Fixed-dose Group Research Articles

Protamine Dosing for Heparin Reversal Following Cardiopulmonary Bypass: A Double-Blinded Prospective Randomized Control Trial Comparing Two Strategies.

Drug shortages are a frequent challenge in current clinical practice. Certain drugs, (e.g., protamine) lack alternatives and inadequate supplies can limit access to services. Conventional protamine dosing uses heparin ratio-based calculations for heparin reversal following CPB and may result in excess protamine utilization, and potential harm due to its intrinsic anticoagulation. We hypothesized that a fixed 250-mg protamine dose would be comparable, as measured by the activated clotting time, to a 1:1 (1 mg for every 100 U) protamine to heparin ratio-based strategy for heparin reversal and that protamine would be conserved. In a single-center, double-blinded trial, consenting elective adult cardiac surgical patients without pre-existing coagulopathy or ongoing anticoagulation, and a calculated initial heparin dose of ≥ 27500 U were randomized to receive, following CPB, protamine as a fixed dose (250 mg) or a ratio-based dose (1 mg:100 U heparin). The primary outcome was the activated clotting time following initial protamine administration, assessed by Student's t-test. Secondary outcomes included total protamine, the need for additional protamine, and the cumulative 24-h chest tube output. There were 62 and 63 patients in the fixed- and ratio-based dose groups, respectively. The mean post-protamine ACT was not different between groups (-2.0 s, 95% CI -7.2 to 3.3 s, P = 0.47). Less total protamine per case was administered in the fixed-dose group (2.1 50-mg vials, 95% CI -2.4 to -1.8, P < 0.0001). There was no difference in the cumulative 24-h chest tube output (difference = -77 ml, 95% CI 220 to 65 ml, P = 0.28). A 1: 1 heparin ratio-based protamine dosing strategy compared to a fixed 250-mg dose resulted in the administration of a larger total dose of protamine no difference in either the initial ACT or the amount postoperative chest-tube bleeding.

The Effect of the Gonadotropin Dose Increment During Controlled Ovarian Hyperstimulation on Live Birth Rates of POSEIDON Group 3-4 Patients

This retrospective study seeks to explore whether modifying the gonadotropin dose in cases of poor ovarian response during controlled ovarian hyperstimulation contributes to improved live birth rates in Poseidon Group 3-4 patients. The study took place at a tertiary level university. The electronic database spanning 2012-2021 was scrutinized to identify patients with diminished ovarian reserve (DOR) who underwent intra-cytoplasmic sperm injection – embryo transfer (ICSI-ET). Diminished ovarian reserve was determined using the POSEIDON criteria. Patients were categorized into two groups based on whether dose adjustment was implemented during the initial ultrasound assessment in controlled ovarian hyperstimulation (COH). There were 188 patients in the dose adjustment (DA) group and 310 patients in the fixed-dose (FD) group. The demographic parameters were similar between the groups. The started gonadotropin dose was similar in both groups (300 IU). The median dose adjustment on the first control was +75 IU in the DA group. The follicle output rates, follicle to oocyte indexes, and the embryology parameters were comparable between the groups. The positive pregnancy rate was 19.7% (36/188) in the DA group vs. 19.1% (61/310) in the FD Group (p=0.4). The primary outcome of the study; live birth rates were 12% in the DA group vs. 9% in the FD group, and the results were statistically similar (p=0.3). Our research revealed that adjusting the gonadotropin dose in cases of inadequate ovarian response during COH results in comparable live birth rates to those observed in the fixed-dose group. For patients exhibiting an inadequate response, dose adjustment may be deemed necessary.

Analysis and evaluation of factors contributing to the occurrence of immune-related adverse events with immune checkpoint inhibitors.

