Application of the Win Ratio Method in the ENGAGE AF-TIMI 48 Trial Comparing Edoxaban With Warfarin in Patients With Atrial Fibrillation.

BACKGROUND: Cardiovascular trials often use a composite end point and a time-to-first event model. We sought to compare edoxaban versus warfarin using the win ratio, which offers data complementary to time-to-first event analysis, emphasizing the most severe clinical events. METHODS: ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a double-blind, randomized trial in which patients with atrial fibrillation were assigned 1:1:1 to a higher dose edoxaban regimen (60/30 mg daily), a lower dose edoxaban regimen (30/15 mg daily), or warfarin. In an exploratory analysis, we analyzed the trial outcomes using an unmatched win ratio approach. The win ratio for each edoxaban regimen was the total number of edoxaban wins divided by the number of warfarin wins for the following ranked clinical outcomes: 1: death; 2: hemorrhagic stroke; 3: ischemic stroke/systemic embolic event/epidural or subdural bleeding; 4: noncerebral International Society on Thrombosis and Haemostasis major bleeding; and 5: cardiovascular hospitalization. RESULTS: 21 105 patients were randomized to higher dose edoxaban regimen (N=7035), lower dose edoxaban regimen (N=7034), or warfarin (N=7046), yielding >49 million pairs for each treatment comparison. The median age was 72 years, 38% were women, and 59% had prior vitamin K antagonist use. The win ratio was 1.11 (95% CI, 1.05-1.18) for higher dose edoxaban regimen versus warfarin and 1.11 (95% CI, 1.05-1.18) for lower dose edoxaban regimen versus warfarin. The favorable impacts of edoxaban on death (34% of wins) and cardiovascular hospitalization (41% of wins) were the major contributors to the win ratio. Results consistently favored edoxaban in subgroups based on creatine clearance and dose reduction at baseline, with heightened benefit among those without prior vitamin K antagonist use. CONCLUSIONS: In a win ratio analysis of the ENGAGE AF-TIMI 48 trial, both dose regimens of edoxaban were superior to warfarin for the net clinical outcome incorporating ischemic and bleeding events. As the win ratio emphasizes the most severe clinical events, this analysis supports the superiority of edoxaban over warfarin in patients with atrial fibrillation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00781391.

Educational intervention to adopt selective laser trabeculoplasty as first-line glaucoma treatment: Randomized controlled trial: Educational intervention on selective laser trabeculoplasty.

PURPOSE: To determine the efficacy of an educational intervention on patient adoption and attitudes toward selective laser trabeculoplasty (SLT) as first-line treatment for glaucoma. METHODS: This study is a randomized controlled trial. Subjects include 33 patients within 1-year diagnosis of either primary open-angle glaucoma, ocular hypertension, or pseudoexfoliation syndrome. After informed consent, subjects were randomly assigned to a Usual Care or Educational Intervention group. All subjects completed a pre-intervention questionnaire. The Educational Intervention group was shown a slideshow presentation and a 3-min video and given a post-intervention questionnaire. Follow-up examinations were reviewed for 6 months to determine subject completion of SLT, the primary outcome. Secondary outcomes include assessment of attitude toward SLT before and after intervention. RESULTS: Age, gender, and baseline characteristics between the groups did not differ. The Usual Care group had a higher proportion of African Americans (77% vs 31%, p = 0.04). At 6 months following the intervention, 63% of subjects underwent SLT compared to 35% of Usual Care subjects (p = 0.12). Older age was associated with decreased SLT uptake (OR 0.90, 95% CI 0.82-0.99, p = 0.03). Prior to the intervention, there were no differences in attitudes of both groups regarding SLT therapy. Nineteen percent of Educational Intervention subjects changed positively toward SLT (p = 0.08) and 50% scheduled an SLT appointment after intervention (p = 0.005). CONCLUSIONS: A slideshow and video-based educational intervention may positively enhance patient adoption of SLT.Clinical trial registration name, number, URL: Educational Intervention to Adopt SLT as First-Line Glaucoma Treatment, NCT03365778, https://clinicaltrials.gov/ct2/show/NCT03365778.

