ABSTRACT
Background: In 2019, the European Atherosclerosis Society (EAS) published updated guidelines, recommending even lower blood cholesterol targets than previously. In patients with familial hypercholesterolaemia (FH), who have very elevated blood cholesterol levels and are at ('Very') 'High risk' of atherosclerotic cardiovascular disease (ASCVD), this represents a real challenge. Anti-Proprotein convertase subtilisin/kexin type 9 monoclonal antibody (anti-PCSK9 mAb) has been commercially available for FH in Belgium since 2015. Our study aims to investigate the real-life efficacy of anti-PCSK9 mAb in FH patients. Method: We sourced patients from the EAS FH Studies Collaboration database (an international database on FH in which Belgium participates). We only retained patients using anti-PCSK9 mAb and followed at our Lipid Clinic. Results: Of the 239 subjects included in this study (mean age: 56 years), 85% were considered at 'Very High Risk' (56% with a history of ASCVD), the remaining 15% were at 'High Risk'. The PCSK9 mAb treatment reduced LDL-C levels by 54% within the first year. This reduction was maintained over the follow-up (FU) period (3.0 ± 1.8 years). The EAS targets were reached in 50% of the subjects, 93% of whom were also treated with statins. The treatment was very well tolerated. At the end of the observation period, 96% patients continued receiving PCSK9 mAb. Conclusions: Anti-PCSK9 mAb are a safe and effective therapeutic option for lowering LDL-C levels in FH patients. It allowed a significant portion of our FH patients to reach their lipid targets, mainly in those with combined therapy with statin and/or ezetimibe.
ABSTRACT
BACKGROUND: The HAUSER-RCT study showed that 24 weeks of evolocumab (a proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitor) in paediatric patients with heterozygous familial hypercholesterolaemia was safe and improved lipid parameters compared to placebo. Here, we aimed to evaluate the safety and efficacy of evolocumab in this population for an additional 80 weeks. METHODS: HAUSER-OLE was an 80-week, single-arm, open-label extension of HAUSER-RCT, a randomised controlled trial, and was conducted at 46 centres in 23 countries. Paediatric patients aged 10-17 years with heterozygous familial hypercholesterolaemia who completed 24 weeks of monthly treatment with subcutaneously administered placebo or 420 mg evolocumab in HAUSER-RCT with no serious treatment-emergent adverse events were eligible to enrol in HAUSER-OLE. All patients received open-label subcutaneous evolocumab 420 mg monthly with background statins with or without ezetimibe for 80 additional weeks. The primary endpoint was treatment-emergent adverse events. Efficacy was evaluated by changes in lipids from the baseline of HAUSER-RCT to the end of HAUSER-OLE (104 weeks). This study is registered with ClinicalTrials.gov (NCT02624869) and is now completed. FINDINGS: Between Sept 10, 2016, and Nov 25, 2019, 157 patients were enrolled in HAUSER-RCT and received randomised treatment; 150 continued to HAUSER-OLE, received evolocumab treatment, and were included in the full analysis set, presented here. 146 (97%) of 150 patients completed the open-label extension. The incidence of treatment-emergent adverse events in HAUSER-OLE was 70% (105 of 150). Overall, the most common treatment-emergent adverse events were nasopharyngitis (22 [15%] of 150), headache (14 [9%]), and influenza-like illness (13 [9%]). Serious treatment-emergent adverse events occurred in four (3%) of 150 patients (perforated appendicitis and peritonitis, wrist fracture, anorexia nervosa, and headache); none was considered related to evolocumab. No treatment-emergent adverse events led to treatment discontinuation. At week 80, the mean percentage change from baseline in LDL cholesterol was -35·3% (SD 28·0). INTERPRETATION: After 80 weeks of treatment, evolocumab was safe, well tolerated, and led to sustained reductions in LDL cholesterol in paediatric patients with heterozygous familial hypercholesterolaemia. When lipid goals cannot be achieved with conventional treatments, evolocumab is an effective add-on therapy in paediatric patients. FUNDING: Amgen. TRANSLATIONS: For the French, Spanish, Spanish, Portuguese, Italian and Dutch translations of the abstract see Supplementary Materials section.
Subject(s)
Anticholesteremic Agents , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Hyperlipoproteinemia Type II , Antibodies, Monoclonal , Antibodies, Monoclonal, Humanized , Anticholesteremic Agents/adverse effects , Anticholesteremic Agents/therapeutic use , Child , Cholesterol, LDL , Double-Blind Method , Ezetimibe/therapeutic use , Headache , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hyperlipoproteinemia Type II/drug therapy , Proprotein Convertase 9 , Subtilisins/therapeutic use , Treatment OutcomeABSTRACT
BACKGROUND: As lipid targets became more stringent in the latest ESC/EAS guidelines, many patients on statin monotherapy are left above their risk-based target, increasing the need for lipid-lowering therapies. The results of the ODYSSEY APPRISE study were recently published by Gaudet et al In this trial, alirocumab (a PCSK9 inhibitor) was investigated in high cardiovascular risk patients in a real-life setting. OBJECTIVE: We aim at analysing the characteristics, safety and efficacy of alirocumab in the Belgian population of the ODYSSEY APPRISE trial and, based on literature research, we aim to evaluate the importance and the need for the add-on, non-statin lipid-lowering therapy in clinical practice. METHODS AND RESULTS: ODYSSEY APPRISE is a multicentric, prospective, single-arm, Phase 3b open-label trial. A total of 68 Belgian patients were enrolled, 63 patients had heterozygous familial hypercholesterolaemia (HeFH). Baseline mean LDL-c was 188.7 mg/dL (SD ± 51.8). At week 12, 65 patients had an evaluable efficacy end point with a mean LDL-c reduction of 59.9% from baseline. The overall incidence of treatment-emergent adverse events (TEAEs) was 75.0%. The most frequent TEAE was back pain (10.3%), nasopharyngitis (10.3%) and injection site erythema (8.8%). Based on the literature, a majority of patients do not reach their risk-based lipid target despite statin therapy alone. CONCLUSION: In a real-life setting, alirocumab is both well-tolerated, safe and very effective in reducing LDL-c in this Belgian cohort. In clinical practice, more patients should be initiated on the add-on, non-statin lipid-lowering therapy in order to reach their risk-based lipid target.
