A Very Early Rehabilitation Trial (AVERT):

What we know, what we think and what’s

to come

The AVERT Trial Collaboration group

Joshua Kwant, Blinded Assessor

17th May 2016

NIMAST

Disclosure

• Nothing to disclose

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

Clinical hypotheses

1. Improve functional outcome (mRS 0-2) at 3 months 2. Lead to fewer immobility complications at 3 months post stroke 3. Lead to more patients regaining the ability to walk early 4. Improve quality of life at 12 months 5. Be cost effective

Eligibility

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 110-220 mmHG;

O2 sats > 92%; HR 40-110; temp <

38.2o; rouseable to voice

rtPA permitted

TIA

Mod – severe premorbid disability

Admitted directly to ICU

Unstable cardiac conditions, severe

heart failure

Progressive neurological conditions

For palliative care

Inclusion criteria Exclusion criteria

What was Very Early Mobilisation (VEM)?

• Out of bed, sitting, standing and walking, task specific activity – guided by a detailed protocol

• VEM had 4 levels of intervention, dependant on functional ability and adjusted or with recovery

Rehabilitation treatment package: 1) Time to first mobilisation, 2) frequency per day, 3) amount per day

Sitting out of bed: resting time in/out of bed not measured What VEM was not

With intervention monitoring we achieved significant differences between groups in each of the criteria: time, frequency, amount

Trial pathway

Stroke

Stratified by

stroke severity & site

Arrive hospital, screened, recruited <

24 hrs

12 month Ax

Very Early Mobilisation + Usual Care

First intervention, < 24 hrs PT /Nurse team, 6 days/wk

3 month Ax 1o outcome

1o Efficacy endpoint Favourable outcome (mRS 0-2)

Safety outcomes: death, SAEs, immobility, neurological

Day 14 Treatment ceases

Usual stroke unit care

Sample size, n=2104

3+ additional sessions out of bed activity

Key elements of 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

Methods: Key analyses

Efficacy 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

Bernhardt IJS 2015 Statistical Analysis Plan

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

Figure 1: Trial profile

Trial Performance

56 sites 5 countries: Australia New Zealand Malaysia Singapore UK

July 06 – October 14

Follow up complete in

2083 patients (99%)

VEM (n=1054)

Usual care

(n=1050)

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%)

Diabetes mellitus 239 (23%) 228 (21%)

Smoker 227 (22%) 204 (19%)

Atrial Fibrillation 229 (22%) 237 (23%)

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)

TACI 224 (21%) 232 (22%)

PACI 340 (32%) 328 (31%)

POCI 93 (9%) 106 (10%)

LACI 255 (24%) 268 (26%)

ICH 142 (14%) 116 (11%)

rtPA treatment, yes 247 (23%) 260 (25%)

Well balanced baseline characteristics

26% patients over 80 years

45% patients mod-severe stroke (NIHSS>7)

12% patients ICH 24% rtPA

Intervention achieved significant differences

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)

<0·000

1 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) <0·000

1 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) <0·000

1 21·0 (20–22·5)

Total amount per person

(mins over the intervention

period)

201·5 (108–340) 70 (32–130) <0·000

1 117 (107–128) * Minutes derived from physiotherapy data only

Time reduced by 28mins/year 95% CI 11·3–44·6, p=0·001

75% of all patients started out of bed activity <24 hours

9.2

8.7

19.5

19.3

21.5

18.2

20.9

22.9

12.2

13.5

9.9

8.8

6.9

8.4

Usual care

VEM

mRS=0 mRS=1 mRS=2 mRS=3 mRS=4 mRS=5 mRS=6

Favourable outcome (mRS 0-2)

480, 46%

525, 50%

OR 0.73, 95% CI 0.59–0.90, p=0.004

VEM

Usual care

9.2

8.7

19.5

19.3

21.5

18.2

20.9

22.9

12.2

13.5

9.9

8.8

6.9

8.4

Usual care

VEM

mRS=0 mRS=1 mRS=2 mRS=3 mRS=4 mRS=5 mRS=6

Assumption free ordinal analysis (GenOR 0.94, 95% CI 0.85–1.03, p=0.193)

Favourable outcome (mRS 0-2)

Time to walking 50 metres unassisted

0.0

00.2

50.5

00.7

51.0

0

1051 342 263 215 198 0VEM:

1049 359 276 231 200 0Usual care:

Number at risk

0 20 40 60 80 100Analysis time

Usual care VEM

Kaplan-Meier failure estimates

Days post stroke

Number of patients who had not achieved walking

Pro

po

rtio

n w

alk

ing

50

m u

nas

sis

ted

VEM Usual care

HR 1.04 95%CI0.94-1.15, p=0.459

UK

AUST/NZ

ASIA

Recruitment Region

>24h

12-24h

<12h

Time to firs t mobilisation

Yes

No

rtPA treated

Haemorrhage

Infarct

Stroke Type

Severe

Mod

Mild

Stroke Severity

>80

65-80

<65

Age

Subgroup

  601

1238

  244

  515

1194

  374

  503

1580

  255

1828

  291

  635

1157

  545

  924

  614

pts

No.

0.74 (0.51, 1.08)

0.73 (0.55, 0.96)

0.74 (0.40, 1.35)

0.78 (0.42, 1.43)

0.56 (0.42, 0.75)

1.02 (0.62, 1.68)

0.71 (0.46, 1.09)

0.74 (0.58, 0.94)

0.48 (0.25, 0.92)

0.77 (0.62, 0.97)

0.35 (0.11, 1.18)

0.76 (0.53, 1.08)

0.75 (0.57, 0.98)

0.76 (0.50, 1.14)

0.70 (0.52, 0.96)

0.74 (0.49, 1.11)

exp(b) (95% CI)

1 2.5 4.25 8.125

Favours UC Favours VEM

n OR

Favours Usual care Favours VEM

Outcome by subgroup (mRS 0-2)

No significant treatment by group interactions p>0.05

Safety VEM Usual Care Analysis

n (%) 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) p value

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

None 1000 (94·9%) 997 (95·0%)

0·92 (0·62–1·35) 0·665 1 50 (4·7%) 46 (4·4%)

2 4 (0·4%) 5 (0·5%)

3 0 (0%) 2 (0·2%)

≥4 0 (0%) 0 (0%)

Neurological SAEs

None 947 (89·9%) 967 (92·1%)

1·26 (0·95–1·66) 0·108 1 104 (9·9%) 78 (7·4%)

2 3 (0·3%) 4 (0·4%)

3 1 (0·1%) 1 (0·1%)

4 0 (0%) 0 (0%)

Main causes of death (64% of total) VEM UC Stroke progression 31 19 Pneumonia 19 15 Recurrent stroke 11 7

What ‘dose’ of mobilisation improves

outcome?

Pre-specified dose response analysis

of A Very Early Rehabilitation Trial

Julie Bernhardt, Leonid Churilov, Richard Lindley, Peter

Langhorne, Helen Dewey, Amanda Thrift, Marjorie Moodie,

Geoffrey Donnan on behalf of The AVERT Trial

Collaboration group

@AVERTtrial

Bernhardt et al IJS 2015 SAP

1. Regression models: Efficacy: intervention criteria, 3 months mRS (0-2), walking (% and time to walking), baseline NIHSS & age

Safety: intervention criteria, death, SAEs (immobility and neurological)

2. Classification and regression tree CART®

analyses

Prespecified dose response analysis – all patients, no group

Key intervention criteria: 1) Time to first mobilisation (hours after stroke onset) 2) Frequency, median sessions per day (nurse, PT data) 3) Amount activity out of bed, median minutes per day (PT only)

favourable outcome

(mRS 0–2)

Walking unassisted

Efficacy Odds ratio (95% CI)

p value

Binary Odds ratio (95%

CI)

p value

Cox Hazard ratio (95%

CI) p value

Time to first mobilisation (per extra hour)

0·99 (0·98–1·0) 0·036 1·0 (0·99–1·0) 0·40 0·99 (0·98–

0·99) <0·001

Frequency, median daily sessions (per one extra session)

1·13 (1·09–1·18)

<0·001

1·66 (1·53–1·80)

<0·001

1·10 (1·09–1·13)

<0·001

Daily amount, median (per extra 5 minutes)

0·94 (0·91–0·97)

<0·001

0·85 (0·81–0·89)

<0·001

0·96 (0·94–0·97)

<0·001

More frequent but lower dose

“keeping minutes of out of bed therapy and time to first mobilisation constant, increasing frequency of daily sessions improved the chance of a good outcome”.

