Emicizumab prophylaxis has been approved in Canada for the prevention or reduction of bleeding episodes in people with congenital hemophilia A (PwHA). Using routinely collected health data from the Canadian Bleeding Disorders Registry (CBDR), this observational cohort study aimed to evaluate the long-term safety and effectiveness of emicizumab in PwHA. De-identified data from the CBDR were collected for PwHA who had received ≥1 dose of emicizumab from 2018 up to December 31, 2023. Intra-patient comparisons of annualized bleeding rates (ABRs) for all reported bleeds pre- and post-emicizumab were performed using a negative binomial regression model. Overall, 710 PwHA received ≥1 emicizumab dose and 539 (75.9%) had >1 year of emicizumab exposure. During the observational period, the safety profile was in keeping with previous reports; 34 adverse events were observed, including two thrombotic events (one unlikely related to emicizumab; one probably related to previous use of eptacog alfa and/or possibly related to previous emicizumab, and associated with a central venous access device). Over a median (Q1-Q3) follow-up time of 549 (374-690) days, 439 (61.8%) PwHA had no recorded bleeds. Mean ABR (95% confidence interval [CI]) decreased from 1.00 (0.87-1.14) pre-emicizumab to 0.47 (0.40-0.55) post-emicizumab (rate ratio [95% CI], 0.47 [0.41-0.55]; P < .001). A notable decrease in bleeds and sustained bleed control were observed in this population for up to a 5-year follow-up period. Continued follow-up will allow for greater quantification of this impact over time, providing valuable information to healthcare practitioners and regulatory authorities.

Background Bone diseases, such as low bone mineral density and osteoporosis is an emerging concern in people with haemophilia (PWH). As a consequence, PWH might experience fractures more frequently than the general population. Our primary aim was to compare the incidence of bone fractures in PWH and controls without bleeding disorders. The secondary aim was to identify factors associated with fractures in PWH.Methods This was a retrospective, matched cohort, study based on data from the Canadian Bleeding Disorders Registry and data from the Institute for Clinical Evaluative Sciences (ICES). PWH were eligible if alive on 1 January 2017. They were followed up to 31 March 2018. Age- and sex-matched controls were randomly selected with a 20:1 ratio. We analysed the data using multivariate regression models, adjusting for age, severity, inhibitor status, and comorbidities (Charlson Comorbidity index).Results 1080 PWH and 21,597 controls were included. 8.7% of PWH and 5.7% of controls experienced a fracture during the follow-up period. The adjusted hazard ratio (aHR) for a fracture was 1.46 [95% confidence interval (CI) 1.19; 1.80] in PWH. Severe haemophilia [adjusted odds ratio (aOR) 1.72, 95% CI 1.02; 2.93] and the presence or history of an inhibitor (aOR 2.42, 95% CI 1.08; 5.42) were risk factors for a fracture, after adjusting for age and comorbidities.Conclusions PWH have a higher risk of bone fractures than the general population. Amongst PWH, the severity of haemophilia and the presence or history of an inhibitor are risk factors for a bone fracture.

Abstract Introduction: Guidelines for thromboprophylaxis after hip fracture surgery suggest parenteral anticoagulants, based on low-certainty evidence. Emerging data suggest that direct oral anticoagulants (DOACs) or acetylsalicylic acid (ASA) might be safe and effective alternatives. We conducted a survey to inform the design of a randomized controlled trial (RCT) in this setting. Methods: We recruited a convenience sample of physicians who could prescribe thromboprophylaxis after hip fracture surgery. The survey was disseminated in Aug–Dec 2023. Participants answered 14 questions on demographics, current practices for thromboprophylaxis after hip fracture surgery, the need for an RCT on this topic, and acceptable interventions for a future RCT. Results: 204 participants from 28 countries completed the survey. Of these, 172 (84%, 95% CI 79%;89%) indicated the need for an RCT. Respondents reported using the following regimens: low-molecular-weight heparin (LMWH) alone (59%, 95% CI: 52%;66%), LMWH followed by rivaroxaban/apixaban (27%, 95% CI: 21%;33%), and rivaroxaban/apixaban without LMWH (25%, 95% CI: 19%;31%). LMWH or LMWH followed by rivaroxaban/apixaban were ranked highest among interventions to be tested in an RCT. Only 64 participants (31%, 95% CI: 25%;37%) were comfortable with ASA alone, and 82 (40%, 95% CI: 33%;47%) with ASA after a short course of anticoagulation. Conclusions: Among respondents, LMWH and DOACs were the most prescribed agents for thromboprophylaxis after hip fracture surgery. For an RCT, respondents were most comfortable with comparing LMWH with LMWH followed by rivaroxaban/apixaban.

