This review concluded that statins significantly reduced low density lipoprotein levels in children with heterozygous familial hypercholesterolemia. The included data appeared to support the review findings, but the poor quality of a number of studies and pooling of data that appeared to vary both clinically and statistically, suggested some caution is required.

To assess the efficacy and safety of statins for the treatment of children with heterozygous familial hypercholesterolemia (heFH).

MEDLINE, EMBASE and DARE were searched for studies written in any language from 1970 to 2006. Search terms were reported and included a search filter designed to retrieve randomised controlled trials (RCTs). Citation lists were checked for further studies.

RCTs that assessed effects of statins in children (less than 18 years) with heFH were eligible for inclusion in the review. Studies were excluded if more than 50% of the population was at least 18 years old. If data sets included both children and adults, paediatric data were extrapolated. Eligible studies had to report the primary outcome of change in lipid profile including LDL (low density lipoprotein), HDL (high density lipoprotein), cholesterol, total cholesterol, triglycerides and VLDL (very low density lipoprotein).Secondary outcomes included changes in height/weight and adverse events (further detail of specific events reported in the review).

Included studies assessed various doses of lovastatin, pravastatin and simvastatin; most studies used individually titrated doses of statins. All studies except one compared statin use to placebo; the remaining trial compared different statin doses. Mean age of participants ranged from 12 to 15 years. The proportion of female participants ranged from 0 to 100%; approximately one third of studies were carried out in male-only populations. Definition of heFH varied between trials. Studies varied in terms of inclusion/exclusion criteria, participant characteristics, intervention and outcome measures. However, all studies reported levels of total cholesterol, LDL, HDL and triglycerides; most trials also reported apoprotein-B (Apo-B) and apoprotein-A (Apo-AI) levels. Various safety parameters were assessed and further details were reported in the review. Follow-up durations ranged from six to 48 weeks.

Studies were assessed by two reviewers. Disagreements were resolved through consultation with a third reviewer until consensus was reached.

The methodological quality of studies was assessed using Jadad criteria (method of randomisation, blinding and follow-up); use of an intention-to-treat analysis and allocation concealment was also reported.

The authors did not state how many reviewers performed quality assessment.

Lipid levels at final follow-up assessment were extracted by two reviewers and data converted to common units. Cholesterol measurements were converted to mmol/L (38.67mg/dL equal to 1mmol/L). Dichotomous data were used to calculate relative risks (RRs) with 95% confidence intervals (CIs). Means and standard deviations were reported for continuous outcomes. Authors of primary studies were contacted for further information where necessary. Disagreements were resolved through consultation with a third reviewer until consensus was reached.

Studies were grouped according to outcome and pooled relative risks using a random-effects model or standardised mean differences (SMD) using the inverse-variance method and 95% CIs calculated. Heterogeneity was assessed using the Χ² statistic and a cutoff of p<0.1. Publication bias was assessed using funnel plots and the Begg's test.

Seven studies (n=761) met criteria for inclusion in the review. Four studies (n=575) were included in the meta analysis. Two studies reported using adequate randomisation methods, one reported allocation concealment, all were blinded, one reported 100% follow-up and four used an intention-to-treat analysis. Three studies scored 4 out of 5 points, one scored 3 and three scored 2.

In comparison with placebo there were statistically significant changes in lipid levels in favour of statins including a significant reduction in LDL (SMD 1.6, 95% CI 1.40 to 1.80mmol/L; four studies), a significant increase in HDL (SMD 0.21 CI 0.03mmol/L to 0.38mmol/L; four studies) and a significant decrease in total cholesterol (SMD 3.0, CI 3.8mmol/L to 2.2mmol/L; number of studies not reported). Statistically significant increases in height (SMD 0.35, CI 0.16cm to 0.55cm; number of studies not reported) and weight (SMD 0.23, CI 0.03kg to 0.44kg; number of studies not reported) in favour of statins were also reported. Significant heterogeneity was detected in these analyses.

No significant differences were found in body mass index (number of studies not reported), and Tanner stage progress in statin-treated males (two studies) and females (two studies). Results for testes volume were conflicting (two studies). Studies could not be pooled for triglycerides, VLDL, apolipoproteins, creatine kinase, aspartate aminotransferase, alanine aminotransferase and many side effects of statins, but individual trials tended to show no significant adverse effects.

There was no evidence of publication bias.

Statins significantly reduced low density lipoprotein levels in children with heterozygous familial hypercholesterolemia.

This review answered a clearly defined research question. A number of databases were searched for relevant data, but it is unclear whether unpublished studies were eligible for inclusion. The authors reported that statistical tests suggested no evidence of publication bias, but the reliability of this finding was unclear given the small number of included studies. No limitations were placed on language and so risk of language bias appeared low. The risk of reviewer error and bias also appeared low, although the authors did not report how many reviewers assessed methodological quality of the studies. Relevant published criteria were used to assess methodological quality of the studies. The authors reported that all studies showed some evidence of methodological weaknesses. Studies were combined using relevant statistical methods. However, data were pooled despite evidence of significant clinical and statistical heterogeneity (results not reported), which may affect the reliability of the findings. Overall, the included data appeared to support the review findings, but the poor quality of a number of studies and pooling of data that appeared to vary both clinically and statistically, suggest some caution is required.

Practice: The authors stated that after implementation of appropriate dietary and lifestyle changes, statins should be considered for treatment of all children with heterozygous familial hypercholesterolemia and increased low density lipoprotein. Children should be monitored frequently for side effects throughout the treatment period.

Research: The authors stated that epidemiologic and multicentre studies were required in order to determine optimum age for initiation of therapy, risk of adverse events and long-term beneficial and adverse effects of statin treatment. Future trials should include standardised outcome measures and statistical methods.

Not reported.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.