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HYDRA: Rosuvastatin reduces LDL in children with homozygous FH
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Children with homozygous familial hypercholesterolemia who were treated with rosuvastatin in addition to ezetimibe and/or apheresis reduced their LDL safely and effectively, according to a randomized, double blind crossover study published in the Journal of the American College of Cardiology.
Evan A. Stein, MD, PhD, director emeritus of the Metabolic and Atherosclerosis Research Center in Cincinnati, and colleagues analyzed data from 14 children (mean age, 11 years; 50% boys) with homozygous familial hypercholesterolemia (HoFH), 13 of whom completed the HYDRA study. A 4-week lead-in phase preceded the study, when patients discontinued all lipid-lowering therapies except apheresis (50%) and/or ezetimibe (57%) and received 10 mg rosuvastatin daily with dietary advice.
Rosuvastatin vs. placebo
Patients were then assigned to 20 mg rosuvastatin daily or placebo for a crossover period of 12 weeks, which was followed by a 12-week, open-label maintenance phase with 20 mg rosuvastatin. Fasting blood samples and genotyping were reviewed throughout the study period.
Researchers also assessed the LDL response based on underlying genetic mutations in the 13 patients who completed the study and seven children with HoFH from a prior trial who were treated with diet for 4 weeks and 20 mg rosuvastatin daily for 6 weeks. Data from 33 adult patients from a prior trial were included.
Patients assigned placebo had a mean LDL of 481 mg/dL vs. 396 mg/dL in those assigned rosuvastatin. The mean relative difference in LDL reduction was 22.3% (95% CI, –33.5 to –9.1).
Similar efficacy was seen regardless of age or the use of apheresis or ezetimibe, which was maintained for 12 weeks.
Additional genetic mutations
Patients with two defective mutations had an LDL reduction of 23.5% (P = .0044) vs. 14% in patients with two negative mutations (P = .038).
“Rosuvastatin did provide a good foundation on which to add further LDL reducing agents such as ezetimibe, apheresis and the PCSK9 inhibitor evolocumab (Repatha, Amgen), which, when added to stable statin therapy, has been shown to be effective, well tolerated and approved for children with [homozygous familial hypercholesterolemia] 13 years of age or older,” Stein and colleagues wrote.
“Given that atherosclerosis develops over many decades, no study can completely evaluate the safety of long-term intervention in cohorts where lifetime risk [for CVD] is high,” Samuel S. Gidding, MD, chief of pediatric cardiology at A. I. DuPont Hospital for Children in Wilmington, Delaware, wrote in a related editorial. “Evidence for long-term safety of statin and other lipid-lowering medications should be sought in older populations and assessed for generalizability to younger populations with more specific high-risk conditions, such as HoFH, to address this critical issue. Both traditional treatments and new therapeutics in development offer the hope of safe and efficacious treatment for HoFH in the near future.” – by Darlene Dobkowski
Disclosures: The study was funded by AstraZeneca. Stein reports receiving consultant and expert witness fees from AstraZeneca. Gidding reports consulting for Regenxbio. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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James A. Underberg, MD
The HYDRA trial is the first to be done in children with HoFH on a large scale like this. It speaks to the safety of using rosuvastatin in younger patients, children and adolescents with HoFH. It was a short trial, so long-term safety could not really be assessed, but at least in the short term, there did not seem to be any safety issues.
More importantly, it shows that in a group of patients for whom many believe statins may not play much of a role in therapy, many patients did respond with significant lipid lowering.
That degree of lipid lowering seemed to be best predicted by the genetics of the condition, meaning that patients with HoFH have a variable genetic profile with a degree of LDL receptor functionality, which can be predicted by the type of mutations. This was what determined how well people responded to a statin.
The take-home message is that statins are an important part still of managing patients with HoFH and should be used in children with HoFH based on the approved FDA indications for the drugs and appropriate starting ages. Also, genetic testing potentially may inform us as to who might best respond to statins — and ultimately other medications that lower LDL — in patients with inherited lipid disorders such as FH.
Severe FH is often an overlap syndrome between heterozygous and homozygous FH. There is often a belief that drugs that work via upregulating the LDL receptor — statins and PCSK9 inhibitors, or even ezetimibe and bile acid sequestrants — don’t have much of a role because theoretically these patients have minimal LDL receptor activity. However, what we have learned repeatedly from this and other trials is that patients with HoFH do have a variability in LDL receptor activity that can be predicted to a large extent by genetic testing. That seems to determine the degree of response to a statin. It has a significant implication for translation to clinical practice.
We would like to see an expansion of clinical trials in other drugs in pediatric patients with HoFH and possibly heterozygous FH too.
It was an interesting trial and one that has a significant amount of clinical translational utilization.
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