Type 1 VWD classification revisited: novel insights from combined analysis of the LoVIC and WiN studies.

ABSTRACT: There is significant ongoing debate regarding type 1 von Willebrand disease (VWD) defintion. Previous guidelines recommended patients with von Willebrand factor (VWF) levels <30 IU/dL be diagnosed type 1 VWD, whereas patients with significant bleeding and VWF levels from 30 to 50 IU/dL be diagnosed with low VWF. To elucidate the relationship between type 1 VWD and low VWF in the context of age-induced increases in VWF levels, we combined data sets from 2 national cohort studies: 162 patients with low VWF from the Low VWF in Ireland Cohort (LoVIC) and 403 patients with type 1 VWD from the Willebrand in The Netherlands (WiN) studies. In 47% of type 1 VWD participants, VWF levels remained <30 IU/dL despite increasing age. Conversely, VWF levels increased to the low VWF range (30-50 IU/dL) in 30% and normalized (>50 IU/dL) in 23% of type 1 VWD cases. Crucially, absolute VWF antigen (VWF:Ag) levels and increase of VWF:Ag per year overlapped between low VWF and normalized type 1 VWD participants. Moreover, multiple regression analysis demonstrated that VWF:Ag levels in low VWF and normalized type 1 VWD patients would not have been different had they been diagnosed at the same age (ß = 0.00; 95% confidence interval, -0.03 to 0.04). Consistently, no difference was found in the prevalence of VWF sequence variants; factor VIII activity/VWF:Ag or VWF propeptide/VWF:Ag ratios; or desmopressin responses between low VWF and normalized type 1 VWD patients. In conclusion, our findings demonstrate that low VWF does not constitute a discrete clinical or pathological entity. Rather, it is part of an age-dependent type 1 VWD evolving phenotype. Collectively, these data have important implications for future VWD classification criteria.

Rilzabrutinib, an Oral BTK Inhibitor, in Immune Thrombocytopenia.

BACKGROUND: Rilzabrutinib, an oral, reversible covalent inhibitor of Bruton's tyrosine kinase, may increase platelet counts in patients with immune thrombocytopenia by means of dual mechanisms of action: decreased macrophage (Fcγ receptor)-mediated platelet destruction and reduced production of pathogenic autoantibodies. METHODS: In an international, adaptive, open-label, dose-finding, phase 1-2 clinical trial, we evaluated rilzabrutinib therapy in previously treated patients with immune thrombocytopenia. We used intrapatient dose escalation of oral rilzabrutinib over a period of 24 weeks; the lowest starting dose was 200 mg once daily, with higher starting doses of 400 mg once daily, 300 mg twice daily, and 400 mg twice daily. The primary end points were safety and platelet response (defined as at least two consecutive platelet counts of ≥50×103 per cubic millimeter and an increase from baseline of ≥20×103 per cubic millimeter without the use of rescue medication). RESULTS: Sixty patients were enrolled. At baseline, the median platelet count was 15×103 per cubic millimeter, the median duration of disease was 6.3 years, and patients had received a median of four different immune thrombocytopenia therapies previously. All the treatment-related adverse events were of grade 1 or 2 and transient. There were no treatment-related bleeding or thrombotic events of grade 2 or higher. At a median of 167.5 days (range, 4 to 293) of treatment, 24 of 60 patients (40%) overall and 18 of the 45 patients (40%) who had started rilzabrutinib treatment at the highest dose met the primary end point of platelet response. The median time to the first platelet count of at least 50×103 per cubic millimeter was 11.5 days. Among patients with a primary platelet response, the mean percentage of weeks with a platelet count of at least 50×103 per cubic millimeter was 65%. CONCLUSIONS: Rilzabrutinib was active and associated with only low-level toxic effects at all dose levels. The dose of 400 mg twice daily was identified as the dose for further testing. Overall, rilzabrutinib showed a rapid and durable clinical activity that improved with length of treatment. (Funded by Sanofi; ClinicalTrials.gov number, NCT03395210; EudraCT number, 2017-004012-19.).

Isatuximab plus carfilzomib and dexamethasone in patients with early versus late relapsed multiple myeloma: IKEMA subgroup analysis.

