Trial Evidences. Marjet Braamskamp Departement of Vascular Medicine/ Pediatrics Lipidology in Pediatrics 24 September 2015

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1 Trial Evidences Marjet Braamskamp Departement of Vascular Medicine/ Pediatrics Lipidology in Pediatrics 24 September 2015

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3 Rosuvastatin in adults LDL reduction of 45-60% Less side effects

4 Rosuvastatin in adults Crouse JR JAMA 2007

5 Rosuvastatin:effective in children yrs HeFH

6 CHARON hypercholesterolaemia in children and Adolescents taking Rosuvastatin OpeN label The objectives of the study 1. To assess the safety and efficacy of rosuvastatin over 2 years in HeFH children and adolescents aged 6-17 years 2. To assess the effect of rosuvastatin on c-imt in children with HeFH compared with unaffected (non-hefh) siblings

7 Methods The study enrolled HeFH children/adolescents aged 6 17 years fasting LDL-C >4.9 mmol/l (>190 mg/dl) or >4.1 mmol/l (>158 mg/dl) plus other CV risk factors Rosuvastatin 5 mg once daily - up-titration to 10 mg (6 9 years old), or - 20 mg (10 17 years old) if an LDL-C target of <2.85 mmol/l (<110 mg/dl) was not achieved

8 Methods 2 c-imt measurements at three locations in the left and right carotid arteries at baseline, 12 and 24 months Enrolment of unaffected siblings

9 Outcome Efficacy: 1. Change in LDL-C 2. Reaching LDL-C treatment goal (LDL < 2.85 mmol/l) 3. Change in cimt Safety: 1. Growth 2. Sexual development (tanner stadia) 3. Side effects

10 Study flow chart Siblings (N= 65)

11 Baseline characteristics Parameter Enrolled patients (n=198) Healthy siblings (n=65) Age in years, mean (SD) 11.6 (3.3) 11.5 (3.5) Gender, n (%) Girls 110 (56) 32 (49) Boys 88 (44) 33 (51) Baseline LDL-C in mmol/l (sd) 6.1 (1.3) NA Baseline c-imt in mm (sd) (0.049) (0.045) Kusters DM, et al. Circ Res. 2014;114:

12 Significant change in LDL-C from baseline in all age groups

13 Patients reaching LDL-C < 2.85 mmol/l (<110)

14 cimt: significant differently at baseline; not after 2 years of treatment Visit Treated HeFH children Unaffected siblings 6 9 years (n=64) years (n=72) years (n=61) Total (n=197) 6 9 years (n=21) years (n=22) years (n=22) Total (n=65) Baseline* Month Month *Difference between treated HeFH and unaffected siblings was significant at p ,2 1. Kusters DM, et al. Circ Res. 2014;114: Kusters DM, et al. J Clin Lipidol. 2013;7:

15 No major safety issues No significant change in liverenzymes, renal function or CK No treatment related SAE Height and weight within the normal range 82% progression of at least one in Tanner stage

16 Conclusions CHARON study Significant decrease in LDL-C compared to baseline up to 45% The mean c-imt difference between HeFH children and unaffected siblings was significant at the start of the study and no longer significant after 12 and 24 months of treatment with rosuvastatin 5 20 mg No untowards safety concerns

17 Statin treatment in children with FH Short term safety and efficacy well established Current guidelines: consider statin therapy from 8 years onwards HOWEVER: Long-term follow-up is lacking!

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19 Aim of AfterTen study Efficacy of statin treatment Safety of statin treatment Tolerability of statin treatment Adherence to statin treatment => 10 years after initiation in childhood

20 Lipids Trial ( ) Aim to evaluate the 2-years efficacy and safety of statin therapy in FH children Methods randomized, placebo controlled trial 214 FH children, 8-18 years Primary Efficacy Outcome c-imt Primary Safety Outcomes growth, maturation, liver/muscle toxicity

21 Lipids Trial Mean changes from baseline in intima-media thickness after two years Wiegman, JAMA 2004

22 Methods AfterTen study 214 FH patients 95 unaffected siblings c-imt, blood sample analysis, physical examination, questionnaires

23 Outcome AfterTen study Efficacy: Change lipid profile Change mean carotid IMT Safety: Tolerability: Adherence: Growth and maturation Reported adverse events Changes of muscle and liver enzymes Questionnaire MARS/ MASRI questionnaire

