462505 -2553/1

What is ischaemic heart disease?

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.
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 2

Assist Prof. Surarong Chinwong, Ph.D. Department of Pharmaceutical Care 1 Faculty of Pharmacy. Chiang Mai University.

Ischaemic heart disease

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 angina nonST-segment elevation myocardial infarction (MI) ST-segment elevation MI.
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 3 4

Ischaemic heart disease

Prinzmetals angina: vasospasm in coronary arteries with no or minimal atherosclerotic disease can produce angina and even precipitate ACS less common

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

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

What is atherosclerosis?

Atherosclerosis
7

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 artery Producing a fibro-fatty plaque Thickening of the arterial wall

Normal Arterial Wall

Tunica adventitia Tunica media Tunica intima Endothelium Subendothelial connective tissue Internal elastic membrane Smooth muscle cell Elastic/collagen fibres

External elastic membrane

9 10
Adapted from Weissberg PL. Eur Heart J Supplements 1999:1:T1318

VCAM-1 Adhesion ICAM-1 molecules

oxLDL

TNF, TNF, interferon, IL-1, CRP Matrix metalloproteinase (MMP) fibrogenic mediator, GF

11

12

migration and proliferation of SMC

13

14

15

16

Acute Coronary Syndrome

Ischaemic Discomfort Unstable Symptoms
No ST-segment elevation ST-segment elevation

Abnormal ECG and myocardial infarction

Myocardial ischaemia
T wave inversion, ST segment depression

Myocardial injury
ST segment elevation

Myocardial infarction (necrosis)

Unstable angina Non-Q AMI Q-Wave AMI

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

Coronary Syndrome (ACS)

Non-ST-segment elevation ACS

20

ST-segment elevation MI

Hamm Lancet 358:1533,2001

Time Dependent: Emergency Evaluation of ACS

Presentation Chest pain or Short of Breath ST-segment Depression ST-segment Elevation

Presentation Working Dx

Ischemic Discomfort Acute Coronary Syndrome

Davies MJ Heart 83:361, 2000

ECG

Normal

ECG
Markers

+
Biochem. Marker

No ST Elevation NSTEMI

ST Elevation

Diagnosis

Rule-Out

Unstable Angina

Acute MI

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

Final Dx Unstable Angina

Myocardial Infarction NQMI Qw MI

Acute Coronary Syndrome No ST Elevation

NSTEMI

1. 2. 3. 4.

ST Elevation

Uns Angina

Myocardial Infarction NQMI Qw MI

Fibrinolytics Antiplatelet Rx Antithrombin Rx

acute coronary syndrome

25

3.

2.

1.

, , , , , . ; 2007.

ASC

Initial treatment of patients with chronic stable angina

A: Aspirin, Antiplatelet and Antianginal therapy B: Beta blocker and Blood pressure C: Cigarette smoking and Cholesterol D: Diet and Diabetes E: Education and Exercise

* short acting dihydropyridine CCB

28 26

(modifiable risk factors) atherosclerosis atherosclerosis plaques plague rupture thrombus embolus acute coronary syndrome

, , , , , . ; 2007.

30

31

29

27

, , , , , . ; 2007.

Aspirin
Indication (secondary prevention) Dosage and administration 160-325 mg. 75-325 mg/ Caution/precaution bronchospasm, angio-edema, anaphylaxis (active bleeding)

33

Clopidogrel, ticlopidine
Indication ASA ( ASA) (coronary stents) ASA 1 (Thai) ASA 1-9 (Thai) Dosage and administration Clopidogrel 300 mg. 75 mg/ Ticlopidine 500 mg. 250 mg. 2
34

Clopidogrel, ticlopidine
Dosage and administration

clopidogrel 75mg/ aspirin 12 acute coronary syndrome (AHA/ACC 2006 I (B) clopidogrel 75mg/ aspirin 1 bare metal stent, 3 sirolimus-eluting stent 6 paclitaxel-eluting stent (AHA/ACC 2006 I (B) rash, severe neutropenia, thrombotic, thrombocytopenic purpura (TTP) ticlopideine clopidogrel
35

Caution/precaution

Clinical Efficacy of Clopidogrel

Clinical Benefit of Clopidogrel in more than 30,000 Patients from CAPRIE to CURE
Trial Patients Design Maximum follow-up
3 years

Number of patients
19,185

CAPRIE1

Myocardial infarction, stroke, peripheral arterial disease Coronary stenting

Clopidogrel vs ASA

CLASSICS2

Clopidogrel* vs ticlopidine*

4 weeks

1,020

CURE3

Acute coronary syndrome

Clopidogrel* vs placebo*

1 year

12,562

CURE Study
*On

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

1. CAPRIE Steering Committee. Lancet 1996; 348: 132939. 2. Bertrand NE et al. Circulation 2000; 102: 6249 3. The CURE Trial Investigators. N Engl J Med 2001; 345: 494502.

