Alirocumab efficacy in patients with double heterozygous, compound heterozygous, or homozygous familial hypercholesterolemia

Background: Mutations in the genes for the low-density lipoprotein receptor (LDLR), apolipoprotein B, and proprotein convertase subtilisin/kexin type 9 have been reported to cause heterozygous and homozygous familial hypercholesterolemia (FH). Objective: The objective is to examine the influence of double heterozygous, compound heterozygous, or homozygous mutations underlying FH on the efficacy of alirocumab. Methods: Patients from 6 alirocumab trials with elevated low-density lipoprotein cholesterol (LDL-C) and FH diagnosis were sequenced for mutations in the LDLR, apolipoprotein B, proprotein convertase subtilisin/kexin type 9, LDLR adaptor protein 1 (LDLRAP1), and signal-transducing adaptor protein 1 genes. The efficacy of alirocumab was examined in patients who had double heterozygous, compound heterozygous, or homozygous mutations. Results: Of 1191 patients sequenced, 20 patients were double heterozygotes (n = 7), compound heterozygotes (n = 10), or homozygotes (n = 3). Mean baseline LDL-C levels were similar between patients treated with alirocumab (n = 11; 198 mg/dL) vs placebo (n = 9; 189 mg/dL). All patients treated with alirocumab 75/150 or 150 mg every 2 weeks had an LDL-C reduction of ≥15% at either week 12 or 24. At week 12, 1 patient had an increase of 7.1% in LDL-C, whereas in others, LDL-C was reduced by 21.7% to 63.9% (corresponding to 39–114 mg/dL absolute reduction from baseline). At week 24, LDL-C was reduced in all patients by 8.8% to 65.1% (10–165 mg/dL absolute reduction from baseline). Alirocumab was generally well tolerated in the 6 trials. Conclusion: Clinically meaningful LDL-C–lowering activity was observed in patients receiving alirocumab who were double heterozygous, compound heterozygous, or homozygous for genes that are causative for FH

L’influence des relations familiales et sociales sur la consommation de médicaments psychotropes chez les personnes âgées

Les psychotropes occupent le deuxième rang dans la consommation de médicaments chez les personnes âgées. L'objectif de cette étude est de vérifier un modèle explicatif de la consommation de psychotropes dans cette population. Notre principale hypothèse est que la qualité des relations qu'entretient une personne âgée avec autrui, et particulièrement avec ses enfants, a une influence directe sur son bien-être psychologique, lequel a une influence directe sur la non-consommation de psychotropes. Une enquête a été réalisée auprès d'un échantillon de 500 personnes âgées de 65 à 84 ans, vivant à domicile. Au cours des trois mois précédant l'entrevue, 31,8 % des répondants ont consommé des psychotropes. Les données empiriques n'ayant pas permis de vérifier le modèle théorique retenu, des analyses multivariées ont conduit à l'élaboration d'un modèle explicatif de la consommation qui met en évidence que le bien-être psychologique et la santé sont les meilleurs prédicteurs de cette consommation. Un bien-être psychologique élevé diminue la consommation alors qu'un mauvais état de santé l'augmente. Les relations sociales influencent directement le bien-être psychologique alors que les relations familiales ont un effet de moindre importance. Le modèle explicatif proposé explique 13 % du phénomène de la consommation de psychotropes chez les personnes âgées.Psychotropic drugs are the second most commonly used medication by Quebec's elderly. The objective of this study is to test a theoretical model of psychotropic drug use in the elderly. The principal hypothesis is that the quality of relationships the elderly person has with others, particularly with his or her children, has a direct influence on his or her psychological well-being, which, in turn, directly affects the consumption of psychotropic agents. A survey was conducted on a sample of 500 elderly people, aged 65-84 years, living at home. 31.8% of the respondents used psychotropic drugs during the three-month period preceding the interview. Path analysis led to the elaboration of a modified model for the consumption of psychotropic drugs by the elderly which indicates that the best predictors of consumption are both the psychological well-being and the state of health of the individual. More elevated is the psychological well-being, less is the consumption of psychotropic drugs, whereas poor health condition increases it. The quality of an individual's social relationships has a direct influence on his or her psychological well-being, whereas family relationships are of lesser importance. Our model accounts for 13% of the predictors of psychotropic consumption by the elderly

