Bempedoic acid safety analysis: Pooled data from four phase 3 clinical trials

Background An ongoing need exists for safe and effective lipid-lowering therapies (LLTs) for patients unable to achieve desired lipid levels with current treatment options. Objective The objective of this study was to describe the safety profile of bempedoic acid, an oral, first-in-class, adenosine triphosphate (ATP)–citrate lyase inhibitor that significantly reduces low-density lipoprotein cholesterol (LDL-C) levels by 17.4%–28.5% vs placebo. Methods This was a pooled analysis of four phase 3, randomized (2:1), double-blind, placebo-controlled studies in patients with hypercholesterolemia who required additional LDL-C lowering, despite stable maximally-tolerated LLT. Patients received 180 mg of bempedoic acid (n = 2424) or placebo (n = 1197) once daily for 12 to 52 weeks. Assessments included treatment-emergent adverse events (TEAEs) and clinical laboratory tests. Results Of 3621 patients (the median drug exposure: 363 days), exposure-adjusted TEAE rates were 87.1/100 and 82.9/100 person-years (PY) for bempedoic acid and placebo, respectively. No single TEAE influenced the difference in rates. TEAEs leading to discontinuation occurred at rates of 13.4/100 and 8.9/100 PY for bempedoic acid vs placebo, with the most common cause being myalgia, which occurred less frequently with bempedoic acid vs placebo (1.5/100 vs 2.0/100 PY). Rates of myalgia and muscle weakness were comparable vs placebo. Bempedoic acid was associated with mild increases in blood urea nitrogen, creatinine, and uric acid and decreases in hemoglobin. These laboratory abnormalities were apparent by week 4, stable over time, and reversible after treatment cessation. Gout incidence was 1.6/100 vs 0.5/100 PY in the bempedoic acid vs placebo groups. New-onset diabetes/hyperglycemia occurred less frequently with bempedoic acid vs placebo (4.7/100 vs 6.4/100 PY). The safety profile was consistent across subgroups. Conclusions Bempedoic acid is generally safe and well tolerated among patients with hypercholesterolemia who require additional LLT

Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation

TCT-48: Medical therapy and clinical outcomes with spontaneous coronary artery dissection

Background Conservative management is currently the preferred therapy for patients with spontaneous coronary artery dissection (SCAD). However, the optimal medical regime remains controversial. Our objective is to evaluate the use of cardiac medications in contemporary clinical management of SCAD, and their potential association with clinical outcomes. Methods We reviewed non-atherosclerotic SCAD patients who were prospectively followed at the Vancouver General Hospital SCAD clinic, and enrolled in our SCAD registries. Baseline characteristics, medications on admission, discharge, and follow-up were examined. Major adverse cardiac events (MACE) at follow-up were recorded and included repeat MI, death, stroke/TIA. Results We prospectively followed 286 consecutive SCAD patients. Mean age was 52.5±9.4 years, and most were women (90.2%). All presented with myocardial infarction (MI). After an acute event, patients were discharged on aspirin (93.7%), P2Y12 inhibitor (64.5%, predominantly clopidogrel), beta-blocker (BB) (82.8%), angiotensin-converting-enzyme inhibitors or angiotensin-II-receptor blocker (RAAS) (53.5%), calcium channel blocker (CCB) (15.7%), and statin (52.9%). There were 195 patients followed for at least 1 year. At 1 year, the majority remained on aspirin (92.8%) and BB (75.4%), but there were lower usage of RAAS (47.7%), statin (40.0%), P2Y12 inhibitor (26.7%), and CCB (19%). The overall median follow-up was 3.1 (IQR 2.0-5.7yr) and MACE was 20.5%. The use of CCB at last follow-up was associated with higher incidence of repeat MI (29.7% vs. 15.2%, p=0.038), and the use of BB at last follow-up was associated with a trend to lower incidence of repeat MI (15.0% vs. 27.1%, p=0.058). Conclusion Our observational data showed that aspirin and BB were commonly used for SCAD management. Patients on CCB appeared to have higher repeat MI at long-term follow-up. Whereas, BB was associated with a trend in reduction of repeat MI. Future studies are warranted to assess the relationship between medications and outcomes in SCAD patients

Epidemiology and treatment of heart failure with chronic obstructive pulmonary disease in Canadian primary care

Abstract Aims Heart failure (HF) and chronic obstructive pulmonary disease (COPD) are largely managed in primary care, but their intersection in terms of disease burden, healthcare utilization, and treatment is ill‐defined. Methods and results We examined a retrospective cohort including all patients with HF or COPD in the Canadian Primary Care Sentinel Surveillance Network from 2010 to 2018. The population size in 2018 with HF, COPD, and HF with COPD was 15 778, 27 927, and 4768 patients, respectively. While disease incidence declined, age–sex‐standardized prevalence per 100 population increased for HF alone from 2.33 to 3.63, COPD alone from 3.44 to 5.96, and COPD with HF from 12.70 to 15.67. Annual visit rates were high and stable around 8 for COPD alone but declined significantly over time for HF alone (9.3–8.1, P = 0.04) or for patients with both conditions (14.3–11.9, P = 0.006). For HF alone, cardiovascular visits were common (29.4%), while respiratory visits were infrequent (3.5%), with the majority of visits being non‐cardiorespiratory. For COPD alone, respiratory and cardiovascular visits were common (16.4% and 11.3%) and the majority were again non‐cardiorespiratory. For concurrent disease, 39.0% of visits were cardiorespiratory. The commonest non‐cardiorespiratory visit reasons were non‐specific symptoms or signs, endocrine, musculoskeletal, and mental health. In patients with HF with and without COPD, angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor–neprilysin inhibitor use was similar, while mineralocorticoid receptor antagonist use was marginally higher with concurrent COPD. Beta‐blocker use was initially lower with concurrent COPD compared with HF alone (69.3% vs. 74.0%), but this progressively declined by 2018 (74.5% vs. 73.5%). Conclusions The prevalence of HF and COPD continues to rise. Although patients with either or both conditions are high utilizers of primary care, the majority of visits relate to non‐cardiorespiratory comorbidities. Medical therapy for HF was similar and the initially lower beta‐blocker utilization disappeared over time