Mutational landscape, inhibitor development, and health-care burden in non-severe haemophilia A: A single-centre Australian experience.

AIM: To characterise non-severe haemophilia A (HA) patients enrolled on the Australian Bleeding Disorders Registry (ABDR) treated through a state-wide Haemophilia Treatment Centre (HTC) with respect to their mutational profile, inhibitor risk and health-care burden. METHOD: We conducted a single-centre observational study of all non-severe HA patients treated at the Alfred Health HTC registered on the ABDR as of the 26th July 2023. Data were extracted from the ABDR and electronic medical record (EMR) regarding demographics, severity, genetic testing, treatment, inhibitors, bleeding events and procedures. Inhibitor risk was calculated as a function of exposure days (EDs) of FVIII replacement. RESULTS: There were 289 non-severe HA patients treated at the Alfred HTC registered on the ABDR as of July 2023, all of whom were adult patients aged > 18 years old. Genotyping had been performed in 228/289 (78.9%). Of the inhibitor analysis population, 14/193 (7.3%) had an inhibitor. The cumulative incidence of inhibitor development at 75 EDs was 31% (95% CI 13%-46%). The median cost of bypassing agents per inhibitor patient was $57,087.50/year. CONCLUSION: These results demonstrate a relatively high inhibitor prevalence and incidence risk in non-severe HA compared to previously published work, although this may partly reflect a smaller population size. High rates of genotyping have allowed representative mutational characterisation. The burden of care imposed by non-severe HA in terms of bleeding events, procedures and bypassing agent cost is larger than expected, particularly within the inhibitor population.

Congenital fibrinogen disorders: Strengthening genotype-phenotype correlations through novel genetic diagnostic tools.

Congenital fibrinogen disorders or CFDs are heterogenous, both in clinical manifestation and array of culprit molecular lesions. Correlations between phenotype and genotype remain poorly defined. This review examines the genetic landscape discovered to date for this rare condition. The question of a possible oligogenic model of inheritance influencing phenotypic heterogeneity is raised, with discussion of the benefits and challenges of sequencing technology used to enhance discovery in this space. Considerable work lies ahead in order to achieve diagnostic and prognostic precision and subsequently provide targeted management to this complex cohort of patients.

Adherence and persistence to direct factor Xa inhibitors in the community following newly diagnosed venous thromboembolism: a retrospective pharmacy-linkage study.

OBJECTIVES: To assess adherence and persistence to the direct factor Xa inhibitor oral anticoagulants in the community following newly diagnosed venous thromboembolism (VTE). METHODS: We retrospectively reviewed community pharmacy dispensing data on all patients with newly diagnosed VTE who were prescribed direct factor Xa inhibitors, apixaban or rivaroxaban, between January 2018 and December 2019 at our institution. Proportion of days covered (PDC) was used to assess adherence at 90 days, and 6- and 12 months. Persistence was measured by participants having both dispensed supply of a factor Xa inhibitor at the end of the treatment period and no significant gaps (maximum of 60 days) in supply. KEY FINDINGS: There were 225 patients identified. Overall PDC at 90 days, 6- and 12 months were 84.6%, 86.2% and 86.1%, respectively. Apixaban had a higher mean overall PDC than rivaroxaban (86.2% and 80.6%, respectively). Females demonstrated higher PDC compared with males (87.3% versus 81.2%). Overall, 133 patients (64%) were persistent with therapy. CONCLUSIONS: In patients with newly diagnosed VTE treated with a factor Xa inhibitor, adherence rates are high at >80%, with females and those prescribed apixaban exhibiting higher adherence. These findings may assist clinicians in identifying those patients with VTE at risk of poor adherence.

Improving the rate of inferior vena cava filter retrieval through multidisciplinary engagement.

