Edoxaban versus Vitamin K Antagonist for Atrial Fibrillation after TAVR.

BACKGROUND: The role of direct oral anticoagulants as compared with vitamin K antagonists for atrial fibrillation after successful transcatheter aortic-valve replacement (TAVR) has not been well studied. METHODS: We conducted a multicenter, prospective, randomized, open-label, adjudicator-masked trial comparing edoxaban with vitamin K antagonists in patients with prevalent or incident atrial fibrillation as the indication for oral anticoagulation after successful TAVR. The primary efficacy outcome was a composite of adverse events consisting of death from any cause, myocardial infarction, ischemic stroke, systemic thromboembolism, valve thrombosis, or major bleeding. The primary safety outcome was major bleeding. On the basis of a hierarchical testing plan, the primary efficacy and safety outcomes were tested sequentially for noninferiority, with noninferiority of edoxaban established if the upper boundary of the 95% confidence interval for the hazard ratio did not exceed 1.38. Superiority testing of edoxaban for efficacy would follow if noninferiority and superiority were established for major bleeding. RESULTS: A total of 1426 patients were enrolled (713 in each group). The mean age of the patients was 82.1 years, and 47.5% of the patients were women. Almost all the patients had atrial fibrillation before TAVR. The rate of the composite primary efficacy outcome was 17.3 per 100 person-years in the edoxaban group and 16.5 per 100 person-years in the vitamin K antagonist group (hazard ratio, 1.05; 95% confidence interval [CI], 0.85 to 1.31; P = 0.01 for noninferiority). Rates of major bleeding were 9.7 per 100 person-years and 7.0 per 100 person-years, respectively (hazard ratio, 1.40; 95% CI, 1.03 to 1.91; P = 0.93 for noninferiority); the difference between groups was mainly due to more gastrointestinal bleeding with edoxaban. Rates of death from any cause or stroke were 10.0 per 100 person-years in the edoxaban group and 11.7 per 100 person-years in the vitamin K antagonist group (hazard ratio, 0.85; 95% CI, 0.66 to 1.11). CONCLUSIONS: In patients with mainly prevalent atrial fibrillation who underwent successful TAVR, edoxaban was noninferior to vitamin K antagonists as determined by a hazard ratio margin of 38% for a composite primary outcome of adverse clinical events. The incidence of major bleeding was higher with edoxaban than with vitamin K antagonists. (Funded by Daiichi Sankyo; ENVISAGE-TAVI AF ClinicalTrials.gov number, NCT02943785.).

A Randomized Controlled Trial of Topical Analgesia Post-Hemorrhoidectomy (TAPH Trial).

BACKGROUND: Postoperative pain remains the greatest problem after hemorrhoidectomy. Pain is hypothesized to arise from bacterial infection, sphincter spasm, and local inflammation. OBJECTIVE: A randomized controlled factorial trial was conducted to assess the effects of metronidazole, diltiazem, and lidocaine on post-hemorrhoidectomy pain. DESIGN: A double blinded randomized controlled factorial trial. SETTINGS: A multicenter trial was conducted in Auckland, New Zealand. PATIENTS: 192 Participants were randomized (1:1:1:1) into four parallel arms. INTERVENTIONS: Participants were randomized into one of four groups receiving topical treatment with 10% metronidazole (M), 10% metronidazole + 2% diltiazem (MD), 10% metronidazole + 4% lidocaine (ML), or 10% metronidazole + 2% diltiazem + 4% lidocaine (MDL). Participants were instructed to apply to the anal verge 3 times daily for 7 days. MAIN OUTCOME MEASURES: The primary outcome was pain on the visual analogue scale on day 4. The secondary outcomes included analgesia usage, pain on bowel motion, and functional recovery index. RESULTS: There was no significant difference in the pain and recovery scores when diltiazem or lidocaine was added to metronidazole (score difference between presence and absence of D in the formulation: -3.69, 95% CI: -13.3, 5.94, p = 0.46; between presence and absence of L: -5.67, 95% CI: -15.5, 3.80, p = 0.24). The combination of MDL did not further reduce pain. Secondary analysis revealed a significant difference between the best (ML) and worst (MDL) groups in both pain and functional recovery scores. There were no significant differences in analgesic usage, complications, or return to work between the groups. No clinically important adverse events were reported. The adverse event rate did not change in the intervention groups. LIMITATIONS: Topical metronidazole was utilized in the control group, rather than a pure placebo. CONCLUSION: There was no significant difference in pain when topical diltiazem or lidocaine, or both, was added to topical metronidazole. CLINICAL TRIAL REGISTRATION IDENTIFIER: NCT04276298.