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

Cumulative Event Rate
(Myocardial Infarction, Ischemic Stroke or Vascular Death)
16

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

5

Cumulative event rate (%)

ASA

Cumulative event rate (%)

8.7%* Overall relative risk reduction

ASA 3.6%
4

19.2%* Relative risk reduction Clopidogrel

ASA

12

Clopidogrel

Clopidogrel 2.9%

p = 0.008, n = 19,185
0 0 3 6 9 12 15 18 21 24 27 30 33 36

p = 0.043, n = 19,185
0 0 3 6 9 12 15 18 21 24 27 30 33 36

Months of follow-up
*ITT analysis 1. Gent M. Circulation 1997; 96(suppl 8): I-467.

Months of follow-up
*ITT analysis CAPRIE Steering Committee. Lancet 1996; 348: 132939.

CURE: Design1
C 3 lo do 00m p i d se g og lo re ad l in g

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

Cumulative Events
(Myocardial Infarction, Stroke, or Cardiovascular Death)
0.14

n = 12,562 28 countries

Cummulative hazard rate

Clopidogrel
75mg o.d. (n = 6,259)

0.12 0.10 0.08 0.06 0.04 0.02 0.00 0

Patients with acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction)

ASA 75325 mg o.d.

Placebo* (n = 6,303)

Double-blind treatment up to 12 months

Clopidogrel* (n = 6,259)

20% Relative risk reduction p = 0.00009

ASA 75325 mg o.d.

eb o lo Day Di sc adin 1 ha g d rg e v ose isi t

or 1 2 m fin a l o n th vis it

vis i

vis i

th

th

vis i

th

th

vis i

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

Placebo

1m on

3m on

6m on

9m on

12

Pl ac

Months of follow-up
*On top of standard therapy (including ASA) 1. The CURE Trial Investigators. N Engl J Med 2001; 345: 494502. 2. Data on file, 2002, p73 internal CSR-EFC 3307.

R = Randomization

1. The CURE Study Investigators. Eur Heart J 2000; 21: 203341.

Warfarin
Indication

Beta-adrenergic blockers
Indication ( ) AF ventricular rate
45

systemic emboli ASA

Dosage and administration

warfarin INR 2 3 paroxymal chronic atrial fibrillation flutter ( atrial fibrillation, left ventricular thrombus) drug-drug food drug interaction

Caution/precaution

44

Beta-adrenergic blockers
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)
46

Beta-adrenergic blockers
Dosage and administration Atenolol 50-200 mg/ Metoprolol 50-200 mg/ Propranolol 20-80 mg. 2 Bisoprolol 5-10 mg/

47

Beta-adrenergic blockers
Caution/precaution -blockers (<60 ) SBP <100 mmHg PR interval >0.24 sec second third degree AV block bifascicular block
48

Calcium channel blockers

Indication blockers -blockers nitrates -blockers AF ventricular rate -blockers ( verapamil diltiazem)
49

Calcium channel blockers

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)
50

Calcium channel blockers

Dosage and administration

Diltiazem 120-320 mg/ Verapamil 120-480 mg/ Amlodipine 5-10 mg/ Felodipine 5-10 mg/

51

Calcium channel blockers

Caution/precaution LVEF<0.40 (pulmonary congestion) 2nd 3rd degree AV block bifascicular block

ACE inhibitors
Indication (secondary prevention) LVEF<0.40, large anterior wall MI, LVEF<0.40 / -blockers nitrates
52 53

ACE inhibitors
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
Dosage and administration

Captopril 150 mg/ Enalapril 40 mg/ Lisinopril 40 mg/ Fosinopril 40 mg/ Ramipril 10 mg/ Quinapril 40 mg/

54

55

ACE inhibitors
Caution/precaution

Angiotensin receptor blockers

Indication (ACC/AHA 2006) ACEI left ventricular ejection fraction 40% - I (A) ACEI I (B) Caution/precaution 2 (bilateral renal artery stenosis)

ACEIs ( ) 2 (bilateral renal artery stenosis) angioedema ACEIs

56

57

Aldosterone antagonist
Indication

Nitrates
Indication ( ) Dosage and administration NTG 1 1 5 NTG 10 g/min 5 IV NTG 200 g/min long-acting nitrates 24
58 59

ACEI -blocker, left ventricular ejection fraction 40% - I (A)

Isosorbide dinitrate
Treatment & prophylaxis of angina pectoris Oral tablet: 5 20mg daily 4 maintenance 10 40mg 4 30 Sublingual: 1 2 tab 2 3 Acute angina Sublingual: 1 tab ( 15 )
60

Isosorbide mononitrate
Prophylaxis of angina pectoris Immediate release 5 -20mg 5mg 10mg 2-3 20mg twice/day 7 Sustained release 1 tab 2 tab tab daily
61

Nitrates Caution/precaution

SBP <90 mmHg <50 right ventricular MI sildenafil, tadalafil, vardenafil

62

Antidyslipidaemic agents
63

I IIa IIb III IV V

lipoprotein Chylomicrons Low-density lipoprotein cholesterol (LDL-C) Low-density lipoprotein cholesterol (LDL-C) and Very-low-density lipoprotein cholesterol (VLDL-C) Intermediate-density lipoprotein cholesterol (IDL-C) Very-low-density lipoprotein cholesterol (VLDL-C) Very-low-density lipoprotein cholesterol (VLDL-C) Chylomicrons
64

