Aurora PPT.ppt

New Insights Into the

Management of

Global Burden of Cardiovascular Disease

According to WHO estimates:

• 16.6 million people die of CVD worldwide

each year

• CVD contributed to approximately

one third

of global deaths

In 2001:

• 7.2 million deaths from CHD

• 5.5 million deaths from stroke

Risk Factors for Cardiovascular Disease

•

Modifiable

–

Smoking

–

Dyslipidaemia

•

raised LDL cholesterol

•

low HDL cholesterol

•

raised triglycerides

–

Raised blood pressure

–

Diabetes mellitus

–

Obesity

–

Dietary factors

–

Thrombogenic factors

–

Lack of exercise

–

Excess alcohol consumption

• Non-modifiable

–

Personal history of CHD

–

Family history of CHD

–

Age

Levels of Risk Associated with Smoking,

Hypertension and Hypercholesterolaemia

x1.6

_x4

x3

x6

x16

x4.5

x9

Hypertension

(SBP >195 mmHg)

Serum cholesterol level

(>8.5 mmol/L, 330 mg/dL)

Smoking

Cholesterol: A Major Risk Factor

• In the USA, 102 million people have elevated

total cholesterol (>200 mg/dL, 5.2 mmol/L)

1

• In EUROASPIRE II, 58% of patients with established

CHD had elevated total cholesterol

(



5 mmol/L, 190 mg/dL)

2

• 10% reduction in total cholesterol results in:

–

15% reduction in CHD mortality (P<0.001)

–

11% reduction in total mortality (P<0.001)

• LDL-C

is the primary target to prevent CHD

Adapted from: 1. American Heart Association. Heart and Stroke Statistical Update; 2002; 2. EUROASPIRE II Study Group. Eur Heart J 2001;22:554–572; 3. Gould AL et al. Circulation 1998;97:946–952.

Many Patients in Need of Lipid Lowering

Therapy Remain Untreated –

EUROASPIRE II

39% untreated

Lipid management assessed in 5226 patients with CHD at least 6

months after discharge who qualify for treatment

LDL Cholesterol Levels and

CHD Event Rates in Major Statin Trials

31

1.8

35

131

1677

LIPS

24

2.6

35

150

9014

LIPID

35

2.0

39

158

2102

ALERT

36

0.9

39

131

10305

ASCOT-LLA

19

3.8

39

147

5804

PROSPER

27

2.3

39

131

20536

HPS

24

2.6

39

140

4159

CARE

37

1.0

39

150

6605

AFCAPS

32

1.5

50

193

6595

WOSCOPS

34

5.2

66

190

4444

4S

CHD

risk reduction

(%)

CHD

event

rate/year

LDL-C net

change

(mg/dL

)*

Baseline

LDL

(mg/dL

)

Sample

size (n)

Study

CHD events refers to cardiac death or nonfatal MI, unless otherwise indicated.

*Placebo-subtracted change from baseline;

†for placebo treated patients;

‡including silent MI plus resuscitated cardiac arrest;

§including unstable angina.

Relationship Between Changes in

LDL-C and HDL-C Levels and CHD Risk

Third Report of the NCEP Expert Panel. NIH Publication No. 01-3670 2001. http://hin.nhlbi.nih.gov/ncep_slds/menu.htm

1%

decrease

in

LDL-C

reduces

CHD risk by

1%

1%

increase

in

HDL-C

reduces

CHD risk by

3%

NCEP ATP III LDL Cholesterol Goals

CHD

≥2

<2

LD

L

cho

le

stero

l

le

vel

(mg/dL

)

Risk factors

70 -

130 -

100 -

160 -

(National Cholesterol Education Program, Adult Treatment Panel III, 2004)

Target

70

mg/dL

Target

100

mg/dL

2004 NCEP-ATP III Guidelines

Risk Category

LDL Goal

Initiate TLC

(Therapeutic

Lifestyle Changes)

