(SHARP)

, MD, FESC, FAHA

-
--

-- .
--

INTER-HEART: Population-attributable risk of

acute MI in the overall population
Risk factor
ApoB/ApoA-1 (fifth
quintile compared with
first)
Current smoking
Diabetes
Hypertension
Abdominal obesity
Psychosocial
Vegetable and fruits
daily
Exercise
Alcohol intake
All combined

PAR adjusted for age, PAR adjusted for all

sex, smoking
(99% CI)
54.1 (49.6-58.6)
49.2 (43.8-54.5)

36.4 (33.9-39.0)
12.3 (11.2-13.5)
23.4 (21.7-25.1)
33.7 (30.2-37.4)
28.8 (22.6-35.8)
12.9 (10.0-16.6)

35.7 (32.5-39.1)
9.9 (8.5-11.5)
17.9 (15.7-20.4)
20.1 (15.3-26.0)
32.5 (25.1-40.8)
13.7 (9.9-18.6)

25.5 (20.1-31.8)
13.9 (9.3-20.2)
90.4 (88.1-92.4)

12.2 (5.5-25.1)
6.7 (2.0-20.2)
90.4 (88.1-92.4)

PAR=population-attributable risk

Is Lower Better? Elevated Cholesterol Levels are Associated

with an Increased Risk of Mortality

Death rate per 1000 m en

18
16
14
12
10
8
6
4
2
0
3.62
(140)

Data from MRFIT study.

Martin MJ et al. Lancet 1986;ii:933936.

4.14
(160)

4.65
(180)

5.17
(200)

5.69
(220)

6.21
(240)

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

6.72
(260)

7.24
(280)

7.75
(300)

Genes and environment

in type 2 diabetes and atherosclerosis

Diet and Lipids

Results from clinic ward studies show that diet can reduce total
cholesterol 15%.
In free-living subjects decrease seems to be 3% the 1st year for
AHA 1 step diet and 6% for AHA step 2 diet.
It is important to have realistic expectations for the reduction
levels we expect.
Dietary compliance was clearly an issue as the dietary targets
were only met in a few of the studies
Tang et alQ BMJ 1998;316:1213-1220

Akira
Endo

HO
Compactin
O
H3C

O
O

O
H

CH3

Patients with CHD event (%)

Effects of lipid-lowering therapy on

CHD events in statin trials
Secondary
Prevention

4S-P

25

Primary
Prevention

20
4S-S

Simvastatin

LIPID-P

15

CARE-P
HPS-P
LIPID-S

10

CARE-S

Pravastatin
Lovastatin
Atorvastatin

WOSCOPS-P
WOSCOPS-S

HPS-S
ASCOT-P*
ASCOT-S*

S=statin treated
P=placebo treated

AFCAPS -P

AFCAPS -S

*Extrapolated to 5 years

0
90

110

130

150

170

LDL-C (mg/dL)
Modified from Kastelein JJP. Atherosclerosis. 1999;143(Suppl 1): S17-S21.

190

210

Intensive LDLLDL-C Goals for High

Risk Patients
Recommended LDL-C treatment goals
ATP III
Update 20041
<100 mg/dL:
Patients with CHD or
CHD risk equivalents
(10 year risk >20%)1

AHA/ACC
guidelines
for patients with
CHD*,2

<100 mg/dL

<70 mg/dL:
Therapeutic option
for very high risk
patients1

<70 mg/dL

2006
Update

<100 mg/dL:
Goal for all patients
with CHD,2
<70 mg/dL:
A reasonable goal
for all patients with
CHD2
If it is not possible to attain LDL-C <70
mg/dL because of a high baseline LDL-C,
it generally is possible to achieve LDL-C
reductions of >50% with more intensive
LDL-Clowering therapy, including drug
combinations.

