Junkfood Science: Junkfood Science Special: Statin kids

May 16, 2007

Junkfood Science Special: Statin kids

Two new clinical guidelines were recently released for managing blood “cholesterol” in children. Before we all worry about another risk factor or rush to put our children on statins for life, let’s take a careful look at what the evidence showed.

The new Scientific Statement from the American Heart Association on “Drug Therapy of High-Risk Lipid Abnormalities in Children and Adolescents,” has been in the news and the take home message given to both consumers and healthcare professionals is that more kids need to be screened and placed on statins because research is conclusively showing that statins prevent heart disease. As the news reported:

Heart Association Recommends Statins for Kids with High Cholesterol

When diet and exercise fail to lower cholesterol in children with high-risk lipid abnormalities, statins should be first-line drug therapy, declared the American Heart Association in a new scientific statement.

Brian W. McCrindle, M.D., M.P.H., who chaired the AHA committee that wrote the statement, [said]... several trials in children with familial hypercholesterolemia have shown the use of statins had similar safety and effectiveness as in adults.... Currently, lovastatin, simvastatin, pravastatin and atorvastatin have pediatric labeling from the FDA on the basis of clinical trials performed in children with familial hypercholesterolemia.

The AHA said there is now definitive evidence that the atherosclerotic disease process begins in childhood, and the rate of progression is greatly increased by lipid abnormalities and their severity. But “if you lower cholesterol in these kids, you can improve the function of their arteries and reverse early atherosclerotic change," he said.

Drug therapy should be considered in children with an LDL of 190 mg/dL or higher, or if the LDL is 160 mg/dL or higher and the child has positive family history of premature cardiovascular disease or has two risk factors for cardiovascular disease. The minimum treatment target for statin therapy in children is an LDL of less than 130 mg/dL, but as with adults-lower is better. So the AHA said the ideal LDL goal is less than 110 mg/dL.

According to the AHA recommendations, the news reported, boys as young as ten, and girls after they begin menses, should be considered for statin therapy, “but younger children should be considered for statin therapy if they have additional risk factors such as male gender, strong family history of premature cardiovascular disease or events, associated low HDL, high triglycerides, and small dense LDL.”

The main focus of attention was on fat children, and the AHA Statement said that “overweight and obesity should trigger screening with a fasting lipid profile.”

The Medpage Today version of the report gave healthcare professionals two Action Points: “Explain to parents that overweight or obese children should be screened for lipid abnormalities. Explain to parents that diet and exercise interventions have been shown to reduced LDL cholesterol and increase HDL cholesterol in children and adults.”

Both of these are rather odd, since nowhere did the AHA Statement present any research that obesity in children causes or is even linked to heart disease or familial hypercholesterolemia. The belief that cholesterol levels are determined by diet and exercise is popular, but not evidence-based. Concerning the role of physical activity in managing lipid profiles, the AHA Committee clearly said: “[S]tudy results have been inconsistent with regard to the changes seen in various lipoproteins. Data from the pediatric and adolescent populations are far more limited than data from adult populations.... Methodological issues, especially selection bias and imprecise measures of physical activity, are problems in most of these studies, making it difficult to establish a clear cause-and-effect relationship between physical activity and lipoprotein profiles.” And about dietary interventions in infants, children and teens, they said the evidence shows diets “result in only modest improvements in hyperlipidemia.”

Given these admissions by the AHA, it’s not surprising that the focus of their recommendations led to drugs. The public was given the added impression of scientific consensus on the importance of cholesterol from another story that hit the news on Sunday, which also promoted management in kids. It claimed that cholesterol levels are “a window into these youngsters’ futures” and that “measuring kids’ cholesterol in a really detailed way may make sense.” As Forbes reported:

New Cholesterol Check Gauges Kids’ Heart Risk

... “There is growing scientific evidence indicating that cholesterol levels in childhood and adolescence have an effect on the development of plaque in the arteries, which is a clear indication of cardiovascular disease risk," explained study leader Ian Janssen, an assistant professor in the School of Kinesiology and Health Studies at Queens University in Ontario, Canada.

“There is also strong evidence indicating that children and youth with high cholesterol will continue to have high cholesterol in adulthood," he added. “Thus, it is important to start treatment and prevention efforts early."

