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

Prevention of CV Disease with Statins

葉宏一 MD, PhD

馬偕醫學院醫學系教授兼主任台北醫學大學醫學科學研究所兼任教授

馬偕紀念醫院內科部副主任

Content

• Epidemiology

• Pathophysiology

• Pharmacological Treatment

• Guidelines

• Statin clinical trials

• Adverse effects

• Real world practice

Content

• Epidemiology

• Pathophysiology


• Guidelines


• Adverse effects


Framingham: HDL-C vs LDL-C as a predictor of CHD risk

0

0.5

1

1.5

2

2.5

3

Ris

k o

f C

AD

ove

r 4

year

s o

f fo

llo

w-u

p*

100 mg/dL160 mg/dL220 mg/dL

LDL-C

*Men aged 50–70

85 mg/dL65 mg/dL

45 mg/dL25 mg/dL

CHD RR

HDL-C

Gordon, Castelli et al. Am J Med 1977;62:707–714

0

2

4

6

8

10

12

14

16

18

Serum Total-C, mmol/L (mg/dL)

Dea

th r

ate

per

1000

men

Data from MRFIT study.Martin MJ et al. Lancet 1986;ii:933–936.

Elevated Cholesterol Levels are Associated with an Increased Risk of CHD Death

3.62(140)

4.14(160)

4.65(180)

5.17(200)

5.69(220)

6.21(240)

6.72(260)

7.24(280)

7.75(300)

n=12866, follow-up mean 7 years

0

5

10

15

20

25

30

35

Serum Total-C, mmol/L (mg/dL)

CH

D m

orta

lity

rate

s (%

)

Northern Europe

Southern Europe,Mediterranean

United States

Serbia

Southern Europe,Inland

Japan

Correlation Between Total-C and CHD Mortality in Men from Seven Countries

Data are from the Seven Countries Study of 12,467 men from Southern European Countries, the USA and Japan.Verschuren WM et al. JAMA 1995;274:131–136.

2.60(100)

3.25(125)

3.90(150)

4.50(175)

5.15(200)

5.80(225)

6.45(250)

7.10(275)

7.75(300)

8.40(325)

9.05(350)

S.E. AsiaChina

90.4

90.4

98.7

89.489.5

93.789.989.497.495.072.594.0

All 9 RF

49.232.520.19.917.9Overall 2

53.828.833.712.423.4Overall 1

50.551.459.67.918.9N. America

47.635.645.412.832.8S. America43.428.961.67.222.8Australia/NZ

67.726.758.021.038.443.835.65.510.022.158.715.937.012.119.4S. Asia74.140.058.317.129.9Africa70.541.626.715.59.7Middle East35.04.928.09.124.5E/C Europe44.638.963.614.922.0W. Europe

Lipids %All PS%Abd Obes %Diab %HTN %Region

NON-LIFESTYLE RISK FACTORS

Yusuf et al. Lancet, 2004

INTERHEARTPopulation Attributable Risk for 1st MI by Region and Overall

Definition: total cholesterol > 240 mg/dl or taking lipid-lpwering drugs

Data from Taiwan 3H survey

Prevalence of Hypercholesterolemia in Taiwan

高總膽固醇比例

Age

Content

• Epidemiology

• Pathophysiology


• Guidelines


• Adverse effects


Disease progression

PHASE I: Initiation PHASE II: Progression PHASE III: Complication

Atherosclerosis and Thrombosis

Adapted from Fan J, Watanabe T. J Atheroscler Thromb. 2003;10:63–71.

Monocyte

Induction of adhesionmolecules and chemotaxis

AdhesionVCAM-1ICAM-1P-selectinE-selectin

MigrationMCP-1CCR-2oxLDL

oxidation

CytokinesMMPsEndothelin-1

Endothelialcells

Smooth muscle cells

Inti

ma

Internal elastic lamina

Lu

men

CD36SR-A

Differentiation(GM-CSF)

MacrophageFoam cell

T lymphocyte

CD40

IFN-gamma

LDL, β-VLDL, Lp(a)

Development of an Atheromalipid + inflammation

Content

• Epidemiology

• Pathophysiology


• Guidelines


• Adverse effects


*Selective inhibitor of intestinal cholesterol absorption

Adapted from 1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486–2497. 2. Ezetrol (ezetimibe) product information. WPC 072005. Merck Sharp and Dohme. NSW, Australia. 2006. 3. Nippon Rinsho. 1994 Dec;52(12):3279-84.

