Statins for children with familial hypercholesterolemia

Alpo Vuorio; Jaana Kuoppala; Petri T Kovanen; Steve E Humphries; Serena Tonstad; Albert Wiegman; Euridiki Drogari; Uma Ramaswami

doi:10.1002/14651858.CD006401.pub4

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Figure 1

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Analysis 1.1

Comparison 1 Statins versus control, Outcome 1 Change in carotid intima‐media thickness (mm).

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Analysis 1.2

Comparison 1 Statins versus control, Outcome 2 Change in serum LDL cholesterol level (%).

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Analysis 1.3

Comparison 1 Statins versus control, Outcome 3 Change in puberty (Tanner stage ≧ 1 level).

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Analysis 1.4

Comparison 1 Statins versus control, Outcome 4 Change in aspartate aminotransferase levels (> 3x ULN).

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Analysis 1.5

Comparison 1 Statins versus control, Outcome 5 Change in alanine aminotransferase levels (> 3x ULN).

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Analysis 1.6

Comparison 1 Statins versus control, Outcome 6 Myopathy: Change in creatine kinase levels (> 10x ULN).

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Analysis 1.7

Comparison 1 Statins versus control, Outcome 7 Change in flow‐mediated dilatation of brachial artery (%).

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Analysis 1.8

Comparison 1 Statins versus control, Outcome 8 Change in serum total cholesterol levels (%).

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Analysis 1.9

Comparison 1 Statins versus control, Outcome 9 Change in serum HDL cholesterol levels (%).

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Analysis 1.10

Comparison 1 Statins versus control, Outcome 10 Change in serum triglyceride levels (%).

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Analysis 1.11

Comparison 1 Statins versus control, Outcome 11 Adverse events.

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Statins compared with placebo for children with familial hypercholesterolemia
Patient or population: children with familial hypercholesterolemia Settings: outpatients Intervention: statins Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Statins
Change in carotid intima‐media thickness (mm) ‐ At 2 years Follow‐up: 2 years	The mean change in carotid intima‐media thickness was 0.005 mm in the placebo group.	The mean change in carotid intima‐media thickness was 0.01 mm lower (0.03mm lower to 0.00mm lower) in the stains group.	NA	211 (1 study)	⊕⊕⊝⊝ low¹
Change in serum LDL cholesterol level (%) ‐ At end of follow‐up Follow‐up: up to 48 weeks	The mean change in serum LDL cholesterol level ranged from a 5% increase to a 4% decrease across placebo groups.	The mean change in serum LDL cholesterol level was 32.15% lower (34.90% lower to 29.40% lower) in the stains group.	NA	669 (6 studies)	⊕⊕⊕⊝ moderate^1,2	Heterogeneity: I² = 89% This outcome was also reported at at 1 month (228 participants, 3 studies), 6 months (528 participants, 4 studies) and at 1 year (254 participants, 2 studies). All pooled results were in favour of statins; the latter two analyses were also very heterogeneous (I² > 85%)
Change in measures of growth and maturation: change in puberty proportion with Tanner stage ≧ 1 level ‐ At 2 years Follow‐up: 2 years	636 per 1000	604 per 1000 (489 to 750 per 1000)	RR 0.95 (95% CI 0.77 to 1.18)	211 (1 study)	⊕⊕⊝⊝ low^1,3	This outcome was also reported at at 6 months (355 participants, 2 studies) and at 1 year (139 participants, 1 study). Results of analysis at all time points showed no significant differences between statins and placebo.
Liver dysfunction: proportion with changed aspartate aminotransferase or alanine aminotransferase levels (> 3x ULN) ‐ At all time points Follow‐up: up to 2 years	There were two cases of changed aspartate aminotransferase levels and no cases of changed alanine aminotransferase levels in the placebo groups (at all time points).	There were four cases of changed aspartate aminotransferase levels and four cases of changed alanine aminotransferase levels in the statins groups (at all time points).	See comment	up to 924⁴ (7 studies)	⊕⊕⊝⊝ low^1,5	There were no significant differences between the number of cases at any time point for either measurement and confidence intervals of pooled results were wide due to very low numbers of events.
Myopathy: proportion with changed serum creatine kinase levels (>10x ULN) ‐ At all time points Follow‐up: up to 1 year	There were two cases of changed serum creatine kinase levels in the placebo groups (at all time points).	There were five cases of changed serum creatine kinase levels in the placebo groups (at all time points).	See comment	up to 669⁴ (6 studies)	⊕⊕⊝⊝ low^1,5	There were no significant differences between the number of cases at any time point and confidence intervals of pooled results were wide due to very low numbers of events.
Change in endothelial function: Change in flow‐mediated dilatation of brachial artery (%) Follow‐up: up to 1 year	The mean change in flow‐mediated dilatation of brachial artery was 1.2% in the placebo group.	The mean change in flow‐mediated dilatation of brachial artery was 2.70% higher (0.42% to 4.98% higher) in the statins group.	NA	50 (1 study)	⊕⊕⊝⊝C low¹
Adverse events ‐ At one year Follow‐up: up to 1 year	399 per 1000	402 per 1000 (323 to 502 per 1000)	RR 1.01 (95% CI 0.81 to 1.26)	276 (2 studies)	⊕⊕⊕⊝ moderate¹	This outcome was also reported at at 1 months (248 participants, 2 studies) and at 6 months (416 participants, 3 studies). Results of analysis at all time points showed no significant differences between statins and placebo.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; NA: not applicable; RR: risk ratio; ULN: upper limit of normal
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
1. Downgraded once due to unclear risk of bias: methods of allocation concealment not described for any included studies and method of randomisation not described for more than half of the included studies. 2. Downgraded once due to inconsistency: a large amount of statistical heterogeneity present, despite studies being clinically comparable. 3. Downgraded once due to applicability: unclear whether changes in puberty are due to a treatment effect of the statins or due to natural changes in puberty of the age group. 4. Some studies contributed data to more than one time point, participants only counted once at the first time point reported. 5. Downgraded once due to imprecision: wide confidence intervals of pooled effects due to very low numbers of events.