Is routine histopathological analysis of hemorrhoidectomy specimens necessary? A systematic review and meta-analysis.

BACKGROUND: Hemorrhoidectomy is a common procedure used to treat symptomatic hemorrhoids. However, the necessity and cost-effectiveness of routinely conducting histopathological analysis on excised tissue samples are uncertain. METHODS: A systematic review was conducted using MEDLINE and EMBASE up to December 2023 for studies assessing the histopathological outcomes of hemorrhoidectomy specimens. Meta-analysis was performed on articles with combinable results to determine the pooled proportions of cancer and anal intraepithelial neoplasia (AIN) using the random effects model. RESULTS: From 2974 initial search results, 12 studies were included in the review, with 48,365 resected specimens from hemorrhoidectomy. Among these, there were 11 retrospective studies and one prospective study. A meta-analysis of 11 studies revealed that the prevalence of anal cancer was low, at 0.13% (95% CI: 0.05%-0.31%). The prevalence of anal cancer and AIN combined was 1.16% (95% CI: 0.53%-2.52%). CONCLUSION: This literature review estimated the probability of malignancy detection in hemorrhoid specimens sent for histopathological evaluation. The low incidence of malignant findings implies that routine analysis of hemorrhoidectomy samples may not be cost-effective. However, existing studies have yet to establish definitive risk factors for abnormal histological diagnoses to aid in the selection of specimens for selective histopathology.

Management of edoxaban therapy and clinical outcomes in patients undergoing major or nonmajor surgery: a subanalysis of the EMIT-AF/VTE study.

BACKGROUND: Optimising periprocedural management of direct oral anticoagulation in patients with atrial fibrillation on chronic treatment undergoing major surgeries is an important aspect of balancing the risk of surgery-related bleeding with the risk of thromboembolic events, which may vary by surgery type. METHODS: This subanalysis of the prospective EMIT-AF/VTE programme assessed periprocedural-edoxaban management, according to physicians' decisions, and bleeding and thromboembolic event rates in patients who underwent major vs. nonmajor surgeries. Edoxaban interruption and clinical outcomes were compared between major vs. nonmajor surgeries and between renal function subgroups (creatinine clearance [CrCL] ≤ 50 mL/min vs. > 50 mL/min). RESULTS: We included 276 major and 512 nonmajor surgeries. The median pre- and postprocedural duration of edoxaban interruption in major vs. nonmajor surgeries was 4 vs. 1 days, whereas median duration of interruption for those with preprocedural-only and postprocedural-only interruption was 2 vs. 1 days and 2 vs. 0 days, respectively (P < 0.0001). Rates of all bleeding and clinically relevant nonmajor bleeding were numerically higher in major vs. nonmajor surgeries. Event rates (number of events per 100 surgeries) were low overall (< 6 events per 100 surgeries), independent of renal function subgroups. CONCLUSION: In this subanalysis of the EMIT-AF/VTE programme, periprocedural-edoxaban interruption was significantly longer in patients undergoing major vs. nonmajor surgery. This clinician-driven approach was associated with low rates of bleeding and thromboembolic events following both major and nonmajor surgeries. TRIAL REGISTRATION: NCT02950168, registered October 31, 2016; NCT02951039, registered November 1, 2016.