In recent years, there has been a growing trend in the use of immune checkpoint inhibitors (ICIs) for treating a larger patient population. However, it is important to note that immune-related adverse events (irAEs) frequently arise as a result. Therefore, precise patient monitoring becomes essential. We present the findings of a retrospective study conducted at the International University of Health and Welfare Narita Hospital (referred to as "our hospital") that aimed to identify risk factors linked to the occurrence of irAEs. The study focused on analyzing various factors, including therapeutic and lifestyle backgrounds, as well as laboratory values of patients who received ICI treatment and were subsequently diagnosed with irAE. The study included patients who met the eligibility criteria for ICIs (both single agent and combination therapy) as well as ICI in combination with anticancer drugs. The inclusion period for the study encompassed April 2020 to May 2022 at our hospital. The fifty patients were divided into two groups based on the severity of irAEs: the first group consisted of patients with irAE Grade 2 or lower (referred to as irAE Grade under 2), while the second group included patients with irAE Grade 3 or higher (referred to as irAE Grade over 3). Statistical analysis revealed significant differences in age (p=0.027) and CRP (C-reactive protein) levels (p=0.008) among the background factors when comparing the two groups. Additionally, statistically significant differences were observed among different ICI treatment groups in the occurrence of irAEs (p=0.035). however, it was indicated to be a relatively weak correlation. Moving forward, we shifted our focus to examine the frequency of irAEs in relation to exposure. However, we did not observe any significant correlation between exposure and irAE grade. Additionally, even when exposure was doubled through the use of ipilimumab in combination with ICIs (referred to as "Mod exposure"), no correlation was found. Exposure was further categorized into three groups: the PD-1 group, PD-L1 group, and PD-1 + CTLA-4 group. However, no significant correlation was observed between exposure in any of these groups and the grade of irAEs. Similarly, no significant correlation was observed between the dosage of ICI in the fixed-dose group and the weight-based dosage group with exposure and irAE Grade. Based on our study findings, there is a suggestive relationship between age and CRP levels and the occurrence of irAEs of Grade 3 or higher. These factors may play a role in contributing to the development of more severe irAEs.

Decreased portal vein attenuation and liver enhancement with reduced intravenous contrast dosage during the national iodinated contrast shortage of 2022.

The worldwide shortage of intravenous (IV) Omnipaque iodinated contrast (Iohexol, GE Healthcare; Milwaukee, WI, USA) forced institutions to adopt various policies regarding contrast allocation. We sought to evaluate the impact of our hospital's response to the shortage, which was to decrease the dose of IV contrast from 100 mL to 75 mL for patients weighing between 45.4 and 136 kg (100-300 lbs) undergoing abdominal computed tomography (CT) examinations. The main objective was to assess for any differences in liver attenuation and enhancement between contrast dosages. Secondary outcomes included assessing differences in aortic and portal vein attenuation, the variance in attenuation measurements, and whether radiology reports included the correct IV contrast dose. Consecutive CT abdomen or CT abdomen and pelvis examinations without and with contrast were analyzed for the 3 months before the contrast shortage and for 3 months during the contrast shortage. Attenuation in Hounsfield units (HUs) was measured in the liver on pre-contrast and portal venous phase images. Vessel attenuation was measured in the aorta (arterial phase) and main portal vein (portal venous phase). Standard deviation of liver attenuation measurements was recorded as an indicator of signal-to-noise. Liver enhancement was calculated as the difference between liver portal venous phase attenuation and pre-contrast attenuations. Thirty-nine fixed dose (100 mL) and 36 reduced dose (75 mL) consecutive CT studies were included in the study. There were no significant differences between the two groups with respect to baseline characteristics such as age, weight, body mass index, and gender. There was no significant difference in pre-contrast liver attenuation between groups, but there was statistically significant greater liver attenuation (99.6 vs. 91.2 HU, P = 0.04) and liver enhancement (51.5 vs. 39.1 HU, P < 0.0001) during the portal venous phase for the fixed-dose group compared to the reduced dose group. There was significantly greater main portal vein opacification during the portal venous phase for the fixed dose group (146.6 vs. 122.2 HU, P < 0.0001). No significant difference was found in aortic opacification during the arterial phase (245 vs. 254 HU, P = 0.52). There was no difference in the standard deviation of liver attenuation measurements on the portal venous phase between the groups. The dose was reported correctly in all the patients receiving the fixed dose and in 92% of patients receiving the reduced dose, which was not statistically significant (P = 0.11). Reducing the IV contrast dose from 100 mL to 75 mL Omnipaque 350 in patients weighing 45.4-136 kg (100-300 lbs) undergoing an abdominal CT examination resulted in significantly decreased portal vein opacification and liver enhancement. In particular, liver enhancement and calculated iodine concentrations fell below suggested thresholds for adequate conspicuity of liver lesions. The change in contrast administration protocol also led to more errors in contrast dose reporting in the radiologist's report. These findings are broadly applicable to many practice settings and can help inform strategies in response to any potential future-iodinated contrast shortage.

Weight-Based Dosing for Low-Molecular-Weight Heparin (Enoxaparin) Administration to Achieve Optimal VTE Prophylaxis in Trauma Patients.