Falsely high rebound tonometry.

BACKGROUND: Rebound tonometry (RBT) can be used to measure intraocular pressure (IOP) in children unable to tolerate measurement with applanation tonometry (AT) while awake. RBT readings are often 2-3 mm Hg higher than AT. We have experienced children with a repeatedly higher difference between RBT and AT measurements (≥6 mm Hg). The purpose of this study was to identify demographic and ocular characteristics that contribute to this artifactuous discrepancy. METHODS: The medical records of pediatric patients with IOP measured by RBT followed by AT within 6 months without intervening surgery or change in medical management were retrospectively reviewed to identify potential predictors of greater difference between RBT and AT readings. RESULTS: A total of 123 eyes of 65 patients were included. In patients with normal IOP (≤24 mm Hg), 18.5% had a ≥6 mm Hg difference between RBT and AT, with RBT being higher. Risk factors for this included presence of persistent fetal vasculature (PFV), increased corneal diameter, and higher initial RBT value (>20). In patients with elevated IOP (>24 mm Hg), 77% had ≥6 mm Hg difference, with larger corneal diameter being the sole predictor. Eyes were less likely to have significant RBT-AT difference if there was corneal opacity or iris abnormalities in eyes with elevated IOP (>24 mm Hg). CONCLUSIONS: In some children, RBT readings are ≥ 6 mm Hg higher than AT readings. Caution should be taken when interpreting RBT values in patients with PFV, increased corneal diameter, and higher initial RBT values.

Edoxaban versus warfarin in patients with atrial fibrillation in relation to the risk of stroke: A secondary analysis of the ENGAGE AF-TIMI 48 study.

INTRODUCTION: The efficacy and safety of the oral factor Xa inhibitor edoxaban compared to warfarin stratified by CHA2DS2VASc scores have not been described. METHODS: The ENGAGE AF-TIMI 48 trial randomized patients with atrial fibrillation to once-daily edoxaban or warfarin. We classified patients based on CHA2DS2VASc score and compared pharmacokinetics (edoxaban concentration), pharmacodynamics (anti-factor Xa [FXa] with edoxaban, time-in-therapeutic range for warfarin), efficacy (stroke or systemic embolism [SSE]), safety (major bleeding [MB], intracranial hemorrhage), and cardiovascular mortality, for the approved edoxaban regimen vs warfarin. RESULTS: The distribution CHA2DS2VASc score were:≤3, N = 4159 (29.6%); 4, N = 4066 (28.9%); 5, N = 3165 (22.5%); and ≥6, N = 2681 (19.1%). Increasing rates of SSE (1.05 to 2.99%/year) and MB (2.27 to 4.66%/year) were observed in the warfarin arm as the CHA2DS2VASc score increased. The hazard ratios per unit increase of CHA2DS2VASc score were 1.29 (1.21-1.38) and 1.26 (1.17-1.36) for SSE, and 1.20 (1.13-1.27) and 1.19 (1.12-1.27) for MB, with warfarin and edoxaban, respectively. Time-in-therapeutic range in warfarin-treated patients was similar and high (median 68%-69%) across CHA2DS2VASc scores, whereas edoxaban trough concentration, exogenous anti-FXa activity and %inhibition of endogenous FXa were higher at increasing CHA2DS2VASc scores. Edoxaban reduced SSE, MB, intracranial hemorrhage, and cardiovascular mortality vs warfarin to a similar degree across the range of CHA2DS2VASc scores (P-int = 0.90, 0.96, 0.21, and 0.37, respectively). Because of higher event rates the number of events prevented with edoxaban tended to be greater in patients with higher CHA2DS2VASc scores. CONCLUSION: The benefit and safety of edoxaban versus warfarin is maintained across CHA2DS2VASc scores. While the relative risk reductions remain similar, edoxaban provides incrementally larger absolute reductions in outcomes over warfarin in patients with higher CHA2DS2VASc scores.

