Transcript Document

JUPITER
Justification for the Use of
statins in Primary prevention: an
Intervention Trial Evaluating
Rosuvastatin
Rosuvastatin is not indicated for the treatment of
patients with high C-Reactive Protein (CRP).
For complete therapeutic and safety information please consult the CRESTOR® Product Monograph.
JUPITER

JUPITER is the first large-scale, prospective study to
examine the role of statin therapy in individuals with low to
normal LDL-C levels, but with increased cardiovascular risk
identified by elevated CRP

It assessed the long-term impact of rosuvastatin
(CRESTOR™) in individuals potentially at increased
cardiovascular (CV) risk due to elevated CRP levels who do
not qualify for lipid-lowering treatment according to current
guidelines
Ridker P et al. N Eng J Med 2008;359: 2195-2207
For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.
JUPITER - Rationale

Nearly half of all cardiovascular events occur in patients who
are apparently healthy and who have low or normal levels of
LDL-C

hsCRP predicts cardiovascular disease independent of LDL-C
levels

Along with improved screening there is a need to examine
the use of lipid-lowering agents as a method of reducing the
risk of cardiovascular events
Ridker PM. New Engl J Med 2002; 347: 1557–1565
For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.
Prevalence of conventional risk factors† in
male patients with CHD
Four
Three
(0.9%)
None
8.9%
19.4%
Two
27.8%
43.0%
One
Total male patients=87 869
CHD=coronary heart disease
†smoking, hypertension, hypercholesterolaemia and diabetes mellitus
Khot UN et al. JAMA 2003; 290: 898–904.
For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.
CRP Epidemiology
CRP levels in the US, NHANES 1999-2000
8
7
6
Percentile
33.3
50
66.7
Men
Women
5
4
3
2
1
0
30-39 40-49 50-59 60-69 70-79 80+ 30-39
Age (yrs)
40-49
50-59
60-69
Age (yrs)
Ford ES, Giles WH, Myers GL, Mannino DM. Clin Chem 2003; 49(4):686-90.
Ford ES, Giles WH, Mokdad AH, Myers GL. Clin Chem 2004; 50(3):574-81.
For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.
70+
CRP contributes to all stages of atherosclerosis
Roles
of CRP
Endothelial
Dysfunction
 Vasodilation
 NO
Endothelial
activation
 Monocyte
adhesion
 Endothelial
progenitor cells
Plaque
progression
 Monocyte
migration
 VSMC
proliferation
Plaque Rupture
/Thrombosis
 Cap thinning
 TF secretion
 Fibrinolysis
Progression of atherosclerosis
NO: Nitric oxide, VSMC: Vascular Smooth Muscle Cell, TF: Tissue factor
Bisoendial RJ, Kastelein JJP, Stroes ESG. Atherosclerosis 2007; 195:e10-18
Packard RRS, Libby P. Clin Chem 2008; 54:24-38
For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.
CRP is a stronger predictor of future events
compared with other markers in women
Lp(a)
Homocysteine
IL-6
TC
LDL-C
sICAM-1
SAA
ApoB
TC/HDL-C
CRP
CRP + TC/HDL-C
0
1.0
2.0
4.0
6.0
Relative risk of future cardiovascular events
CRP=C-reactive protein; Lp(a)=lipoprotein (a); IL=interleukin; TC=total cholesterol; LDL-C=low-density
lipoprotein cholesterol; sICAM-1=soluble intercellular adhesion molecule 1; SAA=serum amyloid A;
Apo=apolipoprotein; HDL-C=high-density lipoprotein cholesterol
Blake GJ, Ridker PM. Circ Res 2001; 89: 763–771.
For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.
CRP predicts risk of MI and stroke in apparently
healthy men
3.5
2.0
***
3.0
1.5
2.5
Relative
risk
of MI
*
Relative
risk of
ischaemic
stroke
2.0
1.5
1.0
1.0
0.5
0.5
0
1
2
3
4
Quartile of CRP
CRP=C-reactive protein; MI=myocardial infarction
*p=0.03 vs quartile 1; ***p<0.001 vs quartile 1
0
1
2
3
4
Quartile of CRP
Quartile 1: ≤ 0.55 ; Quartile 2: ≤ 0.56-1.14;
Quartile 3: 1.15-2.10 ; Quartile 4:  2.11.
Ridker PM et al. N Engl J Med 1997; 336: 973–979.
For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.
Rate of cardiovascular events in women in
relation to LDL-C and CRP
100
10
CRP
(mg/L)
1
0.1
1.3
2.6
3.9
5.2
LDL-C (mmol/L)
LDL-C=low-density lipoprotein cholesterol; CRP=C-reactive protein
Ridker PM et al. N Engl J Med 2002; 347: 1557–1565.
For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.
6.5
Cardiovascular event-free survival in women using
combined LDL-C and CRP measurements
1.00
0.99
Probability
of event- 0.98
free
survival
Low LDL-C, low CRP
High LDL-C, low CRP
Low LDL-C, high CRP
0.97
0.96
High LDL-C, high CRP
0
LDL-C=low-density lipoprotein cholesterol; CRP=C-reactive protein
Median LDL-C=3.2 mmol/L (124 mg/dL)
Median CRP=1.5 mg/L
Ridker PM et al. N Engl J Med 2002; 347: 1557–1565.
For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.
LDL-C and CRP as markers of cardiovascular events – the
AFCAPS/TexCAPS study
Study group
Rate of cardiovascular
events
NNT
Lovastatin
Placebo
Low LDL-C/low CRP
0.025
0.022
na
Low LDL-C/high CRP
0.029
0.051
48
High LDL-C/low CRP
0.020
0.050
33
High LDL-C/high CRP
0.038
0.055
58
Median LDL-C=3.9 mmol/L (149 mg/dL). Median CRP=1.6 mg/L
LDL-C=low-density lipoprotein cholesterol; CRP=C-reactive protein; NNT=number needed to treat to
prevent one coronary event; na=not applicable.
Ridker PM et al. N Engl J Med 2001; 344: 1959–1965.
For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.
CRP is a strong independent predictor of
future CV events

