Practice Guidelines

AHA Publishes Statement on Drug Therapy for Lipid Abnormalities in Children and Adolescents

SHERRI DAMLO

Drug therapy for patients with high-risk lipid abnormalities has resulted in advances in the treatment and prevention of atherosclerotic cardiovascular disease (CVD) in adults. Evidence suggests that atherosclerotic CVD begins in childhood and that its progression is accelerated by lipid abnormalities. Being overweight during childhood and having associated lipid abnormalities may persist into adulthood. Effective population-based strategies are essential to reversing this trend, but drug therapy may benefit selected persons with associated high-risk conditions, risk factors, or more extreme lipid abnormalities in whom lifestyle modifications are not sufficiently effective.

There is a reluctance to use drug therapy to treat lipid abnormalities in children, but evidence suggests that drug therapy is as effective at lowering cholesterol in children as in adults, with similar short-term safety. Therefore, the American Heart Association (AHA) examined the challenges with existing guidelines and published a scientific statement on patient selection, monitoring, initiation, and maintenance of drug therapy for the treatment of high-risk lipid abnormalities in children and adolescents.

Existing Guidelines

Existing guidelines for the screening and management of lipid abnormalities in children and adolescents are based on a consensus report from the National Cholesterol Education Program (NCEP) Expert Panel on Blood Cholesterol Levels in Children and Adolescents. To help lower elevated cholesterol levels in children and adolescents, the panel recommended a population-based approach that would shift the population distribution of cholesterol levels. It also recommended a targeted screening approach that would identify persons with elevated low-density lipoprotein cholesterol (LDL-C) levels who need additional monitoring and management.

population-based approach

Dietary Modification. The diets of all healthy children older than two years should be fat- and cholesterol-restricted, with the appropriate amount of calories to support proper development and growth and to maintain a desirable body weight. Children and adolescents should consume a wide variety of foods to achieve an average daily food intake that includes no more than 10 percent of total calories from saturated fat, no more than 30 percent of total calories from fat, and no more than 300 mg of dietary cholesterol.

Lifestyle modifications and a more restrictive diet should be implemented in children whose LDL-C levels remain greater than 130 mg per dL (3.35 mmol per L) despite compliance with the recommended fat- and cholesterol-restricted diet. For these children, saturated fat intake should be limited to less than 7 percent of total daily caloric intake, and cholesterol intake should be less than 200 mg per day.

Drug Therapy. Lipid-lowering drug therapy is recommended for children 10 years and older whose LDL-C levels remain extremely elevated after six months to one year of dietary modification. Drug therapy also can be considered for children with LDL-C levels of 190 mg per dL (4.90 mmol per L) or greater. Children who may also require treatment are those whose levels are 160 mg per dL (4.15 mmol per L) or greater and who have two or more risk factors for CVD or a family history of premature CVD.

targeted screening approach

Universal cholesterol screening is not recommended because not all children with high cholesterol levels will have high enough cholesterol levels as adults to warrant treatment. There also is not sufficient evidence to suggest the effectiveness and long-term safety of treating children to reduce the risk of coronary heart disease morbidity or mortality into adulthood. However, therapy should be initiated at an early age for children with a family history of premature CVD, parental hypercholesterolemia, or both. Therefore, in the context of regular health care, selective screening is recommended (Figure 1).

Limitations

selective screening

The NCEP guidelines do not consider the variability in total cholesterol and high-density lipoprotein cholesterol (HDL-C) levels based on sexual maturation, race, or sex. This has a significant impact on the specificity and sensitivity of screening.

Black children tend to have higher levels of total cholesterol and HDL-C compared with white children.In addition, girls tend to have higher total cholesterol levels than boys, so sensitivity may be higher in girls, but specificity will be lower.

patient compliance

Patient compliance with screening recommendations can impact the effectiveness of the guidelines, and noncompliance occurs at all levels. Multiple office visits and blood draws are barriers in children, and parents may not understand variability in cholesterol levels.

cholesterol levels

The existing guidelines primarily focus on elevated LDL-C levels and do not address decreased HDL-C levels, hypertriglyceridemia, or other lipoprotein abnormalities. These abnormalities, which are associated with obesity and the metabolic syndrome, may be more prevalent in children and adolescents.

dietary modifications

Evidence suggests that a fat- and cholesterol-restricted diet may have only a limited effect on LDL-C levels and may increase triglyceride levels. Therefore, many children will not achieve target LDL-C levels, but they may also transition to combined hyperlipidemia.

