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International Atherosclerosis Society dyslipidemia guidelines are based on multiple lines of evidence.
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Non-high-density lipoprotein cholesterol as a major form of atherogenic cholesterol.
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Cardiovascular risk is adjusted according to baseline risk of different nations or regions.
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Primary emphasis of guidelines is on lifestyle intervention; secondary emphasis on drug therapy.
Abstract
An international panel of the International Atherosclerosis Society has developed a new set of recommendations for the management of dyslipidemia. The panel identifies non-high-density lipoprotein cholesterol as the major atherogenic lipoprotein. Primary and secondary prevention are considered separately. Optimal levels for atherogenic lipoproteins are derived for the two forms of prevention. For primary prevention, the recommendations emphasize lifestyle therapies to reduce atherogenic lipoproteins; drug therapy is reserved for subjects at greater risk. Risk assessment is based on estimation of lifetime risk according to differences in baseline population risk in different nations or regions. Secondary prevention emphasizes use of cholesterol-lowering drugs to attain optimal levels of atherogenic lipoproteins.
The International Atherosclerosis Society (IAS) has developed a guide for intervention regarding dyslipidemia. This guide is based on deliberations of an IAS committee with international representation. Its recommendations are based on an interpretation of available data from a majority of the panel members. The Position Paper was developed as follows. Fifteen committee members were nominated by the IAS Executive Committee and were invited to participate on the writing panel. They were both experts and representative of different regions of the world. Timely questions relating to lifestyle and drug management of dyslipidemia were selected and shared with the panel. Responses were organized as IAS panel deliberations. From the deliberations, key recommendations were abstracted. Before each deliberation, a background section was developed for perspective. A draft document was constructed and shared with IAS panel members. Responses were incorporated, and a revised draft was again shared. The second draft was also provided to the IAS Executive Board. All comments were collated and incorporated into a final draft; this was provided to the IAS Executive Committee for approval. Finally, the document was shared with IAS member societies for their comment and ratification. Many member organizations provided useful comments that led a final modification of the document.
The recommendations are based on international consensus. Three major lines of evidence underpinned the recommendations: epidemiologic studies, genetic studies, and clinical trials. Where appropriate, the recommendations were further informed by pathologic studies, pharmacology, metabolic studies, smaller clinical trials, meta-analyses of clinical trials, animal studies, and the basic sciences. Each line of evidence contains strengths and weakness. Epidemiologic studies are worldwide in scope. A vast database of population research relates cholesterol and lipoproteins to atherosclerotic cardiovascular diseases (ASCVDs). The consistency and strength of these relationships make it possible to determine optimal cholesterol levels for the prevention of ASCVDs. Although epidemiology is subject to confounding factors, consistency of results from many studies helps to overcome this weakness. Genetic epidemiology reduces the possibility of confounding factors by having single variables-genetic mutations. Although genetic data are limited, they are highly informative for linking cholesterol levels to risk for ASCVD. Finally, clinical trials, especially randomized clinical trials (RCTs), allow the testing of single variables-usually drug therapies. This fact has led many guideline panels to give priority to RCTs over other lines of evidence. However, most RCTs are drug trials. Allowing RCTs to dominate guideline development largely restricts them to drug recommendations; reliable RCTs for lifestyles therapies are few. Drug RCTs, moreover, have not been carried out in a diversity of populations. Volunteers for RCTs commonly do not reflect the population at large. And finally, RCTs are mostly sponsored by the pharmacological industry. They are designed primarily to obtain regulatory registration, not to answer critical questions in clinical intervention. The IAS panel recognized the enormous fund of useful information provided by RCTs but it also has placed RCTs in the context of epidemiologic and genetic findings.
Most investigators in the field of lipid research contend that atherosclerosis is largely a lifestyle problem. This belief derives from epidemiology and not RCTs. Creating guidelines exclusively from drug RCTs makes pharmacology a solution to unhealthy life habits. Drug treatment may of necessity supersede lifestyle in secondary prevention, but a drug paradigm may not be the best for primary prevention. Some investigators are promoting the concept that drugs should be used as public health measures in primary prevention. The IAS panel instead favored the use of lifestyle intervention to reverse unhealthy life habits. Drugs are reserved for patients at greater risk.
Although RCTs are limited, their results are largely congruent with epidemiologic evidence. Epidemiology shows that high levels of serum cholesterol impart increased risk for coronary heart disease (CHD), whereas low levels coincide with low rates of CHD.
Pooling Project Research Group Relationship of blood pressure, serum cholesterol, smoking habit, relative weight and ECG abnormalities to incidence of major coronary events: final report of the Pooling Project.
Is the relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT).
Lipid Research Clinics Program The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease.
Scandinavian Simvastatin Survival Study Group Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).
Effect of pravastatin on cardiovascular events in older patients with myocardial infarction and cholesterol levels in the average range. Results of the Cholesterol and Recurrent Events (CARE) trial.
Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS: Air Force/Texas Coronary Atherosclerosis Prevention Study.
The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.
Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial.
Heart Protection Study Collaborative Group MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.
Lescol Intervention Prevention Study (LIPS) Investigators Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial.
PROSPER Study Group PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.
Assessment of LEscol in Renal Transplantation (ALERT) Study Investigators Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo controlled trial.
ASCOT Investigators Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower than-average cholesterol concentrations, in the ANGLO-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicenter randomised controlled trial.
CARDS Investigators Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicenter randomised placebo-controlled trial.
National Heart, Lung, and Blood Institute; American College of Cardiology Foundation; American Heart Association Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines [Erratum in: Circulation. 2004;110:763].
Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial [Erratum in: JAMA. 2005;294:3092].
PROVE IT-TIMI 22 Investigators Early and late benefits of high-dose atorvastatin in patients with acute coronary syndromes: results from the PROVE IT-TIMI 22 trial.
These congruent findings are the cornerstone of cholesterol guidelines.
The writing panel recognized different populations can differ in many important ways. Although the panel attempted to make the recommendations as uniform as possible, adjustments were made as needed for particular countries or populations.
Other organizations likewise have crafted treatment guidelines for dyslipidemia. For more than 25 years, the US National Heart Lung and Blood Institute has sponsored a National Cholesterol Education Program. Its major product has been the reports of the Adult Treatment Panel (ATP). The most recent report is ATP III.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).