CRP is a strong independent predictor of
cardiovascular events1

Addition of CRP to the Framingham
algorithm improves global cardiovascular
risk prediction2

CRP and LDL-C are complementary
biomarkers for identifying at-risk individuals3
1. Ridker PM. JACC 2007;49:2129-38.
2. Ridker PM. JAMA 2007;297:611-9.
3. Ridker PM et al. N Engl J Med 2002; 347: 1557–1565.
For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.
JUPITER - Objective
• The primary objective was to investigate
whether long-term treatment with
rosuvastatin 20 mg decreases the rate of first
major cardiovascular events compared with
placebo in patients with low to normal LDL-C
but at increased cardiovascular risk as
identified by elevated CRP levels
Ridker PM. Circulation 2003; 108: 2292–2297
For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.
JUPITER – study design
No history of CAD
men ≥50 yrs
Rosuvastatin 20 mg (n~8900)
Placebo
women ≥60 yrs
LDL-C <3.36 mmol/L
run-in
Placebo (n~8900)
CRP ≥2.0 mg/L
Visit:
Week:
1
–6
2
–4
Lead-in/
eligibility
3
0
4
13
6-month
intervals
Final
3–4 y
Randomisation
Lipids
CRP
Tolerability
Lipids
CRP
Tolerability
Lipids
CRP
Tolerability
HbA1C
CAD=coronary artery disease; LDL-C=low-density lipoprotein cholesterol; CRP=C-reactive protein; HbA1c=glycated haemoglobin
Ridker PM. Circulation 2003; 108: 2292–2297. Ridker PM. Am J Cardiol 2007; 100: 1659–1664.
For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.
JUPITER - Study Endpoints
 Primary Endpoint
– Time to the first occurrence of a major cardiovascular event,
composite of:
• cardiovascular death
• Stroke
• MI
• unstable angina
• arterial revascularisation
 Secondary Endpoints:
– total mortality
– non-cardiovascular mortality
– development of diabetes mellitus
– development of venous thromboembolic events
– bone fractures
– discontinuation of study medication due to adverse effects.
Ridker PM. Circulation 2003; 108: 2292–2297
JUPITER – study design
No history of CAD
men ≥50 yrs
Rosuvastatin 20 mg (n~8900)
Placebo
women ≥60 yrs
LDL-C <3.36 mmol/L
run-in
Placebo (n~8900)
CRP ≥2.0 mg/L
Visit:
Week:
1
–6
2
–4
Lead-in/
eligibility
3
0
4
13
6-month
intervals
Final
3–4 y
Randomisation
Lipids
CRP
Tolerability
Lipids
CRP
Tolerability
Lipids
CRP
Tolerability
HbA1C
CAD=coronary artery disease; LDL-C=low-density lipoprotein cholesterol; CRP=C-reactive protein; HbA1c=glycated haemoglobin
Ridker PM. Circulation 2003; 108: 2292–2297. Ridker PM. Am J Cardiol 2007; 100: 1659–1664.
For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.
JUPITER – study endpoints