Can Targeting Sphincter Spasm Reduce Post-Haemorrhoidectomy Pain? A Systematic Review and Meta-Analysis.

BACKGROUND: Haemorrhoidectomy is often complicated by significant post-operative pain, to which spasm of the internal anal sphincter is thought to be a contributing factor. This study appraises the evidence behind interventions aimed at lowering sphincter spasm to relieve post-haemorrhoidectomy pain. METHODS: A Preferred Reporting Items for Systematic Reviews and Meta-analyses compliant systematic review was conducted. Medline, EMBASE, and CENTRAL databases were systematically searched. All RCTs which compared interventions targeting the internal anal sphincter to relieve pain post excisional haemorrhoidectomy were included. The primary outcome measure was pain on the visual analogue scale. RESULTS: Of the initial 10,221 search results, 39 articles were included in a qualitative synthesis, and 33 studies were included in a meta-analysis. Topical glyceryl trinitrate (GTN) reduced pain on day 7 (7 studies, 485 participants), with a mean difference and 95% confidence interval (MD, 95% CI) of -1.34 (-2.31; -0.37), I2 = 91%. Diltiazem reduced pain on day 3 on the VAS, and the MD was -2.75 (-398; -1.51) shown in five studies (n = 227). Botulinum toxin reduced pain on day 7, in four studies with 178 participants, MD -1.43 (-2.50; -0.35) I2 = 62%. The addition of Lateral Internal Sphincterotomy to haemorrhoidectomy reduced pain on day 2 in three studies with 275 participants, MD of -2.13 (-3.49; -0.77) I2 = 92%. The results were limited by high heterogeneity and risk of bias. CONCLUSION: Evidence suggests that lateral sphincterotomy, administration of botulinum toxin and the application of topical diltiazem or GTN can reduce post-operative pain after haemorrhoidectomy. Lateral sphincterotomy should not be routinely used due to the risk of incontinence.

Detection of Anastomotic Leakage Following Elective Colonic Surgery: Results of the Prospective Biomarkers and Anastomotic Leakage (BALL) Study.

BACKGROUND: Anastomotic leakage (AL) is an infrequent but life-threatening surgical complication following colorectal surgery. Early diagnosis remains clinically difficult but is a necessity to reduce associated morbidity and mortality. Clinical review and radiological modalities for the diagnosis of leakage remain non-specific and often only detect AL once it is well developed. Inflammatory biomarkers however have shown promise in early pre-clinical detection of leakage following colorectal surgery. METHODS: A multi-center, prospective observational study was conducted across four public hospitals in Auckland and Christchurch, New Zealand. Consecutive adults undergoing elective colectomy were initially recruited over a 3-y period. Perioperative blood samples were collected to measure interleukin (IL)-6, IL-1ß, tumor necrosis factor α, IL-10, C-reactive protein (CRP), leukocyte and neutrophil counts. Statistical analysis was performed to compare patients with an uncomplicated recovery with patients with AL. RESULTS: Sixteen patients developed AL (5.7%), diagnosed at a median post-operative (POD) day 7. CRP and IL-6 were consistently elevated in the early post-operative period in patients with AL, and had the best diagnostic accuracy on POD 3 (area under the curve 0.70; P = 0.02) and POD 1 (area under the curve 0.69; P = 0.02), respectively. IL-10, once adjusted for body mass index and surgical approach, was the sole biomarker significantly elevated in patients with AL on POD 4. CONCLUSIONS: Early post-operative elevations of CRP and IL-6 provide utility for early detection of AL after elective colectomy. Application of these inflammatory biomarkers and their combinations in daily practice warrants further investigation.

Edoxaban vs. Vitamin K Antagonist for Atrial Fibrillation After Transcatheter Aortic Valve Replacement in Japanese Patients　- A Subanalysis of the ENVISAGE-TAVI AF Trial.

