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PRIORITY PRESS - 59th Annual Scientific Session of the American College of Cardiology

Atlanta, Georgia / March 14-16, 2010

Even after a statin has been given an indication for lowering cardiovascular (CV) risk in patients with normal LDL-C, new evidence continues to accumulate to support the change in labelling. The recently revised indication, based on JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin), is the most recent evolution in the statin story. In Canada, the statin used in that study is now approved for reducing the risk of CV events in adult patients without documented history of CV or cerebrovascular events, as long as they have two or more conventional risk factors for CV disease.

A similar indication for this statin was announced just weeks earlier in the US. “The new indication recognizes that there is a large group of patients who can benefit from rosuvastatin even though they do not have elevated LDL-C by historical definitions,” stated Dr. Paul M. Ridker, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. “This represents a change in the way that we have been thinking about LDL-C and its relationship to risk.”

Benefit Regardless of LDL-C Levels

It has long been known that major risk factors including elevated LDL-C only explain about 50% of vascular events such as myocardial infarction (MI). JUPITER tested the hypothesis that even individuals with normal LDL-C by traditional definitions can benefit from aggressive lipid lowering if they have other CV risk factors. For this reason, the trial, published at the end of 2008 (Ridker et al. N Engl J Med 2008;359:2195-207) was limited to otherwise healthy individuals with no history of CV event who had a LDL-C <3.4 mmol/L and just two risk factors. These risk factors were age greater than 50 years in men and 60 years in women and a high-sensitivity C-reactive protein (hsCRP) =2.0 mg/L. On the basis of these and other criteria, rosuvastatin was associated with a 44% reduction (HR 0.56; 95% CI, 0.46-0.69; P<0.00001) in the primary end point of MI, stroke, arterial revascularization, hospitalization for unstable angina, or death from CV causes. It was also associated with a 20% reduction (HR 0.80; 95% CI, 0.67-0.97; P=0.02) in death from any cause.

Patients with Chronic Kidney Disease

In addition to the consistency of benefit across subgroups identified at the time that the results were initially presented, including participants stratified by gender, age, family history of CV disease, body mass index and smoking history, new subgroup data continue to generate similar results. In the data presented at the 2010 ACC meeting by Dr. Ridker and his co-investigators (Ridker et al. JACC 2010;55(suppl A): Abstract 1077-117), the risk reduction for the primary end point in patients with chronic kidney disease (CKD) was 45% (HR 0.55; 95% CI, 0.38-0.82; P=0.002). While there were no adverse events on estimated glomerular filtration rate relative to placebo in this subgroup, the most impressive result was that the statin was associated with a 44% reduction (HR 0.56; 95% CI, 0.37-0.85; P=0.005) in total mortality in the CKD subpopulation. The benefits were independent of gender and particularly noteworthy over the relatively short follow-up of the study.

In patients with CKD and a low LDL-C but elevated hsCRP, “rosuvastatin is a safe and effective agent to reduce first ever CV events and all-cause mortality,” Dr. Ridker told delegates. He noted that JUPITER has provided the first large database with which to explore the benefit from statins in CKD patients without known CV disease and a low baseline LDL-C.

Exploring Combinations

The use of combination therapies is another potentially important step in reducing the risk of CV events through better control of dyslipidemia. At this year’s ACC, however, there was disappointment in the lack of benefit associated with combining simvastatin and fenofibrate in patients with type 2 diabetes (T2DM). In this study called ACCORD (Action to Control Cardiovascular Risk in Diabetes), there was no significant difference in rates of major CV events among 5518 T2DM patients randomized to fenofibrate plus simvastatin vs. simvastatin alone. The lack of benefit may have been due to all-comers entry criteria which permitted T2DM patients without baseline dyslipidemias. Indeed, a post-hoc analysis did suggest benefit in those with high triglycerides.

While efforts to identify new targets for therapy are ongoing, the importance of meeting established targets to reduce risk cannot be ignored. In new data from GRAVITY (Gauging the lipid effects of RosuvAstatin plus ezetimibe Versus sImvastatin plus ezetimibe TherapY), the ability of two combination strategies were compared for reaching target LDL-C levels. At the end of 12 weeks, the proportion of patients at the LDL-C goals of <1.8 mmol/L was 77% in the 204 patients randomized to 20 mg rosuvastatin plus 10 mg ezetimibe vs. 55.3% for the 199 randomized to 40 mg simvastatin plus 10 mg ezetimibe (P<0.001) and 67.7% randomized to 80 mg simvastatin plus 10 mg ezetimibe (P<0.05).

“Reaching the treatment goals is clearly associated with reductions in the risk of events, and this study shows that combining ezetimibe with rosuvastatin rather than a high dose of simvastatin is more likely to get you there,” reported the senior investigator, Dr. Christie M. Ballantyne, Baylor College of Medicine, Houston, Texas.

Beyond LDL-C Lowering: The Value of Raising HDL-C

“Statins have been very easy to use and they are very effective, but the key question now that we are reaching the maximum reductions in LDL-C is what else we can do,” remarked Dr. Peter H. Jones, Baylor College of Medicine, here at the ACC. He suggested that one of the most obvious targets has been to increase HDL-C levels, but clinicians are looking for agents that can be added onto statins without sacrificing safety or compliance. This was the basis for a study he conducted evaluating a combination of fenofibric acid and rosuvastatin. The study was conducted over two years.

“This was not an end point study, it was a feasibility study. What we found was that 135 mg of fenofibric acid and 20 mg of rosuvastatin was generally well tolerated and had a favourable safety profile over two years,” Dr. Jones reported. In the 161 patients with mixed dyslipidemias evaluated over the course of 116 weeks, the combination was associated with a 19.1% increase in HDL-C, a 40.9% reduction in LDL-C, a 48.2% reduction in triglycerides and a 38.7% reduction in total cholesterol.

One compelling reason to pursue HDL-C raising in addition to LDL-C lowering are the atherosclerosis research studies that have been conducted by Dr. Steven Nissen, Cleveland Clinic, Ohio. While his pioneering studies with intravascular ultrasound (IVUS) have confirmed that LDL-C lowering changes the natural history of atherosclerosis by reducing atheroma volume, he summarized data from his institution at the 2010 ACC that shows this reduction in volume is almost tripled (-8.8 mm³ vs. -2.8 mm³) when HDL-C is increased by a median of 7.5% at the same time that LDL-C is reduced to a median level of 2.25 mmol/L.

Dr. Michael Davidson, University of Chicago, amplified this point by noting that current therapies are lowering LDL-C to levels that might now be difficult to surpass. As a result, new risk reductions may depend on treating other targets, including HDL-C, hsCRP and apolipoprotein B (ApoB).

“We have the data showing higher rates of major CV events with other potential targets, and this may be where the future lies for building on the benefits that we have achieved with the statins,” Dr. Davidson said. However, each step has to be tested with clinical outcomes regardless of theoretical benefits.

Summary

A statin has now been approved for the first time for primary prevention of CV disease in individuals with CV risk factors but without elevated LDL-C as traditionally defined. This is a major evolution in the ongoing statin story in risk management. The JUPITER trial provides more evidence that statin therapy is effective in reducing CV risk among individuals who have a plasma LDL-C level below the conventional threshold for pharmacology if they have additional risk factors. This indication is an important step forward for reaching at-risk individuals missed by previous criteria.