You are on page 1of 64

pick

HDL-C
8, 9 10 TC LDL-C
H



4S (1021 >65 )

PROVE IT (730 >70 )


1 13
LDL-C <70mg/dl 43 (4)

MIRACL, HPS -

HPS: : Lancet 2002;360:7-22


TNT: : N Engl J Med 2005;352: 14251435
PROVE-IT: : N Engl J Med
2004;350: 1495-1504
IDEAL: : JAMA
2005;294: 2437-2445
CARDS: : Lancet 2004;364: 685-696
ASCOT: : Lancet 2003;361: 1149-1156
SPARCL: : N Engl J Med 2006;355: 549559

Relationship between LDL-C and atheroma burden


Data from recent IVUS trials
1.8
CAMELOT
Placebo

1.2
Median
in percent
atheroma volume
(%)

REVERSAL
Pravastatin

0.6

A-Plus
Placebo

REVERSAL
Atorvastatin

0
0.6

r2 = 0.97
P < 0.001

ASTEROID
Rosuvastatin

1.2
0

60

70

80

90

100

110

120

Mean LDL-C (mg/dL)


Nissen SE et al. JAMA. 2006295:1556-65.


5
, ..

..

EKTIMH

( , -, ,
, , , , , , ).

CHD

0-1
2+

42
: 24.3

: 115/75

mg/dl
: 265
: 128
HDL : 48
LDL : 182
: 86

LDL 160 mg/dl



( , )

: 228
: 104
HDL : 50
LDL : 157

2 +

LDLc 130 mg/dl

A 58 ,
. .
= 230 mg/dl
= 160 mg/dl
HDLc = 42 mg/dl
LDLc = 150 mg/dl
O .
1.LDLc < 160 mg/dl
2.LDLc <130 mg/dl
3.LDLc < 100 mg/dl

WOSCOPS:
200

50

192

40

175

LDL-C 150
(mg/dL)

159

%
30
pravastatin
20

125

31
22

10
0

Shepherd J et al. N Engl J Med. 1995333:1301-1307.




(p<0.001)

(p=0.051)

Fatal/Nonfatal MI, Sudden Cardiac Death,


Unstable Angina: AFCAPS/TexCAPS

Cumulative incidence

0.07

placebo
lovastatin

0.06
0.05
0.04

37%
relative
risk
reduction
p<0.001

0.03
0.02
0.01
0.00
0.0

>5

Years of follow-up

Downs JR et al. JAMA 1998;279:16151622.

Primary End Point: Nonfatal MI


and Fatal
CHD
Atorvastatin 10 mg Number of events
100
Cumulative Incidence (%)

Placebo

Number of events

154

36%
reduction

Baseline LDL-C=133 mg/dL

HR = 0.64 (0.50-0.83)
0
0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Years

Sever PS, Dahlf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

p=0.0005

Regression
line through
the origin

(Regression
line through origin)
95%
95 % confidence

limits

Relative
risk
reduction
(%)
%

60

50

40

JUPITER

ASCOT
AF/TEX

CARDS

WOSCOPS

30

4S

LIPID
20

CARE
HPS

LIPS

ALERT

SPARCL

PROSPER

10

ASPEN

0
0

10

20

30

40

50

60

%
LDL-C
%
Reduction
in LDL-C
Fabbri G, Maggioni AP. Adv Ther. 2009 26: 469487

Prevalence of conventional risk factors in


patients with CHD
Four
Three

(0.9%)

None
8.9%
19.4%

Two

27.8%

43.0%

One
Total patients=87 869
CHD=coronary heart disease
smoking, hypertension, hypercholesterolaemia and diabetes mellitus

Khot UN et al. JAMA 2003; 290: 898904

JUPITER population compared with previous trials


in patients without established CHD
AFCAPS

WOSCOPS

JUPITER

Patients, n

6605

6595

17 802

% male, n

85

100

62

Duration, years

5.2

4.9

1.9

total cholesterol

221

272

183

LDL-C

150

192

104

HDL-C

3640

44

51

158

164

138

0.2

NA

4.3

Lovastatin
2040 mg

Pravastatin
40 mg

Rosuvastatin
20 mg

Diabetes, %
Baseline lipids,
mg/dL*

triglycerides
hsCRP, mg/L
Statin

CVD=cardiovascular disease; CHD=coronary heart disease; LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density


lipoprotein cholesterol; hsCRP=high sensitivity C-reactive protein; *Baseline lipid levels are mean values.
Ridker PM et al. Am J Cardiol 2007; 100: 16591664
Ridker PM et al. N Engl J Med. 2001 344: 1959-65

