

ASCOT - Rx

ALLHAT - RxALLHAT - Pl

4S - Rx

HPS - Pl

LIPID - Rx

4S - Pl

CARE - Rx

LIPID - Pl

PROSPER - PlCARE - Pl

HPS - Rx

PROSPER - Rx

0

5

10

15

20

25

30

70 (1.8) 90 (2.3) 110 (2.8) 130 (3.4) 150 (3.9) 170 (4.4) 190 (5.0) 210 (5.4)

Even

t ra

te (

%)

- Secondary prevention

- Primary prevention

Rx - Statin therapy

Pl - Placebo

Before 2001

74

CHDRisk

100 LDL-C (mg/dL)

Threshold:Unnecessary to

go very low

Linear: The lower, the better

Curvilinear:The lower, the better,

with diminishing returns

0

1

Possible relationship between LDL-C and CHD risk

75

Intensive or standard statin therapy?

PRavastatin Or atorVastatin Evaluation and Infection Therapy (TIMI 22)

Disclosure Statement: Dr. Cannon currently receives research grant support from Bristol-Myers Squibb, Merck and Sanofi-Synthelabo. He

serves as a consultant to AstraZeneca, Glaxo Smith Kline, Guilford Pharmaceuticals and Vertex

Background

Statin therapy is highly effective vs. placebo in long-term treatment of CHD

l Are statins effective in reducing events in patients with an acute coronary syndrome (ACS)?

l Does “intensive” LDL-C lowering to an average of 65 mg/dL achieve a greater reduction in clinical events than “standard”LDL-C lowering to an average of 95 mg/dL?

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 (Post-ACS) Baseline in Median LDL-C

Note: Changes in LDL-C may differ from prior trials: • 25% of patients on statins prior to ACS event• ACS response lowers LDL-C from true baseline

LDL-C (mg/dL)

20

40

60

80

100

120

Rand. 30 Days 4 Mos. 8 Mos. 16 Mos. Final

Pravastatin 40mg

Atorvastatin 80mg49% ↓

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

0 3 18 21 24 27 306 9 12 15

% with

Event

Months of Follow-up

Pravastatin 40mg(26.3%)

Atorvastatin 80mg(22.4%)

16% RR(P = 0.005)

30

25

20

15

10

5

0

Events RatesRR Atorva 80 Prava

40

17% 1.9% 2.2%

18% 6.3% 7.7%

14% 12.2% 14.1%

16% 22.4%* 26.3%*

30 Days

90 Days

180 Days

End of Follow-up

Primary Endpoint Over Time

Atorvastatin 80mg Better0.5 0.75 1.0 1.251.5 Pravastatin 40mg Better *2-year event rates

Reductions in Major Cardiac Endpoints

2 Year Event RatesRR Atorva 80 Prava 40

28% 2.2% 3.2%

30% 1.1% 1.4%

13% 6.6% 7.4%

18% 8.3% 10.0%

14% 16.3% 18.8%

29% 3.8% 5.1%

25% 12.9% 16.7%

0.5 1.0 1.5

All-Cause Mortality

Death or MI

Death/MI/Urg.Revasc

MI

Revasc > 30 dUA Req Hosp

0.75 1.25Atorvastatin 80 mg Better Pravastatin 40 mg Better

CHD Death

A to Z: Phase Z, Early Intensive verses Delayed Simvastatin in Acute Coronary

Syndromes

DesignMulticenter, randomized, double-blind, placebo-controlled

Patients4497 patients, aged 21-80 years, with non-ST-segment-elevation ACS or ST-elevation MI and total cholesterol ≤ 250 mg/dL. Patients receiving statin therapy, or scheduled for CABG or PCI within two weeks, or increased ALT or creatinine were excluded

Follow up and primary endpointPrimary endpoint: composite of cardiovascular death, non-fatal MI, readmission for ACS and stroke. Median follow-up: 721 days.

TreatmentPlacebo (4 months) then simvastatin 20 mg/day or simvastatin 40 mg/day (1 month) then simvastatin 80 mg/day

87

TNT: Treating to New Targets

PurposeTo determine whether cardiovascular risk can be incrementally reduced by lowering LDL cholesterol beyond currently recommended levels

ReferenceLaRosa JC, Grundy SM, Waters DD et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. NEJM 2005;352:1425–1435.

