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Efficacy of UVC-treated platelets
Table 3. Efficacy endpoints (based on intention-to-treat analysis). Parameter
UVC
87
320 316
12.70 ± 5.98
11.42 - 13.97 2.83 (0.99-4.67) 18.24 (6.40-30.08)
22.05 ± 11.35 19.63 - 24.47 15.07 ± 9.65 13.01 - 17.12 8.77 ± 5.52 7.59 - 9.94 3.68 ± 2.38 3.47 ± 2.16 11.45 ± 7.23 2.62 ± 1.75 2.71 ± 2.39
Control
84
248 245
15.53 ± 6.09 14.18 - 16.88
27.06 ± 12.25 24.35 - 29.76 18.94 ± 11.69 16.37- 21.51 10.85 ± 6.16 9.50 - 12.21 2.95 ± 2.22 2.77 ± 1.95 9.27 ± 6.50 2.80 ± 1.97 2.20 ± 2.37
P
0.041 0.038
Patients
Platelet transfusions
Platelet transfusion episodes* Primary endpoint†
1-hour CCI
Secondary endpoints† 1-hour CI
24-hour CI 24-hour CCI
Platelet transfusions per patient
Platelet transfusion episodes per patient* Total dose of platelets transfused per patient‡ Interval between platelet transfusions
Red cell transfusions per patient
n
n n
mean ± SD
CI 95%
mean difference (CI 95%) mean difference (%) (CI 95%)
mean ± SD
CI 95% mean ± SD
CI 95% mean ± SD
CI 95%
n, mean ± SD n, mean ± SD
x 1011, mean ± SD Days, mean ± SD
n, mean ± SD
0.041
0.030
0.040
0.586
0.163
*Transfusion episode, two or more platelet transfusions on the same day, whereby the interval between two consecutive transfusions is less than 2 hours: †The mean corrected count increment (CCI) and count increment (CI) values were calculated as the mean of the average CCI/CI of all transfusions per patient. ‡ Only per-protocol transfusions were included in this analysis. UVC: ultraviolet C; SD: standard deviation; CI: Confidence Interval.
effects on the platelets, such as increased activation, as described for the other PR methods.28
Despite the difference in mean 1-hour CCI of less than 20% between control and UVC-treated platelets, the non- inferiority margin of 30% was narrowly missed with upper bounds of 30.1% for the ITT-analysis and 31.1% for the PP-analysis. Although the 1-hour CCI results of this study do not allow to claim non-inferiority of UVC-treat- ed platelets compared to untreated reference platelets, they are well within the range of those reported for the other PR methods.29 In addition, despite lower mean post- transfusion count increments of UVC-treated platelets, the mean 1-hour and 24-hour CCI values are far above the thresholds that have been established to define successful transfusion.30
As platelet transfusions are used to treat and prevent bleeding, there is an obvious need for clinical trials of pathogen-reduced platelet products to assess their efficacy with regard to clinically relevant bleeding. However, the results of previous studies consistently suggest that it is probably unlikely that transfusion studies comparing the clinical efficacy of two different platelet preparations can show a significant difference in the prevention of clinically relevant bleeding unless the products differ substantially.5 The PLADO trial demonstrated that when following a prophylactic platelet transfusion strategy, which is still the standard of care for most hematology-oncology patients, products with reduced count increments may increase the transfusion frequency but do not necessarily increase the number of clinically relevant bleeding events.26 In addi- tion, even large studies investigating prophylactic versus therapeutic platelet transfusion therapy for hematological cancers in up to 300 patients per arm were too small to detect differences in clinically more relevant bleeding of
WHO grade 3 and 4.31,32 All completed studies of pathogen-reduced platelets, including our trial, followed a prophylactic transfusion regimen and tested products with count increments that were lower than those of the reference product. As expected, a recent Cochrane review and two recently published clinical trials investigating the effectiveness of pathogen-reduced platelets for the pre- vention of bleeding did not find a difference in the risk of developing clinically severe bleeding compared to stan- dard platelets, although a slight increase in clinically irrel- evant WHO grade 2 bleeding was detected in patients in the PR arms.25,33,34
It is an ongoing discussion whether CCI can be used as surrogate efficacy marker in platelet transfusion studies.29 However, in the absence of a suitable relevant bleeding outcome for platelet transfusion studies, we decided to use the 1-hour CCI as primary efficacy endpoint in our study.35 It is at least a measure for the availability of circu- lating platelets and was used in almost all previous clinical studies with pathogen-reduced platelets, allowing com- parison between the different products.29
In accordance with previous studies of pathogen- reduced platelets,17,18,20,23,25,34 the transfusion of UVC-treated platelets was associated with an increased rate of platelet product utilization. The explanation for the higher usage of pathogen-reduced platelet products compared to the reference products may be that, due to a lower platelet increment, the transfusion trigger was met sooner. It remains to be elucidated whether the lower levels of recovery of pathogen-reduced platelets in the circulation could be the result of the early removal of damaged platelets or of the rapid utilization of activated platelets at sites of injury. However, the fact that there was no signif- icant difference in RBC usage between study arms sug-
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