Amichai Perlman

Can SGLT2 Inhibitors Cause Acute Renal Failure? Plausible Role for Altered Glomerular Hemodynamics and Medullary Hypoxia

Sodium–glucose co-transporter-2 inhibitors (SGLT2i) provide outstanding long-term cardiovascular and renal protection in high-risk patients with type 2 diabetes mellitus. Yet, despite encouraging renal safety outcomes reported in the EMPA-REG study, scattered reports suggest that there might be a risk for acute kidney injury (AKI), which may occasionally be fatal or might require renal replacement therapy. Reduced trans-glomerular pressure with a modest decline in kidney function, an inherent characteristic of SGLT2i therapy, conceivably forms the basis for the long-term renal protection, resembling agents that block the renin–angiotensin–aldosterone (RAAS) axis. Yet, a major decline in kidney function occasionally occurs, often associated with an acute illness or with specific co-administered medications. SGLT2i may lead to AKI by (a) effective volume depletion, due to excessive diuresis, particularly in hemodynamically unstable and volume-depleted patients; (b) excessive decline in trans-glomerular pressure, specifically in patients on RAAS blockade; and (c) induction of renal medullary hypoxic injury, related to enhanced distal tubular transport, especially with concomitant use of agents impairing medullary oxygenation, such as non-steroidal anti-inflammatory drugs and radiocontrast agents. The risk of developing renal impairment with SGLT2i and the role of these suggested mechanisms are yet to be defined, as there are conflicting data and inconsistent reporting with the various agents currently in use.

Prenatal Exposure to Acetaminophen and Risk for Attention Deficit Hyperactivity Disorder and Autistic Spectrum Disorder: A Systematic Review, Meta-Analysis, and Meta-Regression Analysis of Cohort Studies

Acetaminophen is the analgesic and antipyretic most commonly used during pregnancy. Evidence of neurodisruptive properties is accumulating. Therefore, we sought to evaluate the risk for attention deficit hyperactivity disorder (ADHD) and autistic spectrum disorder (ASD) in the offspring of women exposed to acetaminophen during pregnancy. We searched MEDLINE, Embase, and Cochrane databases for relevant studies up to January 2017. Data were independently extracted and assessed by 2 researchers. Seven eligible retrospective cohorts included 132,738 mother-child pairs, with follow-up periods ranging from 3 to 11 years. The pooled risk ratio for ADHD was 1.34 (95% confidence interval (CI): 1.21, 1.47; I2 = 72%); for ASD, the risk ratio was 1.19 (95% CI: 1.14, 1.25; I2 = 14%), and for hyperactivity symptoms, it was 1.24 (95% CI: 1.04, 1.43; I2 = 93%). In meta-regression analysis, the association between exposure and ADHD increased with the childs age upon follow-up (β = 0.03, 95% CI: 0.00, 0.07) and with the mean duration of exposure (β = 0.00, 95% CI: 0.00, 0.01). The available data is of observational nature only. Studies differed widely in exposure and outcome assessment. Acetaminophen use during pregnancy is associated with an increased risk for ADHD, ASD, and hyperactivity symptoms. These findings are concerning; however, results should be interpreted with caution given that the available evidence consists of observational studies and is susceptible to several potential sources of bias.

Association of Acetaminophen and Ibuprofen Use With Wheezing in Children With Acute Febrile Illness

Background: Many infants and children receive acetaminophen and/or ibuprofen during febrile illness. Previously, some studies have linked acetaminophen and ibuprofen use to wheezing and exacerbation of asthma symptoms in infants and children. Objective: To assess whether acetaminophen or ibuprofen use are associated with wheezing in children presenting to the emergency department (ED) with febrile illness. Methods: This was a cross-sectional study of children who presented with fever to the pediatric ED between 2009 and 2013. The data were collected from questionnaires and from the children’s medical files. Patients with wheezing in the ED were compared with nonwheezing patients. Associations between medication use and wheezing were assessed using univariate and multivariate analyses. The multivariate analysis adjusted for potential confounding variables (ie, age, atopic dermatitis, allergies, smoking, antibiotics use, etc) via propensity scores. Results: During the study period, 534 children admitted to the ED met our inclusion criteria, of whom 347 (65%) were included in the study. The use of acetaminophen was similar in children diagnosed with wheezing compared with those without wheezing (n = 39, 81.3%, vs n = 229, 82.7%, respectively). Ibuprofen use was significantly lower in children diagnosed with wheezing (n = 22, 52.4%, vs n = 168, 69.4%, respectively). In multivariate analysis, acetaminophen was not associated with a higher rate of wheezing during acute febrile illness (adjusted odds ratio [OR] = 0.76, 95% CI = 0.24- 2.39), whereas ibuprofen was associated with a lower risk of wheezing (adjusted OR = 0.36, 95% CI = 0.13-0.96). Conclusions: Our study suggests that acetaminophen and ibuprofen are not associated with increased risk for wheezing during acute febrile illness.

