Bridging the gap: Survey highlights challenges and solutions in outreach and identification of people with inherited bleeding disorders.

INTRODUCTION: Inherited bleeding disorders (IBD) are genetic conditions that affect blood clotting, leading to complications such as prolonged or spontaneous bleeding into muscles or joints. Early identification and treatment are crucial to prevent complications and improve outcomes. However, effective patient outreach and identification programs for IBD face significant challenges globally. AIM: This study aimed to identify successful patient outreach initiatives for IBD, barriers encountered during implementation, and approaches used to overcome them. METHODS: The World Federation of Haemophilia (WFH) conducted a survey of its national member organizations and other patient associations, totalling 153 organizations, to identify common strategies, barriers to their implementation, and solutions for outreach and the identification of people with IBD. The survey consisted of both closed-ended and open-ended questions, and the data were analysed using descriptive statistics and thematic analysis. RESULTS: Common challenges included resource and sustainability-related aspects such as financial constraints, limited lab equipment for diagnosis, and inadequate government commitment. Significant barriers also encompassed physical/geographical challenges like difficulty accessing remote areas, and inadequate logistical support and transportation. Seven themes emerged to enhance patient outreach: resource mobilization; awareness-raising and advocacy; knowledge and capacity building; collaboration and partnership; decentralization of services; improved logistical support and infrastructure; utilization of technology and innovation; and financial aid and incentives. CONCLUSION: Multistakeholder collaboration, coupled with secured government commitment, is crucial for improving global outreach, diagnosis rates, and access to care for individuals with IBD. Customized outreach programs should consider regional contexts, financial constraints, and prioritize innovation.

High-sensitivity cardiac troponin and the diagnosis of myocardial infarction in patients with kidney impairment.

The benefit and utility of high-sensitivity cardiac troponin (hs-cTn) in the diagnosis of myocardial infarction in patients with kidney impairment is unclear. Here, we describe implementation of hs-cTnI testing on the diagnosis, management, and outcomes of myocardial infarction in patients with and without kidney impairment. Consecutive patients with suspected acute coronary syndrome enrolled in a stepped-wedge, cluster-randomized controlled trial were included in this pre-specified secondary analysis. Kidney impairment was defined as an eGFR under 60mL/min/1.73m2. The index diagnosis and primary outcome of type 1 and type 4b myocardial infarction or cardiovascular death at one year were compared in patients with and without kidney impairment following implementation of hs-cTnI assay with 99th centile sex-specific diagnostic thresholds. Serum creatinine concentrations were available in 46,927 patients (mean age 61 years; 47% women), of whom 9,080 (19%) had kidney impairment. hs-cTnIs were over 99th centile in 46% and 16% of patients with and without kidney impairment. Implementation increased the diagnosis of type 1 infarction from 12.4% to 17.8%, and from 7.5% to 9.4% in patients with and without kidney impairment (both significant). Patients with kidney impairment and type 1 myocardial infarction were less likely to undergo coronary revascularization (26% versus 53%) or receive dual anti-platelets (40% versus 68%) than those without kidney impairment, and this did not change post-implementation. In patients with hs-cTnI above the 99th centile, the primary outcome occurred twice as often in those with kidney impairment compared to those without (24% versus 12%, hazard ratio 1.53, 95% confidence interval 1.31 to 1.78). Thus, hs-cTnI testing increased the identification of myocardial injury and infarction but failed to address disparities in management and outcomes between those with and without kidney impairment.

Sex-Specific Thresholds of High-Sensitivity Troponin in Patients With Suspected Acute Coronary Syndrome.

BACKGROUND: Major disparities between women and men in the diagnosis, management, and outcomes of acute coronary syndrome are well recognized. OBJECTIVES: The aim of this study was to evaluate the impact of implementing a high-sensitivity cardiac troponin I assay with sex-specific diagnostic thresholds for myocardial infarction in women and men with suspected acute coronary syndrome. METHODS: Consecutive patients with suspected acute coronary syndrome were enrolled in a stepped-wedge, cluster-randomized controlled trial across 10 hospitals. Myocardial injury was defined as high-sensitivity cardiac troponin I concentration >99th centile of 16 ng/l in women and 34 ng/l in men. The primary outcome was recurrent myocardial infarction or cardiovascular death at 1 year. RESULTS: A total of 48,282 patients (47% women) were included. Use of the high-sensitivity cardiac troponin I assay with sex-specific thresholds increased myocardial injury in women by 42% and in men by 6%. Following implementation, women with myocardial injury remained less likely than men to undergo coronary revascularization (15% vs. 34%) and to receive dual antiplatelet (26% vs. 43%), statin (16% vs. 26%), or other preventive therapies (p < 0.001 for all). The primary outcome occurred in 18% (369 of 2,072) and 17% (488 of 2,919) of women with myocardial injury before and after implementation, respectively (adjusted hazard ratio: 1.11; 95% confidence interval: 0.92 to 1.33), compared with 18% (370 of 2,044) and 15% (513 of 3,325) of men (adjusted hazard ratio: 0.85; 95% confidence interval: 0.71 to 1.01). CONCLUSIONS: Use of sex-specific thresholds identified 5 times more additional women than men with myocardial injury. Despite this increase, women received approximately one-half the number of treatments for coronary artery disease as men, and outcomes were not improved. (High-Sensitivity Troponin in the Evaluation of Patients With Acute Coronary Syndrome [High-STEACS]; NCT01852123).

