Objective: We examined fatal and non-fatal Serious Adverse Events (SAEs) at 14 days within AVERT.

Method: A prospective, parallel group, assessor blinded, randomized international clinical trial comparing very early intensive mobilization training (VEM) with usual care (UC); with follow up to 3 months. Included: Patients with ischaemic and haemorrhagic stroke within 24 hours of onset and physiological parameters within set limits. Treatment with thrombolytics allowed. Excluded: Patients with severe premorbid disability and/or comorbidities. Interventions continued for 14 days or hospital discharge if less. The primary early safety outcome was fatal SAEs within 14 days. Secondary outcomes were non-fatal SAEs classified as neurological, immobility-related, and other. Mortality influences were assessed using binary logistic regression adjusted for baseline stroke severity (NIHSS) and age.

Results: 2104 participants were randomized to VEM (n=1054) or UC (n=1050) with a median age of 72 years (IQR 63-80) and NIHSS 7 (IQR 4-12). By 14 days, 48 had died in VEM, 32 in UC, adjusted Odds Ratio of 1.76 (95% CI 1.06-2.92, P=.029). Stroke progression was more common in VEM. Exploratory subgroup analyses showed higher odds of death in those; >80 years, and with intracerebral haemorrhage, but there was no significant treatment by subgroup interaction. No difference in non-fatal SAEs found.

Conclusions: While the overall case fatality at 14 days post-stroke was only 3.8%, age and severity adjusted mortality was increased with high dose, intensive training compared to usual care. Stroke progression was more common in VEM. Data suggests that older people and those with intracerebral haemorrhage are at higher risk.

Classification of Evidence: This study provides Class I evidence that very early mobilization increases mortality at 14 days post stroke.

e-Figure 1. Individual profiles of those who died within 14 days of stroke.

Each box represents one participant (age; baseline NIHSS; stroke type: Ischemic [ISC], Haemorrhage [H] are presented in the grey bar at the top), Yellow highlight indicates death from stroke event (stroke progression or recurrent stroke). Vertical coloured bars above the grey line=daily functional level; Red=Level 1: fully dependent, unable to sit on edge of bed without assistance of 1-2 people; Orange=Level 2: can sit on edge of bed with assistance or supervision, able to stand with assistance; Blue=Level 3: can walk with moderate to maximum assistance; Level 4=able to walk with minimal / no assistance (note that no level 4 participants died within 14 days of stroke onset). Y axis=Daily dose (minutes) out of bed mobilization from physiotherapist; daily count (frequency) of sessions with physiotherapist (purple circle), and nurse (green circle). Day of serious adverse event (SAE, red hashed line); day of death (black line). Not mobilized VEM=9, UC=10. X axis=Days post stroke.