Statins and CAD Prevention:

Rosuvastatin

Rising burden of CVD in India (2005)

Lancet 2005;366:1744-9

Estimated proportions of total deaths and DALYs lost by cause in India (all ages, 2005)

CAD risk factors in Indians

0

10

20

30

40

50

60

36.9 38.8

29.3

59.05

30.97

18.0213.28

%

J Assoc Physicians India. 2004 Feb;52:103-8

Fraction of CAD patients with various risk factors (n=5748)

Dyslipidaemia is a major CVD risk factor in

Indians

Secondary Prevention

NCEP ATP 3. Circulation 2002; 106;3143

“NCEP-ATP III specifies an LDL cholesterol <100 mg/dL as the goal of therapy in

secondary prevention”

LDL-C is the primary target

“NCEP-ATP III identifies the sum of LDL+VLDL [termed non-HDL cholesterol (Total-CL minus HDL-CL)] <130

mg/dL as a secondary target of therapy in persons with high triglycerides (≥200 mg/dL)”

Non-HDL-C as the secondary target

“The Lower, the Better”

RelativeRisk

for CHD (Log Scale)

3.7

2.9

2.2

1.7

1.3

1.0

LDL-C

40 70 100 130 160 190

0

1

Grundy SM et al. Circulation 2004;110:227–239.

mg/dL1.05 1.80 2.60 3.35 4.10 4.90 mmol/L

1% decreasein LDL-C reduces

CHD risk by1%

NCEP-ATP 3 Guidelines for LDL Cholesterol

NCEP ATP 3. Circulation 2002; 106;3143

*

NCEP-ATP 3 Update

Circulation. 2004;110:227-239

*When LDL-lowering drug therapy is employed in high-risk or moderately high-risk persons, it is advised that intensity of therapy be sufficient to achieve at least a 30% to 40% reduction in LDL-C levels

Drugs for hyperlipidaemia

•LDL ↓18-55%

•HDL ↑5-15%

•TG ↓7-30%

Statins

•LDL ↓15-30%

•HDL ↑3-5%

•TG No change

Fibrates

•LDL ↓5-25%

•HDL ↑15-35%

•TG ↓20-50%

Nicotinic acid

•LDL ↓5-20%

•HDL ↑10-20%

•TG ↓20-50%

Bile acid sequestrants

LDL-C goal: an unmet need

The lipid treatment assessment project (L-TAP)

63% of patients with 2 risk factors and no CHD

did not reach NCEP goal

63% 82%

82% of CHD patients did not reach NCEP

goal

Arch Intern Med. 2000;160:459-467

Many Patients With CHD Fail to Achieve LDL-C and Non-HDL-C Goals Even With

Dose Titration

LDL-C Non-HDL-C0

10

20

30

40

50

60

70

80

90

100Atorvastatin 10 - 80 mg

Simvastatin 10 - 40 mg

Lovastatin 20 - 80 mg

Fluvastatin 20 - 80 mg

Pravastatin 10 - 40 mg

Pat

ien

ts, %

at

go

al

ACCESS STUDY. Ballantyne CM, et al. Am J Cardiol. 2001;88:265-269

n = 2,543†

At Wk 54

GAP

Reasons for the unmet gap

Variations in drug potency

Drug interactions

Variations in drug tolerability

affecting compliance

Rosuvastatin

“Superstatin”

Statins: Comparison of standard doses

† For every doubling of the dose above standard dose, an approximate 6% decrease in LDL-C level can be obtained

Circulation. 2004;110:227-239

Change from baseline LDL-C level according to rosuvastatin dose

Olsson AG 2000

LDL-C: % Change From Baseline at week 6

Rosuvastatin 10 to 40 mg vs Comparators

-45.87

-52.34-54.96

-36.73

-42.57-47.79

-51.05

-20.13-24.29

-29.67-28.3

-34.98-38.81

-45.78

-70

-60

-50

-40

-30

-20

-10

010 20 40 80

Dose, mg

% c

ha

ng

e f

rom

ba

se

lin

e

Rosuvastatin (n = 156 - 160)Atorvastatin (n = 158 - 165)Pravastatin (n = 158 - 165)Simvastatin (n = 161 - 164)

P <0.001 vs comparators on a mg-to-mg basis. Data presented as means.

http://www.fda.gov/OHRMS/DOCKETS/ac/03/slides/3968S1_01_B-AstraZeneca-Efficacy.ppt#14

STELLAR Study. Am J Cardiol 2003;92:152–160)

Rosuvastatin

“Less drug interactions”

Statins: Differences in Pharmacokinetics

Natural Synthetic

Lovastatin

Simvastatin

Pravastatin

Atorvastatin

Fluvastatin

Rosuvastatin

Lipophilic

Hydrophilic

Metabolized bycyt P (450) 3A4/2C9

Limited metabolism by cyt P (450)