24 Baseline -start RCT- 214 FH children randomized 95 Siblings enrolled 106 Pravastatin 108 Placebo 5 Did not complete RCT 5 Did not complete RCT 2 Years -end RCT- 101 Completed RCT and continued on statin 103 Completed RCT and continued on statin 214 Eligible for follow-up 95 Eligible for follow-up 20 Not enrolled (vital/disease status confirmed) 14 Declined participation 11 not motivated/too busy 1 stomach-reduction surgery 1 normalisation lipid profile 1 just given birth 5 Lived abroad 1 Died in traffic accident 12 Not enrolled (vital/disease status confirmed) 12 Declined participation 10 not motivated/too busy 2 fear of needles 10 Years -end follow-up- 194 Included in efficacy analysis 194 Included in safety analysis 83 Included in efiicacy analysis 83 Included in safety analysis

25 Kusters et al JAMA 2014 Results: Characteristics FH n=194 At baseline Sibling n=83 P Value FH n=194 After 10 years follow-up Sibling n=83 P Value Age yr 12.9 ± ± ± ± Male sex no. (%) 90 (46.4) 46 (55.4) (46.4) 46 (55.4) 0.17 Height m 1.56 ± ± ± ± Weight kg 48.8 ± ± ± ± Body-mass index 19.4 ± ± ± ± Blood pressure mm Hg Systolic ± ± ± ± Diastolic 61.5 ± ± ± ± Risk factors no.(%) Diabetes 0 (0) 0 (0) - 1 (0.5) 1 (1.2) 0.52 Hypertension 0 (0) 0 (0) - 7 (3.6) 5 (6.2) 0.35 Current smoking 22 (11) 6 (7) (27.3) 27 (32.5) 0.38 Statin use no. (%) 0 (0) 0 (0) (84) 0 (0) <0.001

26 Statin use 84% lipid lowering therapy 62% statin monotherapy 37% statins in combination with ezetimibe 79 % adherence (> 80% tablets in preceding month)

27 Ten years of statin therapy: significantly higher LDL-C LDL-C, FH: 4.49 mmol/l (173 mg/dl) LDL-C, sib: 3.22 mmol/l (124 mg/dl) Kusters et al JAMA 2014

28 Carotid IMT (mm) Ten years of statin therapy: cimt significantly different Carotid IMT (mm) Baseline After 10 years P= P= FH Siblings n=194 n= FH Siblings n=194 n=83 Kusters et al JAMA 2014

29 Ten years of statin therapy: cimt progression not significant Carotid IMT progression (mm) P = FH n=194 Siblings n=83 Kusters et al JAMA 2014

30 Ten years of statin therapy: no safety concerns FH n=194 Sibling n=83 P Value ASAT IU/l Median (IQR) 25.0 [ ] 26.0 [ ] 0.44 > 3x ULN no. (%) 1 (0.5%) 1 (1.1%) 0.55 ALAT IU/l Median (IQR) 18.0 [ ] 17.0 [ ] 0.63 > 3x ULN no. (%) 1 (0.5%) 0 (0.0%) 0.51 CK IU/l Median (IQR) [ ] [ ] 0.28 > 10x ULN no. (%) 0 (0.0%) 2 (2.1%) 0.03 Kusters et al JAMA 2014

31 Ten years of statin therapy: no safety concerns FH n=194 Sibling n=83 P Value Height m 1.74 ± ± Weight kg 74.2 ± ± Body-mass index 24.4 ± ± No differences in educational level

32 Conclusion 1 - Early initiation of statin therapy reduces c-imt progression - Earlier initiation might lead to smaller c-imt - No major safety issues

33 Ten years of statin therapy: good adherence 89.9 % still on lipid lowering medication Adherence > 80 %: 78.7% 19 patients completely non adherent: forgotten to take medication (N=8) unwillingness (N=6) side effects (N=3) unknown (N=2)

34 Ten years of statin therapy: no major side effects 19.5 % patients had ever experienced side effects No major side effects 1.5% stopped statin therapy because of side effects Braamskamp et al Pediatric drugs 2015

35 Ten years of statin therapy Similar hormone levels in HeFH and siblings Braamskamp et al Atherosclerosis 2015

36 Ten years of statin therapy: Similar hormone levels in HeFH and siblings Braamskamp et al Atherosclerosis 2015

37 Conclusions 2 Long-term statin treatment might prevent very premature CVD Good adherence No major side effects No significant differences in hormone levels

38 Treatment not optimal: Clinical implications more potent statins lifestyle (BMI, smoking status)

39 Meeike Kusters Hans Avis Eric de Groot Johan Gort Paul van Trotsenburg Maud Vissers Frits Wijburg John Kastelein Albert Wiegman Barbara Hutten Acknowledgements

40 Extra slides

41 Mean carotid IMT (mm) est. IMT increase = mm/year mm/year p= est. IMT increase = mm/year.40 fh controls AGE (years)