Reduction In Transfusion Research Articles

Overview of Systematic Reviews (SRs) of Erythropoiesis-Stimulating Agents (ESAs) As Standards of Care for Non-Myeloid Cancer Patients with Chemotherapy-Induced-Anemia (CIA)

OBJECTIVES: While chemotherapy is fundamental to the treatment of many cancers, it is associated with adverse events (AEs), including anemia. CIA is linked to many symptoms, including fatigue and cognitive impairment. Most cancer patients receiving chemotherapy experience CIA. ESAs are indicated for treatment of CIA in non-myeloid cancers. Given the extensive data available, we reviewed SRs of the existing evidence on ESAs for treatment of CIA, to assess their relative efficacy and safety.METHODS: A search for published SRs of ESAs for the treatment of CIA in adults with non-myeloid cancers was conducted across seven databases and three online resources, from inception to July 2020. Data were extracted on hemoglobin-related (Hb)-outcomes; mortality; health-related quality of life (HRQoL), iron use, red blood cell (RBC) transfusions, cancer-related outcomes, and serious AEs (SAEs) including thromboembolic events. Risk of bias was assessed by two reviewers using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) 2 tool.RESULTS: Of 1027 records assessed, 33 records met eligibility criteria; from these, 14 SRs (from 19 publications) were considered core and were extracted. The majority of SRs (n=13) were meta-analyses of randomized, controlled trials. Mortality was evaluated in 9 SRs: 5 reported no difference between ESA vs. control (best supportive care (BSC) and/or placebo and/or no treatment) and 2 reported higher mortality with ESA vs. control (standard care (no iron or oral iron) and/or placebo and/or no treatment). Cancer-related overall survival was not significantly different for ESA vs. control (BSC or placebo) in 2 SRs, or vs. no ESA treatment in 1 SR. Relapse-free, recurrence-free and progression-free survival did not differ between ESA vs. BSC, no treatment, or placebo, according to 1 SR.Two SRs reported a significantly improved change in Hb from baseline for ESA vs. placebo or BSC. Four SRs reported significantly improved hematological response (definitions varied by study) for ESA vs. control (BSC and/or placebo and/or no treatment) (Table). RBC transfusion requirements were reported for 5 treatment comparisons in 12 SRs. For 3 comparisons (ESA vs. control (BSC and/or placebo and/or no treatment); IV iron + ESA vs. standard care; and IV iron + ESA vs. no iron + ESA), there was a consistent statistically significant reduction in transfusion rates with ESA-based treatment. For 2 other comparisons, 1 SR reported no significant difference in transfusion rates with oral iron + ESA vs. no iron + ESA, and 2 SRs found no difference between darbepoetin vs. epoetin. ESA was associated with a requirement for significantly fewer RBC units per patient vs. control (BSC or placebo) in 1 SR.Functional Assessment of Cancer Therapy-Anemia (FACT-An, 6 SRs) and FACT-Fatigue (FACT-F, 7 SRs) were the only HRQoL measures reported. Two SRs reported clinically important improvements in FACT-An with ESA vs. control (BSC and/or placebo); the remaining SRs reported difficulty in interpreting results due to study heterogeneity. Five SRs reported significant improvements in FACT-F with ESA vs. control (BSC and/or placebo and/or no treatment). One SR did not present a meta-analysis, stating that FACT-F results did not differ for ESA vs. placebo groups, and 1 SR reported a significant improvement in FACT-F for IV iron + ESA vs. standard care (no iron or oral iron).Of 2 SRs reporting SAEs, 1 found no difference in incidence for IV iron + ESA vs. standard care (no iron or oral iron) and 1 found significantly greater incidence for ESA vs. no treatment. Of 6 SRs that compared ESA vs. control, 3 reported an increased risk of thromboembolic events with ESAs in the treatment of CIA and 2 reported no significant difference between treatment groups. The remaining SR reported numerically higher incidences of thromboembolic events with ESA vs. control (no statistical comparison).Several outcomes of interest were not reported, including time to first rescue therapy and supplementary iron use. Most SRs did not report on study quality.CONCLUSIONS: In all SRs reporting efficacy, there were improvements in Hb change from baseline, Hb response, and reduction in RBC transfusions for patients with CIA treated with ESAs vs. control. Results were less consistent across SRs for mortality, thromboembolic events, and HRQoL for ESA vs. control. Lack of study quality reporting may affect the strength of these findings. [Display omitted] DisclosuresMorga: Astellas Pharma Europe Ltd.: Current Employment. Atzinger: Astellas Pharma Inc.: Current Employment. Arber: York Health Economics Consortium Ltd: Current Employment. King: York Health Economics Consortium Ltd: Current Employment. Phalguni: York Health Economics Consortium Ltd: Current Employment. Sanderson: York Health Economics Consortium Ltd: Current Employment. Alexandre: Astellas Pharma Europe B.V.: Current Employment.

