Preterm neonates benefit from low prophylactic platelet transfusion threshold despite varying risk of bleeding or death

Abstract

The Platelets for Neonatal Thrombocytopenia (PlaNeT-2) trial reported 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 (7% absolute-risk reduction). However, some neonates in the trial may have experienced little benefit or even harm from the 25 × 109/L threshold. We wanted to assess this heterogeneity of treatment effect in the PlaNet-2 trial, to investigate whether all preterm neonates benefit from the low threshold. We developed a multivariate logistic regression model in the PlaNet-2 data to predict baseline risk of major bleeding and/or mortality for all 653 neonates. We then ranked the neonates based on their predicted baseline risk and categorized them into 4 risk quartiles. Within these quartiles, we assessed absolute-risk difference between the 50 × 109/L- and 25 × 109/L-threshold groups. A total of 146 neonates died or developed major bleeding. The internally validated C-statistic of the model was 0.63 (95% confidence interval, 0.58-0.68). The 25 × 109/L threshold was associated with absolute-risk reduction in all risk groups, varying from 4.9% in the lowest risk group to 12.3% in the highest risk group. These results suggest that a 25 × 109/L prophylactic platelet count threshold can be adopted in all preterm neonates, irrespective of predicted baseline outcome risk. Future studies are needed to improve the predictive accuracy of the baseline risk model. This trial was registered at www.isrctn.com as #ISRCTN87736839.

Graphical abstract

Figure 1.

Validation of the prediction model showing observed incidences of major bleeding and/or death within 28 days of randomization for patients in each of the 4 quartiles of baseline risks. The triangles indicate the observed incidences (proportion of patients with an event) in each of the 4 quartiles of predicted baseline risks (very low, <13%; low, 13%-16%; intermediate, 17%-24%; and high, >24%). The diagonal line represents a situation of perfect prediction when the observed incidences would be identical to the predicted baseline risks. The distribution of predicted baseline risks of major bleed and/or death is shown at the bottom of the graph.

Figure 2.

Distribution of predicted baseline risks of the outcome major bleed and/or death (N = 653). Predicted baseline risk of outcome is represented on the x-axis and the frequency (number of patients) of each predicted baseline risk category (eg, 0%-0.05%, 0.05%-0.1%, and 0.1%-0.15%) in the PlaNet-2 trial population on the y-axis. The vertical lines represent the cutoff points to group patients according to quartiles of predicted baseline risk at 12.6%, 17.4%, and 24.1%.

Figure 3.

Comparison of the occurrence of major bleeding and/or death within 28 days of randomization. The data of the 2 trial arms are expressed as observed incidence (A), odds ratios (B), and risk differences (C) for the included preterm neonates with severe thrombocytopenia in each of the 4 quartiles of their baseline risks (very low, <13%; low, 13%-16%; intermediate, 17%-24%; and high, >24%). Vertical lines represent 95% CI. Horizontal lines represent the previously published overall trial result, applicable to the nonexisting “average patient.” (A) In all 4 quartiles of baseline risk, the event rates of major bleeding and/or death among patients in the 25 × 10⁹/L intervention arm were lower than the event rates in the 50 × 10⁹/L intervention arm. (B) In all 4 quartiles of baseline risk, the ORs comparing patients in the 50 × 10⁹/L intervention arm with those in the 25 × 10⁹/L arm of the trial are similar. The horizontal line indicates the overall trial result (OR, 1.57). (C) In all 4 quartiles of baseline risk, the risk differences (incidence in the 25 × 10⁹/L arm − incidence in the 50 × 10⁹/L arm) and a horizontal line indicating the overall trial result (−7% absolute-risk difference). The absolute-risk difference indicated harm of the 50 × 10⁹/L transfusion trigger in all 4 quartiles of baseline risk, which was less pronounced among patients with the very low baseline risk, compared with patients with the highest baseline risk.