Incidence of Hypotension Associated With Two Different Vasopressin Discontinuation Strategies in the Recovery Phase of Septic Shock.

Introduction: Safe and effective vasopressor withdrawal strategies during the recovery phase of septic shock lack consensus and are not addressed in clinical practice guidelines. The purpose of this study was to compare the incidence of clinically relevant hypotension associated with different vasopressin (AVP) discontinuation strategies. Methods: This was a single-center, retrospective, cohort study, conducted at a university medical center over a three-year period. Adult patients ≥18 years with septic shock were included in the study. Patients were stratified into two groups; patients incrementally weaned from AVP and patients in which AVP was abruptly discontinued. The primary endpoint was to compare the incidence of clinically relevant hypotension between study groups up to 24 hours following discontinuation. Secondary analyses included the incidence of any hypotensive event up to 24 hours after AVP cessation, intensive care unit and hospital length of stay, and in-hospital mortality. Results: A total of 74 patients (n = 46 AVP wean and n = 28 AVP no-wean) met inclusion criteria and were included in the study. The primary outcome was not statistically different between groups. Clinically relevant hypotension occurred in 24 patients (52.3%) and 16 patients (57.1%) in the AVP wean and AVP no-wean groups, respectively (P = .68). There were no significant differences in any secondary clinical outcome between the two study groups. Conclusion: No differences were found in the incidence of clinically relevant hypotension, length of stay, or mortality between AVP weaning and no-weaning discontinuation strategies. These findings suggest incremental weaning and abrupt withdrawal of AVP are both acceptable discontinuation strategies.

Vancomycin with concomitant piperacillin/tazobactam vs. cefepime or meropenem associated acute kidney injury in the critically ill: A multicenter propensity score-matched study.

PURPOSE: The risk of acute kidney injury (AKI) associated with concomitant vancomycin and piperacillin/tazobactam in the intensive care unit (ICU) remains controversial. The aim of this study was to compare the AKI incidence associated with concomitant vancomycin and piperacillin/tazobactam compared to either cefepime or meropenem with vancomycin in the ICU. MATERIALS AND METHODS: A multicenter, retrospective, propensity score-matched cohort study was conducted in adult ICU patients administered vancomycin in combination with either piperacillin/tazobactam, cefepime, or meropenem were included. Patients developing AKI ≤48 h following combination therapy initiation were excluded. The primary endpoint was to compare the incidence of AKI associated with concomitant antimicrobial therapy. Multivariable Cox regression modeling in predicting AKI was also conducted. RESULTS: A total of 1044 patients were matched. The AKI incidence in vancomycin- piperacillin/tazobactam and vancomycin-cefepime/meropenem groups were 21.9% and 16.8%, respectively (p = 0.068). Multivariable prediction models showed concomitant vancomycin-piperacillin/tazobactam was an independent risk factor of AKI using serum creatinine only (HR 1.52, 1.10-2.10, p = 0.011) and serum creatinine with urine output-based KDIGO criteria (HR 1.77, 1.18-2.67, p = 0.006). No significant differences between groups were observed for AKI recovery patterns or mortality. CONCLUSION: Concomitant vancomycin and piperacillin/tazobactam administration in adult ICU patients was independently associated with an increased risk of AKI.

Ecto-5'-Nucleotidase (CD73) Regulates the Survival of CD8+ T Cells.

Ecto-5'-nucleotidase (CD73) is an enzyme present on the surface of tumor cells whose primary described function is the production of extracellular adenosine. Due to the immunosuppressive properties of adenosine, CD73 is being investigated as a target for new antitumor therapies. We and others have described that CD73 is present at the surface of different CD8+ T cell subsets. Nonetheless, there is limited information as to whether CD73 affects CD8+ T cell proliferation and survival. In this study, we assessed the impact of CD73 deficiency on CD8+ T cells by analyzing their proliferation and survival in antigenic and homeostatic conditions. Results obtained from adoptive transfer experiments demonstrate a paradoxical role of CD73. On one side, it favors the expression of interleukin-7 receptor α chain on CD8+ T cells and their homeostatic survival; on the other side, it reduces the survival of activated CD8+ T cells under antigenic stimulation. Also, upon in vitro antigenic stimulation, CD73 decreases the expression of interleukin-2 receptor α chain and the anti-apoptotic molecule Bcl-2, findings that may explain the reduced CD8+ T cell survival observed in this condition. These results indicate that CD73 has a dual effect on CD8+ T cells depending on whether they are subject to an antigenic or homeostatic stimulus, and thus, special attention should be given to these aspects when considering CD73 blockade in the design of novel antitumor therapies.

