Evolocumab in Pediatric Heterozygous Familial Hypercholesterolemia

BACKGROUND Evolocumab, a fully human monoclonal antibody directed against proprotein convertase subtilisin–kexin type 9, is widely used in adult patients to lower low-density lipoprotein (LDL) cholesterol levels. Its effects in pediatric patients with heterozygous familial hypercholesterolemia are not known. METHODS We conducted a 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of evolocumab in pediatric patients with heterozygous familial hypercholesterolemia. Patients 10 to 17 years of age who had received stable lipid-lowering treatment for at least 4 weeks before screening and who had an LDL cholesterol level of 130 mg per deciliter (3.4 mmol per liter) or more and a triglyceride level of 400 mg per deciliter (4.5 mmol per liter) or less were randomly assigned in a 2:1 ratio to receive monthly subcutaneous injections of evolocumab (420 mg) or placebo. The primary end point was the percent change in LDL cholesterol level from baseline to week 24; key secondary end points were the mean percent change in LDL cholesterol level from baseline to weeks 22 and 24 and the absolute change in LDL cholesterol level from baseline to week 24. RESULTS A total of 157 patients underwent randomization and received evolocumab (104 patients) or placebo (53 patients). At week 24, the mean percent change from baseline in LDL cholesterol level was −44.5% in the evolocumab group and −6.2% in the placebo group, for a difference of −38.3 percentage points (P<0.001). The absolute change in the LDL cholesterol level was −77.5 mg per deciliter (−2.0 mmol per liter) in the evolocumab group and −9.0 mg per deciliter (−0.2 mmol per liter) in the placebo group, for a difference of −68.6 mg per deciliter (−1.8 mmol per liter) (P<0.001). Results for all secondary lipid variables were significantly better with evolocumab than with placebo. The incidence of adverse events that occurred during the treatment period was similar in the evolocumab and placebo groups. CONCLUSIONS In this trial involving pediatric patients with familial hypercholesterolemia, evolocumab reduced the LDL cholesterol level and other lipid variables. (Funded by Amgen; HAUSER-RCT ClinicalTrials.gov number, NCT02392559. opens in new tab.

Short-Term Effect of Different Teaching Methods on Nasopharyngeal Carcinoma for General Practitioners in Jakarta, Indonesia

In Indonesia, Nasopharyngeal Carcinoma (NPC) is the most frequent cancer of the head and neck region. At first presentation in the hospital most patients already have advanced NPC. Our previous study showed that general practitioners (GPs) working in Yogyakarta, Indonesia lack the knowledge necessary for early detection of NPC. By providing training on early symptoms of NPC we hope that the diagnosis and referral will occur at an earlier stage. Here we assess the current NPC knowledge levels of GPs in Jakarta, evaluate improvement after training, compare the effectiveness of two training formats, and estimate the loss of recall over a two week period

Efficacy and safety of lipoprotein apheresis in children with homozygous familial hypercholesterolemia: A systematic review

Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder that may cause life-threatening cardiovascular disease (CVD) at childhood. Marginal effectiveness of statins in reducing low-density lipoprotein cholesterol (LDL-C) is the reason why extracorporeal removal of LDL-C by lipoprotein apheresis (LA) is recommended at the earliest possible age. Objective: It is, however, unknown to what extent LA effectively reduces the burden of CVD in children with HoFH. We therefore systemically reviewed the literature on the efficacy and safety of LA in children with HoFH. Methods: We conducted a systematic literature search using Embase Classic and Embase on studies that evaluated LA in patients with HoFH aged <19 years and reported on at least one of the following outcome measures: cholesterol levels, xanthoma, CVD, or surrogate outcome markers for CVD. Adverse events were also reported on. Results: We selected 76 studies on 209 patients, 45 of these were case series and 31 were case reports. Mean LDL-C reduction per session was 63% and 71% for nonselective and selective modes of LA, respectively. HDL-C levels were best preserved with selective LA. Xanthomata regressed or disappeared in 83% of patients during LA treatment, surrogate parameters of CVD remained stable in most patients. Of 123 patients, 24 experienced a CVD event of whom 10 had experienced a CVD before LA onset. Six patients died at follow-up. Reported side effects were overall minor. Conclusion: LA seems to be a safe therapy and substantially reduces LDL-C and xanthomata in children with HoFH. The efficacy with respect to CVD protection as compared with only pharmacologic and dietary treatment remains unclear

Efficacy and safety of lipoprotein apheresis in children with homozygous familial hypercholesterolemia: A systematic review

Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder that may cause life-threatening cardiovascular disease (CVD) at childhood. Marginal effectiveness of statins in reducing low-density lipoprotein cholesterol (LDL-C) is the reason why extracorporeal removal of LDL-C by lipoprotein apheresis (LA) is recommended at the earliest possible age. Objective: It is, however, unknown to what extent LA effectively reduces the burden of CVD in children with HoFH. We therefore systemically reviewed the literature on the efficacy and safety of LA in children with HoFH. Methods: We conducted a systematic literature search using Embase Classic and Embase on studies that evaluated LA in patients with HoFH aged <19 years and reported on at least one of the following outcome measures: cholesterol levels, xanthoma, CVD, or surrogate outcome markers for CVD. Adverse events were also reported on. Results: We selected 76 studies on 209 patients, 45 of these were case series and 31 were case reports. Mean LDL-C reduction per session was 63% and 71% for nonselective and selective modes of LA, respectively. HDL-C levels were best preserved with selective LA. Xanthomata regressed or disappeared in 83% of patients during LA treatment, surrogate parameters of CVD remained stable in most patients. Of 123 patients, 24 experienced a CVD event of whom 10 had experienced a CVD before LA onset. Six patients died at follow-up. Reported side effects were overall minor. Conclusion: LA seems to be a safe therapy and substantially reduces LDL-C and xanthomata in children with HoFH. The efficacy with respect to CVD protection as compared with only pharmacologic and dietary treatment remains unclear

Intima-media thickness in treated and untreated patients with and without familial hypercholesterolemia: A systematic review and meta-analysis

Familial hypercholesterolemia (FH) is a common genetic disorder of lipoprotein metabolism leading to premature atherosclerosis. From early onset, status and progression of atherosclerosis of the large peripheral arterial walls can be quantified by ultrasound intima-media thickness (IMT) measurements. Here we describe differences in IMT in treated and untreated FH patients versus unaffected controls over a broad age range. We conducted a systematic literature search using MEDLINE, EMBASE and Trials.gov up to April 2020 for studies addressing IMT in FH patients and controls. Our search yielded 558 articles of which 42 (6,143 participants) were included. Meta-analysis showed a mean (95%CI) difference between FH patients vs controls of 0.11 (95%CI 0.06-0.15) mm in carotid IMT (p<0.001), and 0.47 (0.19-0.74) mm in femoral IMT (p <0.001). We found a smaller mean (95%CI) difference in carotid IMT in treated FH patients vs controls: 0.05 (0.03-0.08) mm (p <0.001), than in untreated FH patients vs controls 0.12 (0.03-0.21) mm (p=0.009). When plotted against age, the mean (95%CI) difference in carotid IMT between FH patients vs controls increases with 0.0018 (-0.0007-0.0042) mm/year. This increase was smaller in treated vs untreated FH patients, when compared to controls (0.0023 (0.0021 to 0.0025) mm/year vs 0.0104 (0.0100-0.0108) mm/year, respectively). Our findings suggest that more robust earlier treatment initiation and achieving treatment targets could be beneficial to reduce cardiovascular risk in patients with FH

Intima-media thickness in treated and untreated patients with and without familial hypercholesterolemia: A systematic review and meta-analysis

Familial hypercholesterolemia (FH) is a common genetic disorder of lipoprotein metabolism leading to premature atherosclerosis. From early onset, status and progression of atherosclerosis of the large peripheral arterial walls can be quantified by ultrasound intima-media thickness (IMT) measurements. Here we describe differences in IMT in treated and untreated FH patients versus unaffected controls over a broad age range. We conducted a systematic literature search using MEDLINE, EMBASE and Trials.gov up to April 2020 for studies addressing IMT in FH patients and controls. Our search yielded 558 articles of which 42 (6,143 participants) were included. Meta-analysis showed a mean (95%CI) difference between FH patients vs controls of 0.11 (95%CI 0.06-0.15) mm in carotid IMT (p<0.001), and 0.47 (0.19-0.74) mm in femoral IMT (p <0.001). We found a smaller mean (95%CI) difference in carotid IMT in treated FH patients vs controls: 0.05 (0.03-0.08) mm (p <0.001), than in untreated FH patients vs controls 0.12 (0.03-0.21) mm (p=0.009). When plotted against age, the mean (95%CI) difference in carotid IMT between FH patients vs controls increases with 0.0018 (-0.0007-0.0042) mm/year. This increase was smaller in treated vs untreated FH patients, when compared to controls (0.0023 (0.0021 to 0.0025) mm/year vs 0.0104 (0.0100-0.0108) mm/year, respectively). Our findings suggest that more robust earlier treatment initiation and achieving treatment targets could be beneficial to reduce cardiovascular risk in patients with FH

The clinical and molecular diversity of homozygous familial hypercholesterolemia in children: Results from the GeneTics of clinical homozygous hypercholesterolemia (GoTCHA)study

