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Missingness matters: a secondary analysis of thromboelastography measurements from a recent prehospital randomized tranexamic acid clinical trial
Donohue, J. K., Iyanna, N., Lorence, J. M., Brown, J. B., Guyette, F. X., Eastridge, B. J., Nirula, R., Vercruysse, G. A., O'Keeffe, T., Joseph, B., et al
Trauma surgery & acute care open. 2024;9(1):e001346
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Abstract
BACKGROUND Tranexamic acid (TXA) has been hypothesized to mitigate coagulopathy in patients after traumatic injury. Despite previous prehospital clinical trials demonstrating a TXA survival benefit, none have demonstrated correlated changes in thromboelastography (TEG) parameters. We sought to analyze if missing TEG data contributed to this paucity of findings. METHODS We performed a secondary analysis of the Study of Tranexamic Acid During Air Medical and Ground Prehospital Transport Trial. We compared patients that received TEG (YES-TEG) and patients unable to be sampled (NO-TEG) to analyze subgroups in which to investigate TEG differences. TEG parameter differences across TXA intervention arms were assessed within subgroups disproportionately present in the NO-TEG relative to the YES-TEG cohort. Generalized linear models controlling for potential confounders were applied to findings with p<0.10 on univariate analysis. RESULTS NO-TEG patients had lower prehospital systolic blood pressure (SBP) (100 (78, 140) vs 125 (88, 147), p<0.01), lower prehospital Glascow Coma Score (14 (3, 15) vs 15 (12, 15), p<0.01), greater rates of prehospital intubation (39.4% vs 24.4%, p<0.01) and greater mortality at 30 days (36.4% vs 6.8%, p<0.01). NO-TEG patients had a greater international normalized ratio relative to the YES-TEG subgroup (1.2 (1.1, 1.5) vs 1.1 (1.0, 1.2), p=0.04). Within a severe prehospital shock cohort (SBP<70), TXA was associated with a significant decrease in clot lysis at 30 min on multivariate analysis (β=-27.6, 95% CI (-51.3 to -3.9), p=0.02). CONCLUSIONS Missing data, due to the logistical challenges of sampling certain severely injured patients, may be associated with a lack of TEG parameter changes on TXA administration in the primary analysis. Previous demonstration of TXA's survival benefit in patients with severe prehospital shock in tandem with the current findings supports the notion that TXA acts at least partially by improving clot integrity. LEVEL OF EVIDENCE Level II.
PICO Summary
Population
Patients at risk for haemorrhage receiving tranexamic acid before hospitalization, enrolled in the Study of Tranexamic Acid During Air Medical and Ground Prehospital Transport (STAAMP) Trial (n= 903).
Intervention
Prehospital tranexamic acid (TXA) (n= 447).
Comparison
Placebo (n= 456).
Outcome
This study was a secondary analysis of the STAAMP trial, comparing patients that received thromboelastography (TEG) (YES-TEG, n= 837) and patients unable to be sampled (NO-TEG, n= 66) to analyze subgroups in which to investigate TEG differences. NO-TEG patients had lower prehospital systolic blood pressure (SBP) (100 (78, 140) vs. 125 (88, 147)), lower prehospital Glascow Coma Score (14 (3, 15) vs. 15 (12, 15)), greater rates of prehospital intubation (39.4% vs. 24.4%) and greater mortality at 30 days (36.4% vs. 6.8%). NO-TEG patients had a greater international normalized ratio relative to the YES-TEG subgroup (1.2 (1.1, 1.5) vs. 1.1 (1.0, 1.2)). Within a severe prehospital shock cohort (SBP< 70), TXA was associated with a significant decrease in clot lysis at 30 min on multivariate analysis (β= -27.6; 95% CI [-51.3, -3.9].
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Desmopressin to reduce periprocedural bleeding and transfusion: a systematic review and meta-analysis
Wang, C., Lebedeva, V., Yang, J., Anih, J., Park, L. J., Paczkowski, F., Roshanov, P. S.
