Preventing the Clinical Manifestations of CV Disease in Asia:Opportunities for Lipid Management

Prof John JP Kastelein

Academic Medical Centre

Amsterdam, The Netherlands

Slides prepared and presented by

WHO CVD Atlas. 2002. WHO Stroke Atlas. 2002.

The Burden of CVD in Asia: CHD Deaths by Country, 2002

2

WHO CVD Atlas. 2002. WHO Stroke Atlas. 2002.

The Burden of CVD in Asia: Stroke Deaths by Country, 2002

3

Age-Standardized Stroke and CHD Death Rates by Country, 2002

Ueshima H et al. Circulation. 2008;118:2702-2709. 4

Projected Stroke and CHD Increase to 2030 in China

Moran et al. Circ Cardiovasc Qual Outcomes. 2010;3;243-252. 5

Increase in Age-Standardized MeanTotal Cholesterol Levels in Asia 1980-2008

Farzadfar et al. Lancet. 2011;377:578-586.

Southeast Asia: Cambodia, Indonesia, Lao People’s Democratic Republic, Malaysia, Maldives, Myanmar, Philippines, Sri Lanka, Thailand, Timor-Leste, VietnamEast Asia: China, Hong Kong (China), Macau (China), Democratic People’s Republic of Korea, Taiwan,Brunei, Darussalam, Japan, Republic of Korea, Singapore, islands of Oceania

6

Men Women

Discoveryof statins

Discoveryof LDLreceptors

Endo, 1976Brown andGoldstein,1974

Statins raise LDLreceptors in the liver

Plasma LDL is reduced

Primary prevention trialsSecondary prevention trials

50 70 110 130 150 170 19090 210 % P

ati

ents

wit

h C

HD

Eve

nt

LDL cholesterol

CARE-Rx

4S-Rx

LIPID-PL

4S-PL

CARE-PL

LIPID-Rx

AFCAPS-Rx

WOSCOPS-Rx

WOSCOPS-PL

AFCAPS-PL

25

20

15

10

5

0

ASCOT-PL

ASCOT-Rx

HPS-Rx

HPS-PL

HPS

LRC-PLLRC-Rx

POSCH-PL

POSCH-Rx

non statin trials

Statin trials

(mg/dL)

1.3 1.8 2.3 2.8 3.4 3.9 4.4 4.9 5.4 (mmol/L)

TNT-80A

TNT-10A

Clear Cardiovascular Benefits of Intensive Lipid-Lowering Therapy

Study Treatment comparison

N Target population

Entry lipid criteria

PROVE-IT A 80 vs. P 40 4162 ACS TC ≤240 mg/dL

A to Z S 40 then S 80 vs. placebo then S 20

4497 ACS TC ≤250 mg/dL

TNT A 80 vs. A 10 10,001 Prior CHD LDL-C 130-250 mg/dL TG ≤600 mg/dL

IDEAL A 80 vs. S 20-40 8888 Prior CHD TG ≤600 mg/dL

SEARCH S 80 vs. S 20 12,064 Prior CHD TC ≥4.5 mmol/L or ≥3.5 if on statins

Second CTT cycle:

More vs less intensive statin therapy

Less statin

Proportional effects on MAJOR VASCULAR EVENTS per mmol/L reduction in LDL cholesterol

0.4 0.6 0.8 1 1.2 1.4

No. of events (% pa)Statin/

More statinContr ol/ Relative risk (CI)

Statin/morestatin better

Control/lessstatin better

Nonfatal MICHD death

Any major coronary event

CABGPTCAUnspecified

Any coronary revascularisation

Ischaemic strokeHaemorrhagic stroke

Unknown strokeAny stroke

Any major vascular event

3485 (1.0)1887 (0.5)5105 (1.4)

1453 (0.4)1767 (0.5)2133 (0.6)5353 (1.5)

1427 (0.4)257 (0.1)618 (0.2)

2302 (0.6)

10973 (3.2)

4593 (1.3)2281 (0.6)6512 (1.9)

1857 (0.5)2283 (0.7)2667 (0.8)6807 (2.0)

1751 (0.5)220 (0.1)709 (0.2)

2680 (0.8)

13350 (4.0)

0.73 (0.69 - 0.78)0.80 (0.74 - 0.87)0.76 (0.73 - 0.78)

0.75 (0.69 - 0.82)0.72 (0.65 - 0.80)0.76 (0.70 - 0.82)0.75 (0.72 - 0.78)

0.79 (0.72 - 0.87)1.12 (0.88 - 1.43)0.88 (0.76 - 1.01)0.84 (0.79 - 0.89)