NCEP. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.
ATP IV preparation has been suspended. The American Heart Association (AHA) and American College of Cardiology Foundation also issues guidelines; among these, secondary prevention guidelines are the most recent.
World Heart Federation and the Preventive Cardiovascular Nurses Association AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and other Atherosclerotic Vascular Disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation.
European Society of Cardiology (ESC); European Atherosclerosis Society (EAS) ESC/EAS Guidelines for the management of dyslipidaemias The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS).
Organizations in other countries have developed guidelines both on lipid management and on cardiovascular risk reduction. The IAS stores all of these guidelines on its website (www.athero.org/); they provide a treasure trove of information for those interested.
Primary prevention
Introduction
Primary prevention seeks to prevent new-onset ASCVDs. These diseases include CHD, stroke, and other atherosclerotic vascular diseases. ASCVD constitutes the leading cause of death in the world
Because the prevalence of ASCVD increases with advancing age, the reduction in early deaths from infections and malnutrition increases ASCVD prevalence later in life. To reduce the worldwide burden of ASCVD, new onset disease must be decreased.
Pathogenesis of atherosclerosis
Some elevation of LDL seemingly is required for atherogenesis and hence ASCVD.
NCEP. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.
European guidelines on cardiovascular disease prevention in clinical practice. Third Joint Task Force of European and other Societies on Cardiovascular Disease Prevention in Clinical Practice.
Working Group on Hypercholesterolemia and Other Dyslipidemias Recommendations for the management of dyslipidemia and the prevention of cardiovascular disease: summary of the 2003 update.
LDL accounts for more than 75% of atherogenic lipoproteins, the others being cholesterol-enriched remnants of triglyceride-rich lipoproteins. The latter play a larger role when triglycerides are increased. When LDL infiltrates into the arterial wall, it initiates and promotes atherosclerosis; indeed, an increased LDL level acting alone can cause ASCVD. The role of LDL is best exemplified in patients with familial hypercholesterolemia (FH).
No other risk factor can do the same. In populations with low levels of LDL, the presence of other risk factors-cigarette smoking, hypertension, low HDL, or diabetes-does not lead to premature ASCVD.
These other risk factors appear to accelerate atherogenesis when LDL is high enough to initiate atherosclerosis. For this reason, the prime focus of prevention of ASCVD must be on lowering LDL and keeping it low throughout life. LDL promotes atherosclerosis in several ways. After entering the arterial wall, LDL is trapped and modified in a variety of ways; this leads to its uptake by macrophages.
Lipid-engorged macrophages are called foam cells. Expansion of regions of foam cells creates a fatty streak. The latter initiates smooth muscle proliferation, and this response forms a fibrous cap (fibrous plaque).
The expression of IGFs and IGF binding proteins in human carotid atherosclerosis, and the possible role of IGF binding protein-1 in the regulation of smooth muscle cell proliferation.
Continued LDL infiltration, however, creates superficial lipid-rich areas in fibrous plaques. These areas are prone to breaking though the surface of the plaque; this breakage is called plaque rupture.
When rupture occurs, plaque contents exude and precipitate a thrombosis. Plaque rupture and thrombosis in coronary arteries are responsible for acute coronary syndromes. Ruptures of carotid artery plaques produce strokes. All of these steps occur in patients with FH and demonstrate how increased levels of LDL alone can cause clinical ASCVD.
Because LDL is the predominant cholesterol-carrying lipoprotein, it has received the most attention in the atherosclerosis field. Yet very-low-density lipoproteins (VLDLs) also are cholesterol enriched and have atherogenic potential.
Liposome-like particles isolated from human atherosclerotic plaques are structurally and compositionally similar to surface remnants of triglyceride-rich lipoproteins.
The most atherogenic form of VLDL consists of partially degraded VLDL, called remnants. The atherogenic component of VLDL is its cholesterol, not its triglyceride. VLDL remnants are particularly enriched in cholesterol. The importance of VLDL as an atherogenic lipoprotein is greatest in persons with hypertriglyceridemia.
Risk factors for ASCVD accelerate the process described previously. The major risk factors include cigarette smoking, hypertension, low HDL-C, and diabetes.
NCEP. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.
They act at one or more steps in atherogenesis to enhance the formation of plaques or cause plaque rupture. The emerging risk factors are those that relate to atherosclerosis or its complications, although their mechanistic linkage to ASCVD is less well understood. These factors include proinflammatory and prothrombotic states, and some forms of dyslipidemia. Underlying risk factors are atherogenic diets, obesity, physical inactivity, and genetic tendencies. They underlie the development of major and emerging risk factors. Advancing age is usually listed as a major risk factor, but age per se is not a cause of atherosclerosis. Because atherogenesis progresses throughout life, a person's age commonly reflects atherosclerotic burden; importantly, however, the extent of atherosclerotic burden at a given age varies greatly from one individual to another. Age, therefore, is an imprecise indicator of risk for individuals.
Besides cholesterol lowering, primary prevention aims to reduce the accelerating risk factors-both major and emerging risk factors. Public health approaches to prevention focus on identifying and treating individuals with risk factors, especially smoking and hypertension. Primary prevention promotes lifestyle behaviors to prevent the development of accelerating risk factors as well as elevated LDL-C.
on behalf of the American Heart Association Strategic Planning Task Force and Statistics Committee Defining and setting national goals for cardiovascular health promotion and disease reduction: the American Heart Association's strategic impact goal through 2020 and beyond.
When any of the major risk factors are identified, they too become targets for clinical intervention.
Lipoprotein classes
Three major classes of lipoproteins are LDL, VLDL, and high-density lipoproteins (HDLs). VLDL, derived from liver, carries both triglycerides and cholesterol. An elevated VLDL occurs with hypertriglyceridemia. Clinically, LDL is identified as LDL cholesterol (LDL-C). Calculation of LDL-C is as follows: L = C-H-kT, where L is LDL cholesterol, C is total cholesterol, H is HDL cholesterol, T is triglycerides, and k is 0.20 if the quantities are measured in mg/dL and 0.45 if in mmol/L.
