New Guidelines for Lipids: Clinical and Biological Evidence

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.

Canadian Cardiovascular Congress 2006

Vancouver, British Columbia / October 21-25, 2006

The updated Canadian Cardiovascular Society (CCS) position statement on the diagnosis and treatment of dyslipidemia (McPherson et al. Can J Cardiol 2006;22(11):913-27) recommends lowering LDL-C to less than 2.0 mmol/L and, optimally, at least a 50% reduction in LDL levels in individuals with coronary disease or a calculated 10-year cardiovascular (CV) risk of >20%. It features “intervention points” rather than treatment targets for patients at low and moderate risk (Table 1), noted Dr. Ruth McPherson, Professor of Medicine and Biochemistry and Director, Lipid Clinic, University of Ottawa Heart Institute, Ontario. After the LDL-C levels, the CCS continues to emphasize the total cholesterol (TC):HDL-C ratio in primary prevention as a secondary target. “[This is] one of the best indices of future risk of coronary disease,” Dr. McPherson remarked.

Table 1. CCS Guidelines for Lipid Treatment

The new guidelines suggest that moving beyond a Framingham score can enhance risk stratification in patients deemed at intermediate risk by this instrument, Dr. McPherson observed. Extra information may move the patient to a higher or lower risk category. Family history of premature coronary disease doubles the risk score in such patients and “certainly indicates individuals who might well benefit from earlier intervention,” she stressed. In addition, the guidelines highlight the advisability of fasting plasma glucose or HbA1c evaluation for certain patients in this group, given the continuous and graded relationship between HbA1c and 10-year risk of cardiovascular disease (CVD).

The LDL intervention point for individuals deemed at low risk is now 5.0 rather than 4.5 mmol/L. “We were concerned we were overtreating low-risk individuals [but] we haven’t softened the guidelines as much as people might think because the more critical intervention point, theTC:HDL ratio [of 6.0], has not changed,” Dr. McPherson commented. “That encompasses maybe as much as 15% of the population, so it is a significant number.”

Why Even Lower Targets?

The evidence for the more aggressive treatment targets for high-risk individuals emanates from both clinical trials with hard end points and studies that have investigated the impact of therapy on atherosclerotic burden. These have all made the point that “there is clearly a benefit to lowering LDL more aggressively, and when you think about it in terms of getting at least a 50% reduction in LDL or hitting an LDL of <2 mmol/L, certainly there does appear to be incremental benefit,” Dr. McPherson stated.

Some physicians may be reluctant to institute more intensive lipid lowering or impose the new treatment targets on their high-risk patients. This group might believe that overall risk management, including attention to smoking cessation and lifestyle, hypertension and thrombotic risk, is as important, suggested Dr. Beth Abramson, Assistant Professor, University of Toronto, and Director, Cardiac Prevention Centre and Women’s Cardiovascular Health, St. Michael’s Hospital, Toronto, Ontario. Moreover, she acknowledged, many patients have failed to achieve the target of <2.5 mmol/L set in 2003. According to a poster presented here by Dr. Raymond Yan, Canadian Heart Research Centre, University of Toronto, and colleagues, less than half of a group of 8056 patients at high risk achieved this goal after six months of treatment. However, Dr. Abramson argued, the new targets are based on strong evidence, and the success of other contemporary risk-reducing strategies is not a rationale for disregarding them. Dr. Anatoly Langer, Chair, Canadian Heart Research Centre, St. Michael’s Hospital, and Professor of Medicine, University of Toronto, concurred, “If you are in the business of CV risk reduction, you are in the business of LDL reduction... LDL lowering is an independent way of lowering mortality in our patients regardless of any other strategy that we undertake.”

Drs. Abramson and Langer both cited the finding that a 1-mmol/L decrease in LDL reduces absolute risk by 1% and relative risk by 20% over five years. “In the two million Canadians with CVD, an aggressive strategy can result in almost 30,000 fewer CV events per year. If we take into account patients with diabetes and CVD together, more aggressive lipid lowering increases that number to 50,000,” Dr. Abramson emphasized.