Background: The placement of retrievable inferior vena cava (IVC) filters occurs commonly, but retrieval rates remain low. Consequently, there is an unmet clinical need to ensure appropriate follow-up and retrieval of these devices. Objectives: To determine the association between an IVC filter surveillance team with filter retrievals or a documented filter plan, time to retrieval, and incidence of filter complications or recurrent venous thromboembolism. Methods: Ambidirectional cohort study evaluating consecutive IVC filter insertions before and after the implementation of a multidisciplinary surveillance team (MDST). We report an odds ratio (OR) with 95% CIs, adjusted by age, sex, weight, and malignancy status. Results: Overall, 453 patients were included, with 272 individuals in the pre-MDST cohort and 181 individuals in the post-MDST cohort. The MDST was associated with a higher composite primary outcome of IVC filter retrieval or a documented filter plan from 79.4% in the pre-MDST cohort to 96.1% in the post-MDST cohort (OR, 6.44; 95% CI, 3.06-15.84). Compared with the pre-MDST cohort, IVC filter retrieval rates were higher in the post-MDST cohort (52.6%-73.5%, respectively; (OR, 2.50; 95% CI, 1.67-3.78). The MDST was associated with a shorter median time-to-filter retrieval (187-150 days, hazard ratio, 1.78; 95% CI, 1.39-2.29), but there was no significant difference when comparing symptomatic or clinically significant IVC filter complications, recurrent venous thromboembolism, or mortality. Conclusion: Our study demonstrates the importance of a structured program to ensure timely IVC filter retrieval and ultimately improve patient care.

Predictors and outcomes of dose reduction of methotrexate and cyclosporin graft-versus-host disease prophylaxis following allogeneic haemopoietic cell transplantation.

BACKGROUND: Concern regarding dose-related toxicities of methotrexate (MTX) and cyclosporin (CYA) graft-versus-host disease (GVHD) prophylaxis occasionally leads to dose alterations post allogeneic haemopoietic cell transplant (alloHCT). AIMS: To clarify causes of MTX and CYA dose alteration and assess impact on patient outcomes, including GVHD, relapse, non-relapse mortality (NRM) and overall survival (OS). METHODS: Analysis of retrospective data was performed in a single tertiary centre of patients who underwent alloHCT for any indication and who received GVHD prophylaxis with CYA and MTX between the years 2011 and 2015. Univariate analysis was conducted using the log-rank test for OS and using competing risk regression for NRM, relapse and GVHD. Fisher exact tests were used to determine if an association existed between each of the pre-transplant variables and MTX alteration. Multivariate models for OS and NRM were constructed using Cox proportional hazards modelling and competing risk regression respectively. RESULTS: Fifty-four (28%) of 196 had MTX alterations and 61/187 (33%) had CYA alterations. Reasons for MTX alteration included mucositis, renal or liver impairment, fluid overload and sepsis. Causes of CYA alteration were numerous, but most commonly due to acute kidney impairment. MTX alteration was associated with inferior OS (hazard ratio 2.4; P = <0.001) and higher NRM (odds ratio (OR) 4.6; P < 0.001) at 6 years post-landmark. CYA alteration was associated with greater NRM (OR 2.7; P = 0.0137) at 6 years. GVHD rates were unaffected by dose alteration. CONCLUSIONS: Our findings suggest dose alteration in MTX and CYA GVHD prophylaxis is associated with adverse survival outcomes in alloHCT, without a significant impact on GVHD rates.

Cellular distribution of IDH mutations in AML during morphologic remission.

Limited information exists about the cellular distribution of mutations which persist in remission in acute myeloid leukemia (AML) (variably considered pre-leukemic mutations). We hypothesized that mutations detectable in all cell compartments may be less pathogenic than those that are myeloid-restricted. Here, we describe the cellular compartments that have IDH mutations in five patients with IDH-mutated AML in morphologic remission. Unlike pre-leukemic clones harboring the more common DNMT3A, TET2 and ASXL1 (DTA) mutations, we show that IDH mutations are myeloid-restricted. This finding provides an explanation for the reports that IDH mutations carry a higher risk for relapse than DTA mutations. Detailed analysis of one case also shows acquisition of additional mutations in distinct cellular compartments, illustrating subclonal complexity associated with therapeutics.