High-Sensitivity Troponin and the Application of Risk Stratification Thresholds in Patients With Suspected Acute Coronary Syndrome.

BACKGROUND: Guidelines acknowledge the emerging role of high-sensitivity cardiac troponin (hs-cTnl) for risk stratification and the early rule-out of myocardial infarction, but multiple thresholds have been described. We evaluate the safety and effectiveness of risk stratification thresholds in patients with suspected acute coronary syndrome. METHODS: Consecutive patients with suspected acute coronary syndrome (n=48 282) were enrolled in a multicenter trial across 10 hospitals in Scotland. In a prespecified secondary and observational analysis, we compared the performance of the limit of detection (<2 ng/L) and an optimized risk stratification threshold (<5 ng/L) using the Abbott high-sensitivity troponin I assay. Patients with myocardial injury at presentation, with ≤2 hours of symptoms or with ST-segment elevation myocardial infarction were excluded. The negative predictive value was determined in all patients and in subgroups for a primary outcome of myocardial infarction or cardiac death within 30 days. The secondary outcome was myocardial infarction or cardiac death at 12 months, with risk modeled using logistic regression adjusted for age and sex. RESULTS: In total, 32 837 consecutive patients (61±17 years, 47% female) were included, of whom 23 260 (71%) and 12,716 (39%) had hs-cTnl concentrations of <5 ng/L and <2 ng/L at presentation. The negative predictive value for the primary outcome was 99.8% (95% CI, 99.7%-99.8%) and 99.9% (95% CI, 99.8%-99.9%) in those with hs-cTnl concentrations of <5 ng/L and <2 ng/L, respectively. At both thresholds, the negative predictive value was consistent in men and women and across all age groups, although the proportion of patients identified as low risk fell with increasing age. Compared with patients with hs-cTnl concentrations of ≥5 ng/L but <99th centile, the risk of myocardial infarction or cardiac death at 12 months was 77% lower in those <5 ng/L (5.3% vs 0.7%; adjusted odds ratio, 0.23 [95% CI, 0.19-0.28]) and 80% lower in those <2 ng/L (5.3% vs 0.3%; adjusted odds ratio, 0.20 [95% CI, 0.14-0.29]). CONCLUSIONS: Use of risk stratification thresholds for hs-cTnl identify patients with suspected acute coronary syndrome and at least 2 hours of symptoms as low risk at presentation irrespective of age and sex. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01852123.

High-sensitivity troponin in the evaluation of patients with suspected acute coronary syndrome: a stepped-wedge, cluster-randomised controlled trial.

BACKGROUND: High-sensitivity cardiac troponin assays permit use of lower thresholds for the diagnosis of myocardial infarction, but whether this improves clinical outcomes is unknown. We aimed to determine whether the introduction of a high-sensitivity cardiac troponin I (hs-cTnI) assay with a sex-specific 99th centile diagnostic threshold would reduce subsequent myocardial infarction or cardiovascular death in patients with suspected acute coronary syndrome. METHODS: In this stepped-wedge, cluster-randomised controlled trial across ten secondary or tertiary care hospitals in Scotland, we evaluated the implementation of an hs-cTnI assay in consecutive patients who had been admitted to the hospitals' emergency departments with suspected acute coronary syndrome. Patients were eligible for inclusion if they presented with suspected acute coronary syndrome and had paired cardiac troponin measurements from the standard care and trial assays. During a validation phase of 6-12 months, results from the hs-cTnI assay were concealed from the attending clinician, and a contemporary cardiac troponin I (cTnI) assay was used to guide care. Hospitals were randomly allocated to early (n=5 hospitals) or late (n=5 hospitals) implementation, in which the high-sensitivity assay and sex-specific 99th centile diagnostic threshold was introduced immediately after the 6-month validation phase or was deferred for a further 6 months. Patients reclassified by the high-sensitivity assay were defined as those with an increased hs-cTnI concentration in whom cTnI concentrations were below the diagnostic threshold on the contemporary assay. The primary outcome was subsequent myocardial infarction or death from cardiovascular causes at 1 year after initial presentation. Outcomes were compared in patients reclassified by the high-sensitivity assay before and after its implementation by use of an adjusted generalised linear mixed model. This trial is registered with ClinicalTrials.gov, number NCT01852123. FINDINGS: Between June 10, 2013, and March 3, 2016, we enrolled 48 282 consecutive patients (61 [SD 17] years, 47% women) of whom 10 360 (21%) patients had cTnI concentrations greater than those of the 99th centile of the normal range of values, who were identified by the contemporary assay or the high-sensitivity assay. The high-sensitivity assay reclassified 1771 (17%) of 10 360 patients with myocardial injury or infarction who were not identified by the contemporary assay. In those reclassified, subsequent myocardial infarction or cardiovascular death within 1 year occurred in 105 (15%) of 720 patients in the validation phase and 131 (12%) of 1051 patients in the implementation phase (adjusted odds ratio for implementation vs validation phase 1·10, 95% CI 0·75 to 1·61; p=0·620). INTERPRETATION: Use of a high-sensitivity assay prompted reclassification of 1771 (17%) of 10 360 patients with myocardial injury or infarction, but was not associated with a lower subsequent incidence of myocardial infarction or cardiovascular death at 1 year. Our findings question whether the diagnostic threshold for myocardial infarction should be based on the 99th centile derived from a normal reference population. FUNDING: The British Heart Foundation.