Patients admitted after traumatic injuries are at high risk for developing venous thromboembolism (VTE). Low-molecular-weight heparin (LMWH) is commonly used to prevent VTE in this patient population; however, the optimal dosing strategy has yet to be determined. To address this question, a fixed-dosing strategy of LMWH was compared to a weight-based dosing strategy of LMWH for VTE prophylaxis. A retrospective, pre-post implementation cohort study compared a fixed vs a weight-based dosing strategy of LMWH for VTE prophylaxis. Patients admitted to our level 1 trauma center were included if they had an estimated glomerular filtration rate >30mL/min/1.73m2, received at least 3 doses of LMWH, and had an appropriately drawn anti-Xa level on their initial dosing regimen. Patients in the pre-cohort received 30mg LMWH subcutaneously twice daily as the initial dosing regimen. Patients in the post-cohort received .5mg/kg (max 60mg) LMWH subcutaneously every 12h as the initial dosing regimen. A goal anti-Xa of .2-.4 IU/mL was targeted for prophylaxis. There were 817 patients in the fixed-dosing group (FDG) and 874 patients in the weight-based dosing group (WBDG). In the FDG, 42.8% of the patients achieved the goal initial anti-Xa level, with 54.1% and 3.1% reaching sub- and supratherapeutic doses, respectively. In the WBDG, 66.5% of patients reached goal initial anti-Xa levels, with 23.5% and 10.1% at sub- and supratherapeutic levels. The distribution of dose ranges was significantly different between the dosing strategies (P-value <.001). There was no difference in the number of patients who received blood products (39.1% vs 41.7%. P-value = .299). In our study, weight-based dosing of LMWH yielded a significantly higher proportion of patients who achieved goal prophylactic anti-Xa levels than fixed-dosing of LMWH. Larger-scale studies are needed to assess the risk of VTE events and bleeding with these dosing strategies.

Retrospective comparison of a weight-based dose every 2 weeks with a fixed dose every month: a real-life analysis of nivolumab in the treatment of advanced melanoma.

Nivolumab was first authorized at a weight-based dose (WBD) of 3 mg/kg every two weeks (Q2W). Since 2017, a fixed dose (FD) regimen [first 240 mg Q2W and then 480 mg per month (Q4W)] was allowed. The objective of the study was to compare a WBD regimen and an FD regimen with regard to effectiveness and safety. We conducted a single-center, retrospective, real-life study of consecutive adult patients who had received a WBD of nivolumab or an FD of 480 mg Q4W. The primary endpoint was the occurrence of grade ≥3 immune-related adverse events (irAEs). The secondary endpoints were overall survival and cost of the treatment. In all, 342 patients were included: 71 in the WBD cohort and 271 in the FD cohort. Of these patients, 201 patients (59.6%) experienced an irAE, and 24 of these events were graded as ≥3. At 12 months, there was no significant difference in irAE occurrence between the two cohorts [hazard ratio (95% confidence interval): 0.54 (0.21-1.36), P = 0.19]. The 12-month overall survival rate was significantly lower in the WBD cohort ( P < 0.001). Switching from a fortnightly weight dose to a fixed monthly dose halves the cost of hospitalization. Our results did not show a significant difference between WBD and FD cohort in the occurrence of severe irAEs. However overall survival appeared to be significantly higher in FD group. Some clinical trials are investigating a hybrid dosing regimen in which a WBD is capped by an FD. The present results need to be confirmed in prospective studies.

Hemostatic Efficacy and Safety of Weight-Based Versus Fixed-Dose 4F-PCC for Vitamin K Antagonist Reversal

Background: Four-factor prothrombin complex concentrate (4F-PCC) is indicated for vitamin K antagonist (VKA) reversal but is associated with thrombotic events (TE). In 2018, the institution revised 4F-PCC dosing for VKA reversal from INR and weight-based dosing to a fixed-dose of 1500 units. Objective: The purpose of this study was to compare hemostatic efficacy and TE rate of fixed-dose 4PCC to weight-based dosing. Methods: This was a retrospective, single-center, quasi-experimental study of adult patients who received 4F-PCC for VKA reversal from January 2014 through May 2016 (INR and weight-based dosing) or April through October 2018 (fixed-dosing). The primary endpoint was hemostatic efficacy, defined by achieving an INR of ≤1.4, or an INR of ≤1.7 with evidence of hemostasis. The key secondary endpoint was TE within 14 days of 4F-PCC administration. Data were analyzed using descriptive statistics, chi-squared for nominal data and Mann-Whitney U for ordinal and continuous data. Results: The study included 163 patients who received weight-based dosing and 45 who received fixed-dose 4F-PCC. Hemostatic efficacy was 76.9% of patients in the weight-based group and 77.4% of patients in the fixed-dose group (P = .229). TE occurred in 13.5% of the weight-based vs 6.7% of the fixed-dose group (P = .181). Conclusion: This study found no difference in hemostatic efficacy with fixed-dose 4F-PCC for VKA reversal compared to INR and weight-based dosing. The occurrence of TE was reduced by 50% with the 4F-PCC fixed-dose strategy; however, this difference was not statistically significant. Further randomized studies are needed to confirm these results.

Comparison of Fixed Versus Weight-Based Prothrombin Complex Concentrate Dosing Strategies for Factor Xa Inhibitor Reversal.