Immunohistochemical Profiling of Conjunctival Melanocytic Intraepithelial Lesions, Including SOX10, HMB45, Ki67, and P16.

PURPOSE: To determine the usefulness of melan-A, SOX10, HMB45, and p16 immunohistochemical stains in the distinction between the low-grade and high-grade conjunctival melanocytic intraepithelial lesions, either independently or as components of an immunohistochemical panel. DESIGN: Retrospective observational case series. METHODS: Institutional pathology records between 2014 and 2018 were searched for all patients with conjunctival melanocytic intraepithelial lesions. Biopsies without supporting clinical history or tissue available for review and immunohistochemical analysis were excluded. Clinical, histopathologic, and immunohistochemical (p16, SOX10, HMB45, and Ki-67) findings were recorded. RESULTS: Thirty-one patients underwent 47 biopsies for conjunctival melanocytic lesions between 2014 and 2018. Pathologic diagnoses were low-grade conjunctival melanocytic intraepithelial lesion (n = 18, 38%) and high-grade conjunctival melanocytic intraepithelial lesion/melanoma in situ (n = 29, 62%). The addition of melan-A and SOX10 immunohistochemical stains resulted in an upgrade of conjunctival melanocytic intraepithelial lesion from low-grade to high-grade in 2 (4%) of 47 cases. The addition of melan-A and SOX10 immunohistochemical stains did not downgrade any of the histomorphologically high-grade lesions. In a clinical-pathologic multivariable model, the parameters most predictive of high-grade melanocytic intraepithelial lesion/melanoma in situ were involvement of the caruncle (odds ratio [OR] = 19, confidence interval [CI] 1.6-212; P = .02] and p16 cytoplasmic H-score >30 (OR = 81, CI 2.7 to >999; P = .01) CONCLUSION: Although the stains for melanocytic markers melan-A and SOX10 facilitate assessment of melanocytic intraepithelial lesions, the current immunohistochemical panels have limited value in distinction between the low-grade and high-grade intraepithelial melanocytic proliferations and need to be used judiciously.

Predictors of Success in Selective Laser Trabeculoplasty.

PURPOSE: Selective laser trabeculoplasty (SLT) is a common procedure to lower intraocular pressure (IOP) in patients with glaucoma. However, reports are conflicting regarding what factors contribute to SLT success. The purpose of this study was to determine predictors of SLT success. DESIGN: Retrospective case series. PARTICIPANTS: All patients treated with SLT between January 1, 2012, and June 30, 2018. METHODS: Baseline, demographic, procedural, and ophthalmic examination data were recorded at the time of first SLT treatment. Intraocular pressure and medication data were recorded at all follow-up visits. MAIN OUTCOME MEASURES: Selective laser trabeculoplasty success was defined as IOP decrease of 20% or more from baseline at the 3-month, 6-month, and 12-month follow-up visits. Eyes were considered to have failed and were censored when additional SLT or glaucoma surgery was performed. Patients were excluded if they had less than 3 months of follow-up. RESULTS: A total of 997 eyes from 677 patients were included in the study. Mean age was 70.2±11.5 years. Selective laser trabeculoplasty success was achieved in 227 eyes (22.8%), whereas 770 eyes (77.2%) did not meet success criteria. Intraocular pressure before SLT was 21.9±5.2 mmHg while taking 2.0±1.2 medications in eyes with successful SLT, compared with 19.0±5.0 mmHg (P < 0.0001) while taking 2.1±1.3 medications (P = 0.52) in eyes with SLT failure. At the 1-year follow-up, mean IOP in eyes with SLT success was 14.7±3.2 mmHg with 2.0±1.2 medications, compared with 16.3±4.7 mmHg (P = 0.008) with a mean of 1.9±1.3 medications (P = 0.37) in eyes with SLT failure. Eyes with SLT success more often showed greater angle pigment (P = 0.03). Age, glaucoma severity, total SLT power, type of glaucoma, severity of glaucoma, visual field mean defect, and retinal nerve fiber layer thickness were not found to correlate with success. No difference was found between the rate of success based on treatments before SLT, whether surgical or medical. CONCLUSIONS: In this large cohort of eyes undergoing SLT, greater IOP and angle pigment before SLT correlated positively with SLT success. Age, total SLT power, severity of glaucoma, and prior treatments were not associated with SLT success or failure.

