2018 Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation

The Canadian Cardiovascular Society (CCS) Atrial Fibrillation Guidelines Committee provides periodic reviews of new data to produce focused updates that address clinically important advances in atrial fibrillation (AF) management. This 2018 Focused Update addresses: (1) anticoagulation in the context of cardioversion of AF; (2) the management of antithrombotic therapy for patients with AF in the context of coronary artery disease; (3) investigation and management of subclinical AF; (4) the use of antidotes for the reversal of non-vitamin K antagonist oral anticoagulants; (5) acute pharmacological cardioversion of AF; (6) catheter ablation for AF, including patients with concomitant AF and heart failure; and (7) an integrated approach to the patient with AF and modifiable cardiovascular risk factors. The recommendations were developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) standards. Individual studies and literature were reviewed for quality and bias; the literature review process and evidence tables are included as Supplementary Material and are available on the CCS Web site. Details of the updated recommendations are presented, along with their background and rationale. This document is linked to an updated summary of all CCS AF guidelines recommendations, from 2010 to the present 2018 Focused Update, which is provided in the Supplementary Material.     

Inactivation of purified human alpha 2-antiplasmin and purified human C1 inhibitor by synthetic fibrinolytic agents

3-Hydroxypropyl flufenamide (Flu-HPA) is one of a series of flufenamic acid derivatives that enhances blood clot lysis in vitro. Studies of possible mechanisms of action of Flu-HPA were undertaken. The profibrinolytic activity of Flu-HPA in clot lysis assays was found to be dependent on plasminogen. The influence of Flu-HPA on the ability of purified alpha 2-antiplasmin to inhibit purified plasmin was studied. Plasmin activity was determined using 125I-fibrin plates or the spectrophotometric tripeptide substrate, Val-Leu-Lys-paranitroanilide. At Flu-HPA concentrations greater than 1 mM, the inhibitory activity of alpha 2-antiplasmin was abolished in a time-dependent and concentration- dependent manner. The influence of Flu-HPA on the ability of purified Cl inhibitor to inhibit purified plasma kallikrein and beta-Factor XIIa was also studied. Cl inhibitor activity was abolished by Flu-HPA at concentrations greater than 2 mM. Notably, Flu-HPA up to 60 mM did not affect the amidolytic activities of plasmin, kallikrein, or beta-Factor XIIa. Flu-HPA did not release enzyme activity from preformed complexes of either alpha 2-antiplasmin and plasmin of Cl inhibitor and kallikrein. A water-soluble derivative of flufenamic acid, N-flufenamyl- glutamic acid, also inactivated alpha 2-antiplasm and Cl inhibitor. This inactivation was shown to be reversible. These results indicate that synthetic fibrinolytic compounds such as flufenamic acid derivatives may promote fibrinolysis by directly inactivating alpha 2- antiplasmin and Cl inhibitor.     

Managing Novel Oral Anticoagulants in Patients With Atrial Fibrillation Undergoing Device Surgery: Canadian Survey

Background

Approximately 10% of patients who undergo surgical procedures require chronic oral anticoagulation. Physicians must balance the thromboembolic and bleeding risks to make informed decisions on whether to continue anticoagulant medication. Evidence is lacking regarding the perioperative management of novel oral anticoagulant (NOAC) agents. This survey aims to describe the management of perioperative NOAC use during device implantation by Canadian centres.

Methods

A Web-based tool was used to survey all Canadian adult pacemaker/defibrillator implant centres. The survey collected data regarding the perioperative management of NOACs in atrial fibrillation patients at high risk for thromboembolism who undergo device implantation.

Results

Twenty-two centres performed approximately 14,971 device implants; 1150 (8%) of these implants were in patients who were prescribed a NOAC. In 82% of centres, the NOAC is discontinued in anticipation of device implantation; 73% of these centres do not bridge with heparin. In patients with normal renal function at high risk of thromboembolic events (Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack; CHADS₂ ≥ 2), 72% of the centres restart the NOAC within 48 hours of the procedure. For patients with abnormal renal function (glomerular filtration rate < 80 mL/min), the timing of NOAC discontinuation is variable. Hematoma rates vary from 0 to 30%.

Conclusions

Most Canadian centres perform device implantation with NOAC interruption without the use of bridging. The timing of stopping and restarting anticoagulation and incidence of bleeding complications is variable. These findings emphasize the need for randomized controlled studies to guide the optimal approach to management of NOACs during device implantation.     

Learning from preventable deaths: exploring case record reviewers' narratives using change analysis

Objective

To determine if applying change analysis to the narrative reports made by reviewers of hospital deaths increases the utility of this information in the systematic analysis of patient harm.

Design

Qualitative analysis of causes and contributory factors underlying patient harm in 52 case narratives linked to preventable deaths derived from a retrospective case record review of 1000 deaths in acute National Health Service Trusts in 2009.

Participants

52 preventable hospital deaths.

Setting

England.

Main outcome measures

The nature of problems in care and contributory factors underlying avoidable deaths in hospital.

Results

The change analysis approach enabled explicit characterisation of multiple problems in care, both across the admission and also at the boundary between primary and secondary care, and illuminated how these problems accumulate to cause harm. It demonstrated links between problems and underlying contributory factors and highlighted other threats to quality of care such as standards of end of life management. The method was straightforward to apply to multiple records and achieved good inter-rater reliability.

