A Randomized Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among 17,802 Apparently Healthy Men and Women With Elevated Levels of C-Reactive Protein (hsCRP): The JUPITER Trial Paul Ridker, Eleanor Danielson, Francisco Fonseca, Jacques Genest, Antonio Gotto, John Kastelein, Wolfgang Koenig, Peter Libby, Alberto Lorenzatti, Jean MacFadyen, Borge Nordestgaard, James Shepherd, James Willerson, and Robert Glynn on behalf of the JUPITER Trial Study Group JUPITER Trial Presented during AHA 2008 Scientific Sessions
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A Randomized Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among 17,802 Apparently Healthy Men and Women With Elevated Levels of C-Reactive.
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A Randomized Trial of Rosuvastatin in the Preventionof Cardiovascular Events Among 17,802 Apparently Healthy
Men and Women With Elevated Levels of C-Reactive Protein (hsCRP):
The JUPITER Trial
Paul Ridker, Eleanor Danielson, Francisco Fonseca, Jacques Genest,Antonio Gotto, John Kastelein, Wolfgang Koenig, Peter Libby,
Alberto Lorenzatti, Jean MacFadyen, Borge Nordestgaard, James Shepherd, James Willerson, and Robert Glynn
on behalf of the JUPITER Trial Study Group
JUPITER Trial Presented during AHA 2008 Scientific Sessions
Independent Steering Committee :P Ridker (Chair), F Fonseca, J Genest, A Gotto, J Kastelein, W Koenig, P Libby, A Lorenzatti, B Nordestgaard, J Shepherd, J Willerson
Independent Academic Clinical Coordinating Center: P Ridker, E Danielson, R Glynn, J MacFadyen, S Mora (Boston)
Independent Academic Study Statistician: R Glynn (Boston)
Independent Data Monitoring Board: R Collins (Chair), K Bailey, B Gersh, G Lamas, S Smith, D Vaughan
Independent Academic Clinical Endpoint Committee: K Mahaffey (Chair), P Brown,D Montgomery, M Wilson, F Wood (Durham)
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 in individuals potentially at increased cardiovascular risk due to elevated CRP levels who do not qualify for lipid-lowering treatment according to current guidelines
Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.
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
Adapted from: Ridker PM. Circulation 2003; 108: 2292-97.Ridker PM. Am J Cardiol 2007; 100: 1659-64.Ridker PM. New Engl J Med 2002; 347: 1557-65.Ridker PM. Am J Cardiol 2003;92(suppl):17K-22K.
JUPITER: Background and Prior Work
Current guidelines for the prevention of myocardial infarctionstroke, and cardiovascular death endorse statin therapy among patients with established vascular disease, diabetes, and among those with hyperlidemia.
However, these screening and treatment strategies are insufficient as half of all heart attack and stroke events occur among apparently healthy men and women with average or even low levels of cholesterol.
Adapted from Ridker et al .NEJM 2008.
JUPITER: Background and Prior Work
To improve detection of individuals at increased risk forcardiovascular disease, physicians often measure high sensitivity C-reactive protein (hsCRP), an inflammatory biomarker that reproducibly and independently predicts future vascular events and improves global risk classification, even when cholesterol levels are low.
Prior work has shown that statin therapy reduces hsCRP, and that among stable coronary disease patients as well as those with acute ischemia, the benefit associated with statin therapy relates not only to achieving low levels of LDL, but also to achieving low levels of hsCRP.
Adapted from Ridker et al. NEJM 2008.
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/LAFCAPS/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
Adapted from Ridker et al. N Engl J Med 2001;344:1959-65.
JUPITER population compared with previous trials in patients without established CHD
Adapted from JUPITER Trial Study Group, Am J Cardiol 2007.
Comparison of the JUPITER Trial Population to Previous Statin Trials of Primary Prevention
JUPITER: Why Consider Statins for Low LDL, high hsCRP Patients?
In 2001, in an hypothesis generating analysis of apparently healthy individuals in the AFCAPS / TexCAPS trial*, we observed that those with low levels of both LDL and hsCRP had extremely low vascular event rates and that statin therapy did not reduce events in this subgroup (N=1,448, HR 1.1, 95% CI 0.56-2.08). Thus, a trial of statin therapy in patients with low cholesterol and low hsCRP would not only be infeasible in terms of power and sample size, but would be highly unlikely to show clinical benefit.