Relationship between cholesterol and CHD risk

65

The Framingham Study: Relationship Between Cholesterol and CHD Risk

150

Seven Countries Study: Relationship between cholesterol and mortality

35
Death rate from CHD/1000 men Northern Europe 30 25 20 15 10 5 0 2.60 3.25 3.90 4.50 5.15 5.80 6.45 7.10 7.75 8.40 9.05 Serbia Japan Southern Europe, Inland Southern Europe, Mediterranean

125

CHD incidence per 1000

United States

100 75

50

25

0 <204 205234 235264 265294 >295

Serum cholesterol (mg/100 mL)

66
Castelli WP. Am J Med 1984;76:412

Serum total cholesterol (mmol/L) 67

Verschuren WM et al. J Am Med Assoc 1995;274(2):131136

Design of Key Statin Trials

Study Statin
simvastatin 20 mg od pravastatin 40 mg od

Existing CHD
Yes

Patients
4444 male and female, aged 3570 6595 male, aged 4564 4159 male and female, aged 2175 9014 male and female, aged 3175 6605 male and female, aged 4573 20536 male and female, aged 4080 10305 male and female, aged 4079

Cholesterol Raised

Benefits of lipid lowering treatment

68

4S1

Follow-up (years) 5.4

Mean LDL-C 4.87 mmol/L, 188 mg/dL

WOSCOPS2

No MI, angina (5%) Yes

Mean LDL-C 4.97 mmol/L, 192 mg/dL Mean LDL-C 3.59 mmol/L, 139 mg/dL Mean LDL-C 3.80 mmol/L, 147 mg/dL Mean LDL-C 3.89 mmol/L, 150 mg/dL

Raised

4.9

CARE3

pravastatin 40 mg od pravastatin 40 mg od lovastatin 40 mg od

Average

5.0

LIPID4

Yes

Average

6.1

AFCAPS/ TexCAPS5 HPS6

No

Average

5.2

simvastatin 40 mg od

Yes

Mean LDL-C 3.4 mmol/L, 130 mg/dL Mean LDL-C 3.4 mmol/L, 130 mg/dL

Low/average
Low/average

5.0 3.3 69

ASCOT-LLA7 atorvastatin
10 mg od

In some patients

Spectrum of Risk
30 25
CHD/high cholesterol CHD/average to high cholesterol CHD*/average to high cholesterol CHD/average cholesterol Some patients with CHD/ average cholesterol No MI/high cholesterol No CHD/average cholesterol 70

Before 2001
- Primary prevention Rx - Statin therapy Pl - Placebo

Event rate (%)

4S1
Increasing absolute CHD risk

20 15

LIPID2 HPS3 CARE4 ASCOT-LLA5 WOSCOPS6

10 5
ASCOT - Rx ALLHAT - Rx ALLHAT - Pl WOSCOPS - Rx AFCAPS/TexCAPS - Pl ASCOT - Pl 150 (3.9) 170 (4.4) 190 (5.0) 210 (5.4) WOSCOPS - Pl

AFCAPS/TexCAPS7
*CHD or CHD risk equivalent, e.g. diabetes

0
70 (1.8)

AFCAPS/TexCAPS - Rx 110 (2.8)

90 (2.3)

130 (3.4)

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

71

Adapted from Ballantyne CM et al. Am J Cardiol 1998;82:3Q12Q.

Before 2001
30
- Secondary prevention

Before 2001
30
- Primary prevention - Secondary prevention 4S - Pl 4S - Pl

25 Event rate (%)

Rx - Statin therapy Pl - Placebo

25 Event rate (%)

Rx - Statin therapy Pl - Placebo

20 15
LIPID - Rx CARE - Rx PROSPER - Rx HPS - Rx

4S - Rx LIPID - Pl CARE - Pl PROSPER - Pl HPS - Pl

20 15
LIPID - Rx CARE - Rx PROSPER - Rx HPS - Rx

4S - Rx LIPID - Pl CARE - Pl PROSPER - Pl HPS - Pl ALLHAT - Pl WOSCOPS - Rx AFCAPS/TexCAPS - Pl ASCOT - Pl 150 (3.9) 170 (4.4) 190 (5.0) 210 (5.4) WOSCOPS - Pl

10 5 0

10 5

ALLHAT - Rx

ASCOT - Rx

0
90 (2.3) 110 (2.8) 130 (3.4) 150 (3.9) 170 (4.4) 190 (5.0) 210 (5.4) 70 (1.8)

AFCAPS/TexCAPS - Rx 110 (2.8)

70 (1.8)

90 (2.3)

130 (3.4)

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

72

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

73

Adapted from Ballantyne CM et al. Am J Cardiol 1998;82:3Q12Q.

Adapted from Ballantyne CM et al. Am J Cardiol 1998;82:3Q12Q.

