Response to “An unbalanced study that lacks power: a caution about IPTAS”

In reply: We appreciate the opportunity to provide clarifications to the comments made by the manufacturer of one of the two pathogen reduction systems used in our study. Among their critical comments, Benjamin and colleagues correctly report that we observed a higher number of at least Grade 2 bleedings in recipients of INTERCEPT-treated platelets (PLTs), but surprisingly forget to mention that, as we reported, this increment was not significant and we did not detect any safety issue. With regard to blood component use, Benjamin and colleagues note that patients in the INTERCEPT arm, which included more acute myeloid leukemia (AML) patients than the control arm, had more days of leukopenia (a proxy of marrow suppression) than control patients and ask why we disregarded this covariate in our analysis. In spite of a higher number of total days with leukopenia in the INTERCEPT arm (562 days vs. 471 days; 119%), we did not think that this difference could explain the higher PLT use (154%) observed in INTERCEPT-treated PLT recipients. Interestingly, increased use of PLTs and red blood cells (RBCs) was found not only in the INTERCEPT trial, but also in the IPTAS-Mirasol trial performed in parallel, where the frequency of leukemia patients was comparable in the two arms. To support our view, in consideration of the higher number of AML patients in the INTERCEPT arm (67 vs. 51; 131%), we performed an analysis on AML patients only, which was reported in Tables S8 to S12 of the Supporting Information. This analysis confirmed a higher PLT use in recipients of INTERCEPT-treated PLTs and showed that the mean 6 SD number of days with leukopenia in the AML patients given INTERCEPTtreated PLTs (6.42 6 4.30 days) was comparable to that of the AML recipients transfused with control PLTs (5.73 6 4.32 days). To further corroborate our conclusions, we have carried out the adjusted analysis on AML patients suggested by Benjamin and colleagues. As reported in Table 1, the number of PLT units transfused was higher in the INTERCEPT arm, both in the whole group and in the AML subgroup before and after adjustment for the duration of leukopenia. The odds ratio (OR) and the difference (D) were highly significant independently of the analysis. The use of RBC units was slightly higher (123%, 0.87 units) in the INTERCEPT arm. This result was partly ascribable to the higher RBC use (113%, 0.64 units) in AML patients. For this reason the OR and D became not significant in the AML subgroup both in unadjusted and adjusted analyses. The study had not enough power to detect any difference in the number of days with at least Grade 2 bleeding, even (as we expected) after adjustment for the duration of leukopenia. With regard to the other issues, Benjamin and colleagues support their critical comments with “pragmatic published experience of three independent European clinical centers that demonstrates no increase in PLT, RBC, or plasma use with the introduction of INTERCEPT-treated PLTs in routine use. ” Although the latter pragmatic data and hemovigilance studies provide useful information, in our opinion they must be critically viewed in light of the evidence collected in the controlled clinical trials. Our study and the euroSPRITE, the SPRINT, and the HOVON studies showed 54, 36, 35, and 12% higher mean number of PLT transfusions in recipients of INTERCEPT-treated PLTs versus controls, respectively. Only the controlled study by Janetzko and coworkers, which confirmed significantly lower posttransfusion PLT count increments with INTERCEPT PLTs in 22 treated versus 21 control patients, did not detect increased PLT use by recipients of pathogenreduced PLTs. The studies performed with Mirasoltreated PLTs showed 34% increased PLT use (our study) and 4.5 versus 3.0 (i.e., 50% higher) median number of PLT transfusions in pathogen-reduced PLT recipients. In conclusion, we confirm the validity of the results of the ITPAS study and strongly believe that the increased PLT use that we observed in both the INTERCEPT and the Mirasol trials was mainly due to significantly lower posttransfusion PLT count increments obtained with pathogen-reduced PLTs. The latter were well documented in a number of controlled clinical trials and were invariably associated with shorter intertransfusion intervals (Table 2). This negative effect could be at least partially offset by increasing the PLT dose to account for processing losses associated with pathogen reduction. This strategy was performed in some centers participating in two trials by increasing the target for plateletpheresis collections by 10% or by using five versus four (i.e., 25% more) buffy coats for pathogen-reduced versus conventional PLTs. Despite its potential positive effect, cost to benefit evaluations should take into account that the routine application of this strategy would increase PLT requirements. doi:10.1111/trf.14210