* And other forms of atherosclerotic disease.2

Factors that place a patient at very high risk: established cardiovascular disease plus: multiple major risk
factors (especially diabetes); severe and poorly controlled risk factors (e.g., cigarette smoking);
metabolic syndrome (triglycerides 200 mg/dL + nonHDL-C 130 mg/dL with HDL-C <40 mg/dL); and
acute coronary syndromes.1
Slide Source
1. Grundy SM et al. Circulation 2004;110:227239.
Lipids Online Slide Library
2. Smith SC Jr et al. Circulation 2006; 113:23632372.
www.lipidsonline.org

100

99
90

90

80
78
60
40

69

68
61

83
66

47

20
0

(n=78)
(n=76)
(n=78)
(N=308)
(n=76)

Brown AS J Am Coll Cardiol 1998;32:665672.

Slide Source
Lipids Online Slide Library
www.lipidsonline.org


6% LDLC

LDL-C (%)

6%
6%
6%

10

20

30

40

50

60

70

80

(mg)
Slide Source

Knopp RH et al N Engl J Med 1999;341:498509; Stein E Am J Cardiol 2002;89(suppl):50C57C.Lipids Online Slide Library
www.lipidsonline.org

Slide 14

 VYTORIN (/)
(VYVA)

, , ,
, 6

/ 10/10, 10/20, 10/40, 10/80 mg
(n=951)
10, 20, 40, 80 mg
(n=951)

1879
LDL-C NCEP ATP III (3.4 4.9
mmol/L [130 190 mg/dl])
TG 3.95 mmol/L (350 mg/dl)
Ballantyne CM et al Am Heart J 2005;149:464473.
VYTORIN (/) MSP Singapore Company, LLC.
Slide 15

 % , ,
LDL-C*
, LDL-C, INEGY
atorvastatin
p<0.001
Pooled
atorva

Pooled Atorva
INEGY 10 mg

INEGY Atorva
10/10 20 mg

INEGY Atorva
10/20 40 mg

INEGY Atorva
10/40 80 mg

INEGY
10/80

, LDL-C

0
-10

-20
-30
-36.1

-40
-50

-60

-43.7

-45.3

-47.1
-53.4

-50.6

-48.3
-52.9

-57.4

-58.6

-70

*Ballantyne CM, Abate N, Zhong Y et al. Am Heart J. 2005;149:464-473.

Slide 16

 INEGY
LDL--C
LDL
Ezetimibe/simvastatin
Rosuvastatin
10/20 mg
(n=476)

10 mg
(n=475)

10/40 mg
(n=477)

20 mg
(n=478)

10/80 mg
(n=474)

40 mg
(n=475)

10/20
10/80 mg
(n=1427)

1040 mg
(n=1428)

Mean % change from

baseline to week 6

0
45
45.8%
50

51.5%a
55

51.6%

52.3%

54.8%b
56.7%

55.8%a

60
61%a
65

aP<0.001; bP=0.001

vs rosuvastatin

Adapted from Catapano AL et al Curr Med Res Opin. 2006;22:20412053.

Slide 17

SETTLE
Simvastatin / Ezetimibe Therapy to
Target Lipids Elevation

ezetimibe/simvastatin
18



LDL-C 2
( )
LDL

26.2%

(n=397)

(n=1117)

73.8%

106




1.
7
,


LDL-C

1.

19

Min

Max

247.8

37.4

245.0

119.0

450.0

1513

LDL-C (mg/dl)

163.7

31.2

162.0

74.0

350.0

1509

HDL-C (mg/dl)

45.1

11.6

42.0

16.0

152.0

1509

173.8

80.4

160

42.0

890.0

1511

Total Cholesterol (mg/dl)

TG

Total Cholesterol (mg/dl)

182.1

Min

Max

28.9

182.0

95.0

385.0

1494

LDL-C (mg/dl)

106.9

23.8

103.6

34.0

322.0

1493

HDL-C (mg/dl)
TG

48.1
136.7

10.5
46.3

46.0
135.0

22.0
15.0

135.0
613.0

1493
1493

, 98.5% (n=1491)
LDL-C 2, 1.5% 20
LDL-C

Presented by
Terje R. Pedersen
Oslo
Disclosure:
Research grants and/or speaker- / consulting fees from
Merck, MSP, Astra-Zeneca, Pfizer