JUPITER - Primary Endpoint


Placebo

0.04

Rosuvastatin 20 mg

0.02

0.06

Hazard Ratio 0.56


(95% CI 0.46-0.69)
P<0.00001

NNT for 2y = 95
5y* = 25

0.00

Cumulative Incidence

0.08

Time to first occurrence of a CV death, non-fatal stroke, non-fatal


MI, unstable angina or arterial revascularization

Follow-up (years)

Number at Risk
Rosuvastatin
Placebo

8,901
8,901

8,631
8,621

8,412
8,353

6,540
6,508

*Extrapolated figure based on Altman and Andersen method

3,893
3,872

1,958
1,963

1,353
1,333

983
955

544
534

157
174

Ridker P et al. N Eng J Med 2008;359: 2195-2207

JUPITER - Primary Endpoint Components


Placebo

Rosuvastatin

[n=8901]

[n=8901]

n (rate**)

n (rate**)

HR

95% CI

p-value

Primary Endpoint
251 (1.36)
142 (0.77)
0.56
0.46-0.69 <0.001*
(Time to first occurrence of CV death, MI, stroke, unstable angina, arterial revascularisation)
Non-fatal MI
Fatal or non-fatal MI

62 (0.33)
68 (0.37)

22 (0.12)
31 (0.17)

0.35
0.46

0.22-0.58 <0.001*
0.30-0.70 0.0002

Non-fatal stroke
Fatal or non-fatal stroke

58 (0.31)
64 (0.34)

30 (0.16)
33 (0.18)

0.52
0.52

0.33-0.80
0.34-0.79

Arterial Revascularization

131 (0.71)

71 (0.38)

0.54

0.41-0.72 <0.0001

Unstable angina

27 (0.14)

16 (0.09)

0.59

0.32-1.10

CV death, stroke, MI

157 (0.85)

83 (0.45)

0.53

0.40-0.69 <0.001*

Revascularization
or unstable angina

143 (0.77)

76 (0.41)

0.53

0.40-0.70 <0.001*

0.003
0.002

0.09

** Rates are per 100 person years; Hospitalisation due to unstable angina; *Actual p-value was < 0.00001
HR Hazard Ratio; CI Confidence Limit

Ridker P et al. N Eng J Med 2008;359: 2195-2207

JUPITER Subgroup analysis


Placebo better

Rosuvastatin better

0.53
10,208
7,586
0.51
6,041
11,761
0.14
7,375
10,296
0.07

Family history of CHD


Yes
No

2,045
15,684
0.99

Framingham risk score


10%
>10%

1.2

12,683
5,117

Metabolic syndrome
Yes
No

0.57

Region
US or Canada
Other

0.8

11,001
6,801

Hypertension
Yes
No

0.6

0.80

Race
White
Non-white

Hazard ratio (95% CI)

8,541
9,261

Gender
Males
Females

0.4

65 years
>65 yrs

0.2

Age

P- value*
0.32

8,882
8,895

Ridker P et al. N Eng J Med 2008;359: 2195-2207

JUPITER - Total Mortality


0.06

Death from any cause

Placebo

0.02

0.03

0.04

Rosuvastatin 20mg

0.00

0.01

Cumulative Incidence

0.05

Hazard Ratio 0.80


(95% CI 0.67-0.97)
p=0.02

0
Number at Risk
Rosuvastatin 8,901
Placebo
8,901

Follow-up (years)
8,847
8,852

8,787
8,775

6,999
6,987

4,312
4,319

2,268
2,295

1,602
1,614

1,192
1,196

683
684

227
246

Ridker P et al. N Eng J Med 2008;359: 2195-2207

JUPITER - Dual Treatment Target


Hazard Ratios for Incident CV Events According to Achieved Concentrations
of LDL-C and hsCRP
Group
Placebo

N (Event rate*)
7832 (1.11)

HR**

95% CI

P-value

1.00

Rosuvastatin
[Dual target: LDL-C < 70mg/dL, hsCRP < 2mg/L]
Dual target achieved
2685 (0.38)
0.35
Dual target not achieved
5031 (0.74)
0.64
P-value (active treatment)
P-value (trend across groups)
LDLC 70mg/dL
2110 (0.91)
LDLC < 70mg/dL
5606 (0.51)
P-value (trend across hsCRP strata)