Chitosan-Based Delivery of Avian Reovirus Fusogenic Protein p10 Gene: In Vitro and In Vivo Studies towards a New Vaccine against Melanoma.

Reovirus is known to have an anticancer effect in both the preclinical and clinical assays. Current evidence suggests that the reovirus-mediated impact on tumor growth depends on the activation of specific antitumor immune responses. A feasible explanation for the oncolytic effects and immune system activation is through the expression of the fusogenic reovirus protein. In this work, we evaluated the in vivo antitumor effects of the expression of fusogenic protein p10 of avian reovirus (ARV-p10). We used chitosan nanoparticles (CH-NPs) as a vehicle for the ARV-p10 DNA in murine B16 melanoma models both in vitro and in vivo. We confirmed that ARV-p10 delivery through a chitosan-based formulation (ARV-p10 CH-NPs) was capable of inducing cell fusion in cultured melanoma cells, showing a mild cytotoxic effect. Interestingly, intratumor injection of ARV-p10 CH-NPs delayed tumor growth, without changing lymphoid populations in the tumor tissue and spleen. The injection of chitosan nanoparticles (CH-NPs) also delayed tumor growth, suggesting the nanoparticle itself would attack tumor cells. In conclusion, we proved that in vitro ARV-p10 protein expression using CH-NPs in murine melanoma cells induces a cytotoxic effect associated with its cell fusion. Further studies are necessary for establishing a protocol for efficient in vivo DNA delivery of fusion proteins to produce an antitumoral effect.

Plan de estudios modular en la formación médica de la Universidad Xochicalco en Mexicali, Baja California, México / Modular curricula in medical training in Xochicalco University, Mexicali, Baja California, Mexico

INTRODUCCIÓN: Un plan de estudios organizado por módulos busca la integración de contenidos de acuerdo a un campo de conocimiento, función, aparato o sistema a estudiar. La Universidad Xochicalco en la Ciudad de Mexicali, Baja California, México, oferta la Licenciatura de Médico General bajo un plan de estudios modular. Se presentan resultados de una investigación que tuvo como objetivo: explorar los antecedentes de los planes de estudio modulares para la formación de médicos en México, así como identificar la percepción de los alumnos de la Licenciatura de Médico General sobre estos planes de estudio. MATERIAL Y MÉTODOS: Investigación cualitativa en un diseño exploratorio; se aplica la técnica de entrevistas clave y a profundidad a estudiantes de octavo semestre por poseer una perspectiva global de su carrera. La investigación cualitativa no tiene por objeto la representación estadística, sino la comprensión de los fenómenos mediante el apoyo de diversas teorías y herramientas interpretativas. RESULTADOS Y DISCUSIÓN: Los resultados muestran opiniones favorables respecto al logro de la integración de contenidos teóricos y habilidades para el entendimiento y manejo de casos clínicos. Los planes de estudio modulares -poco experimentados en México- representan una alternativa viable para la formación de médicos, y altamente valorada por los estudiantes de medicina

INTRODUCTION: A plan of studies was organised by modules for the integration of content according to a field of knowledge, function, equipment or system to study. The Xochicalco University in the city of Mexicali, Baja California, Mexico, offers a general medical degree using modular curriculum. The results are presented of a study that had as its goal to examine the history of modular curricula for the training of doctors in Mexico, as well as to identify the perception of students of general medicine degree about these curricula. MATERIAL AND METHODS: A qualitative study of exploratory design was conducted using the technique of key and in-depth interviews with students enrolled in the 8th semester in order to have an overall perspective of their careers. The qualitative study did not use statistical representation, but expressed the understanding of the phenomena through the support of various theories and interpretive tools. RESULTS AND DISCUSSION: The results showed favourable opinions about the achievement of the integration of theoretical content and skills to the understanding and management of clinical cases. Modular curricula -little experienced in Mexico- represent a viable alternative for the training of doctors, and highly valued by the students of medicine

Effectiveness and safety of rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation and coronary or peripheral artery disease.

