Assessing recombinant Factor VIIa and Hematoma Expansion Using a Shift Analyses Model

Dar Dowlatshahi (PI)
Vignan Yogendrakumar (trainee + statistics)
Tim Ramsay (supervising statistician)
Stephan Mayer
Thorstein Steiner
Joe Broderick

1.1 Defining Hematoma Expansion remains a challenge
Our current hematoma expansion (HE) definitions consist of either descriptive measures of central tendency, or dichotomous thresholds known to correspond to clinical outcomes[1]. While these definitions are intuitive and easy to use, they may underestimate the biological activity of therapies targeting HE. For example, it is possible that agents used in “neutral” trials can reduce HE in a proportion of patients, perhaps by providing better stabilization of the baseline hemorrhage. This degree of granularity is not possible when dichotomous definitions are utilized. A more thorough assessment of the distributions of hematoma volume change between treatment groups may provide a better assessment of the biological effect.

1.2 If there is no clinical effect, why does a biological effect matter?
A decade of neutral ICH clinical trials has led to a sense of nihilism in the medical and research communities. Yet, the lessons learned from prior trials have led to exciting changes in ICH study design. To maximize the chance of success, future ICH trials targeting HE are adopting one of two approaches: 1) very early/pre-hospital enrollment with rapid administration of HE therapy (ex: using mobile stroke units and deferral of consent), or 2) a clinical decision rule to enrich the study population with patients at highest risk of HE (ex: expansion scores[2] or non-contrast CT markers[3]). Both of these approaches will require a biologically active therapy that can reduce HE. We propose that candidate therapies can be identified by reevaluating their biological effects in published ICH trials using a novel method: a hematoma expansion shift analysis.

1.3 The Hematoma Expansion Shift Analysis Model
In 2021, Dowlatshahi and colleagues proposed a hematoma expansion shift analysis model for assessing hematoma growth in acute ICH[4]. In an exploratory analysis of the ATACH-2 trial[5], traditional dichotomous thresholds were recategorized as: “stabilized” (zero expansion or shrinkage), “mild expansion” (less than 33%) and “significant expansion” (greater than 33%) and an ordinal analysis of hematoma expansion was performed comparing the control and intervention (intensive blood pressure lowering) arm. We also assessed an alternate model by dividing hematoma growth into quartiles (0-25%, 25-50%, 50-75%, >75%). In both treatment groups, approximately one-third of patients exhibited no HE. Using a trichotomous HE stratification, the highest strata of ≥33% revealed a 5.8% reduction in hematoma growth for those randomized to the intervention arm (aOR: 0.77 [95% CI: 0.60-0.99]). Using percentile quartiles of hematoma volume change, we observed a favorable shift to reduce growth in patients in the intervention arm: aOR: 0.73 (0.57-0.93).

A shift analysis model of HE provided additional insights into the biological effects of intensive blood pressure lowering and our findings suggested that intensive blood pressure reduction may preferentially mitigate growth in patients at risk of high volume HE. We propose that a shift analysis model may be an additional way to assess hemostatic agents in future studies.

Proposal + Hypothesis
We propose a re-evaluation of recombinant Factor VIIa and hematoma growth using a shift analysis model. We hypothesize that a shift analysis approach will provide additional insights into how recombinant Factor VIIa affects hematoma growth and may therefore aid in study population selection for future ICH treatment trials.

We request access to the FAST trial[6] dataset, including data from both the treatment and control arms. Similar to the approach already published, patients would be divided by treatment assignment and we would explore HE shift using the following techniques:

1. Trichotomous HE analyses: We would create trichotomotous definitions that explored no HE, minimal HE, and significant HE, with significant HE thresholds drawn from prior definitions used in the literature: an absolute intraparenchymal hematoma volume expansion trichotomy (≤0mL, <6mL, ≥6mL); a relative intraparenchymal hematoma volume expansion trichotomy (≤0%, <33%, ≥33%); and combined intraparenchymal expansion (≤0, <6mL or 33%, ≥6mL or 33%).

2. Polychotomous Hematoma Volume Change Analyses: We would create an analyses defined by quartiles of hematoma volume percentile growth. We would measure total hematoma volume change as the sum change of both intraparenchymal and intraventricular compartments.

We would assess the relationship between treatment allocation and hematoma growth using proportional odds models. Proportional odds assumptions would be assessed using the Brandt test. In all models, we would adjust for baseline intraparenchymal volume and time from symptom onset to treatment initiation. If possible, we would perform an additional analysis using the same techniques described above in patients who are treated within two hours of symptom onset and compare the treatment effect of hematoma growth using an interaction analysis to patients treated beyond two hours from symptom onset. We would perform all statistical analysis using SPSS v27.0 (IBM, Armonk, NY, USA) and STATA v17 (StataCorp, College Station, TX, USA).

1. Dowlatshahi D, Demchuk AM, Flaherty ML, et al. Defining hematoma expansion in intracerebral hemorrhage: relationship with patient outcomes. Neurology 2011; 76: 1238–44.
2. Yogendrakumar V, Moores M, Sikora L, et al. Evaluating Hematoma Expansion Scores in Acute Spontaneous Intracerebral Hemorrhage: A Systematic Scoping Review. Stroke 2020; 51: 1305–1308.
3. Boulouis G, Morotti A, Brouwers HB, et al. Noncontrast Computed Tomography Hypodensities Predict Poor Outcome in Intracerebral Hemorrhage Patients. Stroke 2016; 47: 2511–6.
4. Yogendrakumar V, Ramsay T, Menon BK, et al. Hematoma Expansion Shift Analysis to Assess Acute Intracerebral Hemorrhage Treatments. Neurology 2021; 97: e755–e764.
5. Qureshi AI, Palesch YY, Barsan WG, et al. Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage. N Engl J Med 2016; 375: 1033–43.
6. Mayer SA, Brun NC, Begtrup K, et al. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2008; 358: 2127–37.

Dr. Dowlatshahi will use existing discretionary funding to offset VISTA fees.