Direct oral anticoagulants for treatment of HIT: update of Hamilton experience and literature review.

Direct oral anticoagulants (DOACs) are attractive options for treatment of heparin-induced thrombocytopenia (HIT). We report our continuing experience in Hamilton, ON, Canada, since January 1, 2015 (when we completed our prospective study of rivaroxaban for HIT), using rivaroxaban for serologically confirmed HIT (4Ts score ≥4 points; positive platelet factor 4 [PF4]/heparin immunoassay, positive serotonin-release assay). We also performed a literature review of HIT treatment using DOACs (rivaroxaban, apixaban, dabigatran, edoxaban). We focused on patients who received DOAC therapy for acute HIT as either primary therapy (group A) or secondary therapy (group B; initial treatment using a non-DOAC/non-heparin anticoagulant with transition to a DOAC during HIT-associated thrombocytopenia). Our primary end point was occurrence of objectively documented thrombosis during DOAC therapy for acute HIT. We found that recovery without new, progressive, or recurrent thrombosis occurred in all 10 Hamilton patients with acute HIT treated with rivaroxaban. Data from the literature review plus these new data identified a thrombosis rate of 1 of 46 patients (2.2%; 95% CI, 0.4%-11.3%) in patients treated with rivaroxaban during acute HIT (group A, n = 25; group B, n = 21); major hemorrhage was seen in 0 of 46 patients. Similar outcomes in smaller numbers of patients were observed with apixaban (n = 12) and dabigatran (n = 11). DOACs offer simplified management of selected patients, as illustrated by a case of persisting (autoimmune) HIT (>2-month platelet recovery with inversely parallel waning of serum-induced heparin-independent serotonin release) with successful outpatient rivaroxaban management of HIT-associated thrombosis. Evidence supporting efficacy and safety of DOACs for acute HIT is increasing, with the most experience reported for rivaroxaban.

Strategies for eliciting and synthesizing evidence for guidelines in rare diseases.

BACKGROUND: Rare diseases are a global public health priority. Though each disease is rare, when taken together the thousands of known rare diseases cause significant morbidity and mortality, impact quality of life, and confer a social and economic burden on families and communities. These conditions are, by their nature, encountered very infrequently by individual clinicians, who may feel unprepared to address their diagnosis and treatment. Clinical practice guidelines are necessary to support clinical and policy decisions. However, creating guidelines for rare diseases presents specific challenges, including a paucity of high certainty evidence to inform panel recommendations. METHODS: This paper draws from the authors' experience in the development of clinical practice guidelines for three rare diseases: hemophilia, sickle cell disease, and catastrophic antiphospholipid syndrome. RESULTS: We have summarized a number of strategies for eliciting and synthesizing evidence that are compatible with the rigorous, internationally accepted standards for guideline development set out by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. These strategies include: use of pre-existing and ad hoc qualitative research, use of systematic observation forms, use of registry data, and thoughtful use of indirect evidence. Their use in three real guideline development efforts, as well as their theoretical underpinnings, are discussed. Avenues for future research to improve clinical practice guideline creation for rare diseases - and any disease affected by a relative lack of evidence - are also identified. CONCLUSIONS: Rigorous clinical practice guidelines are needed to improve the care of the millions of people worldwide who suffer from rare diseases. Innovative evidence elicitation and synthesis methods will benefit not only the rare disease community, but also individuals with common diseases who have rare presentations, suffer rare complications, or require nascent therapies. Further refinement and improved uptake of these innovative methods should lead to higher quality clinical practice guidelines in rare diseases.

Transfusion of fresher vs older red blood cells in hospitalized patients: a systematic review and meta-analysis.