Using data from the NHANES on more than 6,000 kids aged 12 to 20, Janssen and his colleagues developed age- and gender-specific reference points for total cholesterol, LDL (“bad") cholesterol, HDL (“good) cholesterol and triglyceride fat levels. The new tables, published last year in the journal Circulation, take into account fluctuations in cholesterol and fat that occur as a child matures. The new reference data are meant to improve upon current guidelines, published by the U.S. National Cholesterol Education Program (NCEP)...

If that reads like a marketing piece, perhaps it was. The story was taken from a paper published more than a year ago! It’s doubtful the reporter actually read it, however, because in it Dr. Janssen and colleagues had written that the current cut-off numbers used to identify young people with abnormal and borderline-abnormal levels of total, LDL- and HDL- cholesterol levels, and triglyeride, “were chosen arbitrarily and have no clinical or health meaning.... Research indicates that these percentiles have a limited ability to predict the youth who, when adults, will have high-risk lipoprotein levels [These are important points to remember as we look at the AHA recommendations.].... Several other concerns underlie the pediatric NCEP classification system. First, lipoprotein concentrations change considerably with normal growth and maturation and vary by gender.” These authors admitted they weren’t able to directly link their new adolescent lipoprotein thresholds to cardiovascular disease risk, either, because heart disease is a chronic disease of late onset.

Nevertheless, their paper was “the first attempt to create age- and gender-specific lipoprotein thresholds for adolescents.” They didn’t base their system on any available research evidence, but on “several hypotheses that have been proposed to explain the changes in lipoprotein concentrations that occur during adolescence.” They created a lipoprotein growth curve, extrapolating defined cutoffs at various ages corresponding to adult risk cutoffs, adding arbitrary 5th, 25th, 50th, 75th, and 95th percentiles. Dr. Janssen wrote that “it is only intuitive that lipoprotein risk curves be developed, given that pediatricians have used height, weight, body mass index, and blood pressure growth curves for years.”

In other words, it was improvised. Yet, incredibly, their paper concluded by saying: “We encourage clinicians and researchers to adopt this new classification system because it should provide a more accurate diagnosis of adolescents with high-risk lipoprotein values and associated cardiovascular health risks.”

Perhaps these inconsistencies were why Dr. Marc S. Jacobson, director of the Center for Atherosclerosis Prevention at Schneider Children’s Hospital in New Hyde Park, N.Y., told the HealthDay News that it’s still unclear how the new tables will actually be received. He noted that high-risk teens are already screened every year or two, but that the risk factors are continually being expanded and will now cover a lot of kids who will be triggered for cholesterol screening.

The evidence

We recently saw for ourselves the importance of looking at the actual evidence, even when we might be tempted to take things we hear at face value. The new AHA guidelines on the primary prevention of heart disease in women, for example, surprised us by having no clinical evidence to support cardiac “risk factors,” most notably “cholesterol” management or statin use, for the primary prevention of heart disease and reduction of premature deaths in healthy women. And such interventions weren’t especially impressive for men, either. Yet that wasn’t the first or only review to find the evidence for cholesterol management to be shakey. As doctors, Beatrice Golomb M.D., Ph.D. and Michael Criqui M.D., MPH with the Statin Effects Study at the University of California, San Diego, concluded:

No study has shown statins or any other cholesterol drugs to lower overall mortality in women...indeed, lower cholesterol is linked to a slightly higher risk in some studies....No studies have examined the impact of statins in randomized trials in those over age 75, [either]. Epidemiological studies show higher cholesterol to be protective, rather than harmful, in this age group, so it cannot be assumed that lowering cholesterol confers benefit exceeding risk.

There is even less evidence for children and teens.