Schachter M. Fundam Clin Pharmacol 2005; 19: 117-125

Rosuvastatin: less chance of

drug interaction

Rosuvastatin

“Ease of administration”

Longer half-life

Hepatic cholesterol synthesis is maximal between midnight and 2:00 A.M

Most statins attain peak plasma concentrations 1-4 hours after oral administration and have a half-life of 1-4 hours requiring them to be administered in the evening

Rosuvastatin has a long half-life like atorvastatin (approximately 20 hrs) which permits it to be administered any time in a day

Rosuvastatin“Effects on other atherogenic lipid

parameters”

Effect on total cholesterol

-33

-27-25

-19

-35

-30

-25

-20

-15

-10

-5

0

Mean

% c

han

ge i

n T

C f

rom

b

ase

lin

e

** p<0.001 vs. other statins

Rosuvastatin 10mg

Atorvastatin 10mg

Simvastatin 20mg

Pravastatin 20mg

n=389 n=393 n=249 n=252

Coron Artery Dis 2004;15:115-23.

Effect on triglycerides

-19-18

-12 -12

-20

-18

-16

-14

-12

-10

-8

-6

-4

-2

0

Mean

% c

han

ge i

n T

G f

rom

b

ase

lin

e

** p<0.001 vs. simvastatin & pravastatin

Rosuvastatin 10mg

Atorvastatin 10mg

Simvastatin 20mg

Pravastatin 20mg

n=389 n=393 n=249 n=252

Am J Cardiol 2003;91(Suppl):3C-10C.

Effect on small dense LDL-C: % change from baseline after 6

weeks of treatment

-53

-46

-54

-52

-50

-48

-46

-44

-42

Rosuvastatin40mg (n=135)

Atorvastatin80mg (n=136)

** p< 0.001 vs. atorvastatin

STELLAR Trial . Am J Cardiol 2008;101:315–318.

Effect on HDL-C: % Change From Baselineat week 6

9.69.5

7.7

2.1

4.44.85.7 5.6

4.53.2

6.8

5.26.0

5.3

0

2

4

6

8

10

12

10 20 40 10 20 40 80 10 20 40 10 20 40 80

Treatment, mg

% c

ha

ng

e f

rom

ba

se

lin

e

Rosuvastatin Atorvastatin

Pravastatin Simvastatin

P < .002 RSV 10 mg vs PRA 10 mg. P < .002 RSV 20 mg vs ATV 20 mg, 40 mg, 80 mg; PRA 20 mg, 40 mg; SIM 40 mg.P < .002 RSV 40 mg vs ATV 40 mg, 80 mg; PRA 40 mg; SIM 40 mg.Data presented as LS means ± SE.

N = 156 160 157 158 155 156 165 160 164 161 165 162 158 163

STELLAR Study. Am J Cardiol 2003;92:152–160)

-49

-56-59

-40-45

-50-52

-32

-38-42

-49

-22-27

-33

-60

-50

-40

-30

-20

-10

010mg 20mg 40mg

10mg 20mg 40mg 80mg

10mg 20mg 40mg 80mg

10mg 20mg 40mg

Rosuvastatin Atorvastatin Simvastatin PravastatinM

ean

% c

han

ge f

rom

base

lin

e i

n L

DL

-C

:HD

L-C

*

† #

*p<0.002 rosuvastatin 10mg vs. atorvastatin 10mg, simvastatin and pravastatin 10, 20, and 40mg

†p<0.002 rosuvastatin 20mg vs. atorvastatin 20 and 40mg, simvastatin 20, 40, and 80mg and pravastatin 20 and 40mg

#p<0.002 rosuvastatin 40mg vs. atorvastatin and simvastatin 40 and 80mg and pravastatin 40mg

Clin Ther. 2004;26:1388-1399

-37

-43-45

-31-34

-38-40

-24

-30-31

-37

-17-20

-25

-45

-40

-35

-30

-25

-20

-15

-10

-5

010mg 20mg 40mg

10mg 20mg 40mg 80mg

10mg 20mg 40mg 80mg

10mg 20mg 40mg

Rosuvastatin Atorvastatin Simvastatin PravastatinM

ean

% c

han

ge f

rom

base

lin

e i

n

TC

:HD

L-C

*

† #

*p<0.002 rosuvastatin 10mg vs. atorvastatin 10mg, simvastatin and pravastatin 10, 20, and 40mg

†p<0.002 rosuvastatin 20mg vs. atorvastatin 20 and 40mg, simvastatin 20, 40, and 80mg and pravastatin 20 and 40mg

#p<0.002 rosuvastatin 40mg vs. atorvastatin and simvastatin 40 and 80mg and pravastatin 40mg