Consider Drug

Therapy

High risk:

CHD or

CHD Risk Equivalents

<100 mg/dl

(Option:

<70 mg/dl)



100 mg/dl



130 mg/dl



100 mg/dl

(<100 mg/dL: consider drug

options)

2+ Risk

Factors

Moderately high

risk:

10-20% risk

<130 mg/dl

(Option: <100

mg/dl)



130 mg/dl



130 mg/dl

(100–129 mg/dL:

consider drug options)

Moderately risk:

<10% risk



160 mg/dl

Lower risk:

0-1 Risk Factor

<160 mg/dl



160 mg/dl



190 mg/dl

(160–189 mg/dL:

LDL-C–lowering drug

optional)

×

Major Risk Factors (Exclusive of LDL

Cholesterol) That Modify LDL Goals



Cigarette smoking



Hypertension (BP



140/90 mmHg or on

antihypertensive medication)



Low HDL cholesterol (<40 mg/dL)

†



Family history of premature CHD



CHD in male first degree relative <55 years



CHD in female first degree relative <65 years



Age (men



45 years; women



55 years)

†

_{HDL cholesterol}

_

_{60 mg/dL counts as a “negative” risk factor; its}

Cholesterol-Lowering Drug Therapy

HMG CoA Reductase

Inhibitors

Lovastatin

Simvastatin

Pravastatin

Atorvastatin

Cerivastatin

(2001/8 withdrawal from market)



Rosuvastatin

Pitavastatin

Niacin/Lovastatin

Amlodipine/Atorvastatin

Aspirin/Pravastatin

Cholestyramine

Colestipol

Colesevelam

Fibrates

Gemfibrozil

Fenofibrate

Clofibrate

Nicotinic Acid

Ezetimibe

Statins

Mechanism

Inhibit HMG CoA reductase which is the rate-limiting step

in cholesterol biosynthesis.

Pharmacodynamics

Most effective class of drugs at lowering LDL-C levels

-



LDL-C by 18-55%

-



HDL-C by 5-15%

-



TG by 7-30%

Adverse reactions

myopathy, rhabdomyolysis, elevations of serum

aminotransferase activity

Mechanism of Action of Statins

Cholesterol Synthesis Pathway

acetyl CoA

HMG-CoA

mevalonic acid

mevalonate pyrophosphate

isopentenyl pyrophosphate

geranyl pyrophosphate

farnesyl pyrophosphate

squalene

cholesterol

dolichols

ubiquinones

HMG-CoA synthase

HMG-CoA reductase

Squalene synthase

Statins

X

Wish List of Features of New Statin



High

efficacy

at start dose

Potent HMG-CoA inhibition

Lowers LDL, VLDL, Lp(a), remnants

Raises HDL

Anti-inflammatory, anti-thrombotic



Good

safety

profile

Selective for target organ – liver

Minimal potential for drug interactions



Useful in a

wide range

of patients



Cost effective

Rosuvastatin:

Well defined pharmacology

Potency on

enzyme

IC

(nM)

Cell selectivity

log ratio

Metabolism

Hepatic

by Cyt P450

3A4

Elimination

Half Life

(hours)

rosuvastatin

pravastatin

5.4

44.1

3.3

3.3

1–2

cerivastatin

10.0

–0.14

Yes

2–3

atorvastatin

8.2

2.2

Yes

14

fluvastatin

_27.6

_–0.04

_No

_1–2

simvastatin

11.2

_0.54

Yes

1–2



19

No

No

Rosuvastatin

is the most effective statin at lowering LDL-C

and produces a significant increase in HDL-C

L

S

me

an

%

chan

ge

f

ro

m b

as

eline

-60

-50

-40

-30

-20

-10

0

10

20

40

80

Dose (mg)

rosuvastatin atorvastatin

simvastatin

pravastatin

Log scale

Rosuvastatin

the most effective statin at lowering LDL- C

Rosuva

Atorva

Simva

Prava

10 20

40

80

Fluva

Statin Dose Required to Achieve

45–50%

LDL-C Reduction

mg

Not achieved with max.