0.78 (0.76 - 0.80)

99% or 95% CI

Absolute effect of statin therapy onMAJOR VASCULAR EVENTS

0 1 2 3 4 5

05

1015

20

LDL cholesterol, mmol/L

Fiv

e ye

ar r

isk

of a

maj

orva

scul

ar e

vent

, %

Control

21% relative riskreduction per mmol/LStatin

15% relative riskreduction per 0.5 mmol/LMore statin

Combined evidence:~33% relative risk reductionper 1.5 mmol/L

ASAP: Atorvastatin Reduced CRP to a Greater Extent Than Simvastatin

van Wissen S et al. Atherosclerosis. 2002;165:361-366.

2 years

P<.001

1 yearBaseline

P<.022

Atorvastatin 80 mg Simvastatin 40 mg

-50

-40

-30

-20

-10

0

Ch

ang

e (%

)

44.9

40.1

19.7

14.0

Additional Findings• No correlation between

CRP and LDL-C reduction • Significant correlation

between decrease in CRP and reduction in IMT (r =.13; P=.03)

• Patients in the highest tertile of change in CRP had the greatest mean reduction in IMT

Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): Study Design

• Nonfatal MI, including silent MI, and fatal CHD

Primary efficacy end point

HTN=hypertension; SBP=systolic blood pressure; DBP=diastolic blood pressure; TC=total cholesterol; CVD=cardiovascular disease.

Sever PS et al. Lancet. 2003;361:1149-1158.

• Men and women aged 40-79 years

• Untreated HTN (SBP 160 mm Hg, DBP 100 mm Hg, or both)

• Treated HTN (SBP 140 mm Hg, DBP 90 mm Hg, or both)

• TC 251.4 mg/dL

• At least 3 additional CVD risk factors

Atorvastatin 10 mg(n=5168)

Placebo(n=5137)

Patient population

5 years

19,342 patientswith HTN

10,305patients with TC 251.4 mg/dL

•Trial stopped at 3.3 years, 2 years earlier than expected

RRR=relative risk reduction.

Adapted from Sever PS et al. Lancet. 2003;361:1149-1158.

ASCOT-LLA: Atorvastatin Reduced the Occurrence of First Major CV Events

4

0

1

2

3

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5Years

36% RRR innonfatal MI and fatal CHDP=.0005

Atorvastatin (10 mg)

Placebo

Pat

ien

ts w

ith

no

nfa

tal

MI

and

fat

al C

HD

(%

)

4162 patients

• Men and women aged 18 years

• Hospitalized within 10 days of acute MI or high-risk unstable angina (UA)

• TC 240 mg/dL

• Stable condition, enrolled after percutaneous coronary intervention (PCI), if planned

Atorvastatin 80 mg(n=2099)

Pravastatin 40 mg(n=2063)

18 to 36 months

PROVE IT: Study Design

Patient population

• Composite of death from any cause, MI, documented UA requiring rehospitalization, revascularization, and stroke

Primary efficacy end point

Cannon CP et al. N Engl J Med. 2004;350:1495-1504.

PROVE IT: Significant Clinical Benefit With Atorvastatin Occurred as Early as 30 Days

Adapted from Cannon CP et al. Circulation. 2004;110(suppl III);III-499.

100 5 15 20 3025Time after entry to trial (days)

Pravastatin (40 mg)

Atorvastatin (80 mg)

4

0

2

1

3

Dea

th,

MI,

urg

ent

reva

scu

lari

zati

on

(%

)

33% RRRP=.043

Composite end point of death, MI, or urgent revascularization

Atorvastatin Is the Only Statin With an Active HMG CoA Reductase Inhibitor Metabolite

CHCH3CH3O

F

NHC N

Atorvastatin parent molecule

ON

H3CCH3

F

OH

OOHOH..

H

O

HSite*

70% of the activity of atorvastatin is attributed to active metabolites

N

O

H

Active ortho-hydroxy-atorvastatin metabolite

*Unique to ortho-hydroxy metabolite.

Data on file (RP Mason). Pfizer Inc., New York, NY.

..O

OOHOH

-

What Accounts for the Added Benefits of Atorvastatin?

Reduction of lipids +

• Endothelial effects

• Anti-inflammatory effects

• Antioxidant effects

• Reduction in plaque progression

• Plaque stabilization

Wassmann S, Nickenig G. Endothelium. 2003;10:23-33.