Perioperative medicine (London, England). 2024;13(1):5
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Abstract
We systematically reviewed the literature to investigate the effects of peri-procedural desmopressin in patients without known inherited bleeding disorders undergoing surgery or other invasive procedures. We included 63 randomized trials (4163 participants) published up to February 1, 2023. Seven trials were published after a 2017 Cochrane systematic review on this topic. There were 38 trials in cardiac surgery, 22 in noncardiac surgery, and 3 in non-surgical procedures. Meta-analyses demonstrated that desmopressin likely does not reduce the risk of receiving a red blood cell transfusion (25 trials, risk ratio [RR] 0.95, 95% confidence interval [CI] 0.86 to 1.05) and may not reduce the risk of reoperation due to bleeding (22 trials, RR 0.75, 95% CI 0.47 to 1.19) when compared to placebo or usual care. However, we demonstrated significant reductions in number of units of red blood cells transfused (25 trials, mean difference -0.55 units, 95% CI - 0.94 to - 0.15), total volume of blood loss (33 trials, standardized mean difference - 0.40 standard deviations; 95% CI - 0.56 to - 0.23), and the risk of bleeding events (2 trials, RR 0.45, 95% CI 0.24 to 0.84). The certainty of evidence of these findings was generally low. Desmopressin increased the risk of clinically significant hypotension that required intervention (19 trials, RR 2.15, 95% CI 1.36 to 3.41). Limited evidence suggests that tranexamic acid is more effective than desmopressin in reducing transfusion risk (3 trials, RR 2.38 favoring tranexamic acid, 95% CI 1.06 to 5.39) and total volume of blood loss (3 trials, mean difference 391.7 mL favoring tranexamic acid, 95% CI - 93.3 to 876.7 mL). No trials directly informed the safety and hemostatic efficacy of desmopressin in advanced kidney disease. In conclusion, desmopressin likely reduces periprocedural blood loss and the number of units of blood transfused in small trials with methodologic limitations. However, the risk of hypotension needs to be mitigated. Large trials should evaluate desmopressin alongside tranexamic acid and enroll patients with advanced kidney disease.
PICO Summary
Population
Children or adults without known inherited bleeding disorders undergoing surgery or other invasive procedures (63 randomised controlled trials, n= 4,163).
Intervention
Desmopressin administered intravenously or subcutaneously before, during, or immediately after a surgical or interventional procedure.
Comparison
Placebo, usual care, or antifibrinolytic agents.
Outcome
Meta-analyses demonstrated that desmopressin likely does not reduce the risk of receiving a red blood cell transfusion (25 trials, risk ratio [RR] 0.95; 95% confidence interval (CI) [0.86, 1.05]) and may not reduce the risk of reoperation due to bleeding (22 trials, RR 0.75; 95% CI [0.47, 1.19]) when compared to placebo or usual care. However, the authors demonstrated significant reductions in number of units of red blood cells transfused (25 trials, mean difference -0.55 units; 95% CI [-0.94, -0.15]), total volume of blood loss (33 trials, standardized mean difference - 0.40 standard deviations; 95% CI [-0.56, -0.23]), and the risk of bleeding events (2 trials, RR 0.45; 95% CI [0.24, 0.84]). The certainty of evidence of these findings was generally low.
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Efficacy and cost-effectiveness of darbepoetin alfa once every 4 weeks versus continuous erythropoietin receptor activator once every 4 weeks for anemia correction in patients with chronic kidney disease not on dialysis
Park, G. N., Lee, K. H., Moon, J. E., Choi, S. J., Park, M. Y., Kim, J. K., Yu, B. C.
