1. Jacqueline Ancliffe MCSP, MSc, FACP
A Very Early Rehabilitation Trial (AVERT): Primary outcome at 3 months post stroke
Jacqueline Ancliffe MCSP, MSc, FACP
on behalf of
The AVERT Trial Collaboration group
The AVERT Trial Collaboration Group. 56 hospitals in five countries. Australia, New Zealand, Singapore, Malaysia, United Kingdom

2. AVERT: A pragmatic, ‘real world’ trial
Design
International, multicentre, parallel group, randomised controlled trial testing efficacy and safety of a very early (<24h) frequent, higher dose out of bed (very early mobilisation) protocol compared to usual care post stroke.
Protocol Bernhardt IJS 2006; Bernhardt IJS 2015 SAP

3. Clinical hypotheses Early rehab delivered by a PT/nurse team will:
Improve functional outcome (mRS 0-2) at 3 months
Lead to fewer immobility complications at 3 months post stroke
Lead to more patients regaining the ability to walk early
Results in better quality of life at 12 months
Be cost effective
12 month outcomes
Bernhardt et al 2015 The Lancet

4. Eligibility Inclusion criteria Exclusion criteria TIA
Confirmed stroke (first / recurrent, IS/ICH)
Less than 24 hrs symptom onset
Age > 18 years, no upper limit
Physiological parameters within set limits: Systolic BP mmHG; O2 sats > 92%; HR ; temp < 38.2o; rouseable to voice
rtPA permitted
Inclusion criteria
TIA
Mod – severe premorbid disability
Admitted directly to ICU
Unstable cardiac conditions, severe heart failure
Progressive neurological conditions
For palliative care
Exclusion criteria

5. 3+additional out of bed sessions/day
Trial pathway
Sample size, n=2104
3+additional out of bed sessions/day
Very Early Mobilisation + Usual Care
Arrive hospital, screened, recruited < 24 hrs
First intervention, < 24 hrs PT /Nurse team, 6 days/wk
Day 14 Treatment ceases
3 month Ax 1o outcome
12 month Ax
Stroke
Stratified by
stroke severity & site
1o Efficacy endpoint Favourable outcome (mRS 0-2)
Safety outcomes: death, SAEs, immobility, neurological
Usual care until discharge
Critical elements of VEM protocol:
commenced within 24 hours
focus on ‘out of bed’ mobilisation activities, and
provided at least three additional (to UC) out of bed sessions per day
Continued for 14 days or until discharge from stroke unit care
Visit by blinded assessor or telephone to assess:
mRS
SAEs
Barthel Index
Rivermead
Irritability, depression and anxiety (IDA) scale
Assessment of Quality of Life (AQoL)
Montreal Cognitive Assessment (MoCA)
Comprehensive cost questionnaire

6. Methods: Key analyses Efficacy Safety
Primary: Favourable outcome mRS 0-2
Secondary: Assumption free ordinal shift analysis
Time to walking unassisted 50 metres
Exploratory: Subgroups – age (<65; 65–79; >80), stroke severity (mild: NIHSS<7; moderate: 8–16; and severe: >16), stroke type (infarct, haemorrhage), rtPA, time to first mobilisation (<12 h; 12–24 h; >24 h)
Safety
Death at 3 months
Serious adverse events with separate review of immobility-related, neurological
Dose of intervention (time to start, frequency, amount)
Change in dose over time
Adjusted for age and baseline NIHSS
Bernhardt IJS 2015 Statistical Analysis Plan

7. Follow up complete in 2083 patients
Trial Performance
25,237 admitted <24 hours of stroke onset
1054 very early mobilisation
23,133 ineligible
5588 premorbid mRS>2
1136 other clinical trial
7080 medically unstable/unwell
7414 no recruiter/weekend
8151 other exclusion reason
446 refused
2104 enrolled
12 never mobilised
21 not stroke
2104 randomised
1050 usual care
14 never mobilised
13 not stroke
1038 assessed at 3 months
950 alive
88 dead
6 unknown
10 refused follow up
1045 assessed at 3 months
973 alive
72 dead
5 refused follow up
1054 included in intention-to-treat primary analysis
1050 included in intention-to-treat primary analysis
July 06 – October 14
56 sites
5 countries:
Australia
New Zealand
Malaysia
Singapore UK
Follow up complete in 2083 patients
(99%)
Figure 1: Trial profile

8. Baseline characteristics
VEM (n=1054)
Usual care (n=1050)
Recruitment region
Australia/New Zealand
617 (59%)
626 (60%)
Asia
126 (12%)
125 (12%) UK
311 (29%)
299 (28%)
Patient Details
Age (Median, IQR)
72·3 (62·3, 80·3)
72·7 (63·4, 80·4)
Female
411 (39%)
407 (39%)
Risk Factors
Hypertension
707 (67%)
717 (68%)
Ischaemic Heart Disease
235 (22%)
251 (24%)
Hypercholesterolaemia
419 (40%)
423 (40%)
Diabetes mellitus
239 (23%)
228 (21%)
Smoker
227 (22%)
204 (19%)
Atrial Fibrillation
229 (22%)
237 (23%)
Premorbid history
Living at home at time of admission
1038 (99%)
1036 (99%)
Time to randomisation (hours)
Median (IQR)
18·2 (12·1–21·8)
18·2 (12·5–21·8)
Stroke history
First Stroke
878 (83%)
843 (80%)
NIHSS Score, Median (IQR)
 7 (4–12)
7 (4–12)
Mild (1–7)
592 (56%)
578 (55%)
Moderate (8–16)
315 (30%)
328 (31%)
Severe (> 16)
147 (14%)
144 (14%)
Stroke type (Oxfordshire Classification)
TACI
224 (21%)
232 (22%)
PACI
340 (32%)
POCI
93 (9%)
106 (10%)
LACI
255 (24%)
268 (26%)
ICH
142 (14%)
116 (11%)
rtPA treatment
247 (23%) 
 260 (25%)
Baseline characteristics
26% patients over age of 80 years
45% patients mod-severe stroke (NIHSS>7)
31% <65years, premorbid mRS 1 or 2 (VEM 24%; US 25%)
86% walking independently witout aide VEM, 88% UC
24% rtPA

