American Society Of Hematology Guidelines Research Articles

Clinical Benefits, Harms, and Cost-Effectiveness of Indefinite Anticoagulant Therapy for First Unprovoked Venous Thromboembolism: A Decision Analytic Modelling Study

Background: Anticoagulation for 3-6 months is the minimum required duration of treatment for patients with venous thromboembolism (VTE). Whether to extend treatment beyond the initial 3-6 months of anticoagulation in patients with a first unprovoked VTE has been debated. The American Society of Hematology guidelines suggest continuing anticoagulation indefinitely over discontinuing anticoagulation after completing 3-6 months of initial treatment for a first unprovoked VTE, except in patients who have a high risk for bleeding (Ortel T, Blood Adv 2018). However, the lifetime clinical benefits, harms, and cost-effectiveness of indefinite anticoagulation have not been formally assessed. While a randomized controlled trial (RCT) would be the optimal study design to provide evidence for or against continuing anticoagulation indefinitely in patients with a first unprovoked VTE, it is unlikely to be conducted due to the lifelong (i.e. until death) follow-up and extremely large sample size that would be required.Decision-analytic modelling can provide evidence to inform guidelines under circumstances in which RCTs are unfeasible. Objective: The aim of this modelling study was to compare the clinical benefits, harms, and cost-effectiveness of continuing versus discontinuing anticoagulation indefinitely after completing initial treatment for a first unprovoked VTE. Methods: We created a probabilistic Markov cohort simulation model [Figure 1] to simulate costs (adjusted to 2022 Canadian dollars) and outcomes (recurrent VTE, major bleeding, and quality-adjusted life-years [QALYs]) for two hypothetical cohorts of patients aged 55 years with a first unprovoked VTE that had completed 3-6 months of initial anticoagulant therapy - one cohort assigned to continue anticoagulation indefinitely with direct oral anticoagulants, and another assigned to discontinue anticoagulation indefinitely. The model adopted a cycle length of 1 month and a lifetime horizon. The economic analysis adopted a third-party payer perspective relating to the Canadian publicly-funded healthcare system. The long-term risks and case-fatality rates of recurrent VTE and major bleeding, with and without extended anticoagulation, were sourced from our recently published systematic reviews (Khan F, BMJ 2019;Khan F, Ann Intern Med 2021). Additional data related to transition probabilities, costs, and utility values were obtained from highest quality published sources identified through a targeted literature search. Future costs and QALYs were discounted at an annual rate of 1.5% as per Canadian guidelines. The model structure, input parameters, and assumptions were validated by clinical experts to ensure that they coincided with current clinical practice. Results: In a hypothetical cohort of 1000 patients, continuing anticoagulation indefinitely, compared to discontinuing anticoagulation, prevented 253 recurrent VTE events (number needed to treat = 4) and induced an additional 69 major bleeding events (number needed to harm = 15). Indefinite anticoagulation resulted in higher health system costs ($70,019.35 vs. $61,438.10 per person) and no improvement in QALYs (15.26 vs. 15.31 per person; incremental difference of -0.05 QALYs or -18.25 quality adjusted life-days) [Table 1]. Model results were most sensitive to the annual risk of major bleeding and case-fatality rate of major bleeding during extended anticoagulation however, in all one-way sensitivity analyses, discontinuing anticoagulation remained economically dominant (i.e., lower costs and similar QALYs) over continuing anticoagulation indefinitely, at a willingness-to-pay (WTP) threshold of Can$50,000 per QALY. In probabilistic analyses, the probability of indefinite anticoagulation being the cost-effective treatment strategy was 0% at a WTP threshold of Can$50,000 or Can$100,000 per QALY. Conclusions: Indefinite anticoagulation for a first unprovoked VTE is unlikely to either result in a net clinical benefit or be cost-effective. With no net gain in QALYs (albeit a small net loss), there is no rationale for continuing anticoagulation indefinitely in all (i.e., unselected) patients with a first unprovoked VTE. However, the clinical and cost-effectiveness of indefinite anticoagulation in subgroups of patients at high risk of recurrent VTE and low risk of major bleeding requires further investigation, and will be an important next step. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Mindfulness Practices for Chronic Pain in Sickle Cell Disease

Background: Patients with sickle cell disease (SCD) suffer from both acute and chronic pain that severely affects their quality of life. Pain is largely managed with opioids, which have significant side effects including dependence, adverse mood effects, and potential for opioid-induced hyperalgesia. The 2020 American Society of Hematology guidelines for SCD suggests cognitive and behavioral pain management strategies (including mind-body interventions). However, there remains low certainty in the evidence of these modalities. We chose to pursue mindfulness-based interventions given their proven efficacy in other chronic pain syndromes and associated mental health disorders. Objective: The purpose of our pilot study was to assess the feasibility and acceptability of weekly group yoga therapy sessions conducted virtually via videoconferencing software in patients with sickle cell disease and chronic pain, defined as pain on more than 15 days per month for the last 6 months. Design: Twenty patients with SCD were recruited for weekly virtual group yoga therapy sessions, which incorporated aspects of mindfulness meditation and low impact movements synchronized with breathing exercises (see Table 1). Results: Twenty out of 22 patients (92%) approached for the study agreed to participate. The median age of participants was 35 (IQR 26-43), with the majority being female (n=13 out of 19, 68%). The baseline survey revealed participants had frequent Emergency Department visits (median 3, IQR 1.25-4) and hospitalizations (median 2, IQR 0-2) in the 6 months prior to the intervention. The study population exhibited high levels of pain catastrophizing (median PCS 40.5, IQR 27.25-52.5, 93%tile), anxiety (median GAD-7 18.5, IQR 10.25-21.5), and depression (median PHQ-9 17, IQR 13.25-22.5). On average, 15% of participants (range 2-32%) attended each session. Barriers to participation included technologic difficulties, time conflicts, and inability to contact participants. The participants who consistently attended the sessions had positive feedback. One participant stated, "It went well for me. Meditation was helpful...[and] the yoga helped with my knee." Another participant commented, "I liked having a community with the other patients." Conclusions and Future Directions: This pilot study was among the first of its kind to examine mindfulness practices for chronic pain in adults with SCD. While there was a high rate of agreement to participate in the study, indicating a willingness and receptiveness to the study intervention, the overall participation per session was low. The study population had high rates of health care utilization despite most participants being on chronic opioid therapy and disease modifying medications, which illustrates the need for additional therapeutic strategies. A striking aspect of the baseline survey was the high rates of pain catastrophizing, anxiety, and depression, which directly impact chronic pain and thus require a holistic approach that includes mindfulness-based interventions. Our future research will draw upon lessons learned from the pilot study to address barriers to participation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Platelet Count Threshold Associated with Bleeding in Adult Patients with Immune Thrombocytopenia Treated with Antiplatelet Drugs. Results from the Carmen-France Registry

