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AVERT

A Very Early Rehabilitation Trial after stroke (AVERT): a Phase III, multicentre, randomised controlled trial

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Year of Publication: 2017

Authors: Langhorne P, Wu O, Rodgers H, ..., on behalf of the AVERT triallists' collaboration.

Journal: Health Technology Assessment (NIHR HTA monograph — full trial report; primary results also published in The Lancet 2015;386:46-55)

Citation: Langhorne P, Wu O, Rodgers H, Ashburn A, Bernhardt J. A Very Early Rehabilitation Trial after stroke (AVERT): a Phase III, multicentre, randomised controlled trial. Health Technol Assess 2017;21(54).

Link: https://doi.org/10.3310/hta21540

PDF: https://www.journalslibrary.nihr.ac.uk/hta/hta21540/

Clinical Question

Does very early mobilisation (VEM) — beginning within 24 hours of stroke onset at higher frequency and dose than usual care — improve functional independence at 3 months compared with standard stroke unit care?

Bottom Line

VEM within 24h was harmful: functional independence (mRS 0-2) at 3 months was significantly lower with VEM (46% vs 50%; adjusted OR 0.73; 95% CI 0.59-0.90; P=0.004). Dose-response analysis revealed a paradox: more frequent short sessions improved outcomes (OR 1.13/session), but more total daily minutes worsened outcomes (OR 0.94 per 5 min) — suggesting short, frequent mobilizations are preferable to prolonged early sessions.

Major Points

  • VEM significantly worsened outcome: 46% vs 50% mRS 0-2 at 3 months (aOR 0.73; 95% CI 0.59-0.90; P=0.004).
  • Intervention delivered: VEM patients mobilised 4.8h earlier, 3 more sessions/day, 21 more minutes/day (all P<0.0001). 92% vs 59% mobilised within 24h.
  • No significant mortality difference: 8% vs 7% at 3 months (OR 1.34; 95% CI 0.93-1.93; P=0.113).
  • No walking recovery difference: 75% vs 76% walking unassisted by 3 months (aOR 0.83, 95% CI 0.64-1.07, P=0.143); time-to-walk also similar (HR 1.04, P=0.459).
  • No QoL difference at 12 months: AQoL 0.47 vs 0.49 (P=0.865).
  • Dose-response paradox: frequency improved outcomes (OR 1.13/session; P<0.001) while duration worsened them (OR 0.94/5min; P<0.001).
  • ICH subgroup signal: OR 0.48 for favorable outcome, OR 3.21 for death (not significant interaction but concerning).
  • Prespecified severe-stroke subgroup (NIHSS >16, n=291): OR 0.35 (0.11-1.18) — direction favours UC but not statistically significant.
  • Shorter hospital stay with VEM: median 16 days vs 18 days total; acute-care-only stay 7 days in both groups.
  • UC temporal drift: TTFM shortened 28 min/year (P=0.001) over 8-year trial, narrowing group contrast.
  • Meta-analysis of 9 RCTs (2,618 patients): early mobilisation showed no benefit — OR 1.10 (0.94-1.29) for death/dependency.

Design

Study Type: Phase III pragmatic parallel-group randomized controlled trial

Randomization: 1

Blinding: Single-blind (blinded outcome assessors). Web-based stratified block randomization (average block size 6), stratified by site and NIHSS (mild 1-7, moderate 8-16, severe >16).

Enrollment Period: July 18, 2006 to October 16, 2014

Follow-up Duration: Primary: 3 months. Secondary: 12 months.

Centers: 56

Countries: UK, Australia, New Zealand, Malaysia, Singapore

Sample Size: 2104

Analysis: Intention-to-treat. Binary logistic regression adjusted for baseline NIHSS and age. Power: 80% to detect ≥7.1% absolute risk reduction.

Inclusion Criteria

  • Age ≥18 years with clinical diagnosis of first or recurrent stroke (infarct or ICH).
  • Admitted to hospital within 24 hours of stroke onset.
  • Admitted to acute stroke unit.
  • Able to react to verbal commands (minimum consciousness level).
  • Thrombolysis patients eligible if attending physician permitted mobilisation within 24h.

Exclusion Criteria

  • Prestroke mRS 3-5.
  • TIA.
  • Direct ICU admission, palliative decision, or need for immediate surgery.
  • Rapidly deteriorating disease (e.g., terminal cancer).
  • Lower limb fracture preventing mobilisation.
  • Concurrent recruitment to drug/intervention trials.
  • Unstable coronary/medical condition.
  • Unstable physiology: SBP <110 or >220, SpO2 <92%, HR <40 or >110, temp >38.5°C.

