Dr. James H. Stein, in his recent post on CardioExchange, presents several arguments against cholesterol screening in childhood. I would like to present the view of those who drafted the document and suggest that some of Dr. Stein’s arguments are incorrect.
First, given that conflicts of interest were part of his argument, I must be transparent about mine. I have never participated in a drug-industry-sponsored trial of a cholesterol-lowering medication. I had no conflicts with industry until late 2009, after the main work on the guideline was complete. Both of these are related to evidence gaps identified in the literature review for the guideline. The first is as a member of the Data and Safety Monitoring Board for a trial of losartan to lower blood pressure in severely hypertensive children younger than 6 years of age. The reimbursement for this work is deposited into a research fund for medical students and residents who lack another source of support for their research. The second is to conduct a clinical trial of fish oil for elevated triglycerides in adolescents. No clinical trial data on medication use for elevated triglycerides in children exist, and the NHLBI-sponsored statement made no recommendations about use of medications for this purpose. This money is provided as a grant, the trial is completely of my design, and my research program manages the trial without input from the company. The company has no oversight role for the trial, other than that I have to recruit a specified number of patients and complete a manuscript to receive payment. My reimbursement from the grant is for managing the coordinating center of the trial (there are 3 sites), analyzing the data, and performing various medical duties in conducting the trial.
The NHLBI guideline was strictly conducted according to the recommendations of the Institute of Medicine (IOM) and other bodies that are interested in guideline integrity. Several thousand research papers meeting preselected criteria as evidence were considered in the evaluation of recommendations for 14 different risk factors. A paper describing the panel’s process has recently been published. The Lipid section of the guideline was drafted by the three members of the panel who have the most knowledge about lipids. However, this group’s recommendation was debated and voted on by the entire committee, which had a diverse composition, consistent with IOM recommendations. NHLBI officials, cognizant of conflict of interest issues, were also present and contributed to the discussion. With one exception, none of the other 11 committee members had participated in an industry-sponsored cholesterol-drug trial.
All the arguments discussed in critiques of the guideline emerged in this debate; in fact, the committee felt so strongly about the evidence limitations that a specific chapter of the guideline was written to include them, particularly the cost issue. Nonetheless, the committee, with one exception, voted for universal screening because the weight of the evidence review favored this decision despite evidence gaps. The weight came from these facts: atherosclerosis begins in the second decade of life; this atherosclerosis (including future atherosclerosis) is strongly related to non-HDL cholesterol levels; a small but significant number of children can be identified with high cardiovascular risk; treatments highly likely to be successful are available; and genetic diseases causing both high and low LDL cholesterol were highly suggestive of the risk of high LDL cholesterol and of the benefit of lifetime low LDL cholesterol levels.
It is inaccurate of Dr. Stein to say that the evidence evaluation for the cholesterol treatment recommendation does not reflect the types of studies included to support the recommendation. The grade given is B (not A): evidence from clinical trials with potential flaws, high-quality and consistent observational studies, and Mendelian randomization (genetic research). I hope that the guideline will ultimately lead to high-quality clinical trials of lipid-lowering treatment, initiated by sponsors other than industry.
Included in guideline development (and recommended by the IOM) was a period for public comment, review by several interested professional organizations, and internal review by both NHLBI and DHHS. Notably, despite receiving over a thousand critiques, only one challenged the universal screening for cholesterol recommendation, and that critique presented only opinion rather than evidence against the recommendation. Given the committee’s deliberations and the extensive external review prior to publication, it is my opinion that the argument against cholesterol screening in children is a well-considered — but a minority — position.
I would like to challenge several other arguments in Dr. Stein’s post — as the extensive evidence review, conducted using a process now considered “state of the art,” did not support these assertions. Most important, no published evidence of harm from cholesterol screening exists. Guidelines regarding cholesterol testing have been in place for about 20 years, with no research demonstrating harm from this practice. In West Virginia, where universal screening of cholesterol occurs in schools voluntarily, over 60% of children consent to testing, and no harm has been identified in this program. Our evidence review specifically sought publications with side effects or unintended consequences of screening — and none were found. The age for cholesterol screening was chosen partly because most states require a medical examination for admission to a public school, and blood is often drawn for other purposes. Girls, on average, do have slightly higher total-cholesterol levels than boys — but women have equal rates of heart disease as men, only at slightly older ages. The number of cases of familial hypercholesterolemia missed by current guidelines is significant. Indeed, one of the reasons for the universal screening recommendation was that numerous studies conducted since the 1992 guideline was published suggest that 25% to 30% of cases are missed by selective screening. Given the frequency of 1:300-500 in the population, this is not a trivial number (and there is no gender bias in these levels). The dietary guidelines presented are for all children, not just those with high cholesterol. One of the reasons for delay in publication was the need to synchronize the recommendations with the evidence-based 2010 Dietary Guidelines for Americans.
The cardiovascular health of children has deteriorated significantly, principally because of the obesity epidemic and poor nutrition habits. Many, indeed almost one third of U.S. children, have a different type of dyslipidemia (low HDL cholesterol and high triglycerides), and it has been recommended, prior to the publication of the universal screening recommendations, that these children have their lipids checked. I am concerned that the debate about the usefulness of checking cholesterol might send the wrong message to the general population — namely, that accurately knowing your cardiovascular risk is not useful for this vulnerable population.
A key tenet of the IOM recommendations for development of guidelines is that they undergo periodic review with reconsideration of the evidence. For the lipid section in particular, the evidence gaps identified by Dr. Stein and others cited in his post had insufficient weight as evidence compared with the many studies supporting the final recommendations. Nonetheless, the current guideline should not be the last word. Evidence gaps point the way for future research, and this new work should inform future deliberations about this important issue.
Note: In addition to James Stein’s post, Larry Husten has written a post on industry PR efforts to influence the debate on cholesterol screening for children.