Introduction: In 2019, international guidelines for the management of immune thrombocytopenia (ITP) stated that ITP treatment is rarely indicated in case of platelet count >20 x109/L. The threshold associated with significant bleeding in ITP patients treated with antiplatelet agents is unknown, and 2019 American society of hematology guidelines for ITP management stressed the need for studies to determine it. This was the aim of this study. Methods: The source of data was the CARMEN-France registry, a prospective, real-world registry of incident ITP adults in the French Midi-Pyrénées region since June 2013, implemented in other centers of the French Autoimmune cytopenia referral center network since 2016. Inclusion criteria were adult patients (aged ≥18 years) newly diagnosed with ITP (platelet count <100 x 109/L and exclusion of other causes of thrombocytopenia). We designed a transversal study to correlate the platelet count to bleeding at ITP diagnosis, before any ITP treatment. Study population consisted in the patients included in the registry up to November 2021 and treated with antiplatelet agents at the time of ITP diagnosis, without concomitant exposure to anticoagulant. We quantified the percentages of patients with overall bleeding, cutaneous bleeding, non-serious mucosal bleeding and serious bleeding (defined by intracranial bleeding, gastro-intestinal bleeding or gross hematuria with anemia) by categories of platelet count (by 109/L up to 50 x 109/L then ≥50 x 109/L). Analyses were conducted by subgroups of antiplatelet agents due to suspected differences in pharmacological effect in patients with ITP who have a high platelet turn over: patients treated with clopidogrel and ticagrelor, two reversible ligands to P2Y12 receptor with longer half-life, may be at a higher risk of bleeding than those treated with acetylsalicylic acid alone, an irreversible ligand to COX-1. Results: Out of 1171 adult patients with incident primary ITP included in the registry during the study period, 143 (12.2%) were exposed to an antiplatelet drug at the time of ITP diagnosis: 108 to acetylsalicylic acid alone, 20 to clopidogrel alone and 15 to an association of antiplatelet agents (acetylsalicylic acid + clopidogrel, n=13; acetylsalicylic acid + ticagrelor, n=2). In the acetylsalicylic acid group, the median age was 75.5 years, 73 (67.6%) were men, median platelet count at ITP diagnosis was 15 x 109/L and 66 (61.1%) had bleeding: 60 (55.6%) a cutaneous bleeding, 35 (32.4%) a non-serious mucosal bleeding and 4 (3.7%) a serious bleeding (3 gastrointestinal bleeding with anemia and 1 gross hematuria with anemia). The pattern of bleeding by platelet count categories is shown in Figure 1. The frequency of overall bleeding was 97.6% (41/42) in the < 10 x 109/L group, 66.7% (14/21) in the 10 - 19 x 109/L group and 22.2% (10/45) in the ≥20 x 109/L group (similar pattern by all categories ≥20 x 109/L). The receiver operating characteristics curve had an area under the curve of 88.3% (95% confidence interval: 81.9-94.6%). The threshold of <20 x 109/L had a sensitivity of 83.3% and a specificity of 81.0%. The pattern for cutaneous and non-serious mucosal bleeding was similar (Figure 1). All four serious bleeding occurred in patients with a platelet count <20 x 109/L. In the clopidogrel and association of antiplatelet drug groups, bleeding was observed in 14 (70.0%) and 10 (66.7%) patients, respectively. No clear correlation with the platelet count was shown, limited by the low number of patients. One serious bleeding occurred in each group (two intracranial bleeding), in patients with platelet counts < 10 x 109/L. Conclusion: This study shows that the bleeding risk in ITP patients treated with acetylsalicylic acid alone is similar to other ITP patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

28-Year-Old Man With Joint Pain

28-Year-Old Man With Joint Pain

Cost-effectiveness of second-line therapies in adults with chronic immune thrombocytopenia.

