Starting statin therapy as young as age 8 safely and effectively delays the early artery damage caused by familial hypercholesterolemia (FH), according to a Dutch study reported in the Aug. 7th print issue of Circulation: Journal of the American Heart Association.
"Our data support early initiation of statin therapy in FH children, which might yield a larger benefit in the prevention of atherosclerosis later in life," said Barbara A. Hutten, Ph.D., senior author of the study. "In our opinion, physicians should consider statin treatment for all FH children who are 8 or older."
FH leads to severely elevated levels of low-density lipoprotein (LDL) cholesterol, commonly called "bad cholesterol," beginning at birth. The result is an early thickening of the artery walls, premature cardiovascular disease (5 percent by age 30; 50 percent by age 50), and an increased risk of early heart attack, Hutten said.
The disorder also interferes with normal artery functioning. "Dilation is reduced in children with FH, which reflects an increased stiffness of the vessel wall. This is the first sign of atherosclerosis," said Dr. Hutten, an assistant professor of clinical epidemiology at the University of Amsterdam's Academic Medical Centre in the Netherlands.
When Hutten and colleagues began their long-term trial, several previous studies had demonstrated the short-term safety of statins in FH children. But none of them had followed patients for more than 48 weeks.
Researchers enrolled 214 children between ages 8 and 18 into the single-center, randomized, double-blind, placebo-controlled study at the Academic Medical Centre. Participants were admitted if they had one parent with a clinical or molecular diagnosis of FH and met other criteria, including elevated LDL.
The children were randomized to receive the drug pravastatin or placebo for two years. Those younger than 14 received 20 milligrams (mg) of the statin daily, and those 14 or older received a 40-mg dose. At the end of the two years, the pravastatin-treated group continued taking the drug and the placebo group switched to pravastatin.
To assess the drug's effectiveness, the team used ultrasound to measure intima media thickness (IMT) in the carotid artery in the neck. IMT is the combined thickness of the intima and media, two layers of the artery wall.
"Carotid IMT is widely accepted as a standardized and validated surrogate marker for atherosclerotic vascular disease," said Maud N. Vissers, Ph.D., co-author of the study and a senior scientist in vascular medicine at the Academic Medical Centre. In 2004, the team reported that two years of therapy had reduced the progression of atherosclerosis in the pravastatin group when compared to the placebo group.
This study reflects the findings from 186 of the original participants -- 96 who had started on pravastatin and 90 from the placebo group. These patients received pravastatin for between 2.1 and 7.4 years, and for an average of 4.5 years. The children were an average 13.7 years old at enrollment; 49 percent were male. After all patients were on the statin drug, 83 percent continued with pravastatin and 17 percent switched to another statin.
Analyses of 4.5-year data showed that the age of statin initiation was a strong, independent predictor for the increased thickening between the intima and media. This held true even after the researchers considered the patients' gender, intima-media thickness when treatment began, and the length of statin therapy.
The researchers projected that the artery wall thickening would increase 0.003 millimeters for each year that statin therapy was delayed.
"The results show that earlier initiation of statin treatment results in a smaller carotid IMT at a later age," said John J. P. Kastelein, M.D., Ph.D., co-author of the study and professor and chair of vascular medicine at the Academic Medical Centre. "However, each child will differ with respect to the family history, lipid profile, other risk factors, or lifestyle. To decide whether or not to start treatment, physicians should balance benefit and risk based on the personal situation of each individual child."
None of the children in the study suffered increases in liver and muscle enzymes attributed to their medication, a major concern with statins. Two boys had temporary increases in muscle enzymes apparently related to their extreme physical exercise. Four patients complained of muscle pain but had no elevated muscle enzymes, Hutten said.
During the average 4.5 years of follow-up, "no serious clinical or laboratory adverse events were reported, as well as any untoward effects on sexual maturation or growth," Kastelein said. "However, the number of children in our study is not sufficient to appropriately estimate the incidence of adverse events in children on statin treatment."
Optimal age for beginning statin therapy in FH children remains unknown and will require further clinical trials to resolve, Vissers said. "We intend to continue to monitor the children in our study as long as possible."
The American Heart Association recommends implementing diet and lifestyle modifications for children with high cholesterol. If needed, a statin, started at the lowest dose, is recommended as the first line of treatment for children who meet criteria for starting lipid-lowering drug therapy.
Currently, lovastatin, simvastatin, pravastatin and atorvastatin have pediatric labeling from the U.S. Food and Drug Administration based on clinical trials performed in children with FH.
Other co-authors are Jessica Rodenburg, M.D., Ph.D.; Albert Wiegman, M.D., Ph.D; A. S. Paul van Trotsenburg, M.D., Ph.D.; Anouk van der Graaf, Ph.D.; Eric de Groot, M.D., Ph.D.; and Frits A. Wijburg, M.D., Ph.D. The study was funded by Bristol-Myers Squibb.
Statements and conclusions of study authors that are published in the American Heart Association scientific journals are solely those of the study authors and do not necessarily reflect association policy or position. The American Heart Association makes no representation or warranty as to their accuracy or reliability.