CRP Screening, and Aggressive Statin Therapy-implications for the Primary Prevention of Cardiovascular Disease

From Therapeutic Advances in Cardiovascular Disease
The Jupiter Study,
Richard Kones

Abstract
CRP levels are strong, independent predictors of cardiovascular risk and can enhance risk stratification.
Jupiter enrolled 17 802 apparently healthy middle-aged men and women with CRP levels over 2.0 mg/l, and LDL less than 130 mg/dl.
They were randomized to receive rosuvastatin 20mg daily or placebo, and followed for a primary endpoint of nonfatal myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or cardiovascular death for 1.9 years.
Rosuvastatin lowered CRP (37%), LDL (50%), nonfatal myocardial infarction (55%), nonfatal stroke (48%), hospitalization and revascularization (47%), all-cause mortality (20%), and benefited women and minority subgroups. Rosuvastatin was tolerated relatively well, with a small rise in physician-reported diabetes.

Jupiter data suggest that patients with high levels of CRP should receive statins. Approximately 4.3% of the population satisfies Jupiter inclusion criteria. A review of the assessment of cardiovascular risk is under way at the National Institutes of Health to guide practitioners.

Introduction
Controversy about the clinical role of inflammatory biomarkers has heightened over the past decade [Ware, 2008; Wang et al. 2006; Greenland et al. 2001; Koenig, 2001; Rifai and Ridker, 2001; Kannel et al. 1961].
In addition, there has been growing concern about the shortcomings of current risk assessment point scores designed to stratify cardiovascular risk [Wilson, 2008; Ridker et al. 2004; Pearson et al. 2003].
C-reactive protein is an inflammatory marker which has been proposed for inclusion in risk factor assessment grids [Everett and Ridker, 2008; Capuzzi and Freeman, 2007; Ridker, 2001], and new data about its value now appear compelling.

The plenary session of the American Heart Association Annual Scientific Session last year began with a landmark report, The JUPITER Trial—Rosuvastatin in the Prevention of Cardiovascular Events Among 17 802 Men and Women with Elevated Levels of C-Reactive Protein, showing a surprisingly high reduction in cardiovascular events among healthy individuals with elevated C-reactive protein (CRP) as a result of rosuvastatin therapy.
The study, simultaneously published online in the New England Journal of Medicine [Ridker et al. 2008a], generated data which were remarkable in several ways, and will surely impact both the thinking and practice of primary prevention.
The characteristics of the Jupiter study, an acronym for Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin, have been previously described [Ridker et al. 2007a; Ridker, 2003]. Debate about Jupiter and its implications has continued unabated through 2009 as well, which only attests to its potential significance.

Jupiter enrolled 17 802 apparently healthy middle-aged men (≥50 years) and women (≥60 years) from 1315 sites in 26 countries.
Patients were free of diabetes and heart disease, with normal low-density lipoprotein levels (LDL < 130 mg/dl), but high hs-C reactive protein (CRP) levels (≥2.0 mg/l, median, 4.2 mg/l).
Participants were randomly assigned into two groups: either treated with rosuvastatin, 20mg daily, or placebo. Salient baseline patient data are summarized in Table 1. Enrollees were followed for a primary composite end point of myocardial infarction, hospitalization for unstable angina, heart-related death, arterial revascularization or stroke. Although planned as a 4-year study, the trial was stopped after a median follow-up time of 1.9 years based upon advice from an independent monitoring board and study steering committee.

Rosuvastatin lowered CRP levels by 37% (down to a 12-month mean, in the treated group, of 2.2; lowered LDL by 50% (down to a 12-month mean, in the treated group, of 55) and sharply decreased the number of cardiovascular events and all-cause mortality.
At the end of 1.9 years, rosuvastatin therapy significantly lowered the primary composite end point by 44% compared with placebo.
In particular, there was a 55% lowering of nonfatal MI, 48% fall in the risk of non-fatal stroke, and a 47% fall in the risk of serious cardiac events (Table 2).
The reduction in vascular risk was greater in Jupiter than in previous statin trials.

The number of physician-reported new cases of diabetes was 270 in the rosuvastatin group and 216 in the untreated group, with a small rise in median glycosylated hemoglobin (A1c), previously noted in statin studies. Ten instances of myopathy, and one case of rhabdomyolysis were reported in the treatment group, with nine and none, respectively, in the untreated group.
At the end of the trial, 75% of participants were taking rosuvastatin. The number needed to treat for 2 years to prevent one primary event was 95; treatment for 4 years lowered it to 31, and for 5 years, the number to treat fell to 25.