Patients with multiple myeloma (MM) who experience early relapse within 12 months of therapy initiation are considered functional high-risk and represent an unmet need, needing better therapies to improve outcomes. The final IKEMA (clinicaltrials gov. identifier: NCT03275285) progression-free survival (PFS) analysis confirmed the significant PFS improvement reported at interim analysis with isatuximab (Isa) plus carfilzomib and dexamethasone (Kd; Isa-Kd) versus Kd in patients with relapsed MM (updated median PFS: 35.7 vs. 19.2 months; hazard ratio [HR] =0.58, 95% confidence interval [CI]: 0.42- 0.79). This IKEMA subgroup analysis examined efficacy and safety of Isa-Kd versus Kd in patients who experienced early (n=61 [Isa-Kd], n=46 [Kd]) vs. late relapse (n=104 [Isa-Kd], n=72 [Kd]). As expected, more aggressive features in baseline characteristics were observed in early relapse patients. Consistent with IKEMA overall population results, median PFS (early relapse: 24.7 vs. 17.2 months, HR=0.662, 95% CI: 0.407-1.077; late relapse: 42.7 vs. 21.9 months, HR=0.542, 95% CI: 0.355- 0.826), minimal residual disease negativity (MRD-) (early relapse: 24.6% vs. 15.2%; late relapse: 37.5% vs. 16.7%), and MRD- complete response (≥CR) rates (early relapse: 18.0% vs. 10.9%; late relapse: 30.8% vs. 13.9%) were higher with Isa-Kd versus Kd, respectively, in both early and late relapse patients. Grade ≥3, serious treatment-emergent adverse events, and death rates were higher in the late relapse Isa-Kd arm. However, the numbers of deaths were low and treatment exposure was significantly longer in Isa-Kd versus Kd late relapse patients. These results support the addition of Isa to Kd as standardof- care therapy for relapsed and/or refractory MM regardless of relapse timing.

Effect of fasedienol (PH94B) pherine nasal spray and steroidal hormones on electrogram responses and autonomic nervous system activity in healthy adult volunteers.

OBJECTIVE: Fasedienol (PH94B) is a pherine compound formulated as a nasal spray that is hypothesized to regulate olfactory-amygdala circuits of fear and anxiety. Fasedienol's effect on the local electrogram of nasal chemosensory neurons (EGNR) and autonomic nervous system (ANS) responses versus steroidal hormones and controls in healthy adults is reported. METHODS: Eight males and 8 females randomly received aerosolized control (propylene glycol) and study drugs (fasedienol, 17ß-estradiol, progesterone, cortisol, and testosterone, 0.4 µg each in propylene glycol) onto the nasal septum mucosal lining at 30-min intervals over 2 sessions. EGNR was continuously monitored; autonomic parameters were recorded before and after administration. RESULTS: Fasedienol significantly increased EGNR amplitude (males: 5.0 vs. 0.6 mV, p < 0.001; females:5.7 vs. 0.6 mV, p < 0.001), and rapidly reduced respiratory rate (p < 0.05), heart rate (p < 0.01), and electrodermal activity (p < 0.05) versus control. EGNR and ANS responses after steroidal hormone administration were similar to control. 81% reported feeling less tense/more relaxed after receiving fasedienol, but not after receiving either control or steroidal hormones. CONCLUSIONS: Intranasal fasedienol, but not control or steroidal hormones, activated EGNR and rapidly reduced ANS responses, consistent with sympatholytic effects. Combined with subjective reports, results suggest fasedienol may provide acute relief in anxiety conditions.

How I treat bleeding disorder of unknown cause.

Recent studies have demonstrated that only 30% of patients referred for assessment of a possible bleeding tendency will eventually be diagnosed with a mild bleeding disorder (MBD) such as von Willebrand disease (VWD) or platelet function defect (PFD). Rather, most of these patients will be diagnosed with bleeding disorder of unknown cause (BDUC). There remains an important unmet need to define consensus regarding the clinical and laboratory criteria necessary for a formal BDUC diagnosis. Accumulating recent data suggest that BDUC is being diagnosed with increasing frequency. Objective assessment of bleeding phenotype using a standardized bleeding assessment tool (BAT) therefore represents a fundamental first step in the diagnosis of BDUC. Because BDUC is a diagnosis by exclusion, accurate quantification of bleeding phenotype is critical because this will be the primary determinant on which a diagnosis of BDUC is reached. Importantly, BAT scores suggest that patients with BDUC display bleeding phenotypes comparable to those seen in patients with VWD or PFD. Despite the prevalence of BDUC, diagnosis and management of these patients commonly pose significant clinical dilemmas. We consider these challenges in the context of a number of typical case studies, discuss the available evidence, and outline our approach to the management of these patients.

Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial.