AIMS: There are scarce data evaluating the effectiveness and safety of rivaroxaban vs. warfarin in non-valvular atrial fibrillation (NVAF) patients with concomitant coronary artery disease (CAD) and/or peripheral artery disease (PAD) treated in routine practice. METHODS AND RESULTS: Using MarketScan data from January 2012 to December 2017, we identified oral anticoagulant (OAC)-naïve NVAF patients receiving rivaroxaban (15-20 mg once daily) or warfarin, with comorbid CAD and/or PAD and ≥12 months of insurance coverage before OAC initiation. Differences in baseline covariates between cohorts were adjusted using inverse probability-of-treatment weights based on propensity scores (standardized differences <0.1 achieved for all covariates after adjustment). Endpoints included a composite of major thrombotic vascular events (MTVEs) (including ischaemic stroke, myocardial infarction, or need for lower limb revascularization/major amputation) and major bleeding. Patients were followed until an event-of-interest, discontinuation/switch of index OAC, insurance disenrolment, or end-of-data availability. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression. We identified 3257 rivaroxaban (30.4% received a 15 mg dose) and 5046 warfarin users with NVAF and comorbid CAD and/or PAD. Rivaroxaban was associated with a 32% (95% CI = 8-50%) reduction in the composite of MTVE. No significant difference in major bleeding was observed (HR = 1.13, 95% CI = 0.84-1.52). No statistical interactions were noted in subgroup analyses performed on the MTVE (P-interaction ≥ 0.35 for all) or major bleeding endpoints (P-interaction ≥ 0.09 for all). CONCLUSION: Among patients with NVAF and comorbid CAD and/or PAD, rivaroxaban use was associated with a reduced risk of MTVEs vs. warfarin, without significantly increasing major bleeding risk.

Comparative Effectiveness of Analgesics to Reduce Acute Pain in the Prehospital Setting.

Objectives: The objectives of this study were to assess comparative effectiveness and harms of opioid and nonopioid analgesics for the treatment of moderate to severe acute pain in the prehospital setting. Methods: We searched MEDLINE®, Embase®, and Cochrane Central from the earliest date through May 9, 2019. Two investigators screened abstracts, reviewed full-text files, abstracted data, and assessed study level risk of bias. We performed meta-analyses when appropriate. Conclusions were made with consideration of established clinically important differences and we graded each conclusion's strength of evidence (SOE). Results: We included 52 randomized controlled trials and 13 observational studies. Due to the absence or insufficiency of prehospital evidence we based conclusions for initial analgesia on indirect evidence from the emergency department setting. As initial analgesics, there is no evidence of a clinically important difference in the change of pain scores with opioids vs. ketamine administered primarily intravenously (IV) (low SOE), IV acetaminophen (APAP) (low SOE), or nonsteroidal anti-inflammatory drugs (NSAIDs) administered primarily IV (moderate SOE). The combined use of an opioid and ketamine, administered primarily IV, may reduce pain more than an opioid alone at 15 and 30 minutes (low SOE). Opioids may cause fewer adverse events than ketamine (low SOE) when primarily administered intranasally. Opioids cause less dizziness than ketamine (low SOE) but may increase the risk of respiratory depression compared with ketamine (low SOE), primarily administered IV. Opioids cause more dizziness (moderate SOE) and may cause more adverse events than APAP (low SOE), both administered IV, but there is no evidence of a clinically important difference in hypotension (low SOE). Opioids may cause more adverse events and more drowsiness than NSAIDs (low SOE), both administered primarily IV. Conclusions: As initial analgesia, opioids are no different than ketamine, APAP, and NSAIDs in reducing acute pain in the prehospital setting. Opioids may cause fewer total side effects than ketamine, but more than APAP or NSAIDs. Combining an opioid and ketamine may reduce acute pain more than an opioid alone but comparative harms are uncertain. When initial morphine is inadequate, giving ketamine may provide greater and quicker acute pain relief than giving additional morphine, although comparative harms are uncertain. Due to indirectness, strength of evidence is generally low, and future research in the prehospital setting is needed.