The effect of type of femoral component fixation on mortality and morbidity after hip hemiarthroplasty:A systematic review and meta-analysis

Background: Hip hemiarthroplasty is a well-established treatment of displaced femoral neck fracture, although debate exists over whether cemented or uncemented fixation is superior. Uncemented prostheses have typically been used in younger, healthier patients and cemented prostheses in older patients with less-stable bone. Also, earlier research has suggested that bone cement has cytotoxic effects and may trigger cardiovascular and respiratory adverse events. Questions/Purposes: The aim of this systematic review and meta-analysis was to compare morbidity and mortality rates after cemented and uncemented hemiarthroplasty for the treatment of displaced femoral neck fractures in elderly patients. Methods: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched seven medical databases for randomized clinical trials and observational studies. We compared cemented and uncemented hemiarthroplasty using the Harris Hip Score (HHS), as well as measures of postoperative pain, mortality, and complications. Data were extracted and pooled as risk ratios or standardized mean difference with their corresponding 95% confidence intervals in a meta-analysis model. Results: The meta-analysis included 34 studies (12 randomized trials and 22 observational studies), with a total of 42,411 patients. In the pooled estimate, cemented hemiarthroplasty was associated with less risk of postoperative pain than uncemented hemiarthroplasty. There were no significant differences between groups regarding HHS or rates of postoperative mortality, pulmonary embolism, cardiac arrest, myocardial infarction, acute cardiac arrhythmia, or deep venous thrombosis. Conclusions: While we found that cemented hemiarthroplasty results in less postoperative pain than uncemented hemiarthroplasty in older patients with femoral neck fracture, the lack of significant differences in functional hip scores, mortality, and complications was surprising. Further high-level research is needed

Efficacy and Safety of Pitavastatin in Children and Adolescents at High Future Cardiovascular Risk

Objectives To assess the safety and efficacy of pitavastatin in children and adolescents with hyperlipidemia. Study design A total of 106 children and adolescents with hyperlipidemia, ages 6 to 17 years, were enrolled in a 12-week randomized, double-blind, placebo-controlled study and randomly assigned to pitavastatin 1 mg, 2 mg, 4 mg, or placebo. During a 52-week extension period, subjects were up-titrated from 1 mg pitavastatin to a maximum dose of 4 mg in an effort to achieve an optimum low-density lipoprotein cholesterol (LDL-C) treatment target of <110 mg/dL (2.8 mmol/L). Adverse events rates, including abnormal clinical laboratory variables, vital signs, and physical examination were assessed. Results Compared with placebo, pitavastatin 1, 2, and 4 mg significantly reduced LDL-C from baseline by 23.5%, 30.1%, and 39.3%, respectively, and in the open-label study 20.5% of the subjects reached the LDL-C goal <110 mg/dL (2.8 mmol/L). No safety issues were evident. Conclusions Pitavastatin at doses up to 4 mg is well tolerated and efficacious in children and adolescents aged 6-17 years. Trial registration Registered with EudraCT 2011-004964-32 and EudraCT 2011-004983-32. © 2015 Elsevier Inc

Eprotirome in patients with familial hypercholesterolaemia (the AKKA trial): a randomised, double-blind, placebo-controlled phase 3 study

