voyager an individual patient data meta- analysis of statin therapy in at risk groups: effects of...

VOYAGER

An indiVidual patient data meta-analysis Of statin therapY in At risk

Groups: Effects of Rosuvastatin, atorvastatin and simvastatin

Please see slide 27 for prescribing information

VOYAGER

A unique Individual Patient Data Meta-analysis (of 32 258 patients) Review of individual patient data from comparative randomised

studies comparing rosuvastatin with either atorvastatin or simvastatin in high-risk populations

Studies were identified by a comprehensive search of the Cochrane Controlled Trials Registry, Medline, EMBASE, Citeline, Trialtrove, and collection of all published research on rosuvastatin.

37 randomised comparative studies >4 weeks duration were identified as suitable for inclusion in the VOYAGER database, in which baseline and on-treatment lipids were recorded for each patient, as well as lab methods for determining these parameters

Integrated database of >30 000 patients

VOYAGERWhole population and high-risk goal analysis

Meta-analysis of comparative efficacy of increasing dose of

atorvastatin versus rosuvastatin versus simvastatin on lowering

levels of atherogenic lipids (from VOYAGER)

Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76

Background

Statins are used widely to reduce cardiovascular risk in primary and secondary prevention

Consequently, treatment guidelines have been developed which take into account a patient’s estimated risk of cardiovascular disease

However, the incremental benefit of increasing statin dose on lipid levels and goal attainment has not been fully established


Objectives

To use the VOYAGER individual patient data meta-analysis to explore relationships between increasing dose of rosuvastatin, atorvastatin and simvastatin, and the ability of these agents to – decrease the levels of atherogenic lipids – allow patients to achieve treatment goals


Patient baseline characteristicsWhole population

Parameter Cohort (n=32 258)

Mean (SD) age (y) 60.0 ± 11.1

Males (%) 56.7

Race (%) Caucasian Black Oriental Asian

79.95.15.6

High-risk patients (%)†

Diabetes mellitus Atherogenic dyslipidaemia Atherosclerotic disease

67.127.518.848.0

Mean (SD) lipid levels (mg/dL) LDL-C HDL-C NonHDL-C ApoB

170.9 ± 38.748.7 ± 12.7205.2 ± 41.8159.3 ± 37.2

Median (IQR) TG (mg/dL) 161.2 (120.4–215.0)

Median (IQR) C-reactive protein (mg/L) 0.38 (0.15–0.93)ApoB=apolipoprotein B; HDL-C=high-density lipoprotein cholesterol; IQR=interquartile range; LDL-C=low-density lipoprotein cholesterol; SD=standard deviation †Defined as established atherosclerotic disease, diabetes or atherogenic dyslipidaemia (TG ≥150 mg/dL or HDL-C <40 mg/dL) Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76

Adapted by permission from Elsevier Inc.

Change in LDL-C levels with increasing dose of each statin Results from the whole population VOYAGER

individual patient data meta-analysis

-60

-50

-40

-30

-20

-10

0

SimvastatinAtorvastatinRosuvastatin

*p<0.001 rosuvastatin 10 mg vs atorvastatin 10 mg and 20 mg; simvastatin 10 mg, 20 mg and 40 mg †p<0.001 rosuvastatin 20 mg vs atorvastatin 20 mg and 40 mg; simvastatin 20 mg ,40 mg and 80mg ‡p<0.001 rosuvastatin 40 mg vs atorvastatin 40 mg and 80 mg; simvastatin 40 mg and 80 mg#p<0.05 atorvastatin 20 mg vs rosuvastatin 5 mg ##p<0.05 atorvastatin 80 mg vs rosuvastatin 5 mg and 10 mg

Ch

an

ge in

LD

L-C

fro

m

baselin

e (

%)

Dose (log scale)

5 mg 10 mg 20 mg 40 mg 80 mg

-27(n=365)

-33 (n=2929)

-39 (n=548)

-45 (n=479)

-50##

(n=2072) -55‡

(n=2983)

-50† (n=3554)

-44* (n=11690)

-39 (n=670)

-36 (n= 7837)

-41#

(n=3908)-46

(n=1324)

Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76Adapted by permission from Elsevier Inc.

Favours rosuvastatin Favours atorvastatin

DosageRSV 5 mg versus:

RSV 10 mg versus:

RSV 20 mg versus:

RSV 40 mg versus:

Difference between treatments in mean % change from baseline (95% CI)

n

0 5-5 10-10-15-20-25 15 20 25

ATV 40 mg 80

ATV 40 mg 399

ATV 80 mg 1651

ATV 10 mg 861***

ATV 10 mg 17 295***

ATV 20 mg 4583***

ATV 20 mg 4624***

ATV 40 mg 1316***

ATV 40 mg 2182***

ATV 80 mg 3358***

ATV 20 mg 77†

ATV 80 mg 79†††

ATV 80 mg 406†††

***p<0.001 vs ATV; †p<0.05 vs RSV; †††p<0.001 vs RSV

Effect of increasing statin dose on reduction of LDL-CResults from the whole population VOYAGER individual

patient data meta-analysisrosuvastatin (RSV) versus atorvastatin (ATV)

Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76Reprinted by permission from Elsevier Inc.