LDL is derived from the catabolism of VLDL and exits the circulation mainly via LDL receptors on the surface of liver cells. Another triglyceride-rich lipoprotein is the chylomicron; this lipoprotein carries triglycerides derived from dietary fat. Although chylomicrons apparently are not atherogenic, chylomicron remnants may be. The sum of LDL-C and VLDL-C is called non-HDL-C (calculated as non-HDL-C = total-C-HDL-C). Several studies show that non-HDL-C is more strongly related to risk for ASCVD than LDL-C.
Relationships between lipoprotein components and risk of myocardial infarction: age, gender and short versus longer follow-up periods in the Apolipoprotein MOrtality RISk study (AMORIS).
In this document, the term atherogenic cholesterol can be applied to either LDL-C or non-HDL-C. It should be noted that total cholesterol is often used in risk assessment algorithms. Total cholesterol is less reliable as a target of therapy, but it can be used if lipoprotein cholesterol values are not available.
HDL is derived in part through products released during triglyceride catabolism; other components are made by liver and gut. Epidemiologic evidence suggests that HDL may protect against ASCVD.
for the European Atherosclerosis Society Consensus Panel Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management.
NCEP. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.
Executive Summary of the Japan Atherosclerosis Society (JAS) Guidelines for the Diagnosis and Prevention of Atherosclerotic Cardiovascular Diseases in Japan - 2012 Version.
Clinical trials are currently underway to determine whether HDL-increasing drugs will reduce the risk of ASCVD. Regardless of outcome, HDL is a powerful indicator of risk and plays a key role in global risk assessment.
Lifestyle influence on lipoproteins and ASCVD risk
The prevalence of ASCVD differs greatly in different regions of the world.
INTERMAP Research Group Nutrient intakes of middle-aged men and women in China, Japan, United Kingdom, and United States in the late 1990s: the INTERMAP study.
on behalf of the American Heart Association Strategic Planning Task Force and Statistics Committee Defining and setting national goals for cardiovascular health promotion and disease reduction: the American Heart Association's strategic impact goal through 2020 and beyond.
The former three affect LDL or other lipoproteins. If healthy life habits were to be adopted in high-risk populations, the prevalence of ASCVD almost certainly would decline.
Dietary lipids
Dietary fats in particular affect lipoprotein levels.
NCEP. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.
In populations in which dietary saturated fatty acids and cholesterol are high, serum cholesterol levels are 10%-25% greater than where intakes are low.
Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials.
Diets high in carbohydrates will cause mild-to-moderate increases in VLDL and often reduce HDL levels. Unsaturated fatty acids do not affect LDL-C levels relative to carbohydrates. Replacement of carbohydrates with monounsaturated fatty acids has the advantage that it does not lower HDL-C.
However, there is little evidence that a greater VLDL and lower HDL-C on high carbohydrate diets are atherogenic; populations consuming low-fat, high-carbohydrate diets often have low rates of ASCVD, especially CHD.
Epidemiologic studies indicate that countries having high intakes of saturated fats and cholesterol carry an increased prevalence of CHD.
Peoples Republic of China-United States Cardiovascular and Cardiopulmonary Epidemiology Research Group An epidemiological study of cardiovascular and cardiopulmonary disease risk factors in four populations in the Peoples Republic of China: baseline report from the P.R.C.-U.S.A. [Collaborative Study].
In contrast, when intakes of saturated fats and cholesterol are low, whether from diets low in total fats or high in unsaturated fats, rates of CHD are relatively low. A few RCTs have evaluated the effects of saturated fats and unsaturated fats on incidence of CHD; those on a diet high in unsaturated fats had fewer CHD events.
Other dietary factors have been implicated in ASCVD risk (or protection there from). These include fruits and vegetables, fish, n-3 fatty acids, nuts, seeds, moderate alcohol intake, and low sodium/high potassium intakes.
In particular, available evidence indicates that increased consumption of some natural foods, such as tree nuts and peanuts, legumes, whole grains rich in soluble fiber like oats and barley, and cocoa products like chocolate, can reduce blood cholesterol by themselves, independently of the background diet.
Part of the cholesterol-lowering effects of seeds may be due to fiber content. It is has been demonstrated that high intakes of soluble fiber will reduce serum cholesterol levels.
Incremental reduction of serum total cholesterol and low-density lipoprotein cholesterol with the addition of plant stanol ester-containing spread to statin therapy.
Intakes of approximately 2 g per day of these products will reduce serum LDL-C levels about 10%.
None of these factors have been subjected to rigorous RCTs except for n-3 fatty acids. In the Japan eicosapentaenoic acid (EPA) lipid intervention study, a primary and secondary prevention study in patients with hypercholesterolemia, EPA reduced the risk for major coronary events when combined with a statin.
Japan EPA lipid intervention study (JELIS) Investigators Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis [Erratum in: Lancet. 2007 Jul 21;370:220].
Excess body fat adversely affects all of the lipoproteins. In some people, obesity increases LDL-C levels but it more consistently increases VLDL and lowers HDL-C.
HDL-C can decrease during active weight loss, with a typical return to baseline, or increase above baseline longer term if weight loss is maintained. In addition to improvement in lipid blood levels with nutritional and physical activity interventions, overweight, dyslipidemic patients may simultaneously experience improvement in lipid blood levels with fat weight loss promoted by weight management drug therapies as well as bariatric surgery.
American Heart Association Council on Clinical Cardiology Subcommittee on Exercise, Rehabilitation, and Prevention; American Heart Association Council on Nutrition, Physical Activity, and Metabolism Subcommittee on Physical Activity Exercise and physical activity in the prevention and treatment of atherosclerotic cardiovascular disease: a statement from the Council on Clinical Cardiology (Subcommittee on Exercise, Rehabilitation, and Prevention) and the Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on Physical Activity).
on behalf of the EACPR Writing Group Importance of characteristics and modalities of physical activity and exercise in the management of cardiovascular health in individuals with cardiovascular risk factors: recommendations from the EACPR (Part II).
Adverse risk factors induced by obesity and physical inactivity can aggregate to produce a multiplex risk factor for ASCVD and diabetes called the metabolic syndrome. This syndrome consists of atherogenic dyslipidemia (high triglyceride and low HDL-C), high blood pressure, elevated plasma glucose, a prothrombotic state, and a proinflammatory state. In many countries, the prevalence of the metabolic syndrome ranges between 20% and 30% of the adult population; in some populations, the prevalence can be even greater.