Background: Our institution introduced fixed-dose prothrombin complex concentrate (PCC) to streamline order verification and medication administration. Previous studies using fixed-dose PCC for vitamin K antagonist reversal showed comparable efficacy to weight-based dosing. Objective: To compare fixed versus weight-based PCC dosing for reversal of Factor Xa Inhibitor (FXaI) effects. Methods: Retrospective cohort study conducted at a tertiary care academic medical center. Patients who received PCC to reverse the effects of apixaban or rivaroxaban were eligible. Subjects in the fixed-dose group (5000 units or 2000 units) were compared to weight-based PCC (50 units/kg). The primary outcome was time between order entry and medication administration. Secondary outcomes included: average PCC dose, postadministration procedures, achieved hemostasis, 30-day mortality, hospital length of stay, and adverse drug events. Results: 72 patients received fixed-dose PCC and 101 received weight-based PCC. Median time between order entry and administration was 4.5 min shorter in the fixed-dose group compared to weight-based (34.5 vs 39 min, P = .10). In patients who received fixed-dose, 79.2% achieved hemostasis versus 71.3% in the weight-based group (RR = 1.11, 95% CI = 0.94-1.32). There was no difference in the number of subsequent hemorrhage-related surgeries (29.2% vs 36.7%, RR = 0.80, 95% CI = 0.51-1.24) or mortality rate (26.4% vs 35.6%, RR = 0.73, 95% CI = 0.46-1.17). There were zero adverse drug events reported. Rates of thrombosis were 2.8% and < 1% (P = .57) in the fixed and weight-based groups, respectively. Conclusion and Relevance: The fixed-dosing strategy did not reduce time to PCC administration nor impact hemostasis or mortality. These data support that the fixed-dosing method is a viable option.

Outcomes of weight-based vs. fixed dose of Pembrolizumab among patients with non-small cell lung cancer.

This study aims to assess outcomes among patients with non-small cell lung cancer (NSCLC) who received treatment with pembrolizumab on a weight-based dose (WBD) or fixed-dose (FD) regimen using a non-inferiority (NI) analysis. This retrospective cohort study included adult patients with NSCLC weighing under 100 kg who received pembrolizumab between 1 January 2015 and 31 December 2020. Patients were grouped into either WBD or FD cohort based on the initial pembrolizumab dose and dosing regimen. The primary effectiveness outcome was overall survival (OS), analyzed using NI analysis with a lower margin of 10% comparing WBD to FD. Safety outcomes were all-cause emergency room visits or hospitalizations and incidence of selected immune-related adverse events (irAEs) and analyzed using NI analysis with an upper margin of 10%. All patients were followed until the end of health plan membership, death, or 30 June 2022, whichever occurred first. A total of 1413 patients were evaluated. OS was observed in 36.6% of the FD group, and 37.7% in the WBD group (rate difference: 1%, 90% CI: -6%-8%, NI p-value < 0.01). NI was met in all three safety outcomes: proportion of all-cause emergency room visits (rate difference: 1.1%, NI p-value < 0.01); proportion of hospitalizations (rate difference: 2%, NI p-value < 0.01); and composite incidence of irAEs (rate difference: -2.2%, NI p-value = 0.03). These findings suggest that WBD of pembrolizumab may be as appropriate as FD for the treatment of lung cancer.

Weight-based vs fixed dosing of darbepoetin alfa for anemia following kidney transplantation.

Post-transplantation anemia (PTA) is common in kidney transplant recipients, with patients frequently treated with erythropoietin-stimulating agents such as darbepoetin alfa. The optimal dosing for darbepoetin alfa remains controversial. This retrospective cohort study involved kidney transplant recipients who received darbepoetin alfa at 2 clinics. Patients were stratified into 2 groups: those who received a fixed dose of 200 μg and those who received a weight-based dose of 0.45 μg/kg. The dosing interval varied depending on clinical response, clinic visit timing, and frequency allowed by insurance. The primary outcome was achieving a hemoglobin concentration of at least 10 g/dL without blood transfusion by 12 weeks after darbepoetin alfa initiation. Of the 110 patients in the study, 45% received weight-based dosing and 55% received fixed dosing. Darbepoetin alfa was initiated significantly earlier after transplantation in the fixed-dose group (median of 14 vs 20 days; P = 0.003). The weight-based group received more doses of darbepoetin alfa (median of 4 vs 2 doses; P = 0.002) and had a significantly lower cumulative exposure to darbepoetin alfa (125 vs 590 μg; P < 0.001). The median time between doses was 9 days (interquartile range, 7-14 days) in the weight-based group and 12 days (7-32 days) in the fixed-dose group (P = 0.04). Patients in the weight-based group more frequently achieved the primary outcome (67.3% vs 47.5%; P = 0.059). There was no significant difference in secondary or safety outcomes between the groups. Weight-based and fixed dosing approaches for darbepoetin alfa were not different in the achievement of a hemoglobin concentration of at least 10 g/dL without blood transfusion at 12 weeks after darbepoetin alfa initiation, with significantly lower cumulative darbepoetin alfa utilization in the weight-based group. Weight-based dosing of darbepoetin alfa in PTA appears to be safe and effective, with the potential for significant patient and health-system cost savings.