Primary
– time to the first occurrence of a major
cardiovascular event (cardiovascular death,
stroke, MI, unstable angina or arterial
revascularisation)

Secondary
– Efficacy (incident diabetes mellitus, venous
thromboembolic events, bone fractures)
– Safety (total mortality noncardiovascular
mortality, adverse events)
Ridker PM. Circulation 2003; 108: 2292–2297.
Ridker PM. Am J Cardiol 2007; 100: 1659–1664.
For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.
Major inclusion criteria

Men aged ≥50 years; women aged ≥60
years

Fasting LDL-C levels 3.36 mmol/L, CRP
levels ≥2.0 mg/L and TG levels 5.65
mmol/L on initial screening
Ridker PM. Circulation 2003; 108: 2292–2297.
Ridker PM. Am J Cardiol 2007; 100: 1659–1664.
For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.
Major exclusion criteria

Current use of statins or other lipid-lowering therapies

Prior history of cardiovascular or cerebrovascular
events, such as MI, unstable angina, prior arterial
revascularisation or stroke, or CHD-risk equivalents

Chronic inflammatory condition, such as severe arthritis,
lupus or inflammatory bowel disease

CK 3 x ULN
MI=myocardial infarction; CHD=coronary heart disease; ULN=upper limit of normal
Ridker PM. Circulation 2003; 108: 2292–2297.
Ridker PM. Am J Cardiol 2007; 100: 1659–1664.
For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.
JUPITER - Major exclusion criteria

Current use of statins or other lipid-lowering therapies

Current use of hormone replacement therapy

Prior history of cardiovascular or cerebrovascular events, such as MI,
unstable angina, prior arterial revascularisation or stroke, or CHD-risk
equivalents

Chronic inflammatory condition, such as severe arthritis, lupus or
inflammatory bowel disease and/or treatment with immunosuppressants

Uncontrolled:
– hypertension: SBP > 190 mmHg or DBP > 100 mmHg
– hypothyroidism: TSH > 1.5 x ULN

CK 3 x ULN

Serum creatinine > 2.0 mg/dL

Evidence of hepatic dysfunction (ALT > 2 x ULN)