BACKGROUND: Isatuximab is an anti-CD38 monoclonal antibody approved in combination with pomalidomide-dexamethasone and carfilzomib-dexamethasone for relapsed or refractory multiple myeloma. This phase 3, open-label study compared the efficacy of isatuximab plus carfilzomib-dexamethasone versus carfilzomib-dexamethasone in patients with relapsed multiple myeloma. METHODS: This was a prospective, randomised, open-label, parallel-group, phase 3 study done at 69 study centres in 16 countries across North America, South America, Europe, and the Asia-Pacific region. Patients with relapsed or refractory multiple myeloma aged at least 18 years who had received one to three previous lines of therapy and had measurable serum or urine M-protein were eligible. Patients were randomly assigned (3:2) to isatuximab plus carfilzomib-dexamethasone (isatuximab group) or carfilzomib-dexamethasone (control group). Patients in the isatuximab group received isatuximab 10 mg/kg intravenously weekly for the first 4 weeks, then every 2 weeks. Both groups received the approved schedule of intravenous carfilzomib and oral or intravenous dexamethasone. Treatment continued until progression or unacceptable toxicity. The primary endpoint was progression-free survival and was assessed in the intention-to-treat population according to assigned treatment. Safety was assessed in all patients who received at least one dose according to treatment received. The study is registered at ClinicalTrials.gov, NCT03275285. FINDINGS: Between Nov 15, 2017, and March 21, 2019, 302 patients with a median of two previous lines of therapy were enrolled. 179 were randomly assigned to the isatuximab group and 123 to the control group. Median progression-free survival was not reached in the isatuximab group compared with 19·15 months (95% CI 15·77-not reached) in the control group, with a hazard ratio of 0·53 (99% CI 0·32-0·89; one-sided p=0·0007). Treatment-emergent adverse events (TEAEs) of grade 3 or worse occurred in 136 (77%) of 177 patients in the isatuximab group versus 82 (67%) of 122 in the control group, serious TEAEs occurred in 105 (59%) versus 70 (57%) patients, and TEAEs led to discontinuation in 15 (8%) versus 17 (14%) patients. Fatal TEAEs during study treatment occurred in six (3%) versus four (3%) patients. INTERPRETATION: The addition of isatuximab to carfilzomib-dexamethasone significantly improves progression-free survival and depth of response in patients with relapsed multiple myeloma, representing a new standard of care for this patient population. FUNDING: Sanofi. VIDEO ABSTRACT.

A Multicenter Trial of Vena Cava Filters in Severely Injured Patients.

BACKGROUND: Whether early placement of an inferior vena cava filter reduces the risk of pulmonary embolism or death in severely injured patients who have a contraindication to prophylactic anticoagulation is not known. METHODS: In this multicenter, randomized, controlled trial, we assigned 240 severely injured patients (Injury Severity Score >15 [scores range from 0 to 75, with higher scores indicating more severe injury]) who had a contraindication to anticoagulant agents to have a vena cava filter placed within the first 72 hours after admission for the injury or to have no filter placed. The primary end point was a composite of symptomatic pulmonary embolism or death from any cause at 90 days after enrollment; a secondary end point was symptomatic pulmonary embolism between day 8 and day 90 in the subgroup of patients who survived at least 7 days and did not receive prophylactic anticoagulation within 7 days after injury. All patients underwent ultrasonography of the legs at 2 weeks; patients also underwent mandatory computed tomographic pulmonary angiography when prespecified criteria were met. RESULTS: The median age of the patients was 39 years, and the median Injury Severity Score was 27. Early placement of a vena cava filter did not result in a significantly lower incidence of symptomatic pulmonary embolism or death than no placement of a filter (13.9% in the vena cava filter group and 14.4% in the control group; hazard ratio, 0.99; 95% confidence interval [CI], 0.51 to 1.94; P = 0.98). Among the 46 patients in the vena cava filter group and the 34 patients in the control group who did not receive prophylactic anticoagulation within 7 days after injury, pulmonary embolism developed in none of those in the vena cava filter group and in 5 (14.7%) in the control group, including 1 patient who died (relative risk of pulmonary embolism, 0; 95% CI, 0.00 to 0.55). An entrapped thrombus was found in the filter in 6 patients. CONCLUSIONS: Early prophylactic placement of a vena cava filter after major trauma did not result in a lower incidence of symptomatic pulmonary embolism or death at 90 days than no placement of a filter. (Funded by the Medical Research Foundation of Royal Perth Hospital and others; Australian New Zealand Clinical Trials Registry number, ACTRN12614000963628.).

Isatuximab plus carfilzomib and dexamethasone versus carfilzomib and dexamethasone in relapsed multiple myeloma patients with renal impairment: IKEMA subgroup analysis.

Renal impairment (RI) is common in patients with multiple myeloma (MM) and new therapies that can improve renal function are needed. The phase III IKEMA study (clinicaltrials gov. Identifier: NCT03275285) investigated isatuximab (Isa) with carfilzomib and dexamethasone (Kd) versus Kd in relapsed MM. This subgroup analysis examined results from patients with RI, defined as estimated glomerular filtration rate <60 mL/min/1.73 m². Addition of Isa prolonged progression-free survival (PFS) in patients with RI (hazard ratio: 0.27; 95% confidence interval [CI]: 0.11-0.66; median PFS not reached for Isa-Kd versus 13.4 months for Kd [20.8-month follow-up]). Complete renal responses occurred more frequently with Isa-Kd (52.0%) versus Kd (30.8%) and were durable in 32.0% versus 7.7% of patients, respectively. Treatment exposure was longer with Isa-Kd, with median number of started cycles and median duration of exposure of 20 versus 9 cycles and 81.0 versus 35.7 weeks for Isa-Kd versus Kd, respectively. Among patients with RI, the incidence of patients with grade ≥3 treatment-emergent adverse events was similar between the two arms (79.1% in Isa-Kd vs. 77.8% in Kd). In summary, the addition of Isa to Kd improved clinical outcomes with a manageable safety profile in patients with RI, consistent with the benefit observed in the overall IKEMA study population.