Intensive or Combination Therapy May Be Needed

A shift toward a new LDL target may require higher statin dosing, as evaluated in numerous recent trials, Dr. Langer indicated. In the PROVE-IT study, pravastatin 40 mg/day and atorvastatin 80 mg/day led to mean LDL levels of 2.47 mmol/L and 1.61 mmol/L, respectively. “The difference between pravastatin and atorvastatin over two and a half years was an almost 4% difference in major CV outcomes... An impact of this magnitude is not inconsequential,” he commented. Similarly, in the ASTEROID trial, rosuvastatin 40 mg/day produced a significant 53% drop in LDL and a 59% reduction in the LDL:HDL ratio, Dr. Abramson reported. “It is estimated that about 50 to 75% of patients will achieve [the new lower LDL target] with a higher dose of a newer statin,” she added.

Achieving LDL targets rapidly while minimizing adverse effects of medication may be best achieved with combination therapy, according to Dr. Subodh Verma, Scientist and Assistant Professor, Division of Cardiac Surgery, University of Toronto. “The high-efficacy statins such as atorvastatin and rosuvastatin can bring a large number of people to target as long as the target is fixed. If the target is moving lower and lower, we need combination therapy.” Combining a statin with the cholesterol absorption inhibitor ezetimibe has proven to be a reasonable initial strategy to bring more people to a target LDL level, he remarked.

“The recommendation is always to go with monotherapy and use the highest tolerated dose from a safety and general side effect [point of view]. If that dose is reached and the patient hasn’t achieved the target, you consider additional medication. In addition, if the patient is on a less effective statin at full dose, it might well be more appropriate to switch to a more potent statin and titrate up,” Dr. McPherson summarized.

Intravascular Evidence

Intravascular ultrasound (IVUS) offers a detailed and quantifiable microscopic view of atherosclerotic vessels, noted Dr. Jean-Claude Tardif, Professor of Medicine, Université de Montréal and Director, Montreal Heart Institute Research Centre, Quebec. In separate presentations, Drs. Tardif and interventional cardiologist Stephen Nicholls, Cleveland Clinic Foundation, Ohio, reviewed the increasing body of evidence gathered through IVUS that intensive lipid changes produced by statins and experimental agents such as torcetrapib can have a significant effect on atheroma burden. “The use of imaging modalities that directly visualize atherosclerotic plaque has provided a number of important insights into how we might more optimally use these statin therapies [particularly in patients with established coronary artery disease],” Dr. Nicholls remarked.

While trials such as REVERSAL have indicated atherosclerosis progression could be stalled with intensive lipid modification, the recent ASTEROID study also indicated that it could lead to disease regression. In this trial, 507 patients with defined atherosclerotic parameters received rosuvastatin 40 mg/day for 24 months; 349 had evaluable IVUS images at both baseline and the end of treament. Along with the 53.2% decrease in LDL levels mentioned above (average change was from 3.35 to 1.5 mmol/L), there was a more surprising 14.7% increase in HDL (1.1 to 1.3 mmol/L), Dr. Tardif indicated. Atheroma regression, which was measured by per cent atheroma volume, nominal atheroma volume in the most diseased arterial segment, and change in nominal atheroma volume in the entire artery was observed in 63.6%; progression occurred in 36.4%. The relative reduction in total plaque volume from baseline was 7%. Importantly, regression was more likely in patients with LDL <2.0 mmol/L than in those with higher levels, especially LDL >2.6 mmol/L.

The biological changes exhibited with IVUS in REVERSAL can be linked to the beneficial outcomes with aggressive LDL lowering in PROVE-IT, which used the same statins and doses, Dr. Tardif remarked. It is not clear whether there will be incremental clinical benefit with the regression of atherosclerosis observed in ASTEROID, but the accumulated evidence suggests that attaining the lowest possible level of LDL, as per the 2006 guidelines, is an optimal clinical strategy, he concluded.

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