stellar study (rosuvastatina)
Post on 20-Apr-2015
92 Views
Preview:
TRANSCRIPT
Rosuvastatin Slide Kit May 2004 [1]
STELLAR - Study DesignSTELLAR - Study Design
6 week, randomised, open-label, parallel-group, fixed-dose treatment
2268 adults with primary hypercholesterolaemia
Randomised to 14 groups
– rosuvastatin 10, 20, 40 mg
– atorvastatin 10, 20, 40 or 80 mg
– simvastatin 10, 20, 40 or 80 mg
– pravastatin 10, 20 or 40 mg
Pair-wise comparisons of the data
Percentage change from baseline in lipids assessed after 6 weeks of treatment
Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160
Rosuvastatin Slide Kit May 2004 [2]
STELLAR - Pair-wise ComparisonsSTELLAR - Pair-wise Comparisons
Rosuvastatin
Atorvastatin 80 mg10 mg 20 mg 40 mg
10 mg 20 mg 40 mg
Rosuvastatin
Simvastatin 80 mg10 mg 20 mg 40 mg
10 mg 20 mg 40 mg
Rosuvastatin
Pravastatin 10 mg 20 mg 40 mg
10 mg 20 mg 40 mg
Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160
Rosuvastatin Slide Kit May 2004 [3]
Rosuvastatin Atorvastatin Simvastatin
Pravastatin
*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
Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160
*
X
X
X
–60
–50
–40
–30
–20
–10
0
Dose, mg (log scale)10 20 40 80
X
X
n=648
n=473
n=634
n=485
†‡
Ch
an
ge in
LD
L-C
fro
m
baselin
e (
%)
Rosuvastatin versus Comparators:Rosuvastatin versus Comparators:LDL-C Efficacy Across the Dose RangeLDL-C Efficacy Across the Dose Range
The STELLAR StudyThe STELLAR Study
Rosuvastatin Slide Kit May 2004 [4]
Rosuvastatin versus Comparators: LDL-C Rosuvastatin versus Comparators: LDL-C Efficacy at Low DoseEfficacy at Low Dose
The STELLAR StudyThe STELLAR Study Change in LDL-C from baseline (%)
0 –10 –20 –30 –40 –50 –60
10mg*
–5 –15 –25 –35 –45 –55
20mg†
40mg‡
10mg
20mg
80 mg
10mg
20mg
40mg
80mg
10mg
20mg
40mg Rosuvastatin 10 mg (–46%)
Rosuvastatin
Atorvastatin
Simvastatin
Pravastatin
40mg
*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
Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160
Rosuvastatin Slide Kit May 2004 [5]
Rosuvastatin versus Atorvastatin Rosuvastatin versus Atorvastatin Consistent LDL-C Reduction at Low DoseConsistent LDL-C Reduction at Low Dose
*p<0.001 vs atorvastatin
Jones PH et al. Am J Cardiol 2003;92:152–160 Schuster H et al. Am Heart J 2004; 147: 705-712 Davidson M et al. Am J Cardiol 2002;89:268–75Schwartz G et al. Am Heart J 2004: In PressOlsson AG et al. Am Heart J 2002;144:1044–51Blasetto JW et al. Am J Cardiol 2003;91(Suppl):3C–10C
n=
15
8
n=
53
9
n=
52
9
n=
12
9
n=
12
7
n=
12
8
n=
12
7
n=
13
2
n=
13
9
n=
38
9
n=
39
3
–47–50
–47
–43–46
–47
–36–39
–35–35–37–37
–60
–50
–40
–30
–20
–10
0Jones Schuster Davidson Schwartz Olsson Blasetto
Rosuvastatin 10 mg
Atorvastatin 10 mg
n=
15
6
n=
15
8
n=
53
9
n=
52
9
n=
12
7
n=
12
8
n=
12
7
n=
13
2
n=
13
9
n=
38
9
n=
39
3
6 weeks
STELLAR
8 weeks
MERCURY I
12 weeks
Pooled data
n=
52
9
n=
12
9
**
*
6 weeks
STELLAR
8 weeks
MERCURY I
12 weeks
Pooled data
n=
52
9
***
Ch
an
ge in
LD
L-C
fro
m
baselin
e (
%)
Rosuvastatin Slide Kit May 2004 [6]
*p<0.05, **p<0.001 vs atorvastatin 20 mg
Rosuvastatin 10 mg versus Atorvastatin 20 mg Rosuvastatin 10 mg versus Atorvastatin 20 mg Provides Greater LDL-C ReductionsProvides Greater LDL-C Reductions
Jones PH et al. Am J Cardiol 2003;92:152–160.Schuster H et al. Am Heart J 2004;147:705–712. Franken A et al. Atherosclerosis Supplements 2004; 5 (1): 118 Abs M.513.Jukema J et al. Atherosclerosis Supplements 2004; 5 (1): 125 Abs M.542.