BACKGROUND:Over the past few years, new information has emerged in the management of both immune thrombotic thrombocytopenic purpura (iTTP) and congenital (or hereditary) thrombotic thrombocytopenic purpura (cTTP). METHODS:In March 2024, the International Society on Thrombosis and Haemostasis (ISTH) formed a multidisciplinary panel comprising hematologists, intensivists, nephrologists, pathologists, patient representatives, and a methodology team. The panel discussed all treatment questions related to thrombotic thrombocytopenic purpura (TTP) using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method to appraise evidence and formulate recommendations. RESULTS:For patients with cTTP in remission, a new strong recommendation was issued for the use of recombinant ADAMTS-13 over fresh frozen plasma in the context of moderate certainty evidence. The panel also revised a previous recommendation and suggested using fresh frozen plasma over a watch-and-wait approach for patients with cTTP in remission based on very low certainty evidence should recombinant. The panel reviewed and referenced new publications supporting therapeutic efficacy, potential survival benefit, and cost considerations of adding caplacizumab to therapeutic plasma exchange, corticosteroids, and rituximab, but concluded that no change was warranted to the previous recommendations in the management of iTTP. Good practice statements on the concomitant use of antithrombotic agents were marginally modified. CONCLUSIONS:For patients with iTTP, no change to 2020's recommendations. For patients with cTTP, the panel supports ADAMTS-13 replacement. Where accessible, recombinant ADAMTS-13 provides the most favorable balance of benefits and risks. Otherwise, fresh frozen plasma may still be effective. Shared decision-making should include the benefits, the potential harms, and the burden of care.

Background:Comparative safety data on hemophilia therapies are scarce. Objectives:To compare the risk of adverse drug reactions (ADRs) associated with extended-half-life (EHL) and standard-half-life (SHL) clotting factor therapies, bypassing agents, and emicizumab. Methods and Analysis:We analyzed Canadian Bleeding Disorders Registry data from 2018 to 2022. ADRs were defined as adverse events (AEs) if definitely, possibly, or probably treatment-related. We compared incidence rates of ADRs between therapies to estimate incidence rate ratios and 95% CIs. Results:We found a total of 183 AEs and 67 ADRs. Reported AEs varied from 6.1 to 14.8 events per 1000 patients per year. Allergic reactions were the most prevalent ADRs. A higher incidence of allergic reactions was associated with emicizumab compared with EHL (IRR 3.59; 95% CI, 1.43-9.00) and SHL (IRR 11.86; 95% CI, 4.73-29.72) clotting factor concentrates. Events reflecting inadequate hemostatic control and other unintended events occurred more often with emicizumab compared with SHL (IRR 6.39, 95% CI, 1.29-31.63) and EHL concentrates (IRR 2.77, 95% CI, 0.56-13.72). No inhibitor development was reported with emicizumab or bypassing agents. Cases of neurological events and thrombosis were reported when emicizumab was used in combination with other hemostatic therapies. Conclusion:This study highlights the relative safety of therapies approved for the management of hemophilia A and B. While more ADRs were reported with emicizumab, no inhibitor development was observed. However, novelty bias cannot be ruled out. Our estimates are limited by the use of routinely collected data with no adjustment for confounding due to low event rates and missing data.