Subject(s)
Antibodies, Monoclonal, Humanized , PCSK9 Inhibitors , Antibodies, Monoclonal, Humanized/adverse effects , Belgium , Humans , PCSK9 Inhibitors/adverse effects , Prospective Studies , Treatment OutcomeABSTRACT
BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) is commonly caused by mutations in the LDLR, APOB or PCSK9 genes, with untreated mean low density lipoprotein-cholesterol (LDL-C) concentrations being elevated in APOB mutation carriers, even higher in LDLR mutation and highest in those with a PCSK9 mutation. Here we examine this in children with FH from Norway, UK, The Netherlands, Belgium, Czech Republic, Austria, Portugal and Greece. METHODS: Differences in characteristics and pre- and post-treatment lipid concentrations in those with different molecular causes were compared by standard statistical tests. RESULTS: Data were obtained from 2866 children, of whom 2531 (88%) carried a reported LDLR/APOB/PCSK9 variant. In all countries, the most common cause of FH was an LDLR mutation (79% of children, 297 different), but the prevalence of the APOB p.(Arg3527Gln) mutation varied significantly (ranging from 0% in Greece to 39% in Czech Republic, p < 2.2 × 10-16). The prevalence of a family history of premature CHD was significantly higher in children with an LDLR vs APOB mutation (16% vs 7% p=0.0005). Compared to the LDLR mutation group, mean (±SD) concentrations of pre-treatment LDL-C were significantly lower in those with an APOB mutation (n = 2260 vs n = 264, 4.96 (1.08)mmol/l vs 5.88 (1.41)mmol/l, p < 2.2 × 10-16) and lowest in those with a PCSK9 mutation (n = 7, 4.71 (1.22)mmol/l). CONCLUSIONS: The most common cause of FH in children from eight European countries was an LDLR mutation, with the prevalence of the APOB p.(Arg3527Gln) mutation varying significantly across countries. In children, LDLR-FH is associated with higher concentrations of LDL-C and family history of CHD compared to those with APOB-FH.
Subject(s)
Hyperlipoproteinemia Type II , Proprotein Convertase 9 , Austria , Belgium , Child , Czech Republic/epidemiology , DNA Mutational Analysis , Europe , Greece , Humans , Hyperlipoproteinemia Type II/diagnosis , Hyperlipoproteinemia Type II/epidemiology , Hyperlipoproteinemia Type II/genetics , Lipids , Mutation , Netherlands/epidemiology , Norway , Portugal , Proprotein Convertase 9/genetics , Receptors, LDL/geneticsABSTRACT
BACKGROUND: Familial hypercholesterolaemia (FH) is underdiagnosed in most countries. We report our first experience from a national pilot project of cascade screening in relatives of FH patients. METHODOLOGY: Participating specialists recruited consecutive index patients (IP) with Dutch Lipid Clinic Network (DLCN) score ≥6. After informed consent, the relatives were visited by the nurses to collect relevant clinical data and perform blood sampling for lipid profile measurement. FH diagnosis in the relatives was based on the DLCN and/or MEDPED FH (Make-Early-Diagnosis-to-Prevent-Early-Deaths-in-FH) criteria. RESULTS: In a period of 18 months, a total of 127 IP (90 with definite FH and 37 with probable FH) were enrolled in 15 centres. Out of the 270 relatives visited by the nurses, 105 were suspected of having FH: 31 with DCLN score >8, 33 with DLCN score 5-8 and 41 with MEDPED FH criteria. In a post-hoc analysis, another set of MEDPED FH criteria established in the Netherlands and adapted to Belgium allowed to detect FH in 51 additional relatives. CONCLUSION: In a country with no national FH screening program, our pilot project demonstrated that implementing a simple phenotypical FH cascade screening strategy using the collaboration of motivated specialists and two nurses, allowed to diagnose FH in 127 index patients and an additional 105 of their relatives over the two-year period. Newly developed MEDPED FH cut-offs, easily applicable by a nurse with a single blood sample, might further improve the sensitivity of detecting FH within families.
Subject(s)
Hyperlipoproteinemia Type II , Belgium/epidemiology , Cholesterol, LDL , Feasibility Studies , Humans , Hyperlipoproteinemia Type II/diagnosis , Hyperlipoproteinemia Type II/epidemiology , Hyperlipoproteinemia Type II/genetics , Mutation , Pilot ProjectsABSTRACT
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.).