#4183 A PHENOTYPIC DRIVEN RITUXIMAB MAINTENANCE APPROACH IS EFFECTIVE AND SAFE IN PATIENTS WITH ANCA ASSOCIATED VASCULITIS

Abstract Background and Aims Rituximab (RTX) has emerged as the first-line treatment to maintain remission in ANCA-Associated Vasculitis (AAV). However, the ideal strategy to RTX re-dosing is still unclear [1]. Method In this monocentric and retrospective study we evaluated the efficacy and safety of two RTX-based maintenance regimens in patients with AAV. Fixed-dose (FD) RTX dosing, consisting of at least 3 pre-emptive RTX administrations every 6 months, was preferred in patients judged to be at high relapse risk. Instead, a biomarker-guided on-demand (OD) RTX dosing strategy was preferred for patients deemed at lower risk of relapse; this consisted in RTX re-treatment only in case of B-cell repopulation or rise in ANCA titer. The single patient relapse risk was assessed according to the disease phenotype (granulomatous vs vasculitic), the ANCA specificity and the disease status (onset vs relapse). Relapses were defined as increase of disease activity requiring escalation of immunosuppression; major relapses were defined in case of life/organ-threatening manifestations. Results The study included 100 patients followed for a median of 24 months (IQR 20-30), 51% treated with an OD and 49% with a FD strategy. The main baseline characteristics of our cohort are shown in the Table; patients treated with a FD strategy were more often GPA, PR3-ANCA positive, with relapsing disease and ENT involvement and less frequent renal involvement. The FD group received a median of 4 (IQR 4-4) administrations of RTX for a median cumulative dose of 2 g (IQR 2-2). Only 6 (11.8%) patients in the OD group received RTX as maintenance therapy with a median of 1 (IQR 1-3) administration of RTX for a median cumulative dose of 0.75 g (IQR 0.5-1.75). Thirteen relapses occurred, 6 in the FD group and 7 in the OD one. Remission rates were comparable in the two cohorts, with respectively 87.6% and 85.9% of the patients in remission at 24 months (Figure 1 - panel A). No significant differences in remission rates across the 2 groups were observed after considering only major flares or after stratification according to clinical diagnosis (MPA/GPA) and ANCA specificity (Figure 1 - panel B to F). Ten and 20 severe infections (p = 0.383) and 3 and 1 cancer (p = 0.581) occurred respectively in the FD and OD group. Conclusion In our case series, a phenotypic-driven approach to RTX maintenance showed comparable efficacy and safety between fixed and on-demand dosing, despite different baseline characteristics between the two groups. These results suggest that personalizing RTX maintenance may be a feasible and safe strategy.

Effect of weight-adjusted intermediate-dose versus fixed-dose prophylactic anticoagulation with low-molecular-weight heparin on venous thromboembolism among noncritically and critically ill patients with COVID-19: the COVI-DOSE trial, a multicenter, randomised, open-label, phase 4 trial.

Venous thromboembolism is a major complication of coronavirus disease 2019 (COVID-19). We hypothesized that a weight-adjusted intermediate dose of anticoagulation may decrease the risk of venous thromboembolism COVID-19 patients. In this multicenter, randomised, open-label, phase 4, superiority trial with blinded adjudication of outcomes, we randomly assigned adult patients hospitalised in 20 French centers and presenting with acute respiratory SARS-CoV-2. Eligible patients were randomly assigned (1:1 ratio) to receive an intermediate weight-adjusted prophylactic dose or a fixed-dose of subcutaneous low-molecular-weight heparin during the hospital stay. The primary outcome corresponded to symptomatic deep-vein thrombosis (fatal) pulmonary embolism during hospitalization (COVI-DOSE ClinicalTrials.gov number: NCT04373707). Between May 2020, and April 2021, 1000 patients underwent randomisation in medical wards (noncritically ill) (80.1%) and intensive care units (critically ill) (19.9%); 502 patients were assigned to receive a weight-adjusted intermediate dose, and 498 received fixed-dose thromboprophylaxis. Symptomatic venous thromboembolism occurred in 6 of 502 patients (1.2%) in the weight-adjusted dose group and in 10 of 498 patients (2.1%) in the fixed-dose group (subdistribution hazard ratio, 0.59; 95% CI, 0.22-1.63; P=0.31). There was a twofold increased risk of major or clinically relevant nonmajor bleeding: 5.9% in the weight-adjusted dose group and 3.1% in the fixed-dose group (P=0.034). In the COVI-DOSE trial, the observed rate of thromboembolic events was lower than expected in patients hospitalized for COVID-19 infection, and the study was unable to show a significant difference in the risk of venous thromboembolism between the two low-molecular-weight-heparin regimens. French Ministry of Health, CAPNET, Grand-Est Region, Grand-Nancy Métropole.