The impact of transfusing fresher vs older red blood cells (RBCs) on patient-important outcomes remains controversial. Two recently published large trials have provided new evidence. We summarized results of randomized trials evaluating the impact of the age of transfused RBCs. We searched MEDLINE, EMBASE, CINAHL, the Cochrane Database for Systematic Reviews, and Cochrane CENTRAL for randomized controlled trials enrolling patients who were transfused fresher vs older RBCs and reported outcomes of death, adverse events, and infection. Independently and in duplicate, reviewers determined eligibility, risk of bias, and abstracted data. We conducted random effects meta-analyses and rated certainty (quality or confidence) of evidence using the GRADE approach. Of 12 trials that enrolled 5229 participants, 6 compared fresher RBCs with older RBCs and 6 compared fresher RBCs with current standard practice. There was little or no impact of fresher vs older RBCs on mortality (relative risk [RR], 1.04; 95% confidence interval [CI], 0.94-1.14; P = .45; I(2) = 0%, moderate certainty evidence) or on adverse events (RR, 1.02; 95% CI, 0.91-1.14; P = .74; I(2) = 0%, low certainty evidence). Fresher RBCs appeared to increase the risk of nosocomial infection (RR, 1.09; 95% CI, 1.00-1.18; P = .04; I(2) = 0%, risk difference 4.3%, low certainty evidence). Current evidence provides moderate certainty that use of fresher RBCs does not influence mortality, and low certainty that it does not influence adverse events but could possibly increase infection rates. The existing evidence provides no support for changing practices toward fresher RBC transfusion.

Oral anticoagulant dosing, administration, and storage: a cross-sectional survey of Canadian health care providers.

Direct oral anticoagulant (DOAC) use is increasing worldwide. However, if not taken or prescribed correctly, DOACs have serious side effects. It is crucial that healthcare providers (HCPs) offer patients accurate information and counselling around DOACs, to optimize safe and effective use. To assess knowledge around oral anticoagulant indication, dosing, storage, and administration, an electronic survey was distributed to HCPs across Canada from June to August 2017, with 18 questions on the practical use of oral anticoagulants. A total of 191 responses were received: 100 from nurse practitioners, 42 from pharmacists, 27 from Hematologists, 5 from Thrombosis specialists, 4 from internists, 9 from residents and fellows, and 2 each from family physicians and registered nurses. Only 51 (26.7%) of the respondents correctly identified all the approved indications for warfarin and 4 DOACs. Only 101 (52.9%) correctly identified that DOACs are not approved for treatment of heparin-induced thrombocytopenia, cerebral sinus venous thrombosis, or mechanical prosthetic valves. 112 (58.6%) felt comfortable or very comfortable prescribing oral anticoagulants. Half of the respondents knew that dabigatran should not be crushed, however only 85 (44.5%) knew that it should not be exposed to moisture. 94 (49%) knew that higher dose rivaroxaban should be taken with food. The results of our study demonstrate that there are important knowledge gaps around HCPs' practical understanding of oral anticoagulants. Future research should focus on educational interventions to improve HCPs' knowledge around indications, dosing, storage, and administration, with the goal of enhancing patient safety.

Direct Oral Anticoagulants in the Real World: Insights Into Appropriate Prescribing and Medication Use.

Background Direct oral anticoagulants are convenient because of their fixed dosing and without laboratory monitoring. There are instructions on avoidance of moisture, no crushing of capsules, and administration with food for some direct oral anticoagulants. Whether patients adhere to this and are prescribed appropriate doses are unknown. Aims To assess direct oral anticoagulant dosing and medication use. Methods Patients ≥18 years old, receiving a direct oral anticoagulant for any diagnosis, were prospectively included. Nurses at our perioperative anticoagulation clinic helped patients complete a 12-item questionnaire. Results Ninety-three consecutive patients were recruited. Forty-nine were on dabigatran, 18 on apixaban, and 26 were on rivaroxaban. Sixty-two patients (67%) received appropriate direct oral anticoagulant dosing and administered the medication correctly. Eighteen patients (19%) administered the direct oral anticoagulant properly but at an inappropriate dose. Thirteen patients (14%) received an appropriate dose but administered the direct oral anticoagulant inappropriately: 10 (11%) removed dabigatran from its packaging before administration (exposing it to moisture); 2 (2%) did not take rivaroxaban with food; and 1 (1%) crushed the dabigatran capsule. Conclusion Our study demonstrates a large variability in how direct oral anticoagulants are dosed, and how patients take them. Improved medication literacy around direct oral anticoagulants is needed. Our study highlights opportunities that nurses have to improve patients' medication literacy.

Putting People First: Critical Reforms for Canada's Health Care System.