Favours rosuvastatin Favours simvastatin

***p<0.001 vs SIM

RSV 5 mg versus:

RSV 10 mg versus:

RSV 20 mg versus:

RSV 40 mg versus:

SIM 10 mg 0

SIM 40 mg 0SIM 80 mg 0

SIM 80 mg 319

SIM 10 mg 321***

SIM 20 mg 6001***

SIM 40 mg 314***

SIM 20 mg 1090***

SIM 40 mg 1084***

SIM 80 mg 323***

SIM 80 mg 943***

SIM 40 mg 315***

SIM 20 mg 489***


Dosage n

0 5-5 10-10-15-20-25 15 20 25


Effect of increasing statin dose on reduction of LDL-CResults from the whole population VOYAGER individual

patient data meta-analysisrosuvastatin (RSV) versus simvastatin (SIM)

High-risk patients achieving LDL-C goals <100 mg/dL, stratified according to baseline LDL-C levels ≤160mg/dL

†Represents <10 patients. NA=no data available Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76Adapted by permission from Elsevier Inc.

0

20

40

60

80

100

5 10 20 40 10 20 40 80 10 20 40 80

Pati

en

ts (

%)

ach

ievin

g L

DL-C

<

10

0 m

g/dL

Baseline LDL-C level (mg/dL): <130 130–160

NA

Rosuvastatin Atorvastatin Simvastatin

†

NA

NA

†

Dose (mg)

High-risk patients with baseline LDL-C ≥160mg/dL achieving LDL-C goals

<100 mg/dL



0

20

40

60

80

100

5 10 20 40 10 20 40 80 10 20 40 80

Pati

en

ts (

%)

ach

ievin

g L

DL-C

<

10

0 m

g/dL


Dose (mg)

NA 0

High-risk patients achieving LDL-C goals <70 mg/dL, stratified according to baseline

LDL-C levels ≤160 mg/dL


†

NANA

NA 0

†

Dose (mg)


†Represents <10 patients. NA=no data available Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76Adapted by permission from Elsevier Inc.

0

20

40

60

80

100

5 10 20 40 10 20 40 80 10 20 40 80

Pati

en

ts (

%)

ach

ievin

g L

DL-C

<

70

mg/dL

NA 0


†

NA

NA 0

†

Dose (mg)


High-risk patients with baseline LDL-C ≥160mg/dL achieving LDL-C goals

<70 mg/dL


0

Dose (mg)


0

20

40

60

80

100

5 10 20 40 10 20 40 80 10 20 40 80

Pati

en

ts (

%)

ach

ievin

g L

DL-C

<

70

mg/dL


0

Dose (mg)

***p<0.001 vs ATV; †p<0.05 vs RSV; †††p<0.001 vs RSV


864778079

17 3554590399406

46351317

1651

21823362

RSV 5 mg versus:ATV 10 mgATV 20 mgATV 40 mgATV 80 mg

RSV 10 mg versus:ATV 10 mgATV 20 mgATV 40 mgATV 80 mg

ATV 20 mgATV 40 mgATV 80 mg

RSV 40 mg versus:ATV 40 mgATV 80 mg

***

******

******

******

†

†††

†††


Dosage n

RSV 20 mg versus:

0 5-5 10-10-15-20-25 15 20 25


Effect of increasing statin dose on reduction of nonHDL-CResults from the whole population VOYAGER individual


Change in nonHDL-C levels with increasing dose of each statin

Rosuvastatin

5 10 20 40

Atorvastatin

10 20 40 80

Simvastatin

40 8010 20Dose (mg)

***p<0.001 rosuvastatin vs equivalent or double dose of atorvastatin and simvastatin and rosuvastatin 10 mg vs simvastatin 40 mg and rosuvastatin 20 mg vs simvastatin 80 mg; ‡p<0.05 atorvastatin 20 mg vs rosuvastatin 5 mg; †††p<0.001 atorvastatin 80 mg vs rosuvastatin 5 mg and rosuvastatin 10 mg


-60

-50

-40

-30

-20

-10

0

LSM

% c

hang

e (S

E)

Rosuvastatin

5 10 20 40

Atorvastatin

10 20 40 80

Simvastatin

40 8010 20Dose (mg)