authorised dose

Not achieved with max.

authorised dose

Rosuvastatin

versus Comparators:

LDL-C efficacy at 10mg Dose

Change in LDL-C from baseline (%)

0 –10 –20 –30 –40 –50 –60 10 mg * –5 –15 –25 –35 –45 –55 20 mg † 40 mg ‡ 10 mg mg 20 mg 80 10 mg mg 20 mg 40 mg 80 10 mg mg 20 40 mg

Rosuvastatin 10 mg (–46%)

*p<0.002 vs atorvastatin 10 mg; simvastatin 10, 20, 40 mg; pravastatin 10, 20, 40 mg

†p<0.002 vs atorvastatin 20, 40 mg; simvastatin 20, 40, 80 mg; pravastatin 20, 40 mg ‡p<0.002 vs atorvastatin 40 mg; simvastatin 40, 80 mg; pravastatin 40 mg

0

10

20

30

40

50

60

70

80

90

100

P

at

ients

achie

v

ing

LDL

-C

goal

(%)

p<0.0001

P<0.01

Dose (mg/day)

74

63

80

10

10

20

Rosuvastatin

atorvastatin

•high risk (with CHD or CHD risk equivalent) - Target LDL-C: <100mg/dL (2.59mmol/L)

Baseline mean LDL-C values (mg/dL)

CRESTOR 10 mg: 165.1 (4.28 mmol/L)

atorvastatin 10 mg: 162.6 (4.21) atorvastatin 20 mg: 167.1 (4.33)

Rosuvastatin 10 mg

gets more patients to

NCEP ATP- III LDL-C Goals

Rosuvastatin

effectively raises

HDL-C

1

0

2

4

6

8

10

12

10

20

40

80

Dose (mg)

L

S

me

an

%

chan

ge

f

ro

m b

as

eline

Rosuvastatin

atorvastatin

simvastatin

pravastatin

Log scale

*p<0.002 vs pravastatin 10, 20 mg

**p<0.002 vs simvastatin 40 mg; pravastatin 20, 40 mg †p<0.002 vs simvastatin 40 mg; pravastatin 40 mg

Jones PH, et al. Am J Cardiol 2003;92:152–160

–20 –22.6 –26.8 –28.2 –11.9 –17.6 –14.8 –18.2 10 20 40 80 –23.7

**

†

*

–30

–25

–20

–15

–10

0

–5

Dose (mg)

Rosuvastatin

Atorvastatin

Pravastatin

Simvastatin

Change in

TG from

baseline

(%)

Rosuvastin

reduces in Inflammatory Marker

C-Reactive Protein (ANDROMEDA)

RSV ATV

10 mg 10 mg

20 mg 20 mg

RSV ATV

16 weeks

8 weeks

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

Mean change

from

baseline in

hsC

RP

(%)

Rosuvastatin (RSV)

Atorvastatin (ATV)

-34.0

-21.2

-39.8

-33.8

Statins – Therapeutic Ratio

Therapeutic

Effects

Adverse Effects

Cardiovascular

protection

Muscle

Liver

Drug interactions

Rosuvastatin

Tolerability and Safety –

Withdrawals due to

Adverse Events

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

Percentage of patients with an adverse event

leading to withdrawal

10

0

2

4

6

8

rosuvastatin

simvastatin

pravastatin

P

er

ce

nt

age

of

pat

ients

1

3

5

7

9

2.9%

2.5%

2.5%

3.2%

atorvastatin

Reported Cases of

Fatal Rhabdomyolysis

and

Numbers for All Statins Dispensed in the US Since

These Products Were Launched

Lovastatin Pravastatin Simvastatin Fluvastatin Atorvastatin Cerivasta tin Rosuvastati n * Date approved 8/87 10/91 12/91 12/93 12/96 6/97 11/02# Fatal cases of rhabdomyolysis 19 3 14 0 6 31 0 No. of prescriptions dispensed since marketing began (in thousands) 99,197 81,364 116,145 37,392 140,360 9,815 10,100 Reporting rate (per 1 million prescriptions) 0.19 0.04 0.12 0 0.04 3.16 0

Adapted from: Steffa JA, et al. N Engl J Med. 2002;346:539-540.

