A Very Early Rehabilitation Trial (AVERT): What we know, what we think and what s to come

Transcription

1 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 17 th May 2016 NIMAST

2 Nothing to disclose Disclosure

3 Design AVERT: A pragmatic, real world trial 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. 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 Protocol Bernhardt IJS 2006; Bernhardt IJS 2015 SAP

4 Eligibility Inclusion criteria 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; O 2 sats > 92%; HR ; temp < 38.2 o ; rouseable to voice Exclusion criteria TIA Mod severe premorbid disability Admitted directly to ICU Unstable cardiac conditions, severe heart failure Progressive neurological conditions For palliative care rtpa permitted

5 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 What VEM was not Sitting out of bed: resting time in/out of bed not measured With intervention monitoring we achieved significant differences between groups in each of the criteria: time, frequency, amount

6 Sample size, n=2104 Trial pathway Very Early Mobilisation + Usual Care 3+ additional sessions out of bed activity Arrive hospital, screened, recruited < 24 hrs First intervention, < 24 hrs PT /Nurse team, 6 days/wk Stroke Day 14 Treatment ceases 3 month Ax 1 o outcome 12 month Ax Stratified by stroke severity & site Usual stroke unit care 1 o Efficacy endpoint Favourable outcome (mrs 0-2) Safety outcomes: death, SAEs, immobility, neurological

7 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

8 Bernhardt IJS 2015 Statistical Analysis Plan 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; 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

9 Trial Performance July 06 October sites 5 countries: Australia New Zealand Malaysia Singapore UK 1054 very early mobilisation 25,237 admitted <24 hours of stroke onset 2104 enrolled 2104 randomised 14 never mobilised 13 not stroke 1050 usual care 23,133 ineligible 5588 premorbid mrs> other clinical trial 7080 medically unstable/unwell 7414 no recruiter/weekend 8151 other exclusion reason 446 refused 12 never mobilised 21 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 Follow up complete in 2083 patients (99%) 1054 included in intention-totreat primary analysis 1050 included in intention-totreat primary analysis

10 Well balanced baseline characteristics 26% patients over 80 years 45% patients mod-severe stroke (NIHSS>7) 12% patients ICH Usual care VEM (n=1054) (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 ( ) 18 2 ( ) 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%) 24% rtpa

11 Intervention achieved significant differences VEM Usual Care median, IQR n=1054 n=1050 p value Time to first mobilisation (hrs) 18 5 ( ) 22 4 ( ) n=1042; n=1036; missing=12 missing=14 Frequency per person (median daily sessions of out of bed activity) Daily amount per person* (median minutes per day spent in out of bed activity) 6 5 ( ) 3 ( ) 31 ( ) 10 (0 18) median shift (95% CI) < ( ) < < (3 3 5) 21 0 ( ) Total amount per person 75% of all patients Time started reduced <0 000 out by 28mins/year (mins * Minutes over the derived intervention from physiotherapy ( ) data only of bed 70 activity (32 130) <24 95% hours CI , 117 p=0 001 ( ) 1 period)

12 Favourable outcome (mrs 0-2) mrs=0 mrs=1 mrs=2 mrs=3 mrs=4 mrs=5 mrs=6 VEM VEM , % OR 0.73, 95% CI , p=0.004 Usual care Usual care , %

13 Favourable outcome (mrs 0-2) mrs=0 mrs=1 mrs=2 mrs=3 mrs=4 mrs=5 mrs=6 VEM Usual care Assumption free ordinal analysis (GenOR 0.94, 95% CI , p=0.193)

14 Proportion walking 50m unassisted Time to walking 50 metres unassisted Kaplan-Meier failure estimates VEM Usual care HR %CI , p=0.459 Number at risk Usual care: VEM: Days Analysis post time stroke Number of patients Usual who care had not achieved VEM walking