Systematic review and meta-analysis of catheter ablation of ventricular tachycardia in ischemic heart disease.

BACKGROUND: Patients with ischemic heart disease (IHD) are at risk for ventricular tachycardia (VT). Catheter ablation (CA) may reduce this risk. OBJECTIVE: To perform a systematic review and meta-analysis of randomized controlled trials (RCTs) of CA of VT in patients with IHD. METHODS: Literature searches of MEDLINE, the Cochrane Central Register of Controlled Trials (CENTRAL), and the Cochrane Database of Systematic Reviews (CDSR) were performed from January 2000 through April 2018 to identify RCTs comparing a strategy of CA vs no ablation in patients with IHD and an implantable cardioverter defibrillator (ICD). Outcomes of interest included appropriate ICD therapies, appropriate ICD shocks, VT storm, recurrent VT/ventricular fibrillation (VF), cardiac hospitalizations, and all-cause mortality. Using an inverse variance random-effects model, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each endpoint. RESULTS: A total of 5 RCTs (N = 635 patients) were included, with a duration of follow-up ranging from 6 months to 27.9 months. Patients who underwent CA experienced decreased odds of appropriate ICD therapies (OR 0.49; 95% CI 0.28-0.87), appropriate ICD shocks (OR 0.52; 95% CI 0.28-0.96), VT storm (OR 0.64; 95% CI 0.43-0.95), and cardiac hospitalization (OR 0.67; 95% CI 0.46-0.97) vs those who did not undergo ablation. There was no evidence of a benefit for recurrent VT/VF (OR 0.87; 95% CI 0.41-1.85), although this endpoint was not reported in all trials, or for all-cause mortality (OR 0.89; 95% CI 0.60-1.34). CONCLUSION: In this systematic review and meta-analysis of RCTs, CA was associated with a significant reduction in the odds of appropriate ICD therapies, appropriate ICD shocks, VT storm, and cardiac hospitalizations in patients with IHD.

Adverse Effects of Pharmacologic Treatments of Major Depression in Older Adults.

OBJECTIVES: To assess adverse effects of pharmacologic antidepressants for treatment of major depressive disorder (MDD) in adults 65 years of age or older. DESIGN: Systematic review and meta-analysis. SETTING: Specialist or generalist outpatient setting, rehabilitation facility, and nursing facilities. PARTICIPANTS: Persons 65 years and older with MDD. INTERVENTION: Selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), bupropion, mirtazapine, trazodone, vilazodone, or vortioxetine compared with another antidepressant, placebo, or nonpharmacologic therapy. MEASUREMENTS: Adverse events, arrhythmias, cognitive impairment, falls, fractures, hospitalization, mortality, QTc prolongation, serious adverse events, and withdrawals due to adverse events. RESULTS: Nineteen randomized controlled trials and two observational studies were included. Most studies evaluated treatment of the acute phase (<12 wk) of MDD of moderate severity. SSRIs led to a statistically similar frequency of overall adverse events vs placebo (moderate strength of evidence [SOE]), but SNRIs caused more overall adverse events vs placebo (high SOE) during the acute treatment phase. Both SSRIs and SNRIs led to more study withdrawals due to adverse events vs placebo (SSRIs low SOE; SNRIs moderate SOE). Duloxetine led to a more falls vs placebo (moderate SOE) during 24 weeks of acute and continuation treatment of MDD. CONCLUSION: In patients 65 years of age or older with MDD, treatment of the acute phase of MDD with SNRIs, but not SSRIs, was associated with a statistically greater number of overall adverse events vs placebo. SSRIs and SNRIs led to a greater number of study withdrawals due to adverse events vs placebo. Duloxetine increased the risk of falls that as an outcome was underreported in the literature. Few studies examined head-to-head comparisons, most trials were not powered to evaluate adverse events, and results of observational studies may be confounded. Comparative long-term studies reporting specific adverse events are needed to inform clinical decision making regarding choice of antidepressants in this population. J Am Geriatr Soc 67:1571-1581, 2019.

Influence of Polypharmacy on the Effectiveness and Safety of Rivaroxaban Versus Warfarin in Patients With Nonvalvular Atrial Fibrillation.

