Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - European Society of Cardiology (ESC) 2010 Congress

Stockholm, Sweden / August 28-September 1, 2010

There is a now a global effort to replace LDL-C levels as an isolated variable in risk management so that treatment is based on the level of cardiovascular (CV) risk of total CV disease rather than LDL-C alone. In those identified as being at high risk by accumulated risk factors, there is now objective evidence that LDL-C may be too high regardless of the starting level.

Evolving List of Risk Factors

“The importance of managing total risk rather than focusing on individual risk factors was first emphasized in the 2007 European guidelines. It is not enough to look at LDL-C alone. The influence of additional risk factors, such as body mass index (BMI), age and impaired glucose metabolism, on the likelihood of an event must be considered,” stated Prof. Faiez Zannad, Université Henri Poincaré, Nancy, France, here at the ESC. He predicted that based on clinical trials conducted since 2007, the next set of guidelines would go further. “The central role of inflammation in the pathophysiology of atherosclerosis has gained recognition, and inflammatory biomarkers such as C-reactive protein [CRP] and lipoprotein-associated phospholipase A₂ (Lp-PLA2) have been suggested as adjuncts in patients at moderate or high risk of cardiovascular disease (CVD).”

In Canada, high-sensitivity CRP is already considered a biomarker to predict risk and identify a population that responds particularly well to statin therapy, as seen in the JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) study. JUPITER enrolled men =50 years of age and women =60 years of age with an LDL-C <3.3 mmol/L, without a history of CV disease and an elevated high-sensitivity CRP (hsCRP >2.0 mg/L). The study agent rosuvastatin 20 mg q.d. achieved an impressive 44% reduction relative to placebo (P<0.00001) in a composite primary end point that included CV death, non-fatal myocardial infarction (MI), nonfatal stroke, unstable angina or an arterial revascularization procedure. Partly as a result of that trial, the goal for LDL-C is now <2 mmol/L or a =50% reduction from baseline in intermediate-risk patients who have an LDL-C of >3.5 mmol/L, if they have a total cholesterol:HDL-C ratio of >5.0, or if they are men older than 50 years or women older than 60 years with an hsCRP level >2.0 mg/L.

Risk Management

Intermediate-risk patients are the focus of new guidelines, because clinicians are already aware of the major benefits of aggressive lipid lowering for high-risk patients. While further risk assessment is not likely to be cost-effective in low-risk patients such as young, otherwise healthy individuals, the number and types of risk factors are critical in determining likelihood of an event over the next 10 years in those at intermediate risk.

The two risk scoring systems endorsed in the Canadian guidelines are considered more appropriate for a North American population than for those in other parts of the world. However, all of the emerging strategies to improve risk stratification, including those used in Europe, are attempting to focus attention on the overall risk of CV events rather than simply on single risk factor management. The goal is to prevent vascular disease, not just coronary artery disease (CAD), which is a narrower target that de-emphasizes events in other vascular beds, such as stroke. It is now known that vascular disease involves a variety of pathological changes, such as arterial stiffness, that are not necessarily correlated with the extent of atherosclerotic plaque. The ability of LDL-C reductions to exert favourable changes on vascular function independent of atherosclerosis has been shown in several different ways.

For example, studies with pitavastatin, a statin not yet approved in North America but in widespread use in Asia, have suggested that not all benefits are derived directly from lipid lowering. In a new study that evaluated carotid intima media thickness (IMT) in patients on pitavastatin, there was a significant reduction in thickness at 6 months that did not correlate with lipid changes. Indeed, this agent, which is metabolized by a different hepatic enzyme than most other statins, did lower LDL-C but did not significantly reduce hsCRP, according to Dr. Young Soo Lee, Department of Cardiology, Catholic University of Daegu School of Medicine, South Korea. It is notable that the reduction in IMT correlated with improved arterial distensibility, which may also reduce risk of thrombotic events.

Another new study called COSMOS (COronary atherosclerosis Study Measuring effects Of rosuvastatin using intravascular ultrasound in Japanese Subjects) also added to the evidence that improvement in atherosclerosis is achieved with lipid lowering but this is not an isolated variable. In this study, intravascular ultrasound was used to evaluate plaque burden after 76 weeks of treatment in patients with or without diabetes. Despite a comparable decrease in LDL-C by the statin in both groups, less regression was achieved in the diabetic patients with poorly-controlled HbA_1c level. The lead author of the study, Dr. Tadateru Takayama, Department of Cardiology, Nihon University, Tokyo, Japan, used these data to conclude that statin therapy is a foundation for risk management, but “vigorous control of HbA_1c appears to be clinically important” to further reduce plaque burden, he told delegates at the ESC.

Arterial Stiffness

Another set of data that argues against looking at lipid levels in isolation was derived from a study designed to evaluate the effect on statins on arterial stiffness. In this study, 1225 consecutive hypertension patients were stratified by LDL-C level and by hsCRP level. Arterial stiffness was then measured with femoral artery pulse wave velocity (PWV). After adjustment for potential confounders such as BMI, age, blood pressure and smoking status, both hsCRP and LDL-C were associated with increased arterial stiffness. Importantly, the relative increases in PWV were similar in those with elevated hsCRP but low LDL-C as in those with elevations in both hsCRP and LDL-C.

“The association of [hsCRP] =2.0 mg/L with increased arterial stiffness and consequently CV risk regardless of LDL-C may help to explain the results of studies that show a benefit from lipid lowering even in individuals with low baseline LDL-C levels,” reported Dr. Dimitrios Terentes-Printzios, Hippokration Hospital, University of Athens, Greece, here at the ESC. He noted that there is abundant evidence that statins have pleiotropic effects that appear to be independent of lipid lowering. For example, an anti-inflammatory effect may be relevant to high-risk patients even when LDL-C levels are unremarkable.

Another study that specifically evaluated the effect of rosuvastatin on arterial stiffness showed that the improvement in PWV was significantly correlated with hsCRP. In this study, presented by Dr. Minoru Hongo, Department of Cardiovascular Medicine, Shinshu University, Matsumoto, Japan, 95 hypertensive patients with dyslipidemia were randomized to a low dose of rosuvastatin (up to 5 mg/day) or up to 400 mg/day of bezafibrate. Although hypertension was controlled, the statin still improved PWV, correlating with a lowering of hsCRP levels. Dr. Hongo attributed this set of benefits, which was not observed in control patients, with the pleiotropic effects of the statin.

“Beneficial vascular effects of rosuvastatin persisted for a long period in hypertensive patients with dyslipidemia. This was associated with a strong LDL-C lowering effect of rosuvastatin with improvement in the LDL-C:HDL-C ratio as well as its anti-inflammatory action,” Dr. Hongo told delegates.

Summary

Due to the large proportion of CV events that occur in intermediate-risk patients, new efforts are being introduced to risk-stratify patients more appropriately for more intensive management. As in patients who have already had a CV event, a reduction in LDL-C among high-risk patients who have not yet had a CV event appears to confer benefits almost irrespective of the baseline LDL-C level. These data endorse risk scoring systems, hsCRP levels and other tools to identify intermediate-risk patients who will benefit from intensive lipid lowering. In particular, current data suggest the benefit of intensive lipid lowering can be extended to those with unremarkable baseline LDL-C levels.