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Anticholesteremic Agents/therapeutic use , Cholesterol, LDL/blood , Hyperlipoproteinemia Type II/drug therapy , PCSK9 Inhibitors , Adolescent , Antibodies, Monoclonal, Humanized/adverse effects , Anticholesteremic Agents/adverse effects , Child , Double-Blind Method , Drug Therapy, Combination , Female , Heterozygote , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hyperlipoproteinemia Type II/genetics , Lipids/blood , Male , Treatment OutcomeABSTRACT
BACKGROUND AND AIMS: Infusion of high-density lipoprotein (HDL) mimetics failed to induce regression of atherosclerosis in recent randomized clinical trials. However, patients in these previous trials had normal levels of HDL-cholesterol, which potentially limited efficacy. Patients with very low levels of HDL-cholesterol and impaired cholesterol efflux capacity can be expected to derive the most potential benefit from infusion of HDL mimetics. This randomized clinical trial evaluated the efficacy of infusions of the HDL mimetic CER-001 in patients with genetically determined very low levels of HDL cholesterol. METHODS: In this multicenter, randomized clinical trial, we recruited patients with familial hypoalphalipoproteinemia (due to ABCA1 and/or APOA1 loss-of-function variants). Participants were randomized to intravenous infusions of 8 mg/kg CER-001 or placebo (2:1 ratio), comprising 9 weekly infusions followed by infusions every two weeks. Patients underwent repeated 3T-MRI to assess mean vessel wall area and 18F-FDG PET/CT to quantify arterial wall inflammation. RESULTS: A total of 30 patients with a mean age of 52.7 ± 7.4 years and HDL-cholesterol of 0.35 ± 0.25 mmol/L were recruited. After 24 weeks, the absolute change in mean vessel wall area was not significantly different in the CER-001 group compared with placebo (n = 27; treatment difference: 0.77 mm2, p = 0.21). Furthermore, there was no significant difference in carotid arterial wall inflammation (n = 24, treatment difference: 0.10 target-to-background ratio of the most diseased segment, p = 0.33) after 24 weeks. CONCLUSION: In patients with genetically determined very low HDL-cholesterol, 24 weeks of treatment with HDL mimetic CER-001 did not reduce carotid vessel wall dimensions or arterial wall inflammation, compared with placebo.
Subject(s)
Carotid Artery Diseases , Lipoproteins, HDL , Apolipoprotein A-I , Carotid Artery Diseases/diagnostic imaging , Carotid Artery Diseases/drug therapy , Cholesterol, HDL , Humans , Middle Aged , Phospholipids , Positron Emission Tomography Computed Tomography , Recombinant ProteinsABSTRACT
Importance: Familial hypercholesterolemia (FH) is an underdiagnosed and undertreated genetic disorder that leads to premature morbidity and mortality due to atherosclerotic cardiovascular disease. Familial hypercholesterolemia affects 1 in 200 to 250 people around the world of every race and ethnicity. The lack of general awareness of FH among the public and medical community has resulted in only 10% of the FH population being diagnosed and adequately treated. The World Health Organization recognized FH as a public health priority in 1998 during a consultation meeting in Geneva, Switzerland. The World Health Organization report highlighted 11 recommendations to address FH worldwide, from diagnosis and treatment to family screening and education. Research since the 1998 report has increased understanding and awareness of FH, particularly in specialty areas, such as cardiology and lipidology. However, in the past 20 years, there has been little progress in implementing the 11 recommendations to prevent premature atherosclerotic cardiovascular disease in an entire generation of families with FH. Observations: In 2018, the Familial Hypercholesterolemia Foundation and the World Heart Federation convened the international FH community to update the 11 recommendations. Two meetings were held: one at the 2018 FH Foundation Global Summit and the other during the 2018 World Congress of Cardiology and Cardiovascular Health. Each meeting served as a platform for the FH community to examine the original recommendations, assess the gaps, and provide commentary on the revised recommendations. The Global Call to Action on Familial Hypercholesterolemia thus represents individuals with FH, advocacy leaders, scientific experts, policy makers, and the original authors of the 1998 World Health Organization report. Attendees from 40 countries brought perspectives on FH from low-, middle-, and high-income regions. Tables listing country-specific government support for FH care, existing country-specific and international FH scientific statements and guidelines, country-specific and international FH registries, and known FH advocacy organizations around the world were created. Conclusions and Relevance: By adopting the 9 updated public policy recommendations created for this document, covering awareness; advocacy; screening, testing, and diagnosis; treatment; family-based care; registries; research; and cost and value, individual countries have the opportunity to prevent atherosclerotic heart disease in their citizens carrying a gene associated with FH and, likely, all those with severe hypercholesterolemia as well.
Subject(s)
Hyperlipoproteinemia Type II/prevention & control , Cost of Illness , Global Health , Humans , Hyperlipoproteinemia Type II/diagnosis , Hyperlipoproteinemia Type II/therapy , Practice Guidelines as Topic , Public HealthABSTRACT
The joint consensus panel of the European Atherosclerosis Society (EAS) and the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) recently addressed present and future challenges in the laboratory diagnostics of atherogenic lipoproteins. Total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, and calculated non-HDL cholesterol (=total - HDL cholesterol) constitute the primary lipid panel for estimating risk of atherosclerotic cardiovascular disease (ASCVD) and can be measured in the nonfasting state. LDL cholesterol is the primary target of lipid-lowering therapies. For on-treatment follow-up, LDL cholesterol shall be measured or calculated by the same method to attenuate errors in treatment decisions due to marked between-method variations. Lipoprotein(a)-cholesterol is part of measured or calculated LDL cholesterol and should be estimated at least once in all patients at risk of ASCVD, especially in those whose LDL cholesterol decline poorly upon statin treatment. Residual risk of ASCVD even under optimal LDL-lowering treatment should be also assessed by non-HDL cholesterol or apolipoprotein B, especially in patients with mild-to-moderate hypertriglyceridemia (2-10 mmol/L). Non-HDL cholesterol includes the assessment of remnant lipoprotein cholesterol and shall be reported in all standard lipid panels. Additional apolipoprotein B measurement can detect elevated LDL particle numbers often unidentified on the basis of LDL cholesterol alone. Reference intervals of lipids, lipoproteins, and apolipoproteins are reported for European men and women aged 20-100 years. However, laboratories shall flag abnormal lipid values with reference to therapeutic decision thresholds.
