Maternal Ezetimibe Concentrations Measured in Breast Milk and Its Use in Breastfeeding Infant Exposure Predictions.

BACKGROUND: Lactating mothers taking ezetimibe, an antihyperlipidemic agent, may be hesitant to breastfeed despite the known benefit of breastfeeding to both mother and infant. Currently, no data exist on the presence or concentration of ezetimibe and its main active metabolite, ezetimibe-glucuronide (EZE-glucuronide), in human breast milk. METHODS: Voluntary breast milk samples containing ezetimibe and EZE-glucuronide were attained from lactating mothers taking ezetimibe as part of their treatment. An assay was developed and validated to measure ezetimibe and EZE-glucuronide concentrations in breast milk. A workflow that utilized a developed and evaluated pediatric physiologically based pharmacokinetic (PBPK) model, the measured concentrations in milk, and weight-normalized breast milk intake volumes was applied to predict infant exposures and determine the upper area under the curve ratio (UAR). RESULTS: Fifteen breast milk samples from two maternal-infant pairs were collected. The developed liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay showed an analytical range of 0.039-5.0 ng/mL and 0.39-50.0 ng/mL for ezetimibe and EZE-glucuronide, respectively. The measured concentrations in the breast milk samples were 0.17-1.02 ng/mL and 0.42-2.65 ng/mL of ezetimibe and EZE-glucuronide, respectively. The evaluated pediatric PBPK model demonstrated minimal exposure overlap in adult therapeutic dose and breastfed infant simulated area under the concentration-time curve from time zero to 24 h (AUC24). Calculated UAR across infant age groups ranged from 0.0015 to 0.0026. CONCLUSIONS: PBPK model-predicted ezetimibe and EZE-glucuronide exposures and UAR suggest that breastfeeding infants would receive non-therapeutic exposures. Future work should involve a 'mother-infant pair study' to ascertain breastfed infant plasma ezetimibe and EZE-glucuronide concentrations to confirm the findings of this work.

When Does Treatment in Cancer Care Become Futile?

Futility in medicine has been defined as excessive medical intervention with very little prospect of altering the clinical outcome in a positive manner. If treatments fail to release our patients from the preoccupation with the illness and do not allow them to pursue their life goals, then perhaps that treatment is futile.

Canadian Cardiovascular Society Position Statement on Familial Hypercholesterolemia: Update 2018.

Familial hypercholesterolemia (FH) is the most common monogenic disorder causing premature atherosclerotic cardiovascular disease. It affects 1 in 250 individuals worldwide, and of the approximately 145,000 Canadians estimated to have FH, most are undiagnosed. Herein, we provide an update of the 2014 Canadian Cardiovascular Society position statement on FH addressing the need for case identification, prompt recognition, and treatment with statins and ezetimibe, and cascade family screening. We provide a new Canadian definition for FH and tools for clinicians to make a diagnosis. The risk of atherosclerotic cardiovascular disease in patients with "definite" FH is 10- to 20-fold that of a normolipidemic individual and initiating treatment in youth or young adulthood can normalize life expectancy. Target levels for low-density lipoprotein cholesterol are proposed and are aligned with the Canadian Cardiovascular Society guidelines on dyslipidemia. Recommendation for the use of inhibitors of proprotein convertase kexin/subtilisin type 9 are made in patients who cannot achieve therapeutic low-density lipoprotein cholesterol targets on maximally tolerated statins and ezetimibe. The writing committee used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology in the preparation of the present document, which offers guidance for practical evaluation and management of patients with FH. This position statement also aims to raise awareness of FH nationally, and to mobilize patient support, promote knowledge translation, and availability of treatment and health care resources for this under-recognized, but important medical condition.

Role competency scale on shared decision-making nurses: Development and psychometric properties.

OBJECTIVES: This study aimed to develop a scale that can measure the role competency of oncology nurses during shared decision-making process. METHODS: A total of 226 oncology nurses who actively provide direct care to patients from inpatient and outpatient oncology units in the Midwest and Pacific Northwest completed the online or mail survey. Exploratory factor analysis and parallel analysis showed the multidimensionality of the role competency scale on shared decision-making nurses. RESULTS: The role competency scale on shared decision-making nurses revealed four dimensions: knowledge, attitudes, communication, and adaptability. The 22 items have excellent internal consistency with a Cronbach's alpha of 0.91. The four subscales also have adequate reliability with Cronbach's alpha >0.70 as well as greater than 0.70 Spearman-Brown's correlation coefficients in split-half reliability testing for each subscale. CONCLUSION: The new scale has the potential to be used as a clinical tool to assess the need for shared decision-making education and training in oncology nurses.