A Phase 2, Open-Label, Ascending Dose Study of Ker-050 for the Treatment of Anemia in Patients with Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes

A Phase 2, Open-Label, Ascending Dose Study of Ker-050 for the Treatment of Anemia in Patients with Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes

Trial in Progress: A Phase 2, Open-Label Study Evaluating the Safety and Efficacy of the PKR Activator Etavopivat (FT-4202) in Patients with Thalassemia or Sickle Cell Disease

Trial in Progress: A Phase 2, Open-Label Study Evaluating the Safety and Efficacy of the PKR Activator Etavopivat (FT-4202) in Patients with Thalassemia or Sickle Cell Disease

Phase 1 Study of JNJ-64619178, a Protein Arginine Methyltransferase 5 Inhibitor, in Patients with Lower-Risk Myelodysplastic Syndromes

Phase 1 Study of JNJ-64619178, a Protein Arginine Methyltransferase 5 Inhibitor, in Patients with Lower-Risk Myelodysplastic Syndromes

Real-World Experience of Voxelotor for the Management of Complications in Sickle Cell Disease

Background: Sickle cell disease (SCD) is an inherited systemic disorder characterized by chronic hemolytic anemia and recurrent vaso-occlusion, which can lead to acute and chronic complications, disability, and early mortality. Patients with SCD are hospitalized frequently and most commonly for vaso-occlusive crises (VOCs). Furthermore, most will require a blood transfusion for prevention or acute management of complications, with >90% of adults receiving ≥1 transfusion in their lifetime. Voxelotor (Oxbryta ®) tablets are indicated for treatment of SCD in adults and adolescents aged ≥12 years. Emerging evidence shows that voxelotor, an oral, once-daily sickle hemoglobin-polymerization inhibitor, may improve the clinical symptoms of SCD and reduce VOC rates as well as the need for transfusions. This study sought to assess the real-world impact of voxelotor treatment on the rates and management of SCD-related complications.Methods: Medical and pharmacy claims data for patients aged ≥12 years with SCD who initiated voxelotor therapy between November 2019 and March 2021 were procured from the Symphony Health claims database. Patients with ≥1 year's data before the index date (date of the first voxelotor claim for each patient) were included in the analyses. Baseline demographic and clinical characteristics were summarized using descriptive and inferential statistics. Annualized rates per patient-year (PPY) for transfusions, VOCs, VOC-related and all-cause hospitalizations, before and after voxelotor initiation were compared. Hemoglobin (Hb) responses were evaluated for a subset of patients for whom Hb lab data were available (≥1 Hb value recorded 30 days before initiating voxelotor and ≥1 Hb value recorded after the index date).Results: As of March 2021, a total of 2695 eligible patients from the Symphony Health claims database were included in the analysis (mean age: 34.6 years; 60% female); 915 patients (34%) had ≥1 VOC in the 3 months before initiating voxelotor. Among the subset of patients with pre- and post-voxelotor Hb measurements (n=63), mean (95% CI) Hb was 7.9 (7.5-8.2) g/dL at baseline, and final Hb was 8.9 (8.4-9.4) g/dL after voxelotor initiation. Most patients (38/63; 60.3%) achieved a Hb increase of >1 g/dL at any time point during follow-up. In 357 patients who received ≥1 transfusion in the year before voxelotor initiation, the mean (95% CI) transfusion rate decreased by 43%, from 3.2 (2.8-3.7) to 1.8 (1.4-2.3) PPY (P<0.001) (Table). In 40 patients receiving chronic transfusions (≥8), the mean (95% CI) transfusion rate decreased by 34%, from 9.8 (8.3-11.4) to 6.5 (4.4-8.5) PPY (P=0.007). Among patients who had ≥1 VOC in the 3 months before initiating voxelotor, the mean (95% CI) annualized VOC rate decreased by 22%, from 10.9 (10.4-11.5) to 8.5 (7.8-9.3) (P<0.001); and the mean (95% CI) rate of VOC-related hospitalizations decreased by 32%, from 7.3 (6.9-7.7) to 5.0 (4.4-5.6) (P<0.001). In 636 patients who were previously hospitalized in the 3 months before voxelotor initiation, the mean (95% CI) all-cause hospitalization rate reduced by 36%, from 7.5 (7.1-7.9) to 4.8 (4.3-5.3) (P<0.001) after treatment. Limitations of this analysis include the possibility of secular trend biases or general regression to the mean.Conclusions: In real-world practice, voxelotor increased Hb by ≥1 g/dL, consistent with the HOPE trial. Data suggest statistically significant reductions in transfusions, VOCs, all-cause and VOC-related hospitalizations after voxelotor use. This real-world evidence provides additional support for the use of voxelotor in the treatment of hemolytic anemia and the management of its associated complications. [Display omitted] DisclosuresShah: Novartis: Research Funding, Speakers Bureau; Emmaus: Consultancy; Alexion: Speakers Bureau; GLG: Consultancy; GBT: Consultancy, Research Funding, Speakers Bureau; Guidepoint Global: Consultancy; Bluebird Bio: Consultancy; CSL Behring: Consultancy. Lipato: Global Blood Therapeutics: Speakers Bureau. Alvarez: Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees; GBT: Membership on an entity's Board of Directors or advisory committees. Delea: Global Blood Therapeutics: Research Funding; Amgen: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Merck: Research Funding; Policy Analysis Inc.: Current Employment; AbbVie: Research Funding; Novartis: Research Funding; Regeneron: Research Funding; Sanofi: Research Funding. Lonshteyn: Policy Analysis Inc. (PAI): Current Employment; Global Blood Therapeutics: Research Funding; Novartis: Research Funding. Weycker: Policy Analysis Inc. (PAI): Current Employment, Current equity holder in publicly-traded company; Global Blood Therapeutics: Research Funding; Novartis: Research Funding. Nguyen: Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Beaubrun: Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Agodoa: Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company.

