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Predicting the potential effect of the JUPITER trial
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Cardiovascular disease remains the major cause of morbidity and mortality in the United States.
Estimates suggest 770,000 new cases of MI with an additional 175,000 silent MI’s are expected in 2008. By 50 years of age, most U.S. adults have significant coronary atherosclerosis. This atherosclerotic process remains silent for decades until it finally presents with plaque rupture and thrombosis.
An analysis of the 26-year Framingham Heart Study follow-up data showed that only 50% of individuals who develop CAD are identified using total cholesterol levels alone. Consequently, 80% of individuals who have an MI have similar cholesterol levels to those who did not have an MI, and the median LDL level in CAD is near the median level in the United States (150 mg/dL).
In spite of data from studies such as WOSCOPS, ASCOT-LLA and AFCAPS-TEXCAPS, the use of statins for primary prevention has not been adequately practiced. This is probably a reflection that more thoughtful screening methods are needed in primary prevention. There is also a wide range of opinion as to the role of inflammation in the genesis of acute or chronic ischemic events with even greater differences on the importance of pleiotropic effects of statins in asserting their beneficial effects.
Lipids play an important role in this process but they are also a substrate for a subsequent modification process. In the “view from the blood vessel wall,� atherogenesis is not just a passive process of lipid deposition but is actually a specific type of a systemic chronic inflammation in which acute changes can have important consequences.
There has been increasing evidence that the use of inflammatory markers can improve the identification of patients at increased risk for ischemic events. In particular, the acute-phase reactant high sensitivity C-reactive protein has been demonstrated in several large trials to predict future vascular events and to offer additional prognostic information at all levels of LDL and Framingham Risk Scores. However, most cogent to the upcoming JUPITER study results was the demonstration in the Nurses’ Health Study that apparently healthy subjects with low levels of LDL but high levels of hsCRP were at higher risk for vascular events than those with normal hsCRP with high LDL levels.
Several studies with statin drugs have also suggested that elevated levels of hsCRP identify patients who may benefit from therapy more than those with evidence for lower degrees of inflammation. Notable in this group is AFCAPS/TEXCAPS, a randomized, placebo-controlled, double-blind trial of lovastatin in 5,740 U.S. men and women with average levels of cholesterol and below average HDL levels without evidence for underlying CVD. Treatment with lovastatin resulted in a 37% reduction in the risk of the first acute coronary event. In a post-hoc analysis, event rates increased with higher levels of baseline hsCRP and that this relationship was independent of risk factors, such as the Framingham Risk Score. In addition, lovastatin significantly decreased hsCRP levels by 15% in a manner that was independent of its effect on lipids.
In the last few years, several other inflammatory markers have emerged. Recently, Lipoprotein-associated Phospholipase-A2 (Lp-PLA2) has been proposed as a novel biomarker for the presence of, or impending formation of, rupture-prone plaque. This hypothesis is now supported by 25 prospective epidemiologic studies. In addition, histopathologic staining has shown intense Lp-PLA2 staining in late stage, rupture prone but not early stable plaques. It has now established that lifestyle modification, including exercise, can lower Lp-PLA2 and that combination therapy with lipid lowering agents can be even more effective than statins alone in lowering Lp-PLA2.
Can JUPITER help?
The primary objective of the JUPITER trial is to determine whether long-term treatment with rosuvastatin (20 mg orally per day) would reduce the rate of first major CV events (defined as the composite end point of CV death, stroke, MI, hospitalization for unstable angina, or arterial revascularization) in apparently healthy men and women with LDL levels of <130 mg/dL and hsCRP levels of >2 mg/L.
The exclusion criteria list was quite extensive, as all chronic inflammatory conditions needed to be excluded to avoid interpolation with low-grade inflammation related to atherosclerosis. Hence, people who had received lipid-lowering treatment or at the time were receiving lipid-lowering treatment could not be enrolled. The study also excluded people with a history of diabetes, uncontrolled hypertension, uncontrolled hypothyroidism (thyroid stimulating hormone greater than 1.5 times the upper normal limit), malignancy within the past five years (with the exception of skin basal cell or squamous cell carcinoma), chronic inflammatory condition (severe arthritis, lupus or inflammatory bowel disease), or those taking immunosuppressant medications or chronic oral glucocorticoids or postmenopausal hormone replacement therapy. Other conventional exclusion criteria were based on abnormal liver and renal function.
The mean LDL level in the randomized cohort was 108 mg/dL. The median hs-CRP level was 4.3 mg/L in the randomized cohort. The randomized cohort had a median age of 66, median BMI of 28.4 kg/m2, and median BP of 134 mm Hg/80 mm Hg. Sixteen percent of the population reported being current smokers, and 12% had a positive family history of CHD. The median triglyceride level in the randomized cohort was 118 (85 to 169) mg/dL, and median HDL level was 49 (40 to 60) mg/dL. The median glucose level was 94 (88 to 102) mg/dL and 32% of randomized individuals had metabolic syndrome. Of note, about 15% of study participants were taking aspirin. In JUPITER, 38% of participants were women along with significant numbers of black and Hispanic participants.
Based on the above we can say that JUPITER is unique because it will provide better understanding of the role of inflammation in CVD, and the effectiveness of statin use in primary prevention in a diverse group of patients with an elevated inflammatory response but normal LDL values. It will also address safety issues of getting LDL levels <50 for a good number of patients.
On March 31, 2008 Astra Zeneca announced that the JUPITER trial was stopped early based on recommendation from the Independent Data Monitoring Board and the Jupiter Steering Committee. The recommendation to stop the trial was based on clear and unequivocal evidence of a reduction in CV morbidity and mortality among patients treated with rosuvastatin compared with placebo.
There is little doubt that the results of this study will have significant impact on the screening and treatment of patients who were presumed to be at low risk on the basis of low levels of LDL. The use of inflammatory marker screening to better delineate those at increased risk has already become more widespread and will likely increase further. There has also been an explosion in imaging procedures to better identify atherosclerotic plaque burden in carotid and coronary arteries. The quest for the best method to screen those at risk for their first CV event will be strengthened by this study, but in no way should this be considered the last word or a mandate in all patients.
The ultimate utility of hsCRP may be reflected in the extensive exclusion list that allowed the biomarker to have specificity. Of note, a post-hoc analysis of WOSCOPS found that utilizing both hsCRP and Lp-PLA2 offered much greater diagnostic accuracy than either alone. The strength of the data and the magnitude of benefit in preventing first major CV events will certainly influence our decisions. In addition, they may offer motivation for the clinician to choose rosuvastatin over generic statins that are not as potent in lowering LDL, triglycerides or inflammatory markers and have not been shown to influence HDL as much.
Hence, once all the data is available we may find that this study will force us to continue to look at and then beyond traditional risk factors when we practice primary prevention of CVD and look to intervene in a timely fashion.
Howard Weintraub, MD, is Clinical Associate Professor of Medicine, New York University School of Medicine. Clinical Director, Center for the Prevention of CVD, New York University Medical Center.
Dimitri Gagarin, MD, is from the Department of Medicine, Harbor Hospital; Baltimore.