Drug Therapy

bile acid-binding resins

Atlhough the NCEP guidelines recommend bile acid-binding resins as the initial treatment in children, the AHA notes that this therapy is associated with poor palatability, which can lead to poor compliance; a high prevalence of gastrointestinal complaints; and limited effectiveness. Bile acid-binding resins may interfere with the absorption of fat-soluble vitamins and some medications, and they may cause increases in triglyceride levels. Increased homocysteine levels also have been noted in some patients. Therefore, it is unlikely that bile acid-binding resins will be sufficient to achieve the targeted LDL-C levels in children. A nonresin tablet form of bile acid sequestrant, colesevelam (Welchol), in combination with statin therapy, may be better tolerated in these patients.

statins

Evidence suggests that statin therapy significantly reduces cardiovascular and all-cause mortality rates in adults with, or at risk of, manifested atherosclerotic CVD. Although children do not seem to have more adverse events than adults, the effectiveness and ultra-long-term safety of these drugs and patient compliance remain of concern.

Guidelines recommended by the AHA for the titration, monitoring, and initiation of statin therapy in children and adolescents with hyperlipidemia appear in Table 1.

Table 1. Recommendations for the Use of Statins in Children and Adolescents with Hyperlipidemia

Patient selection Use NCEP guidelines for drug initiation Patient age and LDL level at which statin therapy is initiated may be influenced by the presence, magnitude, and number of other cardiovascular risk factors, as well as the presence of cutaneous xanthomas Consider patient and family preferences In general, therapy should not be initiated before 10 years of age in boys or before the onset of menses in girls. Patients should ideally be at Tanner stage II or higher Ensure that patient does not have contraindications for statin therapy (e.g., significant hepatic disease)

Initiation and titration Choice of statin should be based on patient and family preference Begin therapy with the lowest daily dose, usually at bedtime. Measure baseline CK, ALT, and AST Patient should report potential adverse effects, especially myopathy; if myopathy is present, its relation to recent physical activity should be assessed, treatment should be stopped, and CK should be measured; monitor the patient for resolution of myopathy and any associated increases in CK; medication may be restarted once symptoms and laboratory abnormalities are resolved Advise female patients of concerns related to pregnancy and the need for contraception Advise patients about drug interactions Measure fasting lipoprotein profile, CK, ALT, and AST after four weeks and compare with laboratory-specific reported normal values If target LDL levels are achieved and no laboratory abnormalities exist, continue therapy; recheck at eight weeks and three months If laboratory abnormalities are noted or symptoms are reported, temporarily discontinue treatment and repeat blood work in approximately two weeks; when abnormalities resolve, treatment may be restarted with close monitoring If target LDL levels are not achieved, double the dose and repeat blood work at four weeks; continue stepped titration through the maximum recommended dose until target LDL levels are achieved or there is evidence of toxicity

Monitoring Monitor patient growth, sexual maturation, and development (Tanner staging) Monitor fasting lipoprotein profile, CK, ALT, and AST every three to six months Monitor and encourage patient compliance with lipid-lowering dietary and drug therapy; serially assess and counsel patient for other risk factors, including weight gain, smoking, and inactivity Counsel female patients about contraindications in pregnancy with statin therapy and the need for abstinence or use of contraceptive measures; refer patient to a subspecialist, if appropriate

NCEP = National Cholesterol Education Program; LDL = low-density lipoprotein; CK = creatine kinase; ALT = alanine aminotransferase; AST = aspartate aminotransferase. Adapted with permission from McCrindle BW, Urbina EM, Dennison BA, et al., for the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee; American Heart Association Council of Cardiovascular Disease in the Young; American Heart Association Council on Cardiovascular Nursing. Drug therapy of high-risk lipid abnormalities in children and adolescents: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee, Council of Cardiovascular Disease in the Young, with the Council on Cardiovascular Nursing. Circulation. 2007;115:1959.

niacin

Niacin is rarely used to treat children and adolescents with lipid abnormalities. There are limited data on the use of niacin for the treatment of these patients, but existing evidence suggests that niacin is poorly tolerated, and it has the potential for serious adverse events. Therefore, the AHA does not recommend the routine use of niacin in children and adolescents; however, it may be considered in selected patients.

fibric acid derivatives

Fibric acid derivatives raise HDL-C levels and lower triglyceride levels, but the underlying mechanism of action is complex. If fibric acid derivatives are combined with other agents, especially statins, or used in patients with renal insufficiency, the risk of myopathy and rhabdomyolysis is markedly increased.