International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity.
It is recommended that the International Diabetes Federation cut points be used for non-Europeans and either the IDF or American Heart Association/National Heart, Lung, and Blood Institute cut points used for people of European origin until more data are available (See Table 2).
Population- and country-specific definitions
Increased triglycerides (drug treatment for increased triglycerides is an alternate indicator
The most commonly used drugs for increased triglycerides and reduced HDL-C are fibrates and nicotinic acid. A patient taking 1 of these drugs can be presumed to have high triglycerides and low HDL-C. High-dose n-3 fatty acids presume high triglycerides.
)
≥150 mg/dL (1.7 mmol/L)
Reduced HDL-C (drug treatment for reduced HDL-C is an alternate indicator
The most commonly used drugs for increased triglycerides and reduced HDL-C are fibrates and nicotinic acid. A patient taking 1 of these drugs can be presumed to have high triglycerides and low HDL-C. High-dose n-3 fatty acids presume high triglycerides.
)
<40 mg/dL (1.0 mmol/L) in men <50 mg/dL (1.3 mmol/L) in women
Increased blood pressure (antihypertensive drug treatment in a patient with a history of hypertension is an alternate indicator)
Most patients with type 2 diabetes mellitus will have the metabolic syndrome by the proposed criteria.
(drug treatment of elevated glucose is an alternate indicator)
≥100 mg/dL
HDL-C, high-density lipoprotein cholesterol.
∗ It is recommended that the International Diabetes Federation cut points be used for non-Europeans and either the IDF or American Heart Association/National Heart, Lung, and Blood Institute cut points used for people of European origin until more data are available (See Table 2).
† The most commonly used drugs for increased triglycerides and reduced HDL-C are fibrates and nicotinic acid. A patient taking 1 of these drugs can be presumed to have high triglycerides and low HDL-C. High-dose n-3 fatty acids presume high triglycerides.
‡ Most patients with type 2 diabetes mellitus will have the metabolic syndrome by the proposed criteria.
Table 2 lists country specific recommendations for waist circumference thresholds for abdominal obesity. The presence of the metabolic syndrome essentially doubles the risk for ASCVD.
Diabetes Prevention Program Research Group The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial.
American Heart Association; National Heart, Lung, and Blood Institute Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement [published corrections arrear in Circulation. 2005; 112:3297 and Circulation. 2005;112:e298].
National Institutes of Health Clinical guidelines on the identification, evaluation and treatment of overweight and obesity in adults: the evidence report [published correction appears in Obes Res. 1998;6:464].
Recent American Heart Association/NHLBI guidelines for metabolic syndrome recognize an increased risk for cardiovascular disease and diabetes at waist-circumference thresholds of ≥94 cm in men and ≥80 in women and identify these as optional cut points for individuals or populations with increased insulin resistance.112,121
NCEP. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.
Canadian Hypertension Education Program The 2006 Canadian Hypertension Education Program recommendations for the management of hypertension: part II-therapy.
Cooperative Meta-Analysis Group of the Working Group on Obesity in China Predictive values of body mass index and waist circumference for risk factors of certain related diseases in Chinese adults: study on optimal cut-off points of body mass index and waist circumference in Chinese adults.
AHA, American Heart Association; ATP, Adult Treatment Panel; IDF, International Diabetes Federation; NCEP, National Cholesterol Education Program; WHO, World Health Organization.
∗ Recent American Heart Association/NHLBI guidelines for metabolic syndrome recognize an increased risk for cardiovascular disease and diabetes at waist-circumference thresholds of ≥94 cm in men and ≥80 in women and identify these as optional cut points for individuals or populations with increased insulin resistance.
Cholesterol Treatment Trialists' (CTT) Collaboration Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
Another lifestyle consideration is tobacco use, particularly cigarette smoking. This is a major cause of ASCVD worldwide and a high priority must be given to prevention or cessation of cigarette smoking as a lifestyle intervention.
Statins are powerful LDL lowering drugs. They block cholesterol synthesis in the liver and increase LDL receptors, which remove LDL from the blood stream. Statins also lower VLDL, the other atherogenic lipoprotein. These agents reduce LDL-C by 25%-55%. A wealth of RCT evidence demonstrates that statins decrease risk for ASCVD events in both primary and secondary prevention.
National Heart, Lung, and Blood Institute; American College of Cardiology Foundation; American Heart Association Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines [Erratum in: Circulation. 2004;110:763].
Cholesterol Treatment Trialists' (CTT) Collaboration Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
Cholesterol Treatment Trialists' (CTT) Collaborators The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials.
American College of Cardiology; American Heart Association; National Heart, Lung and Blood Institute ACC/AHA/NHLBI clinical advisory on the use and safety of statins.
National Lipid Association Statin Safety Assessment Task Force Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force.
They do not cause liver disease, cataracts, or hemorrhagic stroke. Rare patients experience muscle damage characterized by marked elevations of creatine kinase, rhabdomyolysis, hemoglobinuria and acute renal failure. This is most likely to occur in who have complex medical problems and/or who are taking multiple medications. Predisposing medications are cyclosporine, fibrates, macrolide antibiotics, certain antifungal drugs. The combination of gemfibrozil with a statin is more likely to cause myopathy than is fenofibrate.
The most common side effect of statins is myalgia. Up to 10% of patients taking statins complain of muscle aches, weakness or other symptoms
For patients who complain of myalgias on statin therapy, alternative approaches thus must be used to obtain the needed LDL reduction. These include maximizing lifestyle therapies or using other lipid-lowering drugs. In some patients, statins can cause moderate rises in transaminases, which are not a sign of true hepatoxicity but may require reassurance.
The risk seems small, is of questionable clinical relevance, and is far outweighed by benefit of risk reduction for ASCVD. Most cases of diabetes appear in to occur in patients who already have borderline diabetes. Occasional patients complain of cognitive dysfunction while taking statins.
The possibility of these side effects indicates that statin therapy must balance benefit versus risk. Fortunately, the risk for serious side effects is low, whereas the benefit for patients at risk for ASCVD can be great.