Copanlisib plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (CHRONOS-3): a double-blind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Copanlisib, an intravenous pan-class I PI3K inhibitor, showed efficacy and safety as monotherapy in patients with relapsed or refractory indolent non-Hodgkin lymphoma who had received at least two therapies. The CHRONOS-3 study aimed to assess the efficacy and safety of copanlisib plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma. METHODS: CHRONOS-3 was a multicentre, double-blind, randomised, placebo-controlled, phase 3 study in 186 academic medical centres across Asia, Australia, Europe, New Zealand, North America, Russia, South Africa, and South America. Patients aged 18 years and older with an Eastern Cooperative Oncology Group performance status of no more than 2 and histologically confirmed CD20-positive indolent B-cell lymphoma relapsed after the last anti-CD20 monoclonal antibody-containing therapy and progression-free and treatment-free for at least 12 months, or at least 6 months for patients unwilling or unfit to receive chemotherapy, were randomly assigned (2:1) with an interactive voice-web response system via block randomisation (block size of six) to copanlisib (60 mg given as a 1-h intravenous infusion on an intermittent schedule on days 1, 8, and 15 [28-day cycle]) plus rituximab (375 mg/m2 given intravenously weekly on days 1, 8, 15, and 22 during cycle 1 and day 1 of cycles 3, 5, 7, and 9) or placebo plus rituximab, stratified on the basis of histology, progression-free and treatment-free interval, presence of bulky disease, and previous treatment with PI3K inhibitors. The primary outcome was progression-free survival in the full analysis set (all randomised patients) by masked central review. Safety was assessed in all patients who received at least one dose of any study drug. This study is registered with ClinicalTrials.gov, NCT02367040 and is ongoing. FINDINGS: Between Aug 3, 2015, and Dec 17, 2019, 652 patients were screened for eligibility. 307 of 458 patients were randomly assigned to copanlisib plus rituximab and 151 patients were randomly assigned to placebo plus rituximab. With a median follow-up of 19·2 months (IQR 7·4-28·8) and 205 total events, copanlisib plus rituximab showed a statistically and clinically significant improvement in progression-free survival versus placebo plus rituximab; median progression-free survival 21·5 months (95% CI 17·8-33·0) versus 13·8 months (10·2-17·5; hazard ratio 0·52 [95% CI 0·39-0·69]; p<0·0001). The most common grade 3-4 adverse events were hyperglycaemia (173 [56%] of 307 patients in the copanlisib plus rituximab group vs 12 [8%] of 146 in the placebo plus rituximab group) and hypertension (122 [40%] vs 13 [9%]). Serious treatment-emergent adverse events were reported in 145 (47%) of 307 patients receiving copanlisib plus rituximab and 27 (18%) of 146 patients receiving placebo plus rituximab. One (<1%) drug-related death (pneumonitis) occurred in the copanlisib plus rituximab group and none occurred in the placebo plus rituximab group. INTERPRETATION: Copanlisib plus rituximab improved progression-free survival in patients with relapsed indolent non-Hodgkin lymphoma compared with placebo plus rituximab. To our knowledge, copanlisib is the first PI3K inhibitor to be safely combined with rituximab and the first to show broad and superior efficacy in combination with rituximab in patients with relapsed indolent non-Hodgkin lymphoma. FUNDING: Bayer.

Impact of agitation in long-term care residents with dementia in the United States.

OBJECTIVES: To describe characteristics and compare clinical outcomes including falls, fractures, infections, and neuropsychiatric symptoms (NPS) among long-term care residents with dementia with and without agitation. METHODS: A cross-sectional secondary analysis of administrative healthcare data was conducted whereby residents with dementia residing in a long-term care facility for ≥12 months were identified from the AnalytiCare LLC database (10/2010-06/2014) and were classified into mutually exclusive cohorts (Agitation Cohort or No-Agitation Cohort) based on available agitation-related symptoms. Entropy balancing was used to balance demographic and clinical characteristics between the two cohorts. The impact of agitation on clinical outcomes was compared between balanced cohorts using weighted logistic regression models. RESULTS: The study included 6,265 long-term care residents with dementia among whom, 3,313 were included in the Agitation Cohort and 2,952 in the No-Agitation Cohort. Prior to balancing, residents in the Agitation Cohort had greater dementia-related cognitive impairment and clinical manifestations compared to the No-Agitation Cohort. After balancing, residents with and without agitation, respectively, received a median of five and four distinct types of medications (including antipsychotics). Further, compared to residents without agitation, those with agitation were significantly more likely to have a recorded fall (OR = 1.58), fracture (OR = 1.29), infection (OR = 1.18), and other NPS (OR = 2.11). CONCLUSIONS: Agitation in long-term care residents with dementia was associated with numerically higher medication use and an increased likelihood of experiencing falls, fractures, infections, and additional NPS compared to residents without agitation, highlighting the unmet need for effective management of agitation symptoms in this population.