On-Target Activity of Imetelstat Correlates with Clinical Benefits, Including Overall Survival (OS), in Heavily Transfused Non-Del(5q) Lower Risk MDS (LR-MDS) Relapsed/Refractory (R/R) to Erythropoiesis Stimulating Agents (ESAs)

On-Target Activity of Imetelstat Correlates with Clinical Benefits, Including Overall Survival (OS), in Heavily Transfused Non-Del(5q) Lower Risk MDS (LR-MDS) Relapsed/Refractory (R/R) to Erythropoiesis Stimulating Agents (ESAs)

Preoperative Hemoglobin Optimization in Jehovah's Witness Cardiovascular Surgery Patients with Anemia and Barriers to Care

Cardiac surgery has a risk for extensive blood loss which poses a particular challenge in individuals refusing blood transfusions. Additionally, preoperative anemia with a hemoglobin (Hb) below 13 g/dL in men and 12 g/dL in women is associated with increased short and long-term complications and mortality and increases the need for blood transfusion support. The current guidelines for perioperative anemia management recommend optimizing hemoglobin levels prior to surgery and utilizing blood conservation techniques during the procedure. At present red blood cell (RBC) transfusions during cardiac surgery are usually recommended when Hb levels are below 7-8 g/dL a restrictive transfusion strategy to reduce complications. However, the use of any RBC transfusions is associated with worse outcomes in cardiac surgery compared with those who do not receive transfusions.We have found that JW seek out quality health care and accept the vast majority of medical treatments once they are educated. The Transfusion Free Medicine Coordinator's role in the Anemia Clinic is to endorse clinical strategies for managing hemorrhage and anemia without blood transfusion. They educate and counsel the patients so they can decide as to what blood fractions and cell salvage techniques they will accept. We have found that some Health Care Providers are unaware that ESAs also contain albumin so JW patients may be given this product without that knowledge. The vast majority of patients will accept the use of ESAs but find the cost prohibitive.Jehovah's Witness patients have provided a natural case study for examining how well adjuvant therapies can improve preoperative anemia without transfusions and continue with good outcomes. Hb optimization is achieved through the use of intravenous iron and, if needed, erythropoiesis stimulating agents (ESAs). In Table 1 we highlight our single center data in which all cardiovascular surgeries were performed by a surgeon experienced in blood-conservation strategies. Our thirty-day re-admission rates for all patients was zero percent, compared to state-specific data, which estimates about an 11.7% rate of re-admission. The data illustrate the need to have a target Hb 13 or above to allow for the decline that may occur during the hospital stay. Of note no thromboembolic events have occurred with the use of an ESA in this group.Although ESAs are approved to optimize Hb in orthopedic surgery, they are not covered for cardiac surgery which has presented a significant challenge to patients who can not safely proceed to surgery until a target Hb between 13 to 15 g/dL is achieved.These data highlight the utility and safety associated with the use of ESAs for patients who do not accept blood products at an experienced Center for Transfusion-Free Medicine, such as ours. At this time, since insurance companies do not cover the cost of ESAs for patients needing life-saving cardiovascular operations, cost is a prohibitive barrier for patients. Unfortunately, it is not uncommon for patients to have to borrow money from others or set up payment plans. We hope that analyses like ours will help drive changes in reimbursement policies, particularly for patients who based on religious convictions, cannot receive blood products, and thus for whom pre-operative hemoglobin optimization is of utmost importance. [Display omitted] DisclosuresNo relevant conflicts of interest to declare. OffLabel Disclosure:Erythropoiesis-stimulating agent (ESA) are indicated for the treatment of anemia due to Chronic Kidney Disease in patients on dialysis and not on dialysis, Zidovudine in patients with HIV-infection, anemia due to myelosuppressive chemotherapy and reduction of allogeneic RBC transfusions in patients undergoing elective, noncardiac, nonvascular surgery

Luspatercept in MDS with Ring Sideroblasts: A Real-Life Multicenter Experience from a Named Patient Program