Conclusion

Analysis of case narratives using change analysis provided a richer picture of healthcare-related harm than the traditional approach, unpacking the nature of the problems, particularly by delineating omissions from acts of commission, thus facilitating more tailored responses to patient harm.     

MRI findings of intracranial anomalies associated with cephalocele—a case series

Introduction

Cephalocele is a relatively rare cranial dysraphism characterised by herniation of intracranial structures through the skull. Surgical management is primarily necessary where a risk of infection through communication of the lesion with the intracranial space exists, a risk of rupture, or for cosmetic purposes. Cephalocele is often associated with venous anomalies such as vertical embryonic positioning of the straight sinus, splitting of the superior sagittal sinus, vein of Galen elongation, along with tenting of the tentorium [Morioka et al. Childs Nerv Syst 25:309–315, 2009]

Patients

Here, we report four cases of cephalocele with pre-operative MRI imaging retrospectively studied, demonstrating associated venous anomalies. Three of these patients went on to have uncomplicated, corrective surgery, while one was managed conservatively.

Results

All four cases demonstrated the main venous drainage going through a persistent falcine sinus to drain into the superior sagittal sinus. Upward tenting of the tentorium was observed in three cases (cases 1, 3 and 4). Two of our cases demonstrated other venous anomalies frequently reported in the literature, namely splitting of the superior sagittal sinus and absence of the transverse sinus (case 1) and communication of the cephalocele with the superior sagittal sinus and absence of the straight sinus (case 2).

Conclusion

The association between cephalocele and venous anomalies suggests that pre-operative MRI should be mandatory for a full evaluation of a suspicious midline cranial lesion in order to evaluate the safety of corrective surgery.     

Arginine deprivation alters microglial polarity and synergizes with radiation to eradicate non-arginine-auxotrophic glioblastoma tumors

New approaches for the management of glioblastoma (GBM) are an urgent and unmet clinical need. Here, we illustrate that the efficacy of radiotherapy for GBM is strikingly potentiated by concomitant therapy with the arginine-depleting agent ADI-PEG20 in a non-arginine-auxotrophic cellular background (argininosuccinate synthetase 1 positive). Moreover, this combination led to durable and complete radiological and pathological response, with extended disease-free survival in an orthotopic immune-competent model of GBM, with no significant toxicity. ADI-PEG20 not only enhanced the cellular sensitivity of argininosuccinate synthetase 1–positive GBM to ionizing radiation by elevated production of nitric oxide (˙NO) and hence generation of cytotoxic peroxynitrites, but also promoted glioma-associated macrophage/microglial infiltration into tumors and turned their classical antiinflammatory (protumor) phenotype into a proinflammatory (antitumor) phenotype. Our results provide an effective, well-tolerated, and simple strategy to improve GBM treatment that merits consideration for early evaluation in clinical trials.     

Real-world Treatment Patterns and Reasons for Therapy Selection in Patients with Advanced Hepatocellular Carcinoma in US Oncology Practices

BackgroundThe treatment landscape for advanced hepatocellular carcinoma (aHCC) is rapidly expanding beyond tyrosine kinase inhibitors (TKIs) in the first-line (1L) setting, with multiple TKIs and immune-checkpoint inhibitors (ICIs) now being evaluated in combination. Real-world evidence describing current treatment patterns and reasons for 1L and 2L treatment selection in aHCC is sparse.Patients and MethodsA retrospective cohort study with a cross-sectional survey element was conducted using Cardinal Health’s Oncology Provider Extended Network. U.S. medical oncologists identified adult aHCC patients initiating 1L systemic therapy between January 1, 2017 and July 31, 2019 and abstracted data from patient medical records. Data included provider characteristics, patient demographics and clinical characteristics, treatment regimens, and physician rationale for treatment regimen choice.ResultsA total of 44 medical oncologists provided data on 284 aHCC patients. The median age at 1L initiation was 61.5 years, and the majority were male (78%) and white (66%). Nearly half (47%) initiated 1L treatment in 2019, 34% were ECOG performance status 2+, and 63% were Child-Pugh Class B/C. Among the 284 aHCC patients, TKIs were used by 94% of patients in the 1L setting, comprised predominantly of sorafenib (54%) and lenvatinib (38%). ICIs were most common among the 90 patients (66%) who received 2L treatment.ConclusionIn the community-oncology practice setting, nearly all aHCC patients received sorafenib or lenvatinib in the 1L setting, while the majority of patients received an ICI in the 2L setting. With recent ICI approvals in aHCC, this marks the beginning of an increased use of ICIs in the 1L setting.     

Sorafenib in Dupuytren and Ledderhose Disease

Palmar and plantar fibromatosis are benign proliferative processes which present as a diffuse thickening or nodules of the hands and/or feet and may lead to flexion contractures, pain, and functional impairment known as Dupuytren and Ledderhose diseases, respectively. Current treatments are noncurative and associated with significant morbidity. Here, we report on the outcomes of 5 patients with advanced disease, no longer surgical candidates, treated with sorafenib. Sorafenib exhibited an expected safety profile. All 5 patients demonstrated objective responses as evaluated by a decrease in tumor size and/or tumor cellularity from baseline and all 5 patients reported subjective pain relief and/or functional improvement. Mechanistically, immunohistochemistry revealed patchy positivity for PDGFRβ, a known target of sorafenib. The outcomes of these 5 patients suggest the safety and efficacy of a relatively well-tolerated oral agent in the treatment of Dupuytren and Ledderhose diseases and suggest the need for future controlled studies.