Lipid-Lowering Strategies and Reduction of Coronary Heart Disease Risk

Lipid-Lowering Strategies and Reduction of Coronary Heart Disease Risk



Byron J. Hoogwerf, Julie C. Huang


Observational studies have shown a relation between dyslipidemia and coronary heart disease risk for several decades.1–3 Intervention trial data over the past two or three decades have demonstrated that cholesterol modification, especially reduction in low-density lipoprotein cholesterol (LDL-C) levels, is associated with favorable effects on reduction in coronary heart disease (CHD) events (in many cases, stroke events), especially in patients at high risk for CHD.4–26 Two major fibrate trials (Helsinki Heart Study [HHS] and the Veterans Affairs HDL Cholesterol Intervention Trial VA-HIT]) have shown reductions in CHD risk, and risk reduction is associated with favorable effects on the lipid profiles.5,9–11 The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial in diabetic patients was confounded by a high percentage of statin drop-in.27,28 Thus, the cholesterol-lowering guidelines have had LDL-C as the primary target for lipid modification.


In 1988, the first National Cholesterol Education Program (NCEP) was begun in an effort to establish targets for cholesterol levels based on assessments of risk.29 (These guidelines were written by a panel of experts and, in subsequent publications, have been referred to as the Adult Treatment Panel [ATP], with Roman number specification for subsequent sets of guidelines—e.g., ATP II, ATP III). The NCEP guidelines were evidence based, used CHD risk assessment for the recommended LDL-C targets and were relatively simple for health care providers, patients, and payers to understand. Over the past two decades, the NCEP guidelines have changed in terms of lipid targets based on information obtained from clinical trials and observational studies.30–35 These guidelines have been supported by other organizations, including the American Heart Association (AHA), American College of Cardiology (ACC), American Diabetes Association (ADA), American Association of Clinical Endocrinologists (AACE), and American College of Physicians (ACP).36–41 Furthermore, nutrition studies and new medications (especially statin therapy) have become available, resulting in accumulating information on lipid-altering strategies.


This chapter reviews the history of the guidelines, how new information has resulted in changing targets, and current approaches to CHD risk assessment and gives a summary of approaches to lowering cholesterol.



HISTORY


The Lipid Research Clinic Coronary Primary Prevention Trial20,21 was the first large-scale randomized, double-blind, placebo-controlled clinical trial of LDL-C lowering in high-risk men between the ages of 30 and 59. At baseline, LDL-C levels were typically in the 175- to 190-mg/dL range. LDL-C values in the cholestyramine-treated subjects approached the 130-mg/dL range. This trial was the underpinning for the first set of NCEP guidelines, which proposed that patients with and without CHD who had two or more risk factors for CHD have an LDL-C target of 130 mg/dL or lower. Lower risk patients with fewer risk factors had correspondingly higher LDL-C targets. The second set of NCEP guidelines came a few years later.33 However, over the next decade, a number of clinical end point cholesterol trials in both high-risk primary prevention (no prior known CHD) and secondary prevention (with known CHD) were carried out across a wide range of entry LDL-C levels. Thus, in 2001, NCEP released the third set of guidelines.34 This set of guidelines incorporated the results of randomized controlled clinical trials into recommendations for the management of high cholesterol levels. Since the publication of the ATP III, several additional five major clinical trials of statin (3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitor) cholesterol-lowering therapy have been published. Consequently, in 2004, an update to the ATP III guidelines was released, suggesting a reset of treatment thresholds and targets.32


In contrast to previous versions of ATP (I and II), ATP III placed greater emphasis on the prevention of CHD in patients with multiple risk factors, in addition to treatment for secondary prevention. The ATP III treatment algorithm divided patients into three risk categories based on clinical characteristics and the Framingham 10-year risk score:


1 Established CHD and CHD risk equivalents: High risk (10-year risk higher than 20%)

2 Multiple (two or more) risk factors: Moderately high risk (10-year risk, 10% to 20%); moderate risk (10-year risk lower than 10%)

3 Zero to one (one or none) risk factor: Lower risk (10-year risk lower than 10%)

ATP III greatly expanded the high risk category by defining CHD risk equivalents, including noncoronary atherosclerotic disease, such as peripheral vascular and carotid disease, and abdominal aortic aneurysm; diabetes mellitus; and multiple CHD risk factors conferring an estimated 10-year risk for a cardiovascular event of more than 20%. ATP III major risk factors include the following:


• Age (men, 45 years; women, 55 years)

• Cigarette smoking

• Hypertension (blood pressure = 140/90 mm Hg or patient is on antihypertensive medications)

• Low high-density lipoprotein (HDL) cholesterol level (lower than 40 mg/dL in men, lower than 50 mg/dL in women; HDL cholesterol ≥60 mg/dL is a negative risk factor)

• Family history of premature CHD: Male first-degree relative younger than 55 years or female first-degree relative younger than 65 years)

According to the ATP III, the LDL-C goal for high-risk patients is less than 100 mg/dL. For all patients in the high-risk category with LDL-C > 100 mg/dL, LDL-C-lowering dietary therapy should be initiated. In addition, for patients with LDL-C higher than 130 mg/dL, an LDL-C-lowering drug should be started. However, in the LDL-C range of 100 to 129 mg/dL, ATP III guidelines did not mandate drug therapy; rather, therapeutic options included intensified dietary therapy, LDL-C-lowering drugs, or drug therapy for elevated triglyceride or low HDL-C levels. At the time of publication of the guidelines for ATP III, there were not enough data to recommend more intensive drug therapy for this intermediate range of LDL-C.


These recommendations were modified in the ATP III update of 2004, which recommended an LDL-C goal lower than 100 mg/dL for high-risk patients, with an optional goal of lower than 70 mg/dL for very high-risk patients (Table 1). This update also recommended initiating dietary therapy and LDL-C-lowering drugs for all patients over goal, with a planned LDL-C reduction of 30% to 40%. The rationale for these changes was based on several randomized clinical trials whose results were published after the release of the ATP III guidelines. These trials included the Heart Protection Study (HPS), which evaluated the effects of simvastatin, 40 mg daily, versus placebo in a group of 20,536 patients aged 40 to 80 years at high risk for CHD.4,7 This included patients with coronary disease, other occlusive arterial disease, or diabetes (analogous to the ATP III CHD risk equivalent designation), followed for a 5-year period. Patients treated with simvastatin had a 24% overall reduction in major adverse cardiovascular events compared to placebo; similar propational risk reduction was seen even in subjects with baseline LDL-C <100 mg/dl. The Pravastatin or Atorvastatin Evaluation and Infection—Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) was designed to test noninferiority of a less aggressive cholesterol-lowering regimen.42 Ultimately, it showed that intensive LDL-C level lowering with atorvastatin, 80 mg daily, reduced cardiovascular risk more than standard drug therapy with pravastatin, 40 mg, in a group of high-risk patients hospitalized for acute coronary syndromes. The mean LDL-C level attained was 95 mg/dL with pravastatin and 62 mg/dL with atorvastatin. The study demonstrated a 16% reduction in the composite cardiovascular end point in the atorvastatin group compared with the pravastatin group (P < 0.005). Other trials used to support these revised guidelines included the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER),17 Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial-Lipid-Lowering Trial (ALLHAT-LLT),19 and Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA),24 a trial that evaluated two antihypertensive regimens and a lipid-lowering arm with atorvastatin.



Table 1 Summary of ATP III Guidelines Update, 200432

image

Finally, in the evolution of the cholesterol guidelines, the AHA/ACC guidelines for secondary prevention of CHD released in 200640 placed more weight behind the optional goal of LDL-C lower than 70 mg/dL in high-risk patients with CHD, based on data accrued from the Treat to New Targets (TNT) and Incremental Decrease in Endpoints through Aggressive Lipid Lowering (IDEAL) trials.43,44 It was formulated as a Class IIa recommendation and stated that




it is reasonable to treat to LDL <70 mg/dL in such (secondary prevention) patients. When the <70-mg/dL target is chosen, it may be prudent to increase statin therapy in a graded fashion to determine a patient’s response and tolerance. Furthermore, if it is not possible to attain LDL-C <70 mg/dL because of a high baseline LDL-C, it generally is possible to achieve LDL-C reductions of >50% with either statins or LDL-C-lowering drug combinations.40



RISK ASSESSMENT


Several variables have been taken into consideration to determine CHD risk. Any patient who has had a CHD event is at markedly increased risk for a subsequent event. Risk models such as the Framingham risk score1 are used in risk adjustment. Any patient who has a higher than 20% risk for a CHD event based on the Framingham risk score is considered to be at equivalent risk to a patient with established CHD. The Framingham risk score does not take into account family history because of difficulty obtaining this measure in all patients. Furthermore, it does not include some of the newer markers such as high-sensitivity C-reactive protein (hsCRP) or albuminuria (see later)45–47 or the components of the metabolic syndrome such as waist circumference and trighycerides.48 Current guidelines and many clinical studies consider diabetes mellitus as a CHD risk equivalent (>20% risk over 10 years) in setting targets for LDL-C and non–HDL-C levels.*