BackgroundLow risk Myelodysplastic syndromes (LR MDS) are a heterogeneous group of clonal disorders of the hematopoietic stem cell characterized by ineffective hematopoiesis, peripheral cytopenias and relative increase of bone marrow blasts [List 2004]. The most common cytopenia is anemia, which occurs in 85-90% of cases (isolated in 35% of cases) [Fenaux 2013], and ranges from mild/asymptomatic to transfusion dependent. The standard of care for anemia remains supportive care and about 70% of cases benefits from erythropoiesis-stimulating agents (ESAs).According to the FAB classification, a low-risk group of MDS characterized by the presence of ring sideroblasts (RS) was recognized. In the 2017 WHO classification, the nosologic entities of MDS uni-linear and multi-linear dysplasia with RS (MDS-UD-RS, MDS-MD-RS) were established, to emphasize the importance of identifying forms with a potential therapeutic target [Arber 2016].Luspatercept is a recombinant fusion protein consisting of the modified extracellular domain of human activin receptor type IIB (ActRIIB) linked to a domain of human immunoglobulin Fc G1. The drug showed efficacy in re-establishing erythropoiesis and was recently approved for the treatment of adult patients with very low- to intermediate-risk MDS-RS failing ESAs[Platzbecker 2017; Fenaux 2020].AimsTo retrospectively assess the efficacy and/or clinical benefit (defined as a reduction in red blood cells transfusions [RBCT] or increase in hemoglobin levels) of luspatercept in patients with LR MDS with RS in a real-life setting. Safety issues were also addressed and clinical and hematological predictors of outcome analyzed.MethodsWe considered all IPSS-R lower-risk MDS with RS patients with unsatisfactory response or unsuitable for ESAs, treated with luspatercept as monotherapy through an expanded access program since November 2020, in 2 tertiary hematologic centers in Milan, Italy. Luspatercept was administered according to the published schedule: starting dose 1,0 mg/kg every three weeks, with the possibility to increase up to 1,33 mg/kg and 1,75 mg/kg if patients did not reach transfusion independence or decreased transfusion burden after two consecutive infusions. Response to luspatercept was evaluated according to IWG 2018 criteria: Hb increase by > 1.5 g/dL and/or relevant reduction of units of RBC transfusions by an absolute number of at least 4 RBC transfusions/8 wk compared with the pretreatment transfusion number in the previous 8 wk.ResultsWe included a total of 17 pts (70% males, 30% females), with a median age of 68 years (range 45-89). The median follow-up from the start of the Luspatercept was 4 months (range 3-6).According to WHO 2017 we included 13 MLD (76%) and 4 ULD (24%); in all of them SF3B1 mutations was confirmed. Moreover, According to IPSS-R classification: 5 (27%)cases were intermediate and 12 (73%) low risk.All patients received at least three doses of luspatercept. Nine patients (53%) needed a dose escalation to 1,33 mg/kg, and 7 (41%) required the maximal dose of 1,75 mg/kg. Interestingly, not all patients received a dose escalation, and 8 (47%) obtained prolonged efficacy with 1 mg/kg dose.Hemoglobin levels increased in 9 pts (53%): 4 (24%), 3 (18%) and 2 (12%) cases at 1 mg/Kg, 1,33 mg/kg and 1,75 mg/dl, respectively. Medina increase was 1,5 g/dl (range 0,2 - 2,2) and these levels were maintained for a median of 4 months (range 3-6).In addition, considering transfusion burden, the independence was reached in 3 pts (18%), after a median time of 6 weeks from treatment start. Importantly, off the 14 patients remaining transfusion-dependent, 6 (35%) reduced the transfusion burden.The most prominent toxicity was increased blood pressure (grade 2) occurring in 3 pts (18%), and dizziness (grade 2) in 2 pts (12%); though the drug was generally well tolerated. No serious adverse events (SAEs) were reported. Therefore, patients were treated as outpatients in all cases.At the last follow up, all patients are alive and free from leukemic evolution.Conclusions:Our real-world experience confirms the efficacy of luspatercept in improving erythropoiesis and decreasing transfusion dependency in very low, low or intermediate risk MDS with RS, with an acceptable toxicity profile. DisclosuresFattizzo: Amgen: Honoraria, Speakers Bureau; Apellis: Speakers Bureau; Annexon: Consultancy; Momenta: Honoraria, Speakers Bureau; Novartis: Speakers Bureau; Alexion: Speakers Bureau; Kira: Speakers Bureau. Barcellini: Agios: Honoraria, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals: Honoraria; Novartis: Honoraria.

Demonstration of a U.S. nationwide reduction in transfusion in general surgery and a review of published transfusion reduction methodologies.

Red blood cell transfusions in surgical procedures can be lifesaving. However, recent studies show transfusions are associated with a dose-dependent increase in postoperative morbidity and mortality; hospitals and physicians have attempted to reduce them. We sought to determine the success of these efforts and review and summarize published reduction methods employed. An analysis of transfusion data from ACS-NSQIP public use files of general surgical procedures for 2012 and 2018; a retrospective review of the literature surrounding general surgical transfusion reduction from 2008 to 2018. The rate of general surgical transfusion in the NSQIP dataset decreased from 5.5% in 2012 to 4.0% in 2018, a 27% relative reduction in transfusion. After extensive multivariable adjustment for patient risk and operative complexity, this effect remained (Odds ratio 0.65, 95% CI 0.63-0.67, p< .001). Furthermore, there was a positive correlation between specific procedure decreases in transfusion and decreases in 30-day morbidity (rho =0.41, p= .003) and mortality (rho=0.37, p= .007). There were 866 published studies matching our search term "red blood cell transfusion reduction." Forty-four were relevant to general surgery. Seven dominant strategies for transfusion reduction by descending frequency of report included restrictive transfusion thresholds, management of preoperative anemia, perioperative interventions, educational programs, electronic clinical decision support, waste reduction, and audits of transfusion practices. Our study demonstrates a 27% decrease in general surgery transfusion between 2012 and 2018 with associated reductions in morbidity and mortality, suggesting published employed strategies have been successful and safely implemented.