88

TNT: Treating to New TargetsDesign

Multicenter, randomized, double-blind, parallel group, dose comparison

Patients10,001 patients aged 35-75 years with clinically evident coronary heart disease defined by ≥ 1 of: previous myocardial infarction, angina with atherosclerosis or coronary revascularization

89

TNT: Treating to New TargetsFollow up and primary endpoint

Primary endpoint: death from CHD, non-fatal MI, resuscitation after cardiac arrest, fatal or non-fatal stroke

TreatmentAtorvastatin 10 mg or 80 mg per day after 1-8 week washout period for previous lipid-regulating drugs

90

53.846.4

54.346.7

Coronary Revascularization (%)• Angioplasty• Bypass

175 ± 24175 ± 24Total Cholesterol(mean, mg/dl)

97 ± 1898 ± 18LDL Cholesterol(mean, mg/dl)

81.881.2Angina (%)

59.057.7Previous MI (%)

81.280.8Male (%)

61.260.9Age (mean; years)

Atorvastatin 80 mg(n=4995)


53.846.4

54.346.7

Coronary Revascularization (%)• Angioplasty• Bypass

175 ± 24175 ± 24Total Cholesterol(mean, mg/dl)

97 ± 1898 ± 18LDL Cholesterol(mean, mg/dl)

81.881.2Angina (%)

59.057.7Previous MI (%)

81.280.8Male (%)

61.260.9Age (mean; years)



92

0.020.75(0.59-0.96)

117 (2.3%)155 (3.1%)Fatal or non-fatal stroke

0.890.96(0.56-1.67)

25 (0.5%)26 (0.5%)Resuscitation after cardiac arrest

0.0040.78(0.66-0.93)

243 (4.9%)308 (6.2%)Non-fatal, non-procedure-related MI

0.090.80(0.61-1.03)

101 (2.0%)127 (2.5%)Death from CHD

<0.0010.78 (0.69-0.89)

434 (8.7%)548 (10.9%)Total major cardiovascular events

P-valueHazard Ratio(95% CI)

Atorvastatin 80 mg

(n=4995)

Atorvastatin 10 mg

(n=5006)

Primary Outcome

0.020.75(0.59-0.96)

117 (2.3%)155 (3.1%)Fatal or non-fatal stroke

0.890.96(0.56-1.67)

25 (0.5%)26 (0.5%)Resuscitation after cardiac arrest

0.0040.78(0.66-0.93)

243 (4.9%)308 (6.2%)Non-fatal, non-procedure-related MI

0.090.80(0.61-1.03)

101 (2.0%)127 (2.5%)Death from CHD

<0.0010.78 (0.69-0.89)

434 (8.7%)548 (10.9%)Total major cardiovascular events

P-valueHazard Ratio(95% CI)

Atorvastatin 80 mg

(n=4995)

Atorvastatin 10 mg

(n=5006)

Primary Outcome

93

Maj

or c

ardi

ovas

cula

r eve

nt (%

)

Years

80 mg ATV

10 mg ATV

HR = 0.78 (0.69-0.89),P<0.001

TNT: Primary endpoint

94

High-dose atorvastatin80 mg/day

If LDL was <40 mg/dL at 24 wks dose could be reduced to 40 mg/day

n=4,439

Primary Endpoint: Composite of major coronary event, defined as coronary death, hospitalization for non-fatal acute MI or resuscitated cardiac arrest.Secondary Endpoint: Major cardiovascular events, anyCHD event, hospitalization with a primary diagnosis of congestive heart failure, peripheral artery disease, any cardiovascular events and all-cause mortality.

IDEAL Trial: Study Design

Presented at AHA

Standard-dose simvastatin20 mg/day

If cholesterol >190 mg/dL at 24 wks dose could be increased to 40 mg/day

n=4,449

8,888 patients ≤80 years with definite history of myocardial infarction and qualified for stain therapy at time of recruitment

Pts. on statin therapy at baseline: simvastatin (50%), atorvastatin (11%), pravastatin (10%); baseline LDL 121.5 mg/dL; total cholesterol 196 mg/dL; median time from last MI 21 mos in atorvastatin group, 22 mos in simvastatin group

19% female, mean age 62 yrs, fasting blood samples were obtained at baseline, 12 weeks, 24 weeks, 1 year and each year thereafter, mean follow-up median of 4.8 years

Randomized

96

IDEAL Trial: Primary Endpoint

9.310.4

0

3

6

9

12

Atorvastatin Simvastatin

9.310.4

0

3

6

9

12


• The primary composite endpoint of major coronary event occurred in 9.3% of the atorvastatin group and 10.4% of the simvastatin group.

Primary Composite of major coronary event * (%)

p = 0.07

Presented at AHA 2005

%

* Major coronary event defined as coronary death, hospitalization for non-fatal acute MI or resuscitated cardiac arrest.

97

IDEAL Trial: Primary Endpoint cont.

%


3.9

0.2

6.0

4.0

0.2

7.2

0

2

4

6

8

CHD death Cardiac arrest withresuscitation

Nonfatal MI


3.9

0.2

6.0

4.0

0.2

7.2

0

2

4

6

8

CHD death Cardiac arrest withresuscitation

Nonfatal MI


p=NS

p=0.02

p=0.90

• Among the components of the primary endpoint, there was no difference in CHD death or cardiac arrest with resuscitation, but nonfatal MI occurred less frequently in the atorvastatin group.