Possible relationship between LDL-C and CHD risk

Threshold: Unnecessary to go very low

CHD Risk

Curvilinear: The lower, the better, with diminishing returns Linear: The lower, the better
0

Intensive or standard statin therapy?

74 75

100

LDL-C (mg/dL)

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

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

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

PROVE IT - TIMI 22: Study Design

4,162 patients with an Acute Coronary Syndrome < 10 days
ASA + Standard Medical Therapy
Double-blind
120 100
LDL-C 80 (mg/dL)

Changes from (Post-ACS) Baseline in Median LDL-C

Median LDL-C (Q1, Q3)

21%

Pravastatin 40mg

95 (79, 113) 62 (50, 79)

Standard Therapy Pravastatin 40 mg

Intensive Therapy Atorvastatin 80 mg

60

49%
40

Atorvastatin 80mg
P<0.001

2x2 Factorial: Gatifloxacin vs. placebo Duration: Mean 2 year follow-up (>925 events)

20
<24h Rand. 30 Days 4 Mos. 8 Mos. 16 Mos. Final

Primary Endpoint: Death, MI, Documented UA requiring hospitalization, revascularization (> 30 days after randomization), or Stroke

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

All-Cause Death or Major CV Events in All Randomized Subjects

30 25

Primary Endpoint Over Time

RR
40 Events Rates Atorva 80 Prava

Pravastatin 40mg (26.3%)

30 Days 17% 1.9% 6.3% 12.2% 22.4%* 2.2% 7.7% 14.1% 26.3%* 90 Days 18% 180 Days 14% End of Follow-up 16%
21 24 27 30 0.5 0.75 Atorvastatin 80mg Better 1.5 1.0 1.25

% with 15 Event
10 5 0 0 3 6 9 12

20

Atorvastatin 80mg (22.4%)

16% RR (P = 0.005)

15

18

Months of Follow-up

Pravastatin 40mg Better

*2-year event rates

Reductions in Major Cardiac Endpoints

2 Year Event Rates RR
Atorva 80 Prava 40

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

Design Multicenter, randomized, double-blind, placebo-controlled Patients 4497 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 endpoint Primary endpoint: composite of cardiovascular death, non-fatal MI, readmission for ACS and stroke. Median follow-up: 721 days. Treatment Placebo (4 months) then simvastatin 20 mg/day or simvastatin 40 mg/day (1 month) then simvastatin 80 mg/day

All-Cause Mortality CHD Death MI Death or MI Revasc > 30 d UA Req Hosp

Death/MI/Urg.Revasc 0.5 0.75 1.0 1.25 1.5

28% 30% 13% 18% 14% 29% 25%

2.2% 1.1% 6.6% 8.3% 16.3% 3.8% 12.9%

3.2% 1.4% 7.4% 10.0% 18.8% 5.1% 16.7%

Atorvastatin 80 mg Better Pravastatin 40 mg Better

TNT: Treating to New Targets

Purpose To determine whether cardiovascular risk can be incrementally reduced by lowering LDL cholesterol beyond currently recommended levels Reference LaRosa JC, Grundy SM, Waters DD et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. NEJM 2005;352:14251435.
87

TNT: Treating to New Targets

Design Multicenter, randomized, double-blind, parallel group, dose comparison Patients 10,001 patients aged 35-75 years with clinically evident coronary heart disease defined by 1 of: previous myocardial infarction, angina with atherosclerosis or coronary revascularization
88

TNT: Treating to New Targets

Follow up and primary endpoint Primary endpoint: death from CHD, non-fatal MI, resuscitation after cardiac arrest, fatal or non-fatal stroke Treatment Atorvastatin 10 mg or 80 mg per day after 1-8 week washout period for previous lipidregulating drugs
89

Atorvastatin 10 mg (n=5006) Age (mean; years) Male (%) Previous MI (%) Angina (%) Coronary Revascularization (%) Angioplasty Bypass LDL Cholesterol (mean, mg/dl) Total Cholesterol (mean, mg/dl) 60.9 80.8 57.7 81.2

Atorvastatin 80 mg (n=4995) 61.2 81.2 59.0 81.8

54.3 46.7 98 18 175 24

53.8 46.4 97 18 175 24

90

Primary Outcome Total major cardiovascular events Death from CHD

Atorvastatin 10 mg (n=5006) 548 (10.9%)

Atorvastatin 80 mg (n=4995) 434 (8.7%)

Hazard Ratio (95% CI) 0.78 (0.69-0.89) 0.80 (0.61-1.03) 0.78 (0.66-0.93) 0.96 (0.56-1.67) 0.75 (0.59-0.96)

P-value

<0.001

127 (2.5%)

101 (2.0%)

0.09

Non-fatal, nonprocedurerelated MI Resuscitation after cardiac arrest Fatal or non-fatal stroke

308 (6.2%)

243 (4.9%)

0.004

26 (0.5%)

25 (0.5%)

0.89

155 (3.1%)

117 (2.3%)

0.02
92

TNT: Primary endpoint

Major cardiovascular event (%) 10 mg ATV 80 mg ATV

IDEAL Trial: Study Design

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

High-dose atorvastatin
HR = 0.78 (0.69-0.89),P<0.001 80 mg/day If LDL was <40 mg/dL at 24 wks dose could be reduced to 40 mg/day

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

n=4,439

n=4,449

Years
93

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 all94 cause mortality. Presented at AHA

IDEAL Trial: Primary Endpoint

Primary Composite of major coronary event * (%)
p = 0.07

12

10.4

9.3

9 6 3 0 Atorvastatin Simvastatin

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

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

96

Presented at AHA 2005

IDEAL Trial: Primary Endpoint cont.