0.85
0.45

hsCRP 2mg/L
4305 (0.77)
hsCRP < 2mg/L
3411 (0.42)
P-value (trend across LDL-C strata)

0.68
0.36

0.23-0.54
0.49-0.84
0.033
<0.0001
0.60-1.21
0.33-0.59
<0.0001
0.51-0.89
0.24-0.54
<0.0001

Conversion: LDL-C < 70 mg/dL = 1.8 mmol/L


* Rates are per 100 person years; **Fully adjusted model controlled for age (years), baseline LDL-C (mg/dL), baseline
hsCRP (mg/L), baseline HDL-C (mg/dL, blood pressure, gender, body mass index (kg/m2), smoking status and parental
history of premature coronary heart disease.
HR Hazard Ratio; CI Confidence Interval

Ridker PM et al. The Lancet 2009. DOI: 10.1016/S0140-6736(09)60447-5

JUPITER
Tolerability and safety data

Adverse Events, (%)


Any serious adverse event
Muscle weakness, stiffness, pain
Myopathy
Rhabdomyolysis
Newly diagnosed cancer
Death from cancer
Gastrointestinal disorders
Renal disorders
Bleeding
Hepatic disorders
Other events, (%)
Newly diagnosed diabetes**
Haemorrhagic stroke

Placebo

Rosuvastatin

[n=8901]

[n=8901]

15.5
15.4
0.1
0.0
3.5
0.7
19.2
5.4
3.1
2.1

2.4
0.1

*Occurred after trial completion; **physician reported newly diagnosed diabetes

p-value

15.2
16.0
0.1
<0.1*
3.4
0.4
19.7
6.0
2.9
2.4

0.60
0.34
0.82
---0.51
0.02
0.43
0.08
0.45
0.13

3.0
0.1

0.01
0.44

Ridker P et al. N Eng J Med 2008;359: 2195-2207

CHD

0-1
2+

Risk of a Second Atherothrombotic


Event
Increased Risk vs General Population (%)
Original Event

MI

Stroke

MI

5-7 risk

3-4 risk

Stroke

2-3 risk

9 risk

4 risk

2-3 risk

PAD

Kannel. J Cardiovasc Risk. 1994, Wilterdink et al. Arch Neurol. 1992, Crique, et al. N Engl J Med. 1992

MONICA Project Circulation 1997; 96:3849-3859

+
-
- (
)
-
-

LDL

LDL

< 70 mg/dl

baseline LDL<100
mg/dl

4S: Clinical Benefits of Simvastatin in Patients


with CHD and Hypercholesterolemia
Total
mortality

Major
coronary
events

Coronary
mortality

Cardiovascular
mortality

Relative risk (%)

0
10
20
30
40
50

30%
p=0.0003

34%
p<0.00001

35%
p<0.0001
42%
p=0.00001

Adapted from Scandinavian Simvastatin Survival Study Group Lancet 1994;344:1383-1389;


Kjekshus J et al Am J Cardiol 1995;76:64C-68C; Data on file, MSD.

STATIN worse

VASCULAR EVENT by PRIOR DISEASE


Baseline
feature

STATIN
(10269)

PLACEBO
(10267)

1007

1255

452

597

CVD

182

215

PVD

332

427

Diabetes

279

369

Previous MI
Other CHD (not MI)

Risk ratio and 95% CI


STATIN better STATIN worse

No prior CHD

ALL PATIENTS

2042
(19.9%)

2606
(25.4%)

24%SE 2.6
24%SE
reduction
(2P<0.00001)
0.4

0.6

0.8

1.0

1.2

1.4

VASCULAR EVENT by AGE & SEX


Baseline
feature

STATIN
(10269)

PLACEBO
(10267)

Risk ratio and 95% CI


STATIN better STATIN worse

Age group (years)


< 65

838

1093

65 - 69

516

677

70-74
70 75

550

628

138

208

1676

2148

366

458

Hetc3 = 4.4
2

Sex
Male
Female
ALL PATIENTS

2042
(19.9%)

Hetc1 = 0.4
2

2606
(25.4%)

24%SE 2.6
24%SE
reduction
(2P<0.00001)
0.4

0.6

0.8

1.0

1.2

1.4

Intensive versus Moderate Lipid Lowering with Statins


after Acute Coronary Syndromes (The PROVEPROVE-IT trial)

N Engl J Med 2004;350:1495-504

Intensive versus Moderate Lipid Lowering with Statins


after Acute Coronary Syndromes (The PROVEPROVE-IT trial)
( ;

N Engl J Med 2004;350:1495-504

(%)

(Treating to New Targets):



30
25

TNT

20

?