Metoclopramide in pregnancy: no association with adverse fetal and neonatal outcomes.

Commentary on: Pasternak B, Svanstrom H, Molgaard-Nielsen D, et al. Metoclopramide in pregnancy and risk of major congenital malformations and fetal death. JAMA 2013;310:1601–11.[OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4] Nausea and vomiting of pregnancy (NVP) affects as many as 50–80% of pregnant women during the first trimester.1 NVP can cause considerable physical and psychological distress, can often be debilitating and sometimes requires hospitalisation. In addition to rehydration and various dietary recommendations, treatment of NVP often requires pharmacological interventions, such as an antihistamine combined with pyridoxine, 5-HT3 antagonist or dopamine antagonist. Despite their widespread use, data regarding the safety of many of these agents in pregnancy are limited, due to the exclusion of pregnant women from clinical … [1]: {openurl}?query=rft.jtitle%253DJAMA%26rft.volume%253D310%26rft.spage%253D1601%26rft_id%253Dinfo%253Adoi%252F10.1001%252Fjama.2013.278343%26rft_id%253Dinfo%253Apmid%252F24129464%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.1001/jama.2013.278343&link_type=DOI [3]: /lookup/external-ref?access_num=24129464&link_type=MED&atom=%2Febmed%2F19%2F3%2F115.atom [4]: /lookup/external-ref?access_num=000325624800023&link_type=ISI

Antihypertensive and Statin Medication Use and Motor Function in Community-Dwelling Older Adults

OBJECTIVES To investigate whether the use of antihypertensive and statin medication in very old adults is associated with the level of motor performance. DESIGN Cross-sectional study. SETTINGS A community-based study recruited from over 40 residential facilities across the metropolitan Chicago area. PARTICIPANTS Community-dwelling very old adults (n = 1520; mean age 80.2; standard deviation 7.7). MEASUREMENTS Eleven motor performances were summarized using a composite motor score. All prescription and over the counter medications taken by participants were inspected and coded using the Medi-Span Data Base System. Demographic characteristics and medical history were obtained by means of detailed interview and medical examinations. RESULTS In multiple linear regression models, antihypertensive medications were associated with global motor score [β = -0.075, standard error (SE) 0.011, P < .001]. Thus, motor function in an individual with antihypertensive medication, was on average, about 7.5% lower than an age-, sex-, and education-matched individual without antihypertensive medication. The number of antihypertensive medications, which were being used had an additive effect, such that a reduction in the level of motor function was observed with each additional medication, and receiving 3 or more antihypertensive medications was associated with about a 15% reduction in the level of motor function. The association between antihypertensive medications and motor function was robust, and remained unchanged after adjusting for confounding by indication using several potentially confounding variables: smoking, hypertension, diabetes, stroke, congestive heart failure, myocardial infarction, and intermittent claudication (β = -0.05, SE 0.015, P = .001). In contrast, the use of statin medications was not related to motor function (unadjusted: β = 0.003, SE 0.015, P = .826; fully adjusted: β = 0.018, SE 0.014, P = .216). CONCLUSIONS The use of antihypertensive medications is associated with a lower level of motor function in very old adults. The nature of this association warrants further investigation.

Correlation between coronary artery calcification by non-cardiac CT and Framingham score in young patients

Background Previous studies have established a correlation between coronary artery calcification (CAC) measured by ECG-gated chest computed tomography (CT) and cardiovascular disease. Recent reports which included asymptomatic patients suggest that CAC measured on non-ECG gated CT is similarly associated with cardiovascular risk. This study investigates the correlation between the Framingham Risk Score (FRS) and an incidental finding of CAC on a non-gated chest CT performed for non-cardiac indications in young and seemingly healthy adults. Methods A cross-sectional study that included 162 CT scans performed in young patients aged 18–50 years old for non-cardiac indications in our institution was conducted. CAC score (CACS) was calculated using the Agatston method. FRS was calculated and compared to the CACS using three different approaches. The correlations between the CACS and several specific factors (i.e. age, body mass index, smoking, statins, etc.), were also evaluated. Results Mean age of patients was 36.43 year old and 105 (64.8%) were male. We found a significant positive correlation between the CACS and the FRS in all three approaches (p<0.05). Increased age, smoking and statin use were the only individual factors clearly associated with an increase in CACS (p = 0.002, p = 0.045 and p = 0.009, respectively). Conclusion This is the first report indicating that incidental CACS identified in non-gated MDCT is also associated with cardiovascular risk evaluated by FRS in a young population. Our findings suggest that young asymptomatic individuals with incidental CAC should be seriously evaluated for cardiovascular risk factors despite presumption of belonging to a low cardiovascular risk category.