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.
8 8 6 6
6.0 6.0

IDEAL Trial: Secondary Endpoints

Major cardiovascular events and any cardiovascular event (%)
p<0.001

p=0.02

7.2 7.2

32 32
26.5 26.5

30.8 30.8

p=0.90 %
3.9 3.9
4.0 4.0

24 24
p=0.02

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 atorvastatin 98 group.
Presented at AHA 2005

4 4 2 2 0 0

16 16 8 8

12.0 12.0

13.7 13.7

p=NS
0.2 0.2
0.2 0.2

CHD death CHD death

Cardiac arrest with Cardiac arrest with resuscitation resuscitation

Atorvastatin Atorvastatin

Nonfatal MI Nonfatal MI

0 0 Major CV events Major CV events

97

Any CV event Any CV event

Simvastatin Simvastatin

Simvastatin Simvastatin
Presented at AHA 2005

Atorvastatin Atorvastatin

99

100

102

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

104

The year 2004 The year 2005

30 25
CHD Events (%)
y = 0.1629x 4.6776 R = 0.9029 p < 0.0001
HPS-P HPS-S A2Z 20 A2Z 80 PROVE-IT-AT 4S-S LIPID-P CARE-P 4S-P

Log-linear relationship between LDL-C and CHD

Relative Risk for CHD (Log Scale)

3.7 2.9 2.2 1.7 1.3 1.0

20 15 10 5 0 30 50 70 90 110

TNT 80

TNT 10 LIPID-S IDEAL S20/40 IDEAL A80 CARE-S

PROVE-IT-PR

40
130 150 170 190 210
105

70

100

130

160

190
107

LDL Cholesterol (mg/dl) Updated from - OKeefe, J. et al., J Am Coll Cardiol 2004;43:2142-6.

LDL-C (mg/dL)
Grundy SM et al. Circulation 2004;110:227239.

ATP III LDL-C Goals and Cutpoints for TLC and Drug Therapy in Different Risk Categories and Proposed Modifications Based on Recent Clinical Trial Evidence
Risk Category High risk: CHD or CHD risk equivalents (10-year risk >20%) Moderately high risk: 2+ risk factors (10-year risk 10% to 20%) Moderate risk: 2+ risk factors (10 year risk <10%) Lower risk: 0-1 risk factor LDL-C Goal <100 mg/dL (optional goal: <70 mg/dL) Initiate TLC Consider Drug Therapy 100 mg/dL (<100 mg/dL: consider drug options) 130 mg/dL (100-129 mg/dL: consider drug options) 160 mg/dL 190 mg/dL (160-189 mg/dL: LDL-lowering drug optional) 108

NCEP ATP III Guidelines

Major risk factors that modify LDL Goals
Cigarette smoking Hypertension (BP 140/90mmHg or on antihypertensive medication) Low HDL cholesterol (<40mg/dl) Family history of premature CHD

100 mg/dL

<130 mg/dL

130 mg/dL

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

<130 mg/dL

130 mg/dL

men 45 years women 55 years

Adapted from Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) 109 Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001; 285:2486-97

<160 mg/dL

160 mg/dL

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

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

Very high risk patients Established 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
110

Role of statins in preventing cardiovascular events

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

Aggressive lipid lowering therapy with statins is effective in preventing cardiovascular events Intensive lipid lowering with highdose statin therapy provides a significant benefit over standard-dose therapy Evidences support the concept that lower is better

111

Drugs affecting lipoprotein metabolism

Drug Class Lipid/lipoprotein effects Side effects Contraindications HMG CoA Myopathy Absolute: active or LDL 18%-55% reductase inhibitor HDL 5%-15% Increased liver enzyme chronic liver disease Relative: concomitant TG 7%-30% use of certain drugs Absolute: Gastrointestinal Bile acid LDL 15%-30% diseases, constipation, dysbetalipoproteinemia; sequestrants HDL 3%-5% decreased absorption TG >400mg/dl TG No change or Relative: TG>200mg/dl of other drugs increase Nicotinic acid Absolute: chronic liver Flushing, LDL 5%-25% disease; severe gout hyperglycaemia, HDL 15%-35% hyperuricaemia, upper Relative: diabetes; TG 20%-50% hyperuricaemia; peptic gastrointestinal distress, hepatotoxicity ulcer disease Fibric acid LDL 5%-20% (many Dyspepsia, gallstones, Absolute: severe renal be increased in patient myopathy, unexplained disease, sever hepatic disease non-CHD deaths in with high TG) WHO study HDL 10-25% TG 20%-50%
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 Panel III). JAMA 113 2001;285:2486-97.