Kidney research and clinical practice. 2024
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Abstract
BACKGROUND For anemia management in patients with chronic kidney disease not on dialysis, darbepoetin alfa (DA), which has a shorter half-life but is more inexpensive than continuous erythropoietin receptor activator (CERA), is preferred in Korea. This study evaluated the efficacy, safety, and cost-effectiveness of once-in-4-weeks DA compared with once-in-4-weeks CERA in patients with chronic kidney disease not on dialysis. METHODS In this randomized, prospective, non-inferiority study, 40 erythropoiesis-stimulating agent-naïve patients with chronic kidney disease not on dialysis were randomized 1:1 to the DA group and CERA group. They received the study drug once in 4 weeks during 10- or 12-week correction period and 24-week efficacy evaluation period. The primary outcomes were the mean difference in the changes in hemoglobin levels between baseline and efficacy evaluation period and hemoglobin response rates during the correction period. The secondary outcomes included differences in adverse events and costs. RESULTS DA was non-inferior to CERA for anemia correction; the mean difference in the change in hemoglobin levels between the groups was -0.070 g/dL (95% confidence interval, -0.730 to 0.590 g/dL). Hemoglobin response rates were 100% with DA and 94.1% with CERA. Adverse events were comparable. The mean cost of DA was approximately one-third that of CERA (34,100 ± 7,600 Korean won/4 weeks vs. 115,500 ± 23,600 Korean won/4 weeks; p < 0.001). CONCLUSION Once-in-4-weeks DA safely corrects anemia in erythropoiesis-stimulating agent-naïve patients with chronic kidney disease not on dialysis and is more cost-effective than once-in-4-weeks CERA.
PICO Summary
Population
Patients with chronic kidney disease not on dialysis (n= 40).
Intervention
Darbepoetin alfa (DA), (n= 20).
Comparison
Continuous erythropoietin receptor activator (CERA), (n= 20).
Outcome
The patients received the study drug once in 4 weeks during 10- or 12-week correction period and 24-week efficacy evaluation period. The primary outcomes were the mean difference in the changes in haemoglobin levels between baseline and efficacy evaluation period and haemoglobin response rates during the correction period. DA was non-inferior to CERA for anaemia correction; the mean difference in the change in haemoglobin levels between the groups was -0.070 g/dL (95% confidence interval [-0.730, 0.590 g/dL]). Haemoglobin response rates were 100% with DA and 94.1% with CERA. Adverse events were comparable. The mean cost of DA was approximately one-third that of CERA (34,100 ± 7,600 Korean won/4 weeks vs. 115,500 ± 23,600 Korean won/4 weeks).
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Reported outcomes in patients with iron deficiency or iron deficiency anemia undergoing major surgery: a systematic review of outcomes
Stangl, S., Popp, M., Reis, S., Sitter, M., Saal-Bauernschubert, L., Schießer, S., Kranke, P., Choorapoikayil, S., Weibel, S., Meybohm, P.
Systematic reviews. 2024;13(1):5
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Abstract
BACKGROUND Iron deficiency (ID) is the leading cause of anemia worldwide. The prevalence of preoperative ID ranges from 23 to 33%. Preoperative anemia is associated with worse outcomes, making it important to diagnose and treat ID before elective surgery. Several studies indicated the effectiveness of intravenous iron supplementation in iron deficiency with or without anemia (ID(A)). However, it remains challenging to establish reliable evidence due to heterogeneity in utilized study outcomes. The development of a core outcome set (COS) can help to reduce this heterogeneity by proposing a minimal set of meaningful and standardized outcomes. The aim of our systematic review was to identify and assess outcomes reported in randomized controlled trials (RCTs) and observational studies investigating iron supplementation in iron-deficient patients with or without anemia. METHODS We searched MEDLINE, CENTRAL, and ClinicalTrials.gov systematically from 2000 to April 1, 2022. RCTs and observational studies investigating iron supplementation in patients with a preoperative diagnosis of ID(A), were included. Study characteristics and reported outcomes were extracted. Outcomes were categorized according to an established outcome taxonomy. Quality of outcome reporting was assessed with a pre-specified tool. Reported clinically relevant differences for sample size calculation were extracted. RESULTS Out of 2898 records, 346 underwent full-text screening and 13 studies (five RCTs, eight observational studies) with sufficient diagnostic inclusion criteria for iron deficiency with or without anemia (ID(A)) were eligible. It is noteworthy to mention that 49 studies were excluded due to no confirmed diagnosis of ID(A). Overall, 111 outcomes were structured into five core areas including nine domains. Most studies (92%) reported outcomes within the 'blood and lymphatic system' domain, followed by "adverse event" (77%) and "need for further resources" (77%). All of the latter reported on the need for blood transfusion. Reported outcomes were heterogeneous in measures and timing. Merely, two (33%) of six prospective studies were registered prospectively of which one (17%) showed no signs of selective outcome reporting. CONCLUSION This systematic review comprehensively depicts the heterogeneity of reported outcomes in studies investigating iron supplementation in ID(A) patients regarding exact definitions and timing. Our analysis provides a systematic base for consenting to a minimal COS. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42020214247.