Reducing the effect of DOAC interference in laboratory testing for factor VIII and factor IX: A comparative study using DOAC Stop and andexanet alfa to neutralize rivaroxaban effects.

INTRODUCTION: Investigation of factors (F) VIII and IX is common, with testing important for diagnosis or exclusion of haemophilia A or B, associated acquired conditions and factor inhibitors. Rivaroxaban, a common direct anti-Xa agent, causes significant interference in clotting assays, including substantial false reduction of factor levels. AIM: To assess whether rivaroxaban-induced interference of FVIII and FIX testing could be neutralized. MATERIALS AND METHODS: An international, cross-laboratory exercise for FVIII (n = 84) and FIX (n = 74), using four samples: (A) pool of normal plasma; (B) pool spiked with rivaroxaban (200 ng/mL); (C) rivaroxaban sample subsequently treated with 'DOAC Stop' and; (D) rivaroxaban sample treated with andexanet alfa (200 µg/mL). Testing performed blind to sample type. RESULTS: All laboratories reported normal FIX and 94% reported normal FVIII in the pool sample. Instead, 55% and 95%, respectively, reported abnormal FIX and FVIII levels for the rivaroxaban sample. DOAC Stop treatment evidenced a correction in most laboratories (100% reported normal FIX and 86% normal FVIII). Andexanet alfa provided intermediate results, with many laboratories still reporting abnormal results (59% for FVIII, 18% for FIX). We also identified reagent-specific issues. CONCLUSIONS: As expected, rivaroxaban caused false low values of FVIII and FIX. This might lead to increased testing to identify the cause of low factor levels and potentially lead to false identification of (mild) haemophilia A or B if unrecognized by clinicians/laboratories. DOAC Stop effectively neutralized the rivaroxaban effect, but andexanet alfa less so, with reagent-related effects evident, and thus, false low values sometimes persisted.

Efficacy and Safety of Brexpiprazole for the Treatment of Agitation in Alzheimer's Dementia: Two 12-Week, Randomized, Double-Blind, Placebo-Controlled Trials.

OBJECTIVE: To assess the efficacy, safety, and tolerability of brexpiprazole in patients with agitation in Alzheimer's dementia (AAD). DESIGN: Two 12-week, randomized, double-blind, placebo-controlled, parallel-arm studies (NCT01862640; NCT01922258). SETTING: Study 1: 81 sites in 7 countries. Study 2: 62 sites in 9 countries. PARTICIPANTS: Patients with AAD (Study 1: 433 randomized; Study 2: 270 randomized) in a care facility or community-based setting. Stable Alzheimer disease medications were permitted. INTERVENTION: Study 1 (fixed dose): brexpiprazole 2 mg/day, brexpiprazole 1 mg/day, or placebo (1:1:1) for 12 weeks. Study 2 (flexible dose): brexpiprazole 0.5-2 mg/day or placebo (1:1) for 12 weeks. MEASUREMENTS: Cohen-Mansfield Agitation Inventory (CMAI) (Total score range: 29-203; higher scores indicate more frequent agitated behaviors), and Clinical Global Impression - Severity of illness (CGI-S) as related to agitation. Safety was also assessed. RESULTS: In Study 1, brexpiprazole 2 mg/day demonstrated statistically significantly greater improvement in CMAI Total score from baseline to Week 12 than placebo (adjusted mean difference, -3.77; confidence limits, -7.38, -0.17; t(316) = -2.06; p = 0.040; MMRM). Brexpiprazole 1 mg/day did not show meaningful separation from placebo (0.23; -3.40, 3.86; t(314) = 0.12; p = 0.90; MMRM). In Study 2, brexpiprazole 0.5-2 mg/day did not achieve statistical superiority over placebo (-2.34; -5.49, 0.82; t(230) = -1.46; p = 0.15; MMRM). However, a benefit was observed in post hoc analyses among patients titrated to the maximum brexpiprazole dose of 2 mg/day compared with similarly titrated placebo patients (-5.06; -8.99, -1.13; t(144) = -2.54; p = 0.012; MMRM). On the CGI-S, a greater numerical improvement than placebo was demonstrated for brexpiprazole 2 mg/day in Study 1 (-0.16; -0.39, 0.06; t(337) = -1.42; nominal p = 0.16; MMRM), and a greater improvement for brexpiprazole 0.5-2 mg/day in Study 2 (-0.31; -0.55, -0.06; t(222) = -2.42; nominal p = 0.016; MMRM). In Study 1, treatment-emergent adverse events (TEAEs) with incidence ≥5% among patients receiving brexpiprazole 2 mg/day were headache (9.3% versus 8.1% with placebo), insomnia (5.7% versus 4.4%), dizziness (5.7% versus 3.0%), and urinary tract infection (5.0% versus 1.5%). In Study 2, TEAEs with incidence ≥5% among patients receiving brexpiprazole 0.5-2 mg/day were headache (7.6% versus 12.4% with placebo) and somnolence (6.1% versus 3.6%). In both studies, the majority of TEAEs were mild or moderate in severity. CONCLUSIONS: Brexpiprazole 2 mg/day has the potential to be efficacious, safe, and well tolerated in the treatment of AAD.