Major options for second-line therapy in adults with chronic immune thrombocytopenia (ITP) include splenectomy, rituximab, and thrombopoietin receptor agonists (TRAs). The American Society of Hematology guidelines recommend rituximab over splenectomy, TRAs over rituximab, and splenectomy or TRAs while noting a lack of evidence on the cost-effectiveness of these therapies. Using prospective, observational, and meta-analytic data, we performed the first cost-effectiveness analysis of second-line therapies in chronic ITP, from the perspective of the U.S. health system. Over a 20-year time-horizon, our six-strategy Markov model shows that a strategy incorporating early splenectomy, an approach at odds with current guidelines and clinical practice, is the cost-effective strategy. All four strategies utilizing TRAs in the first or second position cost over $1 million per quality-adjusted life-year, as compared to strategies involving early use of splenectomy and rituximab. In a probabilistic sensitivity analysis, early use of splenectomy and rituximab in either order was favored in 100% of 10000 iterations. The annual cost of TRAs would have to decrease over 80% to begin to become cost-effective in any early TRA strategy. Our data indicate that effectiveness of early TRA and late TRA strategies is similar with the cost significantly greater with early TRA strategies. Contrary to current practice trends and guidelines, early use of splenectomy and rituximab, rather than TRAs, constitutes cost-effective treatment in adults with chronic ITP.

Standardized wording to improve efficiency and clarity of GRADE EtD frameworks in health guidelines

BackgroundGrading of Recommendations Assessment, Development and Evaluation (GRADE) Evidence-to-Decision (EtDs) frameworks are increasingly applied by health guideline developers to improve the use of evidence and transparency of health recommendations. Typically, EtDs include 12 criteria but these are flexible and EtDs have been adapted to different types of health decisions. However, developers of health recommendations struggle with the content that they should include in the EtD. The goal of this work was to provide a standardized template that facilitate the development of GRADE EtDs in health guidelines and examples for practical training. MethodsWe began by establishing the need for standardized wording templates in 10 American Society of Hematology guidelines with over 250 recommendations. We drafted template wording, and examples, and sought iterative feedback from methodologists and guideline panels in this guideline and two additional guidelines. ResultsWe generated templates for all EtD criteria describing the type of research evidence considered, ideally based on systematic reviews, using standardized reporting of effect size, integrating the certainty of evidence and additional considerations. We also produced templates to inform the completion of the EtD conclusions section that includes recommendations, justification, implementation considerations, monitoring and evaluation and research priorities. ConclusionWe developed a pragmatic and useful tool to support clarity, transparency, and efficiency of the guideline EtD process.

Anticoagulation in COVID-19

Anticoagulation in COVID-19

Cost-Effectiveness of Second-Line Therapies in Adult Patients with Chronic Immune Thrombocytopenia

Introduction: Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by accelerated platelet clearance and impaired platelet production. Up to 75% of cases in adults assume a chronic course. Standard second-line treatment options include rituximab, thrombopoietin receptor agonists (TPO-RAs), and splenectomy. The 2019 American Society of Hematology (ASH) guidelines provide three dichomotous evaluations of these treatments with conditional recommendations for 1) splenectomy or TPO-RA, 2) rituximab over splenectomy, and 3) TPO-RA over rituximab. The guideline panel noted that there were no studies available to evaluate the cost-effectiveness of these therapies. We sought to address this knowledge gap by conducting the first cost-effectiveness analysis of second-line therapies for chronic ITP. Methods: We built a Markov model comparing the cost-effectiveness of all six treatment pathways utilizing rituximab, TPO-RA (romiplostim or eltrombopag), and splenectomy. We assumed a median age of 50 at diagnosis and a 20-year time-horizon. Costs were assessed from the health system perspective. Effectiveness was calculated in quality-adjusted life-years (QALYs). The costs of splenectomy treatment included the cost of surgery, postoperative care, accessory spleen imaging and repeat splenectomy, treatment for post-splenectomy sepsis and thromboembolism. The annual risks of post-splenectomy sepsis and thromboembolism were assumed to be the highest reported, every post-splenectomy infectious complication was assumed to be severe septic shock, and patients with thromboembolism accrued the costs of indefinite anticoagulation. To minimize bias against TPO-RAs, TPO-RA therapy was assumed to have no adverse events, a constant high overall response without any loss of effectiveness, and the highest reported rate of successful TPO-RA therapy discontinuation after two years, which we assumed to be permanent. Rituximab treatment was assumed to have no adverse events and overall response rates as previously reported. Cost-effectiveness of each treatment pathway was calculated as the incremental cost-effectiveness ratio (ICER), calculated as ratio of costs to QALYs. The ICER was compared against a 2019 US willingness-to-pay (WTP) threshold of $195,300. We then performed one-way deterministic sensitivity analyses varying all parameters including the costs of splenectomy, TPO-RA, rituximab, splenectomy complications, splenectomy complete response rates, TPO-RA and rituximab overall response rates, utilities of the well and diseases states, annual post-splenectomy septic shock mortality and perioperative splenectomy mortality. We concluded with a probabilistic sensitivity analysis running 10,000 Monte Carlo simulations. Results: The most cost-effective treatment pathway was #5 (splenectomy->rituximab->TPO-RA; Figure). The next most cost-effective pathway was #4 (rituximab followed by splenectomy and then TPO-RA therapy), with an ICER of $369,289. All four remaining treatment pathways (#1-3, 6) utilizing TPO-RA therapy early (first or second) had an ICER above $1 million, far above the US WTP of $195,300, and/or were dominated. Of these, pathways #1 and #3 were externally dominated and #2 was absolutely dominated. No parameter change in one-way deterministic sensitivity analysis in any of the 4 pathways featuring TPO-RA early brought down the ICER to under $1 million. In the probabilistic sensitivity analysis, pathway #5 was favored in 100% of 10,000 Monte Carlo simulations. The cost of TPO-RA would have to be decreased to under $20,000 annually (e.g., >80% reduction in the cost of eltrombopag or romiplostim) before it could become cost-effective in any TPO-early treatment pathway.Conclusion: Four treatment pathways (#1-#4) are consistent and two pathways (#5-#6) are at variance with the ASH guidelines. Although it does not align with the ASH guidelines, pathway #5 (splenectomy->rituximab->TPO-RA) was most cost-effective. Over a 20-year time-horizon, all pathways featuring early use of a TPO-RA exceeded an ICER >$1 million or were dominated. Because our model was designed to maximize the cost-effectiveness of TPO-RA, it is likely that the actual ICER of pathways featuring early use of TPO-RA are higher than what we report here. Preferred second-line treatment strategies in adults with chronic ITP may be worth considering in light of our findings. [Display omitted] DisclosuresCuker: Synergy: Consultancy; Novo Nordisk: Research Funding; Alexion: Research Funding; UpToDate: Patents & Royalties; Novartis: Research Funding; Bayer: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Sanofi: Research Funding; Spark Therapeutics: Research Funding.