Eprotirome is a liver-selective thyroid hormone receptor agonist that has been shown to lower plasma LDL cholesterol concentrations in previous phase 1 and 2 studies of patients with dyslipidaemia. We aimed to assess the long-term safety and efficacy of 50 μg and 100 μg eprotirome in patients with familial hypercholesterolaemia. Methods For this randomised, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial, we enrolled patients between Oct 3, 2011, and Feb 14, 2012, at 53 sites in 11 countries in Europe, Africa, and south Asia. Patients were eligible for enrolment if they were aged 18 years or older, diagnosed with heterozygous familial hypercholesterolaemia, and had not reached target LDL cholesterol concentrations after at least 8 weeks of statin therapy with or without ezetimibe. We used a computer-generated randomisation sequence to allocate patients to one of three groups: 50 μg eprotirome, 100 μg eprotirome, or placebo. This trial was planned for 52–76 weeks, with primary efficacy analysis at 12 weeks, but it was prematurely terminated when another study found that eprotirome causes cartilage damage in dogs. Although it was impossible to meet the predefined study outcomes, we analysed changes in the concentrations of LDL cholesterol and other lipids, liver parameters, thyroid hormone concentrations, and adverse effects of treatment with eprotirome versus placebo at 6 weeks of treatment. Analysis was done in all patients who received 6 weeks of treatment. This study is registered with ClinicalTrials.gov, number NCT01410383. Findings We enrolled 236 patients, randomly allocating 80 to receive placebo, 79 to receive 50 μg eprotirome, and 77 to receive 100 μg eprotirome. 69 patients reached the 6 week timepoint (23 given placebo, 24 given 50 μg eprotirome, and 22 given 100 μg eprotirome). Mean LDL cholesterol concentrations increased by 9% (95% CI −2 to 20) in the placebo group, decreased by 12% (−28 to 4%; p=0·0677 vs placebo) in the 50 μg eprotirome group, and decreased by 22% (−32 to −13%; p=0·0045 vs placebo) in the 100 μg eprotirome group. We noted statistically significant increases between both eprotirome groups and placebo in aspartate aminotransferase (AST; p<0·0001), alanine aminotransferase (ALT; p<0·0001), conjugated bilirubin (p=0·0006), and gamma-glutamyltranspeptidase (p<0·0001). Four patients had to discontinue or interrupt study treatment before trial termination due to AST increases between the upper limit of normal (ULN) and six times ULN, and ALT concentrations between three and seven times ULN. Although we detected no changes in serum concentrations of thyroid-stimulating hormone or free tri-iodothyronine, free tetra-iodothyronine decreased by 19% (23 to 16) in the 50 μg eprotirome group and 27% (30 to 23) in the 100 μg eprotirome group (p<0·0001 vs placebo for both groups). Interpretation Our findings show that eprotirome can lower LDL cholesterol concentrations in patients with familial hypercholesterolaemia when added to conventional statin treatment with or without ezetimibe, but that it has the potential to induce liver injury. These findings, along with findings of cartilage damage in dogs, raise serious doubts about selective thyroid hormone mimetics as a therapeutic approach to lower LDL cholesterol concentrations.B. Sjouke, G. Langslet, R. Ceska, S.J. Nicholls, S.E. Nissen, M. Öhlander, P.W. Ladenson, A.G. Olsson, G.K. Hovingh and J.J.P. Kastelei

Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia not adequately controlled with current lipid-lowering therapy: design and rationale of the ODYSSEY FH studies

Individuals with heterozygous familial hypercholesterolemia (heFH) have higher levels of low-density lipoprotein cholesterol (LDL-C) and are predisposed to premature cardiovascular disease. Alirocumab is a fully-human, monoclonal antibody targeted to proprotein convertase subtilisin/kexin type 9 currently in Phase 3 development for the treatment of hypercholesterolemia. Described here are three ODYSSEY Phase 3 trials, FH I (NCT01623115), FH II (NCT01709500) and HIGH FH (patients with heFH and LDL-C levels ≥160 mg/dL) (NCT01617655), in which alirocumab is further evaluated in the heFH population. Multicenter, multinational, randomized, double-blind, placebo-controlled studies have been designed to evaluate efficacy and safety of alirocumab in more than 800 patients with heFH who are not adequately controlled with a maximally-tolerated stable daily dose of statin for ≥4 weeks prior to the screening visit, with or without other lipid-lowering therapy. Patients are randomized (2:1) to receive alirocumab or placebo via a 1-mL subcutaneous auto-injection every 2 weeks (Q2W) for 78 weeks. In studies FH I and II, if their Week 8 LDL-C level is ≥70 mg/dL, patients will undergo a dose uptitration from 75 to 150 mg alirocumab Q2W at Week 12. In HIGH FH, patients will receive alirocumab 150 mg Q2W throughout the entire treatment period. The primary efficacy endpoint in all three studies is the percent change in calculated LDL-C from baseline to Week 24. The ODYSSEY FH studies are three Phase 3 studies aiming to further evaluate the efficacy and long-term safety of alirocumab as an effective therapeutic option for patients with heF