↓ 18%

↓ 15–30%

↓ 8%Ezetimibe*2

No change or increase

Bile acid sequestrants1

↑ 1%

↑ 3–5%

↓ 18–55% ↓ 7–30%Statins1 ↑ 5–15%

↓ 5–20% ↓ 20–50%Fibric acids1 ↑ 10–20%

↓ 5–25% ↓ 20–50%Nicotinic acid1 ↑ 15–35%

LDL-C effect

Triglyceride effectDrug class/agents

HDL-C effect

↓ 10–17% No changeProbucol3 ↓ up to 40%

Impact of Existing Drug Therapies on Lipid Parameters

HMG-CoAHMG-CoAreductasereductase

AcetylCoA

HMG-CoA

Mevalonate Farnesylpyrophosphate

Squalene Cholesterol

Farnesylatedproteins

Dolichol

E,E,E-Geranylgeranylpyrophosphate

Geranylgeranylatedproteins

Ubiquinones

Rasprotein

Farnesyl-transferase

Cholesterol Biosynthesis Pathway

HMG-CoA Reductase inhibitirors

TXA2 t-PAPAI-1

+

RhoA

N0

SMChypertrophy

Vascularinflammation

Endothelialdysfunction

hs-CRPMMPsTF Adhesion molecule

ROS

ET-1

RhoARac1 AT1 receptor

Atherosclerosis Hypertension

Cardiovascular Diseases

Plaquestability

Thrombotic effect

Platelet activatin

SMCproliferation Vasoconstriction

Macrophage growth

Takemoto and Liao, 2001

Double dose of statins results in ~6% reduction of LDL

Change in LDL-C From Baseline (%)0 -10 -20 -30 -40 -50 -60

10mg*

-5 -15 -25 -35 -45 -55

20mg**

40mg†

10mg

20mg

80 mg

10mg

20mg

40mg

80mg

10mg

20mg

40mg

RosuvastatinAtorvastatinSimvastatinPravastatin

40mg

*P<.002 vs atorvastatin 10 mg; simvastatin 10, 20, 40 mg; pravastatin 10, 20, 40 mg.**P<.002 vs atorvastatin 20, 40 mg; simvastatin 20, 40, 80 mg; pravastatin 20, 40 mg.†P<.002 vs atorvastatin 40 mg; simvastatin 40, 80 mg; pravastatin 40 mg.Adapted from Jones et al. Am J Cardiol 2003;92:152–160.

The STELLAR Trial

STELLAR = Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin.

Content

• Epidemiology

• Pathophysiology


• Guidelines


• Adverse effects


Risk factors: FHx, HTN, smoking, male ≥45, female ≥55, HDL-C <40 mg/dL

ATP III: Lipid-Lowering Treatment Guidelines

Reimbursement guidelines from BNHI, Taiwan

血脂異常之

起步治療準則血脂濃度

≧2 個危險因子

( 如附註二 )

TC/HDL-C>5 或

HDL-C<40mg/dl 治療目標

有

心

血

管

疾

病

患

者

同時予以非藥物治療

TC 200mg/dl≧ × × <160mg/dl(87/7/1)

LDL-C 130mg/dl≧ × × ≦100mg/dl(87/7/1)

TG 200mg/dl ≧( 需同時合併有 TC/HDL-C>5 或是 HDL-C <40mg/dl)

× ˇ < 150mg/dl(87/7/1)

冠狀動脈粥狀硬化 , 腦血管病變 , 周邊血管粥狀硬化

*

*

或

糖

尿

病

(ˇ)需符合此項條件 (×)不需符合此項條件周邊血管粥狀硬化有缺血性症狀且經血管都卜勒超音波或血管攝影證實者

全民健保降血脂藥物給付規定（畫線部分為91/9/1 後適用）

血脂異常之

起步治療準則血脂濃度

≧2 個危險因子

( 如附註二 )