Primary Endpoint MCE

Percentage of Patients With
First Event

50

Intention to Treat Population

Placebo
40
Hazard ratio: 0.96, p=0.591
30
EZ/Simva 10/40 mg

20

10

0
0

No. at Risk

2
3
Years in Study

EZ/Simva 10/40 mg

906

817

713

618

53

Placebo

884

791

696

586

56

Rosseb et al. NEJM. 2008;359

Ischemic CV Events

30

Intention to Treat Population

Percentage of Patients With

First Event

2nd EP:

20

Hazard ratio: 0.78, p=0.024

Placebo

EZ/Simva 10/40 mg

10

0
0
No. at risk
EZ/Simva 10/40 mg
Placebo
Rosseb et al. NEJM. 2008;359

3
Years in Study

917
898

867
838

823
788

769
729

76
76

Coronary Artery Bypass Grafting (CABG)

30
Percentage of Patients With
First Event

Intention to Treat Population

20

Hazard ratio: 0.68, p=0.015

Placebo
10
EZ/Simva 10/40 mg
0
0

EZ/Simva 10/40 mg

925

887

848

797

80

Placebo

909

862

819

761

80

No. at risk

Rosseb et al. NEJM. 2008;359

3
4
Years in Study

The results of the Study of Heart

and Renal Protection (SHARP)
Colin Baigent, Martin Landray
on behalf of the SHARP Investigators
Disclosure: SHARP was sponsored, designed, run, and analysed by the
University of Oxford. Funding was received from Merck, the UK MRC,
British Heart Foundation, and Australian NHMRC.

SHARP: Rationale
Risk of vascular events is high among patients
with chronic kidney disease
Lack of clear association between cholesterol
level and vascular disease risk
Pattern of vascular disease is atypical, with a
large proportion being non-atherosclerotic
Previous trials of LDL-lowering therapy in
chronic kidney disease are inconclusive

SHARP: Eligibility
History of chronic kidney disease
not on dialysis: elevated creatinine on 2 occasions
Men: 1.7 mg/dL (150 mol/L)
Women: 1.5 mg/dL (130 mol/L)

on dialysis: haemodialysis or peritoneal dialysis

Age 40 years
No history of myocardial infarction or
coronary revascularization
Uncertainty: LDL-lowering treatment not
definitely indicated or contraindicated

CKD Subgroup

Age-standardized event rate (per 100 person-yr)

Relationship Between Estimated GFR

(eGFR) and Clinical Outcomes
Death from any cause

Cardiovascular events

Any hospitalization

Total events = 51,424

Total events = 139,011

Total events = 554,651

eGFR (mL/min/1.73 m2)

Kaiser Permanente Renal Registry, n=1,120,295 adults aged 20 years
Median followfollow-up = 2.84 years
Go AS et al. N Engl J Med. 2004;351:1296-1305.

VBWG

4D Trial: Neutral effect of statin in

hemodialysis patients with diabetes
N = 1.255 randomized to atorvastatin 20 mg or placebo for 4 years
Fatal stroke 103%*
P = 0.04

20

12%*

10
0
-10
%
Change
-20
-30

Baseline
LDL-C
121 mg/dL

-40
-50

*Relative risk reduction

LDL-C

8%*
18%*
NS

P = 0.03

NS

Nonfatal MI
CHD death
Stroke

Coronary
events

Cerebrovasc
events

Wanner C et al. N Engl J Med. 2005;353:238-48.

4D study in diabetic hemodialysis

patients: no benefit of statin therapy
60

Placebo

50

p=0.37

40

Atorvastatin

Cumulative
incidence of 30
primary
endpoint
20
(%)
10
0
0

Time (years)

No. at risk:
Placebo

636

532

383

252

136

51

19

Atorvastatin

619

515

378

252

136

58

29

4D=Die Deutsche Diabetes Dialyse Studie

Wanner C et al. N Engl J Med 2005; 353: 238248

AURORA: study design

Screening

Month:
14
Visit:
days 1
Patients (n~2750)
Inclusion criteria
ESRD, on hemodialysis
for
3 months
5080 years
Exclusion criteria
Statin within 6 months
Kidney transplant likely
within 1 year
Creatine kinase >3xULN
ALT >3xULN
TSH >1.5xULN

