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.

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.

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.

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.

OBJECTIVE:

To determine the feasibility of a pivotal randomised clinical trial of intravenous (IV) iron and erythropoietin in adult survivors of critical illness with anaemia requiring treatment in the intensive care unit.

DESIGN:

An investigator-initiated, parallel group, placebo-controlled, randomised feasibility trial.

SETTING:

A tertiary intensive care unit (ICU) in Perth, Western Australia.

PARTICIPANTS:

Adults with anaemia (haemoglobin <100 g/L), requiring ICU-level care for more than 48 h, and likely to be ready for ICU discharge within 24 h.

INTERVENTIONS:

A single dose of IV ferric carboxymaltose and Epoetin alfa (active group) or an equal volume of 0.9% saline (placebo group).

MAIN OUTCOME MEASURES:

Study feasibility was considered met if the pilot achieved a recruitment rate of ≥2 participants per site per month, ≥90% of participants received their allocated study treatment, and≥ 90% of participants were followed up for the proposed pivotal trial primary outcome - days alive and at home to day 90 (DAH90).

RESULTS:

The 40-participant planned sample size included twenty in each group and was enrolled between 1/9/2021 and 2/3/2022. Participants spent a median of 3.4 days (interquartile range 2.8-5.1) in the ICU prior to enrolment and had a mean baseline haemoglobin of 83.7 g/L (standard deviation 6.7). The recruitment rate was 6.7 participants per month [95% confidence interval (CI) 4.8-9.0], DAH90 follow-up was 100% (95% CI 91.2%-100%), and 39 (97.5%, 95% CI 86.8%-99.9%) participants received the allocated study intervention. No serious adverse events were reported.

CONCLUSION:

The iron and erythropoietin to heal and recover after intensive care (ITHRIVE) pilot demonstrated feasibility based on predefined participant recruitment, study drug administration, and follow-up thresholds.

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.

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.

PURPOSE:

To determine the efficacy and safety of trajectory infiltration with 1:150 000 Norepinephrine (NE) in reducing blood loss during percutaneous nephrolithotomy (PCNL).

MATERIALS AND METHODS:

This is a prospective randomized double-blinded placebo-controlled trial. In all, 140 consecutive patients underwent PCNL for the management of large renal calculi. They were randomly assigned (1:1) to one of either study groups, the NE-PCNL group (70 patients whose PCNL-trajectory was infiltrated by NE) or the Placebo group (saline PCNL) (70 patients whose PCNL tracts were infiltrated by normal saline). Procedure-related blood loss (the primary outcome) was assessed and statistically analyzed. Also, all other procedure-related events and complications were recorded and compared.

RESULTS:

The median blood loss was 378 ml (IQR: 252-504) in the NE-PCNL group versus 592 ml (IQR: 378-756) in the S-PCNL group (p < 0.0001). In addition, Hemoglobin and Hematocrit deficits were lower in NE-PCNL (p < 0.05). Patients who were randomized to the NE-PCNL group had a higher immediate stone-free rate (SFR) (80%) compared with those of the S-PCNL group (70%) (p = 0.034). However, no statistical differences were found in the final SFR. The reported overall complications between the 2 groups were similar (p > 0.05). Indeed, bleeding-related complications were 1 (1.4%) versus 10 (14.3%) for NE-PCNL and S-PCNL, respectively (p = 0.009).

CONCLUSIONS:

Trajectory infiltration of PCNL tracts by NE was found to be effective and safe in mitigation of PCNL-related blood loss. This step is a timeless and cost-effective as NE is readily available in surgical theaters and of very low cost.

INTRODUCTION:

Roxadustat is an orally administered hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor that represents a novel therapeutic option for patients with anemia of chronic kidney disease (CKD).

METHODS:

Conducted in Japan, CL-0307 (NCT02952092) and CL-310 (NCT02988973) were phase 3, darbepoetin alfa (DA)-controlled studies conducted in dialysis-dependent (DD) and non-DD (NDD) patients with CKD, respectively, where patients were randomized to receive roxadustat or DA. Ophthalmic imaging and assessments of visual acuity were performed up to week 24 or at study discontinuation. Ophthalmic imaging was centrally evaluated by independent readers masked to the study treatment.

RESULTS:

In CL-0307, 302 patients (roxadustat, n = 150; DA, n = 152) received ≥1 dose of the study drug and were included in this analysis. In CL-0310, 262 patients (roxadustat, n = 131; DA, n = 131) received ≥1 dose of the study drug and were included in this analysis. Proportions of DD patients with new or worsening retinal hemorrhages (RHs) in the roxadustat group and DA group were 32.4% (46 of 142) and 36.6% (53 of 145), respectively. Proportions of NDD patients with CKD with new or worsening RH in the roxadustat and DA groups were 31.4% (38 of 121) and 39.8% (51 of 128), respectively. Similar trends were apparent in subgroup analyses: patients with/without RH at baseline and with/without diabetes mellitus at baseline. In both studies, there were no differences in retinal thickness, visual acuity, presence of hard exudates or cotton wool spots, or presence of intra- and subretinal fluid between groups, at any given time point.

CONCLUSION:

In these studies, roxadustat, compared with DA, was not associated with an increased risk of adverse ophthalmologic events in these cohorts.