TC/HDL-C>5 或

HDL-C<40mg/dl 治療目標

無

心

血

管

疾

病

患

者

有下列情況之一時

，應給予

TC

LDL-C

≧200mg/dl

≧240mg/dl

≧130mg/dl

≧160mg/dl

TG 200mg/dl≧

( 需同時合併有 TC/HDL-C>5 或是HDL-C<40mg/dl)

ˇ

×

ˇ

×

×

×

×

×

<200mg/dl

<240 mg/dl

<130mg/dl

<160mg/dl

× ˇ <200mg/dl(87/4/1)

︵

如

附

註

一

︶

三至六個月非藥物治療

*

*高血壓 , 糖尿病 , 男≧ 45歲 , 有早發性冠心病家族史 , 女≧ 55歲或停經沒有雌激素療法, 吸菸

Content

• Epidemiology

• Pathophysiology


• Guidelines


• Adverse effects


Statin Clinical Trials

ComparatorsStatin vs placebo

- statin alone

- combined with non-statinStatin vs statin

- different statins

- same statin, different dose

- combined with non-statin

End pointsDisease outcomeSurrogate marker

Statin Clinical Trials


- statin alone


- different statin




On-treatment LDL-C & CHD Events in Statin Trials

Adapted from Rosensen, Exp Opin Emerg Drugs 2004;9:269; LaRosa J et al, N Engl J Med, 2005;352:1425

NCEP2004

ASCOT - PBO

ASCOT - Rx

PROVE-IT - PRAPROVE-IT - ATV80

TNT - ATV10TNT - ATV80

AFCAPS - Rx

HPS - Rx WOSCOPS - PBO

AFCAPS - PBO

AFCAPS - Rx

WOSCOPS - Rx

4S - Rx

LIPID - Rx

4S - PBO

CARE - Rx

LIPID - PBO

CARE - PBO

0

10

20

30

40(1.0)

60(1.6)

80(2.1)

100(2.6)

120(3.1)

140(3.6)

160(4.1)

180(4.7)

Secondary Prevention

Primary Prevention

200(5.2)

Eve

nt

rate

(%

)

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

HPS - PBO

HPS - Rx

NCEP 2001Eur Joint 2003

Cholesterol Treatment Trialists’ CollaborationCholesterol Treatment Trialists’ Collaboration

Lancet Vol 376 November 13, 2010Lancet Vol 376 November 13, 2010Lancet Vol 376 November 13, 2010Lancet Vol 376 November 13, 2010

• randomised trials involving at least 1000 participants and at least 2 years’ treatment duration

• more versus less intensive statin regimens (5 trials; 39612 individuals; median follow-up 5.1 years)

• statin versus control (21 trials; 129526 individuals; median follow-up 4.8 years).

Cholesterol Treatment Trialists’ CollaborationCholesterol Treatment Trialists’ Collaboration

MVE per 1.0 mmol/L reduction in LDL-C, by baseline prognostic factor

MVE per 1.0 mmol/L reduction in LDL-C, by baseline prognostic factor

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

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

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

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

On-treatment LDL-C & CHD Events in Statin Trials

Adapted from Rosensen, Exp Opin Emerg Drugs 2004;9:269; LaRosa J et al, N Engl J Med, 2005;352:1425

NCEP2004

ASCOT - PBO

ASCOT - Rx

PROVE-IT - PRAPROVE-IT - ATV80

TNT - ATV10TNT - ATV80

AFCAPS - Rx

HPS - Rx WOSCOPS - PBO

AFCAPS - PBO

AFCAPS - Rx

WOSCOPS - Rx

4S - Rx

LIPID - Rx

4S - PBO

CARE - Rx

LIPID - PBO

CARE - PBO

0

10

20

30

40(1.0)

60(1.6)

80(2.1)

100(2.6)

120(3.1)

140(3.6)

160(4.1)

180(4.7)