Doses of Currently Available Statins Required to Attain an Approximate 30% to 40% Reduction of LDL-C Levels (Standard Doses)
Drug
Atorvastatin Lovastatin Pravastatin Simvastatin Fluvastatin Rosuvastatin
Dose, mg/d

LDL Reduction, % 39 31 34 35-41 25-35 39-45

10 40 40 20-40 40-80 5-10

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
114

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

Pleiotropic effects of statins

115 116

NAD(P)H activity supperoxide production GTPbinding protein

Prolonging eNOS Increase eNOS mRNA half-life expression

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

117

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

The dose-response limitations of statins

downregulating AT1 receptor expression

Failure to achieve LDL-C goal Each doubling of a statin dose provides only 6% additional LDL-C reduction Rule of six
inhibit Rac1 mediated NAD(P)H oxidase activity
119 121

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

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

SPARCL: Study design

Stroke or TIA in 6 months, no known CHD, LDL-C 100190 mg/dL N = 4731

SPARCL: Baseline characteristics

Male (%) Age (years) Systolic BP (mm Hg) Lipid profile (mg/dL) LDL-C HDL-C Triglycerides Risk factors (%) Hypertension Diabetes Current smoker Former smoker Atorvastatin n = 2365 60 63 139 133 50 144 62 17 19 41 Placebo n = 2366 59 63 138 134 50 143 61 17 19 39

Atorvastatin 80 mg daily n = 2365

Randomized Double blind

Placebo n = 2366

Primary end point: Fatal/nonfatal stroke Secondary end points: Major coronary or CV events Follow-up: ~5 years (until >540 primary end points)
SPARCL Investigators. N Engl J Med. 2006;355:549-59.

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

SPARCL: Entry events

N = 4731
Atorvastatin n (%) Entry event* Stroke Ischemic Hemorrhagic Other type or not determined TIA Unknown 1655 (70) 1595 (67) (2) 45 15 (0.6) 708 (30) 1613 1559 48 6 752 1 (68) (66) (2) (0.3) (32) (<0.1) Placebo n (%)

SPARCL: Concomitant medications

N = 4731
Atorvastatin n (%) Concomitant therapy Antiplatelet agent ACE inhibitor Dihydropyridine derivative -blocker ARB Vitamin K antagonist, including warfarin Prior statin therapy 2067 (87) 683 (29) 350 (15) 414 (18) 110 139 57 (5) (6) (2) 2063 (87) 667 (28) 359 (15) 422 (18) 102 154 63 (4) (7) (3) Placebo n (%)

2 (0.1)

*Ischemic stroke or TIA in >97% of patients

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

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

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

Primary outcome
16 Placebo 16% RRR* HR 0.84 (0.710.99) P = 0.03 NNT = 46 patients for 5 years

SPARCL: Treatment effect on stroke and TIA

N = 4731
Aggressive statin therapy Primary outcome Stroke (total) Fatal Better Worse 0.84 (0.710.99) 0.57 (0.350.95) 0.87 (0.731.03) 0.03 0.03 0.11 HR* (95% CI) P

12 Fatal/ nonfatal stroke (%)

Atorvastatin

Nonfatal Secondary outcomes Stroke or TIA

0.77 (0.670.88) 0.74 (0.600.91) 0.3 1.0 Hazard ratio 1.7

<0.001 0.004

0 0 1 2 3 4 5 Time since randomization (years) 6

TIA

*Adjusted

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

*Adjusted

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

SPARCL: High-dose statin reduces major coronary events and stroke

30 20% RRR HR 0.80 (0.690.92) P = 0.002

SPARCL: Reductions in major coronary events

10 8 6 Major coronary events* 4 (%) 2 35% RRR HR 0.65 (0.490.87) P = 0.003

20 Major CV events* (%)

Placebo

NNT = 29 patients for 5 years

Placebo

10

Atorvastatin

Atorvastatin

0 0 1 2 3 4 5 Time since randomization (years) 6

0 0 1 2 3 4 5 Time since randomization (years) 6

*Cardiac death, MI, resuscitated cardiac arrest, and stroke

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

*Cardiac death, MI, resuscitated cardiac arrest

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

SPARCL: Adverse events

N = 4731
Atorvastatin n Musculoskeletal AE Myalgia Myopathy Rhabdomyolysis ALT or AST >3x ULN Creatine kinase >10x ULN 129 7 2 51 2 (5.5) (0.3) (0.1) (2.2) (0.1) 141 7 3 11 0 (6.0) (0.3) (0.1) (0.5) (%) Placebo n (%)

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

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%)

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

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

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

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

ASTEROID Trial
Patients with coronary artery disease who require coronary angiography
Open-label; mean age 58.5 years; mean follow-up at 2 years; 29% female.

All enrolled patients: 40 mg rosuvastatin, IVUS of a single vessel not intervened upon at baseline n=507
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.

