Transcript Document

JUPITER
Justification for the Use of
statins in Primary prevention: an
Intervention Trial Evaluating
Rosuvastatin
Ridker P et al. N Eng J Med 2008;359: 2195-2207
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
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
Prevalence of conventional risk factors† in
patients with CHD
Four
Three
(0.9%)
None
8.9%
19.4%
Two
27.8%
43.0%
Total patients=87 869
CHD=coronary heart disease
†smoking, hypertension, hypercholesterolaemia and diabetes mellitus
Khot UN et al. JAMA 2003; 290: 898–904
One
CRP is a strong independent predictor of CV
events 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 CV events
Apo=apolipoprotein; CRP=C-reactive protein; CV=cardiovascular; HDL-C=high-density lipoprotein cholesterol; IL=interleukin;
LDL-C=low-density lipoprotein cholesterol; Lp(a)=lipoprotein (a); SAA=serum amyloid A; sICAM-1=soluble intercellular
adhesion molecule 1; TC=total cholesterol
Blake GJ, Ridker PM. Circ Res 2001; 89: 763–771
CRP predicts risk of MI and stroke in apparently
healthy men
3.5
2.0
*
***
3.0
1.5
2.5
Relative
risk of
1.0
ischaemic
stroke
Relative 2.0
risk
1.5
of MI
1.0
0.5
0.5
0
1
2
3
4
Quartile of CRP
CRP=C-reactive protein; MI=myocardial infarction
*p=0.02 versus quartile 1; ***p<0.001 versus quartile 1
Ridker PM et al. N Engl J Med 1997; 336: 973–979
0
1
2
3
Quartile of CRP
4
CV event-free survival in women using combined LDL-C
and hsCRP measures
1.00
0.99
Probability
of event- 0.98
free
survival
Low LDL-C, low hsCRP
High LDL-C, low hsCRP
Low LDL-C, high hsCRP
0.97
0.96
High LDL-C, high hsCRP
0
CV=cardiovascular; hsCRP=high-sensitivity C-reactive protein; LDL-C=low-density lipoprotein cholesterol
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
Efficacy of lovastatin in AFCAPS/TexCAPS subgroups by
baseline LDL-C and hsCRP
Study group
Rate of cardiovascular events
NNT
Lovastatin
Placebo
Low LDL-C/low hsCRP
0.025
0.022
N/A
Low LDL-C/high hsCRP
0.029
0.051
48
High LDL-C/low hsCRP
0.020
0.050
33
High LDL-C/high hsCRP
0.038
0.055
58
Median LDL-C=3.9 mmol/L (149 mg/dL). Median hsCRP=1.6 mg/L
AFCAPS/TexCAPS=Air Force/Texas Coronary Atherosclerosis Prevention Study; hsCRP=high-sensitivity C-reactive protein;
LDL-C=low-density lipoprotein cholesterol; N/A=not applicable; NNT=number needed to treat to prevent one coronary
event
Ridker PM et al. N Engl J Med 2001; 344: 1959–1965
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
JUPITER – study design
No history of CAD
men ≥50 yrs
Rosuvastatin 20 mg (n=8901)
Placebo
women ≥60 yrs
LDL-C <130 mg/dL
run-in
Placebo (n=8901)
CRP ≥2.0 mg/L
Visit:
Week:
1
–6
2
–4
Lead-in/
eligibility
3
0
4
13
6-monthly
Final
Randomisation
Lipids
CRP
Tolerability
Lipids
CRP
Tolerability
Lipids
CRP
Tolerability
HbA1C
Median follow-up 1.9 years
CAD=coronary artery disease; LDL-C=low-density lipoprotein cholesterol; CRP=C-reactive protein; HbA1c=glycated haemoglobin
Ridker P et al. N Eng J Med 2008;359: 2195-2207
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 - Major inclusion criteria

Men aged ≥50 years; women aged ≥60 years

Fasting LDL-C levels  130 mg/dL (3.4 mmol/L) ,
CRP levels ≥2.0 mg/L and TG levels  500 mg/dL
(5.7 mmol/L) on initial screening
Ridker PM. Circulation 2003; 108: 2292–2297
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
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
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
186 (168-200)
108 (94-119)
49 (40-60)
118 (85-169)
4.2 (2.8-7.1)
94 (87-102)
5.7 (5.4-5.9)
185 (169-199)
108 (94-119)
49 (40-60)
118 (86-169)
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
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
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
1.9
6
1
0
total cholesterol
221
272
183
LDL-C
150
192
104
HDL-C
36–40
44
51
158
164
138
0.2
NA
4.3
Lovastatin
20–40 mg
Pravastatin
40 mg
Rosuvastatin
20 mg
Diabetes, %
Baseline lipids,
mg/dL*
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
0.53
10,208
7,586
0.51
6,041
11,761
0.14
7,375
10,296
0.07
Family history of CHD
Yes
No
2,045
15,684
0.99
Framingham risk score
≤10%
>10%
1.2
12,683
5,117
Metabolic syndrome
Yes
No
1
0.57
Region
US or Canada
Other
0.8
11,001
6,801
Hypertension
Yes
No
0.6
0.80
Race
White
Non-white
Hazard ratio (95% CI)
8,541
9,261
Gender
Males
Females
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
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
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
-50
p<0.001
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
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