98

IDEAL Trial: Secondary Endpoints

12.0

26.5

13.7

30.8

0

8

16

24

32

Major CV events Any CV event


12.0

26.5

13.7

30.8

0

8

16

24

32

Major CV events Any CV event


• Major cardiovascular events, defined as any primary event plus stroke, occurred less often in the atorvastatin group.

•Any cardiovascular event, defined as major CV event plus hospitalization for CHF and peripheral artery disease, also occurred less often in the atorvastatingroup.

Major cardiovascular events and any cardiovascular event (%)


%

p=0.02

p<0.001

99 100

102 104

16% reduction in the risk of coronary death or myocardial infarction

105Updated from - O’Keefe, J. et al., J Am Coll Cardiol 2004;43:2142-6.

y = 0.1629x · 4.6776R² = 0.9029p < 0.0001

LDL Cholesterol (mg/dl)

CH

D E

vent

s (%

)

PROVE-IT-PR

PROVE-IT-AT CARE-S

LIPID-S

HPS-S4S-S

HPS-P

CARE-P

LIPID-P

4S-P

0

5

10

15

20

25

30

30 50 70 90 110 130 150 170 190 210

TNT 80TNT 10A2Z 80

A2Z 20

IDEAL S20/40IDEAL A80

The year 2004The year 2005

107

Rel

ativ

e Ris

kfo

r CH

D (

Log S

cale

)

3.7

2.9

2.2

1.7

1.3

1.0

LDL-C (mg/dL)40 70 100 130 160 190

0

1

Grundy SM et al. Circulation 2004;110:227–239.

Log-linear relationship between LDL-C and CHD

108

ATP III LDL-C Goals and Cutpoints for TLC and Drug Therapyin Different Risk Categories and Proposed Modifications

Based on Recent Clinical Trial Evidence

Grundy SM. et al., Circulation 2004;110:227-39.

Risk Category LDL-C Goal Initiate TLC Consider Drug Therapy

High risk:CHD or CHD risk equivalents (10-year risk >20%)

<100 mg/dL(optional goal:

<70 mg/dL)≥100 mg/dL

≥100 mg/dL(<100 mg/dL: consider drug

options)

Moderately high risk:2+ risk factors (10-year risk 10% to 20%)

<130 mg/dL ≥130 mg/dL

≥ 130 mg/dL(100-129 mg/dL: consider drug

options)Moderate risk:2+ risk factors (10 year risk <10%)

<130 mg/dL ≥130 mg/dL ≥ 160 mg/dL

Lower risk:0-1 risk factor <160 mg/dL ≥160 mg/dL

≥ 190 mg/dL(160-189 mg/dL:

LDL-lowering drug optional) 109

Cigarette smokingHypertension (BP ≥140/90mmHg or on antihypertensive medication)Low HDL cholesterol (<40mg/dl)Family history of premature CHD

CHD in male first-degree relative < 55 yearsCHD in female first-degree relative < 65 years

Age men ≥45 yearswomen ≥55 years

Adapted from Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP)Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment PanelIII). JAMA 2001; 285:2486-97

Major risk factors that modify LDL GoalsNCEP ATP III Guidelines

110

Very high risk patientsEstablished atherosclerotic CVD

plus multiple risk factors (esp. diabetes)plus severe and poorly controlled risk

factors (e.g., cigarette smoking)plus metabolic syndrome (high TG, low

HDL-C)plus acute coronary syndromes

Candidates for Very Low LDL-C Goal of <70 mg/dL

Grundy, S. et al., Circulation 2004;110:227-39.111

Role of statins in preventing cardiovascular events

Aggressive lipid lowering therapy with statins is effective in preventing cardiovascular events

Intensive lipid lowering with high-dose statin therapy provides a significant benefit over standard-dose therapy

Evidences support the concept that “lower is better”

113

Drug Class Lipid/lipoprotein effects Side effects Contraindications HMG CoA reductase inhibitor

LDL ↓ 18%-55% HDL ↑ 5%-15% TG ↓ 7%-30%

Myopathy Increased liver enzyme

Absolute: active or chronic liver disease Relative: concomitant use of certain drugs

Bile acid sequestrants

LDL ↓ 15%-30% HDL ↑ 3%-5% TG No change or increase

Gastrointestinal diseases, constipation, decreased absorption of other drugs

Absolute: dysbetalipoproteinemia; TG >400mg/dl Relative: TG>200mg/dl

Nicotinic acid LDL ↓ 5%-25% HDL ↑ 15%-35% TG ↓ 20%-50%

Flushing, hyperglycaemia, hyperuricaemia, upper gastrointestinal distress, hepatotoxicity

Absolute: chronic liver disease; severe gout Relative: diabetes; hyperuricaemia; peptic ulcer disease

Fibric acid LDL ↓ 5%-20% (many be increased in patient with high TG) HDL ↑ 10-25% TG ↓ 20%-50%

Dyspepsia, gallstones, myopathy, unexplained non-CHD deaths in WHO study

Absolute: severe renal disease, sever hepatic disease

Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel onDetection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001;285:2486-97.