STUDY OBJECTIVE: Patients with nonvalvular atrial fibrillation (NVAF) often have multiple comorbidities requiring concomitant medications in addition to their oral anticoagulant (OAC). The objective of this study was to evaluate the impact of polypharmacy on the effectiveness and safety of rivaroxaban versus warfarin in patients with NVAF managed in routine clinical practice. DESIGN: Retrospective claims analysis. DATA SOURCE: United States Truven MarketScan database (November 2012-March 2017). PATIENTS: Adults who were OAC naïve during the 12 months before the day of the first qualifying rivaroxaban or warfarin dispensing (index date); had at least two International Classification of Diseases, Ninth or Tenth Revision diagnosis codes for atrial fibrillation without codes suggesting valvular heart disease; had at least 12 months of continuous insurance coverage prior to the qualifying OAC dispensing; and were experiencing polypharmacy (concomitant prescription claims for five or more unique chronic medication claims) were included. Patients who had concomitant prescription claims for ≥ 10 unique chronic medication claims constituted the substantial polypharmacy cohort used in the secondary analysis. Patients receiving rivaroxaban were propensity-score matched in a 1:1 ratio to patients receiving warfarin (13,981 patients in each polypharmacy OAC group, and 1765 patients in each substantial polypharmacy OAC group). MEASUREMENTS AND MAIN RESULTS: Patients were followed until occurrence of an event (stroke or systemic embolism [SSE] combined [primary effectiveness outcome] or major bleeding [primary safety outcome]), OAC discontinuation or switch (30-day permissible gap), insurance disenrollment, or end of follow-up period. Rates of SSE, ischemic stroke, and major bleeding were compared by using Cox regression, reported as hazard ratios (HRs) and 95% confidence intervals (CIs). In patients with NVAF taking five or more chronic medications, rivaroxaban was associated with a 34% (95% CI 12-50) and 40% (95% CI 16-57) hazard reduction of SSE and ischemic stroke, respectively. Occurrence of major bleeding was similar between OAC cohorts (HR 1.08, 95% CI 0.92-1.28). A secondary analysis in patients with NVAF with substantial polypharmacy (taking ≥ 10 chronic medications) was also performed. Similar trends in SSE (HR 0.44), ischemic stroke alone (HR 0.62), and major bleeding (HR 1.07) were observed in patients with NVAF who had substantial polypharmacy, although 95% CIs crossed 1.0 for each outcome in this smaller study cohort. CONCLUSION: This real-world study suggests that in the setting of polypharmacy and NVAF, rivaroxaban is an effective and safe alternative to warfarin.

Anticoagulant Bridge Comparison in Mechanical Circulatory Support Patients.

Maintaining mechanical circulatory support (MCS) device patients in a specified therapeutic range for anticoagulation remains challenging. Subtherapeutic international normalized ratios (INRs) occur frequently while on warfarin therapy. An effective anticoagulant bridge strategy may improve the care of these patients. This retrospective review of MCS patients with subtherapeutic INRs compared an intravenous unfractionated heparin (UFH) strategy with a subcutaneous enoxaparin or fondaparinux strategy. Native thromboelastography (n-TEG) was used to evaluate anticoagulant effect with coagulation index (CI) as the primary outcome measure. Enoxaparin 0.5 mg/kg subcutaneously (SC) every 12 hours or fondaparinux 2.5-5 mg SC daily were compared with an initial UFH rate of 5 units/kg/hr and titrated to stated n-TEG goal range. The anticoagulant groups UFH, enoxaparin, and fondaparinux were found to be statistically similar with regard to frequency in n-TEG goal range, above range (hypercoagulability), or below range (hypocoagulability). Clinical outcomes were similar among groups with three gastrointestinal bleeds in UFH, one in enoxaparin, and one in fondaparinux groups. Device thrombosis occurred in one UFH patient, while UFH and fondaparinux groups had one ischemic cerebrovascular accident event each. These strategies provided comparable n-TEG results and clinical outcomes when compared with intravenous UFH. Low-dose enoxaparin or fondaparinux may provide an alternative anticoagulant bridging option in MCS patients presenting with subtherapeutic INR.

Effectiveness and safety of rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation and heart failure.