Conjunctival nevi and melanoma: multiparametric immunohistochemical analysis, including p16, SOX10, HMB45, and Ki-67.

The role of p16 in the diagnosis and prognosis of conjunctival melanocytic lesions in the context of other clinical and immunohistochemical parameters has not been systematically explored. This study was conducted to determine whether p16 is a useful parameter in the diagnosis and prognosis of conjunctival melanocytic nevi and melanoma, either independently or as a component of immunohistochemical panels. Sixty-one patients underwent 61 biopsies for conjunctival melanocytic lesions between 2014 and 2018. Pathologic diagnoses were melanoma (n = 25, 41%), nevus (n = 21, 34%), and conjunctival melanocytic lesion of uncertain malignant potential (n = 15, 25%). The biopsies were assessed for expression of p16, SOX10, HMB45, and Ki-67. In a multivariable model, the parameters most predictive of melanoma versus nevus were diffuse HMB45 staining (odds ratio [OR] = 45, confidence interval [CI] = 4.4-457, P = .02] and p16 nuclear H-score≤115 (OR = 9.5, CI = 1.2-77; P = .04). There was no association of p16 expression with melanoma thickness. Next-generation sequencing identified no CDKN2A mutations or copy number alterations in 12 conjunctival melanomas, including the tumors with absent p16 expression. This study demonstrates that p16 immunohistochemical stain is useful in distinguishing conjunctival melanocytic nevi from melanoma, particularly in combination with HMB45. P16 expression does not appear to correlate with CDKN2A status and melanoma thickness.

Outcomes of Ahmed Glaucoma Valve Implantation With Viscoelastic Fill at Both Beginning and End of Surgery.

PRéCIS:: Intracameral injection of viscoelastic at the beginning of Ahmed FP7 implantation did not reduce early postoperative complication rates. PURPOSE: To evaluate early postoperative complication rates after a modified technique in which the anterior chamber (AC) is filled with viscoelastic at the beginning of Ahmed FP7 implantation before conjunctival peritomy. SUBJECTS AND METHODS: A retrospective chart review was performed of eyes that underwent Ahmed FP7 implantation with or without viscoelastic fill to ~20 mm Hg by finger tension by a single surgeon (M.R.M). Viscoelastic prevented the AC from becoming shallow at any time during surgery, and additional viscoelastic was injected into the AC at the end of surgery to achieve a final intraocular pressure (IOP) of 20 mm Hg. RESULTS: A total of 159 eyes of 159 patients were included. Mean age was 76.4±10.4 years. Mean preoperative IOP was 30.3±9.7 mm Hg on 2.7±1.2 glaucoma medications. On postoperative day 1, there was an IOP spike ≥30 mm Hg in 0% of patients. Within the first postoperative month, hypotony (<5 mm Hg) occurred in 19 (21.8%) eyes that received viscoelastic fill compared with 5 (13.2%) eyes that did not receive viscoelastic fill (P=0.26). During the early postoperative period (≤3 mo), there was no difference in AC depth, microhyphema, choroidal effusion, or leakage between the 2 groups (P≥0.30 for all). There was a higher rate of layered hyphemas in the viscoelastic-fill group at postoperative week 1 (P=0.01). At 3-month follow-up, mean IOP was 14.9±5.5 mm Hg on 1.6±0.8 medications in the viscoelastic-fill group and 16.0±5.2 mm Hg on 1.0±1.2 medications in the nonviscoelastic-fill group (IOP P=0.35). Compared with baseline, change in IOP at 3 months was similar between both groups (P=0.15). Rates of additional medications and procedures did not differ between the 2 groups at any postoperative visit. CONCLUSIONS: Early intracameral injection of viscoelastic during Ahmed glaucoma valve implantation did not reduce early postoperative complication rates.