INTRODUCTION:The Patient Reported Outcomes, Burdens and Experiences (PROBE) questionnaire can be used to measure quality of life in persons with haemophilia (PWH) and is integrated in the Canadian Bleeding Disorders Registry (CBDR). This offers the opportunity to compare the same data inputted by patients in PROBE and their treating team in CBDR. AIM:Our objectives were to assess the feasibility of collecting PROBE data through CBDR and to compare the data collected from these two sources. METHODS:We conducted a prospective observational study among PWH using MyCBDR. Participants were invited to digitally complete the PROBE questionnaire at baseline and to repeat it at 6 and 12 months. Additional data were passively collected through CBDR. Data from PROBE and CBDR were compared using Kappa agreement, intraclass correlation (ICC) and Pearson correlation. RESULTS:A total of 142 PWH participated. Recruitment ratios were 21.1% and 12.0% for the two phases. Retention rates were 40.8% at 6 months and 32.4% at 12 months. Three hundred thirteen subjects were involved in the comparison between PROBE and CBDR data. The agreement was good to very good (κ > 0.75) or the correlation very strong, with the exception of the history of inhibitor (κ = 0.57), recent bleeds (κ = 0.48) and current treatment regimen (κ = 0.57). CONCLUSION:The integration of PROBE with CBDR is feasible and PROBE is a reliable tool for routine PRO data collection. Its use in clinical practice may improve data quality and personalized and patient-centred care.

The safety of home treatment for patients with low-risk acute pulmonary embolism (PE) has been confirmed in several studies; however, these studies have used varying triaging criteria and outcomes, leading to inconsistencies in defining safe discharge parameters. This study aimed to identify adverse outcomes that make home discharge inappropriate, their timeframe, and clinical criteria indicating high risk for such events.Following a systematic literature review, an international expert panel participated in three Delphi survey rounds. Experts evaluated each proposal using a Likert scale, and consensus required 75% agreement. Items without consensus were reassessed in subsequent rounds until agreement was achieved.Of the 55 invited experts, 38 from 13 countries participated (69%). Consensus was reached on six adverse events for a composite outcome, with a 7-day post-discharge timeframe and a maximum acceptable incidence of 2.0%. The panel defined a triaging rule with 14 clinical criteria as contraindications for home treatment, grouped into four categories: hemodynamic (3), respiratory (1), hemorrhagic (7), and medico-social (3). An extended rule, adding three optional biological or imaging criteria, was developed to further refine risk assessment.The expert panel established a consensus-based triaging rule for the home treatment of PE patients. This framework defines adverse outcomes, a 7-day safety timeframe, and an acceptable risk threshold for assessing patient safety. Future prospective studies are needed to validate the EARTH rule before its implementation in clinical practice.

OBJECTIVES:Published systematic reviews display a heterogeneous methodological quality, which can impact decision-making. Large language models (LLMs) can support and make the assessment of the methodological quality of systematic reviews more efficient, aiding in the incorporation of their evidence in guideline recommendations. We aimed to develop an LLM-based tool for supporting the assessment of the methodological quality of systematic reviews. METHODS:We assessed the performance of 8 LLMs in evaluating the methodological quality of systematic reviews. In particular, we provided 100 systematic reviews for eight LLMs (five base models and three fine-tuned models) to evaluate their methodological quality based on a 27-item validated tool (Reported Methodological Quality (ReMarQ)). The fine-tuned models had been trained with a different sample of 300 manually assessed systematic reviews. We compared the answers provided by LLMs with those independently provided by human reviewers, computing the accuracy, kappa coefficient and F1-score for this comparison. RESULTS:The best performing LLM was a fine-tuned GPT-3.5 model (mean accuracy = 96.5% [95% CI = 89.9%-100%]; mean kappa coefficient = 0.90 [95% CI = 0.71-1.00]; mean F1-score = 0.91 [95% CI = 0.83-1.00]). This model displayed an accuracy >80% and a kappa coefficient >0.60 for all individual items. When we made this LLM assess 60 times the same set of systematic reviews, answers to 18 of 27 items were always consistent (ie, were always the same) and only 11% of assessed systematic reviews showed inconsistency. CONCLUSION:Overall, LLMs have the potential to accurately support the assessment of the methodological quality of systematic reviews based on a validated tool comprising dichotomous items.