Treatment

0
2

3
3

6
4

12
5

6monthly
6

Final

Rosuvastatin 10 mg daily (n~1350)

Randomization 1:1

Matching placebo (n~1350)

Study

medication was administered until 620 patients had experienced a major

CV event
Fellstrm B et al. Curr Control Trials Cardiovasc Med 2005; 6: 9

AURORA: primary endpoint

Kaplan-Meier estimate of time to
Kaplanfirst major CV event
40

Placebo

35
30
Cumulative
incidence of
primary
endpoint
(%)

Rosuvastatin

25
20
15
10

HR=0.96 (95% CI 0.841.11)

P=0.59

5
0
0
No. at risk:
Rosuvastatin
Placebo

1390
1384

1
2
3
4
Years from randomization
1152
1163

962
952

826
809

551
534

5
148
153

N Engl J Med. 2009;360:1395-407

SHARP: Assessment of LDL-lowering

SHARP: Baseline characteristics

Characteristic
Age
Men
Systolic BP (mm Hg)
Diastolic BP (mm Hg)
Body mass index
Current smoker
Vascular disease
Diabetes mellitus
Non-dialysis patients only
eGFR (ml/min/1.73m2)
Albuminuria

Mean (SD) or %
62 (12)
63%
139 (22)
79 (13)
27 (6)
13%
15%
23%
(n=6247)
27 (13)
80%

SHARP: Compliance and LDL-C reduction

at study midpoint
Eze /simv

Placebo

Compliant

66%

64%

Non-study statin

5%

8%

Any lipid-lowering

71%

8%

~2/3 compliance

LDL-C reduction of 32 mg/dL with 2/3 compliance,

equivalent to 50 mg/dL with full compliance

SHARP: Main outcomes

Key outcome
Major atherosclerotic events (coronary death, MI,
non-haemorrhagic stroke, or any revascularization)
Subsidiary outcomes
Major vascular events (cardiac death, MI, any
stroke, or any revascularization)
Components of major atherosclerotic events
Main renal outcome
End stage renal disease (dialysis or transplant)

SHARP: Major Atherosclerotic Events

Proportion suffering event (%)

25

Risk ratio 0.83 (0.74 0.94)

Logrank 2P=0.0022

20

Placebo
15

Eze/simv
10

0
0

Years of follow-up

CTT: Effects on Major Atherosclerotic Events

Proportional reduction in
atherosclerotic event rate (95% CI)

30%

Statin vs control
(21 trials)

25%
20%
More vs Less
(5 trials)

15%

SHARP
32 mg/dL

10%
5%
0%
0

10

20

30

Mean LDL cholesterol difference

between treatment groups (mg/dL)

40

CTT: Effects on Major Atherosclerotic Events

Proportional reduction in
atherosclerotic event rate (95% CI)

30%

Statin vs control
(21 trials)

25%
20%

SHARP
17% risk
reduction

More vs Less
(5 trials)

15%

SHARP
32 mg/dL

10%
5%
0%
0

10

20

30

Mean LDL cholesterol difference

between treatment groups (mg/dL)

40

SHARP:
Major
Atherosclerotic
Events
SHARP:
Major
Vascular Events
Event

Eze/simv
(n=4650)

Placebo
(n=4620)

Major coronary event

Non-haemorrhagic stroke
Any revascularization

213 (4.6%) 230 (5.0%)

131 (2.8%) 174 (3.8%)
284 (6.1%) 352 (7.6%)

Major atherosclerotic event

526 (11.3%) 619 (13.4%)

Other cardiac death

Haemorrhagic stroke

162 (3.5%) 182 (3.9%)

45 (1.0%) 37 (0.8%)

Risk ratio & 95% CI

16.5% SE 5.4
reduction
(p=0.0022)

Other major vascular events 207 (4.5%) 218 (4.7%)

5.4% SE 9.4
reduction
(p=0.57)