Clin Ther. 2004;26:1388-1399

-46

-52-55

-38-42

-47-48

-29

-36-38

-45

-21-25

-31

-60

-50

-40

-30

-20

-10

010mg 20mg 40mg

10mg 20mg 40mg 80mg

10mg 20mg 40mg 80mg

10mg 20mg 40mg

Rosuvastatin Atorvastatin Simvastatin PravastatinM

ean

% c

han

ge f

rom

base

lin

e i

n N

on

H

DL

-C:H

DL

-C

*

† #

*p<0.002 rosuvastatin 10mg vs. atorvastatin 10mg, simvastatin and pravastatin 10, 20, and 40mg

†p<0.002 rosuvastatin 20mg vs. atorvastatin 20 and 40mg, simvastatin 20, 40, and 80mg and pravastatin 20 and 40mg

#p<0.002 rosuvastatin 40mg vs. atorvastatin and simvastatin 40 and 80mg and pravastatin 40mg

Clin Ther. 2004;26:1388-1399

-41

-46-48

-32

-38-41-42

-26

-30-35

-39

-17

-24-27

-50-45

-40-35

-30-25-20

-15-10

-50

10mg 20mg 40mg

10mg 20mg 40mg 80mg

10mg 20mg 40mg 80mg

10mg 20mg 40mg

Rosuvastatin Atorvastatin Simvastatin PravastatinM

ean

% c

han

ge f

rom

base

lin

e i

n

Ap

oB

:Ap

oA

-1

*

† #

*p<0.002 rosuvastatin 10mg vs. atorvastatin 10mg, simvastatin and pravastatin 10, 20, and 40mg

†p<0.002 rosuvastatin 20mg vs. atorvastatin 20, simvastatin 20, 40, and 80mg and pravastatin 20 and 40mg

#p<0.002 rosuvastatin 40mg vs. atorvastatin and simvastatin 40 and 80mg and pravastatin 40mg

Clin Ther. 2004;26:1388-1399

Rosuvastatin

“Clinical implications”

Earlier achievement of targets

POLARIS study. Atherosclerosis 194 (2007) e154–e164

-0.0014

0.0131

-0.005

0.000

0.005

0.010

0.015• 984 asymptomatic

patients with moderately elevated cholesterol and low risk of CVD acc to NCEP-ATP 3 criteria

• Rosuvastatin 40mg (n=702) Vs Placebo (n=282) for 2 years

Cha

nge

in C

IMT

for

12

Car

otid

Art

ery

site

s (m

m/y

ear)

Change in CIMTChange in CIMT

n = 702

n = 282

p < 0.001

METEOR Trial. ACC 2007METEOR Trial. ACC 2007

Rosuvastatin

Placebo

ASTEROID: Effect on atheroma volume measured by IVUS

Mean % atheroma volume (N = 349)

39.6 38.6

0

35

40

45

50

Baseline 24 months

Mean atheroma volume in most diseased segment

(n = 319)

65.159

0

60

70

80

90

100

Baseline 24 months

Nissen SE et al. JAMA. 2006;295:1556-65.

mm3

P < 0.001 P < 0.001

%

Primary Prevention With LDL-Lowering Therapy

Reduced intakes of saturated fat and

cholesterol

Increased physical activity

Weight control

Statins

JUPITER trial

Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating

RosuvastatinRidker et al, N Engl J Med 2008

JUPITERMulti-National Randomized Double Blind Placebo

Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular

EventsAmong Individuals With Low LDL and Elevated

hsCRP

Ridker et al, Circulation 2003;108:2292-2297.

JUPITERTrial Design

Rosuvastatin 20 mg (N=8901) MIStroke

Unstable Angina

CVD DeathCABG/PTCA

4-week run-in

No Prior CVD or DMMen >50, Women >60

LDL <130 mg/dL hsCRP >2 mg/L

Placebo (N=8901)

0

1

2

3

4

5

hsC

RP

(m

g/L

)

0

20

40

60

80

100

120

140

LD

L (

mg

/dL

)

Months0 12 24 36 48

0

10

20

30

40

50

60

0

20

40

60

80

100

120

140

0 12 24 36 48

TG

(m

g/d

L)

HD

L (

mg

/dL

)

Months

JUPITEREffects of rosuvastatin 20 mg on LDL, HDL, TG, and hsCRP

LDL decrease 50 percent at 12 months

hsCRP decrease 37 percent at 12 months

HDL increase 4 percent at 12 months

TG decrease 17 percent at 12 months

Ridker et al NEJM 2008

0 12 24 36 48

0 12 24 36 48 0 12 24 36 48

______ ______Placebo Rosuvastatin

LDL-C decrease 50 percent at 12 months

JUPITERPrimary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Placebo 251 / 8901