Background: Homozygous familial hypercholesterolemia (hoFH)is either diagnosed on the identification of pathogenic genetic variants in LDLR, APOB, or PCSK9 or by phenotypic parameters of which an extremely elevated LDL-C level >13 mmol/L (>500 mg/dL)is the most prominent hallmark. Little is known about the clinical spectrum in children with hoFH. Objective: We set out to investigate the phenotypical spectrum of genetically defined hoFH in our pediatric cohort and evaluated how many pediatric patients, now classified as heterozygous, carry a second mutation, which would reclassify these patients as hoFH. Methods: We analyzed the data of a total of 1903 children with molecularly proven FH. Subsequently we performed candidate gene sequencing in the cohort of heterozygous familial hypercholesterolemia children in whom the LDL-C level was above the lowest level measured in the pediatric patients with hoFH. Results: Of our 13 hoFH children, 8 (62%)had LDL-C levels below the clinical hoFH criteria of 13 mmol/L (500 mg/dL). In the remaining 1890 patients with heterozygous familial hypercholesterolemia, 64 (3.4%)had LDL-C levels equal to or above the lowest LDL-C level in a patient with hoFH carrying 2 deleterious variants (8.36 mmol/L or 323.3 mg/dL). No additional pathogenic variants in LDLR and APOB were identified. In 2 related patients, a PCSK9 gain of function mutation was found. Conclusion: We show that LDL-C levels vary among pediatric patients with molecularly proven hoFH, and that most of these patients do not meet the clinical LDL-C criteria for hoFH. The levels overlap with LDL-C levels in true heterozygous patients. This warrants a critical reappraisal of the current LDL-C cutoffs for the phenotypic diagnosis of hoFH in children

Coronary computed tomography angiography and echocardiography in children with homozygous familial hypercholesterolemia

Background and aims: Homozygous familial hypercholesterolemia (hoFH)is a rare genetic disease, hallmarked by a lifelong exposure to very high levels of low-density lipoprotein cholesterol (LDL-C). Untreated, patients can experience a cardiovascular event in the first decade of life. Early detection and monitoring of subclinical atherosclerosis in these patients is therefore extremely important. We set out to assess the diagnostic yield of low-dose coronary computed tomography angiography (cCTA)compared to echocardiography in detecting subclinical atherosclerosis. Methods: For this single-center cross-sectional study, we included all pediatric hoFH patients treated with lipoprotein-apheresis (LA)in Amsterdam UMC. We performed both cCTA and echocardiography in all patients as part of routine follow-up. Results: Six hoFH patients were included. Median ages at diagnosis, onset of LA and cardiovascular assessment (cCTA and echocardiography)were 2.6, 6.5, 10.8 and 11.1 years, respectively. Echocardiography revealed no signs of atherosclerosis in any of the six patients. In two patients, mild dilatation of the cardiac chambers was detected and two patients showed signs of mitral or aortic insufficiency. On cCTA, however, non-calcified plaques without stenosis were detected in four patients. In two patients calcified coronary plaques were found at the ostia of the right coronary artery or the left main coronary artery. Aortic root calcifications were found in two patients. Conclusions: Our findings suggest that in hoFH children, low-dose cCTA is superior to echocardiography for the detection of subclinical coronary and aortic root atherosclerosis and should therefore be considered in the routine cardiovascular monitoring of these high-risk children

Coronary computed tomography angiography and echocardiography in children with homozygous familial hypercholesterolemia

Background and aims: Homozygous familial hypercholesterolemia (hoFH)is a rare genetic disease, hallmarked by a lifelong exposure to very high levels of low-density lipoprotein cholesterol (LDL-C). Untreated, patients can experience a cardiovascular event in the first decade of life. Early detection and monitoring of subclinical atherosclerosis in these patients is therefore extremely important. We set out to assess the diagnostic yield of low-dose coronary computed tomography angiography (cCTA)compared to echocardiography in detecting subclinical atherosclerosis. Methods: For this single-center cross-sectional study, we included all pediatric hoFH patients treated with lipoprotein-apheresis (LA)in Amsterdam UMC. We performed both cCTA and echocardiography in all patients as part of routine follow-up. Results: Six hoFH patients were included. Median ages at diagnosis, onset of LA and cardiovascular assessment (cCTA and echocardiography)were 2.6, 6.5, 10.8 and 11.1 years, respectively. Echocardiography revealed no signs of atherosclerosis in any of the six patients. In two patients, mild dilatation of the cardiac chambers was detected and two patients showed signs of mitral or aortic insufficiency. On cCTA, however, non-calcified plaques without stenosis were detected in four patients. In two patients calcified coronary plaques were found at the ostia of the right coronary artery or the left main coronary artery. Aortic root calcifications were found in two patients. Conclusions: Our findings suggest that in hoFH children, low-dose cCTA is superior to echocardiography for the detection of subclinical coronary and aortic root atherosclerosis and should therefore be considered in the routine cardiovascular monitoring of these high-risk children