BACKGROUND: Japanese patients undergoing transcatheter aortic valve replacement (TAVR) are often female and have a small body size, potentially impacting bleeding risk with antithrombotic therapy. Outcomes of direct oral anticoagulant use in these patients with atrial fibrillation (AF) need to be clarified.Methods and Results: This prespecified analysis included Japanese patients from ENVISAGE-TAVI AF, a prospective, randomized, open-label, adjudicator-masked trial that compared treatment with edoxaban and vitamin K antagonists (VKAs) in patients with AF after TAVR. The primary efficacy and safety outcomes were net adverse clinical events (NACE; composite of all-cause death, myocardial infarction, ischemic stroke, systemic embolic event, valve thrombosis, and International Society on Thrombosis and Haemostasis [ISTH]-defined major bleeding) and ISTH-defined major bleeding, respectively. Intention-to-treat (ITT) and on-treatment analyses were performed. Overall, 159 Japanese patients were enrolled (edoxaban group: 82, VKA group: 77) and followed for on average 483 days. Mean patient age was 83.8 years; 52.2% were female. In the ITT analysis, NACE rates were 10.9%/year with edoxaban and 12.5%/year with VKA (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.38-1.90); major bleeding occurred in 8.9%/year and 7.3%/year, respectively (HR, 1.17; 95% CI, 0.45-3.05). In edoxaban- and VKA-treated patients, rates of ischemic stroke were 1.8%/year and 1.0%/year, respectively; fatal bleeding rates were 0.9%/year and 2.0 %/year. On-treatment results were similar to ITT. CONCLUSIONS: In Japanese patients with AF after successful TAVR, edoxaban and VKA treatment have similar safety and efficacy profiles.

A systematic review and meta-analysis of the efficacy of topical sphincterotomy treatments for anal fissure.

BACKGROUND: Anal fissure is a common condition that can be treated medically or surgically. Chemical sphincterotomy is often used before surgical intervention. This study aims to evaluate the effectiveness of topical agents for chemical sphincterotomy on healing of anal fissures and side-effects. METHODS: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) compliant systematic review was performed using MEDLINE, EMBASE, Scopus, and CENTRAL databases. Eligible studies included randomized controlled trials which compared topical sphincterotomy agents with topical placebo agents or each other. Studies that included surgical treatments were excluded. Overall evidence was synthesized according to the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. RESULTS: Thirty-seven studies met the study selection criteria. Seventeen studies show that glyceryl trinitrate (GTN) was significantly more likely to heal anal fissure than placebo (relative risk (RR) = 1.96, 95% confidence interval (95%CI) = 1.35-2.84, I2 = 80%). Eleven studies showed a marginally significant difference between healing rates for diltiazem vs GTN, RR = 1.16, (1.01-1.33) I2 = 48%. There was no significant difference in healing between diltiazem and placebo, RR = 1.65, (0.64-4.23), I2 = 92%. GTN significantly reduced pain on the visual analog scale compared to the placebo group, MD-0.97 (-1.64 to -0.29) I2 = 92%. There was high certainty of evidence that GTN was significantly more likely to cause headache than placebo (RR = 2.73 (1.82-4.10) I2 = 58%) and diltiazem RR = 6.88 (2.19-21.63) I2 = 17%. CONCLUSION: There is low certainty evidence topical nitrates are an effective treatment for anal fissure healing and pain reduction compared to placebo. Despite widespread use of topical diltiazem, more evidence is required to establish the effectiveness of calcium channel blockers compared to placebo.

Thromboembolic and bleeding risks in edoxaban patients with pacemaker and cardiac monitoring procedures: Outcomes of the Global EMIT program.