PICO Summary
Population
Patients with iron deficiency or iron deficiency anaemia undergoing major surgery (13 studies: 5 randomised controlled trials and 8 observational studies).
Intervention
Systematic review to identify and appraise outcomes reported for preoperative or perioperative treatment of iron deficiency, with or without anemia.
Comparison
Outcome
Overall, 111 outcomes were structured into five core areas including nine domains. Most studies (92%) reported outcomes within the 'blood and lymphatic system' domain, followed by ‘adverse event’ (77%) and ‘need for further resources’ (77%). All of the latter reported on the need for blood transfusion. Reported outcomes were heterogeneous in measures and timing. Merely, two (33%) of six prospective studies were registered prospectively of which one (17%) showed no signs of selective outcome reporting.
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Mitapivat improves ineffective erythropoiesis and iron overload in adult patients with pyruvate kinase deficiency
van Beers, E. J., Al-Samkari, H., Grace, R. F., Barcellini, W., Glenthøj, A., DiBacco, M., Wind-Rotolo, M., Xu, R., Beynon, V., Patel, P., et al
Blood advances. 2024
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Abstract
Pyruvate kinase (PK) deficiency is a rare, hereditary disease characterized by chronic hemolytic anemia. Iron overload is a common complication regardless of age, genotype, or transfusion history. Mitapivat, an oral, allosteric PK activator, improves anemia and hemolysis in adult patients with PK deficiency. Mitapivat's impact on iron overload and ineffective erythropoiesis was evaluated in adults with PK deficiency who were not regularly transfused in the phase 3 ACTIVATE trial and long-term extension (LTE) (NCT03548220/NCT03853798). Patients in the LTE received mitapivat throughout ACTIVATE/LTE (baseline to Week [W] 96; mitapivat-to-mitapivat [M/M] arm) or switched from placebo (baseline to W24) to mitapivat (W24 to 96; placebo-to-mitapivat [P/M] arm). Changes from baseline in markers of iron overload and erythropoiesis were assessed to W96. Improvements in hepcidin (mean [95% confidence interval ⟨CI ⟩] 4770.0 ng/L [-1532.3, 11,072.3], erythroferrone (-9834.9 ng/L [-14,328.4, -5341.3]), soluble transferrin receptor (-56.0 nmol/L [-84.8, -27.2]), and erythropoietin (-32.85 IU/L [-54.65, -11.06]) were observed in the M/M arm (n=40) from baseline to W24, sustained to W96. No improvements were observed in the P/M arm (n=40) to W24; however, upon transitioning to mitapivat, improvements similar to the M/M arm were seen. Mean (95% CI) changes from baseline in liver iron concentration (LIC) by magnetic resonance imaging (MRI) at W96 were -2.0 mg Fe/g dry weight (dw) (-4.8, -0.8; M/M arm) and -1.8 mg Fe/g dw (-4.4, 0.80; P/M arm). Mitapivat is the first disease-modifying pharmacotherapy shown to have beneficial effects on iron overload and ineffective erythropoiesis in patients with PK deficiency.
PICO Summary
Population
Adults with pyruvate kinase deficiency not regularly transfused, enrolled in the phase 3 ACTIVATE clinical trial and long term extension (LTE) (n= 80).
Intervention
Mitapivat throughout ACTIVATE/LTE baseline to week (W) 96 (mitapivat-to-mitapivat M/M arm, n= 40).
