To date, efforts toward primary prevention of cardiovascular disease (CVD) have been focused on identifying patients who have a high estimated short-term risk. According to Donald M. Lloyd-Jones, MD, Feinberg School of Medicine, Northwestern University, Chicago, IL, “Focusing solely on short-term risk does not adequately address younger and middle-aged individuals with moderate risk factor levels who may have low short-term but substantial lifetime risks for development of CVD” [Lloyd-Jones DM et al. Circulation 2006].

To assist clinicians in determining how best to treat these patients, Dr. Lloyd-Jones and others have proposed the use of lifetime risk estimates as an adjunct to the standard 10-year risk estimates (Table 1). Lifetime risk is the absolute cumulative risk of an individual developing a given disease before death. It accounts for the risk of development of the disease of interest, remaining life expectancy, and competing causes of death. “Such an approach reflects real-life risks better than Kaplan-Meier cumulative incidence,” said Dr. Lloyd-Jones.

In addition to identifying younger individuals who have low short-term but high lifetime risk, lifetime risk estimates can support a strategy to improve communication about CVD risk, raise disease awareness, and motivate lifestyle changes and adherence to therapy, similar to the way that dissemination of lifetime estimates of developing breast cancer was associated with an increase in breast cancer screening [National Center for Health Statistics 1996].

There is adequate clinical evidence for the efficacy of statins in a variety of populations. They have been shown to provide significant benefit in individuals who have high cholesterol [Shepard J et al. N Engl J Med 1995], as well as those who have average low-density lipoprotein (LDL) cholesterol levels [Downs JR et al. JAMA 1998]. Subgroup analyses of data from the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TEXCAPS) showed that individuals with metabolic syndrome and those who have lower high-density lipoprotein (HDL) cholesterol levels seem to have the greatest relative risk reduction Clearfield M et al. Am J Cardiol 2005] and that those who had ≥2 risk factors benefitted more than those who had <2 risk factors [Gotto AM. Atherosclerosis Supplements 2007]. We also have learned that there is a significant benefit from statins in individuals with multiple risk factors but relatively low LDL-cholesterol levels [Sever PS et al. Lancet 2003] and that decreasing events early on may very well have a positive effect on mortality later [Sever PS et al. Eur Heart J 2008].

All of this evidence has shaped our approach to statin therapy and, according to Roger Blumenthal, MD, Johns Hopkins, Baltimore, MD, the recently released results of the JUPITER trial [Ridker PM et al. N Engl J Med 2008] provide new information that will “no doubt change our approach to using statins in primary prevention.”

The entry criteria for JUPITER were different from other cardiovascular primary prevention studies in several respects. LDL-cholesterol levels were lower (<130 mg/dL vs a range of 131 to 192 mg/dL in other trials), and JUPITER was unique in using a high-sensitivity C-reactive protein (hsCRP) level ≥2 mg/L as an entry requirement. JUPITER also used a much more potent statin (rosuvastatin 20 mg) than those that were used in other trials.

Important new questions that arise from JUPITER, noted Dr. Blumenthal, include whether hsCRP can help clinicians discriminate between who will benefit from statins and who will not and whether potent brand names or less potent generic statins are more cost-effective for lipid-lowering in primary prevention.

Results from the ILLUSTRATE trial [Nissen SE et al. N Engl J Med 2007], which compared the effect of atorvastatin alone versus atorvastatin+torcetrapib on the progression of coronary atherosclerosis raised the question of whether raising HDL-cholesterol levels is always beneficial.

Alan M. Fogelman, MD, David Geffen School of Medicine at UCLA, Los Angeles, CA, discussed the relationship between HDL and inflammation, noting that this may be more useful than blood concentration when deciding whether or not to raise HDL levels.

In the absence of systemic inflammation, when there is no acute phase response, HDL is anti-inflammatory; however, in the presence of systemic inflammation with an acute phase response, HDL is pro-inflammatory. The ability of HDL to inhibit or to enhance inflammation, lipid oxidation, plaque growth, and thrombosis reflects changes in specific enzyme and protein components [Watson KE et al. Rev Cardiovasc Med 2007]. Importantly, these changes in the inflammatory properties of HDL can occur independently of changes in HDL levels [Navab M et al. Trends Cardiovasc Med 2005]; understanding them may lead to new diagnostic and therapeutic approaches to atherosclerosis and other inflammatory conditions.

The HDL Inflammatory Index (HII) is a measure of the pro- or anti-inflammatory properties of an individual's HDL. It can be determined by comparing LDL-induced monocyte migration in an artery wall cell coculture assay with HDL from healthy controls. Studies have shown that the HII is better able to distinguish CHD patients from controls than HDL-cholesterol level [Ansell BJ et al. Circulation 2003]. It also has been shown to correlate with poor outcomes in hemodialysis patients [Kalantar-Zadeh K et al. Kidney Int 2007].

In closing, Dr. Fogelman noted that “changing HDL-cholesterol levels alone may not be enough. HDL-altering strategies should also take into account the functional properties of HDL.”

While admitting that he was not a psychologist, James H. Stein, MD, University of Wisconsin, Madison, WI, said that many doctors believe that “it just makes sense” that providing personalized biomarker or imaging results to patients would positively influence their adherence to treatment and their decision to engage in lifestyle changes. Several studies have attempted to determine whether this is the case. Although abnormal test results appear to influence clinician prescribing practices and appear to influence patient awareness of CVD risk, they do not seem to influence patient behavior in any consistent way [Korcarz CE et al. J Am Soc Echocardiogr 2008; O'Malley PG et al. JAMA 2003; Lederman J et al. J Clin Epidemiology 2007].

Dr. Stein proposed that the reason for these inconsistencies may be explained by The Extended Parallel Process Model [Shahab L et al. Br J Health Psychol 2007], which suggests that individuals engage in protective behaviors when they perceive themselves to be at risk (threat appraisal) and feel that they can control or modify risk (efficacy appraisal). In general, when both the threat appraisal and efficacy levels are high, individuals will accept a threat message and adopt a behavioral solution. However, when the threat appraisal is high and the efficacy appraisal is low, fear may lead to a cognitive solution, such as avoidance and rejection of the threat.

Dr. Stein recommends further investigations that use visual feedback and psychological inventories and interventions to better assess the role of imaging in helping patients achieve preventive cardiology targets.