Combination therapy with predicted body weight-based dexamethasone, remdesivir, and baricitinib in patients with COVID-19 pneumonia: A single-center retrospective cohort study during 5th wave in Japan

BackgroundDexamethasone, remdesivir, and baricitinib reduce mortality in patients with coronavirus disease 2019 (COVID-19). A single-arm study using combination therapy with all three drugs reported low mortality in patients with severe COVID-19. In this clinical setting, whether dexamethasone administered as a fixed dose of 6 mg has sufficient inflammatory modulation effects of reducing lung injury has been debated. MethodsThis single-center retrospective study was conducted to compare the treatment strategies/management in different time periods. A total of 152 patients admitted with COVID-19 pneumonia who required oxygen therapy were included in this study. A predicted body weight (PBW)-based dose of dexamethasone with remdesivir and baricitinib was administered between May and June 2021. After this period, patients were administered a fixed dose of dexamethasone at 6.6 mg/day between July and August 2021. The additional respiratory support frequency of high-flow nasal cannula, noninvasive ventilation, and mechanical ventilation was analyzed. Moreover, the Kaplan–Meier method was used to analyze the duration of oxygen therapy and the 30-day discharge alive rate, and they were compared using the log-rank test. ResultsIntervention and prognostic comparisons were performed in 64 patients with PBW-based and 88 with fixed-dose groups. The frequency of infection or additional respiratory support did not differ statistically. The cumulative incidence of being discharged alive or oxygen-free rate within 30 days did not differ between the groups. ConclusionsIn patients with COVID-19 pneumonia who required oxygen therapy, combination therapy with PBW-based dexamethasone, remdesivir, and baricitinib might not shorten the hospital stay's length or oxygen therapy's duration.

Effects of combined test dose and therapeutic drug monitoring strategy in exposure-directed busulfan.

Although exposure-directed busulfan (BU) dosing can improve allogeneic hematopoietic stem cell transplantation outcomes, there is still large variability in BU exposure with test dose alone due to changes in BU clearance caused by drug interactions. We conducted a single-arm phase II trial using the combined test dose and therapeutic drug monitoring strategy (PK-guided group) and compared the outcomes with an external historical cohort receiving a fixed-dose (fixed-dose group). The first eight and second eight doses were adjusted based on the area under the blood concentration-time curve (AUC) of the test and first doses, respectively, targeting a total AUC of 82.1mg·h/L. All patients received either BU and cyclophosphamide conditioning (BU/CY) or fludarabine (FLU)-containing conditioning. The BU clearance at the first dose decreased more in patients receiving FLU than in those receiving BU/CY; however, BU clearance also declined over time in patients who received BU/CY. The simulated total AUC (sAUC) with test dose only was significantly higher in patients who received FLU than in those who received BU/CY, but sAUC with the combined strategy was comparable. The 100-day progression-free survival was 85.5% (95% confidence interval [CI]: 71.9-92.8%), and was not inferior to that in the fixed-dose group. For the FLU-containing regimens, the PK-guided group showed decreased relapse (0.0% vs. 26.9%, p = 0.03), and favorable overall survival (75.1% vs. 57.0%, p = 0.07) at 1year. The combined strategy effectively controlled the BU exposure close to the target levels, potentially improving efficacy, especially in patients receiving the FLU-containing regimen. Clinical evaluation of efficacy of dose-modified intravenous busulfan in allogeneic hematopoietic stem cell transplantation for hematological malignancy (#UMIN000014077, June 15th, 2014).

Artificial intelligence-based 68Ga-DOTATOC PET denoising for optimizing 68Ge/68Ga generator use throughout its lifetime.