AIMS: Heart failure (HF) is a common co-morbidity in non-valvular atrial fibrillation (NVAF) patients and a potent risk factor for stroke, bleeding, and a decreased time-in-therapeutic range with warfarin. We assessed the real-world effectiveness and safety of rivaroxaban and warfarin in NVAF patients with co-morbid HF. METHODS AND RESULTS: Using US Truven MarketScan Commercial and Medicare supplemental database claims data from 11/2011 to 12/2016, we identified oral anticoagulant (OAC)-naïve NVAF patients with HF (International Classification of Diseases, 10th Revision codes of I50 or I09.81) and ≥12 months of insurance coverage prior to the qualifying OAC dispensing. Rivaroxaban users (20 or 15 mg once daily) were 1:1 propensity score matched to warfarin users, with residual absolute standardized differences <0.1 being achieved for all covariates after matching. Patients were followed up until an event, OAC discontinuation/switch, insurance disenrolment, or end of follow-up. Rates [events per 100 person-years (PYs) of follow-up] for stroke or systemic embolism and major bleeding (using the Cunningham algorithm) were compared between the matched cohorts using Cox proportion hazard regression and reported as hazard ratios (HRs) with 95% confidence intervals (CIs). We matched 3418 rivaroxaban (32% receiving the reduced dose) and 3418 warfarin users with NVAF and HF with a median (interquartile range) available follow-up of 1.4 (0.6, 2.5) years. Median age was 74 (63, 82) years, and median CHA2 DS2 -VASc and HASBLED scores were 4 (3, 5) and 2 (2, 3). Common HF medications included beta-blockers (64%), angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (62%), loop diuretics (46%), digoxin (11%), and aldosterone receptor antagonists (10%). The hazard of developing stroke or systemic embolism (0.98 events/100PY vs. 1.28 events/100PY; HR = 0.82, 95% CI = 0.47-1.44), ischaemic stroke (0.70 events/100PY vs. 1.02 events/100PY; HR = 0.77, 95% CI = 0.41-1.46), or major bleeding (3.86 events/100PY vs. 4.23 events/100PY; HR = 0.98, 95% CI = 0.73-1.31) was not found to be different between rivaroxaban and warfarin users. Intracranial haemorrhage was infrequent in both cohorts and numerically less with rivaroxaban (0.27 events/100PY vs. 0.36 events/100PY; HR = 0.73, 95% CI = 0.25-2.08). CONCLUSIONS: Effectiveness and safety of rivaroxaban vs. warfarin are sustained in NVAF patients with co-morbid HF treated in routine practice. The general consistency between this real-world study and those from phase III randomized trial data of rivaroxaban should provide additional reassurance to clinicians regarding the use of rivaroxaban in NVAF patients with HF.

Effectiveness and Safety of Apixaban, Dabigatran, and Rivaroxaban Versus Warfarin in Frail Patients With Nonvalvular Atrial Fibrillation.

BACKGROUND: Frailty predicts poorer outcomes and decreased anticoagulation use in patients with nonvalvular atrial fibrillation. We sought to assess the effectiveness and safety of apixaban, dabigatran and rivaroxaban versus warfarin in frail nonvalvular atrial fibrillation patients. METHODS AND RESULTS: Using US MarketScan claims data from November 2011 to December 2016, we identified frail oral anticoagulant-naïve nonvalvular atrial fibrillation patients with ≥12 months of continuous insurance coverage before oral anticoagulant initiation. Frailty status was determined using the Johns Hopkins Claims-based Frailty Indicator score (≥0.20 indicating frailty). Users of apixaban, dabigatran, or rivaroxaban were separately 1:1 matched to warfarin users via propensity-scores, with residual absolute standardized differences <0.1 being achieved for all covariates after matching. Patients were followed for up to 2 years or until an event, insurance disenrollment or end of follow-up. Rates of stroke or systemic embolism and major bleeding were compared using Cox regression and reported as hazard ratios (HRs) and 95% confidence intervals (CIs). In total, 2700, 2784, and 5270 patients were included in the apixaban, dabigatran, and rivaroxaban 1:1 matched analyses to warfarin. At 2 years, neither apixaban nor dabigatran were associated with differences in the hazard of stroke or systemic embolism (HR=0.78; 95% CI=0.46-1.35 and HR=0.94; 0.60-1.45) or major bleeding (HR=0.72; 95% CI=0.49-1.06 and HR=0.87; 95% CI=0.63-1.19) versus warfarin. Rivaroxaban was associated with reduced stroke or systemic embolism at 2 years (HR=0.68; 95% CI=0.49-0.95) without significantly altering major bleeding risk (HR=1.07; 95% CI=0.81-1.32). CONCLUSIONS: Our study found rivaroxaban but not apixaban or dabigatran to be associated with reduced SSE versus warfarin in frail nonvalvular atrial fibrillation patients. No direct-acting oral anticoagulants demonstrated a significant difference in major bleeding versus warfarin.