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

250 200 150 100 50 0 LDL-C Total-C HDL-C Triglyceride non-HDL-C

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

Sipahi I, Nicholls S, Tuzcu E, Nissen S. Interpreting the ASTEROID trial: Coronary atherosclerosis can regress with very intensive statin therapy. Cleve Clin J Med, 2006; 73:937-944. Reprinted with permission. Copyright 2006. Cleveland Clinic Foundation. All rights reserved.

Before

After

Endpoint analysis: Change in median percentage atheroma volume

Median Percent Atheroma Volume 0 Change from baseline (%) -0.1 -0.2 -0.3 -0.4 -0.5 -0.6 -0.7 -0.8 -0.9 - 0.79%
n=349

Endpoint analysis: Change in key IVUS parameters

Median Atheroma Volume in the most diseased 10mm subsegment 0 -1 -2 -3 -4 -5 -6 -7 -8 -9 -10 Change from baseline (%)
n=319

Median Normalised Total Atheroma Volume

n=346

- 6.8%

*
- 9.1%

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

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

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

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

ASTEROID Trial
For patients with CHD, Very high-intensity statin therapy using rosuvastatin 40 mg/d achieved an average LDL-C of 60.8 mg/dL and 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.

JUPITER
Multi-National Randomized Double Blind Placebo Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among Individuals With Low LDL and Elevated hsCRP

Ridker et al NEJM 2008

Rosuvastatin (N = 8901)
hsCRP, mg/L LDL, mg/dL 4.2 108 49 118 186 94 5.7 (2.8 - 7.1) (94 - 119) (40 60) (85 - 169) (168 - 200) (87 102) (5.4 5.9)

Placebo (n = 8901)
4.3 108 49 118 185 94 5.7 (2.8 - 7.2) (94 - 119) (40 60) (86 - 169) (169 - 199) (88 102) (5.5 5.9)

No Prior CVD or DM
Men >50, Women >60

Rosuvastatin 20 mg (N=8901)
4-week run-in

LDL <130 mg/dL hsCRP >2 mg/L

Placebo (N=8901)

MI Stroke Unstable Angina CVD Death CABG/PTCA

HDL, mg/dL Triglycerides, mg/L Total Cholesterol, mg/dL Glucose, mg/dL HbA1c, %

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
150

All values are median (interquartile range).

[ Mean LDL = 104 mg/dL ]

151

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

Ridker et al NEJM 2008

JUPITER
Primary Trial Endpoint
0.08

Ridker et al NEJM 2008

: MI, Stroke, UA/Revascularization, CV Death

HR 0.56, 95% CI 0.46-0.69 P < 0.00001
Placebo 251 / 8901

140 120

60 50

LDL (mg/dL)

100 80 60 40 20 0

HDL (mg/dL)

40

0.06

30

10 0

LDL decrease 50 percent at 12 months

HDL increase 4 percent at 12 months

Cumulative Incidence

20

- 44 %

140 120

hsCRP (mg/L)

0.04

TG (mg/dL)

3 2 1

80 60 40 20 0

hsCRP decrease 37 percent at 12 months

0

TG decrease 17 percent at 12 months

0 12 24 36 48

0.00

0.02

100

Rosuvastatin 142 / 8901

0
Number at Risk

2 Follow-up (years)

12

24

36

48

Months

Months

152

Rosuvastatin Placebo

8,901 8,901

8,631 8,621

8,412 8,353

6,540 6,508

3,893 3,872

1,958 1,963

1,353 1,333

983 955

544 534

157 174

153

Ridker et al NEJM 2008 JUPITER Individual Components of the Primary Endpoint

Ridker et al NEJM 2008 JUPITER Secondary Endpoint All Cause Mortality

0.06

Endpoint Primary Endpoint* Non-fatal MI Any MI Non-fatal Stroke Any Stroke

Rosuvastatin 142 22 31 30 33 76 83

Placebo 251 62 68 58 64 143 157

HR 0.56 0.35 0.46 0.52 0.52 0.53 0.53

95%CI 0.46-0.69 0.22-0.58 0.30-0.70 0.33-0.80 0.34-0.79 0.40-0.70 0.40-0.69

P <0.00001 <0.00001 <0.0002 0.003 0.002 <0.00001 <0.00001

Cumulative Incidence

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

Placebo 247 / 8901

0.03

0.04

0.05

- 20 %

Rosuvastatin 198 / 8901

0.00 0

MI, Stroke, CV Death

0.01

Revascularization or Unstable Angina

0.02

1
8,787 8,775 6,999 6,987

2 Follow-up (years)
4,312 4,319 2,268 2,295

3
1,602 1,614 1,192 1,196

4
683 684 227 246

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

154

Number at Risk Rosuvastatin 8,901 8,847 Placebo 8,901 8,852

155

Ridker et al NEJM 2008 JUPITER Statins and the Development of Diabetes

HR
WOSCOPS PROSPER HPS ASCOT-LLA PROVE-IT Pravastatin Pravastatin Simvastatin Atorvastatin Atorvastatin Pravastatin JUPITER Rosuvastatin
0.25 0.5 1.0 2
VS

(95% CI)

0.70 (0.500.98) 1.34 (1.061.68) 1.20 (0.981.35) 1.20 (0.911.44) 1.11 (0.671.83)

1.25 (1.051.54)
4
Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther. 2006;80(6):565-81.