Nomogram for visual acuity outcome after iodine-125 plaque radiotherapy and prophylactic intravitreal bevacizumab for uveal melanoma in 1131 patients.

AIMS: To develop a nomogram for prediction of visual acuity outcome following plaque radiotherapy for uveal melanoma. METHODS: Retrospective review of uveal melanoma treated with plaque radiotherapy and prophylactic intravitreal bevacizumab injections at 4-month intervals for 2 years duration. Two nomograms for poor visual acuity outcome (Snellen <20/200) were developed based on (1) Clinical risk factors. (2) Or clinical and treatment risk factors. RESULTS: There were 1131 included cases. The most important clinical risk factors (points for nomogram) for poor visual acuity outcome included subretinal fluid involving four quadrants (100), tumour thickness >4 mm (69), presenting visual acuity ≤20/30 (65), non-Caucasian race (58), tumour shape mushroom, bilobed, or multilobulated (57), and insulin-dependent diabetes (54). Risk of poor visual acuity at 2 years and 4 years increased from 11% and 24% with 40 points to 97% and >99% with 304 points. A second analysis was performed using both clinical and treatment risk factors. The most important factors included presenting visual acuity ≤20/30 (100), tumour largest basal diameter >11 mm (80), radiation dose rate to tumour base ≥164 cGy/hour (78), tumour thickness >4 mm (76), insulin-dependent diabetes (75) and abnormal foveolar status by optical coherence tomography at presentation (72). Risk of poor visual acuity at 2 years and 4 years increased from 6% and 14% with 56 points to 88% and 99% with 496 points. CONCLUSIONS: A nomogram using clinical or treatment risk factors can predict visual acuity outcome following plaque radiotherapy and prophylactic intravitreal bevacizumab for uveal melanoma and is available online at https://fighteyecancer.com/nomograms/.

Conjunctival Myxoid Lesions: Clinical-Pathologic Multiparametric Analysis, Including Molecular Genetics (An American Ophthalmological Society Thesis).

PURPOSE: To evaluate the clinical and pathologic characteristics of conjunctival myxoid lesions, with specific focus on PRKAR1A studies, in order to distinguish neoplastic conjunctival myxoma from other myxoid conjunctival lesions. METHODS: A retrospective, interventional, multicenter study of all patients with conjunctival myxoma, conjunctival stromal tumor, or reactive fibromyxoid proliferation diagnosed during 1988-2018. Patient and family medical histories and clinical and pathologic characteristics of excised lesions were assessed. RESULTS: There were 28 patients with conjunctival myxoid lesions diagnosed as myxoma (16/28), conjunctival stromal tumor (10/28), or reactive fibromyxoid proliferation (2/28). The patients with abundant myxoid matrix lesions (14/28, 50%) were younger (mean 49 [range 23-68] years) than those with scant-to-moderate myxoid matrix lesions (14/28, mean 61 [range 18-82] years; P = .04). Abundant myxoid matrix lesions more likely contained predominantly stellate cells (6/14 [43%] vs 0/14 [0%]; P = .05) and fibrillar collagen (13/14 [93%] vs 2/14 [14%]; P < .0001), conforming to the standard morphologic definition of myxoma. Absence of PRKAR1A protein expression was found in 2 lesions with morphologic features of myxoma (2/14, 14%), 1 of which demonstrated a pathogenic mutation in the PRKAR1A gene. There was no difference between the lesions with respect to other clinical and pathologic parameters. CONCLUSIONS: PRKAR1A plays a role in the development of a subset of conjunctival myxomas, particularly in tumors fulfilling stringent morphologic criteria for myxoma. With the exception of PRKAR1A studies, current immunohistochemical panels cannot reliably distinguish between neoplastic conjunctival myxomas and other myxoid lesions, underscoring the importance of morphology in establishing accurate diagnosis.

Edoxaban and implantable cardiac device interventions: insights from the ENGAGE AF-TIMI 48 trial.