Rosuvastatin 10 mg Atorvastatin 20 mg
-50
-40
-30
-20
-10
0
-60
6 weeks
MERCURY ISchuster
STELLARJones
ns
-46-43
**
-47-44
*
-46-41
*
-44
-38
FrankenJukema
8 weeks
n=156 n=155 n=230 n=231 n=128 n=131 n=539 n=925
Ch
an
ge in
LD
L-C
fro
m
baselin
e (
%)
Rosuvastatin Slide Kit May 2004 [7]
1. Schuster H & Fox J. Exp Opin Pharmacother 2004;5:1187-1200 2. Kritharides L. Eur Heart J Suppl 2004; 6(Suppl A): A12-A18
Rosuvastatin versus Atorvastatin Rosuvastatin versus Atorvastatin Achievement of Achievement of LDL-C Goals at Low DoseLDL-C Goals at Low Dose
Rosuvastatin 10 mg vs atorvastatin 10 and 20 mg; patients achieving 2003 European LDL-C goals‡
#p<0.001 vs atorvastatin 10 mg & 20 mg *p<0.001 vs atorvastatin 10 mg
‡LDL-C <3mmol/l (115mg/dl) in general;<2.5mmol/l (97mg/dl) for patients with clinically established CVD or type 2 diabetes
77%
66%
52%57%
36%
13%
67%
0%
20%
40%
60%
80%
100%
All patients All patients Patients with CVD or type 2 diabetes
Rosuvastatin 10 mg
Atorvastatin 10 mg
Atorvastatin 20 mg*
n=538 n=925n=529 n=389 n=393 n=196n=201
*
#
12 weeksPooled dataKritharides2
8 weeksMERCURY ISchuster1
Pati
en
ts a
ch
ievin
g 2
003
Eu
rop
ean
LD
L-C
goal (%
)
Rosuvastatin Slide Kit May 2004 [8]
1. Schuster H & Fox J. Exp Opin Pharmacother 2004;5:1187-1200 2. Kritharides L. Eur Heart J Suppl 2004; 6(Suppl A): A12-A18
Rosuvastatin vs Simvastatin and PravastatinRosuvastatin vs Simvastatin and PravastatinAchievement of Achievement of LDL-C Goals at Low DoseLDL-C Goals at Low Dose
77%74%
55%49%
37%
11%
38%
20mg 3%
0%
20%
40%
60%
80%
100%
All patients All patients Patients with CVD or type 2 diabetes
Pati
en
ts a
ch
ievin
g 2
003
Eu
rop
ean
LD
L-C
goal (%
)
*
n=538n=543 n=226 n=249 n=86n=64
*
#
n=74n=252n=521
#p<0.001 vs simvastatin & pravastatin *p<0.001 vs simvastatin & pravastatin
12 weeksPooled dataKritharides2
8 weeksMERCURY ISchuster1
‡LDL-C <3mmol/l (115mg/dl) in general;<2.5mmol/l (97mg/dl) for patients with clinically established CVD or type 2 diabetes
Rosuvastatin
Simvastatin
Pravastatin
Rosuvastatin 10 mg vs simvastatin 20 mg and pravastatin 20 & 40 mg; patients achieving 2003 European LDL-C goals‡
12%20mg 40mg 20mg10mg
20mg
10mg
10mg
20mg
Rosuvastatin Slide Kit May 2004 [9]
Rosuvastatin versus other statinsRosuvastatin versus other statinsAchievement of Achievement of LDL-C Goals Across Dose RangeLDL-C Goals Across Dose Range
Patients achieving 2003 European LDL-C goals‡
Kritharides L. Eur Heart J Suppl 2004; 6(Suppl A): A12-A18
*p<0.002 vs atorvastatin 10 mg; simvastatin 10, 20, 40 mg; pravastatin 10, 20, 40 mg†p<0.002 vs atorvastatin 20 mg; simvastatin 20, 40 mg; pravastatin 20, 40 mg#p<0.002 vs atorvastatin 40 mg; simvastatin 40, 80 mg; pravastatin 40 mg
Rosuvastatin
69%
44%
20%
3%
87%
58%
36%
12%
83%
72%
48%
22%
75%
66%
0%
20%
40%
60%
80%
100%
n=925 n=189
*
†#
Atorvastatin
PravastatinSimvastatin
10 20 40 10 20 40 80 10 20 40 10 20 40 80
Dose (mg)
Pati
en
ts a
ch
ievin
g 2
003
Eu
rop
ean
LD
L-C
goal (%
)
‡LDL-C <3mmol/l (115mg/dl) in general; <2.5mmol/l (97mg/dl) for patients with clinically established CVD or type 2 diabetes
Rosuvastatin Slide Kit May 2004 [10]
Rosuvastatin versus AtorvastatinRosuvastatin versus Atorvastatin Achievement of LDL-C Goal Achievement of LDL-C Goal Across Dose Across Dose
RangeRangePatients achieving NCEP ATP-II LDL-C goals over 52 weeks
*p=0.006 rosuvastatin 10–40 mg vs atorvastatin 10–80 mg
Olsson AG et al. Am Heart J 2002;144:1044–51 Schuster H. Cardiology 2003;99:126–139