Drug interaction as a predictor of direct oral anticoagulant drug levels in atrial fibrillation patients

Data are limited on the effects of drug interactions on direct-acting oral anticoagulant (DOAC) levels. We evaluated the effects of the use of interacting drugs on DOAC levels in patients with atrial fibrillation (AF). We reviewed data of AF patients tested for DOAC levels in 2013–2017. The primary outcomes were drug levels exceeding the expected steady-state range, and in the highest quartile. A multivariate analysis was performed to evaluate the correlation of treatment by the use of interacting drugs, CYP3A4 and P-glycoprotein (P-gp) inhibitors, with the primary outcomes. Overall, 147 patients underwent DOAC level measurement [dabigatran (n = 31), rivaroxaban (n = 29), apixaban (n = 87)]. Thirty-three (22.4%) had drug levels exceeding the expected range. Seventy-nine (53.7%) patients were treated with at least one interacting drug. In multivariate analysis, the concomitant use of interacting drugs was an independent predictor for drug levels exceeding the expected range (OR 3.3, 95% CI 1.20–9.05). The defined daily dose of the interacting drug correlated positively with DOAC levels (r = 0.29, P = 0.001). Co-treatment with interacting drugs was associated with extremely high levels of dabigatran, (OR 16.6, 95% CI 1.29–215.18) but not of the other DOAC examined. Concomitant use of interacting drugs is associated with high DOAC levels in patients with AF. Further investigation is warranted to establish the differences between specific DOAC, evaluate the effect on patient outcomes, and characterize the role of DOAC monitoring in this setting.

WITHDRAWN: Cognition and Dementia Related Adverse Effects with Sacubitril-Valsartan: Analysis of the FDA Adverse Event Report System Database

The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.cardfail.2018.04.009. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Fluoroquinolones and Cardiovascular Risk: A Systematic Review, Meta-analysis and Network Meta-analysis

IntroductionSeveral fluoroquinolone antibiotics have been associated with cardiac adverse effects, leading to the withdrawal of some of these agents from the market. Cardiac side effects such as QT prolongation and torsades de pointes (TdP) have also been observed with fluoroquinolones currently on the market. In order to evaluate the cardiac risk of fluoroquinolones as a class, and the comparative risk for each individual drug, we conducted a systematic review, meta-analysis, and network meta-analysis.MethodsMEDLINE, EMBASE and the Cochrane Library were searched, up to March 2018, for randomized controlled trials, cohort studies, and case–control studies that investigated the association between fluoroquinolone treatment and the risk of cardiovascular events and cardiovascular mortality. We followed the PRISMA 2009 guidelines for data selection and extraction. Outcomes were pooled using random effects models. Direct and indirect comparisons in network meta-analysis were performed using frequentist methods.ResultsThirteen studies were included in our analyses. Fluoroquinolone use was associated with a statistically significant 85% increase in the risk for arrhythmia (odds ratio [OR] 1.85; 95% confidence interval [CI] 1.22–2.81) and 71% increase in the risk for cardiovascular mortality (OR 1.71; 95% CI 1.39–2.09). Moxifloxacin ranked most likely to have the highest risk for arrhythmia (P-score 0.99) and for cardiovascular mortality (P-score 0.95) by network meta-analysis.ConclusionsOur findings show a significant association between fluoroquinolone use and an increased risk for arrhythmia and cardiovascular mortality. Moxifloxacin ranked with the highest probability for cardiovascular adverse events. Further study is required to determine how to reduce the risk for fluoroquinolone-associated cardiac toxicity.

Managing Direct Oral Anticoagulants in Patients with Antiepileptic Medication

Current guidance recommends avoiding concomitant use of direct-acting oral anticoagulants and enzyme-inducing antiepileptic drugs because of theoretical drug interactions potentially leading to subtherapeutic drug concentrations and treatment failure. We describe a case documenting a significant interaction between phenobarbital and rivaroxaban, and then apixaban. This case illustrates and supports the concerns regarding concomitant use of these medications. Additionally, in this case the interaction was managed with concentration-guided dosing of apixaban, suggesting this approach may represent a feasible strategy for managing patients requiring treatment with direct-acting oral anticoagulants and enzyme-inducing antiepileptic drugs.