Fibric acid derivatives, however, are well tolerated in children and adolescents, and they do not impact growth or development. Therefore, the AHA recommends this class of drugs as the preferred treatment in children with severe elevations in triglyceride levels who are at risk of pancreatitis.

Conclusions

Evidence on drug therapy in children and adolescents with high-risk lipid abnormalities suggests that its effectiveness at lowering lipids and safety are similar to those in adults. However, the AHA suggests that the existing NCEP guidelines have limitations that have been magnified by the number of children who are overweight or obese. In addition, no studies have determined the benefit of initiating treatment in childhood compared with waiting until adulthood. Modifications are needed for these guidelines, and they should incorporate new evidence on multiple risk-factor scoring and its association with atherosclerotic pathology. In addition, drug therapy should be targeted only toward persons with high-risk conditions or lipid abnormalities who have not reached target lipid levels with lifestyle modifications. They should not be used as first-line treatment for persons whose lipid abnormalities are primarily lifestyle related.

editor's note: It is tempting to believe that lowering cholesterol levels in children will improve their long-term health outcomes. However, there is insufficient evidence to suggest that early intervention improves patient-oriented outcomes compared with intervention in adulthood. Given the uncertain effect on all-cause mortality and the high cost and potential risks of drug treatment with fibrates or statins in this population, treatment should be limited to patients who have the highest risk. Research in adults has consistently shown that patients with the highest risk benefit the most from cardiovascular interventions.-MARK H. EBELL, MD, MS

AAN Releases Recommendations for Treating Lyme Disease Neuroborreliosis

Lyme disease is a multisystem, tick-borne infection that often affects the nervous system (neuroborreliosis). Although guidelines are available for the treatment of general Lyme disease, the best treatment option for neuroborreliosis is unclear. The Quality Standards Subcommittee of the American Academy of Neurology (AAN) convened an expert panel to review the literature and determine the following: (1) which antimicrobial agents are effective or ineffective, (2) whether different regimens are preferred for different manifestations, (3) what duration of therapy is needed, and (4) whether prolonged regimens are more beneficial.

The subcommittee concluded that parenteral penicillin, ceftriaxone (Rocephin), cefotaxime (Claforan), and oral doxycycline (Vibramycin) are probably safe and effective therapies for neuroborreliosis without parenchymal involvement. Oral amoxicillin and cefuroxime (Ceftin) are alternatives to doxycycline, although research on their use is lacking. Parenteral regimens are usually used to treat neuroborreliosis; however, doxycycline may be as effective in patients with some neuroborreliosis-related diseases (Table 1).

Table 1. Treatment Options for Manifestations of Lyme Disease Neuroborreliosis
Disease	Treatment options
Meningitis	Parenteral antibiotics, particularly if severe, or oral doxycycline (Vibramycin)
Any neurologic disease with pleocytosis	Parenteral antibiotics, particularly if severe, or oral doxycycline
Peripheral nerve diseases (radiculopathy, diffuse neuropathy, mononeuropathy multiplex, cranial neuropathy); normal cerebrospinal fluid	Oral doxycycline or parenteral antibiotics if severe or if doxycycline therapy fails
Encephalomyelitis	Parenteral antibiotics
Encephalopathy	Parenteral antibiotics
Posttreatment Lyme syndrome	Symptomatic management, antibiotics are not indicated
NOTE: Doxycycline is usually contraindicated in children younger than eight years and in pregnant or lactating women; oral amoxicillin and cefuroxime (Ceftin) are alternatives to doxycycline. Adapted with permission from Halperin JJ, Shapiro ED, Logigian E, et al. Practice parameter: treatment of nervous system lyme disease (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2007;69:99.

Prolonged courses of antibiotics do not improve outcomes in patients with neuroborreliosis and may be associated with adverse effects; therefore, prolonged courses are not recommended. Table 2 presents antimicrobial agents and dosages used to treat neuroborreliosis.