Comparison
Switched from placebo (baseline to W24) to mitapivat W24 to 96 (placebo-to-mitapivat P/M arm, n= 40).
Outcome
Changes from baseline in markers of iron overload and erythropoiesis were assessed to W96. Improvements in hepcidin (mean [95% confidence interval (CI)] 4770.0 ng/L [-1532.3, 11,072.3]), erythroferrone (-9834.9 ng/L [-14,328.4, -5341.3]), soluble transferrin receptor (-56.0 nmol/L [-84.8, -27.2]), and erythropoietin (-32.85 IU/L [-54.65, -11.06]) were observed in the M/M arm from baseline to W24, sustained to W96. No improvements were observed in the P/M arm to W24; however, upon transitioning to mitapivat, improvements similar to the M/M arm were seen. Mean (95% CI) changes from baseline in liver iron concentration by magnetic resonance imaging at W96 were -2.0 mg Fe/g dry weight (dw) (-4.8, -0.8; M/M arm) and -1.8 mg Fe/g dw (-4.4, 0.80; P/M arm).
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Kidney disease in trials of perioperative tranexamic acid
Liu, C. W., Anih, J., Lebedeva, V., Gungor, A., Wang, C., Park, L., Roshanov, P. S.
Journal of clinical anesthesia. 2024;94:111417
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Abstract
STUDY OBJECTIVE To assess how kidney disease is handled in randomized trials evaluating the safety and efficacy of perioperative tranexamic acid, and to evaluate its effects across levels of kidney function. DESIGN Systematic review and meta-analysis of randomized controlled trials. SETTING We screened studies from a previous comprehensive systematic review, and updated its search of PubMed, Embase, and Cochrane CENTRAL to July 31, 2023. PATIENTS Patients undergoing non-obstetric surgery. INTERVENTIONS Intravenous tranexamic acid compared to placebo or usual care without tranexamic acid. MEASUREMENT We summarized the handling of kidney disease in eligibility criteria, dose adjustments for kidney function, and effects of tranexamic acid on thrombotic events, seizures, and bleeding by subgroups of kidney function. MAIN RESULTS We evaluated 300 trials with 53,085 participants; 45,958 participants (86.6%) were enrolled in 228 trials (76.0%) that explicitly excluded patients with kidney disease. Definitions of kidney diseased used for exclusion varied widely. Most were non-specific and some corresponded to mild disease. Only 5 trials adjusted dosing for kidney function. Meta-analysis of two large trials found tranexamic acid unlikely to substantially increase or decrease the occurrence of thrombotic events in patients with eGFR <60 mL/min/1.73m(2) (RR, 0.95; 95% CI: 0.83 to 1.07) or ≥ 60 mL/min/1.73m(2) (RR, 1.00; 95% CI, 0.91 to 1.11; P for subgroup difference = 0.47), but both trials excluded patients with severe kidney disease. No analysis could be performed regarding seizure risk. One large trial in noncardiac surgery reported similar reduction in bleeding across subgroups of kidney function but excluded patients with creatinine clearance <30 mL/min. CONCLUSIONS The large evidence base supporting perioperative tranexamic acid suffers from broad and unjustified exclusion of patients with kidney disease. Typical perioperative dosing of tranexamic acid is likely safe and effective in patients with creatinine clearance >30 mL/min, but effects in more severe kidney disease are unknown.
PICO Summary
Population
Patients undergoing non-obstetric surgery (300 trials, n= 53,085).
Intervention
Intravenous tranexamic acid.
Comparison
Placebo or usual care without tranexamic acid.
Outcome
From all the included studies, 45,958 participants (86.6%) were enrolled in 228 trials (76.0%) that explicitly excluded patients with kidney disease. Definitions of kidney diseased used for exclusion varied widely. Most were non-specific and some corresponded to mild disease. Only 5 trials adjusted dosing for kidney function. Meta-analysis of two large trials found tranexamic acid unlikely to substantially increase or decrease the occurrence of thrombotic events in patients with estimated glomerular filtration rate <60 mL/min/1.73m(2) (RR 0.95; 95% CI [0.83, 1.07]) or ≥ 60 mL/min/1.73m(2) (RR 1.00; 95% CI [0.91, 1.11], but both trials excluded patients with severe kidney disease. No analysis could be performed regarding seizure risk. One large trial in non-cardiac surgery reported similar reduction in bleeding across subgroups of kidney function but excluded patients with creatinine clearance <30 mL/min.