Evaluating the Impact of Thrombopoietin Receptor Agonists Medications on Patient Outcomes and Quality of Life in Pediatric Immune Thrombocytopenia

▪Introduction: The treatment of Immune Thrombocytopenia (ITP) in children has advanced significantly over the last decade with novel therapies and enhanced clinical care guidelines. Recent American Society of Hematology guidelines now recommend the use of thrombopoietin receptor agonist (TPO-RA) medications as the preferred second line therapy for children with ITP. Accompanying this change, recent ASH guidelines also put emphasis on quality of life in managing ITP, acknowledging the detrimental affect ITP and previous managements can have on patient's and family's quality of life. With this change in guidelines, evaluating the impact of these medications on patient reported outcomes outside of clinical trials is important to evaluate the efficacy of therapy. While there is data from adult studies to show that TPO-RAs improve patient's health related quality of life (HRQoL), results were not statistically significant in previous clinical trials in children. Thus, the goal of the present study is to address this gap and describe the real-world experience of using TPO-RAs in pediatric ITP including the impact on patient-reported HRQoL.Methods: We reviewed all children aged 1-18 at our institution with a diagnosis of ITP and started on a TPO-RA medication after March 1, 2017 (date of TPO-RA for pediatric ITP licensure in Canada). A chart review was conducted to collect demographic data (e.g., age, associated diagnoses, previous therapies), TPO-RA data (e.g. dose(s), monitoring, side effects), outcome data (e.g., platelet count, need for emergency treatments). To explore the impact of TPO-RA use on patient-reported HRQoL, semi-structured interviews were conducted by phone with patients over age 7 and/or their guardians with topics including the effects of the TPO-RA on patient symptoms (e.g. bleeding, bruising, need for emergency treatment), activities (e.g. sports, hobbies, social events) mood (e.g. anxiety, stress, fatigue) and financial burden of treatment (e.g. coverage for medication). These interviews were conducted data in parallel to reviewing the Kids ITP Tool (KIT) questionnaire and a qualitative analysis of HRQoL was performed.Results: We identified 25 patients on a TPO-RA medication for pediatric ITP, of these, 3 were on romiplostim, 20 were on eltrombopag and 2 had been on both romiplostim and eltrombopag at different times. The median age at start of TPO-RA was 9 years (range 1 - 16 years). 14/25 responded to TPO-RA medication by meeting platelet count criteria. The average number of treatments per patient in the 6 months prior to commencing a TPO-RA was 3.7 and in the 6 months post commencing a TPO-RA was 0.5. No significant side effects observed with TPO-RA use, although 2 patients had a transient rise in liver enzymes.Of the 25 patients on a TPO-RA, 23 were eligible to participate in the semi-structured interviews (1 family having permanently relocated out of country and was not contactable; one family had a significant language barrier). With interviews ongoing, 11/23 patients and/or families have participated and results to date indicate that the majority (>90%) have seen an improvement in quality of life. All participants interviewed at the time of abstract submission reported improvement in bleeding/bruising symptoms. The majority also noted a reduction in the frequency of emergency treatments and hematology clinic visits. Several participants reported on their ability to resume sports/activities once on a TPO-RA. While there was some reduction in parental stress/worry there was no clear benefit to patient fatigue/mood. Financial concerns about medication costs and duration of therapy were raised, and many parents expressed the cost of medication and source of ongoing funding a significant stressor. There were also concerns related to oral administration for younger children.Discussion: To our knowledge, this is the first post-licensing study to look at the impact of TPO-RA medications on patient-reported HRQoL in children with ITP. At our institution, TPO-RA medications prescribed for pediatric ITP have had a positive impact on patient platelet count and resulted in a reduced need for emergency treatment with minimal noted side effects. There also appears to be a positive impact on patient reported HRQoL reported by the majority of patients and/or families, while issues with medication administration, cost and long-term duration of therapy remain a concern. DisclosuresKlaassen: Agios Pharmaceuticals: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Hoffman-La Roche: Consultancy; Novo Nordisk: Consultancy; Octapharma AG: Consultancy; Sanofi: Consultancy; Takeda: Consultancy.