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Comparison 1. Statins versus control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change in carotid intima‐media thickness (mm) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.1 At 2 years	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Change in serum LDL cholesterol level (%) Show forest plot	6		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

2.1 At 1 month	3	228	Mean Difference (IV, Fixed, 95% CI)	‐24.59 [‐30.11, ‐19.08]
2.2 At 6 months	4	528	Mean Difference (IV, Fixed, 95% CI)	‐34.97 [‐37.51, ‐32.44]
2.3 At 1 year	2	254	Mean Difference (IV, Fixed, 95% CI)	‐26.94 [‐31.64, ‐22.23]
2.4 At end of follow‐up	6	669	Mean Difference (IV, Fixed, 95% CI)	‐32.15 [‐34.90, ‐29.40]
3 Change in puberty (Tanner stage ≧ 1 level) Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 At 6 months	2	355	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.66, 1.50]
3.2 At 1 year	1	139	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.51, 1.54]
3.3 At 2 years	1	211	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.77, 1.18]
4 Change in aspartate aminotransferase levels (> 3x ULN) Show forest plot	7		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 At 1 month	2	175	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 At 6 months	4	538	Risk Ratio (M‐H, Fixed, 95% CI)	2.40 [0.29, 19.85]
4.3 At 1 year	2	254	Risk Ratio (M‐H, Fixed, 95% CI)	2.03 [0.08, 49.09]
4.4 At 2 years	1	211	Risk Ratio (M‐H, Fixed, 95% CI)	0.21 [0.01, 4.23]
5 Change in alanine aminotransferase levels (> 3x ULN) Show forest plot	7		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 At 1 month	2	175	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.2 At 6 months	4	538	Risk Ratio (M‐H, Fixed, 95% CI)	2.03 [0.24, 16.95]
5.3 At 1 year	2	254	Risk Ratio (M‐H, Fixed, 95% CI)	2.03 [0.08, 49.09]
5.4 At 2 years	1	211	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Myopathy: Change in creatine kinase levels (> 10x ULN) Show forest plot	6		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6.1 At 1 month	3	330	Risk Ratio (M‐H, Fixed, 95% CI)	3.23 [0.18, 58.84]
6.2 At 6 months	2	229	Risk Ratio (M‐H, Fixed, 95% CI)	0.22 [0.01, 5.28]
6.3 At 1 year	2	254	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.04, 10.57]
7 Change in flow‐mediated dilatation of brachial artery (%) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

7.1 At 6 months	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
8 Change in serum total cholesterol levels (%) Show forest plot	6		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

8.1 At 1 month	3	228	Mean Difference (IV, Fixed, 95% CI)	‐18.31 [‐22.55, ‐14.06]
8.2 At 6 months	4	528	Mean Difference (IV, Fixed, 95% CI)	‐24.28 [‐26.09, ‐22.47]
8.3 At 1 year	2	254	Mean Difference (IV, Fixed, 95% CI)	‐27.60 [‐30.64, ‐24.57]
8.4 At the end of follow‐up	6	669	Mean Difference (IV, Fixed, 95% CI)	‐26.53 [‐28.54, ‐24.51]
9 Change in serum HDL cholesterol levels (%) Show forest plot	6		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

9.1 At 1 month	3	228	Mean Difference (IV, Fixed, 95% CI)	3.0 [‐2.47, 8.47]
9.2 At 6 months	4	528	Mean Difference (IV, Fixed, 95% CI)	4.18 [1.54, 6.82]
9.3 At 1 year	2	254	Mean Difference (IV, Fixed, 95% CI)	2.56 [‐1.17, 6.29]
9.4 At the end of follow‐up	6	669	Mean Difference (IV, Fixed, 95% CI)	3.11 [0.55, 5.67]
10 Change in serum triglyceride levels (%) Show forest plot	5		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

10.1 At 1 month	3	228	Mean Difference (IV, Fixed, 95% CI)	10.31 [‐5.11, 25.74]
10.2 At 6 months	3	363	Mean Difference (IV, Fixed, 95% CI)	‐9.34 [‐18.90, 0.22]
10.3 At 1 year	1	110	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐18.09, 18.09]
10.4 At the end of follow‐up	5	525	Mean Difference (IV, Fixed, 95% CI)	‐3.27 [‐12.03, 5.50]
11 Adverse events Show forest plot	6		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

11.1 At 1 month	2	248	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.65, 1.13]
11.2 At 6 months	3	416	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.82, 1.27]
11.3 At 1 year	2	276	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.81, 1.26]

Comparison 1. Statins versus control

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