Statin Better

Statin Worse
156 157

158

159

Effect of some agents on AUC

SIM Itraconazole Erythromycin, clarithromycin Verapamil, diltiazem 5-20 ATO FLU PRA ROS 2-4 ~ ~ ~ ~ 2 ~ ~ ~ ~ PIT ~ ~ ~ Fold increase of statin AUC by CYP3A4 inhibitor

Atorvastatin Fluvastatin

4-12 1.5-5 3-8 ?

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

Pravastatin

Rosuvastatin Simvastatin

Percentage decrease of statin AUC by potent inducer Rifampin, carbamazepine 7095 6090 50 30 ? ?
160

Effects of renal/hepatic impairment Plasma levels not affected by renal disease; markedly increased with chronic alcoholic liver disease. Potential drug accumulation with hepatic insufficiency Potential drug accumulation with renal or hepatic insufficiency. Mean AUC varied 18-fold in cirrhotic patients and peak values varied 47fold. Increased plasma concentrations with severe renal impairment and hepatic disease Higher systemic exposure may occur in hepatic and severe renal insufficiency
164

Ezetimibe
Liver
Synthesis*
(~800 mg/day) (~1000 mg/day) (~300700 mg/day)

Cholesterol Absorption in the Intestine

Dietary cholesterol

Biliary cholesterol

Extrahepatic tissues

Absorption (~700 mg/day)

Intestine

Resins

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

*And extrahepatic tissue Adapted 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, 2002:728777; Ginsberg HN, Goldberg IJ. In Harrisons Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998:21382149; Shepherd J Eur Heart J Suppl 2001;3(suppl E):E2E5; Hopfer U. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:10821150; Bays H Expert 165 Opin Investig Drugs 2002;11:15871604.

Plant stanols

NPC1L1

ACAT=acyl-coenzyme A:cholesterol acyltransferase;

NPC1L1=Niemann-Pick C1 Like 1

Adapted from Champe PC, Harvey RA. In Biochemistry. 2nd ed. Philadelphia: Lippincott Raven, 1994; Ginsberg HN, Goldberg IJ. In Harrisons Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998:21382149; Shepherd J Eur Heart J Suppl 2001;3(suppl E):E2E5; Hopfer U. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:1082 166 1150; Davis JP et al Genomics 2000;65:137145.

Ezetimibe
Ezetimibe monotherapy is an option for adults with primary (heterozygous-familial or non-familial) hypercholesterolaemia (at 20% or greater 10year CVD risk) in whom statins are contraindicated or not tolerated Ezetimibe, co-administered with initial statin therapy, 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 statin therapy
167

Ezetimibe
??????? 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 better ENHANCE study (January 2008): no significant difference in carotid intima-media thickness with ezetimibe versus placebo, added to simvastatin 80mg, in familial hypercholesterolaemia SEAS 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=0.01 168

ENHANCE Study Design

Pre-randomization Phase R A N D O M I Z A T I O N

FH: LDL-C 210 mg/dL

Ezetimibe 10 mg-Simvastatin 80 mg

Screening and Fibrate Washout

Placebo Lead-In/ Drug Washout

Simvastatin 80 mg

IMT assessment

-10 to -7

-6

Weeks

12
Months

15

18

21

24

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 echocardiographic evaluation Doppler jet velocity 2.5 - 4.0 m/sec

Normal LV systolic function

Fatal Cancer
20 Cumulative percentage
Intention-to-Treat Population

Fibric acid derivative

Gemfibrozil Lopid cap 300mg Lopid tab 450, 600mg Lopid OD tab 900mg Fenofibrate Fenox cap 300mg Lipanthyl cap 100mg Supralip 160 tab 160mg (microcoated) Supralip NT 145 tab 145mg (nanoparticles)

15

10

Hazard ratio: 1.67 P=0.05 Unadjusted P=0.06 With Log-rank continuity correction Ezetimibe/Simvastatin 10/40 mg n=39 (4.1%) n=23 (2.5%) Placebo 0 1
930 916

600mg 2 900mg (Lopid OD tab) 1 tab : 1.5g/day

0
No. at risk Ezetimibe/Simvastatin 10/40 mg Placebo

2 3 Years in study
912 890 884 865

4
855 835

5
89 94

: (formulation) Micronised formulations: 67mg 3 200mg Non-micronised formulation: 200 300mg/day , 200 400mg/day bioavailability ( nanoparticles) 40 160mg/day : 5mg/kg/day 180

Cardiol Rev 2008;16:129 - 41.

transaminase 3 (upper limit of normal) statins fibrates creatinine 2.0 mg/dl fibrates creatinine 4 mg/dl fibrates
181 182

6 -12 3 6 statins fibrates transaminase 6 12 1 2 2 3 6
183

transaminase 3 CPK 10 myopathy rhabdomyolysis statin fibrate transaminases creatinine SGOT, SGPT CPK 1 2 6 rhabdomyolysis hepatitis
184