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Full Correction of Posttransplant Anemia Is Associated With Stabilized Cardiac Dimensions Among Kidney Transplant Recipients: A Prospective Randomized Controlled Trial
Al-Otaibi, T., Nagib, A. M., Halim, M. A., Abo-Atya, H., Mahmoud, T., Nair, P., Adel, H., Mosaad, A., Fathy, A., Abdul-Hameed, M., et al
Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation. 2024;22(Suppl 1):323-331
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Editor's Choice
Abstract
OBJECTIVES Posttransplant anemia might be associated with cardiovascular morbidity and increased mortality. To our knowledge, the debate on anemia correction has neither been revisited nor decided definitively. We aimed to assess the effects of full correction of posttransplant anemia on the cardiovascular system and quality of life among renal transplant recipients with stable graft function who were using erythropoietin-stimulating agents. MATERIALS AND METHODS We enrolled 247 kidney recipients with stable graft function to be assessed for anemia. Eligible patients were randomized to achieve targeted hemoglobin of 11 to 12 g/dL (group 1, n = 183) or of 13 to 15 g/dL (group 2, n = 64) with the use of erythropoietin-stimulating agents. Patients underwent monthly clinical and laboratory evaluations of kidney graft function. Quality of life and echocardiography were assessed at study start and at 12 months. RESULTS The 2 groups were comparable regarding pretransplant characteristics. In group 2, we observed comparable posttransplant complications (P > .05) but better graft function at 6 months and better cardiac indexes at 1 year of the study (P < .05). At 12 months, quality of life had improved after full correction of posttransplant anemia in the renal transplant recipients who received erythropoietinstimulating agents. CONCLUSIONS Full correction of posttransplant anemia in renal transplant recipients was associated with improved quality of life and cardiac indexes without an effect on cardiovascular comorbidity.
PICO Summary
Population
Adult kidney transplant recipients with stable graft function (n= 247).
Intervention
Targeted haemoglobin of 11 to 12 g/dL with the use of erythropoietin-stimulating agents (ESA) (group 1, n= 183)
Comparison
Targeted haemoglobin of 13 to 15 g/dL with ESA (group 2, n= 64)
Outcome
Patients underwent monthly clinical and laboratory evaluations of kidney graft function. Quality of life and echocardiography were assessed at study start and at 12 months. In group 2, there were comparable post-transplant complications, but better graft function at 6 months and better cardiac indexes at 1 year of the study. At 12 months, quality of life had improved after full correction of post-transplant anaemia in the renal transplant recipients who received erythropoietin-stimulating agents.
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Effectiveness of Tranexamic Acid in the Postoperative Period in Body Contour Surgery: Randomized Clinical Trial
Bayter-Marín, J. E., Hoyos, A., Cárdenas-Camarena, L., Peña-Pinzón, W., Bayter-Torres, A. F., Díaz-Díaz, C. A., McCormick-Méndez, M., Plata-Rueda, E. L., Niño-Carreño, C. S.