Evaluating the sustained effectiveness of a multimodal intervention aimed at influencing PIVC insertion practices in the emergency department.

INTRODUCTION: Multimodal interventions (MMI) are frequently used in various healthcare settings to encourage change in healthcare personnel practices and improve patient safety. In 2013, an MMI conducted in an Australian metropolitan ED used clinician champions, guidelines, education sessions and promotional materials to encourage a reduction in unused and inappropriate peripheral intravenous cannulas (PIVC). A 60-day postintervention demonstrated a successful reduction in the number of unused PIVCs without changes in appropriate insertions. We aimed to investigate if this MMI produced a sustained effect in reducing the frequency of unused PIVCs inserted in this ED. METHODS: A single-centre retrospective cohort study of adult patients presenting to the above ED in Victoria, Australia, was conducted in April 2018. A random sample of 380 patients with a PIVC inserted in ED was assessed to determine if the PIVC was used (termed 'Long-term follow-up'). The appropriateness of unused PIVCs was assessed. Our findings were compared with previously collected data in 2013 ('Pre-Intervention' and 'Immediately Post-Intervention') to determine a sustained reduction in the frequency of unused PIVC insertions was achieved. Long-term analysis of the MMI, including the overall frequency of PIVC insertions in ED before and after the MMI, was also collected. RESULTS: In our Long-term follow-up cohort, 101 of 373 (27.1%, 95% CI 22.6% to 31.9%) PIVCs were unused (seven cases excluded). This was significantly lower than the Pre-Intervention cohort (139/376, 37.0%, 95% CI 32.1% to 42.1%). While not significant, the frequency of unused PIVCs in the Post-Intervention cohort was lower in comparison (73/378, 19.3%, 95% CI 15.4% to 23.7%). No significant change in the appropriateness of unused PIVCs was observed between the Post-Intervention and Long-term follow-up. The overall proportion of patients receiving a PIVC has remained low since the MMI. CONCLUSION: An MMI aimed at reducing unused PIVC insertions in ED has been effective in eliciting sustained change. Unused but appropriately inserted PIVCs seem unaffected by the intervention.

Human factor-designed multimodal intervention reduces the rate of unused peripheral intravenous cannula insertion.

OBJECTIVE: Our objective was to examine the impact of a human factor-designed multimodal intervention on the proportion of unused peripheral i.v. cannula (PIVC) insertion in our ED. METHODS: A pre- and post-multimodal intervention retrospective cohort study was conducted using a structured electronic medical record review within a single adult tertiary ED in Australia. Pre-intervention data was collected 30 days prior to the multimodal intervention, with 30 day post-intervention data collected 3 months after the intervention commenced. The rates of PIVC inserted, the unused rate and the unused but appropriately inserted cannulas were the main outcome measures. RESULTS: Intravenous cannula insertion rates decreased by 12.9% (95% confidence interval [CI] 12.19-13.61) between the pre-intervention (1413/4167 [33.9%]; 95% CI 32.5-35.4) and post-intervention cohort (928/4421 [21.0%]; 95% CI 19.8-22.2). An analysis of 754 cases (376 pre-intervention and 378 post-intervention) showed that 139 of 376 (37.0%; 95% CI 32.1-42.1) i.v. cannulas were unused pre-intervention, while 73 of 378 (19.3%; 95% CI 15.4-23.7) was unused post-intervention; an absolute reduction of 17.7% (95% CI 14.98-20.42). The relative risk of an unused i.v. cannula was 0.52 (95% CI 0.41-0.67). The proportion of unused but appropriately inserted i.v. cannulas remained unchanged in both cohorts, with a relative risk of 0.91 (95% CI 0.58-1.42). CONCLUSION: Our multimodal intervention successfully reduced the number of unused PIVCs inserted in the ED, with a reduction in overall and unused PIVC insertions without any change in appropriate insertions.