ENERGIZE AND ENERGIZE-T: TWO PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDIES OF MITAPIVAT IN ADULTS WITH NON–TRANSFUSION-DEPENDENT OR TRANSFUSION-DEPENDENT ALPHA- OR BETA-THALASSEMIA

Thalassemias are characterized by imbalanced globin-chain production resulting in excess α- or β-globin precipitation, hemolytic anemia, and ineffective erythropoiesis. Adenosine triphosphate (ATP) levels are reduced in thalassemic red blood cells (RBCs), despite increased energy demands. Mitapivat is an oral activator of RBC pyruvate kinase (PKR), a glycolytic enzyme that regulates ATP production. In a phase 2 study of patients (pts) with α- or β-non–transfusion-dependent thalassemia (NTDT), twice-daily (BID) dosing with mitapivat increased hemoglobin (Hb) levels by ≥1.0 g/dL in 80% of pts, supporting the broadening of mitapivat's development in thalassemia. The study designs of ENERGIZE (2021-000211-23) and ENERGIZE-T (2021-000212-34), two phase 3 trials to assess the efficacy and safety of mitapivat in adults with α- or β-NTDT or transfusion-dependent thalassemia (TDT), respectively, are reported here. Both studies are phase 3, multicenter, randomized, double-blind, placebo-controlled trials. In ENERGIZE, approximately 171 eligible adults with NTDT will be randomized (2:1) to receive 100 mg mitapivat BID or placebo for 24 weeks (wks). Upon completion, eligible pts can transition to a 5-year, open-label extension. Key inclusion criteria: documented diagnosis of thalassemia (β-thalassemia ±α-globin mutations, Hb E β-thalassemia, or α-thalassemia [Hb H disease]), Hb concentration ≤10.0 g/dL, and NTDT defined as ≤5 RBC units during the 24-wk period before randomization and no RBC transfusion ≤8 wks prior. The primary endpoint is an Hb response defined as a ≥1.0 g/dL increase in average Hb concentration from Wk 12 through 24 compared with baseline (BL). Secondary endpoints include pt-reported outcomes, changes in Hb, markers of hemolysis and erythropoiesis, and safety. In ENERGIZE-T, approximately 240 eligible adults with TDT will be randomized (2:1) to receive 100 mg mitapivat BID or placebo for 48 wks. Upon completion, eligible pts can transition to a 5-year, open-label extension. Key inclusion criteria: documented diagnosis of thalassemia (same genotypes as detailed for the ENERGIZE study), and TDT defined as 6–20 RBC units transfused and no transfusion-free period ≥6 wks during the 24 wks before randomization. The primary endpoint is a transfusion reduction response, defined as a ≥50% reduction in transfused RBC units with a reduction of ≥2 units of transfused RBCs in any consecutive 12-wk period through Wk 48 compared with BL. Secondary endpoints include additional measures of transfusion burden, changes in iron markers, and safety. Not yet available. ENERGIZE and ENERGIZE-T are the first pivotal studies to assess a potential treatment across a broad spectrum of pts with thalassemia (ie, pts with TDT and NTDT; α- and β-thalassemias). ENERGIZE and ENERGIZE-T will evaluate the efficacy and safety of mitapivat, a novel, first-in-class oral activator of PKR. Both studies will start enrollment in 2021.

Blood transfusion trends in the United States: national inpatient sample, 2015 to 2018

Blood transfusions are among the most common therapeutic procedures performed in hospitalized patients. This study evaluates contemporary national trends in red blood cell (RBC), plasma, platelet, and cryoprecipitate transfusions. National Inpatient Sample, the largest all-payer inpatient database representing 94% to 97% of the US population, was evaluated from the fourth quarter (Q4) of 2015 through 2018. Quarterly trends for the percentage of hospitalizations with a transfusion procedure were separately examined for each blood product using log binomial regression and reported as quarterly percent change (QPC). The percentage of hospitalizations with an RBC transfusion decreased from 4.22% (2015Q4) to 3.79% (2018Q4) (QPC = −0.72; 95% confidence interval [CI], −1.26 to −0.19; Ptrend = .008). Although plasma transfusions also decreased, QPC = −1.33 (95% CI, −2.00 to −0.65; Ptrend < .001), platelet transfusions remained stable QPC = −0.13 (95% CI, −0.99 to 0.73; Ptrend = .766). In contrast, hospitalizations with cryoprecipitate utilization significantly increased QPC = 2.01 (95% CI, 0.57 to 3.44; Ptrend = .006). Significant quarterly reductions in RBC transfusions were also seen among many, but not all, strata of sex, race/ethnicity, patient risk severity, and admission type (elective vs nonelective). Despite significant declines in RBC transfusions among older adults, there were no significant changes among pediatric age-group (<18 years) and those 18 to 49 years. The decline in RBC and plasma transfusions suggests steady incorporation of robust evidence base showing safety of restrictive transfusions. Increased cryoprecipitate use may be reflective of wider adoption of hypofibrinogenemia management and hemostasis testing for coagulopathic patients.

Tranexamic acid for prevention of bleeding in cesarean delivery: An overview of systematic reviews.

Bleeding is the leading cause of maternal mortality in the world. Tranexamic acid reduces bleeding in trauma and surgery. Several systematic reviews of randomized trials have investigated tranexamic acid in the prevention of bleeding in cesarean delivery. However, the conclusions from systematic reviews are conflicting. This overview aims to summarize the evidence and explore the reasons for conflicting conclusions across the systematic reviews. A comprehensive literature search of Medline, Embase, and Cochrane Database of Systematic Reviews was conducted from inception to April 2021. Screening, data extraction, and quality assessments were performed by two independent reviewers. A Measurement Tool to Assess Reviews 2 and the Risk of Bias Assessment Tool for Systematic Reviews were used for study appraisal. A qualitative synthesis of evidence is presented. In all, 14systematic reviews were included in our analysis. Across these reviews, there were 32 relevant randomized trials. A modest reduction in blood transfusions and bleeding outcomes was found by most systematic reviews. Overall confidence in results varied from low to critically low. All of the included systematic reviews were at high risk of bias. Quality of evidence from randomized trials was uncertain. Systematic reviews investigating prophylactic tranexamic acid in cesarean delivery are heterogeneous in terms of methodological and reporting quality. Tranexamic acid may reduce blood transfusion and bleeding outcomes, but rigorous well-designed research is needed due to the limitations of the included studies. Data on safety and adverse effects are insufficient to draw conclusions.