100
0
10
20
30
40
50
60
70
80
90
20 mg
59%
40 mg80 mg
82%
20 mg
40 mg
87%96%
AtorvastatinRosuvastatin
n=106 n=116
10 mg
10 mg
*
Pati
en
ts a
ch
ievin
g
LD
L-C
goals
(%
)
Rosuvastatin Slide Kit May 2004 [11]
*p=0.05 rosuvastatin 40mg vs atorvastatin 80 mg†patients with type 2 diabetes and dyslipidaemia
Adapted from Franken A, Atherosclerosis Supplements 2004; 5 (1): 118 Abs M.513
0
10
20
30
40
50
60
70
80
90
100
Rosuvastatin Atorvastatin
Pati
en
ts a
ch
ievin
g 2
003
Eu
rop
ean
LD
L-C
goal b
y d
ose
(%)
6 weeks
18 weeks
78%83%
90%
70%77%78%
10 mg
12 weeks
*
n=132n=131
20 mg40 mg
20 mg
40 mg
80 mg
Patients achieving 2003 European LDL-C goal (<2.5mmmol/l)†
Rosuvastatin versus AtorvastatinRosuvastatin versus Atorvastatin Achievement of LDL-C Goal Achievement of LDL-C Goal Across Dose Across Dose
RangeRange
Rosuvastatin Slide Kit May 2004 [12]
Rosuvastatin versus Atorvastatin Rosuvastatin versus Atorvastatin Change in HDL-C Change in HDL-C
The STELLAR StudyThe STELLAR Study
*p<0.002 vs atorvastatin 20, 40 and 80 mg†p<0.002 vs atorvastatin 40 and 80 mg
Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160
0
2
4
6
8
10
12
10
AtorvastatinRosuvastatin
20 40 80
ns
* †
n=473
n=634
Dose (mg); log scale
Ch
an
ge in
HD
-C f
rom
b
aselin
e (
%)
Rosuvastatin Slide Kit May 2004 [13]
Rosuvastatin versus Comparators Rosuvastatin versus Comparators Change in HDL-CChange in HDL-C TheThe STELLAR StudySTELLAR Study
*p<0.002 vs pravastatin 10 mg†p<0.002 vs atorvastatin 20, 40, 80 mg; simvastatin 40 mg; pravastatin 20, 40 mg‡p<0.002 vs atorvastatin 40, 80 mg; simvastatin 40 mg; pravastatin 40 mgObserved data in ITT population
Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160
10 20 40
3.2
4.4
5.6
10 20 40 80 10 20 40 0
2
4
6
8
10
12
5.74.8
4.4
2.1
*7.7
†9.5
‡9.6
10 20 40 80
5.3
6.0
5.2
6.8
Dose (mg)
RosuvastatinAtorvastatin
PravastatinSimvastatin
Ch
an
ge in
HD
-C f
rom
b
aselin
e (
%)
Rosuvastatin Slide Kit May 2004 [14]
Rosuvastatin versus Comparators Rosuvastatin versus Comparators Change in TriglyceridesChange in Triglycerides
The STELLAR StudyThe STELLAR Study
*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
Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160
Dose (mg)
–20.0
–22.6
–26.8–28.2
–11.9
–17.6
–14.8
–18.2
10 20 40 80
–23.7
† –26.1
‡
–19.8
*
10 20 40 10 20 40 80
–8.2 –7.7
–13.2
10 20 40
–30
–25
–20
–15
–10
0
–5
RosuvastatinAtorvastatin
PravastatinSimvastatinC
han
ge in
TG
fro
m
baselin
e (
%)
Rosuvastatin Slide Kit May 2004 [15]
Rosuvastatin Efficacy SummaryRosuvastatin Efficacy Summary
Rosuvastatin is the most effective statin at lowering LDL-C- Rosuvastatin has demonstrated highly effective reductions in LDL-C of
up to 63%
- Rosuvastatin lowers LDL-C significantly more than the same and some higher doses of other currently marketed statins
- Rosuvastatin 10 mg lowers LDL-C significantly more than atorvastatin 10 and 20 mg
Rosuvastatin 10 mg enables significantly more patients to achieve their LDL-C goal than the most commonly prescribed doses of other currently marketed statins, thereby reducing the need to titrate to higher doses
Rosuvastatin produces a significant increase in HDL-C which, unlike atorvastatin, is maintained across the dose range
Rosuvastatin Slide Kit May 2004 [16]
Rosuvastatin Tolerability Rosuvastatin Tolerability and Safetyand Safety
– Adverse event profile
– Liver Effects
– Muscle Effects
– Renal Effects
Rosuvastatin Slide Kit May 2004 [17]