Amiodarone-induced thyrotoxicosis in heart failure with a reduced ejection fraction: A retrospective cohort study.

BACKGROUND: Amiodarone-induced thyrotoxicosis (AIT) is associated with significant morbidity and mortality. We aimed to describe AIT and its clinical outcomes in patients with heart failure with reduced ejection fraction (HFrEF). METHODS: We performed a retrospective chart review at a heart failure center in Winnipeg, Canada. We screened 1059 consecutive patients seen over a 12-month period (August 2011 to July 2012) for AIT in patients with HFrEF. Using descriptive and Cox proportional hazard analyses, we explored the association between AIT and mortality. RESULTS: A total of 110 patients with HFrEF who were exposed to amiodarone were included in the analysis. Of these, 13 (11.8%) were diagnosed with AIT. All AIT patients in our cohort were male. Amiodarone was discontinued in nearly half (46.2%) of patients with AIT. All patients were treated with antithyroid medications, and 5 patients (38.5%) also received prednisone. Euthyroidism was achieved in 2 patients (15.4%), hypothyroidism occurred in 6 patients (46.2%), and 5 patients remained thyrotoxic until death or time of chart review (38.5%). CONCLUSION: Thyrotoxicosis is common in patients with HFrEF on amiodarone and is challenging to treat. Due to the sample size, while no association was found in mortality for patients with HFrEF with AIT, a real association could have been missed.

The Role of the Kidney and SGLT2 Inhibitors in Type 2 Diabetes.

Effective glycemic control reduces the risk for diabetes-related complications. However, the majority of patients with type 2 diabetes still do not achieve glycemic targets. Beyond metformin therapy, current practice guidelines for the management of type 2 diabetes recommend individualized treatment based on patient and agent characteristics. The sodium glucose cotransporter type 2 (SGLT2) inhibitors represent a novel treatment strategy, independent of impaired beta-cell function and insulin resistance. SGLT2 inhibitors decrease renal glucose reabsorption, thereby increasing urinary glucose excretion with subsequent reduction in plasma glucose levels and glycosylated hemoglobin concentrations. Current evidence suggests that they are effective as monotherapy or as add-ons to metformin either alone, or in combination with other oral glucose-lowering agents or insulin. They are generally well tolerated, though rates of lower urinary tract and genital mycotic infections are slightly increased. The advantages of this class include modest reductions in body weight and blood pressure, and low risk for hypoglycemia. Long-term safety data and results of ongoing cardiovascular outcome studies are awaited so we can fully understand the role that SGLT2 inhibitors will play in the comprehensive management of type 2 diabetes.

The clinical burden of type 2 diabetes in patients with acute coronary syndromes: prognosis and implications for short- and long-term management.

Type 2 diabetes mellitus (T2DM) is associated with increased morbidity and mortality in patients with acute coronary syndromes (ACS). Cardiometabolic risk factors, including hyperglycaemia, insulin resistance, atherogenic dyslipidaemia, increased visceral fat and inflammation, are associated with increased risk in this population and represent potential targets for treatment. In this review, management strategies for patients with T2DM post-ACS, both in the acute-care setting and in the long-term, are discussed. Although the benefits of long-term, aggressive, multifactorial risk factor modification are well established, a significant burden of recurrent events remains and the search for novel strategies continues. Several studies are assessing the potential cardiovascular (CV) benefits and safety of various classes of newer agents. Of these, AleCardio (aleglitazar), Examination of Cardiovascular Outcomes With Alogliptin versus Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome (EXAMINE; alogliptin) and Evaluation of LIXisenatide in Acute Coronary Syndrome (ELIXA; lixisenatide) specifically address patients with type 2 diabetes post-ACS. The mechanisms of action of these new therapies and aims of the CV outcome studies are briefly reviewed. The prevalence of type 2 diabetes continues to increase worldwide highlighting the need for new strategies that address the complex underlying processes that drive atherosclerosis and CV events in this high-risk patient population.

Preoperative therapeutic apheresis for severe medically refractory amiodarone-induced thyrotoxicosis: a case report.