In contrast, we also observed within AFCAPS/TexCAPS that among those with low LDL but high hsCRP, vascular event rates were just as high as rates among those with overt hyperlipidemia, and that statin therapy significantly reduced events in this subgroup (N=1,428, HR 0.6, 95% CI 0.34-0.98).
Adapted from *Ridker et al. N Engl J Med 2001;344:1959-65.
JUPITER: Why Consider Statins for Low LDL, High hsCRP Patients?
However, while intriguing and of potential public health importance, the observation in AFCAPS/TexCAPS that statin therapy might be effective among those with elevated hsCRP but low cholesterol was made on a post hoc basis. Thus, a large-scale randomized trial of statin therapy was needed to directly test this hypotheses.
Adapted from Ridker et al. New Engl J Med 2001;344:1959-65.
Low LDL, Low hsCRP
Low LDL, High hsCRP
Statin Effective Statin Not Effective
1.0 2.00.5
[A]
[B]
Low LDL, Low hsCRP
Low LDL, High hsCRP
Statin Effective Statin Not Effective
1.0 2.00.5
AFCAPS/TexCAPS Low LDL Subgroups
RR
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.
Adapted from Ridker et al. Circulation 2003;108:2292-97.
Rosuvastatin 20 mg (N=8901) MIMIStrokeStroke
UnstableUnstable AnginaAngina
CVD DeathCVD DeathCABG/PTCACABG/PTCA
JUPITERMulti-National Randomized Double Blind Placebo Controlled Trial of
Rosuvastatin in the Prevention of Cardiovascular EventsAmong Individuals With Low LDL and Elevated hsCRP
4-week 4-week run-inrun-in
Adapted from Ridker et al. Circulation 2003;108:2292-97.
No Prior CVD or DMMen >50, Women >60 LDL <130 mg/dL hsCRP >2 mg/L
JUPITER: Trial Design
Placebo (N=8901)
Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica, Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands, Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.
JUPITER: Inclusion and Exclusion Criteria, Study Flow
89,863 Screened
17,802 Randomized
8,901 Assigned to Rosuvastatin 20 mg
8,901 Assigned toPlacebo
Reason for Exclusion (%)
LDL-C > 130 mg/dL 53hsCRP < 2.0 mg/L 37Withdrew Consent 4Diabetes 1Hypothyroid <1Liver Disease <1TG > 500 mg/dL <1Age out of range <1Current Use of HRT <1Cancer <1Poor Compliance/Other 3
8,600 Completed Study120 Lost to follow-up
8,600 Completed Study120 Lost to follow-up
8,901 Included in Efficacy and Safety Analyses
8,901 Included in Efficacy and Safety Analyses
89,890 Screened
Men > 50 yearsWomen > 60 yearsNo CVD, No DMLDL < 130 mg/dLhsCRP > 2 mg/L
17,802 Randomized
Reason for Exclusion (%)
LDL > 130 mg/dL 52hsCRP < 2.0 mg/L 36Withdrew Consent 5Diabetes 1Hypothyroid <1Liver Disease <1TG > 500 mg/dL <1Age out of range <1Current Use of HRT <1Cancer <1Poor Compliance/Other 3
4 weekPlaceboRun-In
8,857 Completed Study44 Lost to follow-up
8,901 Assigned to Rosuvastatin 20 mg
8,901 Assigned toPlacebo
8,864 Completed Study37 Lost to follow-up
8,901 Included in Efficacy and Safety Analyses
8,901 Included in Efficacy and Safety Analyses
Adapted from Ridker et al. NEJM 2008.
JUPITER - Major Exclusion Criteria
Current use of statins or other lipid-lowering therapies
Current use of post menopausal hormone replacement therapy
Prior history of cardiovascular or cerebrovaascular 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
For hsCRP, values are the average of the values obtained at two screening visits*All values are median (interquartile range) or N (%).
Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.
Current smoker (%) 15.7 16.0
Family history CHD† (%) 11.2 11.8Metabolic syndrome‡ (%) 41.0 41.8Aspirin use (%) 16.6 16.6
Medical History Rosuvastatin Placebo n=8901 n=8901
JUPITER - Medical History
†Family history of premature coronary heart disease (CHD) defined as first degree relative with CHD at age < 55 yrs (male), < 65 yrs (female); ‡ Metabolic syndrome defined according to consensus criteria of American Heart Association and the National Heart, Lung, and Blood Institute
Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.