Let’s walk through these new AHA recommendations and evidence together, and weigh the benefits and risks. The current pediatric guidelines were established in 1992 by the National Cholesterol Education Program. According to the AHA Scientific Statement:

[The NCEP] panel specifically recommended against universal cholesterol screening for several reasons. Tracking of cholesterol levels into adulthood was imperfect in that not all children with high cholesterol levels will have high enough cholesterol levels as adults to warrant treatment. Concerns were raised that universal cholesterol screening could lead to labeling children as having a “disease.” The panel believed that for children who were not from high-risk families, cholesterol-lowering therapies could wait until adulthood. Concerns existed that there was insufficient evidence on the long-term safety and efficacy of treating children to reduce coronary heart disease morbidity and mortality in adulthood. However, the panel did feel that for children at high risk because of a family history of premature cardiovascular disease and/or parental hypercholesterolemia, it was prudent to initiate therapy at an early age.

The AHA Committee examined the considerable problems with cholesterol screening recommendations for kids. Screening recommendations based on parents' lipid levels had been shown in several studies to be ineffective, according to the AHA. Setting cut-off points for screening is also problematic, they said, because they don’t take into account race, gender or maturity. The lower the cholesterol cutoffs are, the more kids who will receive unnecessary screening and intervention, especially Black children and girls during prepuberty, who tend to have higher cholesterol levels. It is well-known in medicine that there is a natural diversity of values between people, but that variations for an individual person are natural, too. And values fluctuate most for children and teens, as the AHA recognized:

Other threats to the sensitivity and specificity of screening include measurement error are ...variability within individuals...regression to the mean, day-to-day variability, seasonal variability, and in children, change with age, growth, and pubertal status. In a study of 646 children 3 to 19 years of age, only 41% of children with a total cholesterol level [200 mg/dL] had a cholesterol level that high one year later.

Despite these efficacy problems, the AHA Scientific Statement went on to conclude that the current NCEP guidelines underestimated the number of children who could be targeted for screening and they went on to expand the criteria for screening! Just as Dr. Jacobson had noted, more kids than ever are falling into the ever-widening screening recommendations.

The clinical trials used by the AHA to support these new recommendations deserve our close attention. They were all small, short-term trials of statins and other medications on children with high-risk lipid abnormalities, namely familial hypercholesterolemia. The significance of this fact, and the fallacies of using these studies to support their recommendations were clearly missed by reporters.

So, here’s the information we didn't hear in the news:

“Familial hypercholesterolemia (FH) is an autosomal dominant disorder that causes severe elevations in total cholesterol and low-density lipoprotein cholesterol,” said Dr. Elena Citkowitz, M.D., Ph.D., FACP, Associate Clinical Professor of Medicine, Yale University School of Medicine and director of the Cardiac Rehabilitation and Cholesterol Management Center at the Hospital of St. Raphael in New Haven, CT. It’s not simply “high cholesterol” as popularly viewed. These are exteme cases, where people are born with a defective LDL receptor gene. Also known as heterozygous FH, it occurs in about 1 in 500 people worldwide, with the homozygous form even rarer, at about 1 in a million. The cholesterol levels in babies and children with heterozygous FH are at least twice normal — 350 to 500 mg/dl — and in the homozygous form with no functioning LDL receptors, cholesterol levels are 700 to 1,000 mg/dl.

Childhood obesity also has absolutely nothing to do with the development of this genetic disorder.

This rare genetic defect is also associated with the development of premature atherosclerosis. FH sufferers have a ninefold higher rate of heart disease and statins have been shown to be an effective treatment for them. (The Simon Broome Registry has documented that people with FH have lived well into their nineties. To complicate matters, even among people with FH, the medical literature has shown that those with the highest cholesterol levels have the same risks as those with the lowest levels, according to Dr. Uffe Ravnskov, M.D., Ph.D., a cholesterol researcher in Lund, Sweden. Cholesterol can be a symptom of the genetic disorder, but still isn't the disease itself.)

There are a variety of other rare lipid abnormalities. Dr. Vanessa Davis, M.D., a pediatric endocrinologist at the University of Florida, described some of those seen in pediatric practices and they include chylomicronemia syndrome, with triglyceride levels 1,000 to 2,000 mg/dl which can go into the tens of thousands if left untreated. She wrote of one 5-week old baby in the medical literature with a triglyceride level of 25,000 mg/dl! Several other medical conditions can place a child at high risk for lipid disorders, such as organ transplantation, HIV infection, systemic lupus erythematosus, and kidney failure.