Secondary Prevention

Primary Prevention

200(5.2)

Eve

nt

rate

(%

)

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

HPS - PBO

HPS - Rx

NCEP 2001Eur Joint 2003

Tx based on hsCRP levelTx based on hsCRP level

JUPITER


- statin alone


- different statin




JUPITERJustification for the Use of Statins in Primary Prevention: a

n Intervention Trial Evaluating Rosuvastatin

• a randomized, double-blind, placebo-controlled primary prevention trial (26 countries)

• studied over 17,802 patients (men>= 50 yrs; women>= 60 yrs; 6,801 women; 5,577 with metabolic syndrome) without evidence of cardiovascular disease and low to normal LDL-C (<130 mg/dl, median 108 mg/dl), but elevated C-reactive protein (hs-CRP 2 mg/L)≧ .

• rosuvastatin (20 mg) vs placebo

ACCACC 2008 2008

JUPITERPrimary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Placebo 251 / 8901

Rosuvastatin 142 / 8901

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

Number Needed to Treat (NNT5) = 25

- 44 %

0 1 2 3 4

0.0

00

.02

0.0

40

.06

0.0

8

Cu

mu

lati

ve In

cid

ence

Number at Risk Follow-up (years)

Rosuvastatin

Placebo

8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157

8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174

Ridker et al NEJM 2008

JUPITERDual Target Analysis: LDLC<70 mg/dL, hsCRP<2 mg/L

LDL > 70 mg/dLand / or

hsCRP > 2 mg/LHR 0.64 (0.49-0.84)

LDL < 70 mg/dL and

hsCRP < 2 mg/L HR 0.35 (0.23-0.54)

Placebo HR 1.0

(referent)

P < 0.0001

0 1 2 3 4

0.00

0.02

0.04

0.06

0.08

Cu

mu

lati

ve

In

cid

en

ce


RosuvastatinPlacebo

7,716 7,699 7,678 6,040 3,608 1,812 1,254 913 508 1457,832 7,806 7,777 6,114 3,656 1,863 1,263 905 507 168

Anti-inflammatory effects of LDL-C reducion on hsCRP

• >90% of the reduction in CRP was directly associated with the magnitude of LDL cholesterol reduction, with no difference between high-dose statins or statin-ezetimibe combinations

Kinlay S. JACC 2007

ANDROMEDA=A raNdomised, Double-blind, double-dummy, multicentre, phase IIIb, parallel-group study to compare the ANDROMEDA=A raNdomised, Double-blind, double-dummy, multicentre, phase IIIb, parallel-group study to compare the efficacy and safety of Rosuvastatin (10 mg and 20 mg) and atOrvastatin (10 Mg and 20 mg) in patiEnts with type II DiAbetes efficacy and safety of Rosuvastatin (10 mg and 20 mg) and atOrvastatin (10 Mg and 20 mg) in patiEnts with type II DiAbetes mellitus; hsCRP=high-sensitivity C-reactive protein; RSV=rosuvastatin; ATV=atorvastatinmellitus; hsCRP=high-sensitivity C-reactive protein; RSV=rosuvastatin; ATV=atorvastatin*p<0.05 vs ATV at same time point; *p<0.05 vs ATV at same time point; ‡‡p<0.001 vs baselinep<0.001 vs baseline

Betteridge DJ et al. Betteridge DJ et al. Am J CardiolAm J Cardiol 2007 in press ;Betteridge DJ et al. 2007 in press ;Betteridge DJ et al. Atheroscler Suppl Atheroscler Suppl 2005; 6: 102 Abs W16-P-0072005; 6: 102 Abs W16-P-007Betteridge DJ et al. EAS April 2005. Poster presentationBetteridge DJ et al. EAS April 2005. Poster presentation

ANDROMEDA – reduction in hsCRP in patients with baseline CRP ≥2 mg/L

Median Median

changechangefrom from

baselinebaseline(%)(%)