For over 70 years, since the Dominion Provincial Conferences at the end of the Second World War, Canadians have viewed health care as a right of citizenship. The Canada Health Act (CHA, 1984) formally entrenched the five principles that guide our current publicly operated, single payer, provincially managed system: public administration, comprehensiveness, universality, portability and accessibility. The health care system that has sprung up around the CHA has become increasingly complex, costly and strained. Our gradual descent through the rankings of major health care suggests that we are reaching the limits of what the current health care system can provide. Unfortunately, constructive political debate around this issue is often choked by intense ideological positioning. System reform is urgently needed to address the rapidly changing biological and demographic drivers of health. We do not feel that diverting ever larger flows of money into the status quo is a sustainable solution. Our nation's health and the means to advance it must be seen as assets rather than costs. We believe it is possible to meet increasing demands by expanding the supply and acknowledging the wealth of resources (scientific, human, managerial and educational) that we currently possess. In this paper we propose a cultural shift from an institution-centered system bent on cost control, to a patient-centered system that fosters a true health economy. We identify a series of interventions (some bold and others less so) to achieve a clear and evaluable goal: maximizing the well-being and debility-free life expectancy of each individual. To achieve a patient-centred system-we discuss strategies to address costs and utilization, the setting of real performance standards, the elimination of conflicts of interest and the provision of truly accessible care for all Canadians. To create a health economy, we discuss the importance of innovation, the need for a reinvigorated public health system and steps to overhaul the health care human resources environment. The goal of health care reform in Canada should be a system that is dynamic, evidence based, wealth creating and a global leader. We believe that, with leadership and vision, this goal is eminently achievable.

Exposure to ABO-nonidentical blood associated with increased in-hospital mortality in patients with group A blood.

BACKGROUND: Transfusing ABO-compatible blood avoids most acute hemolytic reactions, but donor units that are ABO compatible are not necessarily ABO identical. Emerging data have raised concerns that ABO-nonidentical blood products lead to adverse outcomes. STUDY DESIGN AND METHODS: A large multihospital registry (Transfusion Registry for Utilization, Surveillance, and Tracking) was used to determine the association between exposure to ABO-nonidentical blood and in-hospital mortality. Cox regression analyses controlled for sex, age, hemoglobin, creatinine, and in-hospital interventions and stratified by age of blood and admission year. RESULTS: Data from 18,843 non-group O patients admitted between 2002 and 2011 and receiving at least 1 unit of blood were analyzed. Overall, group A patients had significantly increased risk of in-hospital death upon receiving a nonidentical unit (RR , 1.79; 95% CI, 1.20-2.67; p = 0.005). There was no evidence of increased risk for group B or AB patients. Similar results were seen when only patients with circulatory disorders were considered. When patients with an injury or poisoning diagnosis were excluded, the risk of in-hospital death after receiving a non-identical unit was significantly higher in group A patients and significantly lower in Group B patients. CONCLUSION: Our study demonstrates an adverse effect of ABO-nonidentical blood in a broad range of patients with group A blood, after adjustment for potential confounders. Further research in this area is required to study possible mechanisms. Increased mortality associated with exposure to nonidentical blood in these patients would have a substantial impact at the population level; it would challenge how blood suppliers manage inventory and recruit donors and how health care providers administer blood.

Survival after ultramassive transfusion: a review of 1360 cases.