INTRODUCTION: Limited data were published on the management of direct oral anticoagulants in the insertion of pacemaker and cardiac monitoring devices. This study describes the management and outcomes of edoxaban, a direct oral factor Xa inhibitor, in patients undergoing pacemaker or monitoring device implantation in routine clinical practice. METHODS AND RESULTS: EMIT-AF/VTE collected data of patients from Europe, Korea, and Taiwan. Timing and duration of periprocedural interruption of edoxaban were at the treating physician's discretion. Pacemakers or monitoring devices were implanted into 136 patients who were evaluated from 5 days pre- until 30 days post-procedure. The primary outcomes were the incidences of acute thromboembolic events (ATE), ischemic events, and International Society on Thrombosis and Haemostasis-defined Major Bleeding; secondary outcomes included incidence of clinically relevant non-major bleeding (CRNMB) and perioperative edoxaban interruption times. Conformance with European Heart Rhythm Association (EHRA) Guidance on interruption of direct oral anticoagulant therapy was variable: of the cardiac monitoring device patients, where no interruption of therapy would be expected, nonetheless, 62.5% had interruption of treatment, whereas in pacemaker procedures, where interruption would be expected, 23.4% had no interruption. No ATE or ischemic events occurred. One case of CRNMB and two of minor bleeding occurred. All bleedings occurred more than 3 days after the procedure. CONCLUSION/RELEVANCE: The periprocedural complication risk for edoxaban treated patients undergoing pacemaker or invasive cardiac monitoring implantation was low. This population of patients was well managed in routine practice.

Epidemiology of haemorrhoids and publicly funded excisional haemorrhoidectomies in New Zealand (2007-2016): a population-based cross-sectional study.

AIM: Haemorrhoids are frequently encountered by the general or colorectal surgeon. Although a benign disease, those with symptomatic, advanced grades frequently require excisional haemorrhoidectomy for definitive management. Despite their widespread nature, the epidemiological burden of haemorrhoids and haemorrhoidectomies on populations is not well described. This study seeks to establish the incidence of both haemorrhoids diagnosed and haemorrhoidectomies performed in New Zealand. METHOD: This is a population-based cross-sectional study examining the incidence of all patients who were newly diagnosed with haemorrhoids in New Zealand public hospital outpatient clinics and those who received excisional haemorrhoidectomy in New Zealand public hospitals from 2007 to 2016. Data were extracted and linked using the New Zealand National Minimum Dataset and the National Non-Admitted Patient Collection. Variables collected included age group, sex, ethnicity and geographical location. RESULTS: A total of 46 095 recorded diagnoses of haemorrhoids were made, with a total of 18 739 haemorrhoidectomies in the 10-year period recorded. The incidence rate of diagnosis increased from 84.6 to 120.5 per 100 000 and the incidence rate of haemorrhoidectomies performed from 30.4 to 51.1 per 100 000, a significantly increased annual incidence. There was a unimodal peak prevalence in the fifth decade of life with women more affected. Europeans formed the largest group affected, with Asians showing the highest rate of increased incidence. CONCLUSION: There is an increasing incidence of patients with symptomatic haemorrhoids presenting to the New Zealand public healthcare system, with a preponderance in working age adults, especially women.

The Impact of Quality Improvement Interventions in Improving Surgical Infections and Mortality in Low and Middle-Income Countries: A Systematic Review and Meta-Analysis.

BACKGROUND: Morbidity and mortality in surgical systems in low- and middle-income countries (LMICs) remain high compared to high-income countries. Quality improvement processes, interventions, and structure are essential in the effort to improve peri-operative outcomes. METHODS: A systematic review and meta-analysis of interventional studies assessing quality improvement processes, interventions, and structure in developing country surgical systems was conducted according to the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies were included if they were conducted in an LMIC, occurred in a surgical setting, and measured the effect of an implementation and its impact. The primary outcome was mortality, and secondary outcomes were rates of rates of hospital-acquired infection (HAI) and surgical site infections (SSI). Prospero Registration: CRD42020171542. RESULT: Of 38,273 search results, 31 studies were included in a qualitative synthesis, and 28 articles were included in a meta-analysis. Implementation of multimodal bundled interventions reduced the incidence of HAI by a relative risk (RR) of 0.39 (95%CI 0.26 to 0.59), the effect of hand hygiene interventions on HAIs showed a non-significant effect of RR of 0.69 (0.46-1.05). The WHO Safe Surgery Checklist reduced mortality by RR 0.68 (0.49 to 0.95) and SSI by RR 0.50 (0.33 to 0.63) and antimicrobial stewardship interventions reduced SSI by RR 0.67 (0.48-0.93). CONCLUSION: There is evidence that a number of quality improvement processes, interventions and structural changes can improve mortality, HAI and SSI outcomes in the peri-operative setting in LMICs.