The point being, that the lab numbers associated with clear health risks, and where the benefits for statins or other treatments have been demonstrated, are well beyond the ranges seen in the vast majority of children (and adults, for that matter). Yet the AHA relied on clinical trials that treated these rare and extremely high levels as evidence for the need to treat moderate variations in lipid levels. The AHA reported that (of the various drugs) statins were generally most effective in reducing cholesterol levels for children with FH. True enough, but it wasn’t the full story.

These trials were also all short-term trials, ranging from 8 weeks to 2 years in duration. While statins didn’t appear to adversely affect the childrens’ growth during these short trials, small numbers of them showed laboratory abnormalities, such as elevated creatine kinase. [We’ll look at the possible significance of this momentarily.]

Hop, skip and jump

Then, we turn the page of the 21-page AHA Scientific Statement and find their Recommendations for Drug Therapy calling for widespread screening and drug therapy in children with “high” LDL levels of 190 mg/dl, or 160 mg/dl with any risk factors present (such as obesity, being male, smoking, hypertension, or a family history of total cholesterol levels of 240 mg/dl or higher — which pretty much describes much of the adult population). A statin is recommended as first-line treatment.” The AHA also defines treatment goals at a minumun LDL of 130 mg/dl and ideal of 110 mg/dl. [Where did these numbers come from?] “

Did you catch the fallacies in the AHA’s reasoning?

This is important: Just because an extreme level — multiple times normal or off the charts types of exposures — is associated with a health problem, such as heart disease or an increased risk of death, does not mean that moderate levels in the ranges that are found in most healthy, normal children and adults are of similar danger. Yet this tactic is commonly used to scare us about all sorts of things about our bodies, food and health. It’s one of the most popular misapplications of risk factors today. It gets everyone needlessly worried over numbers. “High” risk is magically redefined to include levels far less significant than where the research can support there being a notable risk.

Dr. Harumi Okuyama of the departments of Biological Chemistry and Pharmaceutical Sciences at Nagoya City University in Japan, wrote in the January issue of World Review of Nutrition and Dietetics, that once cases of genetic/familial hypercholesterolemia are removed from population statistics, high cholesterol isn’t found to be a causal factor for heart disease at all. He noted that heart attacks varied 4 to 8 times at the same total cholesterol levels in some populations and that high cholesterol isn’t associated with high heart disease deaths among the general population over the age of 50 to 60. We've come to fear the ranges where most adults fall, being told they are too "high." But, he said: “Little benefit seems to result from efforts to limit dietary cholesterol intake or to total cholesterol values to less than approximately 260 mg/dL,” he wrote.

“High cholesterol levels do not cause heart disease and the benefits of statins have been hyped beyond belief,” according to Dr. Malcomb Kendrick, M.D., who has been writing on cholesterol science for years. In his latest book, The Great Cholesterol Con, he outlined the biological implausibility for how LDL-cholesterol could cause atherosclerosis.

While the AHA chose to focus on lipid disorders with extraordinarily high leveles, the Committee could just have easily looked at lipid disorders that result in extremely low levels. In fact, those have been shown to be more life-threatening. The genetic forms of hypolipidemia include things like abetalipoproteinemia (autosomal recessive), homozygous hypobetalipoproteinemia, heterozygous hypobetalipoproteinemia, abetalipoproteinemia with normotriglyceridemic, and chylomicron-retention disease, said Dr. Davis. The AHA could then, applying the same logic, have promoted higher “cholesterol” levels as being important for everyone’s good health. But they didn’t, of course. That wouldn't sell statins, either.

The missing evidence is extremely important for us to recognize. The AHA failed to provide any evidence to support dangers for children crossing their arbitrary lipid cut-offs in moderate ranges, that getting children’s lipid levels to their recommended low levels improves actual long-term outcomes or reduces adult heart disease, or that it is safe to give children statins for decades. Nor did they evaluate evidence for potential risks of lowering the cholesterol levels of healthy children. Cholesterol has some pretty important functions in our bodies and we don’t know the long-term effects of lowering levels in children. In other words, they didn't carefully and objectively examine the risks and benefits.

These are similar to the concerns noted in a previous post, quoting Dr. Thomas B. Newman, a pediatrician and professor in the department of epidemiology and biostatistics at the University of California, San Francisco. No study has ever examined the long-term safety of statins, he said, but for children “it is all risk and no benefit...because there is no heart disease to prevent at that age.”

