A Very Early Rehabilitation Trial (AVERT) main results ...

A Very Early Rehabilitation Trial (AVERT) main results ...

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 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. Clinical hypotheses Early rehab delivered by a PT/nurse team will: 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. Results in better quality of life at 12 months 12 month outcomes 5. Be cost effective Bernhardt et al 2015 The Lancet Eligibility Exclusion criteria 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 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 Sample size, n=2104 Trial pathway 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 Stroke 3+additional out of bed sessions/day 3 month Ax 1o outcome 12 month Ax Stratified by stroke severity & site

Usual care until discharge 1o Efficacy endpoint Favourable outcome (mRS 0-2) Safety outcomes: death, SAEs, immobility, neurological 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; 6579; >80), stroke severity (mild: NIHSS<7; moderate: 816; and severe: >16), stroke type (infarct, haemorrhage), rtPA, time to first mobilisation (<12 h; 1224 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 Trial Performance 25,237 admitted <24 hours of stroke onset 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

July 06 October 14 2104 enrolled 56 sites 5 countries: Australia New Zealand Malaysia Singapore UK 2104 randomised 1054 very early mobilisation 1050 usual care 14 never mobilised 13 not stroke 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 1054 included in intention-totreat primary analysis 1050 included in intention-totreat primary analysis

Follow up complete in 2083 patients (99%) Baseline characteristics 26% patients over age of 80 years 45% patients mod-severe stroke (NIHSS>7) Recruitment region Australia/New Zealand Asia UK Patient Details Age (Median, IQR) Female Risk Factors Hypertension Ischaemic Heart Disease Hypercholesterolaemia Diabetes mellitus Smoker Atrial Fibrillation Premorbid history Living at home at time of admission Time to randomisation (hours) Median (IQR) Stroke history First Stroke NIHSS Score, Median (IQR) Mild (17) Moderate (816)

Severe (> 16) Stroke type (Oxfordshire Classification) TACI PACI POCI LACI ICH rtPA treatment VEM (n=1054) Usual care (n=1050) 617 (59%) 126 (12%) 311 (29%) 626 (60%) 125 (12%) 299 (28%) 723 (623, 803) 411 (39%) 727 (634, 804) 407 (39%) 707 (67%) 235 (22%) 419 (40%) 239 (23%) 227 (22%) 229 (22%) 717 (68%) 251 (24%) 423 (40%) 228 (21%)

204 (19%) 237 (23%) 1038 (99%) 1036 (99%) 182 (121218) 182 (125218) 878 (83%) 7 (412) 592 (56%) 315 (30%) 147 (14%) 843 (80%) 7 (412) 578 (55%) 328 (31%) 144 (14%) 224 (21%) 340 (32%) 93 (9%) 255 (24%) 142 (14%) 247 (23%) 232 (22%) 328 (31%) 106 (10%) 268 (26%) 116 (11%) 260 (25%) 24% rtPA

Intervention achieved significant differences median, IQR VEM n=1054 Time to first mobilisation (hrs) 185 (128223) Usual Care n=1050 p value median shift (95% CI) 224 (165293) <00001 48 (4157) n=1042; missing*=12 n=1036; missing*=14 Frequency per person (median daily sessions of out of bed activity) 65 (4095) 3 (2045) <00001 3 (335) 31 (165505)

10 (018) <00001 210 (20225) 2015 (108340) 70 (32130) <00001 117 (107128) Daily amount per person* (median minutes per day spent in out of bed activity) Total amount per person (mins over the intervention period) 75% of all patients Timestarted reduced outby 28mins/year * Minutes derived from physiotherapy data only of bed activity <24 95%hours CI 113446, p=0001 Favourable outcome (mRS 0-2) mRS=0 mRS=1 VEM 8.7 mRS=2

mRS=3 19.3 18.2 480, 46% mRS=4 22.9 mRS=5 13.5 mRS=6 8.8 8.4 OR 0.73, 95% CI 0.590.90, p=0.004 Usual care 9.2 19.5 50% 21.5 525, 20.9 12.2 9.9 6.9 Favourable outcome (mRS 0-2) mRS=0

mRS=1 mRS=2 VEM 8.7 19.3 Usual care 9.2 19.5 mRS=3 18.2 21.5 mRS=4 22.9 20.9 mRS=5 13.5 12.2 mRS=6 8.8 8.4 9.9 6.9