Effectiveness of Quality Improvement Processes, Interventions, and Structure in Trauma Systems in Low- and Middle-Income Countries: A Systematic Review and Meta-analysis.

BACKGROUND: Trauma mortality in low- and middle-income countries (LMICs) remains high compared to high-income countries. Quality improvement processes, interventions, and structure are essential in the effort to decrease trauma mortality. METHODS: A systematic review and meta-analysis of interventional studies assessing quality improvement processes, interventions, and structure in developing country trauma systems was conducted from November 1989 to August 2020 according to the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies were included if they were conducted in an LMIC population according to World Bank Income Classification, occurred in a trauma setting, and measured the effect of implementation and its impact. The primary outcome was trauma mortality. RESULTS: Of 37,575 search results, 30 studies were included from 15 LMICs covering five WHO regions in a qualitative synthesis. Twenty-seven articles were included in a meta-analysis. Implementing a pre-hospital trauma system reduced overall trauma mortality by 45% (risk ratio (RR) 0.55, 95% CI 0.4 to 0.75). Training first responders resulted in an overall decrease in mortality (RR 0.47, 95% CI 0.28 to 0.78). In-hospital trauma training with certified courses resulted in a reduction of mortality (RR 0.71, 95% CI 0.62 to 0.78). Trauma audits and trauma protocols resulted in varying improvements in trauma mortality. CONCLUSION: There is evidence that quality improvement processes, interventions, and structure can improve mortality in the trauma systems in LMICs.

Comparing TEE- vs Non-TEE-guided cardioversion of atrial fibrillation: The ENSURE-AF trial.

BACKGROUND: ENSURE-AF (NCT02072434) assessed therapy with edoxaban vs enoxaparin-warfarin in patients with nonvalvular atrial fibrillation (AF) undergoing elective electrical cardioversion (ECV). OBJECTIVES: To evaluate clinical features and primary efficacy (composite of stroke, systemic embolic events, myocardial infarction and cardiovascular mortality during study period) and safety endpoints (composite of major and clinically relevant nonmajor bleeding during on-treatment period) in patients awaiting ECV of AF with a transesophageal echocardiography (TEE)-guided vs a non-TEE-guided strategy. METHODS: In this prospective, randomized, open-label, blinded endpoint study, 2199 patients were randomized to edoxaban 60 mg once-daily (30 mg for creatinine clearance 15-50 mL/min, weight ≤60 kg and/or concomitant use of P-glycoprotein inhibitor) or enoxaparin-warfarin. Primary efficacy endpoint and safety endpoint were reported. Associates of TEE use, efficacy endpoint and safety endpoint were explored using multivariable logistic regression. RESULTS: In total, 589 patients from the edoxaban stratum and 594 from the enoxaparin-warfarin stratum were allocated to the TEE-guided strategy. Primary efficacy was similar regardless of TEE approach (P = .575). There were no significant differences in bleeding rates, regardless of TEE approach (P = .677). Independent predictors of TEE use were as follows: history of ischaemic stroke/ transient ischaemic attack, hypertension and valvular heart disease. Mean CHA2 DS2 VASc and HAS-BLED score were independent predictors of the efficacy endpoint whilst mean age was an independent predictor of the safety endpoint. CONCLUSIONS: Thromboembolic and bleeding events were not different between patients undergoing TEE-guided strategy and in those undergoing an optimized conventional anticoagulation approach for ECV of AF.

Determinants of left atrium thrombi in scheduled cardioversion: an ENSURE-AF study analysis.

