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.

2003
Cardiovascular Deaths

Coronary Heart Disease


0%
1%

13%
Stroke

4%

HF

6%

High Blood Pressure


53%

6%

Diseases of the Arteries


Congenital Cardiovascular
Def ects

17%

Rheumatic Fever/Rheumatic
Heart Disease
Other

CDC/NCHS and NHLBI

1900 - 2003
Deaths from Cardiovascular Disease

800
700
600
500
400
300
200
100
00

90

80

70

60

50

40

30

20

10

0
19
00

Deaths in Thousands

900

Years

CDC

Deaths in Thousands

1979 to 2003
Gender Differences in Deaths from CVD

520
500
480
460
440
420
400
79 80

85

90

95

00

03

Years
Males

Females

CDC/NCHS and NHLBI

Age-Adjusted Cardiovascular
Death is Declining

pick

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

HDL-C

70 HDL-C >40mg/dl



4S (1021 >65 )

PROVE IT (730 >70 )


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

MIRACL, HPS -



75 325 mg / die 25%
20% - 25%
27%
25% - 30%

CHD

0-1
2+

ASCOT-LLA: Study Design


19,342 randomized
to antihypertensive
treatment
10,305 eligible
and randomized in
lipid-lowering arm

5168 assigned
atorvastatin

5137 assigned
placebo

Sever PS et al, for the ASCOT Investigators. Lancet. 2003;361:1149-1158.

ASCOT-LLA: Patient Population Risk


Factor Profile
All Patients in ASCOT-LLA Had Hypertension Plus 3 Risk Factors for CHD
100

Hypertension
Age 55 years
Male
Microalbuminuria/proteinuria
Smoker
Family history of early coronary disease
Type 2 diabetes
Plasma TC-HDL-C 200mg/dL
Certain ECG abnormalities
LVH
Previous cerebrovascular events
Peripheral vascular disease

84
81
62
33
26
24
14
14
14
10
5
0

20

40

60

80

100

Patients With Risk Factor (%)


Sever PS et al, for the ASCOT Investigators. Lancet. 2003;361:1149-1158.

120


10mg

(mm Hg)

170

Placebo
: 164/95
: 138/80

160
150
140
130
0

LLA Close-out

100
(mm Hg)

95
90
85
80
75
LLA Close-out

Sever PS, et al, for the ASCOT Investigators. Paper presented at: 52nd Annual Scientific Session of the American College of
Sever
Cardiology.
PS, Dahlf
April B,
2, Poulter
2003; Chicago,
N, Wedel
IL.H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

ASCOT-LLA: Primary End Point


Nonfatal MI and Fatal CHD
Originally planned length of trial: 5 years

Cumulative Incidence (%)

Actual length of trial: median 3.3 years


4

Atorvastatin 10 mg (n = 5168)
Placebo (n = 5137)

36%
relative risk
reduction
in nonfatal
MI and fatal
CHD

P=.0005
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 et al, for the ASCOT Investigators. Lancet. 2003;361:1149-1158.

5.0

ASCOT-LLA: Reduction in Nonfatal MI


Originally planned length of trial: 5 years

Cumulative Incidence (%)

Actual length of trial: median 3.3 years


3.0

Atorvastatin 10 mg (n = 5168)
Placebo (n = 5137)

45%
relative risk
reduction
in nonfatal
MI
P =.0002

2.0

1.0

0.0
0.0

0.5

1.0

1.5

2.0

Years
Data on file. Pfizer Inc, New York, NY.

2.5

3.0

3.5

5.0

Mortality in People With Diabetes


Causes of Death
50

% of Deaths

40
30
20
10
0
Ischemic Other Diabetes Cancer
heart
heart
disease disease

Stroke Infection

Geiss LS et al. In: Diabetes in America 2nd ed. 1995; chap 11

Other

Relative Risk of CVD in Diabetes: Framingham Heart


Study
Any CVD event

Stroke
Intermittent claudication

Cardiac failure

CAD

Male
Female

MI

Angina pectoris

Sudden death

Coronary mortality
0

Age-adjusted risk ratio


*P<0.001; P<0.05; P<0.01; P<0.1
Kannel WB, et al. Am Heart J 1990;120:672-676.