OBJECTIVES:Clinical practice guideline (CPG) development for rare diseases is challenging due to scarce evidence, small expert groups, limited resources, and heterogeneity and complexity of conditions. Critical appraisals of existing rare disease CPGs reveal variable methodological quality. We aimed to gather the experiences of rare disease guideline developers to identify methodological challenges and strategies and eventually inform methodological guidance for rare disease CPGs. STUDY DESIGN AND SETTING:We conducted semistructured interviews with 15 guideline developers from ten countries and diverse medical fields with hands-on experience in rare disease CPG development. Data were analyzed through a combined deductive and inductive approach following the structure of the GIN-McMaster Guideline Development Checklist. RESULTS:Small rare disease expert groups, while highly dedicated, faced significant risks related to conflicts of interest, limited methodological expertise, resource constraints, and challenges in achieving interest-holder representation. Guideline developers adopted pragmatic approaches to utilize scarce and very low-certainty direct evidence and supplement it with indirect and expert-based evidence, registry data, and mechanistic reasoning. The Grading of Recommendations Assessment, Development and Evaluation methodology was valued for providing transparency, structure, and consistency, but some considered it not feasible in rare disease contexts. Topics beyond the GIN-McMaster Guideline Development Checklist included deciding whether to develop a CPG or another type of quality document and supporting the broader knowledge cycle. CONCLUSION:We gained insight into the most salient methodological issues and identified a need for further guidance and method development to improve guideline development processes for rare diseases.

An evidence-based pathway for pulmonary embolism testing was implemented in two academic emergency departments as part of a prospective management study (the PEGeD study). This study aimed to identify factors associated with emergency physicians not following (deviating from) the PEGeD pulmonary embolism testing pathway. This was a health records review of cases from the PEGeD study which enrolled emergency patients with suspected pulmonary embolism. Emergency physicians documented the Wells score on hard-copy PEGeD pathway forms which guided the use of diagnostic imaging. Patient visits were classified as having pulmonary embolism testing adhering to or else deviating from the PEGeD pathway. Patient data were collected from electronic medical records. We calculated adjusted odds ratios (aORs) for prespecified predictors of deviation: patient age, patient sex, arrival day of week, arrival time of day, documented hypotension, higher Canadian Triage and Acuity Score (CTAS) allocation, active cancer, and a history of venous thromboembolism. The multivariable logistical regression analysis was clustered by individual physician. In total 1570 PEGeD forms were received, 78 were excluded and 1492 patients were included for analysis. The mean age was 55, 62

BACKGROUND:Acute pulmonary embolism (PE) includes clinical presentations with a wide spectrum of severity, making risk stratification essential to guide the decision-making process in daily practice. However, international guidelines differ in their definition of risk classes and consequent treatment recommendations. OBJECTIVES:To summarize high-quality evidence supporting 4 key management decisions in acute PE: hospitalization, intensive care unit admission, reperfusion therapy, and discharge. METHODS:A multidisciplinary International Society on Thrombosis and Haemostasis task force, composed of international experts, conducted a literature review of randomized controlled trials and prospective management studies reporting hard clinical outcomes and assessed as having a low risk of bias, focusing on any of the 4 management decisions detailed above. RESULTS:Available evidence supports the use of either the Hestia criteria or the (simplified) PE Severity Index, combined with clinical judgment, to select PE patients for outpatient treatment. In contrast, no PE-specific evidence exists to guide intensive care unit admission. Reperfusion therapy in hemodynamically unstable patients is supported by 1 small randomized trial, while currently available high-quality evidence does not support routine reperfusion therapy in hemodynamically stable patients; therefore, hemodynamic instability remains the only established indication for reperfusion therapy to date. The decision to discharge a PE patient may be supported by the use of the (simplified) PE Severity Index, combined with clinical assessment of stability. CONCLUSION:Overall, substantial evidence gaps persist, underscoring the need for further research to inform clinical practice and future guidelines.