To treat a child the same way you'd treat a 60-year-old man with a bypass just doesn't make sense. One has to be careful about the use of language. Pathological precursors to atherosclerosis may begin in childhood, but it's not a disease. It doesn't make anybody sick.

Dr. Newman and Dr. Kendrick are not alone among growing numbers of medical professionals concerned about cholesterol screening and putting children on a life-time of drug therapy. A special article in the February issue of Pediatrics, led by Dr. Brook Belay, M.D., at Temple University School of Medicine in Philadelphia, PA, reviewed the evidence on the use of statins in pediatrics and cautioned:

[T]here are important caveats in the extrapolation of [adult statin study] results to children. First, the distinction between primary-prevention studies and secondary-prevention studies should be understood....

Although statins have been shown to be effective in reducing cardiovascular morbidity and mortality in primary-prevention studies, these studies have not definitively demonstrated any reduction in absolute risk for total mortality, and the reductions in coronary and cardiovascular mortality are modest in comparison to those observed in secondary-prevention studies. This observation is crucial; before primary prevention with statins is undertaken on a large scale.... If there is a reduction in the absolute risk for coronary mortality without a reduction in that for total mortality, then it may be postulated that the benefits of statins in reducing coronary mortality have been offset by increases in other-cause mortality. This phenomenon was seen in earlier studies... and, more recently, in primary prevention studies that focused on select groups.

Second, the application of “aggressive lipid lowering” therapy advocated in high-risk adults is not justified by current evidence in children and adolescents. Finally, from a pathologic standpoint, the goal of treating at-risk children is the prevention of atherosclerotic plaque development and maturation, whereas the benefits of treating adults lie generally in mitigating the thrombogenic potential of existing plaque.... statin treatment may particularly benefit advanced atherosclerotic lesions that are much more likely to be present in middle-aged adults.

Last August, an article in the Journal of Family Practice examined the evidence for screening children for high “cholesterols” and concluded: “No clear evidence supports screening all children or just those with family history of cardiovascular disease or hyperlipidemia. Children should [only] be screened...when there is a history of familial hypercholesterolemia.”

Their clinical review took issue with the few groups recommending widespread cholesterol screening and interventions for children, noting: “[T]he relationship of blood cholesterol levels in children without familial hypercholesterolemia to CHD later in life has not been established. A paucity of data exists that links lowering of cholesterol in childhood with reduced CHD morbidity and mortality in adulthood....Neither the American Academy of Family Physicians or the U.S. Preventive Services Task Force makes a recommendation about screening for hyperlipidemia in this age group.”

First do no harm

The long-standing precept in medicine is that unproven or potentially risky therapies and medicines are reserved for those with the most severe diseases who have the most to gain and for which there may not be other available treatments. This cannot be said to include asymptomatic children. This also does not apply to the preventive treatment of a “risk factor,” such as a lipid level, versus an actual disease process.

Statins are not altogether benign and, while they are widely viewed as safe and effective in middle-aged men, the risks and benefits are not equally shared by all populations. Dr. Beatrice A. Golomb, M.D., Ph.D., wrote a comprehensive overview in Geriatric Times, for instance, of the special risks among the elderly and fragile populations. The adverse reactions she documented are being increasingly reported as more people take statins and suggest special caution for the long-term use in pediatric patients. She said:

Perhaps the most feared adverse effect of statins is rhabdomyolysis—a condition in which there is severe breakdown of muscle tissue that may be toxic to the kidneys and result in kidney failure or death. The muscle breakdown commonly leads to a strong elevation in blood levels of muscle enzyme creatine kinase (CK).... Two randomized trials that were designed to assess cognitive effects of statins have shown worsening in cognitive function..... A large variety of other adverse effects have been reported with statins, including (but not limited to) gastrointestinal and neurological effects, psychiatric problems, immune effects (e.g., lupus-like syndrome).... Of particular note for the elderly population, the PROSPER trial found a significant 25% increase in incident cancer in participants over age 70 randomized to statin therapy versus placebo.... Low cholesterol is also linked to infection, including development of postoperative infection and predicts mortality and adverse outcomes in hospitalized patients. While some of this could be due to illness causing lower cholesterol, it may also be that low cholesterol contributes to illness; indeed, animal studies suggest lipoproteins may serve to protect against bacterial endotoxin-induced death....

