Treatment of Homozygous Familial Hypercholesterolemia With ANGPTL3 Inhibitor, Evinacumab.

Homozygous familial hypercholesterolemia (HoFH) is an ultra-rare, life-threatening, genetic condition characterized by markedly elevated levels of low-density lipoprotein cholesterol (LDL-C). Standard lipid-lowering therapies minimally reduce LDL-C in these patients, and lifelong serial apheresis is the mainstay of treatment. Evinacumab is a monoclonal antibody against angiopoietin-like protein 3 that lowers LDL-C levels via a novel LDL receptor-independent mechanism, and is US Food and Drug Administration approved for HoFH in the United States. We present a pediatric HoFH patient from Ontario who has been receiving evinacumab through special access from Health Canada. A 17-year-old boy was diagnosed with severe HoFH due to compound heterozygous LDLR pathogenic variants. Treatment has included a statin, ezetimibe, and LDL apheresis every 2 weeks, with minimal overall effect on LDL-C levels. He remains asymptomatic from a cardiovascular perspective. At age 16, evinacumab infused intravenously every 4 weeks was added to his treatment. After 12 months, his time-averaged LDL-C decreased by 53.4% from 8.75 mmol/L (338.4 mg/dL) to 4.08 mmol/L (157.8 mg/dL), despite reduced frequency of LDL apheresis from biweekly to monthly. He has experienced no adverse events. Overall, treatment has increased quality of life for him and his family. Evinacumab shows great promise for patients with HoFH, a difficult-to-treat and potentially life-threatening condition.

Safety and efficacy of therapies for chylomicronemia.

INTRODUCTION: Primary chylomicronemia is characterized by pathological accumulation of chylomicrons in the plasma causing severe hypertriglyceridemia, typically >10 mmol/L (>875 mg/dL). Patients with the ultra-rare familial chylomicronemia syndrome (FCS) subtype completely lack lipolytic capacity and respond minimally to traditional triglyceride-lowering therapies. The mainstay of treatment is a low-fat diet, which is difficult to follow and compromises quality of life. New therapies are being developed primarily to prevent episodes of life-threatening acute pancreatitis. AREAS COVERED: Antagonists of apolipoprotein (apo) C-III, such as the antisense oligonucleotide (ASO) volanesorsen, significantly reduce triglyceride levels in chylomicronemia. However, approval of and access to volanesorsen are restricted since a substantial proportion of treated FCS patients developed thrombocytopenia. Newer apo C-III antagonists, namely, the ASO olezarsen (formerly AKCEA-APOCIII-LRx) and short interfering RNA (siRNA) ARO-APOC3, appear to show efficacy with less risk of thrombocytopenia. Potential utility of antagonists of angiopoietin-like protein 3 (ANGPTL3) such as evinacumab and the siRNA ARO-ANG3 in subtypes of chylomicronemia remains to be defined. EXPERT OPINION: Emerging pharmacologic therapies for chylomicronemia show promise, particularly apo C-III antagonists. However, these treatments are still investigational. Further study of their efficacy and safety in patients with both rare FCS and more common multifactorial chylomicronemia is needed.

Advances in the care of lipodystrophies.

PURPOSE OF REVIEW: Lipodystrophies are a group of rare, heterogeneous disorders characterized by a lack or maldistribution of adipose tissue. Treatment focusses on the management of complications, including hypertriglyceridemia, which can be severe. Patients are predisposed to early atherosclerotic cardiovascular disease and acute pancreatitis. This review summarizes the recent advances in the treatment of lipodystrophies, with a particular focus on the treatment of hypertriglyceridemia in familial partial lipodystrophy (FPLD). RECENT FINDINGS: Treatment of dyslipidemia in FPLD requires management of secondary exacerbating factors, particularly insulin resistance and diabetes, together with modification of atherosclerotic cardiovascular disease risk factors. In addition, specific lipid-lowering therapies are usually needed, starting with statins and fibrates. Leptin therapy improves triglycerides. Several emerging treatments for hypertriglyceridemia include apo C-III antagonists (volanesorsen, AKCEA-APOCIII-LRx and ARO-APOC3) and angiopoietin-like 3 antagonists (evinacumab, vupanorsen and ARO-ANG3); efficacy observed in clinical trials of these agents in nonlipodystrophic patients with severe hypertriglyceridemia suggests that they may also be helpful in lipodystrophy. SUMMARY: Emerging therapies for dyslipidemia show promise in advancing the care of patients with lipodystrophy. However, these treatments are not yet approved for use in lipodystrophy. Further study of their efficacy and safety in this patient population is needed.