00

––2020

––4040

––6060

––3232

––5252

––4343

n=120n=120 n=121n=121 n=115n=115 n=112n=112

––4444

**‡‡

‡‡

‡‡

‡‡

8 weeks 8 weeks

RSV 10 mg RSV 10 mg ATV 10 mg ATV 10 mg

16 weeks 16 weeks

RSV 20 mg RSV 20 mg ATV 20 mg ATV 20 mg

The history of JUPITER

• 2008 Nov, AHA: JUPITER (paper in NEJM)

• 2009 Feb, ISC : Stroke (09 Dec. paper in circulation)

• 2009 Mar, ACC: VTE / Dual treatment target

• 2009 Sep, ESC: Elderly

• 2009 Sep: NNT (Circulation Cardiovascular Quality and Outcomes. 2009)

• 2009 Nov, AHA: Women / IFG / Very low LDL-C

• 2009 Dec, news: FDA voted

Venous thromboembolismVenous thromboembolism

JUPITERTotal Venous Thromboembolism

0 1 2 3 4

0.0

00

0.0

05

0.0

10

0.0

15

0.0

20

0.0

25

Cu

mu

lati

ve In

cid

ence


Rosuvastatin

Placebo

8,901 8,648 8,447 6,575 3,927 1,986 1,376 1,003 548 161

8,901 8,652 8,417 6,574 3,943 2,012 1,381 993 556 182

HR 0.57, 95%CI 0.37-0.86P= 0.007

Placebo 60 / 8901

Rosuvastatin 34 / 8901

- 43 %

Glynn et al NEJM 2009

Ridker PM et al on behalf of the JUPITER Trial Study Group N Engl J Med 2009;360

Systolic Heart FailureSystolic Heart Failure

CORONA and GISSI-HF


- statin alone


- different statin




CORONA

NEJM 2007

Rosuvastatin in older patients with systolic heart failure

• Patients (≥ 60 yr; n=5011) with systolic heart failure of ischemic cause (EF < 0.4, NYHA II-IV)

• 10 mg rosuvastatin daily• LDL-C 45%; hsCRP 37% • Median follow-up of 32.8 m

onths• Primary outcome: death fr

om CV causes, non-fatal MI, and nonfatal stroke

GISSI-HF / Statin

LANCET 2008

Rosuvastatin in patients with chronic heart failure

• Patients (68±11 yr; n=4631) with heart failure (NYHA II-IV)

• 10 mg rosuvastatin daily• LDL-C 32% (1st yr), 27

% (2nd yr); hsCRP 16% • Median follow-up of 3.9 y

rs, average EF < 0.4, • Primary outcome: death • Secondary outcome: de

ath + CV hospitalization

Death

Death + CV Hospitalization

Stroke / TIAStroke / TIA

SPARCL


- statin alone


- different statin




SPARCLSPARCLThe Stroke Prevention by The Stroke Prevention by Aggressive Reduction in Aggressive Reduction in

Cholesterol LevelsCholesterol Levels

4731 patients who with a stroke or TIA within 1-6 months before study entry

LDL-C 100 to 190 mg/dl

No known coronary heart disease

80 mg of atorvastatin per day or placebo

NEJM. 2006

High-Dose Atorvastatin after Strokeor Transient Ischemic Attack (SPARCL)

NJEM. 2006

73 mg/dl73 mg/dl

129 mg/dl129 mg/dl

Chronic Kidney DiseaseChronic Kidney Disease

4D, AURORA, SHARP


- statin alone


- different statin




4D: primary endpoint(cardiac death, nonfatal MI, and stroke)

NEJM 2005

20 mg

RR = 0.92 (95% CI 0.77-1.10)P=0.37

Placebo

AURORA: primary endpointTime to first major CV event

(cardiac death, nonfatal MI, stroke)

No. at risk:

Rosuvastatin 1390 1152 962 826 551 148

Placebo 1384 1163 952 809 534 153

Cumulative incidence of primary endpoint (%)

Years from randomization

Rosuvastatin

HR=0.96 (95% CI 0.84–1.11)P=0.59

0

5

10

15

20

25

30

35

40

0 1 2 3 4 5

NEJM 2009

10 mg

Statin in Diabetic Hemodialysis Patients- post hoc analysis of the AURORA

J Am Soc Nephrol. 2011 May 12. [Epub ahead of print]