Ezetimibe is another LDL-lowering drug. It blocks the absorption of cholesterol by the intestine. This only moderately lowers LDL-C (15%-25%).
Ezetimibe Study Group Effectiveness and tolerability of ezetimibe in patients with primary hypercholesterolemia: pooled analysis of two phase II studies [Erratum in: Clin Ther. 2001;23:1601].
Ezetimibe appears to be safe but has not been tested in RCTs against placebo in monotherapy for either safety or for efficacy to reduce ASCVD. The rationale for use of ezetimibe therefore is predicated on its ability to lower LDL levels. One use of the drug is for LDL lowering in patients with statin intolerance. Another is in combination with statins in patients with FH. It can further be used with statins to achieve very low LDL-C levels in very-high-risk patients.
IMPROVE-IT Investigators Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): comparison of ezetimibe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes.
SHARP Investigators The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial.
Fibrates are primarily triglyceride-lowering agents that also lower VLDL-C. Clinical experiences attests to their utility for treatment of severe hypertriglyceridemia to prevent development of acute pancreatitis. They also have been tested in many RCTs for prevention of CHD. A meta-analysis of these trials shows reduction for CHD morbidity of about 10%
; however, there was not a reduction in total mortality. Another meta-analysis in patients with hypertriglyceridemia found a CHD risk reduction of approximately 25%.
Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease.
Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group.
; they therefore represent an alternative in people who cannot tolerate statins. The combination of a statin + a fibrate is attractive for mixed hyperlipidemia because of a favorable effect on the lipoprotein pattern; however, evidence in RCTs of incremental risk reduction when a fibrate if added to a statin is lacking. There is a need for a specific clinical trial to test the efficacy of add-on fibrate therapy in patients with mixed hyperlipidemia.
Niacin effectively lowers triglycerides and moderately increases HDL-C. It also moderately reduces LDL-C. In one secondary prevention trial niacin reduced CHD events and total mortality.
Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins [Epub 2004 Nov 10. Erratum in: Circulation. 2005;111:e446. Circulation. 2004;110:3615].
It is well known that niacin is accompanied by a variety of side effects; of note, in Heart Protection Study 2: Treatment of HDL to Reduce the Incidence of Vascular Events (HPS-2 THRIVE), the combination of niacin and simvastatin was accompanied by an increased risk of myopathy in the Chinese population.
HPS2-THRIVE Collaborative Group HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment.
NCEP. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.
European Society of Cardiology (ESC); European Atherosclerosis Society (EAS) ESC/EAS Guidelines for the management of dyslipidaemias The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS).
NCEP. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.
; thus, the claim can be made that combining LDL and VLDL makes non-HDL-C a preferred target in patients with dyslipidemia. Because the major apolipoprotein of both LDL and VLDL is apolipoprotein B (apoB), some investigators propose the use of total apoB as an alternative to non-HDL-C.
Low-density lipoprotein particle concentration, and size as determined by nuclear magnetic resonance spectroscopy as predictors of cardiovascular disease in women.
Relations of lipoprotein subclass levels and low-density lipoprotein size to progression of coronary artery disease in the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC-I) trial.
Multivariate assessment of lipid parameters as predictors of coronary heart disease among postmenopausal women. Potential implications for clinical guidelines.
Low-density lipoprotein subfractions and the long-term risk of ischemic heart disease in men. 13-year follow-up data from the Quebec Cardiovascular Study.
A meta-analysis of low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B as markers of cardiovascular risk.
Therefore, some workers contend that total apoB is the preferred target of lipid-lowering therapy. Other reports suggest that non-HDL-C equals or exceeds the predictive power of apoB.
Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B Levels with risk of cardiovascular events among patients treated with statins.
Meta-analysis of comparison of effectiveness of lowering apolipoprotein B versus low-density lipoprotein cholesterol and non high-density lipoprotein cholesterol for cardiovascular risk reduction in randomized trials.
Thus, if total apoB is more predictive than non-HDL-C, the difference is small. A recent analysis of contemporary statin trials moreover demonstrated that on-treatment levels of non-HDL-C are more strongly associated with future risk of ASCVD events than either apoB or LDL-C.
Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B Levels with risk of cardiovascular events among patients treated with statins.
Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B Levels with risk of cardiovascular events among patients treated with statins.
These findings favor the use of non-HDL-C over LDL-C as targets of therapy. Other reasons to place primacy on non-HDL-C are that it is less expensive to measure than apoB and does not require fasting as does LDL-C.
As for HDL-C, epidemiologic studies show that levels of this lipoprotein are inversely associated with risk for ASCVD.
These studies suggest that HDL may be protective. Clinical trial evidence indicates that risk for ASCVD is modulated by HDL-C levels even when statin treatment has reduced LDL-C levels to below 70 mg/dL (1.8 mmol/L).
But because of a lack of evidence that raising HDL-C reduces risk for ASCVD, current treatment guidelines do not make a low HDL-C concentration a primary target of drug therapy. They do however support maximizing lifestyle therapies in an effort to raise HDL-C concentrations.
IAS panel deliberations
For historical and conceptual reasons, most panel members recognized LDL-C as the first target of clinical intervention for reducing the risk of ASCVD. Non-HDL-C (reflecting all atherogenic lipoproteins) was considered an equal target in patients with or without hypertriglyceridemia. Several panel members in fact favored replacing LDL-C with non-HDL-C as the primary treatment target. Others found apoB attractive as an alternative to non-HDL-C. They nonetheless recognized the increased cost of measuring apoB; most felt that any superiority of apoB over non-HDL-C is not sufficient to justify its routine measurement in either risk assessment or as a target of therapy.
An optimal apoB level for primary prevention remains to be defined. According to one study, in untreated, high-risk patients, an apoB level of <90 mg/dL is roughly equivalent to an LDL-C level <100 mg/dL and a non-HDL-C level <130 mg/dL; during statin therapy, however, to consistently reach an apoB target of <90 mg/dL, it is necessary to reduce non-HDL-C to <100 mg/dL or to reduce LDL-C to <70 mg/dL.
Statin therapy alters the relationship between apolipoprotein B and low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol targets in high-risk patients: the MERCURY II (Measuring Effective Reductions in Cholesterol Using Rosuvastatin) trial.