Subject(s)
Atherosclerosis/etiology , Atherosclerosis/prevention & control , Hyperlipidemias/complications , Hyperlipidemias/drug therapy , Hypolipidemic Agents/therapeutic use , Lipoproteins/physiology , HumansABSTRACT
It has been well established that low-density lipoproteins (LDL) and other apolipoprotein B-containing lipoproteins are causally related to atherosclerotic cardiovascular disease (ASCVD) and that lowering these lipoproteins reduces the risk of ASCVD. By lowering LDL particles as much as possible, ASCVD can be prevented. There seems to be no LDL-cholesterol (LDL-C) threshold below which no further ASCVD prevention can be achieved. Furthermore, a low (an even very low) LDL-C appears to be safe. The new ESC/EAS guidelines based on these concepts are a step towards a benefit-based strategy by focusing on the clinical benefit that can be achieved by treating the cause of ASCVD. It is recommended to lower LDL-C as much as possible to prevent ASCVD, especially in high and very high-risk patients. With these new recommendations come recognition of the importance of combination therapies in high and very high-risk patients, first with statins and ezetimibe, and if needed with a PCSK9 inhibitor. The present paper is a review of some new concepts arising during the past 10 years in the field of lipidology and the description of what is new in the 2019 EAS/ESC guidelines.
Subject(s)
Cholesterol, LDL/blood , Dyslipidemias/physiopathology , Dyslipidemias/therapy , Cardiovascular Diseases/etiology , Cholesterol, LDL/physiology , Dyslipidemias/blood , Dyslipidemias/genetics , Humans , Hypolipidemic Agents/adverse effects , Hypolipidemic Agents/therapeutic use , Practice Guidelines as Topic , Risk FactorsABSTRACT
The joint consensus panel of the European Atherosclerosis Society (EAS) and the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) recently addressed present and future challenges in the laboratory diagnostics of atherogenic lipoproteins. Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDLC), LDL cholesterol (LDLC), and calculated non-HDLC (=total - HDLC) constitute the primary lipid panel for estimating risk of atherosclerotic cardiovascular disease (ASCVD) and can be measured in the nonfasting state. LDLC is the primary target of lipid-lowering therapies. For on-treatment follow-up, LDLC shall be measured or calculated by the same method to attenuate errors in treatment decisions due to marked between-method variations. Lipoprotein(a) [Lp(a)]-cholesterol is part of measured or calculated LDLC and should be estimated at least once in all patients at risk of ASCVD, especially in those whose LDLC declines poorly upon statin treatment. Residual risk of ASCVD even under optimal LDL-lowering treatment should be also assessed by non-HDLC or apolipoprotein B (apoB), especially in patients with mild-to-moderate hypertriglyceridemia (2-10 mmol/L). Non-HDLC includes the assessment of remnant lipoprotein cholesterol and shall be reported in all standard lipid panels. Additional apoB measurement can detect elevated LDL particle (LDLP) numbers often unidentified on the basis of LDLC alone. Reference intervals of lipids, lipoproteins, and apolipoproteins are reported for European men and women aged 20-100 years. However, laboratories shall flag abnormal lipid values with reference to therapeutic decision thresholds.
Subject(s)
Atherosclerosis/diagnosis , Cholesterol, LDL/blood , Lipoprotein(a)/blood , Apolipoproteins B/blood , Atherosclerosis/drug therapy , Biomarkers/blood , Cholesterol, HDL/blood , Consensus , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Pre-Analytical Phase , Societies, MedicalABSTRACT
BACKGROUND AND AIMS: For children with heterozygous familial hypercholesterolaemia (HeFH), European guidelines recommend consideration of statin therapy by age 8-10 years for those with a low density lipoprotein cholesterol (LDL-C) >3.5 mmol/l, and dietary and lifestyle advice. Here we compare the characteristics and lipid levels in HeFH children from Norway, UK, Netherlands, Belgium, Czech Republic, Austria, Portugal and Greece. METHODS: Fully-anonymized data were analysed at the London centre. Differences in registration and on treatment characteristics were compared by standard statistical tests. RESULTS: Data was obtained from 3064 children. The median age at diagnosis differed significantly between countries (range 3-11 years) reflecting differences in diagnostic strategies. Mean (SD) LDL-C at diagnosis was 5.70 (±1.4) mmol/l, with 88% having LDL-C>4.0 mmol/l. The proportion of children older than 10 years at follow-up who were receiving statins varied significantly (99% in Greece, 56% in UK), as did the proportion taking Ezetimibe (0% in UK, 78% in Greece). Overall, treatment reduced LDL-C by between 28 and 57%, however, in those >10 years, 23% of on-treatment children still had LDL-C>3.5 mmol/l and 66% of those not on a statin had LDL-C>3.5 mmol/l. CONCLUSIONS: The age of HeFH diagnosis in children varies significantly across 8 countries, as does the proportion of those >10 years being treated with statin and/or ezetimibe. Approximately a quarter of the treated children and almost three quarters of the untreated children older than 10 years still have LDL-C concentrations over 3.5 mmol/l. These data suggest that many children with FH are not receiving the full potential benefit of early identification and appropriate lipid-lowering treatment according to recommendations.
Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hyperlipoproteinemia Type II/diagnosis , Hyperlipoproteinemia Type II/drug therapy , Child , Child, Preschool , Cholesterol, LDL/blood , Europe , Female , Heterozygote , Humans , Hyperlipoproteinemia Type II/blood , Hyperlipoproteinemia Type II/genetics , Male , Retrospective StudiesSubject(s)
Biological Products/therapeutic use , Dietary Supplements , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hypercholesterolemia/therapy , Biological Products/adverse effects , Biological Products/pharmacokinetics , Biotransformation , Cardiovascular Diseases/chemically induced , Cholesterol/blood , Clinical Trials as Topic , Cytochrome P-450 CYP3A/metabolism , Double-Blind Method , Expert Testimony , Food-Drug Interactions , Gastrointestinal Diseases/chemically induced , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Lovastatin/adverse effects , Lovastatin/chemistry , Lovastatin/pharmacokinetics , Lovastatin/therapeutic use , Medicine, Chinese Traditional , Molecular Structure , Multicenter Studies as Topic , Musculoskeletal Diseases/chemically induced , Prodrugs/pharmacokinetics , Prodrugs/therapeutic use , Randomized Controlled Trials as Topic , Self MedicationABSTRACT
BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) is an autosomal dominant lipoprotein disorder characterized by significant elevation of low-density lipoprotein cholesterol (LDL-C) and markedly increased risk of premature cardiovascular disease (CVD). Because of the very high coronary artery disease risk associated with this condition, the prevalence of FH among patients admitted for CVD outmatches many times the prevalence in the general population. Awareness of this disease is crucial for recognizing FH in the aftermath of a hospitalization of a patient with CVD, and also represents a unique opportunity to identify relatives of the index patient, who are unaware they have FH. This article aims to describe a feasible strategy to facilitate the detection and management of FH among patients hospitalized for CVD. METHODS: A multidisciplinary national panel of lipidologists, cardiologists, endocrinologists and cardio-geneticists developed a three-step diagnostic algorithm, each step including three key aspects of diagnosis, treatment and family care. RESULTS: A sequence of tasks was generated, starting with the process of suspecting FH amongst affected patients admitted for CVD, treating them to LDL-C target, finally culminating in extensive cascade-screening for FH in their family. Conceptually, the pathway is broken down into 3 phases to provide the treating physicians with a time-efficient chain of priorities. CONCLUSIONS: We emphasize the need for optimal collaboration between the various actors, starting with a "vigilant doctor" who actively develops the capability or framework to recognize potential FH patients, continuing with an "FH specialist", and finally involving the patient himself as "FH ambassador" to approach his/her family and facilitate cascade screening and subsequent treatment of relatives.
Subject(s)
Cardiovascular Diseases/therapy , Cholesterol, LDL/blood , Coronary Care Units/standards , Critical Pathways/standards , Decision Support Techniques , Hyperlipoproteinemia Type II/diagnosis , Hyperlipoproteinemia Type II/drug therapy , Algorithms , Belgium/epidemiology , Biomarkers/blood , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/epidemiology , Clinical Decision-Making , Consensus , Genetic Markers , Genetic Predisposition to Disease , Humans , Hyperlipoproteinemia Type II/epidemiology , Hyperlipoproteinemia Type II/genetics , Mutation , Phenotype , Predictive Value of Tests , Prevalence , Prognosis , Risk Assessment , Risk Factors , WorkflowABSTRACT
BACKGROUND: The European Atherosclerosis Society-European Federation of Clinical Chemistry and Laboratory Medicine Consensus Panel aims to provide recommendations to optimize atherogenic lipoprotein quantification for cardiovascular risk management. CONTENT: We critically examined LDL cholesterol, non-HDL cholesterol, apolipoprotein B (apoB), and LDL particle number assays based on key criteria for medical application of biomarkers. (a) Analytical performance: Discordant LDL cholesterol quantification occurs when LDL cholesterol is measured or calculated with different assays, especially in patients with hypertriglyceridemia >175 mg/dL (2 mmol/L) and low LDL cholesterol concentrations <70 mg/dL (1.8 mmol/L). Increased lipoprotein(a) should be excluded in patients not achieving LDL cholesterol goals with treatment. Non-HDL cholesterol includes the atherogenic risk component of remnant cholesterol and can be calculated in a standard nonfasting lipid panel without additional expense. ApoB more accurately reflects LDL particle number. (b) Clinical performance: LDL cholesterol, non-HDL cholesterol, and apoB are comparable predictors of cardiovascular events in prospective population studies and clinical trials; however, discordance analysis of the markers improves risk prediction by adding remnant cholesterol (included in non-HDL cholesterol) and LDL particle number (with apoB) risk components to LDL cholesterol testing. (c) Clinical and cost-effectiveness: There is no consistent evidence yet that non-HDL cholesterol-, apoB-, or LDL particle-targeted treatment reduces the number of cardiovascular events and healthcare-related costs than treatment targeted to LDL cholesterol. SUMMARY: Follow-up of pre- and on-treatment (measured or calculated) LDL cholesterol concentration in a patient should ideally be performed with the same documented test method. Non-HDL cholesterol (or apoB) should be the secondary treatment target in patients with mild to moderate hypertriglyceridemia, in whom LDL cholesterol measurement or calculation is less accurate and often less predictive of cardiovascular risk. Laboratories should report non-HDL cholesterol in all standard lipid panels.