History of prior malignancy, alcohol or drug abuse
Ridker PM. Circulation 2003; 108: 2292–2297
Ridker P et al. N Eng J Med 2008;359: 2195-2207
CHD = coronary heart disease; CK = creatinine kinase; ULN = upper limit of
normal; SBP = systolic blood pressure; DBP = diastolic blood pressure
JUPITER - Patient Flow
89,890 subjects screened
17,802 randomized
Rosuvastatin 20mg
n=8,901
Placebo
n=8,901
Lost to follow up
n=44
Lost to follow up
n=37
Completed study
n=8,857
Completed study
n=8,864
Ridker P et al. N Eng J Med 2008;359: 2195-2207
For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.
JUPITER - Baseline characteristics*
Rosuvastatin
n=8901
Age (years)
Male sex (%)
Race (%)
White
Black
Hispanic
Other
BMI (kg/m2)
Systolic BP (mmHg)
Diastolic BP (mmHg)
Placebo
n=8901
66 (60-71)
61.5
66 (60-71)
62.1
71.4
12.4
12.6
3.6
28.3 (25.3-32.0)
134 (124-145)
80 (75-87)
71.1
12.6
12.8
3.5
28.4 (25.3-32.0)
134 (124-145)
80 (75-87)
*All values are median (interquartile range) or N (%).
Ridker P et al. N Eng J Med 2008;359: 2195-2207
For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.
JUPITER - Baseline laboratory parameters*
Rosuvastatin
n=8901
Total cholesterol (mg/dL)
LDL cholesterol (mg/dL)
HDL cholesterol (mg/dL)
Triglycerides (mg/dL)
hsCRP (mg/L)
Glucose (mg/dL)
HbA1c(%)
Glomerular filtration rate,
(ml/min/1.73m2)
Placebo
n=8901
4.81 (4.34-5.17)
2.69 (2.43-3.08)
1.27 (1.03-1.55)
1.33 (0.96-1.91)
4.2 (2.8-7.1)
94 (87-102)
5.7 (5.4-5.9)
4.78 (4.37-5.15)
2.69 (2.43-3.08)
1.27 (1.03-1.55)
1.33 (0.97-1.90)
4.3 (2.8-7.2)
94 (88-102)
5.7 (5.5-5.9)
73.3
73.6
(64.6-83.7)
(64.6-84.1)
For hsCRP, values are the average of the values obtained at two screening and visits
*All values are median (interquartile range) or N (%).
Ridker P et al. N Eng J Med 2008;359: 2195-2207
For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.
JUPITER - Medical History
Medical History
Current smoker (%)
Family history CHD† (%)
Metabolic syndrome‡ (%)
Aspirin use (%)
Rosuvastatin Placebo
n=8901
n=8901
15.7
11.2
41.0
16.6
16.0
11.8
41.8
16.6
†Family history of premature CHD defined as first degree relative with CHD at age < 55 yrs (male), < 65 yrs
(female); ‡ Metabolic syndrome defined according to consensus criteria of AHA/NHLBI
Ridker P et al. N Eng J Med 2008;359: 2195-2207
For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.
JUPITER population compared with previous trials
in patients without established CHD
AFCAPS
WOSCOPS
JUPITER
Patients, n
6605
6595
17 802
% male, n
85
100
62
Duration, years
5.2
4.9
Ongoing
6
1
0
5.72
7.03
4.73
LDL-C
3.89
4.97
2.69
HDL-C
0.93–1.03
1.14
1.32
1.79
1.85
1.33
0.2
NA
4.3
Lovastatin
Pravastatin
Rosuvastatin
20–40 mg
40 mg
20 mg
Diabetes, %
Baseline lipids
(mmol/L
Total
Cholesterol
Triglycerides
hsCRP, mg/L
Statin
CVD=cardiovascular disease; CHD=coronary heart disease; LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density
lipoprotein cholesterol; hsCRP=high sensitivity C-reactive protein; *Baseline lipid levels are mean values.
Ridker PM et al. Am J Cardiol 2007; 100: 1659–1664
Ridker PM et al. N Engl J Med. 2001 344: 1959-65
JUPITER - Primary Endpoint
Time to first occurrence of a CV death, non-fatal stroke, non-fatal
MI, unstable angina or arterial revascularization
Percent of patients with
primary endpoint
9
Hazard Ratio 0.56
(95% CI 0.46-0.69)
P<0.00001
8
7
Placebo
6
5
Rosuvastatin 20 mg
4
3
NNT for 2y = 95
5y* = 25
2
1
0
0
Number at risk
RSV
8901
Placebo 8901
1
8412
8353
2
3893
3872
*Extrapolated figure based on Altman and Andersen method
Years
3
1353
1333
4
5
538
531
157
174
Ridker P et al. N Eng J Med 2008;359: 2195-2207
JUPITER - Primary Endpoint Components