Rosuvastatin 142 / 8901

HR 0.56, 95% CI 0.46-0.69P < 0.00001

- 44 %

0 1 2 3 4

0.0

00

.02

0.0

40

.06

0.0

8

Cu

mu

lati

ve In

cid

ence

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

Ridker et al NEJM 2008

Number Needed to Treat (NNT5) = 25

JUPITERSecondary Endpoint – All Cause Mortality

Placebo 247 / 8901

Rosuvastatin 198 / 8901

HR 0.80, 95%CI 0.67-0.97P= 0.02

- 20 %

0 1 2 3 4

0.00

0.01

0.02

0.03

0.04

0.05

0.06

Cu

mu

lati

ve I

nci

den

ce

Number at Risk Follow-up (years)

RosuvastatinPlacebo

8,901 8,847 8,787 6,999 4,312 2,268 1,602 1,192 683 2278,901 8,852 8,775 6,987 4,319 2,295 1,614 1,196 684 246

Ridker et al NEJM 2008

JUPITERPrimary Endpoint – Subgroup Analysis

0.25 0.5 1.0 2.0 4.0

Rosuvastatin Superior Rosuvastatin Inferior

MenWomen

Age < 65Age > 65

SmokerNon-Smoker

CaucasianNon-Caucasian

USA/CanadaRest of World

HypertensionNo Hypertension

All Participants

N P for Interaction

11,001 0.80 6,801

8,541 0.32 9,261

2,820 0.6314,975

12,683 0.57 5,117

6,041 0.5111,761

10,208 0.53 7,586

17,802

Ridker et al NEJM 2008

FDA has approved rosuvastatin to reduce the risk of stroke, MI and arterial revascularization procedures in individuals without clinically evident CHD but with an increased risk of CVD based on age (men

≥50 and women ≥60), hsCRP ≥ 2 mg/L, and the presence of at least one additional CVD risk factor, such as hypertension, low HDL-C, smoking, or a family history of premature coronary heart disease.

AURORA

AURORA Trial. N Engl J Med 2009;360:1395-4074D study. N Engl J Med 2005;353:238-48

• 2776 patients, 50-80 years age, undergoing maintenance hemodialysis

• Rosuvastatin 10 mg Vs placebo

• Median follow-up of 3.8 yrs

• Rosuvastatin lowered LDL-C level but had no significant effect on the composite primary end point of death from cardiovascular causes, nonfatal MI, or nonfatal stroke

• Similar results with atorvastatin observed in 4D study

Rosuvastatin

“Safety”

Adverse events

Equal or even lower risk of myopathy compared to other statins because of the lower dose requirement and option of non-daily dosing

Mild transaminitis might occur – Self limiting

Small but significant increases in the rate of physician-reported diabetes and glycated hemoglobin values noted in JUPITER trial

Hematuria, proteinuria, ARF only in very high doses (≥80mg)

Ann Intern Med. 2009;150:858-868. Am J Cardiol. 2000;85:15E-19E

Adverse events

% subjects with adverse events

Rosuvastatin

(n = 700)

Placebo (n = 281)

Myalgia 12.7 12.1

CK > 10 X ULN 0.1‡ 0.7

Rhabdomyolysis 0 0

ALT > 3 X ULN 0.6 0.4

Hepatitis 0 0

Proteinuria shift* 0.3 0.4

Renal failure 0 0

Cardiac SAEs 0.9 0

Neoplasms 1.6 1.1

Deaths 1/702† 0/282*Shift in dipstick urine protein from none/trace at baseline to ≥ 2+ post baseline. †Creutzfeldt-Jakob disease, not related to study treatment. ‡Exercise-associated.

METEOR Trial ACC 2007METEOR Trial ACC 2007

Summary

Lipid abnormalities are proportionately associated with CAD morbidity and mortality

Failure rate in achieving NCEP ATP III goal in CHD patients is very high

Rosuvastatin is more effective in reducing LDL-C and achieving NCEP ATP III goal

Summary Effective in reducing plaque volume,

and hence may be useful for secondary prevention of CAD

May also be useful for primary prevention in select populations

Being a hydrophilic, associated with less chances of drug interactions

Safe and well tolerated

Cost comparison

ZYROVA – Zydus Cadila; 5 mg x 10's (IRP: rupee 90), 10 mg x 10's (IRP: rupee 150), 20 mg x 10's (IRP: rupee 280)

ATORVA – Zydus Cadila; 10 mg x 10's (IRP: rupee 94), 40 mg x 10's (IRP: rupee 190.03)

ORVAS – Systopic; 5 mg x 10's (IRP: rupee 16)10 mg x 10's (IRP: rupee 24.5)20 mg x 10's (IRP: rupee 48)

Source – CIMS (http://cimsasia.com)