Subject(s)
Atherosclerosis/blood , Cholesterol, LDL/blood , Consensus , Precision Medicine , HumansABSTRACT
OBJECTIVES: To put data from our recent systematic review of phase 3 studies of anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies into the context of clinical practice. METHODS: Data from studies previously identified by a systematic review of phase 3 studies of alirocumab and evolocumab and additional references from non-systematic literature searches were used. We evaluated the hypothetical cardiovascular (CV) benefit in cases of typical patients in whom anti-PCSK9 antibodies may be recommended, using preliminary major CV event (CVE) rates from long-term clinical trials of anti-PCSK9 antibodies and from extrapolations derived from correlation between low-density lipoprotein cholesterol (LDL-C) reduction and CV benefit with other lipid-lowering therapies (LLTs). RESULTS: Rapid (within 1-2 weeks) and persistent (8-74 weeks) reductions in LDL-C levels were achieved with anti-PCSK9 antibodies. When combined with statins (± ezetimibe), high rates of LDL-C goal achievement were observed (41%-87% with alirocumab and 63%-100% with evolocumab). In long-term alirocumab and evolocumab studies, reductions in major CVEs of 48% and 53%, respectively, were observed. For every 38.7 mg/dL (1 mmol/L) reduction in LDL-C, a 22% reduction in relative CVE risk is predicted. Applying these assumptions to typical patients who have high-very high risk (15%-60% absolute 10-year CVE risk) and elevated LDL-C despite maximally tolerated statins, the 10-year number needed to treat with an anti-PCSK9 antibody to prevent one additional CVE varies from 4 to 26, depending on baseline LDL-C levels and residual absolute CVE risk. CONCLUSIONS: Anti-PCSK9 antibodies effectively lower LDL-C levels in a broad patient population. While awaiting comprehensive data from CV outcome trials, these agents should be considered in very high risk patients, such as those in secondary prevention and those with familial hypercholesterolaemia who are already receiving maximally tolerated LLTs, have not achieved their LDL-C goal and require substantial reductions in LDL-C.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Anticholesteremic Agents/therapeutic use , Hypercholesterolemia/drug therapy , Primary Health Care , Antibodies, Monoclonal, Humanized , Cardiovascular Diseases/prevention & control , Cholesterol, LDL/blood , Ezetimibe/therapeutic use , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hypercholesterolemia/blood , PCSK9 Inhibitors , Proprotein Convertase 9/immunologyABSTRACT
Objetivos: Evaluar criticamente las implicaciones clinicas de la utilizacion del perfil lipidico sin ayuno en lugar de perfiles de lipidos con ayuno y proporcionar orientacion para la elaboracion de informes de laboratorio sobre perfiles lipidicos anormales con ayuno y sin ayuno. Metodos y Resultados: Abundantes datos observacionales, en los que perfiles lipidicos medidos aleatoriamente sin ayuno se han comparado con perfiles lipidicos determinados en condiciones de ayuno, indican que las variaciones medias maximas de 1-6 h despues de ingestas habituales no son clinicamente significativas [+0,3 mmol/L (+26 mg/dL) para trigliceridos; -0,2 mmol/L (-8 mg/dL) para colesterol total; -0,2 mmol/L (-8 mg/dL) para colesterol-LDL; +0,2 mmol/L (+8 mg/dL) para colesterol de remanentes calculado; -0,2 mmol/L (-8 mg/dL) para el colesterol no-HDL calculado]; las concentraciones de colesterol-HDL, apolipoproteina A1, apolipoproteina B, y lipoproteina(a) no se ven afectados por el estado de ayuno/ no ayuno. Ademas, las concentraciones en ayunas y sin ayuno varian de manera similar con el tiempo y son comparables en la prediccion de la enfermedad cardiovascular. Para mejorar el cumplimiento del paciente con las condiciones para la determinacion del perfil lipidico, por lo tanto, se recomienda el uso rutinario de los perfiles lipidicos sin ayuno, mientras que se puede considerar la toma de muestra en ayunas cuando los trigliceridos sin ayuno son >5 mmol/L (440 mg/dL). Para las muestras sin ayuno, los informes de laboratorio deberian marcar como concentraciones anormales a trigliceridos ≥2 mmol/L (175 mg/dL), colesterol total ≥5 mmol/L (190 mg/dL), colesterol-LDL ≥3 mmol/L (115 mg/dL), colesterol remanente calculado ≥0,9 mmol/L (35 mg/dL), colesterol no-HDL calculado ≥3.9 mmol/L (150 mg/dL), HDL colesterol ≤1 mmol/L (40 mg/dL), apolipoproteina A1 ≤1,25 g/L (125 mg/dL), apolipoproteina B ≥1,0 g/L (100 mg/dL), y lipoproteina(a) ≥50 mg/dL (percentil 80); para muestras con ayuno, las concentraciones anormales corresponden a trigliceridos ≥1,7 mmol/L (150 mg/dL). Aquellas concentraciones que ponen en peligro la vida requieren derivacion inmediata debido al riesgo de pancreatitis cuando los trigliceridos son >10 mmol/L (880 mg/dL), de hipercolesterolemia familiar homocigotica cuando el colesterol-LDL es >13 mmol/L (500 mg/dL) o hipercolesterolemia familiar heterocigota cuando el colesterol-LDL es >5 mmol/L (190 mg/dL), y debido al riesgo cardiovascular muy alto cuando la lipoproteina(a) es >150 mg/dL (percentil 99). Conclusiones: Recomendamos la utilizacion de rutina de muestras de sangre sin ayuno para la evaluacion del perfil lipidico plasmatico. Los informes de laboratorio deberian marcar resultados anormales basandose en valores de corte deseables. Las determinaciones con ayuno y sin ayuno deben ser complementarias, pero no se excluyen mutuamente.