32% P=0.008

0 1 2 3 4 5

Years of follow-up

0

5

10

15

20

25

Prop

ortio

n su

fferin

g ev

ent (

%) Risk ratio 0.83 (0.74 – 0.94)

Logrank 2P=0.0022 Placebo

Eze/simv

SHARP: major atherosclerotic eventsCKD grade 3-5

CKD vs. non-CKDHR=1.35 (95% CI 1.18 –1.54)P<0.0001

CKD in TNTCKD grade 2-4

CKD in TNTCKD grade 2-4

Hypolipidemic therapy in prevention of non-fatal MI and coronary revascularization in CKD patients

Hypolipidemic therapy in prevention of non-fatal MI and coronary revascularization in CKD patients

Lancet 2011

Non-fatal non-hemorragic and non-fatal hemorrhagic stroke

Non-fatal non-hemorragic and non-fatal hemorrhagic stroke

Lancet 2011

Cumulative Incidence of CV End Points in CKD patients from JUPITER Study

*Primary end point: non-fatal MI, nonfatal stroke, hospital stay for unstable angina, arterial revascularization, or CV death*Primary end point: non-fatal MI, nonfatal stroke, hospital stay for unstable angina, arterial revascularization, or CV death

1638 1638 1574 1538 1281 1574 1538 1281 871 550 871 550 352 247 129 39 352 247 129 391629 1629 1557 1510 1234 1557 1510 1234 838 838 516 345 243 131 40 516 345 243 131 407259 7054 7259 7054 6871 6871 5256 3020 1407 1000 736 409 118 5256 3020 1407 1000 736 409 118

7269 7061 6840 5272 3033 1447 988 712 400 1347269 7061 6840 5272 3033 1447 988 712 400 134

Follow-up (years)Follow-up (years)

Cu

mu

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ce

Primary End Point*

No. at RiskNo. at Risk

00

CKDCKD RosuvastatinRosuvastatinPlaceboPlacebo

No CKDNo CKD RosuvastatinRosuvastatinPlaceboPlacebo

110.000.00

22 33 44

CKD, placeboCKD, placebo

0.050.05

0.100.10

0.150.15

No CKD, placeboNo CKD, placebo

No CKD, rosuvastatinNo CKD, rosuvastatin

CKD, rosuvastatinCKD, rosuvastatin

Ridker PM et al. Ridker PM et al. J Am Coll Cardiol.J Am Coll Cardiol. 2010; 2010;5555(12):1266-1273.(12):1266-1273.

Studies using surrogate marker


- statin alone


- different statin




2.7*

Pravastatin

Significant atheroscleroticprogression from baseline

-0.4†

Atorvastatin

No significant change frombaseline; atheroscleroticprogression was stopped

REVERSAL:REVERSAL: Primary end point: % Primary end point: %change in total atheroma volumechange in total atheroma volume

Cha

nge

in T

AV

(%

)

-1

0

1

2

3

*Progression vs baseline (P=0.001); †No change vs baseline (P=0.98)

P=0.02

JAMA. 2004

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

BaselineIVUS

Follow-upIVUS

24 monthsrosuvastatin

Atheroma Area10.16 mm2

Lumen Area6.19 mm2

Atheroma Area5.81 mm2

Lumen Area5.96 mm2

Ref: Nissen S et al. JAMA 2006; 295: e-publication ahead of print

Time (years)

Ch

an

ge in

IM

T o

f 12 c

aro

tid

sit

es (

mm

)

-0.01

+0.01

0.00

+0.02

21

+0.03

Pro

gre

ssio

n

Reg

ressio

n

P=NS(CRESTOR vs. zero slope)

Placebo+0.0131 mm/yr

(n=252)

Rosuvastatin 40 mg-0.0014 mm/yr

(n=624)

P<0.0001 (CRESTOR vs. placebo)

Placebo; Change in CIMT (95% CI)

Rosuvastatin 40 mg; Change in CIMT (95% CI)