Rosuvastatin Clinical Studies Included a Rosuvastatin Clinical Studies Included a Wide Range of PatientsWide Range of Patients
Range of patients reflecting those seen in general medical practice
– 53% male; 47% female (including women of childbearing age)
– no upper age limit (31% ≥65 years)
– 17% with type 2 diabetes
– 52% with hypertension
– 36% with overt cardiovascular disease
– 44% with mild renal impairment (8% moderate renal impairment)
Rosuvastatin Slide Kit May 2004 [18]
Rosuvastatin Tolerability and Safety - Rosuvastatin Tolerability and Safety - Adverse EventsAdverse Events
Rosuvastatin is generally well tolerated with an adverse event profile similar to currently marketed statins
Most common related adverse events - myalgia, asthenia, abdominal pain, nausea; these are generally mild and transient
Well tolerated regardless of age, sex, ethnicity, presence of co-morbidities or concomitant medications
Similar number of adverse events leading to withdrawal (<3%) as other currently marketed statins
Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K
Rosuvastatin Slide Kit May 2004 [19]
Rosuvastatin Tolerability and Safety - Rosuvastatin Tolerability and Safety - Withdrawals due to Adverse EventsWithdrawals due to Adverse Events
Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K
Percentage of patients with an adverse event leading to withdrawal
0
2
4
6
8
rosuvastatin simvastatin pravastatin
Patients (%)
1
3
5
7
2.9%2.5% 2.5%
(n=3074) (n=1457) (n=1278)
3.2%
atorvastatin(n=2899)
10–40 mg10–80 mg10–80 mg10–40 mg
Rosuvastatin Slide Kit May 2004 [20]
Rosuvastatin Tolerability and Safety Rosuvastatin Tolerability and Safety - Liver Effects- Liver Effects
Elevations in liver transaminase levels are an infrequent but recognized complication of treatment with statins
Low incidence of clinically significant increases in serum transaminases* with rosuvastatin 10–40 mg of 0.2% which compares well with that seen with other currently marketed statins1
As with other statins:
– liver function tests recommended
– caution in patients who consume excessive quantities of alcohol and/or have a history of liver disease
– contraindicated in patients with active liver disease
*ALT >3 x ULN on 2 successive occasions
1. Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K Please refer to local Prescribing Information
Rosuvastatin Slide Kit May 2004 [21]
Rosuvastatin Benefit:Risk Rosuvastatin Benefit:Risk – Liver Effects– Liver Effects
ALT >3 ALT >3 ×× ULN: Frequency by LDL-C Reduction ULN: Frequency by LDL-C Reduction
Persistent elevation is elevation to >3 x ULN on 2 successive occasions
Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K
0.0
0.5
1.0
1.5
2.0
2.5
3.0
20 30 40 50 60 70
LDL-C reduction (%)
Fluvastatin (20, 40, 80 mg)
Rosuvastatin (10, 20, 40 mg)
Lovastatin (20, 40, 80 mg)
Atorvastatin (10, 20, 40, 80 mg)
Simvastatin (40, 80 mg)
Occu
rren
ce o
fA
LT >
3
×ULN
(%
)
Rosuvastatin Slide Kit May 2004 [22]
Rosuvastatin Tolerability and Safety Rosuvastatin Tolerability and Safety - Muscle Effects- Muscle Effects
As with other statins, effects on skeletal muscle, e.g. uncomplicated myalgia, myopathy and, rarely, rhabdomyolysis have been reported in patients treated with rosuvastatin
Frequency of treatment-related myopathy* in clinical trials was <0.1% in patients treated with rosuvastatin up to 40 mg which compares well with that seen with other currently marketed statins1
Frequency of rhabdomyolysis with rosuvastatin is similar to that reported for the other marketed statins2