13% improvement each additional session

favourable outcome

(mRS 0–2)

Walking unassisted

Efficacy Odds ratio (95% CI)

p value

Binary Odds ratio (95%

CI)

p value

Cox Hazard ratio (95%

CI) p value

Time to first mobilisation (per extra hour)

0·99 (0·98–1·0) 0·036 1·0 (0·99–1·0) 0·40 0·99 (0·98–

0·99) <0·001

Frequency, median daily sessions (per one extra session)

1·13 (1·09–1·18)

<0·001

1·66 (1·53–1·80)

<0·001

1·10 (1·09–1·13)

<0·001

Daily amount, median (per extra 5 minutes)

0·94 (0·91–0·97)

<0·001

0·85 (0·81–0·89)

<0·001

0·96 (0·94–0·97)

<0·001

More frequent but lower dose

66% improved odds

Deaths Non-fatal Serious Adverse Events

(SAEs)

Neurological SAEs Fatal/non-fatal

Binary Odds ratio

p value

Incident Rate Ratio (IRR)

p value

IRR p value

Time to first mobilisation (per extra hour)

0·99 (0·98–1·0)

0·07 1·0 (0·99–1·0) 0·71 1·0 (0·99–1·0) 0·45

Frequency, median daily sessions (per one extra session)

0·78 (0·7–0·88)

<0·001

0·99 (0·95–1·03)

0·55 0·89 (0·84–0·95)

0·001

Daily amount, median (per extra 5 minutes per day)

0·96 (0·89–1·04)

0·3 0·96 (0·93–0·99)

0·01 1·03 (0·99–1·08)

0·168

More frequent but lower dose

“keeping minutes of out of bed activity and time to first mobilisation constant, increasing frequency of daily sessions reduced the odds of death”.

80% did NOT have a non-fatal SAE, 90% patients did NOT have

a neurological SAE

What we know • Trial Protocol was met • Mobilisation within 24hrs was seen in both groups and is

safe- though more is not necessarily better. • Very early mobilisation may need to be more considered

especially in severe strokes or those with ICH • More frequent activity with lower duration may be of more

benefit in the first 24 hours, improving the chance of a favourable outcome and reducing the chance of dying

• This requires fundamental change to the organisation and method of therapy delivery in comparison with standard methods

• Large rehab studies are feasible and provide the best method of informing our care

What we think

• Possible physiological factors

• Possible psychological, emotional or other physical factors

• Possible organisational issues

• We don’t know

• Further study is needed to try and extract which components are feeding in to a poorer outcome in VEM

What’s to come

• AVERT DOSE- What does the future hold?

• Due in 2017 pending funding provision

• To examine the nursing and therapy hypotheses looking at optimal dose and frequency

• Further investigation based on current pending data analyses

• They need YOU!

• @AVERTtrial

• joshkwant@gmail.com

Publications Efficacy and safety of very early mobilisation within 24 h of stroke onset (AVERT): a randomised controlled trial http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60690-0/abstract

Prespecified dose-response analysis for A Very Early Rehabilitation Trial (AVERT) http://www.neurology.org/content/early/2016/02/17/WNL.0000000000002459.short

AVERT2 (a very early rehabilitation trial, a very effective reproductive trigger): retrospective observational analysis of the number of babies born to trial staff http://www.bmj.com/content/351/bmj.h6432.full

Exploring threats to generalisability in a large international rehabilitation trial (AVERT) http://bmjopen.bmj.com/content/5/8/e008378.full

Economic Evaluation Plan (EEP) for A Very Early Rehabilitation Trial (AVERT): An international trial to compare the costs and cost-effectiveness of commencing out of bed standing and walking training (very early mobilization) within 24 h of stroke onset with usual stroke unit care http://wso.sagepub.com/content/early/recent

Statistical Analysis Plan (SAP) for a Very Early Rehabilitation Trial (AVERT): An International Trial to Determine the Efficacy and Safety of Commencing out of Bed Standing and Walking Training (Very Early Mobilization) within 24 h of Stroke Onset vs. Usual Stroke Unit Care http://wso.sagepub.com/content/10/1/23.long

AVERT Collaboration