Standardizing the Diagnostic and Therapeutic Approach to Newly Diagnosed Children with ITP: An ITP Consortium of North America (ICON) Quality Improvement Initiative

BACKGROUNDPediatric immune thrombocytopenia (ITP) is an acquired disorder of platelet destruction that is associated with an increased risk of bleeding. Despite published guidelines for the management of ITP, the available evidence is of low grade, leading to practice variation in different settings. The use of validated bleeding scores to guide clinical decision making is inconsistent. In addition, many children are initially treated with medications despite the recommendation for observation in newly diagnosed children with ITP and no or mild bleeding symptoms. This approach leads to over-utilization of healthcare resources including hospitalizations, medication administration, and medical encounters for management-related side effects. In 2020, a quality improvement (QI) project of the Pediatric ITP Consortium of North America (ICON) was initiated to improve consistency in clinical practice at ICON sites using national ITP guidelines.DESIGN/METHODSWithin the ICON QI subcommittee, a standardized clinical care pathway (Figure 1) for newly diagnosed childhood ITP was developed based on the American Society of Hematology (ASH) 2019 guidelines. The goal was to unify approach to management, decrease practice variation, identify and learn from deviations in decision making, and decrease resource utilization by increasing observation rates in low-risk pediatric ITP patients. Site investigators shared the care pathway to update institutional providers on national guidelines. For Aim 1 of this project, sites completed a multi-center, retrospective analysis documenting the pre-QI pathway management of children, ages 1-16 years, diagnosed with ITP from January to December 2019. Statistical analysis was performed using R version 4.0.2. For Aim 2, after local dissemination and education of the clinical care pathway, clinicians at all participating sites will review the pathway at the time of managing newly diagnosed children and then complete a short survey documenting a bleeding score and management decisions.RESULTSCurrent data from the retrospective review is summarized in Figure 1. 98 patients across four ICON institutions are included in this analysis. The median age at diagnosis was 6 years (IQR 2.7, 9.2) with 61% being male. 43 (44%) patients had their first hematology encounter in the inpatient setting, 40 (41%) in the outpatient clinic, and 14 (14%) in the emergency room. Buchanan and Adix bleeding scores were obtained from only one patient (1%) at diagnosis. Treatment strategies varied including observation in 47 (48%) patients, IVIG in 40 (41%), corticosteroids in 9 (9%), and anti-D globulin in 3 (3%). 53 (54%) patients were admitted at the time of diagnosis. The prospective QI pathway is being utilized by six ICON institutions and 20 patients have been followed on the pathway since November 2020. An additional seven sites are in various phases of study activation.DISCUSSIONEvidence-based ITP guidelines and an expert consensus report have been recently published. For children with newly diagnosed ITP and a platelet count <20 x 10 9/L who have no or mild bleeding, ASH guidelines suggest against admission to the hospital and suggest observation rather than treatment with corticosteroids. Retrospective analysis of the management at four ICON centers demonstrates the variation in approach to treatment. However, although guidelines suggest initial management based on objective assessment of bleeding symptoms, only one patient (1%) had a documented bleeding score at presentation, suggesting a lack of a standard approach to management and practice variation. These data support the need for this quality initiative, which involves clinicians reviewing the pathway while managing patients and answering a survey at the time of clinical visits to report on bleeding symptoms and management. This initiative will be expanded to include a total of 13 institutions across the United States. Data will be analyzed every 1-2 years and changes will be made to the pathway with the goal of improving care. Further quality initiatives may help to standardize the management approach of pediatric ITP patients and optimize health outcomes in this patient population. [Display omitted] DisclosuresBadawy: Bluebird Bio Inc: Consultancy; Sanofi Genzyme: Consultancy; Vertex Pharmaceuticals Inc: Consultancy. Grace: Novartis: Research Funding; Dova: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Research Funding; Principia: Membership on an entity's Board of Directors or advisory committees. Nakano: Novartis: Consultancy.

Guidelines: the same evidence but different conclusions - relaxation of indications for irradiation of cellular blood components?

Guidelines: the same evidence but different conclusions - relaxation of indications for irradiation of cellular blood components?

How to write a guideline: a proposal for a manuscript template that supports the creation of trustworthy guidelines

AbstractTrustworthy health guidelines should provide recommendations, document the development process, and highlight implementation information. Our objective was to develop a guideline manuscript template to help authors write a complete and useful report. The McMaster Grading of Recommendations Assessment, Development and Evaluation Centre collaborated with the American Society of Hematology (ASH) to develop guidelines for the management of venous thromboembolism. A template for reporting the guidelines was developed based on prior approaches and refined using input from other key stakeholders. The proposed guideline manuscript template includes: (1) title for guideline identification, (2) abstract, including a summary of key recommendations, (3) overview of all recommendations (executive summary), and (4) the main text, providing sufficient detail about the entire process, including objectives, background, and methodological decisions from panel selection and conflict-of-interest management to criteria for updating, as well as supporting information, such as links to online (interactive) tables. The template further allows for tailoring to the specific topic, using examples. Initial experience with the ASH guideline manuscript template was positive, and challenges included drafting descriptions of recommendations involving multiple management pathways, tailoring the template for a specific guideline, and choosing key recommendations to highlight. Feedback from a larger group of guideline authors and users will be needed to evaluate its usefulness and refine. The proposed guideline manuscript template is the first detailed template for transparent and complete reporting of guidelines. Consistent application of the template may simplify the preparation of an evidence-based guideline manuscript and facilitate its use.