Assumption free ordinal analysis (GenOR 0.94, 95% CI 0.851.03, p=0.193) Time to walking 50 metres unassisted 0.75 0.25 0.50 VEM Usual care HR 1.04 95%CI0.94-1.15, p=0.459 0.00 Proportion walking 50m unassisted 1.00 Kaplan-Meier failure estimates 0 20 Analysis time 60 80 100 200 198 0

0 Days post stroke Number at risk Usual care: 1049 VEM: 1051 40 359 342 276 263 Usual care 231 215 VEM Number of patients who had not achieved walking Outcome by subgroup (mRS 0-2) No. pts n Subgroup exp(b) (95% CI) OR

Age <65 614 0.74 (0.49, 1.11) 65-80 924 0.70 (0.52, 0.96) >80 545 0.76 (0.50, 1.14) Mild 1157 0.75 (0.57, 0.98) Mod 635 0.76 (0.53, 1.08) Severe 291 0.35 (0.11, 1.18) 1828

0.77 (0.62, 0.97) 255 0.48 (0.25, 0.92) No 1580 0.74 (0.58, 0.94) Yes 503 0.71 (0.46, 1.09) Stroke Severity Stroke Type Infarct Haemorrhage No significant treatment by group interactions p>0.05 rtPA treated Time to first mobilisation <12h 12-24h >24h 374

1.02 (0.62, 1.68) 1194 0.56 (0.42, 0.75) 515 0.78 (0.42, 1.43) Recruitment Region ASIA AUST/NZ UK 244 0.74 (0.40, 1.35) 1238 0.73 (0.55, 0.96) 601 0.74 (0.51, 1.08) .125 .25 .5 Favours UC care Favours Usual

1 2 4 8 Favours VEM Favours VEM Safety Death Non-fatal SAEs None 1 2 3 4 5 Immobility SAEs None 1 2 3 4 Neurological SAEs None 1 2 3 4 VEM Usual Care

Analysis n (%) n (%) (Adjusted baseline NIHSS, age) N=1048 N=1050 OR (95% CI) 88 (84%) 72 (69%) 134 (093193) 0113 IRR (95% CI) p value 0194 853 (809%) 157 (149%) 32 (30%) 10 (10%) 2 (02%) 0 (0%) 842 (802%) 146 (139%)

41 (39%) 16 (15%) 4 (04%) 1 (01%) 088 (072107) 947 (899%) 104 (99%) 3 (03%) 1 (01%) 0 (0%) 967 (921%) 78 (74%) 4 (04%) 1 (01%) 0 (0%) 126 (095166) p value Main causes of death (64% of total) UC 1000 (949%) 997 (950%) VEM 50 (47%)progression 46 (44%) Stroke 31 19 092 (062135) 0665 4 (04%) 5 (05%) Pneumonia 19 15

0 (0%) 2 (02%) 0 (0%) 0 (0%) Recurrent stroke 11 7 0108 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 nonsignificant differences that suggests signals of harm in ICH and severe stroke Treatment dose versus benefits/harms warrants further exploration Conclusions (2) 1. The high quality data in this international trial provides the best opportunity yet to determine the best pattern of rehabilitation. Further exploration will help underpin clinical practice guidelines 2. The interventions delivered in this trial are complex. Understanding the components that lead to benefit or harm is a priority, pre-specified dose-response analyses important 3. We have shown the world that these trials are feasible AVERT Collaboratio n AVERT Royal Perth Hospital Team 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 http://www.bmj.com/content/351/bmj.h6432.full 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

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