Comparisons of apolipoprotein B levels estimated by immunoassay, nuclear magnetic resonance, vertical auto profile, and non-high-density lipoprotein cholesterol in subjects with hypertriglyceridemia (SAFARI Trial).
Because the measurement of apoB is an immunoassay, it suffers from inconsistencies in measurement technique. Finally, the panel counted a low HDL-C as a major risk factor and recommended it be a component of global risk assessment; moreover, a low HDL-C was considered a reasonable target of lifestyle intervention but not of drug therapy.
Recommendation
Because LDL is the major atherogenic lipoprotein, LDL-C is accepted as the major target of lipid-lowering therapy. Non-HDL-C nonetheless is an alternate target and has growing advantages. Notably it includes atherogenic cholesterol-rich VLDL remnants and it does not require fasting for accurate measurement. Thus, in this document, the term atherogenic cholesterol is used interchangeably with LDL-C and non-HDL-C. It is expected that in future guidelines non-HDL-C will replace LDL-C as the better target of treatment. Total apoB is an optional target, but is not recommended as a primary target treatment. Issues of cost, lack of standardization, and lack of consensus on its use stand in the way of making apoB the primary treatment target. A low HDL-C is a target of intervention, but predominately through lifestyle therapies. Because HDL-C is independently and inversely related to ASCVD risk, it is useful as a component of global risk assessment.
Other lipid measures in primary prevention
Background
Other lipid-related measures are either predictors of ASCVD or they are potential targets of therapy. Among these are triglycerides, lipoprotein subfractions, total cholesterol/HDL-C ratios, triglyceride/HDL-C ratios, lipoprotein (a) (Lp[a]), and lipoprotein-associated phospholipase A(2) (Lp-PLA2). Elevated serum triglycerides are a positive risk predictor for ASCVD
; however, except in cases of severe hypertriglyceridemia, they are not a direct target of therapy. High triglycerides are associated with increased non-HDL-C, and for risk prediction and therapy, they are subsumed by the latter. Small, dense LDL particles likely carry ASCVD prediction.
Low-density lipoprotein particle concentration, and size as determined by nuclear magnetic resonance spectroscopy as predictors of cardiovascular disease in women.
Relations of lipoprotein subclass levels and low-density lipoprotein size to progression of coronary artery disease in the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC-I) trial.
Although positive prediction is undeniable, more small LDL particles occur in the presence of greater non-HDL-C. Effective treatment of the latter probably is sufficient. The total cholesterol/HDL-C ratio was previously promoted by Framingham investigators as a predictor of CHD.
INTERHEART Study Investigators Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study.
INTERSTROKE investigators Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study.
Both total cholesterol and HDL-C appear in Framingham global risk assessment, and so the predictive power of the ratio adds nothing to risk assessment. To date apolipoproteins and their ratios have not been incorporated into Framingham risk scoring. The triglyceride/HDL-C ratio has been shown to correlated with insulin resistance and risk for ASCVD
Accuracy of the ratio of triglycerides to high-density lipoprotein cholesterol for predicting low-density lipoprotein cholesterol particle sizes, phenotype B, and particle concentrations among Asian Indians.
The triglyceride/high-density lipoprotein cholesterol ratio predicts all-cause mortality in women with suspected myocardial ischemia: a report from the Women's Ischemia Syndrome Evaluation (WISE).
; its major usefulness is as a component of the metabolic syndrome. An elevated Lp(a) almost certainly is associated with a greater risk for ASCVD; thus, Lp(a) may have some utility in risk assessment.
Except for a modest effect of niacin, there are no efficacious drugs currently available for reducing Lp(a). Lp-PLA2 is an inflammatory enzyme expressed in atherosclerotic plaques. A collaborative meta-analysis of 32 prospective studies showed that Lp-PLA2 is positively correlated with risk for ASCVD.
Lp-PLA(2) Studies Collaboration Lipoprotein-associated phospholipase A(2) and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies.
At present, however, its use as a predictor of ASCVD has not been fully developed.
IAS panel deliberations
The panel recognized that a variety of other lipid risk factors have predictive power for ASCVD. To date, however, these factors have not been incorporated into standard risk assessment tools such as the Framingham risk scoring. Their utility thus is either limited or uncertain. Furthermore, their measurements add expense to routine risk assessment. Consequently, they cannot be recommended for routine testing. In the hands of lipid specialists some of these tests may provide useful information. For example the panel recognized that the EAS recommends screening for elevated Lp(a) in those at moderately high or high ASCVD risk, and in selected patients, niacin therapy can be employed.
Recommendations
Estimation of fasting triglycerides is useful for calculating LDL-C levels; increased triglycerides further support use of non-HDL-C as a treatment target. Determination of small dense lipoproteins is an option, but usefulness in prediction or therapy is largely subsumed by non-HDL-C. The total cholesterol/HDL-C ratio adds nothing to global risk assessment because the ratio is already part of the latter. Similarly, the triglyceride/HDL-C ratio is contained in the metabolic syndrome. An elevated Lp(a) signifies a greater risk in patients with multiple risk factors; its presence points to a need for more intensive management of other risk factors, notably atherogenic cholesterol. A high Lp-PLA2 appears to be predictive of ASCVD; but at present the test is not widely available.
Nonlipid emerging risk factors
Background
There are several so-called emerging risk factors for ASCVD.
European Society of Cardiology (ESC); European Atherosclerosis Society (EAS) ESC/EAS Guidelines for the management of dyslipidaemias The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS).
Among these are C-reactive protein (CRP), fibrinogen, plasma insulin, Lp-PLA2, homocysteine, and microalbuminuria. Among these, CRP has received the most attention. Without a doubt, CRP carries predictive power. Some investigators contend that elevated CRP signifies need for statin therapy in a person otherwise at borderline risk.
One algorithm uses CRP along with other risk factors to calculate absolute risk; this is the Reynolds risk algorithm (http://www.reynoldsriskscore.org/).
They argue that even if risk prediction with CRP (or other biomarkers of risk) is positive, the number of people who would benefit from screening is too small to justify the financial investment into routine measurement.
Among the several nonlipid risk factors, only CRP was considered worthy of use in risk-assessment algorithms. There was not full agreement on its value, although it was acknowledged that an elevated CRP associates with increased risk for ASCVD. Measurement of CRP is an option in moderate risk patients as a guide the risk-reduction therapy. If CRP is to be measured, use of the Reynolds risk score deserves consideration.