Table 2. Antimicrobial Regimens for the Treatment of Lyme Disease Neuroborreliosis
	Dosage
Medication	Adults	Children
Oral regimens
Doxycycline* (Vibramycin)	100 to 200 mg, twice per day	Children eight years or older: 4 to 8 mg per kg per day in two divided doses, maximum is 200 mg per dose
Amoxicillin†	500 mg, three times per day	50 mg per kg per day in three divided doses, maximum dose is 500 mg per dose
Cefuroxime† (Ceftin)	500 mg, twice per day	30 mg per kg per day in two divided doses, maximum is 500 mg per dose
Parenteral regimens
Ceftriaxone (Rocephin)	2 g IV, once per day	50 to 75 mg per kg IV per day in one dose, maximum is 2 g per dose
Cefotaxime (Claforan)	2 g IV, every eight hours	150 to 200 mg per kg IV per day in three or four divided doses, maximum is 6 g per day
Penicillin G‡	18 to 24 million U per day in divided doses given every four hours	200 to 400,000 U per kg per day in divided doses given every four hours; maximum is 18 to 24 million U per day
NOTE: The recommended duration for all regimens is 14 days. IV = intravenously. *-Preferred therapy; usually contraindicated in children younger than eight years and in pregnant or lactating women. †-When doxycycline is contraindicated. ‡-Reduce dosage in patients with impaired renal function. Adapted with permission from Halperin JJ, Shapiro ED, Logigian E, et al. Practice parameter: treatment of nervous system lyme disease (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2007;69:98.

The subcommittee recommends future research to further clarify the best treatment regimens for neuroborreliosis.

AMBER HUNTZINGER

AHA Guidelines on Cardiac CT for Assessing Coronary Artery Disease

Over the past decade, electron beam computed tomography (CT) and multidetector CT have increasingly been used to identify and measure coronary artery calcification. Calcification levels can be related to the extent and severity of underlying atherosclerosis and can potentially improve cardiovascular risk prediction. However, broad use of these methods for screening is controversial. The American Heart Association (AHA) has released guidelines for the use of cardiac CT when evaluating patients for coronary artery disease (Table 1).

Table 1. AHA Recommendations for the Use of Cardiac CT for the Assessment of CAD
Recommendations	Level of evidence*
Asymptomatic patients should be assessed for cardiovascular risk using tools such as the Framingham Risk Score; those found to be at low risk (10-year risk of less than 10 percent) or high risk (10-year risk of more than 20 percent) do not benefit from coronary calcium assessment	B
In clinically selected, intermediate-risk patients (10-year risk of 10 to 20 percent), it may be reasonable to measure the atherosclerosis burden using electron beam CT or multidetector CT to refine clinical risk prediction and to select patients for more aggressive target values for lipid-lowering therapies	B
Coronary calcium assessment may be reasonable in symptomatic patients, especially in the setting of equivocal treadmill or functional testing	B
Coronary calcium assessment may be considered in symptomatic patients to determine the cause of cardiomyopathy	B
Coronary calcium assessment may be considered in patients with chest pain who have equivocal or normal ECG findings and negative cardiac enzyme test results	B
CT coronary angiography is reasonable for the assessment of obstructive disease in symptomatic patients	B
Electron beam CT and multidetector CT for detecting restenosis after stent placement cannot be recommended	C
CT coronary angiography for the assessment of noncalcified plaque or to track atherosclerosis or stenosis over time is not recommended	C
CT coronary angiography is not recommended in asymptomatic persons for the assessment of occult CAD	C
Serial imaging for the assessment of coronary calcification progression is not indicated	C
The use of hybrid scanning to assess cardiovascular risk or the presence of obstructive disease is not recommended	C
AHA = American Heart Association; CT = computed tomography; CAD = coronary artery disease; ECG = electrocardiogram. *-A = data derived from multiple randomized clinical trials; B = data derived from a single randomized trial or nonrandomized studies; C = consensus opinion of experts.

Asymptomatic patients at low or high risk of cardiovascular disease do not benefit from coronary calcium measurements. However, these measurements may benefit asymptomatic, intermediate-risk patients by refining the risk assessment and prompting lifestyle changes and pharmacologic therapy. Coronary calcium measurements may be reasonable in some symptomatic patients, especially to determine the etiology of cardiomyopathy, to assess patients who have equivocal treadmill or functional test results, and to assess patients with chest pain who have equivocal or normal echocardiography findings and negative cardiac enzyme test results.

Research is lacking on the use of serial cardiac CT in assessing subclinical atherosclerosis over time and in detecting noncalcified plaque, although further evidence is emerging. Research is also ongoing to determine the benefit of hybrid scanning in assessing cardiovascular risk and in detecting obstructive disease.

AMBER HUNTZINGER

Answers to This Issue's Clinical Quiz Q1. B Q2. A Q3. C Q4. B Q5. B Q6. A Q7. B Q8. C Q9. C Q10. A Q11. A Q12. A, C, D Q13. A, C, D

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