BACKGROUND: Information about patient survival after transfusion of multiple blood volumes is limited, and most reports have focused on trauma patients. STUDY DESIGN AND METHODS: Retrospective study of blood use and survival at 11 hospitals in six nations between 2009 and 2013. Ultramassive transfusion (UMT) was defined as transfusion of 20 or more red blood cell (RBC) units over the course of any 2 consecutive calendar days. RESULTS: A total of 1975 patients received UMT and a representative sample of 1360 patients was studied in detail. Patients were grouped into seven diagnostic categories: solid organ transplantation (n = 411), cardiac or major vascular surgery (n = 317), general surgery (n = 228), trauma (n = 221), general medicine (n = 124), obstetrics (n = 23), and other (n = 36). During the 7 days after initiation of UMT, these patients used more than 120,000 blood components. The median (interquartile range) blood use was 35 (26-50) RBC units, 30 (20-47) plasma units, and 7 (4-13) platelet doses. Five- and 30-day survival significantly declined with increasing RBC use. Overall survivals of patients receiving UMT were 71% (5 day) and 60% (30 day), and in the subset of 165 patients receiving 60 or more RBC units over 2 consecutive days, 5-day survival was 54% ranging from 17% (trauma) to 75% (solid organ transplant). The decline in survival with increasing RBC transfusions was minimal for patients undergoing solid organ transplantation and was most pronounced for trauma and nonsurgical bleeding patients. CONCLUSION: Trauma was not the leading cause of UMT. Increasing RBC requirements were significantly associated with decreasing survival. However, survival was more strongly associated with diagnostic category than total RBCs transfused, with highest survival rates in solid organ transplant surgery.

Failure of anticoagulant thromboprophylaxis: risk factors in medical-surgical critically ill patients*.

OBJECTIVES: To identify risk factors for failure of anticoagulant thromboprophylaxis in critically ill patients in the ICU. DESIGN: Multivariable regression analysis of thrombosis predictors from a randomized thromboprophylaxis trial. SETTING: Sixty-seven medical-surgical ICUs in six countries. PATIENTS: Three thousand seven hundred forty-six medical-surgical critically ill patients. INTERVENTIONS: All patients received anticoagulant thromboprophylaxis with low-molecular-weight heparin or unfractionated heparin at standard doses. MEASUREMENTS AND MAIN RESULTS: Independent predictors for venous thromboembolism, proximal leg deep vein thrombosis, and pulmonary embolism developing during critical illness were assessed. A total of 289 patients (7.7%) developed venous thromboembolism. Predictors of thromboprophylaxis failure as measured by development of venous thromboembolism included a personal or family history of venous thromboembolism (hazard ratio, 1.64; 95% CI, 1.03-2.59; p = 0.04) and body mass index (hazard ratio, 1.18 per 10-point increase; 95% CI, 1.04-1.35; p = 0.01). Increasing body mass index was also a predictor for developing proximal leg deep vein thrombosis (hazard ratio, 1.25; 95% CI, 1.06-1.46; p = 0.007), which occurred in 182 patients (4.9%). Pulmonary embolism occurred in 47 patients (1.3%) and was associated with body mass index (hazard ratio, 1.37; 95% CI, 1.02-1.83; p = 0.035) and vasopressor use (hazard ratio, 1.84; 95% CI, 1.01-3.35; p = 0.046). Low-molecular-weight heparin (in comparison to unfractionated heparin) thromboprophylaxis lowered pulmonary embolism risk (hazard ratio, 0.51; 95% CI, 0.27-0.95; p = 0.034) while statin use in the preceding week lowered the risk of proximal leg deep vein thrombosis (hazard ratio, 0.46; 95% CI, 0.27-0.77; p = 0.004). CONCLUSIONS: Failure of standard thromboprophylaxis using low-molecular-weight heparin or unfractionated heparin is more likely in ICU patients with elevated body mass index, those with a personal or family history of venous thromboembolism, and those receiving vasopressors. Alternate management or incremental risk reduction strategies may be needed in such patients.

A benchmarking program to reduce red blood cell outdating: implementation, evaluation, and a conceptual framework.

BACKGROUND: Benchmarking is a quality improvement tool that compares an organization's performance to that of its peers for selected indicators, to improve practice. STUDY DESIGN AND METHODS: Processes to develop evidence-based benchmarks for red blood cell (RBC) outdating in Ontario hospitals, based on RBC hospital disposition data from Canadian Blood Services, have been previously reported. These benchmarks were implemented in 160 hospitals provincewide with a multifaceted approach, which included hospital education, inventory management tools and resources, summaries of best practice recommendations, recognition of high-performing sites, and audit tools on the Transfusion Ontario website (http://transfusionontario.org). In this study we describe the implementation process and the impact of the benchmarking program on RBC outdating. A conceptual framework for continuous quality improvement of a benchmarking program was also developed. RESULTS: The RBC outdating rate for all hospitals trended downward continuously from April 2006 to February 2012, irrespective of hospitals' transfusion rates or their distance from the blood supplier. The highest annual outdating rate was 2.82%, at the beginning of the observation period. Each year brought further reductions, with a nadir outdating rate of 1.02% achieved in 2011. The key elements of the successful benchmarking strategy included dynamic targets, a comprehensive and evidence-based implementation strategy, ongoing information sharing, and a robust data system to track information. CONCLUSION: The Ontario benchmarking program for RBC outdating resulted in continuous and sustained quality improvement. Our conceptual iterative framework for benchmarking provides a guide for institutions implementing a benchmarking program.