AIMS: Pacemaker, implantable cardioverter-defibrillator, and cardiac resynchronization therapy device implantations and generator changes are frequently performed in patients receiving direct oral anticoagulants. In an exploratory analysis, we investigated the outcome of patients undergoing such device procedures in the ENGAGE AF-TIMI 48 trial. METHODS AND RESULTS: During the trial, 1217 device procedures were performed in 1145 patients, with intervention dates available for 1203 procedures. Two hundred and twenty-five procedures (in 212 patients) were performed >30 days after study drug was stopped and are not included in the event analysis. For most interventions (n = 728, 74%), study drug was interrupted >3 days (median for the entire cohort: 5 days, interquartile range 0-11 days); 250 interventions were performed with ≤3 days study drug interruption. During the first 30 days after the procedure, six strokes/systemic embolic events (SEEs) (three each in the lower-dose edoxaban and warfarin arm) and one major bleeding event (in the lower-dose edoxaban arm) occurred; no stroke/SEEs or major bleeds occurred around the 295 device procedures in the higher-dose edoxaban arm. Two ischaemic and one major bleeding event occurred after the 288 device procedures performed with ≤3 days periprocedural interruption of study drug. CONCLUSION: In this first experience of patients undergoing device surgery with edoxaban, a low risk of ischaemic and bleeding events was observed during the first 30 days post-procedure. Our data are in line with current recommendations of no or only brief interruption of non-vitamin K antagonist oral anticoagulants prior to cardiac device surgery.

Clinical outcomes, edoxaban concentration, and anti-factor Xa activity of Asian patients with atrial fibrillation compared with non-Asians in the ENGAGE AF-TIMI 48 trial.

AIMS: Prior studies suggested that the risks of ischaemic stroke and bleeding in patients of Asian race with atrial fibrillation (AF) may be higher than that of non-Asians. In the analysis of ENGAGE AF-TIMI 48 trial, we compared clinical outcomes, edoxaban concentration, and anti-factor Xa (anti-FXa) activity, between Asian and non-Asian races. METHODS AND RESULTS: There were 2909 patients of Asian race and 18 195 non-Asian race in the ENGAGE AF-TIMI 48 trial. The risks of thromboembolism and bleeding events were compared for Asians and non-Asians treated with warfarin. The trough levels of edoxaban concentration and anti-FXa activity were also compared and correlated with the efficacy and safety of edoxaban vs. warfarin. Compared to non-Asian patients, the Asian population was on average 2 years younger and 20 kg lighter. In the warfarin group, the adjusted risk of ischaemic stroke did not differ significantly for patients of Asian and non-Asian race [adjusted hazard ratio (aHR) = 1.12, P = 0.56). Asians treated with warfarin had a higher-adjusted risk of intracranial haemorrhage (ICH: aHR 1.71, P = 0.03) compared with non-Asians. The trough edoxaban concentration and anti-FXa activity were 20-25% lower for Asians compared with non-Asians. Compared to warfarin, higher dose edoxaban significantly reduced ICH while preserving the efficacy of stroke prevention in both Asians and non-Asians. Two of three net clinical outcomes appeared to be more favourably reduced with edoxaban in Asians compared with non-Asians (Pint = 0.063 for primary, 0.037 for secondary, and 0.032 for third net clinical outcomes, respectively). CONCLUSION: Compared to warfarin, higher dose edoxaban preserved the efficacy for stroke prevention and was associated with a favourable safety profile for Asians, which may be due to the lower trough edoxaban concentration and anti-FXa activity achieved in patients of Asian race.

Edoxaban Versus Warfarin in Latin American Patients With Atrial Fibrillation: The ENGAGE AF-TIMI 48 Trial.