AIMS: ENSURE-AF (NCT02072434) was the largest prospective randomized clinical trial of anticoagulation for cardioversion in atrial fibrillation (AF), which also provides the largest prospective dataset for transoesophageal echocardiography (TOE) prior to cardioversion. This ancillary analysis investigated determinants of TOE-detected left atrium thrombi (LAT) in patients scheduled for electrical cardioversion (ECV). METHODS AND RESULTS: The ENSURE-AF multicentre PROBE evaluation trial compared edoxaban 60 mg once daily (QD) with enoxaparin/warfarin in 2199 subjects undergoing ECV of non-valvular AF. Patients were stratified by the use of TOE, anticoagulant experience, and selected edoxaban dose. Electrical cardioversion was cancelled or deferred when TOEdetected LAT. In total, 1183 subjects were stratified to the TOE arm and LAT was reported in 91 (8.2%). In univariate analysis, age ≥75 years (26.4% vs. 16.9%, P = 0.0308), lower weight (86.5 ± 15.0 vs. 90.7 ± 18.0 kg, P = 0.0309), lower creatinine clearance (80.1 ± 30.6 vs. 93.2 ± 33.9 mL/min, P = 0.0007), heart failure (59.3% vs. 43.0%, P = 0.0029), and diuretic treatment (53.9% vs. 40.1%, P = 0.0141) were more prevalent in the LAT group. Non-significant trends were seen for higher mean CHA2DS2-VASc score (3.0 ± 1.41 vs. 2.7 ± 1.48, P = 0.0571) and more prevalent anticoagulation use prior to enrolment (60.4% vs. 50.3%, P = 0.0795) in the LAT group. In logistic regression analysis, age (P = 0.0202) and heart failure (P = 0.0064) were independently associated with LAT. CONCLUSION: Elective ECV is commonly cancelled or deferred due to TOE-detected LAT in patients with non-valvular AF. Age ≥75 years and heart failure were associated with the presence of LAT.

Reduced cell surface levels of GPI-linked markers in a new case with PIGG loss of function.

Glycosylphosphatidylinositol (GPI) is a glycolipid that tethers more than 150 different proteins to the cell surface. Aberrations in biosynthesis of GPI anchors cause congenital disorders of glycosylation with clinical features including intellectual disability (ID), seizures, and facial dysmorphism. Here, we present two siblings with ID, cerebellar hypoplasia, cerebellar ataxia, early-onset seizures, and minor facial dysmorphology. Using exome sequencing, we identified a homozygous nonsense variant (NM_001127178.1:c.1640G>A, p.Trp547*) in the gene Phosphatidylinositol Glycan Anchor Biosynthesis, Class G (PIGG) in both the patients. Variants in several other GPI anchor synthesis genes lead to a reduced expression of GPI-anchored proteins (GPI-APs) that can be measured by flow cytometry. No significant differences in GPI-APs could be detected in patient granulocytes, consistent with recent findings. However, fibroblasts showed a reduced global level of GPI anchors and of specific GPI-linked markers. These findings suggest that fibroblasts might be more sensitive to pathogenic variants in GPI synthesis pathway and are well suited to screen for GPI-anchor deficiencies. Based on genetic and functional evidence, we confirm that pathogenic variants in PIGG cause an ID syndrome, and we find that loss of function of PIGG is associated with GPI deficiency.

Edoxaban versus enoxaparin-warfarin in patients undergoing cardioversion of atrial fibrillation (ENSURE-AF): a randomised, open-label, phase 3b trial.