Long-term safety and efficacy of alirocumab in patients with heterozygous familial hypercholesterolemia: An open-label extension of the ODYSSEY program

Background and aims: ODYSSEY OLE (open-label extension; NCT01954394) included patients diagnosed with heterozygous familial hypercholesterolemia (HeFH), receiving maximally tolerated statins, who had completed one of four Phase 3 double-blind parent studies (all 18 months' duration), with the aim to assess longer-term safety and efficacy of alirocumab. Methods: Patients received starting dose alirocumab 75 mg every 2 weeks (Q2W; patients from FH I, FH II, and LONG TERM) or alirocumab 150 mg Q2W (patients from HIGH FH). Low-density lipoprotein cholesterol (LDL-C) levels were blinded to the patient and physician until Week 8; from Week 8, LDL-C levels were communicated to physicians. From Week 12, dose adjustment from 75 to 150 mg Q2W, or vice versa, was possible per physician's clinical judgment according to patient's LDL-C levels. Results: Patients who had received alirocumab (n = 655) compared with placebo (n = 330) in the parent studies exhibited similar rates of treatment-emergent adverse events (TEAEs; 87.3% vs. 83.9%) during OLE (2.5 years median alirocumab exposure). Overall, 33 patients (3.4%) experienced TEAEs leading to permanent treatment discontinuation. At Week 8, alirocumab reduced mean LDL-C by 44.2% (reduction from 151.9 mg/dL at parent study baseline to 84.9 mg/dL); reduction in LDL-C was consistent to Week 96 of OLE. Reductions in lipid parameters were similar regardless of treatment allocation in the parent study. Conclusions: In patients with HeFH, no unexpected long-term safety concerns were observed with alirocumab compared with previously published data; durability of LDL-C-lowering over 3 years (including 1.5 years of parent trials) was demonstrated

Individualized low-density lipoprotein cholesterol reduction with alirocumab titration strategy in heterozygous familial hypercholesterolemia: Results from an open-label extension of the ODYSSEY LONG TERM trial

Background: Patients with heterozygous familial hypercholesterolemia (HeFH) who completed the double-blind ODYSSEY LONG TERM parent trial and subsequently enrolled in the open-label extension (OLE) study, ODYSSEY OLE (NCT01954394), provide a unique opportunity to investigate effects of 2 doses of alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, within the same patient cohort. Objective: The aim of the study was to characterize long-term efficacy and safety of 2 alirocumab dosages and utility of a dose titration strategy in patients with HeFH. Methods: After an 8-week washout period, patients with HeFH who completed the LONG TERM study (receiving alirocumab 150 mg every 2 weeks [Q2W]) were eligible to enroll in OLE (n = 214) for up to 40 months' treatment duration. In OLE, patients started on alirocumab 75 mg Q2W. From Week 12, dose adjustment from 75 to 150 mg Q2W or vice versa was possible based on physician's clinical judgment. Results: During the LONG TERM trial, alirocumab 150 mg Q2W reduced mean low-density lipoprotein cholesterol (LDL-C) from baseline (162.3 mg/dL) to Week 8 by 63.1%; during OLE, alirocumab 75 mg Q2W reduced mean LDL-C from baseline (166.6 mg/dL) by 47.3% within the same patient cohort. At Week 96, mean LDL-C reduction from OLE baseline was 55.4% vs 46.8% for patients with or without alirocumab dose increase, respectively. Treatment-emergent adverse events leading to permanent treatment discontinuation were observed in 4 patients (1.9%). Conclusions: In patients with HeFH, both alirocumab dosages provided consistent LDL-C reductions over a treatment duration of up to 4 years (including 1.5 years of the LONG TERM trial), allowing an individualized approach to LDL-C lowering, depending on baseline LDL-C levels