Systematic Review and Meta-Analysis of Real-World Studies Evaluating Rivaroxaban for Cancer-Associated Venous Thrombosis.

INTRODUCTION: While not designated as guideline-recommended first-line anticoagulation therapy, about one in five patients in the United States receive rivaroxaban for the treatment of cancer-associated venous thrombosis (CAT). METHODS: A systematic review and meta-analysis were performed to evaluate the incidences of recurrent venous thromboembolism (VTE), major bleeding, and all-cause mortality in rivaroxaban patients treated for CAT in routine practice. Literature searches of MEDLINE and SCOPUS were performed through September 2017 to identify real-world studies of ≥ 20 patients evaluating the incidence of recurrent VTE, major bleeding, or all-cause mortality in CAT patients anticoagulated with rivaroxaban. Using a Hartung-Knapp random-effects model, the pooled incidence estimates and 95% confidence intervals (CIs) were calculated for each end point. RESULTS: Six studies evaluating rivaroxaban for CAT were identified. Of these, three were prospective and three were retrospective. Study sample sizes ranged from 41 to 949 patients, and duration of follow-up ranged from 164 to 496 days. The most frequent active cancer sites reported in studies were gastrointestinal (range: 12.0-56.0%), genitourinary (range: 8.6-26.0%), and breast (range: 9.3-25.5%). The weighted average incidences of recurrent VTE, major bleeding, and all-cause mortality were 4.2% (95% CI = 2.6-6.6%; I2 = 31%), 2.9% (95% CI = 1.6-5.0%; I2 = 59%), and 16.1% (95% CI = 6.0-36.6%; I2 = 96%). CONCLUSIONS: This meta-analysis suggests that incidences of recurrent VTE and major bleeding among rivaroxaban-managed patients are not dissimilar to those seen in recent randomized trials of anticoagulation in CAT. The pooled incidence for mortality was lower than reported in many anticoagulation CAT trials. This may suggest that rivaroxaban is being used in CAT patients who have less severe cancer.

Meta-Analysis of Time in Therapeutic Range in Continuous-Flow Left Ventricular Assist Device Patients Receiving Warfarin.

Continuous-flow left ventricular assist devices (CF-LVADs) prolong survival in advanced heart failure patients. Anticoagulation control is critical in CF-LVAD patients due to increased thromboembolic and bleeding risk. We assessed the quality of INR control in CF-LVAD patients measured by time in therapeutic range (TTR). We performed a systematic literature search of MEDLINE and SCOPUS through July 2017 to identify studies evaluating TTR in anticoagulated adult CF-LVAD patients. Data on key characteristics and the TTR end point were then extracted from each study by two investigators using a standardized tool. Using a Hartung-Knapp random effects model, a weighted mean TTR estimate with accompanying 95% confidence interval (CI) was calculated. Statistical heterogeneity was estimated using the I2 statistic. Five published studies were included. All studies were single-center, retrospective investigations that calculated TTR using the Rosendaal method. Sample sizes ranged from 11 to 115 patients (total of 270 patients) with durations of follow-up ranging from 9 to 76 person-years. On meta-analysis, CF-LVAD patients had a weighted mean TTR of 46.6% (95% CI: 36.0-57.3%, I2 = 94%). This suggests that warfarin is difficult to manage in CF-LVAD patients, which may contribute to high rates of bleeding and thromboembolic complications.

The Emerging Role of Inflammation in Cardiovascular Disease.