INTRODUCTION: Amiodarone is associated with thyroid dysfunction and life-threatening thyrotoxicosis. In medically refractory cases, or where medical therapy is contraindicated, thyroidectomy may be required. To decrease perioperative thyroid storm and to reduce overall surgical risk, apheresis may be considered preoperatively to restore euthyroidism. CASE DESCRIPTION: We report a 46-year-old female with a history of cardiac arrhythmia and tachycardia-induced cardiomyopathy for which she received amiodarone. Months after discontinuation of amiodarone, the patient presented with wide complex tachycardia and symptoms of thyrotoxicosis. Laboratory testing confirmed severe thyrotoxicosis which was subsequently refractory to medical therapy. Total thyroidectomy was required. Following a total of 10 apheresis treatments, thyroid hormone levels were reduced to near normal levels and the patient's symptoms improved. Thyroidectomy was performed without intraoperative or postoperative complication. DISCUSSION: In the setting of life-threatening, medically refractory amiodarone-induced thyrotoxicosis, therapeutic apheresis can effectively reduce thyroid hormone levels and restore a state of clinical and biochemical euthyroidism.

Iodine nutrition during pregnancy in Toronto, Canada.

OBJECTIVE: To evaluate the status of iodine nutrition among pregnant women presenting for routine antenatal care in Toronto, Canada, as determined by the median urine iodine concentration (UIC) of this population. METHODS: A cross-sectional, observational study was conducted involving 142 pregnant women recruited from four low-risk antenatal outpatient clinics in Toronto, Canada. Subjects completed a questionnaire and provided a spot urine sample for the measurement of iodine concentration. RESULTS: Mean maternal age was 33.8 ± 4.3 years. Mean gestational age was 29.3 ± 7.8 weeks. The median UIC was 221 µg/L (interquartile range, 142 to 397 µg/L). Six women (4.2%) had urine iodine levels <50 µg/L, and 36 women (25.4%) had levels between 50 and 150 µg/L. CONCLUSION: This cohort of primarily Caucasian, well-educated, and relatively affluent pregnant women in Toronto, Canada, are iodine sufficient, perhaps due to universal salt iodization and/or other dietary and lifestyle factors.

Drugs targeting high-density lipoprotein cholesterol for coronary artery disease management.

Many patients remain at high risk for future cardiovascular events despite levels of low-density lipoprotein cholesterol (LDL-C) at, or below, target while taking statin therapy. Much effort is therefore being focused on strategies to reduce this residual risk. High-density lipoprotein cholesterol (HDL-C) is a strong, independent, inverse predictor of coronary heart disease risk and is therefore an attractive therapeutic target. Currently available agents that raise HDL-C have only modest effects and there is limited evidence of additional cardiovascular risk reduction on top of background statin therapy associated with their use. It was hoped that the use of cholesteryl ester transfer protein (CETP) inhibitors would provide additional benefit, but the results of clinical outcome studies to date have been disappointing. The results of ongoing trials with other CETP inhibitors that raise HDL-C to a greater degree and also lower LDL-C, as well as with other emerging therapies are awaited.

Use of a treatment optimization algorithm involving statin-ezetimibe combination aids in achievement of guideline-based low-density lipoprotein targets in patients with dyslipidemia at high vascular risk Guideline-based Undertaking to Improve Dyslipidemia Management in Canada (GUIDANC).

BACKGROUND: Despite the well-established benefits of strategies to reduce low-density lipoprotein cholesterol (LDL-C), many patients fail to achieve the guideline recommended targets. The objective of this study was to evaluate the impact of an enhanced 26-week algorithm-based treatment optimization strategy, involving titration of statin monotherapy and/or combination therapy with statin and ezetimibe, on achievement of guideline-based LDL-C targets in patients at high risk for atherosclerotic disease. METHODS AND RESULTS: In this national (172-physician) quality enhancement research initiative involving 2334 Canadian men and women (median age, 65 years) at high vascular risk who were not at the guideline-recommended LDL-C target despite statin therapy, 36.6% and 45.5% of patients achieved an LDL-C <2.0 mmol/L at visit 2 and visit 3, respectively, using the treatment optimization algorithm. The percentage of patients achieving the 2009 Canadian Cardiovascular Society (CCS)-recommended target of either LDL-C <2.0 mmol/L or a 50% or greater reduction from baseline increased from 6.8% at visit 1 to 43.3% at visit 2 and to 52.1% at visit 3. Attainment of LDL-C targets increased significantly with consecutive visits (P < .001). Use of ezetimibe in combination with statin therapy was associated with greater target achievement. CONCLUSIONS: Use of a structured treatment optimization algorithm, based on titration of statin dosages and incorporation of ezetimibe therapy when required, enabled the majority of high-risk patients to achieve guideline-recommended targets, thereby narrowing the care gap that exists in dyslipidemia management.