Aims: To critically evaluate the clinical implications of the use of non-fasting rather than fasting lipid profiles and to provide guidance for the laboratory reporting of abnormal non-fasting or fasting lipid profiles. Methods and Results: Extensive observational data, in which random non-fasting lipid profiles have been compared with those determined under fasting conditions, indicate that the maximal mean changes at 1-6 h after habitual meals are not clinically significant [+0.3 mmol/L (26 mg/dL) for triglycerides; -0.2 mmol/L (8 mg/dL) for total cholesterol; -0.2 mmol/L (8 mg/dL) for LDL cholesterol; +0.2 mmol/L (8 mg/dL) for calculated remnant cholesterol; -0.2 mmol/L (8 mg/dL) for calculated non-HDL cholesterol]; concentrations of HDL cholesterol, apolipoprotein A1, apolipoprotein B, and lipoprotein(a) are not affected by fasting/nonfasting status. In addition, non-fasting and fasting concentrations vary similarly over time and are comparable in the prediction of cardiovascular disease. To improve patient compliance with lipid testing, we therefore recommend the routine use of non-fasting lipid profiles, whereas fasting sampling may be considered when non-fasting triglycerides are >5 mmol/L (440 mg/dL). For nonfasting samples, laboratory reports should flag abnormal concentrations as triglycerides ≥2 mmol/L (175 mg/dL), total cholesterol ≥5 mmol/L (190 mg/dL), LDL cholesterol ≥3 mmol/L (115 mg/dL), calculated remnant cholesterol ≥0.9 mmol/L (35 mg/dL), calculated non-HDL cholesterol ≥3.9 mmol/L (150 mg/dL), HDL cholesterol ≤1 mmol/L (40 mg/dL), apolipoprotein A1 ≤1.25 g/L (125 mg/dL), apolipoprotein B ≥1.0 g/L (100 mg/dL), and lipoprotein(a) ≥50 mg/dL (80th percentile); for fasting samples, abnormal concentrations correspond to triglycerides ≥1.7 mmol/L (150 mg/dL). Life-threatening concentrations require separate referral for the risk of pancreatitis when triglycerides are >10 mmol/L (880 mg/dL), for homozygous familial hypercholesterolemia when LDL cholesterol is >13 mmol/L (500 mg/dL), for heterozygous familial hypercholesterolemia when LDL cholesterol is >5 mmol/L (190 mg/dL), and for very high cardiovascular risk when lipoprotein(a) >150 mg/dL (99th percentile). Conclusions: We recommend that non-fasting blood samples be routinely used for the assessment of plasma lipid profiles. Laboratory reports should flag abnormal values on the basis of desirable concentration cutpoints. Non-fasting and fasting measurements should be complementary but not mutually exclusive.
Subject(s)
Lipid Metabolism , Observational Studies as Topic , TranslationsABSTRACT
AIMS: Two anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies, alirocumab and evolocumab, have been approved for the treatment of hypercholesterolaemia in certain patients. We reviewed data from Phase 3 studies to evaluate the efficacy and safety of these antibodies. METHODS: We systematically reviewed Phase 3 English-language studies in patients with hypercholesterolaemia, published between 1 January 2005 and 20 October 2015. Congress proceedings from 16 November 2012 to 16 November 2015 were also reviewed. RESULTS: We identified 12 studies of alirocumab and nine of evolocumab, including over 10 000 patients overall. Most studies enrolled patients with hypercholesterolaemia and used anti-PCSK9 antibodies with statins. The ODYSSEY FH I, FH II and HIGH FH alirocumab studies and the RUTHERFORD-2 evolocumab study exclusively recruited patients with heterozygous familial hypercholesterolaemia. Two evolocumab studies focused mainly on homozygous familial hypercholesterolaemia (HoFH): TESLA Part B and TAUSSIG (a TESLA sub-study); only those data for HoFH are reported here. All comparator studies demonstrated a reduction in LDL cholesterol (LDL-C) with the anti-PCSK9 antibodies. No head-to-head studies were conducted between alirocumab and evolocumab. Up to 87% of patients receiving alirocumab and up to 98% receiving evolocumab reached LDL-C goals. Both antibodies were effective and well tolerated across a broad population of patients and in specific subgroups, such as those with type 2 diabetes. CONCLUSIONS: Using anti-PCSK9 antibodies as add-on therapy to other lipid-lowering treatments or as monotherapy for patients unable to tolerate statins may help patients with high cardiovascular risk to achieve their LDL-C goals.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Clinical Trials, Phase III as Topic , Hyperlipoproteinemia Type II/drug therapy , PCSK9 Inhibitors , Antibodies, Monoclonal, Humanized , Cholesterol, LDL/blood , Humans , Hyperlipoproteinemia Type II/metabolism , Proprotein Convertase 9/immunologyABSTRACT