Laboratory testing for activated protein C resistance: rivaroxaban induced interference and a comparative evaluation of andexanet alfa and DOAC Stop to neutralise interference.

Background Investigation of hemostasis is problematic when patients are on anticoagulant therapy. Rivaroxaban especially causes substantial interference, extending many clot-based tests, thereby leading to false positive or negative events. In particular, rivaroxaban affects some assays for activated protein C resistance (APCR). Methods We assessed, in an international setting, cross laboratory (n = 31) testing using four samples to evaluate rivaroxaban induced interference in APCR testing, and whether this interference could be neutralised. The samples comprised: (A) pool of normal plasma (APCR-negative control); (B) this normal pool spiked with rivaroxaban (200 ng/mL) to create rivaroxaban-induced interference (potential 'false' positive APCR event sample); (C) the rivaroxaban sample subsequently treated with a commercial direct oral anticoagulant 'DOAC-neutraliser' (DOAC Stop), or (D) treated with andexanet alfa (200 µg/mL). Testing was performed blind to sample type. Results The rivaroxaban-spiked sample generated false positive APCR results for some, but unexpectedly not most APCR-tests. The sample treated with DOAC Stop evidenced a correction in the rivaroxaban-affected APCR assays, and did not otherwise adversely affect the rivaroxaban 'unaffected' APCR assays. The andexanet alfa-treated sample did not evidence correction of the false positive APCR, and instead unexpectedly exacerbated false positive APCR status with many tests. Conclusions DOAC Stop was able to neutralise any APCR interference induced by rivaroxaban. In contrast, andexanet alfa did not negate such interference, and instead unexpectedly created more false-positive APCR events.

Effect of Brexpiprazole on Agitation and Hostility in Patients With Schizophrenia: Post Hoc Analysis of Short- and Long-Term Studies.

BACKGROUND: Managing agitation and hostility represents a significant treatment challenge in schizophrenia. The aim of this analysis was to evaluate the short- and long-term efficacy of brexpiprazole for reducing agitation and hostility in schizophrenia. METHODS: This was a post hoc analysis of data from two 6-week, randomized, double-blind, placebo-controlled studies (ClinicalTrials.gov identifiers, NCT01396421 and NCT01393613) and a 52-week, open-label, extension study (NCT01397786). In the short-term studies, 1094 patients received placebo, 2 mg/d of brexpiprazole, or 4 mg/d of brexpiprazole; 346 brexpiprazole-treated patients rolled over into the long-term study and received 1 to 4 mg/d of brexpiprazole. Agitation was assessed using the Positive and Negative Syndrome Scale (PANSS) Excited Component (EC), and hostility was assessed using the PANSS hostility item (P7). RESULTS: Brexpiprazole improved PANSS-EC score over 6 weeks, with least squares mean differences versus placebo of -0.69 (95% confidence limits, -1.28, -0.11) for 2 mg/d (P = 0.020) and -1.11 (-1.70, -0.53) for 4 mg/d (P = 0.0002). In the subgroup with hostility at baseline (P7 score ≥3; 50.8% of the randomized sample), least squares mean differences versus placebo at week 6 on the PANSS-EC were -0.63 (-1.54, 0.28) for 2 mg/d (P = 0.18) and -1.03 (-1.92, -0.14) for 4 mg/d (P = 0.024), and on P7 (adjusted for positive symptoms) were -0.27 (-0.53, -0.01) for 2 mg/d (P = 0.038) and -0.34 (-0.59, -0.09) for 4 mg/d (P = 0.0080). The improvements were maintained over 58 weeks. Adverse events were generally comparable between treatment groups over 6 weeks; the incidence of akathisia among patients with hostility was 5.9% with placebo, 5.2% with 2 mg/d, and 8.6% with 4 mg/d. CONCLUSIONS: Brexpiprazole has the potential to be an efficacious and well-tolerated treatment for agitation and hostility among patients with schizophrenia.