Number needed to treat for 1 year to:

Cause a GI Bleed1 Cause a Fatal GI Bleed1

Aspirin

Cause Severe Myositis2 Cause Fatal Myositis2

Statins

1Derry S, Loke YK. 20002Thompson PD, et al. 2003

Statin Safety in Perspective

248 2066

100,000 1,000,000

Safety of Atorvastatin 80 mg in Clinical Trials

Follow-up PatientsALT/AST>3x ULN*

CK >10x ULN*

Newman et al† variable 4798 26 (0.6%) 2 (0.06%)

PROVE-IT 2 years 2099 69 (3.3%) NA

TNT 4.9 years 4995 60 (1.2%) 0

IDEAL 4.8 years 4439 61 (1.38%) 0

SPARCL 4.9 years 2365 51 (2.2%) 2 (0.08%)

Total variable 18,696 267 (1.43%) 4 (0.021%)

20

*Consecutive measurements.†Newman C et al. Am J Cardiol. 2006;97:61-67; Cannon CP et al. N Engl J Med. 2004;350:1495-1504; LaRosa JC, et al. N Engl J Med. 2005;352:1425-1435; Pedersen TR et al; for the IDEAL Study Group. JAMA. 2005;294:2437-2445; Amarenco P et al. N Engl J Med. 2006;355:549-559.

Is Current LDL Reduction Enough?C

V e

ven

ts

placebo

treated

700

600

500

400

300

200

100

04S2º prevention trialwith simvastatin

WOSCOPS1º prevention trialwith pravastatin

31.0%reduction

30.6%reduction

The Future of Best Practice“Normal” plasma cholesterol

-

-

-

-

-

- 700(18.0)

300(7.7)

200(5.2)

150(3.9)

100(2.6)

50(1.3)

0

Pla

sma

c ho

les t

e ro

l l e

v el

mg

/dL

(m

mo

l/L

)

Rat

Guinea pig

Sheep

Rabbit

Pig

Newborns

Normal adults

FH homozygotes

FH heterozygotes

Physiologic level forplasma LDL-cholesterolas predicted from receptorstudies25 mg/dL (0.65 mmol/L)

Cow

Camel

REVERSAL: Benefit of Intensive LDL-C Lowering on Plaque Progression

Per

cen

t ch

ang

e in

at

her

om

a vo

lum

e

Progression (P=0.001)

No change (P=0.98)

P=0.02 between treatment groups

pravastatin 40 mg

atorvastatin 80 mg

Nissen SE et al. JAMA 2004;291:1071–1080

3

2

1

0

-1

REVERSALComparison of % LDL Cholesterol Reduction and Change in Atheroma Volume

% Change in LDL Cholesterol

Ch

ang

e in

Ath

ero

ma

Vo

lum

e, m

m3

50% LDL-C reduction

-15

-10

-5

0

5

10

15

20

-80 -70 -60 -50 -40 -30 -20 -10 0 10 20

For any degree reduction in LDL-C, the progression rate was lower with atorvastatin than with pravastatin

REVERSAL: Intensive Lipid Lowering With Atorvastatin Halted Plaque Progression After 18 Months

Nissen SE et al. JAMA. 2004;291:1071-1080.

20

15

10

5

0

-5

-10

-15

Change in LDL-C (%)

Ch

ang

e in

ath

ero

ma

volu

me

(mm

3 )

-80 -70 -60 -50 -40 -30 -20 -10 0 10 20

Pravastatin (40 mg)

Atorvastatin (80 mg)

26

0

2

4

6

8

10

12

14

16

≥60 45–59 30–44 15–29 <15

0

5

10

15

20

25

30

35

40

≥60 45–59 30–44 15–29 <15

0

20

40

60

80

100

120

140

160

≥60 45–59 30–44 15–29 <15

Relationship Between Estimated GFR (eGFR) and Clinical Outcomes

Go AS, et al. N Engl J Med. 2004;351:1296-305.

Death from Any CauseTotal Events = 51,424

Cardiovascular EventsTotal Events = 139,011

Any HospitalizationTotal Events = 554,651

Ag

e-S

tan

da

rdiz

ed

Ev

en

t R

ate

(pe

r 1

00

Pe

rso

n-Y

r)

eGFR (mL/min/1.73 m2)

Proportion of Patients With Decline or Improvement From Baseline eGFR

0

10

20

30

40

50

% o

f pat

ient

s w

ith c

hang

e in

eG

FR Atorvastatin 10 mg

Atorvastatin 80 mg

P<0.0001

P<0.0001

(n=3324) (n=3225) (n=1505) (n=1602)

eGFR decline from eGFR improvement from≥60 mL/min/1.73 m2 <60 mL/min/1.73 m2

9.2%6.6%

37.8%

45.6%