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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 - Canadian Cardiovascular Congress

Toronto, Ontario / October 25-29, 2008

Chronic kidney disease (CKD) is defined as both a low glomerular filtration rate of <60 mL/min plus abnormal albuminuria. Just how CKD affects outcomes was clarified in a sub-analysis of the HOPE study in which approximately 10% of the cohort had chronic renal insufficiency. “Patients with CKD in HOPE had double the hard outcome rate as the rest of the population,” indicated Dr. Sheldon Tobe, Associate Professor of Medicine, University of Toronto, Ontario.

Other studies have shown that the more severe the CKD, the higher the event rate including death, cardiovascular (CV) events and hospitalization. Even the presence of microalbuminuria in patients with diabetes from the HOPE trial almost doubled the mortality rate compared with those who did not have microalbuminuria at baseline. In the general population, PREVEND also showed that “the higher the albumin in the urine, the higher the CV event rate,” Dr. Tobe noted. Thus, what is going on in the kidney appears to reflect global CV risk and lowering that risk with statin therapy should be considered as a pivotal prevention strategy.

Currently, there are no hard outcome data for the role of statins in CKD. However, in established coronary artery disease (CAD), a meta-analysis comparing less intensive statin regimens with more intensive regimens showed that the more intensive regimens reduced the risk of both myocardial infarction (MI) and stroke by approximately 18% with only very small absolute increases in drug discontinuation, elevated liver enzymes or myopathy rates (Josan et al. CMAJ 2008;178(5):576-84). Even so, approximately half of patients in this meta-analysis did not achieve an LDL level of <2.0 mmol/L on intensive statin therapy—thereby fuelling the argument for a combination approach.

In 4D (Deutsche Diabetes Dialyse Studie), patients with diabetes on dialysis and atorvastatin 20 mg did not change the CV event rate compared with placebo—“very likely because patients in 4D were beyond the point where LDL-C lowering has a benefit,” Dr. Tobe suggested. Conversely, 4D did indicate that the statins were well tolerated in a dialysis population, which was not known before.

Currently, the international SHARP study involving some 9000 patients, 6000 of whom are predialysis, will evaluate whether the combination of simvastatin/ezetimibe alters time to first major vascular event in CKD patients who are not yet beyond the benefits of LDL lowering. The same study will also test whether the combination strategy affects progression to early-stage renal disease in the predialysis cohort. So far, safety data at one year have shown no difference between the combination and placebo arms in either elevations of liver enzymes or the incidence of myopathies.

“I think the data shows that CKD patients are at much higher CV risk than your average patient and if we wait for evidence to accumulate, we are going to lose a whole generation of patients who may miss out on the benefits of lipid-lowering therapy,” Dr. Tobe told delegates. “So if there is a guidelines-based reason to treat your patient, do not hold back on lipid-lowering therapy… as using low-dose statin therapy is quite well tolerated and early data from SHARP suggest that the addition of ezetimibe [to simvastatin] is well tolerated as well.”

Primary Prevention

As Dr. Eva Lonn, Professor of Medicine, McMaster University, Hamilton, Ontario, reminded delegates, “Our task is primary prevention”—and to do this effectively, physicians need to stratify patients based on their long-term CV risk. The Framingham risk score is still the most widely used algorithm in North America, even though Framingham underestimates long-term risk, especially in young patients and in women.

Probably the hardest patients to assess and implement prevention strategies in are those who are in an intermediate risk category on Framingham. Here, Dr. Lonn suggested a family history of premature heart disease should tip assessment towards a higher risk category. She also felt it was important for physicians to differentiate among three elements: a risk factor, namely, a variable associated with increased risk of disease; a biomarker, which is a good barometer of disease activity; and a surrogate, which is involved in the causal pathway of the disease and may even capture the effects of an intervention on the disease process, but is distinct from either a risk factor or a biomarker.

Whether soluble biomarkers can refine risk stratification is not yet clear. In some populations, women for one, high-sensitivity C-reactive protein (hsCRP) performs well in terms of predicting first ever CV events. Among patients with established vascular disease, the strongest individual predictor for vascular events at HOPE study end point was N-terminal pro-brain natriuretic peptide and not CRP, Dr. Lonn noted, and HOPE investigators concluded that biomarkers have only modest value in predicting CV event risk. The Reynolds Risk Score (www.reynoldsriskscore.org) may more accurately gauge individual patient risk.

When investigators re-calculated risk in many thousands of intermediate-risk women, between 40% to 50% of the cohort were reclassified to either a higher or a lower level of risk based on their Reynolds risk score (Ridker et al. JAMA 2007;297(6):611-9). Increased levels of lipoprotein-associated phospholipase A2 have also been associated with an increased CV risk, while carotid intima media thickness may again be particularly helpful in deciding how to proceed with primary prevention in intermediate-risk patients, Dr. Lonn suggested.

“Classical risk stratification algorithms remain essential for CV risk assessment and to guide preventive strategies,” Dr. Lonn concluded, “and if patients are reclassified as higher risk with the help of biomarkers or imaging techniques, they may be candidates for lipid-lowering therapy.”

Aggressive Risk Factor Management

Patients with type 2 diabetes, increasingly seen in the pediatric population in North America, require aggressive risk factor management targeting all contributing factors including body weight, a sedentary lifestyle, smoking cessation and aggressive lipid, blood pressure and glucose control.

According to Dr. Sergio Fazio, Professor of Medicine and Pathology, Vanderbilt University Medical School, Nashville, Tennessee, “No statin trial has ever failed in diabetics.” Indeed, regardless of the statin involved, treatment consistently reduced CV events by about one-third in the diabetic population—“so nobody would disagree diabetics should be on a statin,” Dr. Fazio emphasized. Ideally, he remarked, we should all carry the PCSK9 mutation because those who have been able to acquire it have between a 50% and 80% reduced lifetime risk of developing CV disease, depending on ethnicity.

In its absence, intensive-LDL lowering is “the next best thing,” Dr. Fazio suggested, LDL reduction being the number one “absolute priority” in primary prevention because every statin trial has confirmed there is a linear response to it, unlike other lipid subfractions. ASTEROID with rosuvastatin was only one trial to demonstrate that dramatic reductions in LDL stops disease progression, “so you can promise a patient that you can block disease progression by taking the LDL-C to 2 mmol/L and lower,” Dr. Fazio told delegates. With recent guidelines indicating that LDL targets for patients with diabetes are <2.0 mmol/L and the TC:HDL ratio <4.0, physicians need to keep in mind that statin monotherapy, although recommended initially, is not going to get them the optimal treatment desired.

High-dose statin therapy will reduce LDL by between 40% and 50% but low-dose statin therapy plus ezetimibe does even better, reducing LDL by 50% to 55%. When added to high-dose statin therapy, ezetimibe can lower LDL by 55% to 69%. For patients who require even further reductions in LDL, high-dose statin therapy plus ezetimibe plus other agents lower LDL by 60% to 75%

“The best way to prevent CV disease in diabetes is through diabetes prevention,” Dr. Fazio concluded. “But LDL management remains the centerpiece of our prevention strategy and a statin is always warranted even though additional drugs are needed in many cases.”