Treatment patterns and burden of behavioral disturbances in patients with dementia in the United States: a claims database analysis.

BACKGROUND: Although patients with dementia frequently experience neuropsychological symptoms (NPS) such as agitation, which profoundly impacts patients, caregivers, and the healthcare system, few studies have evaluated the associated burden of agitation or agitation-related symptoms in dementia. METHODS: This retrospective analysis of claims data from the Truven Health MarketScan® database (2012-2015) compared clinical characteristics, treatment patterns, healthcare resource utilization, and costs among patients with dementia with behavioral disturbances (BD) versus patients with dementia without BD. Existing BD diagnosis codes 294.11 or 294.21 were used as a means to identify patients with agitation/agitation-related symptoms. RESULTS: From a starting sample of 6.4 million beneficiaries, 103,402 patients with dementia were identified, of whom 16,440 (16%) had BD during an average of 17 months of follow-up. Patients with BD had significantly more medical and psychiatric comorbidities and greater comedication use (i.e., antidementia drugs, antidepressants, and antipsychotics; all values, P < .0001) compared with patients without BD. A significantly greater number of hospitalizations, hospital days, outpatient hospital/clinic visits, number of skilled nursing visits, and number of patients with hospice visit were reported during follow-up in patients with BD compared with patients without BD (all values, P <  0.0001). Costs were also significantly higher among patients with BD versus those patients without BD ($42,284 vs. $32,640, respectively; P <  0.0001). CONCLUSIONS: Patients with dementia with BD had a higher prevalence of comorbidities, greater use of comedications, and greater healthcare utilization and costs than patients with dementia without BD.

New guidelines from the Thrombosis and Haemostasis Society of Australia and New Zealand for the diagnosis and management of venous thromboembolism.

INTRODUCTION: Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third most common cardiovascular disease and, globally, more than an estimated 10 million people have it yearly. It is a chronic and recurrent disease. The symptoms of VTE are non-specific and the diagnosis should actively be sought once considered. The mainstay of VTE treatment is anticoagulation, with few patients requiring additional intervention. A working group of experts in the area recently completed an evidence-based guideline for the diagnosis and management of DVT and PE on behalf of the Thrombosis and Haemostasis Society of Australia and New Zealand (www.thanz.org.au/resources/thanz-guidelines). MAIN RECOMMENDATIONS: The diagnosis of VTE should be established with imaging; it may be excluded by the use of clinical prediction rules combined with D-dimer testing. Proximal DVT or PE caused by a major surgery or trauma that is no longer present should be treated with anticoagulant therapy for 3 months. Proximal DVT or PE that is unprovoked or associated with a transient risk factor (non-surgical) should be treated with anticoagulant therapy for 3-6 months. Proximal DVT or PE that is recurrent (two or more) and provoked by active cancer or antiphospholipid syndrome should receive extended anticoagulation. Distal DVT caused by a major provoking factor that is no longer present should be treated with anticoagulant therapy for 6 weeks. For patients continuing with extended anticoagulant therapy, either therapeutic or low dose direct oral anticoagulants can be prescribed and is preferred over warfarin in the absence of contraindications. Routine thrombophilia testing is not indicated. Thrombolysis or a suitable alternative is indicated for massive (haemodynamically unstable) PE. CHANGES IN MANAGEMENT AS A RESULT OF THE GUIDELINE: Most patients with acute VTE should be treated with a factor Xa inhibitor and be assessed for extended anticoagulation.

Successful switching of patients with acute schizophrenia from another antipsychotic to brexpiprazole: comparison of clinicians' choice of cross-titration schedules in a post hoc analysis of a randomized, double-blind, maintenance treatment study.

OBJECTIVE: To compare the tolerability and efficacy of different antipsychotic cross-titration schedules, using data from a brexpiprazole study (Equator; NCT01668797). METHODS: Patients with schizophrenia were cross-titrated from other antipsychotics to brexpiprazole monotherapy in a 1-4 week open-label conversion phase, then entered a single-blind brexpiprazole treatment phase. Patients were stratified into four "conversion groups," according to the amount of time spent in the conversion phase. Discontinuation rates, treatment-emergent adverse events (TEAEs), and efficacy (Positive and Negative Syndrome Scale [PANSS]) were compared between conversion groups. RESULTS: Of the 404 patients treated with brexpiprazole, the majority (72.0%) spent 22-33 days in the conversion phase. Discontinuation rates due to lack of efficacy or adverse events were low in all conversion groups. Of the 292 patients who successfully switched and completed 8 weeks of brexpiprazole treatment, most were converted to brexpiprazole over 22-33 days (80.1%), and fewer were converted over 1-7 days (2.4%), 8-14 days (6.5%), or 15-21 days (11.0%). The incidence of TEAEs over 8 weeks was lower among those converted over 22-33 days (44.4%) than in other conversion groups (62.5-84.2%), although low patient numbers with shorter conversion times limit the generalizability of this finding. Each conversion group showed comparable improvement in PANSS total score from baseline. CONCLUSION: The majority of patients were cross-titrated to brexpiprazole over a period of 22-33 days, by investigators' choice. Additional data on shorter conversions may help clinicians to choose a switching paradigm that best meets their patients' needs.

