Pre‐operative anaemia and mortality: a reply

We thank Zhang et al. [1] for their comments on our study [2]. They raised concerns about residual confounding related to frailty and the omission of transfusion volume and timing from the analysis. Frailty is a challenging confounder as it encompasses a heterogeneous, multidimensional syndrome that cannot be captured by a single variable [3]. Guidelines have only recently recommended incorporating frailty assessment into the pre-operative evaluation of older adults. Consequently, most registry datasets do not capture this information [3]. The primary aim of our analysis was to approximate causal relationships as closely as possible within the constraints of registry data, using robust statistical methods and accounting for confounders in each pathway of the mediation framework. To quantify residual confounding, we calculated an E-value of 2.48 (lower 95%CI 2.10), indicating that an unmeasured confounder would need to be associated with both pre-operative anaemia and mortality with an odds ratio of at least 2.48 to fully explain the observed association. Given the confounders already adjusted for and the strength of association required, it is unlikely that frailty alone would explain the observed effect. Regarding transfusion quantity and timing, modelling transfusion as a binary variable may obscure clinically relevant dose-dependent effects, limiting our conclusions to red blood cell transfusion vs. no transfusion. Nevertheless, in elective cardiac surgery, high-volume transfusion is uncommon, with most patients receiving 1–2 units due to low baseline haemoglobin and surgical blood loss [4]. Our sensitivity analysis in patients without postoperative cardiac reinterventions ruled out the effect of high-volume transfusions. More importantly, the clinical implications remain clear. The key pillar of patient blood management guidelines is the identification and treatment of pre-operative anaemia to reduce red blood cell transfusion requirements [5]. Regardless of when transfusion occurs or whether this is low- or high-volume, by identifying and treating pre-operative anaemia, clinicians can reduce the need for peri-operative transfusion. We agree that future research should incorporate additional variables including the underlying causes of anaemia. This will help improve patient blood management further.