Major vascular event

15.3% SE 4.7
reduction
(p=0.0012)

701 (15.1%) 814 (17.6%)

0.6

0.8

Eze/simv
better

1.0

1.2

1.4

Placebo
better

SHARP: Effects in subgroups

Among 8384 patients originally randomized to
eze/simv vs placebo, major vascular events
risk ratio = 0.84 (95% CI 0.75 0.93; p=0.0010)
Similar reductions in major atherosclerotic
events in all subgroups studied (including
non-dialysis and dialysis patients)

SHARP: Major Atherosclerotic Events

by renal status at randomization
Eze/simv
(n=4650)
Non-dialysis (n=6247)
Dialysis (n=3023)

Placebo
(n=4620)

Risk ratio & 95% CI

296 (9.5%) 373 (11.9%)

230 (15.0%) 246 (16.5%)

Major atherosclerotic event 526 (11.3%) 619 (13.4%)

No significant heterogeneity between

non-dialysis and dialysis patients (p=0.25)

16.5% SE 5.4
reduction
(p=0.0022)
0.6 0.8 1.0 1.2 1.4

Eze/simv
better

Placebo
better

SHARP: Renal outcomes

Event

Eze/simv
(n=3117)

Placebo
(n=3130)

Risk ratio & 95% CI

Main renal outcome

End-stage renal disease (ESRD) 1057 (33.9%) 1084 (34.6%)

0.97 (0.89-1.05)

Tertiary renal outcomes

ESRD or death

1477 (47.4%) 1513 (48.3%)

0.97 (0.90-1.04)

ESRD or 2 x creatinine

1190 (38.2%) 1257 (40.2%)

0.94 (0.86-1.01)
0.6

0.8

1.0

Eze/simv
better

1.2

1.4

Placebo
better

SHARP: Cancer incidence

Proportion suffering event (%)

25

20

Risk ratio 0.99 (0.87 1.13)

Logrank 2P=0.89

15

Eze/simv
Placebo

10

0
0

Years of follow-up

SHARP: Safety
Eze/simv Placebo
(n=4650) (n=4620)
Myopathy
CK >10 x but 40 x ULN
CK >40 x ULN
Hepatitis
Persistently elevated ALT/AST >3x ULN
Complications of gallstones
Other hospitalization for gallstones
Pancreatitis without gallstones

17 (0.4%)
4 (0.1%)
21 (0.5%)
30 (0.6%)
85 (1.8%)
21 (0.5%)
12 (0.3%)

16 (0.3%)
5 (0.1%)
18 (0.4%)
26 (0.6%)
76 (1.6%)
30 (0.6%)
17 (0.4%)

SHARP: Conclusions
No increase in risk of myopathy, liver and biliary
disorders, cancer, or nonvascular mortality
No substantial effect on kidney disease progression
Two-thirds compliance with eze/simv reduced the risk
of major atherosclerotic events by 17% (consistent
with meta-analysis of previous statin trials)
Similar proportional reductions in all subgroups
(including among dialysis and non-dialysis patients)
Full compliance would reduce the risk of major
atherosclerotic events by one quarter, avoiding
3040 events per 1000 treated for 5 years

IMPROVE-IT
, , -

18,000 ACS,


/ 10/40 mg 40 mg


, ,*

ACS=
* , ,
30
Slide 47

Explaining the fall in CHD deaths in USA 1980

1980--2000 :
RESULTS
NEJM 2007; 356: 2388.
10000

Risk Factors worse +17%

Obesity (increase)
Diabetes (increase)

+7%
+10%

Risk Factors better -65%

- 10000

Population BP fall -20%

Smoking
-12%
Cholesterol (diet) -24%
Physical activity
-5%

Treatments
- 30000

342,000
fewer deaths
in 2000
1980
2000

-47%

AMI treatments
-10%
Secondary prevention -11%
Heart failure
-9%
Angina:CABG & PTCA -5%
Hypertension therapies -7%
Statins (primary prevention) -5%

- 50000

Unexplained

-9%

Slide 48

Slide 49

Slide 50