***

***

***

***

‡

†††

†††

***p<0.001 vs SIM


RSV 5 mg versus:0SIM 10 mg

0SIM 40 mg0SIM 80 mg

RSV 10 mg versus:

RSV 20 mg versus:

RSV 40 mg versus:

319SIM 80 mg

321SIM 10 mg***

5992SIM 20 mg ***

491SIM 20 mg***

314SIM 40 mg***

1091SIM 20 mg***

1090SIM 40 mg***

323SIM 80 mg***

944SIM 80 mg***315SIM 40 mg

***


Dosage n

0 5-5 10-10-15-20-25 15 20 25


Effect of increasing statin dose on reduction of nonHDL-CResults from the whole population VOYAGER individual


High-risk patients achieving nonHDL-C levels <130 mg/dL,

stratified according to baseline levels

RosuvastatinAtorvastatin

Simvastatin


0

10

20

30

40

50

60

70

80

90

100

5 10 20 40 10 20 40 80 10 20 40 80

Pati

en

ts (

%)

ach

ievin

gn

on

HD

L-C

<1

30

mg/dL

Baseline nonHDL-C level (mg/dL): <160 160-190 ≥190


NA

†

NA

NA

Dose (mg)


Change in TG levels with increasing dose of each statin

Results from the whole population VOYAGER individual patient data meta-analysis

Dose (mg)

***p<0.001 rosuvastatin 10 mg vs atorvastatin 10 mg and simvastatin 20 mg, rosuvastatin 20 mg vs simvastatin 20 and 40 mg and rosuvastatin 40 mg vs simvastatin 40 and 80 mg; §p<0.01 rosuvastatin 10 mg vs simvastatin 10 mg; ¶p<0.05 rosuvastatin 20 mg vs simvastatin 80 mg; †p<0.05 atorvastatin 80 mg vs rosuvastatin 5 mg and 40 mg and atorvastatin 40 mg vs rosuvastatin 10 mg; ‡p<0.01 atorvastatin 80 mg vs rosuvastatin 10 mg; #p<0.001 atorvastatin 80 mg vs rosuvastatin 20 mg

***

***

***

§

¶

†

‡

#

†


-30

-25

-20

-15

-10

-5

0

LSM

% c

hang

e (S

E)

Rosuvastatin

5 10 20 40

Atorvastatin

10 20 40 80

Simvastatin

40 8010 20Dose (mg)

***

***

***

§

¶

†

‡

#

†


Dosage n

***p<0.001 vs ATV; †p<0.05 vs RSV; ††p<0.01 vs RSV; †††p<0.001 vs RSV


80

RSV 5 mg versus:864ATV 10 mg77ATV 20 mg

ATV 40 mg †79ATV 80 mg

RSV 10 mg versus:***

17 355ATV 10 mg4591ATV 20 mg †399ATV 40 mg

††407ATV 80 mg

4636ATV 20 mg1317ATV 40 mg †††1650ATV 80 mg

RSV 40 mg versus:2182ATV 40 mg

†3362ATV 80 mg

RSV 20 mg versus:


0 5-5 10-10-15-20-25 15 20 25


Effect of increasing statin dose on reduction of TGResults from the whole population VOYAGER individual


*p<0.05 vs SIM; **p<0.01 vs SIM; ***p<0.001 vs SIM


Dosage n



491SIM 20 mg0SIM 40 mg0SIM 80 mg

RSV 10 mg versus:**

321SIM 10 mg***6014SIM 20 mg

314SIM 40 mg319SIM 80 mg


1091SIM 20 mg***1091SIM 40 mg*323SIM 80 mg


315SIM 40 mg***

944SIM 80 mg

0 5-5 10-10-15-20-25 15 20 25


Effect of increasing statin dose on reduction of TGResults from the whole population VOYAGER individual


Baseline TG level (mg/dL): <200 200-300 >300

0 0

High-risk patients achieving TG levels <150 mg/dL, stratified according to

baseline TG levels

†Represents less than 10 patients


Dose (mg)

†


0

10

20

30

40

50

60

70

80

90

100

5 10 20 40 10 20 40 80 10 20 40 80

Pati

en

ts (

%)

ach

ievin

g

TG

<1

50

mg/dL

Baseline TG level (mg/dL): <200 200-300 >300

0 0


Dose (mg)

†

Rosuvastatin

5 10 20 40

Atorvastatin

10 20 40 80

Simvastatin

40 8010 20Dose (mg)

***p<0.001 rosuvastatin vs equivalent or double doses of atorvastatin or simvastatin, except rosuvastatin 10 mg vs atorvastatin 20 mg (p<0.01) and p<0.001 rosuvastatin 10 mg vs simvastatin 40 mg and rosuvastatin 20 mg vs simvastatin 80 mg; †††p<0.001 atorvastatin 80 mg vs rosuvastatin 5 mg and 10 mg; ‡p<0.01 atorvastatin 80 mg vs rosuvastatin 20 mg. ApoB levels were determined in 24 340 (75.5%) of patients only