15 Outcome by subgroup (mrs 0-2) Subgroup Age <65 No. n pts 614 OR exp(b) (95% CI) 0.74 (0.49, 1.11) (0.52, 0.96) > (0.50, 1.14) Stroke Severity Mild 1157 Mod 635 Severe (0.57, 0.98) 0.76 (0.53, 1.08) 0.35 (0.11, 1.18) No significant treatment by group interactions p>0.05 Stroke Type Infarct 1828 Haemorrhage 255 rtpa treated No 1580 Yes 503 Time to first mobilisation <12h h 1194 >24h (0.62, 0.97) 0.48 (0.25, 0.92) 0.74 (0.58, 0.94) 0.71 (0.46, 1.09) 1.02 (0.62, 1.68) 0.56 (0.42, 0.75) 0.78 (0.42, 1.43) Recruitment Region ASIA 244 AUST/NZ 1238 UK (0.40, 1.35) 0.73 (0.55, 0.96) 0.74 (0.51, 1.08) Favours Usual care Favours VEM Favours UC Favours VEM

16 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 ( ) Non-fatal SAEs IRR (95% CI) p value None 853 (80 9%) 842 (80 2%) (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%) 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 0 88 ( ) Main causes of death (64% of total) VEM UC Stroke progression Pneumonia Recurrent stroke ( ) None 947 (89 9%) 967 (92 1%) (9 9%) 78 (7 4%) 2 3 (0 3%) 4 (0 4%) 3 1 (0 1%) 1 (0 1%) 4 0 (0%) 0 (0%) 1 26 ( ) 0 108

17 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

18 Bernhardt et al IJS 2015 SAP 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) 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

19 More frequent but lower dose Efficacy Time to first mobilisation (per extra hour) Frequency, median daily sessions (per one extra session) Daily amount, median (per extra 5 minutes) favourable outcome (mrs 0 2) Odds ratio (95% CI) Binary Odds p ratio (95% value CI) p value 0 99 ( ) ( ) ( ) 0 94 ( ) < < ( ) 0 85 ( ) Walking unassisted Cox Hazard ratio (95% CI) 0 99 ( ) 13% improvement <0 00 each additional 1 10 (1 09 session ) < ( ) p value <0 001 <0 001 <0 001 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.

20 Efficacy Time to first mobilisation (per extra hour) Frequency, median daily sessions (per one extra session) Daily amount, median (per extra 5 minutes) More frequent but lower dose favourable outcome (mrs 0 2) Odds ratio (95% CI) Binary Odds p ratio (95% value CI) p value 0 99 ( ) ( ) ( ) 0 94 ( ) < < ( ) 0 85 ( ) < < % improved odds Walking unassisted Cox Hazard ratio (95% CI) 0 99 ( ) 1 10 ( ) 0 96 ( ) p value <0 001 <0 001 <0 001

21 More frequent but lower dose Time to first mobilisation (per extra hour) Frequency, median daily sessions (per one extra session) Daily amount, median (per extra 5 minutes per day) Deaths Non-fatal Serious Adverse Events (SAEs) Binary Odds p Incident Rate p ratio 0 99 ( ) 0 78 ( ) 0 96 ( ) Neurological SAEs Fatal/non-fatal IRR p value Ratio (IRR) value value ( ) ( ) 0 45 < ( ) ( ) ( ( ) 1 08) 80% did NOT have a non-fatal SAE, 90% patients did NOT have a neurological SAE keeping minutes of out of bed activity and time to first mobilisation constant, increasing frequency of daily sessions reduced the odds of death.

22 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

23 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

24 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 joshkwant@gmail.com

25 Publications Efficacy and safety of very early mobilisation within 24 h of stroke onset (AVERT): a randomised controlled trial Prespecified dose-response analysis for A Very Early Rehabilitation Trial (AVERT) AVERT 2 (a very early rehabilitation trial, a very effective reproductive trigger): retrospective observational analysis of the number of babies born to trial staff Exploring threats to generalisability in a large international rehabilitation trial (AVERT) 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 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

26 AVERT Collaboration