Recommendations for the management and treatment of dyslipidemia

Despite the steady decline in the rate of death from coronary artery disease (CAD) during the past 25 years, cardiovascular disease remains the leading cause of death in Canada, accounting for 37% of total deaths.1 Although the age-adjusted rate of death from cardiovascular disease is declining, the prevalence of cardiac conditions is increasing because of the growing number of elderly people, better acute care and improved survival.1 People with heart disease often remain in the community, requiring long-term medical care. In quantitative terms, $7.3 billion (17%) of total direct health care costs and $12.3 billion (14.5%) of total indirect health care costs for all disease categories can be attributed to cardiovascular disease.1

The largest proportion of cardiovascular diseases is represented by CAD and cerebral and peripheral vascular disease. During the past 3 decades efficacious strategies have been developed for primary and secondary prevention of these diseases. These strategies involve general lifestyle changes (to promote healthy diet, optimal weight, physical activity, moderate or no alcohol consumption, and smoking cessation), treatment of high blood pressure, control of diabetes mellitus and, in particular, treatment of dyslipidemias.

The causal relation between hypercholesterolemia and atherosclerosis was established more than 80 years ago by Anitschkow.2 Since the 1950s, there have been steady improvements in our ability to treat hypercholesterolemia through diet and the use of lipid-lowering drugs. The earliest angiographic and clinical studies demonstrated that intensive therapy to lower low-density lipoprotein cholesterol (LDL-C) levels slowed the progression of atherosclerosis and decreased the incidence of major coronary events;3,4 however, these early studies did not have sufficient power to detect beneficial mortality trends. The results of these early clinical studies and the extensive epidemiological data on the relation between plasma lipoprotein levels and CAD, as well as experimental information from animal models of atherosclerosis, led to the development of policies to manage and treat lipid disorders. In Canada, guidelines for the management of hypercholesterolemia were first issued in 1988.5

Major clinical trials carried out over the past decade have shown a clear benefit of LDL-C reduction in terms of both CAD events and total mortality. A similar reduction in the relative risk of coronary events has been documented in patients with and without clinically evident CAD and in patients with mild or severe dyslipidemia.6-16 These advances necessitated a re-evaluation of diagnostic and treatment policies. In 1995 the Working Group on Hypercholesterolemia and Other Dyslipidemias was established at the initiative of Health Canada. Its first report was drafted in October 1996; after review by committee members, modifications were made and the next draft document was released in March 1997. The committee continued to work during the next 2 years, collecting information from Canadian health care providers and the scientific community. An interim report was published in April 1998.17 With the rapid progression of research in this area since then, a writing committee was convened to incorporate the most recent scientific data and expert opinion from various organizations and individuals into this new set of recommendations.

Recommendations

The following measures were recommended by the Working Group on Hypercholesterolemia and Other Dyslipidemias in light of the new scientific evidence that became available since the interim report was published. A summary of the changes in recommendations from the previous interim report appears in Table 1.

Interpretation

Since the 1988 Canadian Consensus Conference on Cholesterol,5 there has been enormous progress in our understanding of the pathological basis of atherosclerosis and its complications. Over this same period, many large clinical trials have provided clear evidence that dyslipoproteinemia is a major treatable risk factor for CAD and that lowering LDL-C levels results in a prompt and significant decrease in cardiovascular events, including transient ischemic attacks and stroke. This is true for people at various levels of risk, with and without pre-existing CAD.37 Although identification and treatment of elevated LDL-C levels may be of benefit to many patients, the short-term benefit is clearly the greatest for people at highest risk for CAD. Thus, the most intensive interventions are advised for people with clinically evident cardiovascular disease or diabetes. These patients require an aggressive approach to reach LDL-C and total cholesterol:HDL-C ratio targets and to modify other risk factors.

Recent studies in Canada and the United States have shown that the majority of patients at very high risk for CAD do not achieve and maintain recommended target lipid levels. This failure is rarely accounted for by severe treatment-resistant dyslipidemia but more often by inadequate lifestyle and pharmacological interventions. Simple procedures such as standing orders for lipid measurement within 12 hours after admission to coronary care units and standard hospital or clinic discharge orders stipulating the appropriate lipid treatment for patients with cardiovascular disease and diabetes could be expected to have a major impact on standard of care. General recommendations for managing patients at high and very high risk include prompt intervention with both diet and medication, using an initial drug dose calculated to achieve the necessary reduction in LDL-C levels, and modification of the drug regimen as necessary to achieve and maintain target lipid levels. Inclusion of the patient in decision-making is essential, and a "know your LDL-C level" strategy is likely to improve long-term patient compliance.

For people without clinically evident cardiovascular disease or diabetes, the cost:benefit ratio of lipid-lowering therapy depends on their risk of cardiovascular disease; a comprehensive evaluation of short-term risk is advised using multiple risk-assessment equations such as those provided by the Framingham Heart Study. Although more time-consuming than counting risk factors, risk calculation has a number of advantages, including greater accuracy in the assignment of risk, especially for women. Risk calculation takes into account the relative contribution of individual risk factors to overall risk of cardiovascular disease, the severity of individual risk factors and the sex-specific relative risk. For example, the 10-year risk of a coronary event is much higher for a 55-year-old man with an LDL-C level of 4.5 mmol/L than for a 55-year-old woman with the same LDL-C level. However, a 55-year-old woman with an HDL-C level of 0.9 mmol/L has the same 10-year risk of a major coronary event as a 55-year-old man with a similar HDL-C concentration.38 Risk calculation also provides an opportunity for the physician to review modifiable risk factors with the patient and motivate the patient to make lifestyle changes that will reduce his or her overall risk.

Physicians must realize that this set of recommendations is a general guide and that clinical judgement is required. Many patients at low short-term risk are at high long-term risk for cardiovascular disease. Modifiable risk factors must be addressed at any age, and patients' risk factors should be reassessed periodically. Certain caveats apply to risk calculation. The major prospective population studies such as the Framingham Heart Study38 and the PROCAM Experience39 included a relatively small number of patients with severe dyslipidemias such as familial hypercholesterolemia. Adults with an LDL-C level greater than 5.0 mmol/L are at very high risk of CAD and, even in the absence of other CAD risk factors, are likely to require early pharmacological intervention. The accuracy and precision of risk calculation will continue to evolve. Future data sets are likely to include more detailed information on emerging CAD risk factors such as lipoprotein(a), fibrinogen, homocyst(e)ine, plasminogen activator inhibition-1 (PAI-1) and C-reactive protein; assessment of these factors may further improve the accuracy of risk assessment. Finally, noninvasive assessment of preclinical atherosclerosis, including exercise stress testing, nuclear perfusion scans and B-mode carotid ultrasonography, may aid in the early identification of patients at high risk for cardiovascular events.

The Working Group on Hypercholesterolemia and Other Dyslipidemias wishes to express its gratitude for the invaluable support of Health Canada during the development of these recommendations. In particular, the committee wishes to acknowledge the contribution of Dr. Arun Chockalingam.

Competing interests: The authors did not receive financial support from pharmaceutical companies for their work in developing these guidelines and producing this report. All have received speaker fees from various drug companies; Drs. Frohlich and Genest have been members of advisory boards of various drug companies; Drs. Fodor, Frohlich and Genest have received research grants from drug companies for work in this area; and Drs. Fodor, Frohlich and McPherson have received travel expenses from one or more drug companies to attend scientific meetings.