Article details
Evidence-Based Medicine Journal Club
Edited by Eric B Milbrandt. University of Pittsburgh Department of Critical Care Medicine
Expanded Abstract
Citation
Ridker PM, Danielson E, Fonseca FAH, Genest J, Gotto AM, Kastelein JJP, Koenig W,
Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn
RJ: Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive
Protein. NEJM 2008, 359: 2195-2207 [1].
Background
Increased levels of the inflammatory biomarker high-sensitivity C-reactive protein
predict cardiovascular events. Since statins lower levels of high-sensitivity C-reactive
protein as well as cholesterol, we hypothesized that people with elevated high-sensitivity
C-reactive protein levels but without hyperlipidemia might benefit from statin treatment.
Methods
Objective
To investigate whether treatment with rosuvastatin, 20 mg daily, as compared to placebo,
would decrease the rate of first major cardiovascular events.
Design
Randomized, double-blind, placebo-controlled, multicenter trial.
Setting
1315 sites in 26 countries.
Subjects
17,802 apparently healthy men and women with low-density lipoprotein (LDL) cholesterol
levels of less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity
C-reactive protein levels of 2.0 mg per liter or higher.
Intervention
Subjects were randomly assigned to rosuvastatin, 20 mg daily, or placebo.
Outcomes
The primary outcome was the occurrence of a first major cardiovascular event, defined
as myocardial infarction, stroke, arterial revascularization, hospitalization for
unstable angina, or death from cardiovascular causes. Secondary endpoints included
the components of the primary end point considered individually as well as death from
any cause.
Results
The trial was stopped after a median follow-up of 1.9 years (maximum, 5.0). Rosuvastatin
reduced LDL cholesterol levels by 50% and high-sensitivity C-reactive protein levels
by 37%. The rates of the primary end point were 0.77 and 1.36 per 100 person-years
of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for
rosuvastatin, 0.56; 95% confidence interval [CI], 0.46 to 0.69; P < 0.00001), with
corresponding rates of 0.17 and 0.37 for myocardial infarction (hazard ratio, 0.46;
95% CI, 0.30 to 0.70; P = 0.0002), 0.18 and 0.34 for stroke (hazard ratio, 0.52; 95%
CI, 0.34 to 0.79; P = 0.002), 0.41 and 0.77 for revascularization or unstable angina
(hazard ratio, 0.53; 95% CI, 0.40 to 0.70; P < 0.00001), 0.45 and 0.85 for the combined
end point of myocardial infarction, stroke, or death from cardiovascular causes (hazard
ratio, 0.53; 95% CI, 0.40 to 0.69; P < 0.00001), and 1.00 and 1.25 for death from
any cause (hazard ratio, 0.80; 95% CI, 0.67 to 0.97; P = 0.02). Consistent effects
were observed in all subgroups evaluated. The rosuvastatin group did not have a significant
increase in myopathy or cancer but did have a higher incidence of physician-reported
diabetes.
Conclusions
In this trial of apparently healthy persons without hyperlipidemia but with elevated
high-sensitivity C-reactive protein levels, rosuvastatin significantly reduced the
incidence of major cardiovascular events. (ClinicalTrials.gov number, NCT00239681.)
Commentary
It is well known that statins reduce the risk of myocardial infarction, stroke, and
death from cardiovascular events in patients with established vascular disease and
in those with risk factors, such as diabetes or hyperlipidemia. Yet, half of all myocardial
infarctions and strokes occur among otherwise healthy men and women without known
vascular disease or risk factors [1]. Inflammation is thought to play a central role
in the development and progression of vascular disease. In addition to their lipid-lowering
effects, statins have anti-inflammatory properties, reducing levels of high-sensitivity
C-reactive protein (hsCRP), an acute-phase protein found in the blood that rises in
response to inflammation. HsCRP level is a stronger predictor of cardiovascular events
than the LDL cholesterol level and that it adds prognostic information to that conveyed
by the Framingham risk score [2]. What is not known, however, is whether statins might
also benefit patients with evidence of inflammation but without vascular disease or
hyperlipidemia.
The Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating
Rosuvastatin (JUPITER) trial was designed to look at the effects of rosuvastatin in
healthy patients with elevated hsCRP levels but without hyperlipidemia [1]. It was
conducted in 1315 sites in 26 countries and financially supported by AstraZeneca,
the makers of rosuvastatin. Between 2003 and 2006, over 17,000 subjects were enrolled
with a mean follow-up time of 1.9 years. As expected, treatment with rosuvastatin
reduced LDL and hsCRP levels significantly. Rosuvastatin reduced the primary endpoint
of a first major cardiovascular event (absolute risk 1.6% vs. 2.8%, hazard ratio 0.56,
p < 0.00001) as well as all secondary endpoints with the exception of hospitalization
for unstable angina. The number needed to treat to prevent the occurrence of one primary
endpoint in 2 years was 95, dropping to 31 for 4 years, and 25 for 5 years of therapy.
Results of the study were consistent across clinically important subgroups. Total
adverse events did not differ between groups. Muscle weakness, stiffness, or pain
was fairly common but did not differ between groups (16.0% vs. 15.4%, rosuvastatin
vs. placebo, p = 0.34). Myopathy was uncommon (< 0.1%) and only a single case of rhabdomyolysis
occurred, this in a 90-year old subject with influenza, pneumonia, and trauma-induced
myopathy. Interestingly, physician-reported diabetes was more frequent in the rosuvastatin
group.
This was a very large, well-conducted study using clinically meaningful endpoints
which may expand the use of statins for primary prevention to new patient populations.
A few limitations deserve mention. At baseline characteristics, patients were not
entirely free of risk prior to randomization. Patients were overweight (median body-mass
index 28) and over 40% had features of the metabolic syndrome. Furthermore, 16% were
current smokers and 11% had a family history of premature coronary heart disease.
Even so, prevalence of these risk factors actually increases the generalizability
of this study, given their frequency in Western societies. The study did not include
people with low levels of hsCRP and therefore does not address the use of statins
in patients without evidence of inflammation. However, as the authors note their prior
work showed extremely low event rates and no evidence that statin therapy lowered
vascular risk among healthy subjects with neither hyperlipidemia nor elevated hsCRP
levels [3].
Statins, like many preventative measures, must be taken for years before yielding
a benefit. If guidelines were expanded to address C-reactive protein, it is estimated
that an additional 6 to 8 million adults in the United States would have a statin
indication based on JUPITER inclusion criteria [4]. Though not without cost, statin
therapy is this patient population would be cost-effective, with a cost per quality
adjusted life-year (QALY) of $40,457, well below the traditional cutoff of $50,000
per QALY [4].
Other than general medical interest, one might ask why this study would appeal to
the intensivist. The anti-inflammatory and anti-thrombotic properties of statins have
prompted speculation that they may be useful in the treatment or prevention of severe
sepsis [5], a syndrome characterized by dysregulation of inflammation, coagulation,
and other acute phase responses. In murine models of sepsis, statins improve survival
[6-8]. A variety of observational studies in humans have examined the role of statins
in the prevention or treatment of infection and sepsis, as recently reviewed [9].
Most suggest a clinical benefit for statins, yet others show no benefit, and one shows
possible harm. Based on these findings, several randomized trials of statins in infection
are either planned, underway, or recently completed [10-21]. Unfortunately, these
are small studies that are underpowered to address mortality or other clinically meaningful
endpoints, with their primary endpoints focusing on inflammatory cytokines and markers
of endothelial function. In addition to their potential before or during severe infection,
one study highlights the potential for statins after infection. In subjects who survived
an initial hospitalization for community-acquired pneumonia, circulating IL-6 concentrations
at hospital discharge were higher among subjects who subsequently died of cardiovascular
diseases [22], raising the possibility of statin use to mitigate the effects of ongoing
subclinical inflammation after hospitalization for infection.
Recommendation
Statins reduced risk of first major cardiovascular event in healthy subjects with
elevated hsCRP but without hyperlipidemia. Furthermore, their use appears to be cost-effective
from a societal perspective. Even so, society may wish to focus on aggressive reduction
of traditional risk factors (obesity, hypertension, diabetes) before broadly increasing
statin use. Though the results of statin trials in infection and severe sepsis are
anxiously anticipated, larger studies will be needed before statins are routinely
recommend in the management of severe infections.
Competing interests
The authors declare that they have no competing interests.