Although many diabetic patients are not CHD risk-equivalent based on models such as the UKPDS risk engine, this approach does ensure that high-risk diabetic patients are treated aggressively. Low HDL-C concentrations are associated with increased CHD risk. Studies such as AFCAPS/TEXCAPS have demonstrated that aggressive LDL-C lowering attenuates much of the adverse risk associated with low HDL-C.25,26 There are compelling data showing that hs CRP is associated with increased risk for CHD, even when adjustments are made for other risk factors. Current guidelines suggest that hs CRP be used to help in risk assessment in patients who have intermediate risk for CHD.45,47,56


Other markers of risk have not been consistently included in guidelines but need to be considered in clinical practice. Renal dysfunction is associated with an increased risk for CHD. This is true for markers of renal disease such as albuminuria, but several studies have shown that impaired renal function is associated with marked increases in CHD risk, especially when associated with the need for renal replacement therapy (dialysis or renal transplantation). Peripheral vascular disease and cerebrovascular disease are also associated with increased risk for CHD events. Furthermore, most statin trials have shown a reduction in risk for stroke, although stroke event rates are consistently lower than CHD event rates in most studies. Several observational studies have suggested that patients who have systemic inflammatory disorders such as rheumatoid arthritis and systemic lupus erythematosus, especially if they are treated with glucocorticoids, are at increased risk for CHD. Similarly, organ transplant recipients, especially renal, heart, and lung transplants, may be at increased risk for CHD. Many CHD risk prevention clinics, including the Preventive Cardiology Clinic at the Cleveland Clinic, have set more aggressive LDL-C targets for such patients, even though intervention trial data are lacking. This approach extends the general concept of more aggressive lipid lowering in patients at increased risk of disease.



LIPID-LOWERING TREATMENT



Diet and Lifestyle


All patients, whether in secondary or primary prevention categories, are strongly recommended to implement lifestyle and dietary recommendations as part of a strategy to prevent cardiovascular disease. Healthy eating habits, starting from childhood, are the cornerstone for cardiovascular risk reduction and, together with lifestyle goals, including maintenance of healthy body weight, avoidance of tobacco products, and adherence to a regimen of physical activity, may be termed elements of primordial prevention.


Specifically, the American Heart Association recommends a diet low in fat, particularly saturated and trans fats, enriched in fruits, vegetables, whole grains, and fish, and low in added sugar and salt (Table 2).57 This approach, especially regarding fat intake, is supported by other nutrition guidelines.49,58,59 Controversies regarding the superiority of the Mediterranean diet (including higher proportions of monounsaturated fats and omega-3 fatty acids) over the traditional AHA step II diet may have been settled recently by a study showing their relative equivalence in lipid lowering and risk reduction. In addition, a study of a diet enriched in plant sterols, soy protein, viscous fiber, and almonds has shown comparable reductions in LDL-C and CRP as compared with lovastatin, 20 mg.60 These findings all highlight the importance of dietary intervention in prevention.


Table 2 Therapeutic Lifestyle Changes: Diet Recommendations







































Nutrient Recommended Intake
Total fat 25%-35% of total calories
Saturated fat Less than 7% of total calories
Polyunsaturated fat Up to 10% of total calories
Monounsaturated fat Up to 20% of total calories
Trans fat <1% of total calories
Cholesterol <200 mg/day
Carbohydrate 50%-60% of total calories
Fiber 20-30 g/day
Protein Approximately 15% of total calories
Total calories (energy) Balance energy intake and expenditure to maintain desirable body weight and prevent weight gain.
Other
Consume a diet rich in fruits and vegetables.

Choose whole-grain, high-fiber foods.

Consume fish, especially oily fish, at least twice a week.

Avoid fish with potential for mercury contamination.

Minimize intake of beverages and foods with added sugars.

Choose and prepare foods with little or no salt.

Consume alcohol in moderation. Men, two drinks/day; women, one drink/day

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Jul 18, 2017 | Posted by in GENERAL SURGERY | Comments Off on Lipid-Lowering Strategies and Reduction of Coronary Heart Disease Risk

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