Vignan Yogendrakumar, MD MSc

Wei C, Wang J, Foster LD, Yeatts SD, Moy C, Mocco J, Selim M. Effect of Deferoxamine on Outcome According to Baseline Hematoma Volume: A Post Hoc Analysis of the i-DEF Trial. Stroke. 2021.

Intracerebral hemorrhage is a complex disease because, truly, no two bleeds are ever the same. Hemorrhages can differ in size, location, or compartment, and the varying combinations of these elements can lead to dramatic differences in clinical severity and long-term outcome. A small but well-placed hemorrhage in the internal capsule can lead to contralateral hemiplegia, whilst a moderately sized lobar hemorrhage can sometimes present with minimal clinical symptoms. This heterogeneity has been a point of frustration in treatment trials that aim to improve clinical outcomes because a candidate therapy may have a significant effect on a portion of the trial population, but the treatment effect may be diluted when the whole population is assessed. Past trials have informed subsequent studies regarding patient selection, but even with the numerous lessons learned, identifying patients that are most likely to benefit from a candidate therapy remains a difficult task.

The I-DEF study was a randomized controlled trial that assessed deferoxamine mesylate, an iron chelator that could improve secondary injury after ICH. The trial did not observe a difference in clinical outcomes (defined as mRS 0-2) at 180 days, but Wei and colleagues performed a post-hoc analysis of the trial to determine whether there was any difference in treatment effect when accounting for baseline hemorrhage volume. Patients in the trial were stratified into three groups by hemorrhage size: small volume hemorrhage (<10 mL), mid-volume hemorrhage (10-30 mL) and large volume hemorrhage (>30 mL). The authors found that there were no major differences in clinical outcomes in patients with small or large volume baseline hemorrhages, but a significant difference in outcomes favouring deferoxamine treatment was observed in patients with mid-volume hemorrhages (Figure 1, mRS 0-2 at 180 days: aOR 2.66 (1.13-6.27)). On further assessment, a significant interaction between treatment and baseline hemorrhage volume subgroup was also observed.

Figure 1. The modified Rankin Scale (mRS) scores. mRS at 180 d (A) and 90 d (B) in different hematoma volume (HV) subgroups.
Figure 1. The modified Rankin Scale (mRS) scores. mRS at 180 d (A) and 90 d (B) in different hematoma volume (HV) subgroups.

Even with the treatment interaction observed, the study is limited by varying sample sizes in each of the hemorrhage volume subgroups, and the exact definition of what is small, mid, or large hemorrhage volumes can also be debated. As such, this is a hypothesis generating study that requires further investigation and validation. However, the study findings pose interesting questions regarding the strong influence that baseline hemorrhage volume has on outcome, and the potential role of baseline hemorrhage volume in the future selection for treatment trials. As the authors suggest, patients with very small or very large hemorrhages may not be suitable subjects for certain trials, and their inclusion may dilute the treatment effect of a potentially useful therapy. However, the exclusion of certain groups can reduce generalizability, and make recruitment very difficult. This is an area of ongoing debate within the ICH community, and at this stage, there is no easy answer. In the future, we may find ourselves considering ICH as a heterogeneous disease with different therapeutic approaches for varying clinical scenarios and hemorrhage types.