The yield per elution of a 68Ge/68Ga generator decreases during its lifespan. This affects the number of patients injected per elution or the injected dose per patient, thereby negatively affecting the cost of examinations and the quality of PET images due to increased image noise. We aimed to investigate whether AI-based PET denoising can offset this decrease in image quality parameters. All patients addressed to our PET unit for a 68Ga-DOTATOC PET/CT from April 2020 to February 2021 were enrolled. Forty-four patients underwent their PET scans according to Protocol_FixedDose (150 MBq) and 32 according to Protocol_WeightDose (1.5 MBq/kg). Protocol_WeightDose examinations were processed using the Subtle PET software (Protocol_WeightDoseAI). Liver and vascular SUV mean were recorded as well as SUVmax, SUVmean and metabolic tumour volume (MTV) of the most intense tumoural lesion and its background SUVmean. Liver and vascular coefficients of variation (CV), tumour-to-background and tumour-to-liver ratios were calculated. The mean injected dose of 2.1 (0.4) MBq/kg per patient was significantly higher in the Protocol_FixedDose group as compared to 1.5 (0.1) MBq/kg for the Protocol_WeightDose group. Protocol_WeightDose led to noisier images than Protocol_FixedDose with higher CVs for liver (15.57% ± 4.32 vs. 13.04% ± 3.51, p = 0.018) and blood-pool (28.67% ± 8.65 vs. 22.25% ± 10.37, p = 0.0003). Protocol_WeightDoseAI led to less noisy images than Protocol_WeightDose with lower liver CVs (11.42% ± 3.05 vs. 15.57% ± 4.32, p < 0.0001) and vascular CVs (16.62% ± 6.40 vs. 28.67% ± 8.65, p < 0.0001). Tumour-to-background and tumour-to-liver ratios were lower for protocol_WeightDoseAI: 6.78 ± 3.49 vs. 7.57 ± 4.73 (p = 0.01) and 5.96 ± 5.43 vs. 6.77 ± 6.19 (p < 0.0001), respectively. MTVs were higher after denoising whereas tumour SUVmax were lower: the mean% differences in MTV and SUVmax were + 11.14% (95% CI = 4.84-17.43) and -3.92% (95% CI = -6.25 to -1.59). The degradation of PET image quality due to a reduction in injected dose at the end of the 68Ge/68Ga generator lifespan can be effectively counterbalanced by using AI-based PET denoising.

Four-factor prothrombin complex concentrate for the treatment of oral factor Xa inhibitor-associated bleeding: a meta-analysis of fixed versus variable dosing

BackgroundThe optimal dosing strategy of four-factor prothrombin complex concentrate (4F-PCC) to treat oral factor Xa (FXa) inhibitor-associated bleeding has not been established. ObjectivesTo evaluate the effectiveness and safety of fixed versus variable 4F-PCC dosing for the management of FXa inhibitor-associated bleeding. MethodsA systematic literature search and meta-analysis of clinical studies was performed using PubMed, Embase, and Cochrane databases from inception to January 2022. The primary outcomes included hemostatic effectiveness, mortality, and thromboembolic events. Secondary outcomes included 4F-PCC usage, total length of stay in hospital and in intensive care units, and time to 4F-PCC administration. The pooled incidence or mean was calculated using a random-effects model and compared between the 2 dosing strategies. ResultsTwenty-five studies were included and data from 1,760 patients (fixed dosing, n = 228; variable dosing, n = 1,532) were analyzed. There were no significant differences in hemostatic effectiveness, thromboembolic events, or mortality rates between the dosing strategies. Hospital length of stay was significantly longer in the fixed-dosing group, with a mean stay of 7.4 days (95% CI: 3.6-11.1) compared to 5.9 days (95% CI: 5.5-6.3) in the variable-dosing group (P < 0.001). The mean initial 4F-PCC dose was significantly higher with variable dosing than fixed dosing (38 IU/kg; 95% CI: 32-44 vs. 27 IU/kg; 95% CI: 26-28, P < 0.001). ConclusionsA fixed-dosing strategy appears to be a safe and effective alternative to variable weight-based dosing and was associated with lower 4F-PCC usage. However, direct comparative studies are needed to confirm these results.

Effects of sequential and fixed-dose estradiol valerate administration on premature progesterone rise in frozen-thawed embryo transfer cycles

Aim: This study investigated the risk of premature progesterone (P4) rise in the fixed and sequential estradiol valerate (EV) administration for frozen embryo transfer (FET) cycles.Material and Method: In this cross-sectional case-control study, 1272 cycles of FET were analyzed retrospectively from computer records between January 2015 to August 2020. EV was administrated in 795 patients with a fixed dose and in 477 patients with a sequential dose. P4 values were measured on the day when the endometrial thickness reached 8 mm in the patients.Results: There were 795 patients in the fixed EV administration group with a mean age of 30.75±3.39 and 477 patients in the sequential EV administration with a mean age of 30.75±3.39. P4 of the sequential-dose group (1.05±0.31) was significantly higher than the fixed-dose group (1.01±0.33). The Pairwise Z-Tests found that the abort rate was significantly higher in the sequential-dose group (p=0.04).Conclusion: Our results showed a higher P4 and abortion rate in the sequential-dose group. These findings show that premature P4 rise can be considered a risk factor.