BACKGROUND:Studies on pulmonary embolism (PE) rule-out strategies traditionally recruited patients in the ED. This method is increasingly impractical given excessive pressures experienced in EDs. Attempting to reach patients after leaving the ED may be more feasible. The aim of this study was to assess the feasibility of recruiting and following patients for an ED PE testing study by telephone. METHODS:This was a prospective pilot study conducted in one ED and one urgent care centre in Ontario, Canada. Adult patients tested for PE using Adjust-Unlikely (a simple decision rule combining Gestalt with age-adjusted D-dimer) were called for consent after leaving the ED. Patients were followed for 90 days by medical record review plus telephone, text or email to identify subsequent venous thromboembolism testing. Venous thromboembolism events were independently adjudicated. Feasibility outcomes were recruitment rate, missed eligible rate and follow-up rate. Progression criteria were a recruitment rate of at least five participants per site, per week, a missed eligible rate of no more than two patients per site, per week, and a follow-up rate of at least 90% of enrolled patients. RESULTS:684 patients were tested for PE between 24 March and 10 June 2023. A total of 210 patients were excluded. From 474 eligible patients, 200 were recruited. Median age was 58 years, 72.2% were female, and 3.5% were diagnosed with PE on index visit. Median recruitment rate was 7 participants per site, per week (first-third quartile (Q1-Q3), 4-14) and median missed eligible rate was 6 patients per site, per week (Q1-Q3, 3-8). After 90 days, 2 participants withdrew and 191/198 (96.5%, 95% CI 92.9, 98.3%) were contacted in follow-up. 143/198 (72.2%, 95% CI 65.6, 78.0%) participants did not require pulmonary imaging because PE was excluded by Adjust-Unlikely. 1/143 (0.7%, 95% CI 0.1, 3.9%) of these participants was diagnosed with PE in the segmental pulmonary arteries during follow-up. CONCLUSIONS:Telephone recruitment did not meet predefined feasibility thresholds as the missed eligible rate was high. However, the recruitment rate was higher than in previous studies, and there was minimal loss to follow-up.

Our primary objective was to determine whether the yield of pulmonary embolism imaging in the emergency department (ED) is different for patients presenting with “chest pain with cardiac features” than with other complaints. The yield of imaging was defined as the proportion of imaging tests that were positive for pulmonary embolism. Secondary objectives were to estimate the prevalence of pulmonary embolism, the use of imaging, and the yield of imaging for each presenting complaint category. Our hypothesis was that the presenting complaint influences the physician’s threshold for requesting imaging. We performed an observational health records review study including all adult patient visits between 2018 and 2019 in three EDs in Hamilton (Ontario), Canada. The primary outcome was the diagnostic yield of imaging (computed tomography pulmonary angiogram or ventilation/perfusion scan). We performed a multivariable regression analysis using a generalized linear model, adjusting for confounders. During the study period, 518,787 patients were assessed and 6,700 received imaging for pulmonary embolism. Among the 29,834 triaged as having chest pain with cardiac features, 1,440 (4.8

INTRODUCTION:Damoctocog alfa pegol (BAY 94-9027, Jivi®) is an extended half-life recombinant factor (F)VIII replacement, indicated for the treatment of haemophilia A in patients aged ≥12 years. Following introduction of damoctocog alfa pegol in Canada in 2020, there have been no reports on routine clinical effectiveness and satisfaction, when switching from a previous FVIII product in Canada.AIM:To report changes in pharmacokinetics, effectiveness, utilization and patient satisfaction when switching to damoctocog alfa pegol prophylaxis from previous standard half-life octocog alfa (BAY 81-8973, Kovaltry®) treatment.METHODS:A single-centre, intra-patient comparison of pharmacokinetics and clinical outcomes was performed. Blood samples drawn once pre-dose and ≥2 times post-dose were measured by a one-stage assay to assess pharmacokinetic parameters including area under the curve (AUC, primary endpoint). Patient-reported outcomes data were collected using the Patient-Reported Outcomes, Burdens and Experiences questionnaire (PROBE). Clinical outcomes included annualized bleeding rate (ABR) and factor utilization.RESULTS:Dose-normalized AUC was significantly increased after switch to damoctocog alfa pegol from octocog alfa. Median (quartile [Q]1; Q3) annualized bleeding rates were 0.67 (0.00; 1.33) with damoctocog alfa pegol and 1.33 (0.00; 2.67) with octocog alfa. Half of the patients receiving damoctocog alfa pegol prophylaxis experienced zero bleeds (n = 9, 50.0%) versus 38.9% (n = 7) of patients treated with octocog alfa. Patients' good quality of life was maintained.CONCLUSION:This study provides routine clinical evidence supporting the benefits of switching from octocog alfa to damoctocog alfa pegol for patients with severe haemophilia A.