Évolution et facteurs de risque de transfusion et d’accident thrombo-embolique après arthroplastie primaire et de révision de prothèses totales de hanche et de genou : analyse d’une base nationale sur 736061 cas

BackgroundOver the last years, new transfusion guidelines and pharmaceuticals have been introduced in primary and revision total hip and knee arthroplasty (P-THA, P-TKA, R-THA, R-TKA). In the US, a substantial decrease in transfusions has been observed in recent years. Little data exists on the subject in Europe. In this context we aimed to analyze: 1) Is there also a significant decrease in blood transfusion for these procedures in Germany? 2) Which patient and hospital related factors are associated with the risk of blood transfusion? 3) Is there a trend in complications, especially venous thromboembolism and stroke events that can be linked to tranexamic acid use? HypothesisThere is a significant trend in decreasing blood transfusions in hip and knee arthroplasty. MethodsUsing nationwide healthcare insurance data for inpatient hospital treatment, 736,061 cases treated between January 2011 and December 2017 were included (318,997 P-THAs, 43,780 R-THAs, 338,641 P-TKAs, 34,643 R-TKAs). Multivariable logistic regression was used to model the odds of transfusion as a function of the year of surgery. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated. ResultsIn each cohort the odds of transfusion decreased over time (2017 vs. 2011 (reference): P-THA: OR 0.42 (95%CI 0.39–0.45), P-TKA: OR 0.41 (95%CI 0.37–0.46), R-THA: OR 0.52 (95%CI 0.47–0.58), R-TKA: OR 0.53 (95%CI 0.46–0.61). Patient-related risk factors for blood transfusion included older age, female gender, lower Bodu Mass Index, comorbidities such as renal failure, cardiac arrhythmia, congestive heart failure, valvular disease, coagulopathy, depression, and antithrombotic medication prior to surgery. Venous thromboembolism or stroke events did not increase over the study period. DiscussionThe incidence of blood transfusions in primary and revision TKA and THA decreased over the study period. This may be due to new transfusion guidelines and the introduction of novel pharmaceuticals such as tranexamic acid. A further improved patient blood management and a focus on vulnerable patient groups might lead to a further future reduction of transfusions, especially in R-THA. Level of EvidenceIII; comparative observational Study.

Effects of acute normovolemic hemodilution on post‐cardiopulmonary bypass coagulation tests and allogeneic blood transfusion in thoracic aortic repair surgery: An observational cohort study

Perioperative blood transfusion is associated with increased morbidity and mortality. Acute normovolemic hemodilution (ANH) is a blood conservation strategy associated with variable success, and rarely studied in more complex cardiac procedures. The study aim was to evaluate whether ANH improves coagulopathy and reduces blood transfusions in thoracic aortic surgeries. Single-center observational cohort study comparing ANH and standard institutional practice in patients who underwent thoracic aortic repair with cardiopulmonary bypass (CPB) from 2019 to 2021. A total of 89 patients underwent ANH and 116 standard practice. There were no significant differences between the groups in terms of demographic or major perioperative characteristics. In the ANH group coagulation tests before and after transfusion of autologous blood showed decreased INR and increased platelets, fibrinogen, all with p < 0.0005. Coagulation results in the ANH and control groups were not statistically different. The average number of transfused allogeneic products per patient was lower in the ANH versus control group: FFP 1.1 ± 1.6 versus 1.9 ± 2.3 (p = 0.003), platelets 0.6 ± 0.8 versus 1.2 ± 1.3 (p = 0.0008), and cryoprecipitate 0.3 ± 0.7 versus 0.7 ± 1.1 (p = 0.008). Reduction in red blood cell transfusion was not statistically significant. The percentage of patients who received any transfusion was 53.9% in ANH and 59.5% in the control group (p = 0.42). There was no significant difference in major adverse outcomes. ANH is a safe blood conservation strategy for surgical repairs of the thoracic aorta. Laboratory data suggests ANH can improve some coagulation values after separation from CPB, and significantly reduce the number of transfused FFP, platelets and cryoprecipitate.

Rotational Thromboelastometry-Guided Transfusion Protocol to Reduce Allogeneic Blood Transfusion in Proximal Aortic Surgery With Deep Hypothermic Circulatory Arrest