Drugs affecting lipoprotein metabolism

114

39-455-10 ‡Rosuvastatin

25-35

35-41

34

31

39

LDL Reduction, %

40-80Fluvastatin

20-40 †

40 †

40 †

10 †

Dose, mg/dDrug

Simvastatin

Pravastatin

Lovastatin

Atorvastatin

Doses of Currently Available Statins Required to Attain an Approximate 30% to 40% Reduction

of LDL-C Levels (Standard Doses)

Grundy, S. et al., Circulation 2004;110:227-39.

† All of these are available at doses up to 80 mg. For every doubling of the dose above the standard dose, an approximate 6% decrease in LDL-C level can be obtained.

‡ For rosuvastatin, doses available up to 40 mg; the efficacy for 5 mg is estimated by subtracting 6% from the FDA reported efficacy at 10 mg

115

Pleiotropic effects of statins

116

117Liao JK, et al. Annual Review of Pharmacology and Toxicology 2005;45: 89-118.

118Endres M. Statins: Potential new indications in inflammatory conditions. AtherosclesisSupplement 2006;7: 31-35.

Increase eNOSexpression

Prolonging eNOSmRNA half-life

↓NAD(P)H activity↓supperoxide

productionGTP-

binding protein

119Liao JK, et al. Annual Review of Pharmacology and Toxicology 2005;45: 89-118.

inhibit Rac1 mediated NAD(P)H

oxidase activity

downregulating AT1receptor

expression

121

The dose-response limitations of statins

Failure to achieve LDL-C goal Each doubling of a statin dose

provides only 6% additional LDL-C reduction

“Rule of six”

SPARCL Trial

SPARCL was designed to evaluate whether high-dose statin treatment reduces risk of stroke in patients with a recent stroke or TIA and no history of coronary heart disease

SPARCL: Background and rationale

• Patients with prior stroke/TIA are at risk for future cardiovascular (CV) events

• Statins ↓stroke incidence in patients at risk for CV disease; however, stroke risk reduction with statin therapy has not been demonstrated in patients with a history of stroke or TIA

SPARCL Investigators. Cerebrovasc Dis. 2003;16:389-95.Heart Protection Study Collaborative Group. Lancet. 2004;363:757-67.

SPARCL: Study design

SPARCL Investigators. N Engl J Med. 2006;355:549-59.

Stroke or TIA in ≤6 months,no known CHD, LDL-C 100–190 mg/dL

N = 4731

Atorvastatin 80 mg dailyn = 2365

Placebon = 2366

Randomized Double blind

Primary end point: Fatal/nonfatal strokeSecondary end points: Major coronary or CV events

Follow-up: ~5 years (until >540 primary end points)

SPARCL: Baseline characteristics

1717Diabetes6162Hypertension

3941Former smoker 1919Current smoker

Risk factors (%)143144Triglycerides5050HDL-C

134133LDL-CLipid profile (mg/dL)

138139Systolic BP (mm Hg)6363Age (years)5960Male (%)

Placebon = 2366

Atorvastatinn = 2365


SPARCL: Entry events

(<0.1)1(0.1)2Unknown

(32)752(30)708TIA

(68)(66)

(2)(0.3)

16131559

486

(70)(67)

(2)(0.6)

16551595

4515

Entry event*

StrokeIschemicHemorrhagicOther type or not determined

(%)n(%)nPlaceboAtorvastatin

*Ischemic stroke or TIA in >97% of patients SPARCL Investigators. N Engl J Med. 2006;355:549-59.

N = 4731SPARCL: Concomitant medications


154 (7)139 (6)Vitamin K antagonist, including warfarin63 (3)57 (2)Prior statin therapy

102 (4)110 (5)ARB422 (18)414 (18)β-blocker359 (15)350 (15)Dihydropyridine derivative667 (28)683 (29)ACE inhibitor

2063 (87)2067 (87)Antiplatelet agentConcomitant therapy

Placebon (%)

Atorvastatinn (%)

N = 4731

Time since randomization (years)

SPARCL: High-dose statin treatment reduces fatal/nonfatal stroke

*Adjusted SPARCL Investigators. N Engl J Med. 2006;355:549-59.