*worldwide prescriptions #Netherlands (MR ref state)

Potential Drug Interactions

3A4



Simvastatin



Atorvastatin



Lovastatin



Diltiazem



Clopidogrel



Amiodarone



Cimetidine



Ery/clarithromycin



Ketoconazole



Carbamazepine



St John’s wort



Grapefruit juice

2C9

• Fluvastatin

• Phenytoin

• Fluconazole

• Warfarin

• Rosuvastatin

Low potential for

cytochrome P450

interactions with

rosuvastatin

JUPITER

ACC March 29, 2009

A Randomized Trial of Rosuvastatin in the Prevention

of Venous Thromboembolism:

The JUPITER Trial

Robert Glynn*, Eleanor Danielson, Francisco Fonseca*, Jacques Genest*,

Antonio Gotto*, John Kastelein*, Wolfgang Koenig*, Peter Libby*,

Alberto Lorenzatti*, Jean MacFadyen, Børge Nordestgaard*,

James Shepherd*, James Willerson, and Paul Ridker*

JUPITER

Inclusion and Exclusion Criteria, Study Flow

89,863 Screened

17,802 Randomized

Reason for Exclusion (%)

LDL-C > 130 mg/dL 53 hsCRP < 2.0 mg/L 37 Withdrew Consent 4 Diabetes 1 Hypothyroid <1 Liver Disease <1 TG > 500 mg/dL <1 Age out of range <1 Current Use of HRT <1 Cancer <1 Poor Compliance/Other 3 8,600 Completed Study 120 Lost to follow-up 8,600 Completed Study 120 Lost to follow-up 8,901 Included in Efficacy and Safety Analyses 8,901 Included in Efficacy and Safety Analyses

89,890 Screened

Men > 50 years

Women > 60 years

No CVD, No DM

LDL < 130 mg/dL

hsCRP > 2 mg/L

17,802 Randomized

8,857 Completed Study

44 Lost to follow-up

8,901 Assigned to

Rosuvastatin 20 mg

8,901 Assigned to

Placebo

8,864 Completed Study

37 Lost to follow-up

8,901

8,901

JUPITER

Total Venous Thromboembolism

0 1 2 3 4 0 .0 0 0 0 .0 0 5 0 .0 1 0 0 .0 1 5 0 .0 2 0 0 .0 2 5

Cumula

tive

Inc

ide

nce

Number at Risk Follow-up (years) 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 0.37-0.86

P= 0.007

Placebo

60

/ 8901

Rosuvastatin

34 / 8901

- 43 %

Glynn et al NEJM 2009

JUPITER

Primary Trial Endpoint

:

MI, Stroke, UA/Revascularization, CV Death

Placebo

251 / 8901

Rosuvastatin

142 / 8901

HR 0.56, 95% CI 0.46-0.69

P < 0.00001

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

JUPITER

VTE in JUPITER: Conclusions

VTE is a serious event that occurred about as often as MI and

stroke in the JUPITER study

Rosuvastatin was associated with a significant 43 percent

reduction in risk of VTE with no increase in bleeding.

This benefit was comparable in magnitude and independent of

the effect on arterial events

Widening the treatment target to include prevention

of VTE and death in addition to arterial thrombosis

Rosuvastatin

has Extensive Clinical and

post-Market Experience

Mar

2005

• Approved in

73

countries world-wide

• Over

5 million

patients treated

• Over

20 million

prescriptions written

• Over 45,000 patients have been treated with

rosuvastatin in clinical trial program

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