This week online in the NEJM, the results of a trial known as Jupiter were presented in an article that will likely change the way we approach cardiovascular health protection. The Jupiter trial attempts to answer this perturbing question: “Why do half of all myocardial infarctions and strokes occur in apparently healthy men and women with levels of LDL that are below currently recommended thresholds of treatment?” The study addresses the biomarker C-reactive protein, an inflammatory marker that has long been linked to an increased risk of adverse cardiovascular events. While cholesterol has been a target for decreasing cardiovascular risk, physicians have known less what to do about elevated CRPs, using it more as a harbinger of trouble, than as an indication for action. Statins have been previously shown to decrease levels of CRP as well as lipids, and the magnitude of the benefit of statin therapy is known to be in part due to its lowering of CRP. However, while we have guidelines for lowering cholesterol, lowering CRP alone has not been a target of therapy. The study, sponsored by AstroZeneca, thus took individuals who did not have elevated LDL by current treatment guidelines, but did have elevated CRP, treated them with a statin, and then monitored them for cardiovascular events.
More specifically, 17,802 patients with low LDL levels <130mg/deciliter and high sensitivity C-reactive proteins 2.0 mg/liter or higher, were randomized to receive either 20 mg of rosuvastatin daily or placebo. Men above the age of 50 and women above the age of 60 with these criteria were eligible. Patients with a history of cardiovascular disease were excluded. Also excluded were patients on hormonal therapy, with evidence of liver disease, with an elevated CK or elevated Cr (Cr>2), patients with diabetes, uncontrolled hypertension, cancer (other than basal or squamous skin cancer) within 5 years of enrollment, uncontrolled hypothyroidism, recent drug or alcohol history, or any patients with inflammatory conditions, such as lupus, severe arthritis, or inflammatory bowel disease as well as anyone taking immunosuppressive medications or long term glucocorticoids.
The study results were impressive. Although the study was designed to be continued for 5 years or until a primary cardiac event; namely myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes; when a prespecified interim efficacy analysis was performed after less than 2 years, the trial was terminated given the markedly beneficial results of the statin.
After 1 year of therapy, as compared with the placebo group, the rosuvastatin group had a 50% lower average LDL and a 37% lower CRP level. At the time of the termination of the study, 142 first major cardiovascular events had occurred in the rosuvastatin group as compared with 251 in the placebo group. Rosuvastatin also decreased the number of deaths from any cause (hazard ratio for the rosuvastatin group, 0.80; 95% CI, 0.67 to 0.97; P=0.02) With Kaplan-Meir estimates, the number of patients needed to treat with rosuvastatin for 2 years in order to prevent one primary endpoint is 95, and if the risk is projected over a 5 year period, the number needed to treat to prevent the occurrence of one primary endpoint, is 25.
Given that few adverse events occurred with the rosuvastatin group (increased physician-reported diabetes was reported in the rosuvastatin group; although there were no significant elevations of fasting blood glucose and only minimal differences in HgA1c), this could significantly impact how we risk stratify patients and subsequently initiate treatment with statins for cardiovascular prevention.
Some questions remain to be addressed. Does this study mean we should test for CRP levels in all patients, even those who have no other cardiovascular risk? Should the test only be initiated in individuals above the age criteria in this trial (men >50, women>60)? And given that cardiovascular disease is such a multifactorial illness (obesity, HTN, smoking, cholesterol, all play a part), how does CRP, when looked at alone without the other risk factors, fit in? Also, the study, in addition to cutting CRP levels, also cut down LDL from low levels to even lower levels—perhaps that effect is greater than the effect of the lower CRP? And lastly, perhaps this study paved the way for looking more at the inflammatory nature of heart disease, and potentially the benefit of other anti-inflammatory medications on lowering heart disease.