Placebo
Rosuvastatin
n (rate**)
n (rate**)
[n=8901]
[n=8901]
HR
95% CI
p-value
Primary Endpoint
251 (1.36)
142 (0.77)
0.56
0.46-0.69 <0.001*
(Time to first occurrence of CV death, MI, stroke, unstable angina, arterial revascularisation)
Non-fatal MI
Fatal or non-fatal MI
62 (0.33)
68 (0.37)
22 (0.12)
31 (0.17)
0.35
0.46
0.22-0.58 <0.001*
0.30-0.70 0.0002
Non-fatal stroke
Fatal or non-fatal stroke
58 (0.31)
64 (0.34)
30 (0.16)
33 (0.18)
0.52
0.52
0.33-0.80
0.34-0.79
Arterial Revascularization
131 (0.71)
71 (0.38)
0.54
0.41-0.72 <0.0001
Unstable angina†
27 (0.14)
16 (0.09)
0.59
0.32-1.10
CV death, stroke, MI
157 (0.85)
83 (0.45)
0.53
0.40-0.69 <0.001*
Revascularization
or unstable angina
143 (0.77)
76 (0.41)
0.53
0.40-0.70 <0.001*
0.003
0.002
0.09
** Rates are per 100 person years; † Hospitalisation due to unstable angina; *Actual p-value was < 0.00001
HR – Hazard Ratio; CI – Confidence Limit
Ridker P et al. N Eng J Med 2008;359: 2195-2207
JUPITER – Subgroup analysis
Placebo better
Rosuvastatin better
1.2
1
0.8
0.6
0.80
Males
Females
11,001
6,801
0.57
Race
White
Non-white
12,683
5,117
0.53
Hypertension
Yes
No
10,208
7,586
0.51
Region
US or Canada
Other
6,041
11,761
0.14
Metabolic syndrome
Yes
No
7,375
10,296
0.07
Family history of CHD
2,045
15,684
0.99
Framingham risk score
≤10%
>10%
Hazard ratio (95% CI)
8,541
9,261
Gender
Yes
No
0.4
≤ 65 years
>65 yrs
0.2
Age
P- value*
0.32
0
N
8,882
8,895
Ridker P et al. N Eng J Med 2008;359: 2195-2207
For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.
JUPITER - Total Mortality
Percent total mortality
Death from any cause
7
Hazard Ratio 0.80
(95% CI 0.67-0.97)
p=0.02
6
Placebo
5
Rosuvastatin 20mg
4
3
2
1
0
0
Number at risk
RSV
8901
Placebo 8901
1
2
8787
8775
4312
4319
Years
3
1602
1614
4
5
676
681
227
246
Ridker P et al. N Eng J Med 2008;359: 2195-2207
For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.
JUPITER
Effects on LDL-C, HDL-C, TG and hsCRP at 12 months;
Percentage change between rosuvastatin and placebo
Percentage change
from baseline (%)
10
LDL-C
HDL-C
TG
hsCRP
4%
0
p<0.001*
-10
17%
-20
p<0.001
-30
37%
-40
p<0.001
50%
-50
p<0.001
-60
*P-value at study completion (48 months) = 0.34
Ridker P et al. N Eng J Med 2008;359: 2195-2207
For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.
JUPITER
Tolerability and safety data
Placebo
[n=8901]
Adverse Events, (%)
Any serious adverse event
Muscle weakness, stiffness, pain
Myopathy
Rhabdomyolysis
Newly diagnosed cancer
Death from cancer
Gastrointestinal disorders
Renal disorders
Bleeding
Hepatic disorders
Other events, (%)
Newly diagnosed diabetes**
Haemorrhagic stroke
15.5
15.4
0.1
0.0
3.5
0.7
19.2
5.4
3.1
2.1
2.4
0.1
*Occurred after trial completion; **physician reported newly diagnosed diabetes
Rosuvastatin
[n=8901]
p-value
15.2
16.0
0.1
<0.1*
3.4
0.4
19.7
6.0
2.9
2.4
0.60
0.34
0.82
---0.51
0.02
0.43
0.08
0.45
0.13
3.0
0.1
0.01
0.44
Ridker P et al. N Eng J Med 2008;359: 2195-2207
JUPITER
Laboratory Safety Data
Placebo
Rosuvastatin
10 (0.10)
17 (0.20)
32 (0.40)
16 (0.20)
23 (0.30)
36 (0.50)
0.24
0.34
0.64
66.8 (59.1-76.5)
5.9 (5.7-6.1)
98 (91-107)
0.02
0.001
0.12
[n=8901]
Laboratory Values, N (%)
Serum creatinine‡
ALT > 3 x ULN#
Glycosuria†
Laboratory Values, median values (IQR)
GFR*, (mL/min/1.73m2)
66.6 (58.8-76.2)
% HbA1c**
5.8 (5.6-6.1)
Fasting plasma glucose**, (mg/dL) 98 (90-106)
[n=8901]
p-value
GFR = Glomerular filtration rate, HbA1c = Haemoglobin A1c
# on consecutive visits, ‡ >100% increase from baseline, *at 12 months, **at 24 months, †>trace at 12 months
Ridker P et al. N Eng J Med 2008;359: 2195-2207
JUPITER – summary and perspectives