Muscular problems seen with statin use are well-recognized. The Public Citizen begain warning consumers of potential kidney damage and failure subsequent to rhabdomyolysis for the statin, Crestor, in September, 2003. To clarify these muscular problems, Dr. Eliot A. Brinton, M.D., director of the Metabolism Section of Cardiovascular Genetics, and Associate Professor at the University of Utah School of Medicine, Salt Lake City, Utah, wrote an overview from an industry perspective for Medscape Cardiology in 2004. He explained:

There are 4 interrelated terms for muscle problems that can occur with statins. Myopathy is a general term for disease of the muscles, and it is usually characterized by weakness... Myalgia refers specifically to pain in the muscles... Myositis is inflammation of the muscle confirmed by histologic findings of muscle biopsy....A recent study showed that patients without an elevation of their serum creatine phosphokinase (CPK) level can nevertheless have myositis on biopsy. Thus, we need to have a fairly high index of suspicion for myopathy, realizing that it may be more common than we think, especially if we are looking only for myalgia or only for an elevated CPK.

Finally, rhabdomyolysis is the extreme type of myopathy, in which the muscle tissue is so inflamed that it breaks down in large quantities. It brings large amounts of myoglobin, the predominant muscle protein, to the circulation from which it then has to be removed by the kidney. Since the kidney is not well equipped to handle large amounts of myoglobin, it can become overwhelmed and damaged. Although the kidney usually recovers over time, rhabdomyolysis may be fatal due to acute renal failure and sequelae to other organs

Statins require judicious use and are not appropriate for everyone. While he said he believed statins are generally safe and effective, various statins differ in their risks and benefits for various people and situations, and need close medical management, he advised. He explained that while clinical trials report low incidences of myopathy, “in clinical practice, however, far more than 1% of patients will experience at least one symptom of myopathy. The much lower rate reported in clinical trials may be because eligibility criteria usually exclude patients with significant potential for drug-drug interactions or concurrent health problems, whereas healthcare providers cannot usually exclude those patients in clinical practice.” Acknowledging the muscle damage and kidney failure, especially at higher doses and among certain populations, the FDA Center for Drug Evaluation and Research issued a Public Health Advisory for Crestor on March 2, 2005.

One of the most worrisome risks of putting large numbers of teens and young women of child-bearing age on statins (besides the lack of demonstrated efficacy for females at any age) wasn’t even discussed in the AHA Scientific Statement. While statins are contraindicated for use during pregnancy, unplanned pregnancies happen all the time. Disturbing evidence has been reported of babies born with severe malformations and birth defects due to statin exposure during the first trimester. In the April issue of the New England Journal of Medicine, doctors Robin J. Edison, M.D., MPH, and Maximilian Muenke, M.D., senior neuroscience investigator at the National Institutes of Health, reviewed cases of first-trimester statin exposure from FDA records from 1987 through 2001. They found 20 of 52 babies were born with serious anomalies — severe brain or central nervous system defects and malformed limbs — “such very rare birth defects that one would not expect to find the number we found in a population this small,” they wrote. While the numbers are low, they suggest a rate of birth defects that rival those of thalidomide, which resulted in birth defects in 41% of fetuses exposed in utero.

We’ve spent a lot of time on this risk factor and still haven’t delved into the full complexities surrounding this controversial issue. But hopefully, by showing a different side of the news and presenting information that questions what’s popularly believed about cholesterol, this example has helped to build our critical thinking skills; shown some of the common ways we are misled and frightened about risk factor numbers; and encouraged us to look at the evidence carefully and get as many facts as possible. Even the most credible-sounding sources may not always be giving us the straight scoop. Arming ourselves with information can only help us weigh the risks and benefits in reasoned ways, talk with our doctor constructively, and make the best health decisions for ourselves and our children.

Knowing what you know now, you may see a very different story in that news story at the beginning of this post.

© 2007 Sandy Szwarc

Thanks Lara! :))

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