To determine the impact of a rotational thromboelastometry (ROTEM)-guided transfusion protocol on the use of blood products, patient outcomes, coagulation factor concentrates, and costs. A single-center retrospective cohort study. A tertiary university hospital. Adults undergoing proximal aortic surgery with deep hypothermic circulatory arrest. ROTEM-guided transfusion protocol compared with clinically-guided transfusion. Two hundred seventeen patients were included; seventy-one elective and 24 emergency patients in the clinically-guided group, and 59 elective and 63 emergency patients in the ROTEM-guided transfusion protocol group. In the ROTEM-guided transfusion protocol group, a significant reduction in transfusion of red blood cells (5 [3-8] v 2 [0-4], p < 0.001), platelet concentrate (2 [2-3] v 1 [1-2], p < 0.001), and plasma (1,980 mL [1,320-3,300] v 800 mL [0-1,000], p < 0.001) was seen in elective surgery. Emergency patients received fewer red blood cells (7 [5-10] v 5 [2-10], p=0.040), platelet concentrate (3 [2-4] v 2 [2-3], p=0.023), and plasma (3,140 mL [1,980-3,960] v 1,000 mL [0-1,400], p < 0.001). Prothrombin complex concentrate and fibrinogen concentrate were increased significantly in elective and emergency patients. The surgical reexploration for bleeding rate was decreased in elective patients 33.8% v 5.1%. The implementation of a ROTEM-guided transfusion protocol might have the potential to decrease blood product transfusion and may improve patient outcomes.

Phase 2 study of danicopan in patients with paroxysmal nocturnal hemoglobinuria with an inadequate response to eculizumab

AbstractParoxysmal nocturnal hemoglobinuria (PNH) is characterized by uncontrolled terminal complement activation and subsequent intravascular hemolysis (IVH). C5 inhibitors prevent membrane attack complex formation, but patients may experience extravascular hemolysis (EVH) and continue to require blood transfusions. Danicopan, an oral proximal complement inhibitor of alternative pathway factor D (FD), is designed to control IVH and EVH. In a phase 2 dose-finding trial, eculizumab-treated transfusion-dependent patients with PNH (n = 12) received danicopan, 100 to 200 mg thrice daily, in addition to their eculizumab regimen for 24 weeks. End points included hemoglobin (Hgb) change vs baseline at week 24 (primary), reduction in blood transfusions, and patient-reported outcomes. Safety, tolerability, and pharmacokinetics/pharmacodynamics were measured. Twelve patients received ≥1 danicopan dose; 1 patients discontinued from a serious adverse event deemed unlikely related to danicopan. Eleven patients completed the 24-week treatment period. Addition of danicopan resulted in a mean Hgb increase of 2.4 g/dL at week 24. In the 24 weeks prior to danicopan, 10 patients received 31 transfusions (50 units) compared with 1 transfusion (2 units) in 1 patient during the 24-week treatment period. Mean Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score increased by 11 points from baseline to week 24. The most common adverse events were headache, cough, and nasopharyngitis. Addition of danicopan, a first-in-class FD inhibitor, led to a meaningful improvement in Hgb and reduced transfusion requirements in patients with PNH who were transfusion-dependent on eculizumab. These benefits were associated with improvement of FACIT-Fatigue. This trial was registered at www.clinicaltrials.gov as #NCT03472885.

Clinical Outcome and Risk Factors of Red Blood Cell Transfusion in Patients Undergoing Elective Primary Meningioma Resection.

Simple SummaryThe transfusion of red blood cells (RBC) in patients undergoing major elective cranial surgery is associated with increased morbidity and mortality. This study sought to identify the clinical outcome of RBC transfusions in skull base and non-skull base meningioma patients including the identification of risk factors for RBC transfusion. Data underline that preoperative anaemia rate was significantly higher in transfused patients (17.7%) compared to patients without RBC transfusion (6.2%). We could further show that RBC transfusion was associated with increased postoperative complications and increased hospital length of stay. After multivariate analyses, risk factors for RBC transfusion were preoperative American Society of Anaesthesiologists (ASA) physical status score, tumor size, surgical time, and intraoperative blood loss. We concluded that blood loss due to large tumors or localization near large vessels are the main triggers for RBC transfusion in meningioma patients paired with a potential preselection that masks the effect of preoperative anaemia in multivariate analysis. So far, this has not been investigated in a large cohort (n = 423) of skull base and non-skull base meningioma patients.Transfusion of red blood cells (RBC) in patients undergoing major elective cranial surgery is associated with increased morbidity, mortality and prolonged hospital length of stay (LOS). This retrospective single center study aims to identify the clinical outcome of RBC transfusions on skull base and non-skull base meningioma patients including the identification of risk factors for RBC transfusion. Between October 2009 and October 2016, 423 patients underwent primary meningioma resection. Of these, 68 (16.1%) received RBC transfusion and 355 (83.9%) did not receive RBC units. Preoperative anaemia rate was significantly higher in transfused patients (17.7%) compared to patients without RBC transfusion (6.2%; p = 0.0015). In transfused patients, postoperative complications as well as hospital LOS was significantly higher (p < 0.0001) compared to non-transfused patients. After multivariate analyses, risk factors for RBC transfusion were preoperative American Society of Anaesthesiologists (ASA) physical status score (p = 0.0247), tumor size (p = 0.0006), surgical time (p = 0.0018) and intraoperative blood loss (p < 0.0001). Kaplan-Meier curves revealed significant influence on overall survival by preoperative anaemia, RBC transfusion, smoking, cardiovascular disease, preoperative KPS ≤ 60% and age (elderly ≥ 75 years). We concluded that blood loss due to large tumors or localization near large vessels are the main triggers for RBC transfusion in meningioma patients paired with a potential preselection that masks the effect of preoperative anaemia in multivariate analysis. Further studies evaluating the impact of preoperative anaemia management for reduction of RBC transfusion are needed to improve the clinical outcome of meningioma patients.