METEOR primary endpoint:Rate of change of maximum IMT at 12 carotid sites

Rosuvastatin vs placebo

Crouse JR, et al. JAMA 2007;297:(doi:10.1001/jama.297.12.joc70024)

Content

• Epidemiology

• Pathophysiology


• Guidelines


• Adverse effects


Statins – Therapeutic RatioStatins – Therapeutic Ratio

Therapeutic Effects

Adverse Effects

Cardiovascular protection

Muscle

Liver

Drug interactions

Benefit

Risk

Rhabdomyolysis and % LDL-C ReductionRhabdomyolysis and % LDL-C Reduction

JACCJACC 2007 2007

Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K

Muscle effects - Benefit:Risk CK >10 x ULN: Frequency by LDL-C Reduction

0.0

0.5

1.0

1.5

2.0

2.5

3.0

20 30 40 50 60 70

LDL-C reduction (%)

Occu

rren

ce o

f C

K >

10 ×

ULN

(%

)

Cerivastatin (0.2, 0.3, 0.4, 0.8 mg)

Rosuvastatin (10, 20, 40 mg)

Pravastatin (20, 40 mg)

Atorvastatin (10, 20, 40, 80 mg)

Simvastatin (40, 80 mg)

↑↑Liver Enzymes and % LDL-C ReductionLiver Enzymes and % LDL-C Reduction

JACCJACC 2007 2007

Rate of Elevated Liver Enzymes by Statin Rate of Elevated Liver Enzymes by Statin Dose CategoryDose Category

JACCJACC 2007 2007

Shimada T et al. J Pharmacol Exp Ther 1994;270(1):414.

CYP3A4CYP2D6

CYP2C

CYP1A2CYP2E1

Relative Importance of P450s in Drug Metabolism

CYP450

Potential Drug Interactions3A4

• Simvastatin

• Atorvastatin

• Lovastatin

• Diltiazem

• Clopidogrel

• Amiodarone

• Cimetidine

• Ery/clarithromycin

• Ketoconazole

• Carbamazepine

• St John’s wort

• Grapefruit juice

2C9

• Fluvastatin

• Phenytoin

• Fluconazole

• Warfarin

• Rosuvastatin

No clear difference between statins in terms of diabetes risk

Lancet, Lancet, Published Published Online February 17, 2010Online February 17, 2010

• one additional case of diabetes per 255 patients taking statin therapy for 4 years (12·23 cases per1000 patient-years with statin treatment and 11·25 cases per 1000 patient-years with control therapy).

• Re reduction in major coronary events (coronary heart disease death and non-fat

al myocardial infarction) of 5·4 events per 255 patients treated for 4 years compared with control therapy for a 1 mmol/L reduction in LDLcholesterol concentration.

Lancet 2010; 375: 735–42

: Statins and risk of incident diabetes -a collaborative meta analysis

Content

• Epidemiology

• Pathophysiology


• Guidelines


• Adverse effects


REALITY Asia Study: Objectives

• To evaluate lipid-lowering

therapy prescribing patterns

and cholesterol goal

achievement in patients

with and without CHD and

other risk factors in the “real

world” setting in 6 major

Asian countries

Adapted from REALITY Study Protocol.

Cholesterol Goal Attainment in the Real World:

Results: Comparison of Overall Goal Attainment in Europe and Asia

45%

58%

24%

54%

51%

42%

41%

30%

26%

55%

32%

29%

33%

14%

24%

27%

27%

54%

0% 10% 20% 30% 40% 50% 60% 70%

Overall AsiaSingapore

TaiwanMalaysiaThailand

KoreaOverall EU

SwedenFrance

UKNetherlandsSwitzerland

NorwayItaly

GermanySpain

HungaryFinland

Cholesterol Goal Attainment in the Real World: The REALITY ASIA Study

Results: Cholesterol Goal Attainment by Risk and Country

All Patients

32.4%

15.9%

42.4%36.5% 34.9%

66.7%

42.5%

64.2%

74.1%

52.9%

83.2%

63.3%

80.8%87.5% 84.4%

80.9%

31.5%

61.7%

0.0%

20.0%

40.0%

60.0%

80.0%

100.0%

Singapore Taiwan Thailand Malaysia Korea Overall

CHD/diabetic Patients nonCHD with 2 or more risk factors nonCHD with less than 2 risk factors

Approximately 84% of CHD/diabetic patients and 76% of patients overall failed to attain goal.