BACKGROUND: Edoxaban, an oral factor Xa inhibitor, is non-inferior for prevention of stroke and systemic embolism in patients with atrial fibrillation and is associated with less bleeding than well controlled warfarin therapy. Few safety data about edoxaban in patients undergoing electrical cardioversion are available. METHODS: We did a multicentre, prospective, randomised, open-label, blinded-endpoint evaluation trial in 19 countries with 239 sites comparing edoxaban 60 mg per day with enoxaparin-warfarin in patients undergoing electrical cardioversion of non-valvular atrial fibrillation. The dose of edoxaban was reduced to 30 mg per day if one or more factors (creatinine clearance 15-50 mL/min, low bodyweight [≤60 kg], or concomitant use of P-glycoprotein inhibitors) were present. Block randomisation (block size four)-stratified by cardioversion approach (transoesophageal echocardiography [TEE] or not), anticoagulant experience, selected edoxaban dose, and region-was done through a voice-web system. The primary efficacy endpoint was a composite of stroke, systemic embolic event, myocardial infarction, and cardiovascular mortality, analysed by intention to treat. The primary safety endpoint was major and clinically relevant non-major (CRNM) bleeding in patients who received at least one dose of study drug. Follow-up was 28 days on study drug after cardioversion plus 30 days to assess safety. This trial is registered with ClinicalTrials.gov, number NCT02072434. FINDINGS: Between March 25, 2014, and Oct 28, 2015, 2199 patients were enrolled and randomly assigned to receive edoxaban (n=1095) or enoxaparin-warfarin (n=1104). The mean age was 64 years (SD 10·54) and mean CHA2DS2-VASc score was 2·6 (SD 1·4). Mean time in therapeutic range on warfarin was 70·8% (SD 27·4). The primary efficacy endpoint occurred in five (<1%) patients in the edoxaban group versus 11 (1%) in the enoxaparin-warfarin group (odds ratio [OR] 0·46, 95% CI 0·12-1·43). The primary safety endpoint occurred in 16 (1%) of 1067 patients given edoxaban versus 11 (1%) of 1082 patients given enoxaparin-warfarin (OR 1·48, 95% CI 0·64-3·55). The results were independent of the TEE-guided strategy and anticoagulation status. INTERPRETATION: ENSURE-AF is the largest prospective randomised clinical trial of anticoagulation for cardioversion of patients with non-valvular atrial fibrillation. Rates of major and CRNM bleeding and thromboembolism were low in the two treatment groups. FUNDING: Daiichi Sankyo provided financial support for the study.

A prospective evaluation of edoxaban compared to warfarin in subjects undergoing cardioversion of atrial fibrillation: The EdoxabaN vs. warfarin in subjectS UndeRgoing cardiovErsion of Atrial Fibrillation (ENSURE-AF) study.

We designed a prospective, randomized, open-label, blinded end point evaluation parallel group Phase 3b clinical trial comparing edoxaban (a new oral factor Xa inhibitor) with enoxaparin/warfarin followed by warfarin alone in subjects undergoing planned electrical cardioversion of non-valvular atrial fibrillation. The primary efficacy end point is the composite end points of stroke, systemic embolic event, myocardial infarction, and cardiovascular (CV) mortality, from randomization until the end of follow-up (day 56 post cardioversion). The primary safety end point is the composite of major and clinically-relevant non-major bleeding, from the first administration of study drug to end of treatment (Day 28 post cardioversion) +3 days. The primary efficacy analysis will be conducted on the intention-to-treat population whereas the primary safety analysis, on the safety population. The study includes stratification on the following levels: (i) approach to cardioversion (transoesophagel echocardiography or non-transoesophagel echocardiography) as determined by the Investigator; (ii) subject's experience in taking anticoagulants at the time of randomization (anticoagulant-experienced or anticoagulant-naïve); and (iii) assigned edoxaban dose (full 60 mg QD or reduced 30 mg dose QD). A subject with one or more factors (CrCl ≥15 mL/min and ≤50 mL/min, low body weight [≤60 kg], and concomitant use of p-pg inhibitors (excluding amiodarone) will receive a reduced dose (30 mg) of edoxaban if the subject is randomized to the edoxaban group. ENSURE-AF will be the largest prospective randomised trial of anticoagulation for cardioversion, also involving a Non-VKA Oral Anticoagulant-edoxaban.