Cerebrospinal fluid total protein cannot reliably distinguish true subarachnoid haemorrhage from other causes of raised cerebrospinal fluid net bilirubin and net oxyhaemoglobin absorbances.

BACKGROUND: In cerebrospinal fluid (CSF) spectrophotometry, if the net bilirubin absorbance (NBA) and net oxyhaemoglobin absorbance (NOA) are both raised with a visible oxyhaemoglobin peak, the revised national guidelines for analysis of CSF bilirubin advise interpreting the results as 'Consistent with subarachnoid haemorrhage (SAH)' regardless of the CSF total protein concentration of the specimen. We wanted to study the range of CSF total protein concentrations found in confirmed SAH to establish if the CSF total protein value can give further guidance on the likelihood of SAH. METHODS: Consecutive cases from five different hospital sites were included if the CSF NBA was greater than 0.007 AU and the NOA was greater than 0.02 AU with a visible oxyhaemoglobin peak. For the cases identified, the laboratory information management system and patient records were interrogated to identify the total protein concentration of the CSF specimen and whether SAH had ultimately been confirmed or excluded by other methods and supporting evidence. RESULTS: Results from 132 patients were included. The CSF total protein range in confirmed SAH was 0.23-3.08 g/L with a median concentration of 0.7 g/L (n = 51). In the SAH excluded group, the CSF total protein range was 0.43-29 g/L with a median concentration of 1.9 g/L (n = 81). CONCLUSIONS: Although confirmed SAH was not associated with the very highest concentrations of CSF total protein, a definite CSF protein cut-off concentration above which SAH could reliably be excluded cannot be recommended.

Revised national guidelines for analysis of cerebrospinal fluid for bilirubin in suspected subarachnoid haemorrhage.

It is crucially important to detect subarachnoid haemorrhage (SAH) in all patients in whom it has occurred to select patients for angiography and preventative surgery. A computerized tomography (CT) scan is positive in up to 98% of patients with SAH presenting within 12 h, but is positive in only 50% of those presenting within one week. Cerebrospinal fluid (CSF) bilirubin spectrophotometry can be used to determine the need for angiography in those few CT-negative patients in whom clinical suspicion of SAH remains high; it may remain positive up to two weeks after the event. A lumbar puncture (LP) should only be performed >12 h after the onset of presenting symptoms. Whenever possible collect sequential specimens. Always ensure that the least blood-stained CSF sample taken (usually the last) is sent for bilirubin analysis. Protect the CSF from light and avoid vacuum tube transport systems, if possible. Always use spectrophotometry in preference to visual inspection. All CSF specimens are precious and should always be analysed unless insufficient sample is received. Centrifuge the specimen at >2000 rpm for 5 min as soon as possible after receipt in the laboratory. Store the supernatant at 4 degrees C in the dark until analysis. An increase in CSF bilirubin is the key finding, which supports the occurrence of SAH but is not specific for this. In most positive cases, bilirubin will occur with oxyhaemoglobin.

National audit of cerebrospinal fluid testing.

BACKGROUND: UK National External Quality Assessment Service (NEQAS) Specialist Advisory Group for EQA of CSF Proteins and Biochemistry was interested in current practice for the biochemical investigation of cerebrospinal fluid (CSF) in the UK. METHODS: A questionnaire was sent to laboratories via regional audit committees and the results collated. RESULTS: Most laboratories were analysing CSF in a satisfactory manner. There was some variation in the reference ranges used for glucose, protein and lactate. There was concern about the rejection policies of some laboratories on these unrepeatable samples and the wavelengths used to measure bilirubin. The survey revealed the lack of spectrophotometric scanning for haem pigments and bilirubin in some hospitals. CONCLUSIONS: The current practice for the measurement of CSF samples in the UK is satisfactory in most laboratories responding to the questionnaire. National agreement on reference ranges for glucose, protein and lactate should be achievable. Those performing spectrophotometric scanning of the CSF were doing so in concordance with the national guidelines. Some hospitals in the UK may not have responded to the questionnaire because they did not offer spectrophotometric scanning.