*defined as CK >10 ULN plus muscle symptoms
1. Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K2. Data on File Please refer to local Prescribing Information
Rosuvastatin Slide Kit May 2004 [23]
Rosuvastatin Benefit:RiskRosuvastatin Benefit:Risk - Muscle Effects - Muscle Effects
CK >10 CK >10 xx ULN: Frequency by LDL-C Reduction ULN: Frequency by LDL-C Reduction
Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K
Cerivastatin (0.2, 0.3, 0.4, 0.8 mg)
Rosuvastatin (10, 20, 40 mg)
Pravastatin (20, 40 mg)
Atorvastatin (10, 20, 40, 80 mg)
Simvastatin (40, 80 mg)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
20 30 40 50 60 70
LDL-C reduction (%)
Occu
rren
ce o
f C
K >
10
×ULN
(%
)
Rosuvastatin Slide Kit May 2004 [24]
Rosuvastatin Tolerability and Rosuvastatin Tolerability and SafetySafety
- Renal Effects- Renal Effects
Rosuvastatin Slide Kit May 2004 [25]
Tolerability and Safety - Renal Effects Tolerability and Safety - Renal Effects Types of ProteinuriaTypes of Proteinuria
Glomerulus
Normal Glomerular proteinuria
Tubular proteinuria
Blood Blood Blood
Tubule
Bladder
Waste Products
Low molecular weight proteins (includes small amounts of albumin)
High molecular weight proteins (includes large amounts of albumin)
Rosuvastatin Slide Kit May 2004 [26]
Rosuvastatin Tolerability and Safety - Rosuvastatin Tolerability and Safety - ProteinuriaProteinuria
During the clinical development programme proteinuria* was observed in a small number of patients receiving all statin therapies studied and placebo1
This observation was thoroughly investigated in rosuvastatin patients. It was found to be usually transient, often resolved on continued treatment and not predictive of acute or progressive renal disease1
Proteinuria observed with rosuvastatin was tubular (reduced reabsorption of normally filtered proteins) in origin1
- Development of this tubular proteinuria is likely to be a consequence of the pharmacological action of rosuvastatin, ie. inhibition of HMG-CoA reductase, in the renal tubular cell2,3
- Highly effective inhibition of HMG-CoA reductase together with a greater degree of renal excretion contribute to this being seen with rosuvastatin
*dipstick positive proteinuria defined as a shift from no protein or trace at baseline to ≥++1. Vidt DG et al. Cardiology 2004;102:52-602. Sidaway J et al. Toxicology Letters 2003;144 (supplement 1):s96 Abs 3533. Verhulst A et al. Presented at American Society of Nephrology Nov 2003Please refer to local Prescribing Information
Rosuvastatin Slide Kit May 2004 [27]
Rosuvastatin Tolerability and Safety - Rosuvastatin Tolerability and Safety - ProteinuriaProteinuria
Frequency of Proteinuria*Frequency of Proteinuria*
Treatment Dose n Patients (%)
Placebo 330 0.6
Rosuvastatin 10 mg
20 mg
40 mg
1008
872
1850
0.6
0.7
1.2
Atorvastatin 10 mg
20 mg
40 mg
80 mg
628
438
63
342
0.5
0.5
0
0.3
Simvastatin 20 mg
40 mg
80 mg
452
314
325
1.1
0.3
0
Pravastatin 20 mg
40 mg
162
64
0.6
0
Vidt DG et al. Cardiology 2004;102:52-60
*dipstick positive proteinuria defined as a shift from no protein or trace at baseline to ≥++
Rosuvastatin Slide Kit May 2004 [28]
Rosuvastatin Tolerability and Safety – Rosuvastatin Tolerability and Safety – Maintenance of Renal FunctionMaintenance of Renal Function
• In over 6000 patients receiving rosuvastatin (10-40mg) for up to 3.8 years, renal function† was maintained or tended to improve slightly