Fatal/ nonfatal stroke

(%)

00 1 2 3 4 5 6

16

12

8

4

16% RRR*HR 0.84 (0.71–0.99)P = 0.03

Placebo

Atorvastatin

NNT = 46 patientsfor 5 years

Primary outcomeSPARCL: Treatment effect on stroke and TIA

Hazard ratio

SPARCL Investigators. N Engl J Med. 2006;355:549-59. *Adjusted

HR* (95% CI)

0.84 (0.71–0.99)

0.57 (0.35–0.95)

0.87 (0.73–1.03)

0.77 (0.67–0.88)

0.74 (0.60–0.91)

Primary outcome

Stroke (total)

Fatal

Nonfatal

Secondary outcomes

Stroke or TIA

TIA

P

0.03

0.03

0.11

<0.001

0.004

0.3 1.0 1.7

N = 4731Aggressive statin therapy

Better Worse

SPARCL: High-dose statin reduces majorcoronary events and stroke

SPARCL Investigators. N Engl J Med. 2006;355:549-59. *Cardiac death, MI, resuscitatedcardiac arrest, and stroke

00

30

20

10

1 2 3 4 5 6Time since randomization (years)

Major CV events*

(%)

20% RRRHR 0.80 (0.69–0.92)P = 0.002

Placebo

Atorvastatin

NNT = 29 patientsfor 5 years

SPARCL: Reductions in major coronary events

SPARCL Investigators. N Engl J Med. 2006;355:549-59. *Cardiac death, MI, resuscitated cardiac arrest

00

10

6

2

1 2 3 4 5 6Time since randomization (years)

Major coronary events*

(%)

35% RRRHR 0.65 (0.49–0.87)P = 0.003

Placebo

Atorvastatin

8

4

SPARCL: Adverse events


011

37

141

nPlaceboAtorvastatin

251

27

129

n

(0.5)(2.2)ALT or AST >3x ULN(0.1)Creatine kinase >10x ULN

(6.0)(5.5)Myalgia(0.3)(0.3)Myopathy(0.1)(0.1)Rhabdomyolysis

Musculoskeletal AE(%)(%)

N = 4731

SPARCL: Summary

Atorvastatin 80 mg yielded:

Primary end point↓16% fatal/nonfatal stroke (P = 0.03)

• Significant benefit despite small ↑hemorrhagic stroke with atorvastatin (2.3%) vs placebo (1.4%)

Secondary end points↓35% major coronary events (P = 0.003)↓20% major CV events (P = 0.002)↓42% any coronary events (P < 0.001)↓26% any CV events (P < 0.001)↓45% revascularizations (P < 0.001)


SPARCL: Implications

• Aggressive statin therapy should be strongly considered soon after stroke or TIA

• Magnitude of benefit may vary depending on baseline stroke subtype

• SPARCL results support the concept of stroke or TIA as a CHD risk equivalent


Investigate whether an acute atorvastatin reload before percutaneous coronary intervention (PCI) protects patients receiving chronic statin therapy from periprocedural myocardial damage.

Patients with coronary artery disease who require coronary angiography

Open-label; mean age 58.5 years; mean follow-up at 2 years; 29% female.

Withdrawn consent, withdrawn for other reasons, adverse event (n=63), n=158 Follow-up IVUS at 24

monthsn=349

Primary Endpoint: 1) Change in percent atheroma volume and 2) change in nominal atheroma volume in the 10 mm

subsegment with the greatest disease severity at baseline.Secondary Endpoint: Change in normalized total atheroma

volume for the entire artery.

ASTEROID Trial

All enrolled patients: 40 mg rosuvastatin, IVUS of a single vessel

not intervened upon at baseline n=507

0

50

100

150

200

250

LDL-C Total-C HDL-C Triglyceride non-HDL-C

Before After

Changes in LDL-C, Total-C, HDL-C, Triglyceride and non-HDL-C levels

Sipahi I, Nicholls S, Tuzcu E, Nissen S. Interpreting the ASTEROID trial: Coronary atherosclerosis can regress with very intensive statintherapy.Cleve Clin J Med, 2006; 73:937-944.

Reprinted with permission. Copyright 2006. Cleveland Clinic Foundation. All rights reserved.

Example of regression of atherosclerosis with rosuvastatin in ASTEROID, measured by IVUS

*p<0.001 for difference from baseline values. Wilcoxon signed rank test

-0.9

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0Median Percent Atheroma Volume

Chan

ge

from

bas

elin

e (%

)

- 0.79%

*

n=349

Ref: Nissen S et al. JAMA 2006;295 (13):1556-1565.