Plastic and reconstructive surgery. Global open. 2023;11(11):e5403
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Abstract
BACKGROUND Tranexamic acid (TXA) is used to reduce bleeding in body contouring procedures; however, there are no studies that show the effectiveness of TXA when it is also used in the immediate postoperative period. METHODS A controlled, randomized, parallel, and open-label clinical trial was carried out in adult patients undergoing liposculpture and/or abdominoplasty. A control group administering presurgical TXA and a study group with presurgical and postsurgical TXA were formed. The decrease in hemoglobin and the incidence of blood transfusions between both groups were compared as well as the possible adverse effects of TXA. RESULTS Four hundred twenty-seven subjects were included, 208 (48.7%) in the control group and 219 (51.3%) in the study group. The median age was 34 years (interquartile range 28-42). Median postoperative hemoglobin levels at 24 hours were similar in both groups (study 11.3 g/dL versus control 11.1 g/dL, P = 0.07); however, at 72 hours, postoperative hemoglobin was higher in the study group versus control (10.8 versus 10.0 g/dL, P ≤ 0.001). The incidence of transfusions at 72 hours was 1.8% in the study group and 8.6% in the control group, for a risk ratio of 0.21 (95% confidence interval 0.07-0.61). There were no adverse or thromboembolic events. CONCLUSION TXA proved to be more effective in reducing intra- and postsurgical bleeding and the need for transfusions, when used preoperatively and continued for 48 hours after surgery, than when used only preoperatively, without reporting adverse or thromboembolic effects.
PICO Summary
Population
Patients undergoing liposculpture and/or abdominoplasty (n= 427).
Intervention
Presurgical and postsurgical tranexamic acid (TXA), (study group, n= 219).
Comparison
Presurgical TXA (control group, n= 208).
Outcome
Median postoperative haemoglobin levels at 24 hours were similar in both groups (study 11.3 g/dL versus control 11.1 g/dL). At 72 hours, postoperative haemoglobin was higher in the study group versus control (10.8 versus 10.0 g/dL). The incidence of transfusions at 72 hours was 1.8% in the study group and 8.6% in the control group, for a risk ratio of 0.21; 95% confidence interval [0.07, 0.61]. There were no adverse or thromboembolic events.
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Darbepoetin alfa to reduce transfusion episodes in infants with haemolytic disease of the fetus and newborn who are treated with intrauterine transfusions in the Netherlands: an open-label, single-centre, phase 2, randomised, controlled trial
Ree, I. M. C., de Haas, M., van Geloven, N., Juul, S. E., de Winter, D., Verweij, E. J. T., Oepkes, D., van der Bom, J. G., Lopriore, E.
The Lancet. Haematology. 2023;10(12):e976-e984
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Abstract
BACKGROUND Up to 88% of infants with haemolytic disease of the fetus and newborn who are treated with intrauterine transfusions require erythrocyte transfusions after birth. We aimed to investigate the effect of darbepoetin alfa on the prevention of postnatal anaemia in infants with haemolytic disease of the fetus and newborn. METHODS We conducted an open-label, single-centre, phase 2 randomised controlled trial to evaluate the effect of darbepoetin alfa on the number of erythrocyte transfusions in infants with haemolytic disease of the fetus and newborn. All infants who were treated with intrauterine transfusion and born at 35 weeks of gestation or later at the Leiden University Medical Center, Leiden, Netherlands, were eligible for inclusion. Included infants were randomised by computer at birth to treatment with 10 μg/kg darbepoetin alfa subcutaneously once a week for 8 weeks or standard care (1:1 allocation, in varying blocks of four and six, with no stratification). Treating physicians and parents were not masked to treatment allocation, but the research team, data manager, and statistician were masked to treatment allocation during the process of data collection. The primary outcome was the number of erythrocyte transfusion episodes per infant from birth up to 3 months of life in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT03104426) and has been completed. FINDINGS Between Oct 31, 2017, and April 31, 2022, we recruited 76 infants, of whom 44 (58%) were randomly assigned to a treatment group (20 [45%] were allocated to receive darbepoetin alfa and 24 [55%] were allocated to receive standard care). Follow-up lasted 3 months and one infant dropped out of the trial before commencement of treatment. A significant reduction in erythrocyte transfusion episodes was identified with darbepoetin alfa treatment compared with standard care (median 1·0 [IQR 1·0-2·0] transfusion episodes vs 2·0 [1·3-3·0] transfusion episodes; p=0·0082). No adverse events were reported and no infants died during the study. INTERPRETATION Darbepoetin alfa reduced the transfusion episodes after intrauterine transfusion treatment for haemolytic disease of the fetus and newborn. Treatment with darbepoetin alfa or other types of erythropoietin should be considered as part of the postnatal treatment of severe haemolytic disease of the fetus and newborn. FUNDING Sanquin Blood Supply. TRANSLATION For the Dutch translation of the abstract see Supplementary Materials section.