9. Intervention achieved significant differences
Time reduced by 28mins/year
95% CI 11·3–44·6, p=0·001
VEM
Usual Care
median, IQR
n=1054
n=1050
p value
median shift (95% CI)
Time to first mobilisation (hrs)
18·5 (12·8–22·3)
22·4 (16·5–29·3)
<0·0001
4·8 (4·1–5·7)
n=1042; missing*=12
n=1036; missing*=14
Frequency per person
(median daily sessions
of out of bed activity)
6·5 (4·0–9·5)
3 (2·0–4·5)
3 (3–3·5)
Daily amount per person*
(median minutes per day
spent in out of bed activity)
31 (16·5–50·5)
10 (0–18)
21·0 (20–22·5)
Total amount per person
(mins over the intervention period)
201·5 (108–340)
70 (32–130)
117 (107–128)
75% of all patients started out of bed activity <24 hours
85,000 episodes of care recorded
NOT sitting out of bed
* Minutes derived from physiotherapy data only

10. Favourable outcome (mRS 0-2)
480, 46%
OR 0.73, 95% CI 0.59–0.90, p=0.004
525, 50%

11. Favourable outcome (mRS 0-2)
Assumption free ordinal analysis (GenOR 0.94, 95% CI 0.85–1.03, p=0.193)

12. Time to walking 50 metres unassisted
Days post stroke
Number of patients who had not achieved walking
Proportion walking 50m unassisted
VEM
Usual care
HR %CI , p=0.459

13. Outcome by subgroup (mRS 0-2)n OR
Favours Usual care Favours VEM
Outcome by subgroup (mRS 0-2)
No significant treatment by group interactions p>0.05
None of the individual subgroup analyses revealed a significant treatment by subgroup interaction: p>0.05

14. (Adjusted baseline NIHSS, age)
Safety
VEM
Usual Care
Analysis
n (%)
(Adjusted baseline NIHSS, age)
N=1048
N=1050
OR (95% CI)
p value
Death
88 (8·4%)
72 (6·9%)
1·34 (0·93–1·93)
0·113
Non-fatal SAEs
IRR (95% CI)
None
853 (80·9%)
842 (80·2%)
0·88 (0·72–1·07)
0·194 1
157 (14·9%)
146 (13·9%) 2
32 (3·0%)
41 (3·9%) 3
10 (1·0%)
16 (1·5%) 4
2 (0·2%)
4 (0·4%) 5
0 (0%)
1 (0·1%)
Immobility SAEs
1000 (94·9%)
997 (95·0%)
0·92 (0·62–1·35)
0·665
50 (4·7%)
46 (4·4%)
5 (0·5%) ≥4
Neurological SAEs
947 (89·9%)
967 (92·1%)
1·26 (0·95–1·66)
0·108
104 (9·9%)
78 (7·4%)
3 (0·3%)
Main causes of death (64% of total)
VEM UC
Stroke progression
Pneumonia
Recurrent stroke
Analyses are adjusted for age and baseline NIHSS

15. Conclusions (1)
1. Meeting protocol is a key challenge in rehabilitation trials
We achieved a significant difference in the frequency, amount and timing of rehabilitation
2. The very early, higher dose out of bed activity protocol reduced the odds of favourable outcome, without accelerating walking recovery or reducing immobility-related SAEs
‘more is better’ may not apply in the first few days after stroke
3. There were low rates of death or serious adverse events, with non-significant differences that suggests signals of harm in ICH and severe stroke
Treatment dose versus benefits/harms warrants further exploration

16. Conclusions (2)
The high quality data in this international trial provides the best opportunity yet to determine the best pattern of rehabilitation.
The interventions delivered in this trial are ‘complex’.
We have shown the world that these trials are feasible
Further exploration will help underpin clinical practice guidelines
Understanding the components that lead to benefit or harm is a priority, pre-specified dose-response analyses important

18. AVERT
Collaboration

19. AVERT Royal Perth Hospital Team

20. AVERT (a very early rehabilitation trial, a very effective reproductive trigger): retrospective observational analysis of the number of babies born to staff
Absences owing to parental leave led to delayed recruitment and increased costs
Implications for future trials

21. Further acknowledgements:
Volunteer committees: Steering Committee, Data Safety and Monitoring Committee, Outcomes Committee
Funding: The National Health and Medical Research Council (NHMRC) of Australia. Chest Heart and Stroke Scotland, Northern Ireland Chest Heart and Stroke, Singapore Health, The Stroke Association, UK, the National Institute of Health Research, UK