Endpoint analysis: Change in median percentage atheroma volume

*p<0.001 for difference from baseline. Wilcoxon signed rank test

-10-9-8-7-6-5-4-3-2-10

Median Atheroma Volume in themost diseased 10mm

subsegmentMedian Normalised Total

Atheroma Volume

Chan

ge

from

bas

elin

e (%

)

- 9.1%*

*- 6.8%

n=319 n=346

Ref: Nissen S et al. JAMA 2006;295 (13):1556-1565.

Endpoint analysis: Change in key IVUS parameters

For patients with CHD, Very high-intensity statin therapy using rosuvastatin 40 mg/d achieved an average LDL-C of 60.8 mg/dLand increased HDL-C by 14.7%, resulting in significant regression of atherosclerosis.

Treatment to LDL-C levels below currently accepted guidelines, when accompanied by significant HDL-C increases, can regress atherosclerosis in coronary disease patients.

ASTEROID Trial

150

Rosuvastatin 20 mg (N=8901) MIStroke

UnstableAngina

CVD DeathCABG/PTCA

JUPITERMulti-National Randomized Double Blind Placebo Controlled Trial of

Rosuvastatin in the Prevention of Cardiovascular EventsAmong Individuals With Low LDL and Elevated hsCRP

4-week run-in

Ridker et al, Circulation 2003;108:2292-2297.

No Prior CVD or DMMen >50, Women >60

LDL <130 mg/dLhsCRP >2 mg/L

Placebo (N=8901)

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica, Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands, Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,

United Kingdom, Uruguay, United States, Venezuela

151

Rosuvastatin Placebo(N = 8901) (n = 8901)

hsCRP, mg/L 4.2 (2.8 - 7.1) 4.3 (2.8 - 7.2)

LDL, mg/dL 108 (94 - 119) 108 (94 - 119)

HDL, mg/dL 49 (40 – 60) 49 (40 – 60)

Triglycerides, mg/L 118 (85 - 169) 118 (86 - 169)

Total Cholesterol, mg/dL 186 (168 - 200) 185 (169 - 199)

Glucose, mg/dL 94 (87 – 102) 94 (88 – 102)

HbA1c, % 5.7 (5.4 – 5.9) 5.7 (5.5 – 5.9)

All values are median (interquartile range). [ Mean LDL = 104 mg/dL ]

Ridker et al NEJM 2008

152

0

1

2

3

4

5

hsC

RP

(mg/

L)

0

20

40

60

80

100

120

140

LDL

(mg/

dL)

Months0 12 24 36 48

0

10

20

30

40

50

60

0

20

40

60

80

100

120

140

0 12 24 36 48

TG (

mg/

dL)

HD

L (m

g/dL

)

Months

LDL decrease 50 percent at 12 months

hsCRP decrease 37 percent at 12 months

HDL increase 4 percent at 12 months

TG decrease 17 percent at 12 months


153

Placebo 251 / 8901

Rosuvastatin 142 / 8901

HR 0.56, 95% CI 0.46-0.69P < 0.00001

- 44 %

0 1 2 3 4

0.00

0.02

0.04

0.06

0.08

Cum

ulat

ive

Inci

denc

e

Number at Risk Follow-up (years)RosuvastatinPlacebo

8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 1578,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174

Ridker et al NEJM 2008JUPITERPrimary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

154

JUPITERIndividual Components of the Primary Endpoint

*Nonfatal MI, nonfatal stroke, revascularization, unstable angina, CV death

Endpoint Rosuvastatin Placebo HR 95%CI P

Primary Endpoint* 142 251 0.56 0.46-0.69 <0.00001

Non-fatal MI 22 62 0.35 0.22-0.58 <0.00001Any MI 31 68 0.46 0.30-0.70 <0.0002

Non-fatal Stroke 30 58 0.52 0.33-0.80 0.003Any Stroke 33 64 0.52 0.34-0.79 0.002

Revascularizationor Unstable Angina 76 143 0.53 0.40-0.70 <0.00001

MI, Stroke, CV Death 83 157 0.53 0.40-0.69 <0.00001


155

JUPITERSecondary Endpoint – All Cause Mortality

Placebo 247 / 8901

Rosuvastatin 198 / 8901

HR 0.80, 95%CI 0.67-0.97P= 0.02

- 20 %

0 1 2 3 4

0.00

0.01

0.02

0.03

0.04

0.05

0.06

Cum

ulat

ive

Inci

denc

e

Number at Risk Follow-up (years)RosuvastatinPlacebo

8,901 8,847 8,787 6,999 4,312 2,268 1,602 1,192 683 2278,901 8,852 8,775 6,987 4,319 2,295 1,614 1,196 684 246


156

JUPITERStatins and the Development of Diabetes

0.25 0.5 1.0 2 4

WOSCOPS Pravastatin

HPS Simvastatin

ASCOT-LLA Atorvastatin

JUPITER Rosuvastatin

PROVE-IT AtorvastatinVS

Pravastatin

0.70 (0.50–0.98)

1.20 (0.98–1.35)

1.20 (0.91–1.44)

1.11 (0.67–1.83)

1.25 (1.05–1.54)

Statin Better Statin Worse

HR (95% CI)

PROSPER Pravastatin 1.34 (1.06–1.68)


157Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering drugs: mechanisms and clinicalrelevance. Clin Pharmacol Ther. 2006;80(6):565-81.