744: FIXED-DOSE 4F-PCC IS SUPERIOR TO WEIGHT-BASED DOSING IN DELIVERY TIME AND COST WITH EQUAL REVERSAL

Introduction: Patients who suffer an intracranial hemorrhage (ICH) while on anticoagulation have higher mortality than those who are not. 4-factor prothrombin complex (4F-PCC) has become the standard therapy for emergent warfarin reversal and is traditionally dosed based on patient weight and INR. This strategy can lead to increased time before administration. A fixed-dose strategy has been found comparable in efficacy and may reduce the time to delivery. The goal of this study was to evaluate fixed-dose vs weight-based dosing strategies for 4F-PCC time to administration in patients with an ICH. Methods: A retrospective analysis was conducted at a single rural ACS verified Level 2 Trauma center in pts ≥18 y/o on warfarin with ICH who received 4F-PCC. Continuous variables were summarized using mean (±95% CI) and compared using two-tailed tests; p values ≤0.05 were considered statistically significant. Results: A total of 46 ICH pts were reversed by 4F-PCC (Fixed, n=27 and Weight, n=19). Baseline characteristics including admission GCS, ICH type on admit head CT, and baseline INR were statistically equivalent (p>0.05). Total units of 4F-PCC were reduced in the fixed-dose group (1623.3 (95% CI [1515.1, 1731.4]) vs. 2525.1 units, (95% CI [2091.7, 2895.4]); p=0.001) as was dose per kg (19.2 units/kg (95% CI [17.2, 21.2]) vs. 28.9 units/kg (95% CI [24.8, 33.0]); p < 0.001). This resulted in a mean cost saving of $1461 per patient. Eleven percent of patients required additional 4F-PCC (p=0.951). Total time from order to delivery was significantly reduced with the fixed-dose strategy, 28 (95% CI [25, 31]) vs. 43 (95% CI [33, 53]) minutes (p=0.015). Hospital length of stay (LOS), ICU LOS, and mortality were equivalent in groups with similar mechanism (traumatic vs non-traumatic; p>0.05). INR reversal success (INR ≤1.5 after 4F-PCC) was 84.2% vs. 85.2% (p=1.00) and total INR change was also comparable (2.1 vs. 2.4, p=0.68); with no difference in adverse thromboses between groups (p=1.00). Conclusions: A fixed-dosed strategy reduced time to administration of 4F-PCC for warfarin reversal in ICH as compared to a weight-based strategy. There was no increase in LOS, mortality, or need for additional 4F-PCC dosing. This also resulted in significant cost savings.

215 Fixed-dose vs. Weight-Based 4-Factor Prothrombin Complex Concentrate Dosing for Reversal of Warfarin-induced Intracranial Hemorrhage

215 Fixed-dose vs. Weight-Based 4-Factor Prothrombin Complex Concentrate Dosing for Reversal of Warfarin-induced Intracranial Hemorrhage

Comparison of 2 different inhaled epoprostenol dosing strategies for acute respiratory distress syndrome in critically ill adults: Weight-based vs fixed-dose administration.

Inhaled epoprostenol (iEPO) is a viable, temporizing option for acute respiratory distress syndrome (ARDS), although the optimal iEPO dosing strategy remains inconclusive. The purpose of this study was to evaluate oxygenation and ventilation parameters in a comparison of weight-based and fixed-dose iEPO in adult patients with moderate-to-severe ARDS. A retrospective cohort study was conducted at 2 academic medical centers in adult intensive care unit (ICU) patients administered either fixed-dose or weight-based iEPO for moderate-to-severe ARDS. The primary endpoint was the highest recorded change in the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) within 4 hours of baseline. Secondary analyses compared responder rates within 4 hours of initiation, oxygenation and ventilation parameters, in-hospital mortality rates, mechanical ventilation duration, length of stay (ICU and hospital), and tracheostomy rates between the study groups. A total of 294 patients were included, n = 194 with 100 (34.0%) and 194 (66.0%) in the weight-based and fixed-dose iEPO groups, respectively. The mean (SD) change in the highest recorded PaO2/FiO2 value from baseline up to 4 hours after initiation in the fixed-dose and weight-based groups was 81.1 (106.0) and 41.0 (72.5) mm Hg, respectively (P = 0.0015). The responder rate at 4 hours after iEPO initiation was significantly higher in the fixed-dose group (69.9%) than in the weight-based group (30.1%) (P = 0.02). The only predictor of response was fixed-dose administration (odds ratio, 3.28; 95% confidence interval, 1.6-6.7; P = 0.0012). Clinical outcomes were comparable between the groups. Fixed-dose iEPO was associated with significantly higher response rates then weight-based iEPO during the first 4 hours of therapy. Fixed-dose iEPO is a more convenient strategy than weight-based approaches.