***

***

***

***†††

‡


-50

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

LSM

% c

hang

e (S

E)

Rosuvastatin

5 10 20 40

Atorvastatin

10 20 40 80

Simvastatin

40 8010 20Dose (mg)

***

***

***

***†††

‡

Change in ApoB levels with increasing dose of each statin

Results from the whole population VOYAGER individual patient data meta-analysis

**p<0.01 vs ATV; ***p<0.001 vs ATV; ††p<0.01 vs RSV; †††p<0.001 vs RSV



RSV 5 mg versus:***833ATV 10 mg

76ATV 20 mg79ATV 40 mg †††76ATV 80 mg

RSV 10 mg versus:***7631ATV 10 mg

**4436ATV 20 mg370ATV 40 mg †††379ATV 80 mg

***3905ATV 20 mg***1251ATV 40 mg ††

1562ATV 80 mg


1542ATV 40 mg***3230ATV 80 mg

Dosage n

RSV 20 mg versus:

0 5-5 10-10-15-20-25 15 20 25


Effect of increasing statin dose on reduction of ApoBResults from the whole population VOYAGER individual



***p<0.001 vs SIM



***469SIM 20 mg0SIM 40 mg0SIM 80 mg

RSV 10 mg versus:***300SIM 10 mg

***1824SIM 20 mg***291SIM 40 mg

296SIM 80 mg


***1049SIM 40 mg***295SIM 80 mg


***888SIM 80 mg

Dosage n

0 5-5 10-10-15-20-25 15 20 25


Effect of increasing statin dose on reduction of ApoBResults from the whole population VOYAGER individual


NA

†NA 0

High-risk patients achieving ApoB levels <90 mg/dL, stratified according

to baseline levels

†Represents <10 patients. NA=no data available

Rosuvastatin

†

†

Dose (mg)


0

10

20

30

40

50

60

70

80

90

100

5 10 20 40 10 20 40 80

Pati

en

ts (

%)

ach

ievin

g

ApoB

<9

0 m

g/dL

Baseline ApoB level (mg/dL): <120 120-150 >150

NA

Rosuvastatin Atorvastatin

Dose (mg)

Conclusions

Increasing the dose of rosuvastatin, atorvastatin and simvastatin resulted in incremental greater reductions in atherogenic lipids and allowed patients to achieve treatment goals

The VOYAGER large individual patient database of more than 32 000 patients highlights the importance of choice of statin and dose when selecting treatment


CRESTOR (rosuvastatin) adverse eventsCRESTOR (rosuvastatin) adverse events

Undesirable effects (refer to the SmPC for a full list of side effects): Side effects most frequently reported in controlled clinical studies and post marketing experience: headache, dizziness, constipation, nausea, abdominal pain, myalgia, asthenia, and diabetes mellitus in patients with fasting glucose 5.6–6.9 mmol/L. Rarely: myopathy (including myositis), rhabdomyolysis with or without acute renal failure, hypersensitivity reactions including angioedema, pancreatitis. Very rarely: arthralgia, jaundice, hepatitis, polyneuropathy, haematuria, memory loss. Unknown frequency: diarrhoea, Stevens-Johnson syndrome. Other usually transient side effects: elevations in transaminases and CK levels, proteinuria. The following side effects have been reported with some statins: depression, sleep disturbances, sexual dysfunction and in exceptional cases, interstitial lung disease.

MARKETING AUTHORISATION HOLDER:AstraZeneca UK Ltd., 600 Capability Green, Luton LU1 3LU United Kingdom. Telephone: +44 (0)1582 836 000 Fax: +44 (0)1582 838 000. Medical Information Direct Line: +44 (0)1582 836 836 Medical Information e-mail: [email protected] from Shionogi & Co. Ltd., Osaka, Japan.

Adverse events should be reported.

Reporting forms and information can be

found at www.yellowcard.gov.uk.

Adverse events should also be reported to

AstraZeneca on 0800 783 0033.

CRESTOR™ (rosuvastatin) Summary of Product Characteristics

February 2011

Click on the icon below to access the Summary of Product Characteristics. Consult fullprescribing information for CRESTOR before prescribing.

CRESTOR exhibition VOYAGER non EU ppt, 2011 CRESTOR is a trademark of the AstraZeneca group of companies

CRESTORSMPC.pdf

voyager an individual patient data meta- analysis of statin therapy in at risk groups: effects of...

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ldlc levels

baseline ldlc

ldlc goals highrisk

nonhdlc levels

ldlc goals na

tg levels

interquartile range

hdlc change