• This was evident in all patient groups studied, including those at risk of progressive renal disease such as the elderly, patients with type 2 diabetes, hypertension or with pre-existing renal dysfunction/proteinuria and also in those who developed a positive urine dipstick test during the period of treatment*
*dipstick positive proteinuria defined as a shift from no protein or trace at baseline to ≥++†assessed using derived GFR measurements
Vidt DG et al. Cardiology 2004;102:52-60Please refer to local Prescribing Information
Rosuvastatin Slide Kit May 2004 [29]
66
6768
7070
71
67
6364
6566
6768
6970
7172
Baseline GFR
On-treatmentGFR
Ch
an
ge in
GFR
(m
l/m
in/1
.73m
2)
Rosuvastatin 10 mgRosuvastatin 20 mgRosuvastatin 40 mgPlacebo
6464
68
64
69
Baseline GFR
On-treatmentGFR
Short-term controlled clinical trials (~8 weeks)
Long-term open label treatment (>96 weeks)
n=2909 (10 mg)
n=371 (placebo)
n=1432 (20 mg)
n=2107 (40 mg)
n=893 (10 mg)
n=119 (20 mg)
n=109 (40 mg)
Rosuvastatin Tolerability and Safety – Rosuvastatin Tolerability and Safety – Maintenance of Renal Function Assessed by Maintenance of Renal Function Assessed by
GFRGFRChange in GFR in patients receiving placebo or rosuvastatin in short-term controlled clinical trials and long-term open-label treatment
Vidt DG et al. Cardiology 2004;102:52-60
p<0.001 for rosuvastatin 10 mg, 20 mg and 40 mg vs baseline for both short and long-term treatment
Rosuvastatin Slide Kit May 2004 [30]
0
1
2
3
4
5
6
Age, years Gender Hypertension GFR‡ Type 2diabetes
Urine dipstickprotein†
Mean
ch
an
ge in
GFR
(m
l/m
in/1
.73m
2)
<65 >65 M F Y N Y N -ve +ve>60 <60
‡ ml/min/1.73m2
† negative is ‘none or trace’ positive is >1+ at baseline
Rosuvastatin Tolerability and Safety – Rosuvastatin Tolerability and Safety – Maintenance of Renal Function in Maintenance of Renal Function in
Different Patient GroupsDifferent Patient GroupsChange in GFR in patients receiving long-term (>96 weeks) with rosuvastatin 10 mg
Vidt DG et al. Cardiology 2004;102:52-60
n=
650
n=
243
n=
413
n=
480
n=
356
n=
537
n=
590
n=
303
n=
61
n=
832
n=
836
n=
46
Rosuvastatin Slide Kit May 2004 [31]
Rosuvastatin Tolerability and Safety - Rosuvastatin Tolerability and Safety - Renal Safety SummaryRenal Safety Summary
Rosuvastatin 10–40 mg is well tolerated from the renal perspective
Proteinuria* was seen in a small number of patients receiving all statin therapies studied and placebo
Proteinuria observed with rosuvastatin was thoroughly
evaluated and found to be mostly tubular, usually transient, often resolved on continued treatment and not predictive of acute or progressive renal disease
Renal function was maintained or tended to improve slightly with long-term treatment
*dipstick positive proteinuria defined as a shift from no protein or trace at baseline to ≥++
Rosuvastatin Slide Kit May 2004 [32]
Rosuvastatin - Overall Tolerability and Rosuvastatin - Overall Tolerability and Safety SummarySafety Summary
Tolerability profile has been well-researched in a large number of patients representing ‘real population’
Overall tolerability profile of rosuvastatin comparable with currently marketed statins
– Well tolerated with a low rate of withdrawals due to adverse events (<3%)
– Adverse events usually mild and transient
Low incidence of myopathy and of clinically significant increases in serum transaminases with rosuvastatin 10–40 mg, comparable with currently marketed statins
Renal function was maintained or tended to improve slightly with long-term treatment
