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1. Introduction

The Expert Panel's goal was development of comprehensive evidence-based guidelines addressing all of the major CV risk factors to assist pediatric care providers—pediatricians, family practitioners, nurses and nurse practitioners, physician assistants, and registered dietitians—in both the promotion of CV health and the identification and management of specific risk factors from infancy to young adulthood. An initial assessment indicated that an innovative approach would be needed to develop a comprehensive integrated product for the following reasons:

  • A focus on CV risk reduction in children and adolescents addresses a disease process—atherosclerosis—in which the clinical end point of manifest cardiovascular disease (CVD) occurs much later in life. Therefore, the recommendations would need to address two different goals:  the prevention of risk factor development—primordial prevention—and the prevention of future CVD by effective management of identified risk factors—primary prevention.
  • Most systematic evidence reviews address one or, at most, a small number of finite questions addressing the impact of specific interventions on specific health outcomes. A rigorous literature search and review process involving explicit inclusion and exclusion criteria often results in only a handful of in-scope articles for inclusion in the review. These reviews seek direct, rigorous evidence of the causal effect of an intervention on the designated outcomes or indirect evidence in the form of a chain of causal evidence through surrogate or other intermediate outcomes linking the interventions to the outcomes of interest. Often, in-scope evidence is limited to randomized controlled trials (RCTs), systematic reviews, and meta-analyses published over a defined time period. There is a defined format for abstracting studies, grading the evidence, and presenting the results. The level of evidence leads to the conclusions and recommendations.
  • Because of the scope of the effort by the Expert Panel, this evidence review needed to address a broader array of questions concerning the development, progression, and management of multiple CV risk factors extending from before birth to 21 years of age, including studies with followup into later adulthood—a scope and breadth that had known gaps in the evidence base. In part, this task required assembling and appraising the body of evidence pertaining to the role of single risk factors and risk factor combinations in childhood in the development and progression of atherosclerosis from childhood and adolescence to adulthood. Rather than relying solely on RCTs, much of the evidence for guidelines in youth is available from epidemiologic observational studies, which must be included in the review. In addition, this review required critical appraisal of the body of evidence that addresses the impact of managing risk factors in childhood on the development and progression of atherosclerosis. Finally, because of known gaps in the evidence base relating risk factors and risk reduction in childhood to clinical events in adulthood, the review had to include the available evidence justifying the evaluation and treatment of risk factors in childhood. The process of identifying, assembling, and organizing the evidence was extensive; the review process was complex; and conclusions could be developed only by interpretation of the body of evidence. Thus, there was explicit Expert Panel involvement throughout the evidence review process.

The Expert Panel defined 14 critical questions for the literature search (Table 1-1) and the risk factors to be addressed (Table 1–2). The first phase of the evidence review focused on critical questions 1–9, which address the association between the development of atherosclerosis and the presence and intensity of CVD risk factors in childhood and adolescence. The second phase of the evidence review addressed critical questions 10–14, which aim to assess the evidence for the safety and efficacy of reduction of each risk factor and the impact of risk factor change on the atherosclerotic process.

In addition to the typical RCTs, systematic reviews, and meta-analyses, two additional types of studies were considered to provide evidence pertaining to the development of atherosclerosis. Longitudinal observational studies were included to assess the tracking of risk factors from youth to adulthood and the relationship of risk factors in youth to the development of atherosclerosis. From the many available observational studies in the literature, the Panel identified the 12 listed in Table 1–3 for inclusion in the evidence review. The panel used several criteria to evaluate which studies should be in the evidence review, including sample size, and for longitudinal studies the length of followup. In general, the studies were large, averaging more than 1,000 subjects. Smaller studies that had long-term followup allowing evaluation of the relationship between risk factors identified in infancy and early childhood and adolescent and adult endpoints were also included. In addition, natural history studies of genetic disorders known to alter CV risk status were included to provide models of the consequences of prolonged risk exposure or risk protection.

The Expert Panel selected a literature search start date of January 1,1985, roughly 5 years before the previous expert panel process that had generated guidelines for the management of cholesterol in childhood, the National Cholesterol Education Program's Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents, which was published in 1992.[1]  From an initial group of more than 1 million titles published between January 1, 1985, and June 30, 2007, the search was refined to ultimately include 648 studies: 50 systematic reviews, 33 meta-analyses, 293 RCTs, 194 observational studies, and, in addition, 78 sets of guidelines relevant to pediatric CVD prevention, which were provided as reference material. Each of the first four listed types of studies underwent full text review and abstraction of critical information into evidence tables; each study was graded individually using a unique algorithm developed for these Guidelines. Details of the search methodology and the abstraction and individual study grading processes are provided in Appendix A. Methodology. The evidence tables are available electronically on the NHLBI Web site at http://www.nhlbi.nih.gov/guidelines/cvd_ped/index.htm.