Methodology for adaptation of the ASH Guidelines for Management of Venous Thromboembolism for the Latin American context

AbstractBackground: From 2017 to 2020, the American Society of Hematology (ASH) collaborated with 12 hematology societies in Latin America to adapt the ASH guidelines on venous thromboembolism (VTE).Objective: To describe the methods used to adapt the ASH guidelines on venous thromboembolism.Methods: Each society nominated 1 individual to serve on the guideline panel. The work of the panel was facilitated by the 2 methodologists. The methods team selected 4 of the original VTE guidelines for a first round. To select the most relevant questions, a 2-step prioritization process was conducted through an on-line survey and then through in-person discussion. During an in-person meeting in Rio de Janeiro, Brazil, from 23 April through 26 April 2018, the panel developed recommendations using the ADOLOPMENT approach. Evidence about health effects from the original guidelines was reused, but important data about resource use, accessibility, feasibility, and impact in health equity were added.Results: In the guideline accompanying this paper, Latin American panelists selected 17 questions from an original pool of 49. Of the 17 questions addressed, substantial changes were introduced for 5 recommendations, and remarks were added or modified for 12 recommendations.Conclusions: By using the evidence from an international guideline, a significant amount of work and time were saved; by adding regional evidence, the final recommendations were tailored to the Latin American context. This experience offers an alternative to develop guidelines relevant to local contexts through a global collaboration.

ASH, ABHH, ACHO, Grupo CAHT, Grupo CLAHT, SAH, SBHH, SHU, SOCHIHEM, SOMETH, Sociedad Panameña de Hematología, SPH, and SVH 2021 guidelines for management of venous thromboembolism in Latin America

Venous thromboembolism (VTE) is a common disease in Latin American settings. Implementing international guidelinn Aes in Latimerican settings requires additional considerations. The purpose of our study was to provide evidence-based guidelines about managing VTE for Latin American patients, clinicians, and decision makers. We used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE)-ADOLOPMENT method to adapt recommendations from 2 American Society of Hematology (ASH) VTE guidelines (Treatment of VTE and Anticoagulation Therapy). ASH and local hematology societies formed a guideline panel comprised of medical professionals from 10 countries in Latin America. Panelists prioritized 18 questions relevant for the Latin American context. A knowledge synthesis team updated evidence reviews of health effects conducted for the original ASH guidelines and summarized information about factors specific to the Latin American context (ie, values and preferences, resources, accessibility, feasibility, and impact on health equity). The panel agreed on 17 recommendations. Compared with the original guideline, 4 recommendations changed direction and 1 changed strength. This guideline adolopment project highlighted the importance of contextualization of recommendations suggested by the changes to the original recommendations. The panel also identified 2 implementation priorities for the region: expanding the availability of home treatment and increasing the availability of direct oral anticoagulants (DOACs). The guideline panel made a conditional recommendation in favor of home treatment for individuals with deep venous thrombosis and a conditional recommendation for either home or hospital treatment for individuals with pulmonary embolism. In addition, a conditional recommendation was made in favor of DOACs over vitamin K antagonists for several populations.

Neutropenia Following Intravenous Immunoglobulin Therapy in Adult Patients with Immune Thrombocytopenic Purpura

BackgroundImmune thrombocytopenic purpura (ITP) is an autoimmune disease in which anti-platelet antibodies accelerate the destruction of platelets. Traditional therapies such as steroid therapy, intravenous immunoglobulin (IVIG) therapy, and splenectomy generally reduce the peripheral destruction of platelets. However, they may cause significant side effects. In particular, it has been recently reported that neutropenia sometimes develops in children as an adverse effect after IVIG administration. On the other hand, there is no previous report on neutropenia developing as a complication of IVIG therapy in adult patients with ITP. The aim of this study was to further investigate the incidence and course of neutropenia following IVIG therapy in adults with ITP.MethodsWe performed a retrospective chart review of 88 ITP patients who had received IVIG to manage severe thrombocytopenia between January 2006 and March 2016 at Pusan National University Hospital in Korea. Inclusion criteria were the following: age ≥ 18 years, ITP diagnosis according to the American Society of Hematology guidelines (platelet count of less than 100 × 109/L in the absence of other causes or disorders that may be associated with thrombocytopenia). Exclusion criteria included other diseases known to be associated with ITP, such as human immunodeficiency virus or hepatitis C virus infection, lympho-proliferative disorders, thyroid or liver disease, and definite systemic lupus erythematosus. Patients included in this study had a complete and differential blood count performed before and after the IVIG treatment. Patients were treated according to a standard protocol, consisting of IVIG administration (1 g/kg per day for two days).ResultsThe baseline characteristics of patients are shown in Table 1. Among 88 patients, 24 (27.3%) were male, and 64 (72.7%) were female. The median ages were 45 years in the group that developed neutropenia and 41 years in the group that did not develop neutropenia. The groups were comparable in age, sex distribution, initial white blood cell (WBC) count, and absolute neutrophil count (ANC). Neutropenia developed in 43 patients (48.9%) after IVIG treatment. In patients with a decrease in WBC count and ANC compared to baseline, median WBC count decreased from 6,280/μL to 4,530/μL after IVIG therapy, and median ANC decreased from 3,840/μL to 2,840/μL after IVIG therapy. Only two patients in this study developed a post-treatment ANC of less than 1,000/μL, and only one patient developed neutropenic fever, which subsided soon without any treatment. The neutropenia induced by IVIG had resolved spontaneously after several days, and the mean recovery time was 8.72 days after the completion of the IVIG treatment (Table 1, Figure 1 and 2). Including the present case, we identified previous reports of neutropenia developing as a complication of IVIG therapy in the English literature (Table 2). The majority of reports of neutropenia following IVIG therapy are pediatric patients with ITP. There were two reports on the incidence of neutropenia induced IVIG in adults except for pediatric patients with ITP. Matsuda M et al. reported neutropenia induced by high-dose IVIG in adult patients with neuro-immunologic disorders. And Lemos S et al. reported acute neutropenia in patients with primary antibody-deficiencies, after receiving IVIG. However, as mentioned earlier, there has been no reports of neutropenia following IVIG therapy in adult patients with ITP. Therefore, this study is the first report of neutropenia after IVIG therapy in adult patients with ITP. Although further studies are required in order to clarify the precise mechanism of neutropenia following IVIG treatment, this would be the important report of neutropenia following IVIG therapy in adult patients with ITP.ConclusionsThe results of this study suggest that IVIG may cause neutropenia commonly in adults with ITP, and it seems to be transient and self-limited. This study is meaningful as the first report that not only pediatric ITP patients may develop neutropenia post IVIG administration, but also adult patients suffering ITP. Therefore, an awareness of this common association of neutropenia following IVIG treatment in adult patients with ITP is likely to aid physicians in caring for these patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Venous thromboembolism incidence among patients recommended for pharmacologic thromboembolism prophylaxis after cesarean delivery in selected guidelines