PICO Summary
Population
Infants with haemolytic disease of the fetus and newborn (n= 44).
Intervention
Darbepoetin alfa once a week subcutaneously for 8 weeks (n= 20).
Comparison
Standard care (n= 24).
Outcome
Follow-up lasted 3 months and one infant in the darbepoetin alfa group dropped out of the trial before commencement of treatment. The primary outcome was the number of erythrocyte transfusion episodes per infant from birth up to 3 months of life in the modified intention-to-treat population. A significant reduction in erythrocyte transfusion episodes was identified with darbepoetin alfa treatment compared with standard care (median 1.0 [IQR 1.0, 2.0] transfusion episodes vs. 2.0 [1.3, 3.0] transfusion episodes). No adverse events were reported and no infants died during the study.
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Evaluation of the Safety and Effectiveness of Topical Intrapleural Application of Tranexamic Acid in Thoracic Surgery: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Alzahrani, A., Alkofide, H., Joharji, H., Korayem, G. B., Aljohani, S., Alshareef, H., AlFaifi, M., Alalawi, H., Sulaiman, K. A.
Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2023;29:10760296231218215
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Editor's Choice
Abstract
OBJECTIVES Bleeding remains a common complication post-thoracic surgery. Although intravenous tranexamic acid (TXA) has been shown to decrease blood loss, its use has been associated with adverse effects. Accordingly, topical TXA has been proposed as an alternative to reduce bleeding with fewer systemic complications. METHODS We searched Medline, Embase, and Cochrane Central databases for randomized controlled trials (RCTs) comparing topical TXA versus control (i.e., placebo) in patients undergoing thoracic procedures. The primary outcome was total postoperative blood loss at 24 hours. Secondary outcomes included were the number of red blood cell (RBC) transfusions, and hospital length of stay (LOS). Meta-analyses were pooled using mean difference with inverse-variance weighting and random-effects. RESULTS Out of the 575 unique studies that were screened, we identified three randomized controlled trials (RCTs) involving 399 patients. Out of the three RCTs analyzed, two studies, accounting for 67% of the total, were found to have a low risk of bias. The primary outcome of 24-h post-operative blood loss was significantly lower in patients who received TXA (mean difference [MD] -93.6 ml, 95% CI -121.8 to -65.4 ml, I(2 )= 45%). In addition, the need for RBC transfusion was significantly lower in the topical TXA group compared to control (MD -0.5 units, 95% CI -0.8 to -0.3 units, I(2 )= 60%). However, there was no significant difference in the hospital length of stay (LOS) (MD -0.3 days, 95% CI -0.9 to 0.4 days, I(2 )= 0%). These results remained consistent after several sensitivity analyses. The use of topical intrapleural tranexamic acid has also been found to be safe without any significant safety concerns. CONCLUSION Topical intrapleural TXA reduces blood loss and the need for blood transfusions during thoracic surgery. In addition, there is no evidence of the increased safety concerns associated with its use. Larger trials are necessary to validate these findings and evaluate the safety and efficacy of different dosages.
PICO Summary
Population
Patients undergoing thoracic surgery procedures (3 randomised controlled trials, n= 399).
Intervention
Topical intrapleural tranexamic acid (TXA).
Comparison
Placebo.
Outcome
The primary outcome of postoperative blood loss at 24 hours was significantly lower in patients who received TXA (mean difference [MD] -93.6 ml; 95% CI [-121.8, -65.4 ml], I(2)= 45%). The need for red blood cell transfusion was significantly lower in the topical TXA group compared to control (MD -0.5 units; 95% CI [-0.8, -0.3 units], I(2)= 60%). There was no significant difference in the hospital length of stay, (MD -0.3 days; 95% CI [-0.9, 0.4 days], I(2)= 0%). These results remained consistent after several sensitivity analyses.