JUPITER - Study End Points
Primary End Point– Time to the first occurrence of a major cardiovascular event, composite of:
Secondary End Points:– total mortality– non-cardiovascular mortality– development of diabetes mellitus– development of venous thromboembolic events – bone fractures– discontinuation of study medication due to adverse effects.
Adapted from Ridker et al. Circulation 2003;108:2292-97.
JUPITER: Primary Objectives
To investigate whether rosuvastatin 20 mg compared to placebo would decrease the rate of first major cardiovascular events among apparently healthy men and women with LDL < 130 mg/dL (3.36 mmol/L) who are nonetheless at increased vascular risk on the basis of an enhanced inflammatory response, as determined by hsCRP > 2 mg/L.
To enroll large numbers of women and individuals of Black or Hispanic ethnicity, groups for whom little data on primary prevention with statin therapy exists.
Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin
Adapted from Ridker et al. NEJM 2008.
hsC
RP
(m
g/L
)L
DL
(m
g/d
L)
Months0 12 24 36 48
TG
(m
g/d
L)
HD
L (
mg
/dL
)
Months
JUPITER: Effects 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
Adapted from Ridker et al. NEJM 2008.
JUPITER: Adverse Events and Measured Safety Parameters
GFR = Glomerular filtration rate, HbA1c = Haemoglobin A1c; IQR = interquartile range
‡ >100% increase from baseline;# on consecutive visits; † >trace at 12 months; *at 12 months, **at 24 months
Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.
JUPITER: Conclusions – Efficacy I
Among apparently healthy men and women with elevatedhsCRP but low LDL, rosuvastatin reduced by 47 percent incident myocardial infarction, stroke, and cardiovascular death.
Despite evaluating a population with lipid levels widely considered to be “optimal” in almost all current prevention algorithms, the relative benefit observed in JUPITER was greater than in almost all prior statin trials.
In this trial of low LDL/high hsCRP individuals who do notcurrently qualify for statin therapy, rosuvastatin significantlyreduced all-cause mortality by 20 percent.
Adapted from Ridker et al. NEJM 2008.
JUPITER: Conclusions – Efficacy II
Benefits of rosuvastatin were consistent in all sub-groups evaluated regardless of age, sex, ethnicity, or other baseline clinical characteristic, including those with elevated hsCRP and no other major risk factor.
Rates of hospitalization and revascularization were reducedby 47 percent within a two-year period suggesting that the screening and treatment strategy tested in JUPITER is likely to be cost-effective, benefiting both patients and payers.
The Number Needed to Treat in JUPITER was 25 for the primary endpoint, a value if anything smaller than that associated with treating hyperlipidemia in primary prevention.
Adapted from Ridker et al. NEJM 2008.
JUPITER: Conclusions - Safety
With regard to safety , the JUPITER results show no increase in serious adverse events among thoseallocated to rosuvastatin 20 mg as compared to placeboin a setting where half of the treated patients achievedlevels of LDL< 55 mg/dL (and 25 percent had LDL < 44mg/dL).
show no increase in myopathy, cancer, hepaticdisorders, renal disorders, or hemorrhagic stroke with treatment duration of up to 5 years.
show no increase in systematically monitored glucose orglucosuria during follow-up, but small increases inHbA1c and physician reported diabetes similar to thatseen in other major statin trials.
Adapted from Ridker et al. NEJM 2008.
JUPITER – Summary
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.
Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.
JUPITER: Public Health Implications
Application of the simple screening and treatment strategy tested in the JUPITER trial over a five-year period could conservatively prevent more than 250,000 heart attacks, strokes, revascularization procedures, and cardiovascular deaths in the United States alone.
We thank the 17,802 patients and the >1,000 investigatorsworldwide for their personal time, effort, and commitmentto the JUPITER trial.
www.brighamandwomens.org/jupitertrial
Adapted from Ridker et al. NEJM 2008.
JUPITER: Implications for Primary Prevention
Among men and women age 50 or over :
If diabetic, treatIf LDLC > 160 mg/dL, treat
If hsCRP > 2 mg/L, treat
A simple evidence based approach to statin therapyfor primary prevention.
Adapted from Ridker et al. NEJM 2008.
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
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