Recommendations
CRP measurement is an option in patients at moderate lifetime risk. If CRP is used, the most acceptable risk assessment tool is the Reynolds risk score.
Identifying persons at risk for ASCVD
Short-term risk assessment with major risk factors
Most guidelines adjust intensity of LDL-lowering therapy (and LDL-C goals) to absolute, short-term risk as determined by major risk factors and age. For primary prevention, several categories of risk are defined. Most algorithms estimate 10-year risk for CHD or ASCVD. In the United States, ASCVD is approximately one-third greater than CHD (2012 NHLBI Morbidity and Mortality Chart Book; http://www.nhlbi.nih.gov/resources/docs/cht-book.htm). Although risk categories vary somewhat in different guidelines, risk typically is divided into three categories of 10-year risk: high, intermediate, and low. ATP III guidelines defined high risk as 10-year risk for CHD to be >20%, intermediate risk is 5-20%, and low risk, <5%. Intermediate risk was subdivided into moderately high risk (10-20) and moderate risk (2+ risk factors or ∼ 5-9%). The EAS/ESC
European Society of Cardiology (ESC); European Atherosclerosis Society (EAS) ESC/EAS Guidelines for the management of dyslipidaemias The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS).
classifies risk according to 10-year risk for fatal cardiovascular disease: very high (>10%), high (5%-10%), moderate (intermediate) (≥1% and <5%), and low (<1%). The high risk of EAS/ESC corresponds approximately to 10-year risk for ASCVD events of 15%-30%. The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice propose similar risk assessment.
In recent Canadian guidelines, risk categories were defined in terms of 10-year risk for CHD: high: ≥20%; intermediate: 10%-19%; and low: <10%. Brazilian guidelines used the same classification. Other countries propose similar although not identical categories. Australian guidelines categorized risk for CHD as high: > 15%/5 years (>∼30%/10 years); moderate: 10%-15%/5 years (∼20-30%/10 years); and low: <10%/5 years (<∼20%/10 years). Japanese guidelines defined three categories of 10-year risk for CHD death: high: >2.0%, moderate: 0.5 to <2.0%; and low: <0.5%.
ATP guidelines have used the Framingham risk algorithm to classify risk for hard CHD (myocardial infarction and coronary death).
NCEP. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.
The prevalence in the United States of three categories of 10-year risk for CHD (≥20%; 10%-19%; and <10%) by age is shown in Figure 1.
Figure 1Ten-year risk for CHD by age decade based on National Health and Nutrition Examination Survey III data. Risk levels include high (>20%), intermediate (10%-20%), and low (<10%).
The EAS/ESC uses an algorithm called Systematic COronary Risk Evaluation (SCORE) to determine risk for fatal CVD. Another risk algorithm available in Europe is PROCAM.
The latter is similar to Framingham, except that it is adjusted for the European population (http://www.chd-taskforce.de/). The question has been raised whether Framingham scoring and SCORE overestimate the risk for CHD.
Prediction of coronary heart disease risk by Framingham and SCORE risk assessments varies by socioeconomic position: results from a study in British men.
This is a reasonable question because of the decrease in CHD rates in greater-risk populations. Available evidence indicates that Framingham scoring overestimates risk in many countries (see below).
Risk assessment with major + emerging risk factors
As discussed previously, a host of emerging lipid and nonlipid risk factors has been studied. Surprisingly few studies attempted to incorporate them into global risk assessment (including major risk factors). One exception is the metabolic syndrome, which includes both emerging and major risk factors. In US populations, patients with the metabolic syndrome appear to be at moderately high risk for CHD.
The National Cholesterol Education Program - Adult Treatment Panel III, International Diabetes Federation, and World Health Organization definitions of the metabolic syndrome as predictors of incident cardiovascular disease and diabetes.
Beyond low-density lipoprotein cholesterol: respective contributions of non-high-density lipoprotein cholesterol levels, triglycerides, and the total cholesterol/high-density lipoprotein cholesterol ratio to coronary heart disease risk in apparently healthy men and women.
Framingham investigators have further reported that the trajectory for increasing risk is greater in persons with the metabolic syndrome than in those without.
Thus, the presence of the metabolic syndrome may signify greater lifetime risk for a given Framingham risk score for 10-year risk. In a word, it is doubtful that risk associated with the metabolic syndrome is entirely subsumed by Framingham risk scoring. Moreover, there is little doubt that the metabolic syndrome is a stronger predictor of type 2 diabetes than is Framingham risk scoring.
Framingham risk scoring does not include triglycerides as one of its components. Another risk assessment tool (Prospective Cardiovascular Münster study tool) does in fact include triglycerides in global risk assessment (http://www.chd-taskforce.com/procam_interactive.html).
Simple scoring scheme for calculating the risk of acute coronary events based on the 10-year follow-up of the prospective cardiovascular Munster (PROCAM) study.
Framingham risk function overestimates risk of coronary heart disease in men and women from Germany-results from the MONICA Augsburg and the PROCAM cohorts.
They found small LDL particle number is increased in the patients with the metabolic syndrome, with increases with the number of metabolic syndrome components, and most prominently with triglycerides and HDL-C. Whereas increased small LDL particle number identified the metabolic syndrome with high sensitivity, a higher number of small LDL particle number was not associated with greater CVD event rates in those with the metabolic syndrome. They made no attempt to integrate LDL particle number into Framingham risk scoring.
Finally, there has been much interest in integrating CRP into Framingham risk assessment. One approach has been to use CRP as a "tie-breaker" to decide whether to use cholesterol-lowering drugs for a given Framingham risk score. Framingham investigators indicate that this approach has promise.
But perhaps more promising is the inclusion of CRP values into multivariate analysis so as to produce a risk assessment tool that incorporates this measure. The Reynolds risk score is the best example of this approach (http://www.reynoldsriskscore.org/).
In summary, there is promise for combining emerging risk factors with the major risk factors for estimating risk. To date, however, no consensus has gelled on how best to merge the two categories of risk factors. Consequently, until a consensus has developed, it is preferable to use algorithms that incorporate only the major risk factors. This does not detract from the usefulness of metabolic syndrome as a long-term predictor of ASCVD and type 2 diabetes. Moreover for those who desire to use CRP as a component of risk assessment, Reynolds risk scoring is an option.