The JUPITER study included patients with low to normal LDL-C who
were at increased CV risk as identified by elevated CRP levels and who
did not require statin treatment based on current treatment guidelines

A 44% reduction in the primary endpoint of major cardiovascular
events (composite of: CV death, MI, stroke, unstable angina, arterial
revascularisation) was observed in patients who received rosuvastatin
20 mg compared with placebo (p< 0.00001)

A 20% reduction in total mortality was observed in patients who
received rosuvastatin 20 mg compared with placebo (p=0.02), a
unique finding for statins in a population without established CHD

In JUPITER, long-term treatment with rosuvastatin 20 mg was well
tolerated in nearly 9000 study participants

There was no difference between treatment groups for muscle
weakness, cancer, haematological disorders, gastrointestinal, hepatic
or renal systems

The results from JUPITER highlight the importance of highly effective
statin treatment for these patients with an increased risk of CV disease
Ridker P et al. N Eng J Med 2008;359: 2195-2207
Acknowledgements

The JUPITER Steering Committee
– P Ridker (Chairman), Boston, MA, USA
– A Gotto, New York, NY, USA
– P Libby, Boston, MA, USA
– J Willerson, Houston, TX, USA
– J Genest, Montreal, Canada

The JUPITER Independent Data Monitoring Board

The JUPITER investigators and participating patients

This study is supported by AstraZeneca
DISCLAIMER
This slide presentation may include evolving scientific information that has not been
reviewed and approved by Health Canada. These slides are intended for educational
purposes only.
AstraZeneca Canada Inc. does not recommend the use of CRESTOR® in any other
indication than as described in the Canadian Product Monograph.
INDICATIONS AND CLINICAL USES
CRESTOR® (rosuvastatin calcium) is indicated as an adjunct to diet, at least equivalent to the
Adult Treatment Panel III (ATP III TLC diet), for the reduction of elevated total cholesterol
(Total-C), LDL-C, Apo-B, Total-C/HDL-C ratio and triglycerides (TG) and for increasing HDL-C;
in hyperlipidemic and dyslipidemic conditions, when response to diet and exercise alone has
been inadequate including:
Primary hypercholesterolemia (Type IIa including heterozygous familial
hypercholesterolemia and severe non-familial hypercholesterolemia)
Combined (mixed) dyslipidemia (Type IIb)
Homozygous familial hypercholesterolemia where CRESTOR ® is used either alone or as an
adjunct to diet and other lipid lowering treatment such as apheresis
Rosuvastatin is not indicated for the treatment of patients with high CReactive Protein (CRP).