BACKGROUND: There is limited information about the use of antithrombotic therapies and outcomes of Latin American (LatAm) subjects with atrial fibrillation. The global ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48) trial compared the efficacy and safety of edoxaban versus warfarin over a median follow-up of 2.8 years. OBJECTIVES: The authors aimed to compare adjusted outcomes in Latin America versus outside Latin America and to compare outcomes stratified by anticoagulant treatment and region. METHODS: The authors analyzed clinical characteristics and outcomes, adjusted for baseline characteristics, the Human Development Index, and randomized treatment of 2,661 LatAm versus 18,444 non-Latin American subjects (nLAS). RESULTS: When compared with nLAS, LatAm subjects had a similar overall risk for stroke. After multivariate adjustment, the risks of stroke/systemic embolism (hazard ratio [HR]: 1.19; 95% confidence interval (CI): 0.96 to 1.47; p = 0.11) and major bleeding (HR: 1.10; 95% CI: 0.89 to 1.36; p = 0.39) were similar in LatAm and nLAS. LatAm subjects were at higher adjusted risk of death (HR: 1.48; 95% CI: 1.30 to 1.69; p < 0.001) and intracranial hemorrhage (ICH) (HR: 1.55; 95% CI: 1.00 to 2.41; p = 0.049). In both regions, when compared with warfarin, edoxaban reduced stroke/systemic embolism (HR: 0.64 and 0.91 in LatAm and nLAS, respectively), major bleeding (HR: 0.71 and 0.82), and cardiovascular death (HR: 0.78 and 0.88), without evidence of regional heterogeneity (pint = 0.41, 0.50, and 0.70, respectively). There was a greater reduction in hemorrhagic stroke with edoxaban in LatAm (HR: 0.16) than in nLAS (HR: 0.64; pint = 0.037). CONCLUSIONS: After multivariable adjustment, LatAm subjects with atrial fibrillation had higher rates of intracranial hemorrhage and death than nLAS. Outcomes with higher-dose edoxaban versus warfarin were at least as favorable in LatAm subjects as in nLAS, with an even greater reduction in hemorrhagic stroke seen in LatAm.

Digoxin Use and Subsequent Clinical Outcomes in Patients With Atrial Fibrillation With or Without Heart Failure in the ENGAGE AF-TIMI 48 Trial.

BACKGROUND: Digoxin is widely used in patients with atrial fibrillation despite the lack of randomized controlled trials. Observational studies report conflicting results regarding its association with mortality, perhaps because of residual confounding by the presence of heart failure (HF). METHODS AND RESULTS: In the ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) trial, clinical outcomes of patients with atrial fibrillation with and without HF were examined by baseline digoxin use during a median follow-up of 2.8 years. HF was defined at baseline as prior or current clinical stage C or D HF. Of 21 105 patients enrolled, 6327 (30%) were treated with digoxin at baseline. Among patients without HF (n=8981), digoxin use (20%) was independently associated with sudden cardiac death (adjusted hazard ratio, 1.51; 95% CI, 1.10-2.08), with no significant interaction by age, sex, left ventricular ejection fraction, renal function, or concomitant medications (P>0.05 for each). Consistent results were observed using propensity matching (adjusted hazard ratio for sudden cardiac death, 1.90; 95% CI, 1.36-2.65). Among patients with HF (n=12 124), digoxin use (37%) was associated with an increase in all-cause death, cardiovascular death, sudden cardiac death, and death caused by HF/cardiogenic shock (P<0.01 for each), but not with noncardiovascular death, stroke/systemic embolism, or myocardial infarction. CONCLUSIONS: In this observational analysis of patients with atrial fibrillation without investigator-reported HF, digoxin use was significantly associated with sudden cardiac death. While residual confounding cannot be excluded, the association between digoxin use and worse clinical outcomes highlights the need to examine digoxin use, particularly when prescribed to control heart rate in patients with atrial fibrillation in a randomized trial. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00781391.

Impact of standardized clinical assessment and management plans on resource utilization and costs in children after the arterial switch operation.

