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22nd Annual Cardiovascular Conference at Lake Louise

Lake Louise, Alberta / March 26-30, 2006

There were several important themes surrounding the anticipated new dyslipidemia recommendations to be issued by the Working Group on Hypercholesterolemia and Other Dyslipidemias. The new guidelines will be based on the results of new clinical findings from Canada and from international sites, including the US and the UK. The changing demographics in Canada, including a greater proportion of elderly individuals along with the increasing prevalence of obesity and diabetes, have led Dr. Jacques Genest, Jr., Director of Cardiology, MUHC-Royal Victoria Hospital and Professor of Medicine, McGill University, Montreal, Quebec, and colleagues to conclude that preventive measures are needed to reduce the burden of cardiovascular (CV) disease.

In 2000, the Working Group issued an initial set of guidelines. Based on new findings, an updated set of recommendations was released in 2003 (Genest et al. CMAJ 2003;168(9):921-4). In 2006, the Working Group again anticipates releasing a further update in light of additional research. The recommendations, representing a consensus across a wide range of CV health specialists, may be used to inform other CV specialists, primary care physicians and other specialty organizations such as the Canadian Diabetes Association and the Canadian Hypertension Society, to name a few. The recommendations have typically included high-, moderate- or low-risk levels and two treatment targets: suggested LDL-C levels and the total cholesterol:HDL-C ratio. The ratio measure is described as an “index of CV risk” and this lipid ratio is used as a secondary goal of therapy.

New Recommendations Anticipated

“If you are high-risk, we aim for an LDL-C <2.0 mmol/L or a [total cholesterol:HDL-C] ratio of <4.0 mmol/L,” Dr. Genest told delegates. The upcoming targets are lower when compared to the 2003 recommendations which suggested LDL-C <2.5 mmol/L. “Hunter-gatherers and newborn babies have an LDL-C of between 0.5 and 1.0 mmol/L and that is quite sufficient,” Dr. Genest noted.

Anticipating the release of updated dyslipidemia guidelines, Dr. Genest announced that he and colleagues are going to recommend LDL <2.0 mmol/L should be achieved through a combination of lifestyle and therapeutic options, and reviewed some of the large trials currently underway that demonstrate support for the new targets.

It was a theme echoed by Dr. David Waters, Professor of Medicine, University of California, San Francisco and Chief of Cardiology, San Francisco General Hospital, who reported, “Recent trials in patients with stable coronary artery disease [CAD] indicate that additional benefit can be obtained by lowering LDL-C below the traditional target,” which could have been as high as 2.6 mmol/L. In fact, based on newer study findings, such as the TNT (Treating to New Targets) trial, which randomized over 10,000 patients across 14 countries, Dr. Waters and colleagues recommended that LDL-C levels of 1.9 mmol/L “can provide additional clinical benefit” (Waters et al. Am J Cardiol 2004;93(2):154-8). Similarly, the PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22) trial of 4162 patients found that LDL-C of 1.8 mmol/L was more efficacious than the standard LDL-C lowering to 2.6 mmol/L. At two years, researchers noted a 16% relative reduction in risk in primary end points, including death, myocardial infarction or stroke. They found that the treatment benefits were apparent in as few as 30 days and remained consistent over time (Rouleau J. Am J Med 2005;118(Suppl 12A):28-35). Other studies, such as the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) trial, another large analysis involving 34 centres and 654 patients across the US, have also suggested that there is clinical benefit to these reduced LDL-C targets (Nissen SE. Am J Cardiol 2005;96(5A):61F-68F).

Addressing the Care Gap

There is often a gap between what the research has shown to be advisable and what is a clinical reality. This process of knowledge translation between recommended targets and clinical practice has been variously referred to as the “treatment gap” or the “care gap.” Indeed, one study found that among a survey of 23,129 patients across Canada, only 37% of those with untreated hypertension (defined as being at least 140/90 mm Hg) were aware of their diagnosis and “74% of untreated individuals were aware that their diagnosis of hypertension would require drug therapy,” leading the authors to suggest a “major gap in hypertension control” (Kahn HS. BMC Cardiovasc Disord 2005;5:26). It is reinforced by findings that despite the presence of “cholesterol medications for either primary or secondary prevention of coronary artery disease,” studies show that “all are underutilized by cardiologists, as well as other medical practitioners” (Siegel D. Prev Cardiol 2000; 3(4):167-71).

Referring to the need to address this shortcoming and based upon the findings of the CALIPSO (Canadian Lipid Study–Observational), Dr. Genest and colleagues noted that “many treated patients are not achieving recommended LDL-C targets,” prompting the recommendation that “strategies should be implemented to promote achievement of lipid treatment goals for high-risk patients” (Bourgault et al. Can J Cardiol 2005;21(13):1187-93). Based on statin therapies alone, the cross-sectional CALIPSO reported data on 3721 patients across Canada. The study found that 68% of statin-treated patients were at high CAD risk based on the 2003 Canadian guidelines. The study also identified many of the common comorbidities associated with CAD: 46.4% had established CV disease, 33.9% had diabetes and 59.5% had hypertension. In addition, the results of the study showed that over 36% of patients at high risk for CAD had not been able to achieve even the more modest LDL-C target levels of 2.5 mmol/L.

New Dyslipidemia Treatment Strategies

These findings point to the need for additional or combination therapies that will help patients reach desired LDL-C targets. As Canadian researchers have pointed out, “a substantial minority” of dyslipidemia patients will require combination therapy with a bile acid sequestrant, such as cholestyramine or colestipol, or newer cholesterol absorption inhibitors, such as ezetimibe (Genest et al. CMAJ 2003;169(9):Online 1-10). Ezetimibe appears to be “better tolerated than bile acid sequestrants,” and has been found to be “safe and can decrease LDL-C levels by an additional 10% to 20%.” Cholesterol absorption inhibitors can be useful in helping to reduce plasma LDL, alone or in combination with statins (Yatskar et al. Clin Cardiol 2006;29(2):52-5). A novel class of lipopenic compounds, the cholesterol absorption inhibitor can reduce intestinal absorption of biliary and dietary cholesterol (Jublanc et al. Presse Med 2006;35(3 Pt 2):487-94). For patients who cannot tolerate high-dose statins due to hepatoxicity or myotoxicity, these agents, which act primarily in the gastrointestinal lumen, may be indicated (Toth et al. Curr Drug Targets Cardiovasc Haematol Disord 2005;5(6):455-62).

Summary

“There is no question that coronary disease is multifactorial,” including issues such as obesity, smoking and stress, said Dr. Genest. However, he stressed, “The more you reduce LDL-C—in absolute terms by 1 or 2 mmol/L—the greater the risk reduction for CV events.” Dr. Genest added that every physician should use their own clinical judgment in deciding appropriate therapeutic options for their patient. He reminded delegates, “There is no point below which LDL-C reduction is no longer efficacious.”