15
10

10mg

80mg

S =
P = placebo

0
60
(1.6)

80
(2.1)

100
(2.6)

120
(3.1)

140
(3.6)

160
(4.1)

180
(4.7)

200
(5.2)

LDL-C mg/dL (mmol/L)


Kastelein JJP. Atherosclerosis. 1999143(suppl 1):S17-S21

:
*

0.14

HR= 0.78 (95% CI 0.69, 0,89)


P<0.001

0.12

= 22%

10mg
0.10

80mg

0.08
0.06
0.04
0.02
0
0

3
()

* , , (),
LaRosa JC, et al. N Engl J Med. 2005:352

Angiography underestimates
atherosclerotic burden
Patients (n=44) with suspected CAD
and normal angiograms

Atheroma on IVUS

No atheroma on IVUS

52%

CAD=coronary artery disease; IVUS=intravascular ultrasound


Erbel R et al. Eur Heart J 1996; 17: 880889

48%

The IVUS technique can detect


angiographically silent atheroma
Angiogram
No evidence
of disease

IVUS
Little
evidence of
disease

Atheroma

IVUS=intravascular ultrasound
Nissen S, Yock P. Circulation 2001; 103: 604616

, mm3

LDLC

(n=249)

(n=253)

20
15
10
5
0
-5
-15
-20
-80 -70 -60 -50 -40 -30 -20 -10

10

20

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

10

20

% LDL-

LDL-C >50%
.


LDL-C

.

95% (CI)

IVUS efficacy measures


EEM Area

Change
in Percent
Atheroma
Volume

Lumen
Area

(EEM Lumen)CSA

(EEM Lumen)CSA
=

X 100

X 100

EEMCSA

EEMCSA

(Month 24)

(baseline)

(EEM Lumen)

Most diseased
contiguous
10 cross-sections

Normalized*
Total
Atheroma
Volume

(EEMCSA - LumenCSA)
=

number cross-sections
in patients pullback

median number crosssections for all patients

* Normalized = adjusting for pullbacks of differing lengths thereby resulting in an

equal weighting of each individual patient

Mean baseline lipid levels


Baseline level
(mg/dL)

Baseline level
(mmol/L)

LDL-C

130.4

3.4

TC

204.0

5.3

TG

152.2

1.7

HDL-C

43.1

1.1

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

Baseline and On-Treatment Lipids


N= 292

Mean
Baseline

During
treatment*

Percent
Change

Total Cholesterol
(mg/dL)

204.7

133.9

33.9

LDL-C
(mg/dL)

131.5

61.1

53.3

HDL-C
(mg/dL)

42.8

48.3

+13.8

161.9

85.6

47.0

3.24

1.33

58.2

151.8

123.5

12.3

Non-HDL-C
(mg/dL)
LDL-C/HDL-C
ratio
Triglycerides
(mg/dL)
* Time-weighted average

From least square means; all p<0.001

ASTEROID: PRIMARY ENDPOINTS


(n=349)
Endpoint

Baseline

+2 years

regression

% Atheroma
volume

39.6

38.6

0.98

0.001

Volume in most
diseased 10mm

65.1

59.0

6.1

0.001

Total atheroma
volume (mm3)

212.2

197.5

14.7

0.001

Nissen et al. JAMA March 13, 2006.

Change in Percent Diameter Stenosis


vs On-Treatment HDL-C in QCA Trials
CCAIT

1.4
1.2

PLAC I

MAAS

0.8

Change in
% Stenosis
per year

0.6

LCAS
MARS
CCAIT
PLAC I

MARS

0.4
MAAS

0.2

LCAS

0
-0.2
-0.4

R2= 0.71
p = 0.0011

-0.6
-0.8

ASTEROID

Placebo
Statin*

-1

40

45

On-Treatment HDL-C (mg/dL)


* ASTEROID rosuvastatin
CCAIT lovastatin
LCAS fluvastatin

MAAS simvastatin
MARS lovastatin
PLAC I pravastatin

50

Number (%) of patients showing


regression measured by each IVUS parameter

78 %

Normalised total atheroma volume (TAV)