BackgroundMultiple guidelines regarding risk stratification for venous thromboembolism (VTE) incidence following cesarean delivery have been promulgated. ObjectiveTo estimate the percentage of cesarean delivery patients for which pharmacologic VTE would be recommended and subsequent incidence of VTE, based on several guidelines. Patients/MethodsThis retrospective cohort study used data from the Nationwide Readmissions Database from October 2015 through December 2017. Diagnosis and procedure codes were used to identify patients undergoing cesarean delivery, incidence of VTE, and risk factors used to stratify risk in the existing guidelines. Time‐to‐event analysis was used to analyze data, stratified by risk categorization in 2011 American College of Obstetricians and Gynecologists (ACOG), 2012 American College of Chest Physicians (ACCP), 2015 Royal College of Obstetricians and Gynaecologists (RCOG), and 2018 American Society of Hematology (ASH) guidelines. Results/ConclusionsIn a cohort of 1 235 149 cesarean deliveries, VTE incidence was 2.1 per 1000 deliveries at 330 days following delivery (95% confidence interval: 2.0–2.2). Proportions of patients that would be recommended for pharmacologic prophylaxis ranged from 0.2% in 2018 ASH guidelines to 73.4% in 2015 RCOG criteria. Among groups considered at elevated risk for VTE for which pharmacologic prophylaxis would be recommended, VTE incidence varied from 35.2 per 1000 deliveries based on 2018 ASH criteria to 2.5 per 1000 in 2015 RCOG criteria. In a large cohort of cesarean deliveries in the United States, application of different risk stratification guidelines identified widely different proportions at risk of VTE following delivery, with implications for being categorized as having elevated risk.

Effects of Hydroxyurea and Renin-Angiotensin Blockade on Kidney Function in Sickle Cell Disease

Kidney disease is a common complication that leads to increased morbidity and early mortality in patients with sickle cell disease (SCD). Vaso-occlusion, hyperfiltration, hypertension, and cell-free hemoglobin/heme-mediated toxicity may contribute to the pathophysiology of kidney disease. Treatments for SCD-related kidney disease have been adopted from therapies used to treat other SCD-related complications (hydroxyurea [HU]) or diabetic nephropathy (angiotensin converting enzyme [ACE]-inhibitors or angiotensin receptor blockers [ARBs]), although their effects on kidney function are not clear. We evaluated the effects of HU and ACE-inhibitors or ARBs on kidney function in a longitudinal cohort of 439 SCD patients enrolled into a prospective registry between 2011 and 2019. Patients were considered for the analysis if they had 6 months of kidney function values pre-therapy and remained on therapy for 6 months or longer. Changes in the estimated glomerular filtration rate (eGFR) and urine albumin concentration were compared prior to and after starting therapy using a mixed effects model. The effects of HU on kidney function were evaluated in 49 SCD patients. The mean age was 38 years (standard deviation [SD] 11 years), 43% were male, and 80% were Hb SS/Sβ0-thalassemia genotype. The eGFR improved from an average decline of -3.3 mL/min/1.73m2 in the 6 months prior to starting HU to an increase of +9.5 mL/min/1.73m2 during HU therapy (P = 0.0002) (Table). The average change in albuminuria also improved from an increase of +1.2 mg/g creatinine pre-HU therapy to a decline of -1.2 mg/g creatinine during HU therapy, although the difference was not statistically significant (P = 0.17). In 47 SCD patients started on ACE-inhibitors or ARBs, the mean age was 45 years (SD 11 years), 43% were male, and 87% were Hb SS/Sβ0-thalassemia genotype. During ACE-inhibitor or ARB therapy, there was no observed difference in the change in eGFR pre- versus during therapy (P = 0.9) (Table). Albuminuria improved from an average change of -1.0 mg/g creatinine pre-therapy to -1.6 mg/g creatinine during therapy (P = 0.009). Because clinical data are limited, current American Society of Hematology guidelines have conditional recommendations with low levels of certainty for the use of HU and ACE-inhibitors or ARBs to treat sickle cell nephropathy. In a longitudinal cohort of SCD patients, we demonstrate that during 6 months of therapy, there may be a benefit of HU in improving eGFR and of ACE-inhibitors or ARBs in reducing albuminuria. Larger and longer follow up studies of HU, ACE-inhibitors and ARBs as well as new targeted therapies to treat sickle cell nephropathy are urgently needed. Figure Disclosures Gordeuk: Novartis: Consultancy; Ironwood: Research Funding; CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Imara: Research Funding. Saraf:Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Boards, Speakers Bureau; Novartis, Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer, Global Blood Therapeutics, Novartis: Research Funding.

