Newborns with thrombocytopenia had a lower risk of death or bleeding if they received platelet transfusions according to a lower 25×109/L threshold rather than the commonly used higher transfusion threshold, according to an analysis of data from the Platelets for Neonatal Thrombocytopenia (PlaNeT-2) trial. The benefit of the lower threshold was seen in all patients, regardless of their baseline risk for bleeding or death.
The findings were reported in Blood by lead author Susanna Fustolo-Gunnink, MD, from the Center for Clinical Transfusion Research and Leiden University Medical Center in the Netherlands, and colleagues.
The authors conducted this analysis after observing “an unexpected overall benefit of a prophylactic platelet transfusion threshold of 25×109/L compared [with] 50×109/L for major bleeding and/or mortality in preterm neonates” in the randomized PlaNeT-2 trial. However, “the overall trial result holds only for patients with an average baseline risk [and may not] hold true for patients with different baseline risks.”
To understand the heterogeneity of treatment effect in the trial – and which patients are likely to benefit from or be harmed by an approach using a lower transfusion threshold – the researchers assessed PlaNet-2 participants’ baseline risk for major bleeding and/or mortality. Next, they ranked newborns according to risk level and measured absolute risk difference between the high-threshold group (50×109/L) and the low-threshold group (25×109/L).
“All neonates experienced benefit from the low threshold, as the low threshold was associated with absolute risk reduction in all risk groups.”
—Susanna Fustolo-Gunnink, MD
PlaNet-2 enrolled 653 preterm neonates with severe thrombocytopenia (defined as platelet count 50×109/L). The median gestational age was 26.7 weeks (interquartile range [IQR] = 24.9-28.7) and the median age at randomization to either the low- or high-threshold group was 7.5 days (IQR=3.9-20.5).
The composite outcome of death and/or major bleeding within 28 days of randomization occurred in 19% of neonates in the low-threshold group (n=61/329) and 26% of neonates in the high-threshold group (n=85/324), for an absolute risk difference of 7% (p=0.02).
In their baseline risk prediction model, the following factors were associated with an increased risk of death and/or major bleeding: presence of a previous major bleed, lower gestational age, and assignment to the 50×109/L group (TABLE).
Using this information, the authors categorized patients into quartiles of risk: very low (<13%), low (13-16%), intermediate (17-24%), and high (>24%).
Next, they compared the incidence of the composite outcome between patients in the low- and high-threshold groups across risk levels, finding that the risk was significantly higher in the group assigned to the 50×109/L threshold regardless of baseline risk.
In all four quartiles of baseline risk, the risk differences (defined as incidence in the 25×109/L arm minus incidence in the 50×109/L arm) indicated that the high-threshold approach was associated with a higher risk of harm. Also, the risk difference was less pronounced among patients with very low baseline risk compared with patients with the highest baseline risks, the researchers reported.
“Our results suggest that all neonates experienced benefit from the low threshold, as the low threshold was associated with absolute risk reduction in all risk groups,” Dr. Fustolo-Gunnink and co-authors wrote. “However, the absolute benefit varied considerably, from 4.9% in the lowest- to 12.3% in the highest-risk group.”
The finding that newborns are vulnerable to harm from a high-threshold transfusion approach, regardless of their underlying risk, is “contradictory to recommendations found in some guidelines that suggest to use platelet transfusion thresholds above 25×109/L for neonates with suspected higher baseline risks,” the authors noted. “For example, these guidelines suggest using [higher] thresholds for sick neonates with lower gestational age and/or birthweight. Clinicians who may have been reluctant to implement the results of PlaNet-2 in the smallest and sickest neonates can now be more confident that even this population is likely to benefit from using a lower platelet transfusion threshold.”
The findings from the study are limited by the fact that several participants experienced major bleeding prior to randomization, and 39% received platelet transfusions prior to randomization, potentially complicating the interpretation of these data. “Further studies are needed to confirm previous major bleeding as a predictor for a second major bleeding [event] and/or death after onset of severe thrombocytopenia,” the authors noted.
Also, the subgroup analysis that determined independent risk factors for death and/or major bleeding in the baseline risk model was underpowered because the trial was powered only for the primary analysis.
“The model will need to be externally validated before it can be implemented in future studies or clinical settings,” they concluded. “Ultimately, an improved and validated model will allow for further refined prediction of individualized treatment effects for platelet transfusion in preterm neonates.”
Fustolo-Gunnink S, Fijnvandraat K, van Klaveren D, et al. Preterm neonates benefit from low prophylactic platelet transfusion threshold despite varying risk of bleeding or death. Blood. 2019 October 24. [Epub ahead of print]
There is substantial variation in the existing threshold for platelet transfusion in non-bleeding neonates. Surveys of U.S. and Canadian neonatologists found the cut-off varied from 20 to 100×109/L. The authors of the present analysis were prompted to study a higher and lower threshold because of this variability in current practice, as well as the lack of randomized studies indicating which cut-off is better. In general, if a lower threshold for transfusion of a blood product has equivalent outcomes to a higher threshold, the lower threshold is considered better because it will result in fewer transfusions. Subsequently, this lowers the risk for transfusion complications, such as alloimmunization or transfusion-transmitted infectious disease, and lowers costs.
This study had an unexpected result in that the neonates transfused at the lower threshold had lower risk for death or major bleeding within 28 days. So, the lower threshold was actually safer than the higher threshold. The authors also wanted to determine whether the subgroup of neonates at highest bleeding and mortality risk benefitted from the lower platelet transfusion threshold, but again found that the lower cut-off was beneficial in all neonates, regardless of their baseline risk.
However, the study was limited by a small sample size, which did not allow for inclusion of interaction terms in the analyses, and the selection of predictors included in the baseline risk model, which may not have been able to predict actual risk in this population.
Alan Mast, MD, PhD
Versiti BloodCenter of Wisconsin