DISCUSSION
traumatic brain injury, ICH, lower systolic blood pressure, TICH-NOAC, hemorrhage
HEMORRHAGE, CLOT
In this first randomized controlled trial of TXA versus placebo in patients with NOAC-associated ICH, we found no evidence that TXA limits HE nor that it improves clinical outcomes by 90 days. However, there were no major safety concerns for the use of TXA, and treatment might hold potential for preventing HE in selected patient subgroups, particularly those treated early after ICH onset.The hemostatic effect reflects the balance between the opposing processes of thrombin generation through the coagulation cascade leading to fibrin clot formation and endogenous fibrinolysis leading to fibrin clot disintegration. TXA does not affect the coagulation factors thrombin or factor Xa, which are the targets of the NOAC, but blocks endogenous fibrinolysis, thus delaying fibrin disintegration and accelerating and stabilizing fibrin clot formation,Currently, no randomized evidence exists for the hemostatic treatment of NOAC-associated ICH. While recent guidelinesAlthough TICH-NOAC did not reach its target sample size, which precludes any definitive conclusions, there was no clear signal for potential efficacy in any of the predefined outcomes. The rate of HE, which we chose as our primary dichotomous outcome based on considerations discussed elsewhere,Although our subgroup analyses, limited by the small participant numbers leading to high imprecision, are highly exploratory, their hypothesis-generating results might help inform the design of future trials. Notably, we found a signal for interaction of treatment with time from onset, suggesting that there might be potential for benefit from TXA with earlier treatment administration. This also seems to drive the aforementioned association in the subgroup of ANNEXa-I–eligible participants and adds to the accumulating evidence from recent trials on TXA in spontaneous non–NOAC-associated ICH but also traumatic brain injury and other severe hemorrhage, that early treatment is crucial to achieve better outcomes.The analysis of interaction with admission systolic blood pressure showed a weak signal that participants with lower systolic blood pressure (≤170 mm Hg) might be more responsive to TXA. This is consistent with the findings of the TICH-2 trial, which reported a similar interaction of treatment with blood pressure.Importantly, our study showed no signal for a major safety concern for the use of TXA in addition to standard care in patients with NOAC-associated ICH, consistent with previous evidence for the safety of TXA from trials on non–NOAC-associated ICH.The strengths of TICH-NOAC are as follows: (1) this is the first randomized trial reporting on the hemostatic treatment of NOAC-associated ICH, (2) robust methodology including a double-blind placebo-controlled design, and (3) robust assessment of the primary outcome by 3 raters, which limit the risk of bias. The most important limitations of TICH-NOAC are as follows: (1) failure to reach its target sample size and (2) underpowered sample size. A number of factors led to the premature discontinuation of TICH-NOAC, including lack of additional funding and—most notably—the negative impact of the COVID-19 pandemic on research activities,In summary, our study found no evidence that TXA prevents HE in patients with NOAC-associated ICH, although there were no major safety concerns with TXA and treatment might hold potential for benefit in selected patient subgroups, particularly those treated early after ICH onset. Further trials on hemostatic treatments are urgently needed to improve outcomes in NOAC-associated ICH and should probably target an early treatment window. Including the increasingly important population of patients taking NOAC in ongoing or planned large-scale trials of TXA in ICH is warranted.