158 159

160

SIM ATO FLU PRA ROS PIT

Fold increase of statin AUC by CYP3A4 inhibitor Itraconazole 5-20 2-4 ~ ~ ~ ~

Erythromycin, clarithromycin 4-12 1.5-5 ~ 2 ~ ~

Verapamil, diltiazem 3-8 ? ~ ~ ~ ~

Fold increase of statin AUC by Cyclosporin 6-8 6-15 2-4 5-10 5-10 5 Gemfibrozil 2-3 1.5 ~ 2 2 1.5 Grapefruit juice 2-10 1-4 ~ ~ ~ ~

Percentage decrease of statin AUC by potent inducer

Rifampin, carbamazepine

70-95

60-90 50 30 ? ?

Effect of some agents on AUC

164

Effects of renal/hepatic impairment

Atorvastatin Plasma levels not affected by renal disease;

markedly increased with chronic alcoholic liver disease.

Fluvastatin Potential drug accumulation with hepatic insufficiency

Pravastatin

Potential drug accumulation with renal or hepatic insufficiency. Mean AUC varied 18-fold in cirrhotic patients and peak values varied 47-

fold.

Rosuvastatin Increased plasma concentrations with severe renal impairment and hepatic disease

Simvastatin Higher systemic exposure may occur in hepatic and severe renal insufficiency

165

Ezetimibe

Fecal bile acids and neutral sterols (~700 mg/day)

Extrahepatictissues

*And extrahepatic tissueAdapted from Champe PC, Harvey RA. In Biochemistry. 2nd ed. Philadelphia: Lippincott Raven, 1994; Glew RH. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:728–777; Ginsberg HN, Goldberg IJ. In Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998:2138–2149; Shepherd J Eur Heart J Suppl 2001;3(suppl E):E2–E5; Hopfer U. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:1082–1150; Bays H Expert Opin Investig Drugs 2002;11:1587–1604.

Biliarycholesterol(~1000 mg/day)

Absorption(~700 mg/day)

LiverSynthesis*(~800 mg/day)

Intestine

Dietarycholesterol

(~300–700 mg/day)

166

Cholesterol Absorption in the Intestine

ACAT=acyl-coenzyme A:cholesterol acyltransferase; NPC1L1=Niemann-Pick C1 Like 1Adapted from Champe PC, Harvey RA. In Biochemistry. 2nd ed. Philadelphia: Lippincott Raven, 1994; Ginsberg HN, Goldberg IJ. In Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998:2138–2149; Shepherd J Eur Heart J Suppl2001;3(suppl E):E2–E5; Hopfer U. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:1082–1150;Davis JP et al Genomics 2000;65:137–145.

NPC1L1

Resins

Plant stanols

167

Ezetimibe monotherapy is an option for adults with primary (heterozygous-familial or non-familial) hypercholesterolaemia (at 20% or greater 10–year CVD risk) in whom statins are contraindicated or not tolerated

Ezetimibe, co-administered with initial statintherapy, is an option for patients with primary hypercholesterolaemia taking statins when: TC or LDL ‘is not appropriately controlled’ either after dose titration of initial statin therapy or because dose titration is limited by intolerance to the statintherapy

Ezetimibe

168

???????Although ezetimibe effectively lowers LDL levels, there is currently no published evidence that ezetimibe alone or added to a statin helps patients live longer or live betterENHANCE study (January 2008): no significant difference in carotid intima-media thickness with ezetimibe versus placebo, added to simvastatin80mg, in familial hypercholesterolaemiaSEAS study (September 2008): no significant difference in major CV events with ezetimibe + simvastatin 40mg, versus placebo in patients with aortic stenosis. Hazard Ratio (HR) for new cancer 1.55, P=0.01

Ezetimibe

ENHANCE Study Design

Simvastatin 80 mg

RANDOMIZATION

0 24

Months

3 6 9 12 15 18 21

Pre-randomization Phase

FH:LDL-C ≥ 210 mg/dL

Screening and Fibrate

Washout

Placebo Lead-In/

Drug Washout

Weeks

-6-10 to -7

Ezetimibe 10 mg-Simvastatin 80 mg

IMT assessment

SEAS Study Design• Randomized

• Double-blind

• Placebo-controlled

• Multicentre

• 4 weeks placebo/diet run-in

• Simvastatin 40 mg + ezetimibe 10 mg or placebo

• Median duration: 4.5 years(minimum follow-up 4 years)

