Summary of the key findings
In this observational study, nafamostat mesylate was empirically used within the range of 5–30 mg/hr during CKRT as usual practice. There was no significant association between filter life and doses of nafamostat mesylate.
Context with prior literature
Despite its widespread use for CKRT, particularly in Japan, there are currently no evidence-based guidelines for the indication of nafamostat mesylate. This absence of data-driven guidelines has led to nafamostat mesylate being used based on empirical evidence, often in scenarios with a high risk of bleeding, but without the backing of robust clinical data. The current study highlights the urgent need for comprehensive research to establish evidence-based practices and guidelines for the use of nafamostat mesylate for CKRT.
No previous studies have investigated the dose responsive anticoagulant effect of nafamostat mesylate on filter life when used for CKRT. It is important to note that the administration of nafamostat mesylate currently varies with dosages based on the individual experiences of different facilities, physicians, or technicians. Therefore, we explored the association between nafamostat prescription with experience based sterategy and filter life. Our findings showed no significant relationship between filter life and the doses of nafamostat mesylate.
The recommended dosage of nafamostat mesylate indicated in the brochure ranges from 20 to 50 mg/h. However, the dosage pertains to intermittent dialysis [12], and the optimal dosage for CKRT in critically ill patients remains undetermined [13]. The literature reports a range of nafamostat dosing. Two previous randomised clinical trials (RCTs) started nafamostat mesylate at 20 mg/h, adjusting between 10 mg/h and 30 mg/h based on individual patient’s condition and reported that nafamostat mesylate prolongs filter life effectively compared to the absence of anticoagulant [4, 9, 14]. Conversely, some observational studies reported that the initial dose of 10 mg/h. The reasons for the reduced dose, compared to the recommended dose, might be empirical considerations and the absence of safety data on for CKRT. In other observational studies of patients with cerebral haemorrhage, nafamostat mesylate was administered at a rate of 35 mg/h [15]. Another observational study comparing nafamostat mesylate with citrate administrate nafamostat mesylate with a regimen of 1 mg/kg as a bolus, followed by a maintenance dose of 1 mg/kg/hr, with monitoring via activated clotting time [16].
The mean filter life in this study was 26.4 h. This aligns with previous studies that reported filter lives ranging from 22 to 26.6 h when using nafamostat [17], suggesting that the current study findings could be could be applicable the clinical practice when using nafamostat mesylate in other settings. However, the filter life time around 24 h might not be comparable to ones when other anticoagulants are used (RICH tial) [18]. In the previous clinical trial, regional citrate anticoagulation provided the mean filter life of 44.9 h, while that of 33.3 h when unfractionated heparin was used. Of note, the blood flow rate in the current study settings was low, thus the filter life might have been potentially shortened, while the impact of blood flow rate on filter life has not been definitively concluded [19].
According to a recent systematic review [14], efficacy of nafamostat mesylate has been examined in randomised clinical trials only in comparison with no anticoagulation strategy. Previous observational studies have compared nafamostat mesylate with various anticoagulants, including no anticoagulation, heparin sodium, and citrate, particularly focusing on outcomes like filter life and bleeding events [9, 10, 16, 20, 21]. However, the results from these observational studies have been varied. Consequently, there is currently insufficient evidence to conclusively determine whether the observed filter life in using nafamostat mesylate is comparable to other anticoagulants.
Possible reasons for the observed decreasing trend in ICU and hospital mortalities with increased nafamostat mesylate dose are unclear. However, they may include that nafamostat may have beneficial effects beyond the anticoagulant properties. Nafamostat mesylate is also known for its antifibrinolytic [22] and anti-platelet [23] effects as partly explored in COVID-19. This could imply that nafamostat mesylate may play a role in decreasing of the underlying pathologies in critical illness. Furthermore, the decreasing trend of the required transfusion volume might also indicate a favourable safety profile for the nafamostat mesylate, especially if the higher doses do not lead to increased bleeding risks but instead associated with improved clinical outcomes.
However, the mechanisms behind the observed decrease in mortality and transfusion with increased nafamostat mesylate dosage remain unclear. Therefore, it is essential to investigate whether nafamostat mesylate has causative effects on patient outcomes. In this regard, the current findings needs to be further validated in a randomised trial comparing different doses of nafamostat mesylate for CKRT. The findings will inform further investigation on the optimal dose of nafamostat mesylate to provide adequate filter life with established safety profile. If the optimal dosage of nafamostat mesylate is known, further comparative studies with other drugs (heparin sodium, citrate, etc.) would be possible.
Limitations
This study has several limitations. First, while we adjusted for possible confounders in patient backgrounds, filter types, severity, and filtration volumes, there might be unmeasured confounders that had not been sufficiently adjusted for. In particular, the observed decreased mortalities might be driven by confounding by the indication; that is, clinicians prescribed higher dose of nafamostat mesylate because the patient had been less sick and at lower risk of bleeding. Second, it is also pertinent to note that as an observational study, the findings should be considered exploratory given the possibility of bias due to unmeasured confounders. However, our results may inform the design of future RCTs controlling patient background characteristics and CKRT settings to find the optimal dose of nafamostat mesylate. Third, adjusting doses after initiating CKRT may differ due to the lack of a standardised protocol for achieving an optimal anticoagulation level to maintain circuit patency. Fourth, the causes of deterioration of kidney function or the indications to start CKRT were not specified in medical records; thus, we were unable to systematically collect the information to precisely describe them. Instead, we collected and analysed laboratory data that could reflect the patients’ conditions at the time of initiating CKRT to provide insights into their conditions. Fifth, the study was conducted where relatively low-intensity CHD was delivered. This might have influenced the clearance of nafamostat mesylate, thereby limiting the generalisability of the findings in different clinical settings. Finally, being conducted in two ICUs, the sample size of the study was relatively small, which might limit the power to detect a dose-response relationship in the study population.
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- Source: https://bmcnephrol.biomedcentral.com/articles/10.1186/s12882-024-03506-0