OBJECTIVE: To review the role of inflammatory suppression in patients with atherosclerotic cardiovascular disease (ASCVD) with a focus on the interleukin-1ß blocker canakinumab. DATA SOURCES: An Ovid MEDLINE literature search (1946 to February 2018) was performed using search terms inflammation, ASCVD, atherosclerosis, C-reactive protein, canakinumab. Additional references were identified from a review of literature citations. STUDY SELECTION AND DATA EXTRACTION: English-language studies assessing the impact of pharmacological agents, including canakinumab, on inflammation as measured by high-sensitivity C-reactive protein (hsCRP) and the association with reducing ASCVD events were evaluated. DATA SYNTHESIS: Nine studies were included to describe the effect of ASCVD drugs on hsCRP. Aspirin, angiotensin-converting enzyme inhibitors, gemfibrozil, and statins exhibit varying degrees of hsCRP reduction and are associated with a reduction of ASCVD events. The Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS), showed a significant reduction of ASVCD events in patients with elevated baseline hsCRP levels without affecting cholesterol. CONCLUSIONS: Patients with elevated inflammatory markers such as hsCRP are at risk for ASVCD events. Several drug classes have shown the ability to decrease hsCRP levels, but the extent to which this reduces ASCVD events in lieu of other drug mechanisms was not clear. Canakinumab specifically targets the inflammatory process in ASCVD and was proven to be effective in preventing ASCVD events in patients with elevated hsCRP levels.

Non-modifiable determinants of pharmacy residency match rates.

OBJECTIVE: The purpose of this study was to examine non-modifiable pharmacy program characteristics on residency match rates. METHODS: American Society of Health-System Pharmacists match and non-match lists were de-identified and evaluated for students graduating in 2015. Variables analysed included length of program, type of institution and didactic grading scheme. KEY FINDINGS: Students from 4-year programs, attending a public institution, or using a grade point average had greater odds of matching. Logistic regression model indicated a good model fit (χ2 (2) of 4.44, P = 0.108). CONCLUSIONS: Students considering residency training may benefit from awareness of such factors when choosing a pharmacy program.

Impact of pre-implant amiodarone exposure on outcomes in cardiac transplant recipients.

Amiodarone remains one of the preferred antiarrhythmic medications for patients with advanced heart failure awaiting cardiac transplant. However, the long half-life and rapid redistribution of this agent into donor myocardium expose heart transplant recipients to potential adverse outcomes. In reviewing the current body of literature, we found that pre-operative amiodarone exposure can increase the risk of bradycardia post-transplant; however, this is unlikely to require permanent pacemaker implant. Further, amiodarone has several serious drug-drug interactions with calcineurin inhibitors. Clinicians should therefore consider empiric reduction in initial dosing for tacrolimus or cyclosporine, and carefully monitor blood levels for at least 3 months post-transplant. Although the evidence is conflicting, amiodarone exposure pre-operatively may increase the risk of early graft failure and mortality. Amiodarone use should be minimized whenever possible; if amiodarone cannot practically be discontinued in the pre-transplant phase, judicious monitoring for QTc prolongation and ventricular arrhythmia should be implemented after transplant. As most of the studies included in this review suffered from small sample sizes and limited follow-up, additional research in this area is warranted.

Neighborhood Ethnic Composition and Problem Drinking Among Older Mexican American Men: Results from the Hispanic Established Populations for the Epidemiologic Study of the Elderly.

Ethnic enclaves may be protective for health. This study investigates the effects of neighborhood co-ethnic density on problem drinking among older Mexican American men. Probability sample of 2,086 community-dwelling Mexican Americans aged 75 or older drawn in 2004-2005 residing in communities in Arizona, California, Colorado, New Mexico and Texas. Problem drinking was found among 15.3 % of men (n = 350). For each percent increase in neighborhood percent Mexican American, men had 2 % lower odds of problem drinking [odds ratio (OR) 0.98; P < 0.05]. U.S. born men had lower odds of problem drinking (OR 0.40; P < 0.05) compared with foreign born men, while English language use was associated with greater odds of problem drinking (OR 2.14; P < 0.05). Older Mexican American men in neighborhoods with low levels of co-ethnic density, the foreign born, and those with English language facility had an increased likelihood of problem drinking.