Baseline Characteristics

CharacteristicVEM (N=1,054)Usual Care (N=1,050)
Age mean (IQR)72.3 (62.3-80.3)72.7 (63.4-80.4)
Female411 (39%)407 (39%)
Hypertension707 (67%)717 (68%)
Diabetes239 (23%)228 (21%)
AF229 (22%)237 (23%)
NIHSS median (IQR)7 (4-12)7 (4-12)
NIHSS mild (1-7)592 (56%)578 (55%)
NIHSS moderate (8-16)315 (30%)328 (31%)
NIHSS severe (>16)147 (14%)144 (14%)
ICH142 (14%)116 (11%)
IV tPA247 (23%)260 (25%)
Premorbid mRS 0799 (76%)786 (75%)
First stroke878 (83%)843 (80%)
Time to randomization mean (IQR)18.2h (12.1-21.8)18.2h (12.5-21.8)

Arms

FieldVery Early Mobilisation (VEM)Control
InterventionOut-of-bed sitting, standing, walking within 24h of stroke onset. At least 3 additional sessions/day beyond usual care. Titrated to 4 functional levels (MSAS score). Max seated time 50 min/session for first 3 days. 5-step safety protocol before first mobilisation. Continued 14 days or until stroke unit discharge. Actual: TTFM 18.5h, 6.5 sessions/day, 31 min/day OOB.Standard stroke unit care per site discretion. Mobilisation not prescribed, only recorded. Actual: TTFM 22.4h, 3 sessions/day, 10 min/day OOB. 59% mobilised within 24h (vs 92% VEM).
Duration14 days or until dischargeStandard care

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Favourable outcome (mRS 0-2) at 3 monthsPrimary525/1,045 (50%)480/1,038 (46%)0.004
mRS ordinal shift at 3 monthsSecondary——Adjusted generalised OR 0.940.193
Walking 50m unassisted at 3 months (proportion)Secondary796 (76%)784 (75%)aOR 0.830.143
Time to walk 50m unassisted (median days)Secondary7 (6-8); n=10496 (5-7); n=1051aHR 1.040.459
Death at 3 months (case fatality)Secondary72 (7%)88/1048 (8%)OR 1.340.113
Non-fatal SAEs (incidence rate)Secondary≥1 in 20%≥1 in 19%IRR 0.880.194
AQoL at 12 months (median)Secondary0.49 (IQR 0.08-0.81)0.47 (IQR 0.07-0.81)Adjusted median difference -0.0040.865
Length of hospital stay (median days, acute + rehab)Secondary18 (IQR 6-43)16 (IQR 5-44)
Death at 3 monthsAdverse72 (7%)88/1048 (8%)OR 1.34 (0.93-1.93)0.113
Non-fatal SAEs (≥1 event, all categories)Adverse208 (20%)201 (19%)IRR 0.88 (0.72-1.07)0.194
Immobility-related SAEs (fatal + non-fatal; pulmonary embolism, DVT, UTI, pressure sores, pneumonia)Adverse53 (5%)54 (5%)IRR 0.92 (0.62-1.35)0.665
Neurological SAEs (fatal + non-fatal; stroke progression, recurrent stroke)Adverse83 (8%)107 (10%)IRR 1.26 (0.95-1.66)0.108
Stroke progression (total events)Adverse56 (5%)72 (7%)
Pneumonia (fatal cases contributing to death)Adverse1519
Recurrent stroke (fatal cases contributing to death)Adverse711

Subgroup Analysis

Prespecified subgroup analyses tended to favour UC across most main subgroups, though no interaction was statistically significant (all P>0.05). Key point estimates: mild NIHSS 1-7: OR 0.75 (0.57-0.98); moderate NIHSS 8-16: OR 0.76 (0.53-1.08); severe NIHSS >16 (prespecified, n=291): OR 0.35 (0.11-1.18); infarct: OR 0.77 (0.62-0.97); ICH: OR 0.48 (0.25-0.92) for favorable outcome and OR 3.21 (1.13-9.07) for death; rtPA-treated: OR 0.71 (0.46-1.09); TTFM <12h: OR 1.02 (0.62-1.68) — the only subgroup that was directionally neutral/slightly favouring VEM; TTFM 12-24h: OR 0.56 (0.42-0.75); TTFM >24h: OR 0.78 (0.42-1.43). (The '7% vs 35%' figure sometimes cited for severe stroke comes from an exploratory CART subset, not the prespecified severe-stroke subgroup.)

Criticisms

  • UC contamination: TTFM shortened 28 min/year (P=0.001) over 8-year trial; by end, ~2/3 UC patients mobilised within 24h.
  • Complex intervention difficult to standardize across 56 sites.
  • Unblinded treating staff could influence outcomes beyond mobilisation (attention, reassurance).
  • Physiological monitoring data limited in large pragmatic trial.
  • Subgroup interactions underpowered — ICH/severe stroke trends are hypothesis-generating.
  • Daily amount measured from physiotherapy only, may underestimate total OOB time.
  • Economic analysis not completed.

Funding

NIHR Health Technology Assessment programme (UK). Additional funding from National Health and Medical Research Council (NHMRC) Australia, Singapore Health, Chest Heart and Stroke Scotland, Northern Ireland Chest Heart and Stroke, and The Stroke Association (UK). NHMRC fellowship funding to Julie Bernhardt (1058635); Australian Research Council fellowship (0991086); National Heart Foundation Australia (G04M1571). The Florey Institute of Neuroscience and Mental Health (trial host) acknowledges support from the Victorian Government via the Operational Infrastructure Support Scheme.

Based on: AVERT (Health Technology Assessment (NIHR HTA monograph — full trial report; primary results also published in The Lancet 2015;386:46-55), 2017)

Authors: Langhorne P, Wu O, Rodgers H, ..., on behalf of the AVERT triallists' collaboration.

Citation: Langhorne P, Wu O, Rodgers H, Ashburn A, Bernhardt J. A Very Early Rehabilitation Trial after stroke (AVERT): a Phase III, multicentre, randomised controlled trial. Health Technol Assess 2017;21(54).

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