Expert Panel members were grouped into subcommittees to focus on specific risk factors according to their respective areas of expertise, with many Expert Panel members participating on more than one subcommittee. In addition, two oversight committees were formed: (1) a Science Team to ensure high scientific quality of the entire evidence review and Guidelines development process and (2) a Clinical Team to maintain the relevance of the recommendations to clinical practice throughout Guidelines development. The Science Team, led by Samuel S. Gidding, M.D., addressed the first nine critical questions and summarized the evidence for the origins of atherosclerosis in childhood and the evidence for the role of risk factors in the atherosclerotic process in Section II. State of the Science: Cardiovascular Risk Factors and the Development of Atherosclerosis in Childhood. For each risk factor, the Expert Panel provided an overview of the evidence, focusing on those studies it believed provided the most important information. These summaries are provided in the risk factor-specific sections of this document. Because of the volume and complexity of the literature review, specific information on every study is provided only in the evidence tables. The risk factor subcommittees critically evaluated the body of evidence relative to each risk factor, using an evidence grading system from the American Academy of Pediatrics (AAP) (Table 1–4).[2]  As shown in Table 1–4, the AAP evidence grading system was modified to incorporate genetic natural history studies in the Grade B evidence category. Each risk factor subcommittee then formulated age-specific recommendations with grade and strength of recommendation assigned using the AAP grading system, based on consideration of the entire body of evidence used in developing each recommendation. The age categories corresponded with the system used by the AAP publication Bright Futures: Guidelines for Health Supervision of Infants, Children and Adolescents.[3]  Each risk factor subcommittee reached internal consensus before presenting its recommendations to the full Expert Panel. The final recommendations were then reviewed and approved by the entire Expert Panel. Additional information on the Guidelines development process is provided in Appendix A. Methodology. A draft Guidelines document was reviewed by multiple professional societies and by many individuals within the National Institutes of Health, the Centers for Disease Control and Prevention, and relevant U.S. Department of Health and Human Services organizations. The Guidelines also underwent a 30-day public comment period. In total, individual responses were developed for more than 800 comments.

Section II. State of the Science: Cardiovascular Risk Factors and the Development of Atherosclerosis in Childhood summarizes all the evidence linking the presence of risk factors in childhood and adolescence to the presence and severity of the atherosclerotic process as assessed both pathologically and by imaging studies. An overview of the role of screening for CV risk factors in children is addressed in Section III. Screening for Cardiovascular Risk Factors. The next eight sections (IV–XI) address individual risk factors. Each risk factor section begins with a brief description of the current status of the risk factor in childhood and adolescence. Since this kind of information is often not available from studies that are included in evidence reviews, selected references are used to provide the context within which the recommendations were developed. This text is followed by the Expert Panel's written summary of the evidence review relative to the specific risk factor. As described above, Expert Panel members provided an overview of the evidence, focusing on those studies that in their expert opinions provide the most important information and identifying deficiencies in the evidence. Specific information on each study is provided in the evidence tables available through the NHLBI Web site at http://www.nhlbi.nih.gov/guidelines/cvd_ped/index.htm. The conclusions of the Expert Panel's review of the evidence are then summarized, accompanied by the evidence grades and the strength of the recommendation. Each risk factor section ends with the Expert Panel's age-specific recommendations, accompanied by supportive actions, which represent suggestions developed by Expert Panel consensus to support implementation of the recommendations. The recommendations are integrated across risk factors and developmentally across age groups into the Integrated Cardiovascular Health Schedule (Section XV), which summarizes the age-specific recommendations for all of the risk factors. To optimize accessibility, references are grouped by risk factor and are listed sequentially at the end of each section. References from the evidence review are identified by the unique PubMed identifier (PMID) number that appears in bold text. Additional references do not include the PMID number.

By addressing the major population-based risk factors for CVD in a single evidence-based set of Guidelines, the aim is to support pediatric care providers in optimizing CV health in infancy, early childhood, and adolescenceBy extending risk factor modification into childhood, our goal is to reduce the development of clinical CVD in the future lives of children.