TG
HDL-C
LDL


VLDL

VLDLR

IDL

TG

apo B

LDL

LDL


4S
Placebo
n = 97

SimvaStatin
n = 105

R.R ()

24 (24.7%)

15 (14.3%)

CHD

17 (17.5%)

12 (11.4%)

36%

CHD

44 (45.4%)

14 (13.3%)

55%

50 (51.5%)

18 (17.2%)

32%

CHD = Coronary Heart Disease

43%

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

CARDS: Primary Prevention of CVD


With Atorvastatin in Type 2 Diabetes
Patient population:
Age: 40-75 years
LDL-C 160 mg/dL
Triglycerides 600 mg/dL
Type 2 diabetes
No prior MI or CHD
1+ CHD risk factor

Atorvastatin 10 mg/day
(n=1428)

2838 patients
Placebo
(n=1410)
4-year followfollow-up

Primary end point:


Incidence of major cardiovascular events:
Cardiovascular-related death
Nonfatal MI
Stroke
Resuscitated cardiac arrest
Unstable angina
Coronary revascularization procedures

Study completion date


Anticipated: Early 2005
Actual: Halted 2 years early
due to significant results

CARDS -

40--75
40

,
,

LDL--C 160 mg/dL


LDL

TG 600 mg/dL

:
:
, ,
,

CARDS -

LDL
HDL


(IQR)

(IQR)

207 (185(185-229)

207 (186(186-228)

118 (100
100--137
137))

119 (100
100--138
138))

53 (46(46-61)

52 (45(45-60)

150 (106(106-212)

150 (106(106-212)


(mmol/L)

LDL (mmol/L)

-26%

-40%

1.4 mmol/L (54mg/dL) p<0.0001

1.2 mmol/L (46mg/dL) p<0.0001

3
4
2
2
1
0

0
0

4.5

4.5

(%)



37% (95% CI: 17-52)
P=0.001

15

Placebo
127

37%

10

83

0
0
Placebo 1410
Atorva
1428

4.75

1351
1392

1306
1361

1022
1074

651
694

305
328

Placebo*

Atorva*



(CI))
(CI

127 (9.0%) 83 (5.8%)

37% (17(17-52)
p=0.001

77 (5.5%)

51 (3.6%)

36% (9(9-55)

34 (2.4%)

24 (1.7%)

31% ((-16
16--59)

39 (2.8%)

21 (1.5%)

48% (11(11-69)
.2 .4 .6 .8

* N (% )

1 1.2

Placebo

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

+
-


( )

LDL

LDL

< 70 mg/dl

baseline LDL<100
mg/dl

(%)

(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. 1999;143(suppl 1):S17-S21

LDL-C

140
120

10mg (n= 5006)

4.0

80mg (n= 4995)

3.5
3.0

LDL-C = 101mg/dL

100

2.5

80

2.0

P<0.001

60

LDL-C = 77mg/dL

1.5

40

1.0

20

0.5

0
0 3

12

24

36

48

60

LDL-C (mmol/L)

LDL-C (mg/dL)

160

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

:
*

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

Mortality on AMI
Mortality after AMI

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

PAI-1, factor VIIc


activation of prothrombin to thrombin

HDL

PPL

VLDL

LDL

NCEP ATP III


Risk Stratification of Triglycerides

< 150 mg/dl


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

vs.

6-8

16-18

24

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)

Atheroma area = (EEM area) (Lumen area)


Atheroma Area:
EEM area: , Lumen area:

REVERSAL:
-

**

Placebo
Run--in
Run
Phase

80 mg

654

* IVUS

40 mg

18-

: , , -,
34
Nissen SE, et al. JAMA. 2004;291:1071-1080.

:

P=0.02

TAV (%)

2.7*

-1

-0.4

* vs . (P=0.001); vs. . (P=0.98)

, mm3

LDL-C

(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)

Rp. 1) t. Salospir 100 mg bt.no II ()



2) t. ACE inh bt no II ()

3) t. B-blocker bt no I ()

4) t. Statin bt I ()

5)
10/04/2009

2005.
105091

11%
19%

2%

18%

30%

20%

2005.
105091

11%
19%

2%
18%

30%

20%

25

How often do you check your lipid levels?


50%

43%

40%

27%

30%

30%
20%
10%
0%