BACKGROUND: Standardized Clinical Assessment and Management Plans (SCAMPs) are a quality improvement initiative designed to reduce unnecessary utilization, decrease practice variation, and improve patient outcomes. We created a novel methodology, the SCAMP managed episode of care (SMEOC), which encompasses multiple encounters to assess the impact of the arterial switch operation (ASO) SCAMP on total costs. METHODS: All ASO SCAMP patients (dates March 2009 to July 2015) were compared to a control group of ASO patients (January 2001 to February 2009). Patients were divided into "younger" (<2 years) and "older" (2-18 years) subgroups. Utilization included all cardiology visits, tests, and procedures. Standardized costs were applied to each unit of utilization. RESULTS: There were 100 historical and 63 SCAMP patients in the younger subgroup, and 163 historical and 165 SCAMP patients in the older subgroup. In the younger subgroup, the SCAMP had a 28% reduction in outpatient clinic visits (P < .001), a 52% reduction in chest radiographs (P < .001), a 21% reduction in electrocardiograms (P < .001), and a 30% total reduction in costs. In the older subgroup, the SCAMP had a 21% reduction in outpatient clinic visits (P < .001), a 20% reduction in chest radiographs (P = .05), a 10% reduction in echocardiograms (P = .05), a 25% reduction in exercise stress tests (P = .01), and a 14% total reduction in costs. The total cost savings of the ASO SCAMP was $216 649 in the first 6 years of the SCAMP. There was no difference in clinical outcomes between the historical and SCAMP cohorts. CONCLUSION: SCAMPs can improve resource utilization and reduce costs after the ASO operation while maintaining quality of care.

First experience with edoxaban and atrial fibrillation ablation - Insights from the ENGAGE AF-TIMI 48 trial.

BACKGROUND: Atrial fibrillation (AF) ablation procedures are increasingly being performed in patients receiving direct oral anticoagulants (DOACs). Experience regarding the safety of edoxaban in this context is limited. In an exploratory analysis we therefore investigated the outcome of patients undergoing transcatheter AF ablation in the ENGAGE AF-TIMI 48 trial. METHODS & RESULTS: During the trial, 193 transcatheter AF ablation procedures were performed in 169 patients. For the majority of ablations (n=157, 81%), study drug was interrupted >3days (median time of interruption: 18days, interquartile range 3-30days); 86 ablations were performed with ≤10days, and 36 ablations with ≤3days study drug interruption. During the first 30days after the ablation, one ischemic stroke was observed in the warfarin group and none in the higher-dose edoxaban regimen (HDER) or lower-dose edoxaban regimen (LDER) group. Three clinically relevant non-major (CRNM) bleeding events were observed in the warfarin group; one major bleed was seen in the HDER group; one minor bleed occurred in the LDER group. All bleeding events occurred among the patients with ≤10days study drug interruption; in contrast, no ischemic events or deaths were observed in these patients. CONCLUSIONS: In this pilot evaluation of the ENGAGE AF-TIMI 48 trial, treatment with edoxaban was associated with a low risk of ischemic and bleeding events during the first 30days post ablation.

Dental students' HIV/AIDS-related knowledge, attitudes, and intentions: impact of the U.S. Health Resources and Services Administration's community-based dental partnership program.

Access to oral health care for vulnerable populations is one of the concerns addressed by the U.S. Health Resources and Services Administration HIV/AIDS Bureau's Community-Based Dental Partnership Program (CBDPP). The program introduces dental students and residents at several dental schools to care for vulnerable patients through didactic and clinical work in community-based dental settings. This study of the dental students and residents in this program answered three questions: 1) What are their HIV knowledge, attitudes, and behaviors? 2) How has participation in the CBDPP impacted their knowledge, attitudes, and behaviors? 3) Has the intervention affected their work placement decisions and attitudes after graduation, particularly with respect to treating people living with HIV and other underserved populations? A total of 305 first- through fourth-year dental students and first- and second-year residents at five dental schools across the United States completed surveys before and after a community-based rotation and following graduation. Response rates at each of the five schools ranged from 82.4 to 100 percent. The results showed an increase in the participants' knowledge and positive attitudes regarding treatment for patients with HIV and other vulnerable populations post-rotation compared to pre-rotation. Results after graduation found that most respondents were practicing in private settings or in academic institutions as residents but were willing to treat a diverse patient population. These findings support the role of training programs, such as the CBDPP, for expanding the dental workforce to treating vulnerable populations including people living with HIV/AIDS.