Consistent Efficacy Demonstrated By Avatrombopag in Immune Thrombocytopenia (ITP) Regardless of the Number of Lines of Prior ITP Treatment

Background: Clinical management of ITP depends on both disease severity and risk of bleeding. Treatment typically is considered when platelet counts (PC) fall below 30,000/µL, with a target PC of ≥50,000/µL to mitigate the risk of bleeding. The standard-of-care after failure of 1st line therapy (corticosteroids or intravenous immunoglobulin) has been shifting from splenectomy and rituximab, toward an increased use of thrombopoietin receptor agonists (TPO-RAs), as supported by the recent American Society of Hematology guidelines (Neunert 2019). The TPO-RAs eltrombopag (ELT) and romiplostim (ROMI) have well understood efficacy profiles, but ELT has an FDA boxed safety warning for hepatotoxicity, necessitating hepatic function monitoring. Additionally, ELT is an orally administered chelating agent that requires dosing two hours prior to, or four hours after, meals containing polyvalent cations such as calcium or magnesium to mitigate clinically relevant effects on the pharmacokinetic profile (ELT prescribing information). In addition, ROMI, an injection, is typically is administered by a health care practitioner. Avatrombopag (AVA) is an oral TPO-RA for patients with ITP. In clinical trials, AVA rapidly increased platelet counts as early as day 5 and maintained the median PC in the target range (50 to 150×109/L) with chronic dosing. Further, it has an exposure-adjusted safety profile generally comparable to placebo and no boxed safety warning for hepatotoxicity. AVA does not chelate polyvalent cations; therefore it is administered with food, and there are no restrictions regarding meal composition. Aims: To understand how the number of prior ITP treatments impacted the efficacy of avatrombopag in a Phase 3 study. Methods: A 6-month, multicenter, randomized, double-blind, Phase 3 study enrolled 32 AVA and 17 placebo-treated (PBO) patients with ITP. The primary endpoint was the median number of cumulative weeks of platelet count (PC) response (achieving a PC ≥50,000/µL) over the course of the study without rescue medication. Patients receiving any rescue medication during the study were deemed to be non-responders for the remainder of the study. Due to the limited number of study participants, for the post-hoc analyses reported here, the study population was segmented by whether a patient had received &amp;lt;3 or ≥3 prior ITP treatments upon entering the Phase 3 clinical trial. Analyses of efficacy measures were performed in these two sub-populations and are presented for hypothesis generation. Results: Table 1 shows key differences in baseline characteristics between each group, suggesting that those receiving ≥3 prior ITP medications may have had more refractory disease. The median cumulative number of weeks of PC response for the entire population during the study was 12.4 vs. 0.0 for AVA and PBO respectively (p&amp;lt;0.0001), and the mean was 12.0 vs 0.1. For patients receiving &amp;lt;3 prior ITP treatments (n=13), the median and mean cumulative number of weeks of PC response were 13.7 and 12.2 for AVA and 0.0 and 0.0 for PBO; for patients receiving ≥3 prior ITP treatments (n=19), the median and mean were 11.0 and 11.8 weeks respectively for AVA and 0.0 and 0.2 for PBO. The proportion of AVA patients achieving a PC response at least once during the study was 87.5% for the entire population, 84.6% for those receiving &amp;lt;3 and 89.5% for those with ≥3 prior ITP treatments. Only 1 placebo patient ever achieved a response level PC, and that patient had received ≥3 prior ITP treatments. Similar results were noted for achieving a PC response twice or more during the study. A PC response at Day 8 was noted in 65.6% of the AVA patients and 0.0% in PBO (p&amp;lt;0.0001) overall, with 76.9% and 57.9% of AVA patients receiving &amp;lt;3 and ≥3 prior ITP treatments responding at Day 8 respectively. Finally, a durable PC response (achieving a PC ≥50,000/µL for 6 of the final 8 weeks of the study, calculated in an intent-to-treat fashion) was noted in 34.4% of AVA patients and 0.0% for PBO overall (p=0.009), while 38.5% and 31.6% of AVA patients having received &amp;lt;3 or ≥3 prior ITP treatments respectively. Conclusions: In this Phase 3 study, the number of prior ITP treatments a patient had received did not seem to definitively predict PC response to AVA, though on some measures the group receiving &amp;lt;3 fared slightly better. These data suggest that AVA efficacy is relatively consistent, even if a patient has received multiple prior ITP therapies before AVA initiation. Disclosures Vredenburg: Dova Pharmaceuticals: Current Employment. Tian:Dova Pharmaceuticals: Current Employment. Jamieson:Dova Pharmaceuticals: Current Employment. McCrae:Rigel: Consultancy; Dova: Consultancy; Momenta Pharmaceuticals: Consultancy; Novartis: Honoraria.

Efficacy Analyses from the Immune Thrombocytopenia (ITP) Clinical Development Program for Avatrombopag: Comparisons with Placebo and Eltrombopag

Efficacy Analyses from the Immune Thrombocytopenia (ITP) Clinical Development Program for Avatrombopag: Comparisons with Placebo and Eltrombopag

Immune Thrombocytopenia: American Society of Hematology Guidelines, 2019

Immune Thrombocytopenia is the commonest cause of thrombocytopenia in young children. A thorough history, examination and peripheral smear evaluation is central to diagnosis. The recent American Society of Hematology guidelines 2019, has shed light on diagnosis and management based on latest available literature. We, herein, delineate the important aspects of these guidelines.