AIMS: To critically evaluate the clinical implications of the use of non-fasting rather than fasting lipid profiles and to provide guidance for the laboratory reporting of abnormal non-fasting or fasting lipid profiles. METHODS AND RESULTS: Extensive observational data, in which random non-fasting lipid profiles have been compared with those determined under fasting conditions, indicate that the maximal mean changes at 1-6 h after habitual meals are not clinically significant [+0.3 mmol/L (26 mg/dL) for triglycerides; -0.2 mmol/L (8 mg/dL) for total cholesterol; -0.2 mmol/L (8 mg/dL) for LDL cholesterol; +0.2 mmol/L (8 mg/dL) for calculated remnant cholesterol; -0.2 mmol/L (8 mg/dL) for calculated non-HDL cholesterol]; concentrations of HDL cholesterol, apolipoprotein A1, apolipoprotein B, and lipoprotein(a) are not affected by fasting/non-fasting status. In addition, non-fasting and fasting concentrations vary similarly over time and are comparable in the prediction of cardiovascular disease. To improve patient compliance with lipid testing, we therefore recommend the routine use of non-fasting lipid profiles, whereas fasting sampling may be considered when non-fasting triglycerides are >5 mmol/L (440 mg/dL). For non-fasting samples, laboratory reports should flag abnormal concentrations as triglycerides ≥2 mmol/L (175 mg/dL), total cholesterol ≥5 mmol/L (190 mg/dL), LDL cholesterol ≥3 mmol/L (115 mg/dL), calculated remnant cholesterol ≥0.9 mmol/L (35 mg/dL), calculated non-HDL cholesterol ≥3.9 mmol/L (150 mg/dL), HDL cholesterol ≤1 mmol/L (40 mg/dL), apolipoprotein A1 ≤1.25 g/L (125 mg/dL), apolipoprotein B ≥1.0 g/L (100 mg/dL), and lipoprotein(a) ≥50 mg/dL (80th percentile); for fasting samples, abnormal concentrations correspond to triglycerides ≥1.7 mmol/L (150 mg/dL). Life-threatening concentrations require separate referral for the risk of pancreatitis when triglycerides are >10 mmol/L (880 mg/dL), for homozygous familial hypercholesterolemia when LDL cholesterol is >13 mmol/L (500 mg/dL), for heterozygous familial hypercholesterolemia when LDL cholesterol is >5 mmol/L (190 mg/dL), and for very high cardiovascular risk when lipoprotein(a) >150 mg/dL (99th percentile). CONCLUSIONS: We recommend that non-fasting blood samples be routinely used for the assessment of plasma lipid profiles. Laboratory reports should flag abnormal values on the basis of desirable concentration cutpoints. Non-fasting and fasting measurements should be complementary but not mutually exclusive.
Subject(s)
Atherosclerosis/blood , Chemistry, Clinical/standards , Clinical Laboratory Techniques/standards , Fasting/blood , Lipids/blood , Consensus , Europe , Humans , Societies, MedicalABSTRACT
AIMS: To critically evaluate the clinical implications of the use of non-fasting rather than fasting lipid profiles and to provide guidance for the laboratory reporting of abnormal non-fasting or fasting lipid profiles. METHODS AND RESULTS: Extensive observational data, in which random non-fasting lipid profiles have been compared with those determined under fasting conditions, indicate that the maximal mean changes at 1-6 h after habitual meals are not clinically significant [+0.3 mmol/L (26 mg/dL) for triglycerides; -0.2 mmol/L (8 mg/dL) for total cholesterol; -0.2 mmol/L (8 mg/dL) for LDL cholesterol; +0.2 mmol/L (8 mg/dL) for calculated remnant cholesterol; -0.2 mmol/L (8 mg/dL) for calculated non-HDL cholesterol]; concentrations of HDL cholesterol, apolipoprotein A1, apolipoprotein B, and lipoprotein(a) are not affected by fasting/non-fasting status. In addition, non-fasting and fasting concentrations vary similarly over time and are comparable in the prediction of cardiovascular disease. To improve patient compliance with lipid testing, we therefore recommend the routine use of non-fasting lipid profiles, while fasting sampling may be considered when non-fasting triglycerides >5 mmol/L (440 mg/dL). For non-fasting samples, laboratory reports should flag abnormal concentrations as triglycerides ≥2 mmol/L (175 mg/dL), total cholesterol ≥5 mmol/L (190 mg/dL), LDL cholesterol ≥3 mmol/L (115 mg/dL), calculated remnant cholesterol ≥0.9 mmol/L (35 mg/dL), calculated non-HDL cholesterol ≥3.9 mmol/L (150 mg/dL), HDL cholesterol ≤1 mmol/L (40 mg/dL), apolipoprotein A1 ≤1.25 g/L (125 mg/dL), apolipoprotein B ≥1.0 g/L (100 mg/dL), and lipoprotein(a) ≥50 mg/dL (80th percentile); for fasting samples, abnormal concentrations correspond to triglycerides ≥1.7 mmol/L (150 mg/dL). Life-threatening concentrations require separate referral when triglycerides >10 mmol/L (880 mg/dL) for the risk of pancreatitis, LDL cholesterol >13 mmol/L (500 mg/dL) for homozygous familial hypercholesterolaemia, LDL cholesterol >5 mmol/L (190 mg/dL) for heterozygous familial hypercholesterolaemia, and lipoprotein(a) >150 mg/dL (99th percentile) for very high cardiovascular risk. CONCLUSION: We recommend that non-fasting blood samples be routinely used for the assessment of plasma lipid profiles. Laboratory reports should flag abnormal values on the basis of desirable concentration cut-points. Non-fasting and fasting measurements should be complementary but not mutually exclusive.