Comment to the European Stroke Journal article “Sex differences in treatment, radiological features and outcome after intracerebral haemorrhage: Pooled analysis of Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage trials 1 and 2”

Giuseppe Reale, MD – Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy;

Diana Aguiar de Sousa, MD, PhD – Hospital de Santa Maria, Universidade de Lisboa, Lisbon, Portugal.

In a seminal paper published in 2017, the Women Initiative for Stroke in Europe (WISE) group claimed a political and scientific turnaround about women’s stroke care1. In fact, although the incidence of stroke is higher in women than men, women are less likely to have access to acute care and to have good outcomes in terms of mortality and disability. Moreover, women –especially in their old age– are underrepresented in the most important clinical trials on acute stroke treatment1.

While these differences are better documented for ischemic stroke, it is less clear about their impact on Intracranial Hemorrhage (ICH). ICH accounts for 9-27% of all strokes and is associated to worse outcomes in terms of death and disability, if compared to ischemic stroke2. However, little is known about outcomes differences among genders3,4. Importantly, while there is some suggestion that there are sex differences in the effect of the blood pressure lowering in patients with ICH, data is still scarce5,6.

These are the reasons that led Sandset and colleagues to perform a post-hoc pooled analysis, published today on ESJ 7, aiming to assess such differences among patients enrolled in the INTERACT trials 1 and 2. The INTERACT trials (Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage trials) compared the efficacy of intensive blood pressure control (systolic blood pressure, SBP<140 mmHg in <1 hour) vs. standard blood pressure control (SBP<180 mmHg) in reducing mortality in patients with ICH, within 6 hours from symptom onset. Although no difference between groups was found in terms of death, the patients who had received aggressive therapy were more likely to have better outcomes in terms of disability8.

In this post-hoc analysis, the authors found that women were about one-third of the enrolled patients (n=1131/3233, 37%), were older than men (mean age 65.9 vs. 62.5), were more likely to suffer from hypertension (75.7% vs. 70.9%) and had smaller hematomas but worse neurological symptoms. The blood pressure lowering therapy seemed to be slightly more effective in women than men, while hematoma expansion and perihaematomal edema growth were similar in both groups.

Regarding the primary outcome of the study, men had 38% higher risk of death, while no difference was found about secondary outcomes of disability. No significant interaction between treatment of blood pressure and sex was found for any of the clinical outcomes.

The above-mentioned results are surely interesting. First of all, the underrepresentation of women in the INTERACT trial seems to confirm the findings that are being pointed out by several groups of researchers, as the WISE group1. Together with the higher mean age, it has been proposed that older -and frailer- women tend to live alone, do not have immediate access to acute stroke care and therefore are less likely to be included in clinical trials1. This might be a possible explanation for the reduced enrollment of women in the INTERACT trial. Still, the high mean age, high rates of severe neurological symptoms, less often use of intravenous blood pressure lowering drugs and lower mortality observed in women suggests that there is something more beyond random heterogeneity across groups, or even selection bias. More prospective data are needed to get a deeper insight into this topic. At the moment, it should be considered that both in daily clinical practice and in clinical trials gender can matter. Knowing these differences might help to tailor better preventive, acute and post-acute treatments for stroke patients.


  1. Cordonnier, C., Sprigg, N., Sandset, E. et al. Stroke in women — from evidence to inequalities. Nat Rev Neurol 2017:13;521–532
  2. Steiner T, Al-Shahi Salman R, Beer R, et al. European Stroke Organisation (ESO) guidelines for the management of spontaneous intracerebral hemorrhage. Int J Stroke 2014;9:840-855
  3. Gokhale S, Caplan LR and James ML. Sex differences incidence, pathophysiology, and outcome of primary intracerebral hemorrhage. Stroke 2015; 46: 886–892
  4. Carcel C, Wang X, Sandset EC, et al. Sex differences in treatment and outcome after stroke: pooled analysis including 19,000 participants. Neurology 2019; 93: e2170–e2180
  5. Qureshi AI, Bliwise DL, Bliwise NG, et al. Rate of 24-hour blood pressure decline and mortality after spontaneous intracerebral hemorrhage: a retrospective analysis with a random effects regression model. Crit Care Med 1999; 27: 480–485
  6. Qureshi AI, Palesch YY, Barsan WG, et al. Intensive blood-pressure lowering in patients with acute cerebral hemorrhage. N Engl J Med 2016; 375: 1033–1043
  7. Sandset EC, Wang X, Carcel C, Sato S, Delcourt C, Arima H, Staft C, Robinson T, Lavados P, Chalmers J, Woorward M, Anderson C. Sex differences in treatment, radiological features and outcome after intracerebral hemorrhage: Pooled analysis of Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage trials 1 and 2. European Stroke Journal 2020. DOI: 10.1177/2396987320957513
  8. Anderson CS, Heeley E, Huang Y, et al. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med 2013;368:2355-2365.