High- versus low-dose tranexamic acid as part of a Patient Blood Management strategy for reducing blood loss in patients undergoing surgery for adolescent idiopathic scoliosis.

The administration of tranexamic acid (TXA) has been shown to be beneficial in reducing blood loss during surgery for adolescent idiopathic scoliosis (AIS), but optimal dosing has yet to be defined. This retrospective study compared high- versus low-dose TXA as part of a Patient Blood Management strategy for reducing blood loss in patients undergoing posterior spine fusion surgery. Clinical records were reviewed for 223 patients with AIS who underwent posterior spinal fusion of five or more levels during a 6-year time period. We compared normalized blood loss, total estimated blood loss (EBL), and the need for transfusion between patients receiving high-dose TXA (loading dose of ≥ 30mg/kg) versus low-dose TXA(loading dose < 30mg/kg). Both groups received maintenance TXA infusions of 10mg/kg/h until skin closure. Patient demographics, curves, and surgical characteristics were similar in both groups. The high-dose TXA group had a 36% reduction in normalized blood loss (1.8cc/kg/level fused versus 2.8cc/kg/level fused, p < 0.001) and a 37.5% reduction in total EBL (1000cc versus 1600cc, p < 0.001). Patients in the high-dose group had a 48% reduction in PRBC transfusion, with only 19% receiving a transfusion of PRBC compared to 67% in the low-dose group (p < 0.001). When combined with other proven Patient Blood Management strategies, the use of high-dose TXA compared to low-dose TXA may be beneficial in reducing blood loss for patients with adolescent idiopathic scoliosis undergoing posterior spinal fusion surgery. Level III, retrospective cohort.

Impact of COVID-19 and lockdown regarding blood transfusion.

BackgroundThe outbreak of a SARS‐CoV‐2 resulted in a massive afflux of patients in hospital and intensive care units with many challenges. Blood transfusion was one of them regarding both blood banks (safety, collection, and stocks) and consumption (usual care and unknown specific demand of COVID‐19 patients). The risk of mismatch was sufficient to plan blood transfusion restrictions if stocks became limited.Study design and methodsAnalyses of blood transfusion in a tertiary hospital and blood collection in the referring blood bank between February 24 and May 31, 2020.ResultsWithdrawal of elective surgery and non‐urgent care and admission of 2291 COVID‐19 patients reduced global activity by 33% but transfusion by 17% only. Only 237 (10.3) % of COVID‐19 patients required blood transfusion, including 45 (2.0%) with acute bleeding. Lockdown and cancellation of mobile collection resulted in an 11% reduction in blood donation compared to 2019. The ratio of reduction in blood transfusion to blood donation remained positive and stocks were slightly enhanced.DiscussionReduction of admissions due to SARS‐CoV‐2 pandemic results only in a moderate decrease of blood transfusion. Incompressible blood transfusions concern urgent surgery, acute bleeding (including some patients with COVID‐19, especially under high anticoagulation), or are supportive for chemotherapy‐induced aplasia or chronic anemia. Lockdown results in a decrease of blood donation by cancellation of mobile donation but with little impact on a short period by mobilization of usual donors. No mismatch between demand and donation was evidenced and no planned restriction to blood transfusion was necessary.

Factor VIII inhibitor bypass activity (FEIBA) for the reduction of transfusion in cardiac surgery: a randomized, double-blind, placebo-controlled, pilot trial

BackgroundUncontrolled bleeding after cardiac surgery can be life-threatening. Factor eight inhibitor bypassing activity (FEIBA) is a prothrombin complex concentrate empirically used as rescue therapy for correction of refractory bleeding diathesis post-cardiopulmonary bypass (CPB). FEIBA used as rescue therapy for bleeding diathesis after CPB has been associated with a low incidence of complications and a reduction in transfusion requirement and re-exploration. The feasibility and efficacy of early administration of FEIBA after the termination of CPB have not been studied in a prospective randomized trial.MethodsWe designed a small randomized, double-blinded, placebo-controlled pilot trial to determine the feasibility of a larger trial testing the hypothesis that FEIBA decreases transfusion requirements after CPB. The study was designed to evaluate the feasibility of a larger pivotal trial to determine the effectiveness of FEIBA in reducing the total volume of blood products transfused perioperatively, and its safety profile. Study participants were adult patients undergoing elective major aortic cardiovascular surgery at a tertiary referral hospital, who were equally randomized to receive a single dose of either FEIBA or matched placebo intraoperatively at the end of CPB.ResultsTwenty patients were screened and 12 were randomized and included in the analysis. Protocol adherence was high, and all patients received the study drug per intention-to-treat except one patient. There were no protocol deviations or events of unblinding, and adverse events were not different between groups. Patients in the FEIBA group were older and more likely to be female and had higher BMI, lower hematocrit, and longer hypothermic circulatory arrest. There were no differences in post-randomization blood product transfusions (difference FEIBA vs. placebo −899 mL; 95% CI −5206 to 3409) or in the administration of open-label FEIBA.ConclusionsThis pilot trial confirmed the adequacy of the trial design that involved the early, blinded administration of FEIBA, by demonstrating excellent protocol adherence. We conclude that a larger trial establishing the effectiveness of early prothrombin complex concentrate administration to reduce the use of blood products in the setting of high-risk cardiac surgery is feasible.Trial registrationClinicalTrials.gov, NCT02577614. Registered 16 October 2015