Transcript Impact of Platelet Reactivity After Clopidogrel

Rosuvastatin to Prevent Vascular Events in Men and Women
with Elevated C-Reactive Protein
Paul M Ridker, M.D., Eleanor Danielson, M.I.A., Francisco A.H. Fonseca, M.D.,
et al. for the JUPITER Study Group
(Justification for the Use of Statins in Primary Prevention: an Interventional Trial
Evaluating Rosuvastatin)
The New England Journal of Medicine
November 20th, 2008
Journal Club
Tatyana Danilov
November 21st, 2008
C-Reactive Protein
CRP and Cardiovascular Risk
• Several large prospective epidemiological studies have shown
that hs-CRP is a strong and independent predictor of
cardiovascular disease
– Incidence of first cardiovascular event
– Long term risk of MI
– Recurrence of vascular events
– Ischemic stroke, PVD, sudden death, all cause mortality
• CRP correlates with traditional risk factors
– Correlation persists after adjustment for traditional risk
factors
– Highest CRP in patients with increased number of risk
factors
Screening CRP
• Hs-CRP levels
– <1 mg/liter low risk
– 1 to 3 mg/liter intermediate risk
– >3 mg/liter high risk
– >10 search for other inflammatory source
• Two values measured 2 weeks apart
• Recommended for intermediate risk patients if the
result will change management
• Universal screening currently not recommended
Statins and CRP
• Statin therapy lowers CRP levels by 15-50%
• Intensive statin therapy associated with greater reduction
• Decrease in CRP independent of LDL reduction
– Reduction in IL-6, TNF
– Direct gene suppression
• PROVE IT-TIMI 22
– Levels of hsCRP <2 mg/liter was as important for long-term
event-free survival as was achieving levels of LDL
cholesterol <70 mg/dl
– Best long-term outcomes were found in those who achieved
both these goals
AFCAPS/TexCAPS
Hypothesis/Objective
• Healthy individuals with low-normal LDL levels and
elevated CRP levels may benefit from statin therapy
• To investigate the effect of treatment with Rosuvastatin 20
mg vs. Placebo on the rate of first cardiovascular events
Methods
• Randomized, double-blind, placebo controlled,
multicenter trial
• 1315 sites, 26 countries
• Financially supported by Astra-Zeneca
(collected the trial data and monitored the study
sites but played no role in the analysis of data)
Study Population
Men 50 or older and women 60 or older without a
history of cardiovascular disease
AND
At initial screening LDL cholesterol < 130 mg per
deciliter (3.4 mmol per liter)
AND
high-sensitivity C-reactive protein level of ≥ 2.0
mg per liter.
Exclusion Criteria
•
•
•
•
•
•
•
•
•
•
previous or current use of lipid-lowering therapy
current use of postmenopausal HRT
hepatic dysfunction (ALT > 2x ULN), CK > 3x ULN
Cr >2
Diabetes
Uncontrolled hypertension (>190 /100 mm Hg),
Cancer within 5 years
Uncontrolled hypothyroidism (TSH > 1.5 x ULN)
Recent history of alcohol or drug abuse
Patients with inflammatory conditions such as severe arthritis,
lupus, or inflammatory bowel disease
• Patients taking immunosuppressant agents (cyclosporine,
tacrolimus, azathioprine, or glucocorticoids)
Methods
• 4-week run-in phase during which all participants
received placebo
• Subjects randomly assigned in a 1:1 ratio to
rosuvastatin, 20 mg daily or placebo
• Follow-up visits scheduled at 13 weeks, then 6
months, then every 6 months until 60 months
End Points
• Primary outcome was the occurrence of a first
major cardiovascular event
–
–
–
–
–
Nonfatal myocardial infarction
Nonfatal stroke
Hospitalization for unstable angina
Arterial revascularization procedure
Confirmed death from cardiovascular causes
• Secondary end point: death from any cause
Statistical Analysis
• Event-driven trial
• Statistical power of 90% to detect a 25% reduction in the rate of the
primary end point
• Two-sided significance level of 0.05
• All primary analyses were performed on an intention-to-treat basis
• Cox proportional-hazards models were used to calculate hazard ratios
and 95% C.I. for the comparison of event rates in the two groups
• March 29, 2008, the independent data and safety monitoring board
voted to terminate the trial – the stopping boundary was crossed at the
first prespecified efficacy evaluation
• Adverse-event reporting in a blinded manner continued until each
participant had a formal closeout visit and discontinued therapy.
Results
• 89,890 people were screened for enrollment between
February 4th, 2003 to December 15th, 2006.
• 72,088 were ineligible
– 37,611 (52.2%) with LDL cholesterol levels ≥130
mg per deciliter
– 25,993 (36.1%) with high-sensitivity C-reactive
protein level less than 2.0 mg per liter.
• A total of 17,802 people were randomly assigned to a
study group
Table 1. Baseline Characteristics of the Trial Participants,
According to Study Group
Table 1. Baseline Characteristics Cont.
Hs-CRP Levels during Follow-up
End Points
v
Kaplan–Meier Estimates
NNT to prevent one primary outcome based on treatment with
Rosuvastatin for 2 years is 95
NNT for 4 years is 31
NNT projected to 5 years is 25
Subgroup Analysis
Adverse Events
Number
Needed to
Harm 166
Strengths
• Large randomized double bind controlled trial –
over 17 thousand patients
• Diverse study population
• Hard end points
Limitations
• Early termination of study at less than 2 years
– Safety of very low LDL
– Safety of long term statin use
• No subgroup analysis by CRP level
– Do patients with a higher CRP account for most of
the benefit?
• Does not answer the question if CRP should be used as
a general screening test for CAD
– Did not compare patients with and without CRP
measurements
A few weeks prior…New England Journal
Article
• A study of people with genetic variants of CRP assessed the effects of
lifelong, persistently elevated CRP on ischemic vascular disease
independent of other risk factors
• CRP polymorphisms with high CRP levels were NOT associated with
an increase in ischemic heart disease or cerebrovascular disease
• Suggests that the increased risk of elevated CRP levels may not be
causal but rather a marker of underlying atherosclerosis
Implications/Discussion
• Who should be screened for elevated CRP levels?
– Baseline level on all healthy patients along with
baseline cholesterol
– vs. continue to restrict to intermediate risk
population
– How often to repeat testing?
– Will you change your practice based on this trial?
• Earlier initiation of statin therapy
• Lifestyle modification
• Generally healthy study population
– Absolute risk reduction is small 1.8% 0.9%
– Large NNT
– Cost effectiveness
Future…
• Long term complications/side effects of prolonged high dose
statin therapy
• CRP targets for therapy
• Better mechanistic understanding of CRP and vascular disease
• Direct CRP inhibitors
• Further studies are needed to identify novel vascular inflammatory
markers and treatments