Favourable benefit–risk profile
Rosuvastatin Slide Kit May 2004 [33]
Rosuvastatin - Experience Since LaunchRosuvastatin - Experience Since Launch
As of end April 2004
Rosuvastatin is approved in over 50 countries
>4 million prescriptions issued
>1.5 million patients treated
Benefit–risk profile is consistent with that seen in the clinical development programme and compares favourably with other currently marketed statins
Rosuvastatin Slide Kit May 2004 [34]
Clinical Pharmacology of Clinical Pharmacology of RosuvastatinRosuvastatin
Rosuvastatin Slide Kit May 2004 [35]
Pharmacokinetic Profile of Selected StatinsPharmacokinetic Profile of Selected Statins
*Elimination T1/2 of drug and metabolites, if any.CRESTOR (rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003. Atorvastatin Calcium Prescribing Information 2002, Pfizer Inc, NY, NY; Simvastatin Prescribing Information, Merck & Co., Inc., Whitehouse Station, NJ; Pravastatin Prescribing Information 2003, Bristol-Meyers Squibb Company, Princeton, NJ.
Rosuvastatin Atorvastatin Simvastatin Pravastatin
CYP450 3A4 metabolism
No Yes Yes No
Clinically significant metabolites
No Yes Yes No
Plasma clearance Dual renal / hepatic
Primarily hepatic
Dual renal / hepatic
Dual renal / hepatic
Relatively hydrophilic Yes No No Yes
Hepatoselective Yes Yes Yes Yes
Bioavailability (%) 20 14 <5 17
Elimination half-life* (hours)
19 14 1.9 77
Rosuvastatin Slide Kit May 2004 [36]
Interactions of no clinical significance:– drugs where metabolism involves cytochrome P450 such as fluconazole,
ketoconazole and traconazole
– fenofibrate
– digoxin
Interactions with limited clinical significance:– antacid - 50% rosuvastatin levels
– erythromycin non-significant in rosuvastatin plasma levels
Interactions of clinical significance:– oral contraceptive pill - ethinyl oestradiol and norgestrel levels which may affect
choice of oral contraceptive use
– gemfibrozil – 2x in rosuvastatin plasma levels. Combination not recommended
– cyclosporin – 7x in rosuvastatin plasma levels. Combination contraindicated outside of USA
– warfarin – INR – monitoring of INR required
Rosuvastatin - Limited Drug–Drug InteractionsRosuvastatin - Limited Drug–Drug Interactions
Please refer to local Prescribing Information
Rosuvastatin Slide Kit May 2004 [37]
Rosuvastatin Pharmacokinetics in Special Rosuvastatin Pharmacokinetics in Special Populations Populations
No clinically relevant PK differences:
– between younger and elderly (age ≥65 years)
– between men and women
– between caucasian, hispanic, and black or afro-caribbean groups
– in patients with mild to moderate renal impairment (creatinine clearance ≥30 mL/min/1.73m2)
PK differences which may influence dose selection:
– 2-fold increase in AUC in Japanese in Japan and Chinese in Singapore compared with Caucasians in North America and Europe
– increase in Cmax in moderate/severe hepatic impairment
– 3-fold increase in Cmax in severe renal impairment (CLcr <30 mL/min/1.73m2)
Please refer to local Prescribing Information
Rosuvastatin Slide Kit May 2004 [38]
Rosuvastatin Dosing and Rosuvastatin Dosing and AdministrationAdministration
Rosuvastatin Slide Kit May 2004 [39]
Rosuvastatin - Dosing and AdministrationRosuvastatin - Dosing and Administration
Usual start dose 10 mg
– for all patients (new or switch) as it effectively gets most patients to their LDL-C goal
Dose range 10–40 mg
Maximum LDL-C response within 4 weeks
– significant response within 2 weeks