Table 1–1. Development of the Evidence Base: Critical Questions

  1. What is the evidence that atherosclerosis and atherosclerosis-related target organ damage begin in childhood?
  2. What is the evidence that the presence of risk factors in childhood affects the development and progression of atherosclerosis and atherosclerosis-related target organ damage during childhood?
  3. What is the evidence that the presence of risk factors in childhood affects the progression of atherosclerosis and atherosclerosis-related target organ damage in adulthood?
  4. What is the evidence that indicates the relative importance of each risk factor in the development and progression of atherosclerosis and atherosclerosis-related target organ damage in childhood?
  5. What is the evidence that racial or ethnic background, geographic region, or socioeconomic status affect cardiovascular (CV) risk factor status in childhood/adolescence?
  6. What is the evidence that risk factors cluster in childhood?
  7. What is the evidence that risk factor clustering is consistent in childhood?
  8. What is the evidence that risk factors present in childhood persist (i.e., track) into adulthood?
  9. What is the evidence that an increase in the number and/or intensity of risk factors in childhood alters (a) the development and progression of atherosclerosis and atherosclerosis-related target organ damage in childhood; (b) the development and progression of atherosclerosis and atherosclerosis-related target organ damage in adulthood; and/or (c) the development of clinical CV disease (CVD) in adulthood?
  10. What is the evidence that risk factors in childhood can be decreased?
  11. What is the evidence that a decrease in risk factors in childhood can be sustained?
  12. What is the evidence that a decrease in risk factors in childhood alters (a) the development and progression of atherosclerosis and atherosclerosis-related target organ damage in childhood; (b) the development and progression of atherosclerosis and atherosclerosis-related target organ damage in adulthood; and (c) the development of clinical CVD in adulthood?
  13. What is the evidence that acquisition of risk factors or risk behaviors can be prevented in childhood and adolescence?
  14. What is the evidence that preservation of a low-risk state from childhood, adolescence, or young adulthood to later adult life is associated with (a) decreased development/progression of atherosclerosis and atherosclerosis-related target organ damage and/or (b) decreased incidence of clinical CVD?

Table 1–2. Evaluated Risk Factors

Family history
Age
Gender
Nutrition/ diet
Physical inactivity
Tobacco exposure
Blood pressure
Lipids
Overweight/ Obesity
Diabetes mellitus
Predisposing conditions
Metabolic syndrome
Perinatal factors
Inflammatory markers


Table 1–3. Selected Observational Studies

Abbreviation

Full Title

NHANES

National Health and Nutrition Examination Survey

Bogalusa

Bogalusa Heart Study

PDAY

Pathobiological Determinants of Atherosclerosis in Youth

Muscatine

Muscatine Study

Princeton

Princeton Lipid Research Clinics Follow-Up Study

Young Finns

Cardiovascular Risk in Young Finns Study

NGHS

National Heart, Lung, and Blood Institute Growth and Health Study

STRIP

Special Turku Coronary Risk Factor Intervention Project (observational followup from this randomized controlled trial)

CARDIA

Coronary Artery Risk Development in Young Adults Study

Minnesota

Minnesota Children's Blood Pressure Study

Beaver County

Beaver County Lipid Study

Fels

Fels Longitudinal Study


Table 1–4. Evidence Grading System

EVIDENCE QUALITY GRADES FOR THE BODY OF EVIDENCE

Grade

Evidence

A

Well-designed randomized controlled trials or diagnostic studies performed on a population similar to the guideline's target population

B

Randomized controlled trials or diagnostic studies with minor limitations; genetic natural history studies; overwhelmingly consistent evidence from observational studies

C

Observational studies (case-control and cohort design)

D

Expert opinion, case reports, or reasoning from first principles (bench research or animal studies)


GUIDELINE DEFINITIONS FOR EVIDENCE-BASED STATEMENTS

Statement Type

Definition

Implication

Strong recommendation

The Expert Panel believes that the benefits of the recommended approach clearly exceed the harms and that the quality of the supporting evidence is excellent (grade A or B). In some clearly defined circumstances, strong recommendations may be made on the basis of lesser evidence when high-quality evidence is impossible to obtain and the anticipated benefits clearly outweigh the harms.

Clinicians should follow a strong recommendation unless a clear and compelling rationale for an alternative approach is present.

Recommendation

The Expert Panel feels that the benefits exceed the harms but the quality of the evidence is not as strong (grade B or C). In some clearly defined circumstances, recommendations may be made on the basis of lesser evidence when high-quality evidence is impossible to obtain and when the anticipated benefits clearly outweigh the harms.

Clinicians should generally follow a recommendation but remain alert to new information and sensitive to patient preferences.

Optional

Either the quality of the evidence that exists is suspect (grade D) or well-performed studies (grade A, B or C) show little clear advantage to one approach versus another.

Clinicians should be flexible in their decision-making regarding appropriate practice, although they may set boundaries on alternatives; patient and family preference should have a substantial influencing role.

No recommendation

There is both a lack of pertinent evidence (grade D) and an unclear balance between benefits and harms.

Clinicians should not be constrained in their decision-making and be alert to new published evidence that clarifies the balance of benefit versus harm; patient and family preference should have a substantial influencing role.



REFERENCES

[1] NCEP Expert Panel of Blood Cholesterol Levels in Children and Adolescents. National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics 1992;89:495-501. (PM:1741227)

[2] American Academy of Pediatrics Steering Committee on Quality Improvement and Management. Classifying recommendations for clinical practice guidelines. Pediatrics 2004;114:874-877.

[3] Hagan JF, Duncan PM, eds. 2008. Bright Futures: Guidelines for Health Supervision of Infants, Children and Adolescents, Third Edition. Elk Grove Village, IL: American Academy of Pediatrics.


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