Curr Med Res Opin. 2008

Pan-Asian CEPHEUS (Pan Asian survey on undertreatment of hypercholesterolemia)

Eur J Cardiovasc Prev Rehabil. 2011

LDL goals of patients

49.1%

32.1%

18.5%

0.3%0%

10%

20%

30%

40%

50%

60%

<70 mg/dl (n=3,557) <100 mg/dl (n=2,325) <130mg/dl (n=1,343) <160 mg/dl (n=25)

% o

f P

atie

nts

79

• Half the patients (49.1%) in the study fulfilled the criteria for the very high risk category (< 70 mg/dl) when stratified as per the 2004 updated NCEP ATP III guidelines.

LDL Goals of Patients

Proportion of patients attaining their 2004 updated NCEP ATP III-recommended LDL-C goals

80

% of Patients attaining their 2004 updated NCEP ATP III* guidelines recommended LDL-C goals

• Overall 49.1% LDL-C goal attainment rate among all patients surveyed across Asia.• Proportion of patients attaining their respective LDL-C goal decreased with increasing cardiovascular

risk.

Percentage of Patients at LDL-C goals recommended by the 2004 updated NCEP ATP

III* guidelines

81

% of Patients at LDL-C goals recommended by 2004 updated NCEP ATP III* guidelines

• For patients in Hong Kong the treatment goal attainment rate was 82.9% while patients in other countries had very low LDL-C attainment rate (31.3 – 52.7%).

Changes in the lipid-lowering drug since first prescribed a drug

82

Changes in the lipid-lowering drug since first prescribed a drug

• For 64.1% of patients, initial treatment remained the same.

Achievement of LDL-C goals among patients

83

Achievement of LDL-C goals among patients

• Rate of LDL-C goal attainment was similar in primary and secondary prevention patients.

Prevention Metabolic Syndrome

Comparison of Pan-Asian CEPHEUS with Pan-European CEPHEUS

84

Point of ComparisonPan-European

CEPHEUSPan-Asian CEPHEUS

Proportion of patients achieving NCEP ATP III targets for LDL-C

57.4% 49.1%

Mean baseline LDL-C concentrations

105±36 mg/dl 144.5 ±45.6 mg/dl

Proportion of patients on statins

90.3% 85.1%

• Only about 50% of patients with high LDL-C achieve goal on current lipid lowering therapies

– Non-compliance– Lack of effective treatment– Fear of high dose titration

• More effective cholesterol-loweringagents are needed to attain LDL-C goals1,2

1Kotseva, K, Wood D, de Backer, G et al. 20012Pearson T et al. 2000

Why Only about 50% of patients with high LDL-C achieve goal ?

Unmet Need

• Even with current therapies, many patients, especially those considered at high and very high risk, are not achieving the goals

• Special populations, such as those FH and other forms of severe hypercholesterolemia, do not achieve even old goals

• Perhaps the largest need, however, is for the growing number of patients who are statin adverse

Statin AdversePrimo study (7924 hyperlipidemic patients)

a Percentage values relative to the total number of patients who had or did not have muscular symptoms.

b Odds ratios were calculated using pravastatin as the reference.c P values were determined by Pearson’s Chi-square test.

Cardiovasc Drugs Ther 2005

Conclusion• The beneficial effect of statin is mainly in preve

ntion of CHD caused by atherosclerosis• Statin is not effective in reducing CV events in

patients with systolic HF• Statin is effective in reducing atherosclerotic C

V events in patients with CKD• Hypercholesterolemia is prevalent in Taiwan; h

owever, cholesterol goal attainment is not satisfactory

• A substantial number of patients with hypercholesterolemia can not tolerate statins

Thanks for your attention

Mackay Medical College馬偕醫學院

Documents

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

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