Design of the rivaroxaban for heparin-induced thrombocytopenia study.

Rivaroxaban is an ideal potential candidate for treatment of heparin-induced thrombocytopenia (HIT) because it is administered orally by fixed dosing, requires no laboratory monitoring and is effective in the treatment of venous and arterial thromboembolism in other settings. The Rivaroxaban for HIT study is a prospective, multicentre, single-arm, cohort study evaluating the incidence of new symptomatic venous and arterial thromboembolism in patients with suspected or confirmed HIT who are treated with rivaroxaban. Methodological challenges faced in the design of this study include heterogeneity of the patient population, differences in the baseline risk of thrombosis and bleeding dependent on whether HIT is confirmed or just suspected, and heterogeneity in laboratory confirmation of HIT. The rationale for how these challenges were addressed and the final design of the Rivaroxaban for HIT study is reviewed.

Thrombosis with thrombocytopenia syndrome (TTS) and vaccine-induced immune thrombocytopenia and thrombosis (VITT): Brighton Collaboration case definitions and guidelines for data collection, analysis, and presentation of immunisation safety data.

This is a revision of the online November 2021 Brighton thrombosis with thrombocytopenia syndrome (TTS) case definition and a new Brighton Collaboration case definition for vaccine-induced immune thrombocytopenia and thrombosis (VITT). These case definitions are intended for use in clinical trials and post-licensure pharmacovigilance activities to facilitate safety data comparability across multiple settings. They are not intended to guide clinical management. The case definitions were developed by a group of subject matter and Brighton Collaboration process experts as part of the Coalition for Epidemic Preparedness Innovations (CEPI)-funded Safety Platform for Evaluation of vACcines (SPEAC). The case definitions, each with defined levels of diagnostic certainty, are based on relevant published evidence and expert consensus and are accompanied by specific guidelines for TTS and VITT data collection and analysis. The document underwent peer review by a reference group of vaccine safety stakeholders and haematology experts to ensure case definition useability, applicability and scientific integrity.

Distinguishing ASH clinical practice guidelines from other forms of ASH clinical advice.

ABSTRACT: The American Society of Hematology (ASH) develops a variety of resources that provide guidance to clinicians on the diagnosis and management of blood diseases. These resources include clinical practice guidelines (CPGs) and other forms of clinical advice. Although both ASH CPGs and other forms of clinical advice provide recommendations, they differ with respect to the methods underpinning their development, the principal type of recommendations they offer, their transparency and concordance with published evidence, and the time and resources required for their development. It is crucial that end users be aware of the differences between CPGs and other forms of clinical advice and that producers and publishers of these resources use clear and unambiguous terminology to facilitate their distinction. The objective of this article is to highlight the similarities and differences between ASH CPGs and other forms of ASH clinical advice and discuss the implications of these differences for end users.

How I manage heavy menstrual bleeding.

Heavy menstrual bleeding (HMB) is a common clinical problem; population-based studies estimate that approximately 10-35% of women report this symptom during their lifetime, while about 5% of women consult a physician for evaluation of HMB. Patients with HMB account for 15% of all referrals to gynaecologists and are frequently seen by haematologists in bleeding disorder clinics as well. Heavy menstrual bleeding can be caused by a wide variety of local and systemic factors, so a careful clinical and laboratory evaluation is often necessary to determine the aetiology and guide appropriate management. This review discusses the definition, causes and clinical outcomes of HMB. It outlines a diagnostic approach and focuses on medical (as opposed to surgical) treatments. Throughout, areas of controversy and opportunities for further research are highlighted.