Agitation in patients with dementia: a systematic review of epidemiology and association with severity and course.

OBJECTIVES: More than 90% of individuals with Alzheimer's disease (AD) experience behavioral and neuropsychiatric symptoms (NPS), such as agitation. However, little is known regarding the specific burden of agitation for Alzheimer's patients. DESIGN: A global systematic literature review was conducted in MEDLINE and Embase for studies of clinical, humanistic, and economic burden of agitation in AD/dementia published from 2006-2016. References of identified papers and related literature reviews were examined. Studies meeting predetermined inclusion criteria for burden of agitation/NPS were summarized. RESULTS: Eighty papers met the inclusion criteria for burden of agitation in dementia. Wide ranges of agitation prevalence were reported, but few papers provided information on incidence. The association of agitation with AD severity was presented in multiple studies; a few suggested positive association of agitation with mortality. CONCLUSIONS: High prevalence of agitation is consistent with earlier reports, but several gaps in understanding of agitation in AD need further exploration.

The Symptoms Targeted for Monitoring in a Web-Based Tracking Tool by Caregivers of People With Dementia and Agitation: Cross-Sectional Study.

BACKGROUND: In people with dementia, neuropsychiatric symptoms (NPSs), especially agitation, are associated with worse quality of life and caregiver burden. As NPSs may vary with illness severity, knowledge of how people with dementia and their caregivers describe and rate the importance of agitation symptoms can improve the understanding of the clinical meaningfulness of the manifestations of agitation. The internet provides new opportunities to better understand patient experiences, as patients and caregivers increasingly look to Web-based platforms as a means of managing symptoms. OBJECTIVE: The aim of this study was to examine Web-based reports from a dementia symptom website to better understand the symptoms of agitation and explore how they are being targeted for monitoring by caregivers of people with dementia. METHODS: The Dementia Guide website hosts a Web-based database used by caregivers (97%) and people with dementia (3%). From its 61 dementia symptoms, users can select relevant symptoms that they deem important to monitor or track the effects of treatment. We employed a staging algorithm to determine if individuals had mild cognitive impairment (MCI) or mild, moderate, or severe dementia. Agitation was defined using terms consistent with the International Psychogeriatrics Association's provisional consensus definition. We compared the proportion of people with NPSs and agitation across stages of dementia severity and studied how many agitation-defining descriptors were selected, and how often they occurred, by stage. RESULTS: As of March 2017, 4121 people had used the tracking tool, of whom 2577 provided sufficient data to allow disease severity staging. NPSs were tracked by 2127/2577 (82.54%) and agitation by 1898/2577 (73.65%). The proportion in whom agitation was tracked increased with increasing cognitive impairment: 68.5% (491/717) in people with MCI, and 72.50% (754/1040), 73.3% (378/516), and 90.5% (275/304) in mild, moderate, and severe dementia, respectively (χ23=54.9; P<.001). The number of NPS and agitation descriptors selected also increased with severity (median number of NPSs=1, 2, 2, and 3 for MCI, mild, moderate, and severe dementia, respectively, Kruskal-Wallis H Test H3=250.47; P<.001; median number of agitation descriptors=1, 2, 3, and 4, H3=146.11; P<.001). CONCLUSIONS: NPSs and agitation are common targets for tracking over the course of dementia and appear more frequently with increasing disease severity. These common and distressing symptoms represent clinically meaningful targets in treating people with dementia.

The platelet Fc receptor, FcγRIIa.

Human platelets express FcγRIIa, the low-affinity receptor for the constant fragment (Fc) of immunoglobulin (Ig) G that is also found on neutrophils, monocytes, and macrophages. Engagement of this receptor on platelets by immune complexes triggers intracellular signaling events that lead to platelet activation and aggregation. Importantly these events occur in vivo, particularly in response to pathological immune complexes, and engagement of this receptor on platelets has been causally linked to disease pathology. In this review, we will highlight some of the key features of this receptor in the context of the platelet surface, and examine the functions of platelet FcγRIIa in normal hemostasis and in response to injury and infection. This review will also highlight pathological consequences of engagement of this receptor in platelet-based autoimmune disorders. Finally, we present some new data investigating whether levels of the extracellular ligand-binding region of platelet glycoprotein VI which is rapidly shed upon engagement of platelet FcγRIIa by autoantibodies, can report on the presence of pathological anti-heparin/platelet factor 4 immune complexes and thus identify patients with pathological autoantibodies who are at the greatest risk of developing life-threatening thrombosis in the setting of heparin-induced thrombocytopenia.