Presentation and management of calcific mitral valve disease.

Little is known about the prevalence, presentation and management of calcific mitral valve disease (CMVD). We identified 167 patients (80 ± 10 years; 79% women) with significant CMVD undergoing transthoracic echocardiography at our institution in 2016. Patients presented with significant co-morbidities, 47% had moderate/severe mitral stenosis, 38% had 3+/4+ mitral regurgitation and 15% had a combination of both. Fifty-eight percent were symptomatic. Most symptomatic patients were managed conservatively and incurred higher mortality and mortality/heart failure admission rates than those managed surgically. These data highlight the importance of gaining mechanistic insights into CMVD to prevent its occurrence and avoid the need for high-risk surgery, which is seldom performed in contemporary practice.

A survey of oncology healthcare professionals' knowledge and attitudes toward the use of music as a therapeutic tool in healthcare.

BACKGROUND: Music as a therapeutic tool, defined as "music care," can help manage physical and psychological symptoms in individuals with cancer. There is further need to understand interest level and the potential role of music care among health professionals working in the field of oncology. PURPOSE: To investigate knowledge of and attitudes toward the use of music as a therapeutic tool in cancer and palliative care, as well as to identify barriers associated with learning to use music in care among health professionals. METHODS: Participants (N = 204), mostly nurses working in oncology and palliative care, completed a survey to assess awareness, knowledge, and attitudes toward the use of music in healthcare practice. RESULTS: In total, 55.5% of participants reported being "somewhat or very knowledgeable" about how to apply/use music therapy for the management of symptoms or on how to make a music therapy referral or for any application of music care. Participants demonstrated a high interest level in learning how to incorporate music into practice (mean = 4.05; SD = 1.045). CONCLUSION: While there is generally high interest and perceived value among nurses in music care interventions, knowledge level about such interventions was low. The study has implications for knowledge translation and education needed to further support uptake and use of music care in nursing practice.

Fragility of Results in Ophthalmology Randomized Controlled Trials: A Systematic Review.

PURPOSE: Evidence-based medicine is guided by our interpretation of randomized controlled trials (RCTs) that address important clinical questions. Evaluation of the robustness of statistically significant outcomes adds a crucial element to the global assessment of trial findings. The purpose of this systematic review was to determine the robustness of ophthalmology RCTs through application of the Fragility Index (FI), a novel metric of the robustness of statistically significant outcomes. DESIGN: Systematic review. METHODS: A literature search (MEDLINE) was performed for all RCTs published in top ophthalmology journals and ophthalmology-related RCTs published in high-impact journals in the past 10 years. Two reviewers independently screened 1811 identified articles for inclusion if they (1) were a human ophthalmology-related trial, (2) had a 1:1 prospective study design, and (3) reported a statistically significant dichotomous outcome in the abstract. All relevant data, including outcome, P value, number of patients in each group, number of events in each group, number of patients lost to follow-up, and trial characteristics, were extracted. The FI of each RCT was calculated and multivariate regression applied to determine predictive factors. RESULTS: The 156 trials had a median sample size of 91.5 (range, 13-2593) patients/eyes, and a median of 28 (range, 4-2217) events. The median FI of the included trials was 2 (range, 0-48), meaning that if 2 non-events were switched to events in the treatment group, the result would lose its statistical significance. A quarter of all trials had an FI of 1 or less, and 75% of trials had an FI of 6 or less. The FI was less than the number of missing data points in 52.6% of trials. Predictive factors for FI by multivariate regression included smaller P value (P < 0.001), larger sample size (P = 0.001), larger number of events (P = 0.011), and journal impact factor (P = 0.029). CONCLUSIONS: In ophthalmology trials, statistically significant dichotomous results are often fragile, meaning that a difference of only a couple of events can change the statistical significance. An application of the FI in RCTs may aid in the interpretation of results and assessment of quality of evidence.