IVUS
parameter
measured

Atheroma volume in the most diseased 10 mm subsegment

64 %

Percent atheroma volume (PAV)

10

20

30

40

50

78 %

60

70

80

Percentage of patients showing regression

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

90

100

VBWG

Statins reduce all-cause death:


Meta-analysis of 14 trials = 90,056
Events (%)

Cause of death

RR

Treatment
(45,054)

Control
(45,002)

Vascular causes:
CHD

3.4

4.4

0.81

Stroke
Other vascular
Any non-CHD vascular

0.6
0.6
1.2

0.6
0.7
1.3

0.91
0.95
0.93

4.7

5.7

0.83

Non-vascular causes:
Cancer
Respiratory
Trauma
Other/unknown
Any non-vascular

2.4
0.2
0.1
1.1
3.8

2.4
0.3
0.1
1.2
4.0

1.01
0.82
0.89
0.87
0.95

Any death

8.5

9.7

0.88

Any vascular death

-17%

-12%

0.5
1.0
1.5
Treatment Control
better
better

CTT Collaborators. Lancet. 2005366:1267-78.

52

HDL-C:

Prospective Cardiovascular Mnster (PROCAM) Study

Incidence, per 1000


in 6 Years

120

110

186 events,
4.407 men aged 4065 years

100
80
60
40

30
21

20
0
<35mg/dL

35-55mg/dL

>55mg/dL

HDL-C
HDL-C=high-density lipoprotein cholesterol CHD=coronary heart disease
Adapted from Assmann G et al. In: Lipid Metabolism Disorders and Coronary Heart Disease: Primary Prevention, Diagnosis and Therapy
Guidelines for General Practice. 2nd ed. Munich: MMV Medizin Verlag 1993:1967. Permission pending.

HDL-C

70 HDL-C >40mg/dl

HDL-C

40 mg/dl

NCEP ATP III


Risk Stratification of Triglycerides

< 150 mg/dl


150 200 mg/dl
200 400 mg/dl
> 400 mg/dl

N o n fa s ti n g t r i g l y c e r i d e s
m m o l/ L

m g/dL
M y o c a r d i a l i n f a r c ti o n

M en
1
1 - 1.99
2 - 2.99
3 - 3.99
4 - 4.99
5
W o m en
1
1 - 1.99
2 - 2.99
3 - 3.99
4 - 4.99
5

6400 M en
1 1 0 0 E ve n ts

< 89
8 9 17 6
1 77 2 65
2 66 3 53
3 54 4 42
4 43

76 0 0 W om en
6 9 0 E ve n ts

< 89
8 9 17 6
1 77 2 65
2 66 3 53
3 54 4 42
4 43

0 .5

16

32

Is c h e m ic s tro k e
M en
1
1 - 1.99
2 - 2.99
3 - 3.99
4 - 4.99
5
W o m en
1
1 - 1.99
2 - 2.99
3 - 3.99
4 - 4.99
5

6400 M en
7 8 0 E ve n ts

< 89
8 9 17 6
1 77 2 65
2 66 3 53
3 54 4 42
4 43

7 60 0 W o m en
7 5 0 E ve n ts

< 89
8 9 17 6
1 77 2 65
2 66 3 53
3 54 4 42
4 43

0 .5

16

32

H a z a r d r a tio ( 9 5 % c o n fid e n c e in te rv a l)



FTT

150 mg/dl
180 mg/dl
220 mg/dl

NCEP ATP III


Risk Stratification of Triglycerides

< 150 mg/dl


150 200 mg/dl
200 400 mg/dl
> 400 mg/dl

25

How often do you check your lipid levels?


50%

43%

40%

27%

30%

30%
20%
10%
0%

EUROASPIRE II

61%

47%

25%

50%

51%

42%

25%

75%

50%

EUROASPIRE II Study Group. Eur Heart J (2001) 22, 554-572

75%

CEPHEUS: LDL
LDL--C (
( TJETF)

(%)

: 55% LDL-C
80
70
60

68

65

61

59
49

50

48

41

40

40
30
20
10
0
um
gi
l
Be

d
an
l
n
Fi

ce
n
a
Fr

ce
e
re
G

d
an
l
Ire

s
g
ur
nd
o
a
l
b
er
m
h
e
t
x
e
N
Lu

y
ke
r
Tu

> 3 (n=15.199)

Hermans MP et al. Curr Med Res Opin 2010;26(2);445454