Risk assessment by atherosclerosis imaging
One promising approach to improved risk assessment is through atherosclerosis imaging. Measurement of coronary artery calcium (CAC) is the most widely used approach.
American College of Cardiology Foundation Clinical Expert Consensus Task Force (ACCF/AHA Writing Committee to Update the 2000 Expert Consensus Document on Electron Beam Computer Tomography); Society of Atherosclerosis Imaging and Prevention; Society of Cardiovascular Computer Tomography ACCF/AHA 2007 clinical expert consensus document on coronary artery calcium scoring by computed tomography in global cardiovascular risk assessment and in evaluation of patients with chest pain: a report of the American College of Cardiology Foundation Clinical Expert Consensus Task Force (ACCF/AHA Writing Committee to Update the 2000 Expert Consensus Document on Electron Beam Computed Tomography).
Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group.
Coronary artery calcification compared with carotid intima-media thickness in the prediction of cardiovascular disease incidence: the Multi-Ethnic Study of Atherosclerosis (MESA).
Carotid intima-media thickness and presence or absence of plaque improves prediction of coronary heart disease risk: the ARIC (Atherosclerosis Risk In Communities) study.
These modalities can be a useful guide for stroke prevention. There is little doubt that CAC adds predictive power when combined with Framingham risk scoring.
Distribution of coronary artery calcium scores by Framingham 10-year risk strata in the MESA (Multi-Ethnic Study of Atherosclerosis) potential implications for coronary risk assessment.
Computed tomography-derived cardiovascular risk markers, incident cardiovascular events, and all-cause mortality in nondiabetics: the Multi-Ethnic Study of Atherosclerosis.
According to a recent expert committee report, CAC testing can be used as an adjunct to risk-factor scoring in intermediate risk (moderate-to-moderately high risk) patients.
American College of Cardiology Foundation Clinical Expert Consensus Task Force (ACCF/AHA Writing Committee to Update the 2000 Expert Consensus Document on Electron Beam Computer Tomography); Society of Atherosclerosis Imaging and Prevention; Society of Cardiovascular Computer Tomography ACCF/AHA 2007 clinical expert consensus document on coronary artery calcium scoring by computed tomography in global cardiovascular risk assessment and in evaluation of patients with chest pain: a report of the American College of Cardiology Foundation Clinical Expert Consensus Task Force (ACCF/AHA Writing Committee to Update the 2000 Expert Consensus Document on Electron Beam Computed Tomography).
CAC measurement in these patients could be a guide to intensity of statin therapy. Nonetheless, CAC testing is not widely available and is relatively expensive. How to use it appropriately in risk assessment is not well understood by most physicians. Therefore, CAC testing has not become a part of routine risk assessment.
Long-term risk assessment
The use of 10-year risk assessment as a sole indicator of risk is problematic because the purpose of primary prevention is to reduce lifetime risk, not 10-year risk. Estimates of 10-year risk, of course, underestimate lifetime risk except in the elderly population. This fact has led to increased interest in estimating lifetime risk.
Derivation, validation, and evaluation of a new QRISK model to estimate lifetime risk of cardiovascular disease: cohort study using Q Research database.
Risk factor burden in middle age and lifetime risks for cardiovascular and non-cardiovascular death (Chicago Heart Association Detection Project in Industry).
Distribution of 10-year and lifetime predicted risks for cardiovascular disease in US adults: findings from the National Health and Nutrition Examination Survey 2003 to 2006.
Impact of blood pressure and blood pressure change during middle age on the remaining lifetime risk for cardiovascular disease: the Cardiovascular Lifetime Risk Pooling Project.
was based on Framingham data. Risk factors included total cholesterol, systolic blood pressure, cigarette smoking, and diabetes. Four risk levels of cholesterol and blood pressure were identified. Cigarette smoking and diabetes were named major risk factors. Atherosclerotic CVD events were defined by the occurrence of myocardial infarction, coronary insufficiency, death resulting from CHD, angina pectoris, atherothrombotic stroke, intermittent claudication, or other cardiovascular death. This risk-assessment tool will hence be designated the Lloyd-Jones/Framingham algorithm (Table 3).
A potential weakness of this algorithm is that it is based on estimated risk from age 50. However, it can reasonably be assumed that an individual's risk factors (other than age) will remain constant throughout middle age and into older years. Consequently basing the estimate of long-term risk starting at age 50 should give a fairly good estimate of absolute long-term risk.
the same risk factors were used to estimate CVD mortality by age 80 from age 55 based on these same four risk factors as in the Lloyd-Jones/Framingham Risk Algorithm.
In another long-term risk predictor from the Framingham Heart Study, investigators
related the number of major risk factors to 10-year and 30-year risk for CVD morbidity and mortality in 45-year-old men and women. This algorithm is similar to that developed by Lloyd-Jones.
Derivation, validation, and evaluation of a new QRISK model to estimate lifetime risk of cardiovascular disease: cohort study using Q Research database.
This model was derived from a prospective cohort study with data collected from 563 general practices in the United Kingdom between 1994 and 2010. The study included 2,343,759 subjects in the derivation dataset and 1,267,159 in the validation dataset. Measures included smoking status, ethnic group, systolic blood pressure, total cholesterol/high density lipoprotein cholesterol ratio, body mass index (BMI), and family history of CHD disease in first degree relative aged <60 years. CVD was defined as CHD, stroke, and transient ischemic attack. The QRISK2 lifetime risk calculator is available at www.qrisk.org/lifetime/. This calculator has the advantage that it is ethnic specific, at least for the ethnicities represented in the UK.
Risk assessment calibration
Risk factors affect total risk differently in various populations. This is because of differences in baseline population risk. The latter can be defined as the inherent risk of a population beyond traditional risk factors. A multitude of factors likely contribute to baseline population risk. In an effort to adjust risk scoring for different populations, Framingham Heart Study investigators and others have attempted to recalibrate Framingham scoring for several populations.
Framingham risk function overestimates risk of coronary heart disease in men and women from Germany-results from the MONICA Augsburg and the PROCAM cohorts.
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