Inclusion criteria

• Men and women• Age 45 - 85 years• Asymptomatic• Valvular AS:

– Aortic valve thickening on echocardiographicevaluation

– Doppler jet velocity ≥2.5 - ≤4.0 m/sec

• Normal LV systolic function

Fatal Cancer

PlaceboEzetimibe/Simvastatin 10/40 mg

No. at risk

930 916

912 890

884 865

855 835

89 94

P=0.05 UnadjustedP=0.06 With Log-rank continuity correction

0 1 2 3 4 5Years in study

0

5

10

15

20

Hazard ratio: 1.67

Cum

ulat

ive

perc

enta

ge

Ezetimibe/Simvastatin 10/40 mg

Placebo

Intention-to-Treat Population

n=23 (2.5%)

n=39 (4.1%)

180

ยา ขนาด วธใช

• Gemfibrozil

Lopid® cap 300mg

Lopid® tab 450, 600mg

Lopid OD® tab 900mg

• 600mg วนละ 2 ครง

• 900mg (Lopid OD® tab) 1 tab วนละครง

• ขนาดยาสงสด: 1.5g/day

• ควรรบประทานตอนทอง

วาง

• รบประทานกอนอาหาร

½ ชวโมง

• Fenofibrate

Fenox® cap 300mg

Lipanthyl® cap 100mg

Supralip 160® tab

160mg (microcoated)

Supralip NT 145® tab

145mg (nanoparticles)

• ผใหญ: ขนาดยาขนกบตาหรบยา (formulation)

• Micronised formulations: เรมในขนาด 67mg วนละ 3 ครง หรอ

200mg วนละครง

• Non-micronised formulation: เรมในขนาด 200 – 300mg/day โดย

แบงให, ขนาดรกษาปกต 200 – 400mg/day

• สาหรบตารบทพฒนา bioavailability (เชน nanoparticles) ขนาดใช

40 – 160mg/day วนละครง

• เดก: 5mg/kg/day

• ปรบลดขนาดยาในผปวยทมการทางานของไตบกพรอง

• ควรรบประทานพรอม

อาหาร

• กลนทงเมด หามเคยว

หก แบงหรอ บด

Fibric acid derivative

181

Cardiol Rev 2008;16:129 - 41.

182

กอนทจะใหยาลดระดบไขมนในเลอดควรตรวจการทางานของตบและไตกอนถาระดบ transaminase มคามากกวา 3 เทาของคาปกตสงสด (upper limit of normal) ไมควรใชยาในกลม statins และ fibratesถาระดบ creatinine มคามากกวา 2.0 mg/dl การใชยาในกลม fibrates ตองลดขนาดทใชลง เนองจากยาในกลมดงกลาว มการทาลายทไต หากระดบ creatinine มคามากกวา 4 mg/dl ไมควรใชยาในกลม fibrates เลย

การตดตามการรกษาผปวยทมภาวะไขมนผดปกตในเลอด

183

การตดตามระดบไขมนในเลอดหลงการรกษา ควรทาหลงการรกษาแลวประมาณ 6 -12 สปดาหตอจากนนควรไดรบการตรวจระดบไขมนในเลอดทกตวทก 3 – 6 เดอนตามความเหมาะสม เมอเรมรกษาดวยยาในกลม statins หรอ fibrates ควรตรวจระดบ transaminase หลงจากทไดรบยาไปแลว 6 – 12 สปดาหเพอดอาการไมพงประสงคจากยาดงกลาว ถาอยในเกณฑปกตควรตดตามเปนระยะๆ ปละ 1 – 2 ครงแมจะมขอมลวาการใชยาระยะยาวมความปลอดภย กรณทใชยาขนาดสง หรอ ใชยา 2 ชนดขนไปรวมกน ควรตดตามทก 3 – 6 เดอนหรอตามความเหมาะสม


184

เมอพบระดบ transaminase เพมขนเกน 3 เทาของคาปกตสงสดใหหยดยาหากมอาการปวดเมอยกลามเนอควรตรวจระดบ CPK ดวย ถามคามากกวา 10 เทา บงชวา myopathy ซงอาจรนแรงขนเปน rhabdomyolysis จาเปนตองหยดยาเชนกน ในกรณทตองใช statin รวมกบ fibrate ผปวยควรมการทางานของตบและไตทอยในเกณฑปกตคอระดบ transaminases และ creatinine อยในเกณฑปกตและควรตดตามระดบ SGOT, SGPT และ CPK ทก 1 – 2 เดอนในระยะ 6 เดอนแรก เนองจากอาจ เพมความเสยงตอการเกด rhabdomyolysis และ hepatitis ได


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