Once daily, any time of day, with or without food
Please refer to local Prescribing Information
Rosuvastatin Slide Kit May 2004 [40]
Ongoing Clinical Development Ongoing Clinical Development of Rosuvastatinof Rosuvastatin
Rosuvastatin Slide Kit May 2004 [41]
Ongoing Clinical Development - the Ongoing Clinical Development - the Rosuvastatin GALAXY ProgrammeRosuvastatin GALAXY ProgrammeTMTM
The GALAXY ProgrammeTM is a large, comprehensive, long-term and evolving global research initiative sponsored by AstraZeneca investigating cardiovascular risk reduction and patient outcomes with rosuvastatin
It has been designed to build on current thinking to address important unanswered questions in statin research
Includes studies investigating the effects of rosuvastatin on:
– atherogenic lipid profile and inflammatory markers
– atherosclerosis
– outcomes Will provide additional short- and long-term efficacy and safety data for
rosuvastatin Designed to help physicians to improve the management of patients
with hypercholesterolaemia and others with or at risk of cardiovascular disease
Schuster H & Fox J. Expert Opinion in Pharmacotherapy 2004;5:1187-1200
Rosuvastatin Slide Kit May 2004 [42]
GALAXY GALAXY ProgrammeProgrammeTMTM Studies Studies
AURORACORONAJUPITER
ORIONMETEOR
ASTEROID
STELLARMERCURY IMERCURY II
ORBITALDISCOVERY
COMETSLUNARPLUTO
POLARISPULSARECLIPSE
EXPLORER
GALAXY ProgrammeTM studies with rosuvastatin, investigating:
Atherogenic lipid profile+/- inflammatory markers Atherosclerosis
Reduction in CV morbidity & mortality
Schuster H & Fox J. Exp Opin Pharmacother 2004;5:1187-1200
Rosuvastatin Slide Kit May 2004 [43]
Rosuvastatin has the Largest Number of Rosuvastatin has the Largest Number of Outcomes Studies Ongoing at Launch Outcomes Studies Ongoing at Launch
1. Schuster H & Fox J. Exp Opin Pharmacother 2004;5:1187-1200 2. Fellström B et al. Nephrol Dial Transplant 2003;18(Suppl 4):7133. Ridker P. Circulation 2003;108:2292–2297
STUDY Treatment Subjects Outcome
AURORA Rosuvastatin 10 mg
2700 subjects with end-stage renal disease on chronic haemodialysis1, 2
Mortality and major CV events
CORONA Rosuvastatin 10 mg
4950 patients with heart failure (NYHA class II-IV) of ischaemic aetiology receiving standard treatment1
Mortality and CV events
JUPITER Rosuvastatin 20 mg
15,000 subjects with normal LDL-C levels and raised levels of C-reactive protein1, 3
Primary prevention of CV events
GISSI-HF Rosuvastatin 10 mg or n-3 PUFA (fish oil)
7000 patients with symptomatic heart failure of any aetiology already receiving standard treatment
Mortality and morbidity
Rosuvastatin Slide Kit May 2004 [44]
Rosuvastatin - Overall SummaryRosuvastatin - Overall Summary
Rosuvastatin produces beneficial effects on key lipid parameters at low dose and across the dose range
– rosuvastatin is the most effective statin at lowering LDL-C
– rosuvastatin 10 mg reduces LDL-C more than the same and some higher doses of other currently marketed statins
– more patients to LDL-C goal with rosuvastatin 10 mg than commonly prescribed doses of other currently marketed statins, avoiding the need to titrate to higher doses
– HDL-C increases maintained across the dose range, unlike atorvastatin
Tolerability and safety profile similar to other currently marketed statins
Low potential for significant drug–drug interactions
A comprehensive clinical development programme is ongoing, including a large number of outcomes studies
top related