What can we learn from the AVERT trial (so far)?

Transcription

1 South West Stroke Network Event, 29 th April, 2015 What can we learn from the AVERT trial (so far)? Peter Langhorne, Professor of stroke care, Glasgow University

2 Disclosure PL was AVERT investigator and grant-holder Slides provided by; Julie Bernhardt (Melbourne) Terry Quinn (Glasgow)

3 Acknowledgements: Management, Steering Committee, Data Monitoring Committee and 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

4 AVERT Collaboration

5 A Very Early Rehabilitation Trial

6 Acknowledged Value of Evidence from RCTS To inform practice

7 Early mobilisation is recommended to prevent complications Early mobilization, should be considered for (acute stroke) patients Rehabilitation should start as early as possible once medical stability is reached Patients should be mobilised as early and frequently as possible

8 Early mobilisation is recommended to prevent complications Early mobilization, should be considered for (acute stroke) patients No Grade 1A evidence Rehabilitation should start as early as possible once medical stability is reached Patients should be mobilised as early and frequently as possible

9 Australia Versus Europe Recruitment Targets

10 2104 participants recruited Complete follow up centres 8 countries

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12 Anxious & Vexed about Explaining these Results to our Therapists

13 A Very Early Rehabilitation Trial (AVERT): Primary outcome at 3 months post stroke Peter Langhorne on behalf of the AVERT Trial Collaboration group 29 April 2015 Exeter, UK

14 Protocol Bernhardt IJS 2006; Bernhardt IJS 2015 SAP 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 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

15 Protocol Bernhardt IJS 2006; Bernhardt IJS 2015 SAP 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 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

16 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 rtpa permitted TIA Exclusion criteria Mod severe premorbid disability Admitted directly to ICU Unstable cardiac conditions, severe heart failure Progressive neurological conditions For palliative care

17 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

18 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

19 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 1054 included in intention-totreat primary analysis 1045 assessed at 3 months 973 alive 72 dead 5 refused follow up 1050 included in intention-totreat primary analysis Follow up complete in 2083 patients (99%)

20 Very high quality data 99% of patient followed up to 3 months Face to face visits, >95% cases, very dedicated assessors Outcomes adjudication by expert panel for all SAEs Intervention compliance monitoring & feedback Intervention guided by a detailed protocol, 4 levels of intervention, adjusted with recovery Key intervention criteria: 1) Time to first mobilisation, 2) Frequency per day, 3) Amount (time) per day out of bed activity

21 Well balanced baseline characteristics 26% patients over 80 years 45% patients mod-severe stroke (NIHSS>7) 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%) 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%) 12% patients ICH 24% rtpa

22 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 ( ) 22 4 ( ) < ( ) 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) n=1042; missing=12 n=1036; missing= ( ) 3 ( ) < (3 3 5) 31 ( ) 10 (0 18) < ( ) Total amount per person (mins over the intervention period) ( ) 70 (32 130) < ( ) * Minutes derived from physiotherapy data only

23 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 ( ) 22 4 ( ) < ( ) 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) n=1042; missing=12 n=1036; missing= ( ) 3 ( ) < (3 3 5) 31 ( ) 10 (0 18) < ( ) Total amount per person (mins over the intervention period) ( ) 70 (32 130) < ( ) * Minutes derived from physiotherapy data only 75% of all patients started out of bed activity <24 hours

24 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 ( ) 22 4 ( ) < ( ) 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) n=1042; missing=12 n=1036; missing= ( ) 3 ( ) < (3 3 5) 31 ( ) 10 (0 18) < ( ) Total amount per person (mins over the intervention period) ( ) 70 (32 130) < ( ) * Minutes derived from physiotherapy data only Time reduced by 28mins/year 95% CI , p=0 001

25 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 %

26 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 %

27 Assumption free ordinal analysis Not significant - GenOR 0.94, 95% CI , p=0.193 mrs=0 mrs=1 mrs=2 mrs=3 mrs=4 mrs=5 mrs=6 VEM Usual care

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

29 Outcome by subgroup (mrs 0-2) Subgroup Age < No. n pts OR exp(b) (95% CI) 0.74 (0.49, 1.11) 0.70 (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).125 Favours Usual UCcare Favours Favours VEM VEM

30 Outcome by subgroup (mrs 0-2) Subgroup Age < No. n pts OR exp(b) (95% CI) 0.74 (0.49, 1.11) 0.70 (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).125 Favours Usual UCcare Favours Favours VEM VEM

31 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%) 0 88 ( ) (1 0%) 16 (1 5%) 4 Main 2 (0 2%) causes 4 of (0 4%) death (64% of total) 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 VEM UC Stroke progression Pneumonia Recurrent stroke 11 7 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%) 0 92 ( ) ( ) 0 108

32 Conclusions (1) 1. Meeting protocol is a key challenge in rehabilitation trial 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 Treatment dose versus benefits/harms warrants further exploration

33 Conclusions (1) 1. Meeting protocol is a key challenge in rehabilitation trial 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 Treatment dose versus benefits/harms warrants further exploration

34 Conclusions (1) 1. Meeting protocol is a key challenge in rehabilitation trial 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 Treatment dose versus benefits/harms warrants further exploration

35 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 We are presenting further results on Sunday The Lancet

36 A Veto on all Early Rehabilitation Therapy?

37 AVERT Values, Explanation Requires some Thought

38 Non-efficacy External validity Fidelity Contamination Power

39 Non-efficacy External validity Fidelity Contamination Power

40 Non-efficacy No upper age limit age > 80 (26%) tpa allowed NIHSS 7 (4-12) NIHSS >16 (14%) External validity Fidelity Contamination Power

41 Non-efficacy External validity Time to mobilisation 18.2 hours Fidelity Contamination Power

42 Non-efficacy External validity Time to mobilisation 18.2 hours Fidelity Contamination Power Time to mobilisation 22.4 hours

43 Therapy delivered Subgroup No. n pts Effect (95% CI) ES 95% CI Age < (-4.60, -1.90) (-5.00, -3.00) > (-5.78, -2.22) Stroke Severity Mild (-3.01, -1.31) Mod (-7.17, -4.49) Severe (-11.50, -6.66) Stroke Type Infarct (-4.67, -2.93) Haemorrhage (-7.02, -1.98) rtpa treated No (-4.83, -2.83) Yes (-4.85, -2.31) Recruitment Region ASIA (-2.72, 0.72) AUST/NZ (-5.50, -3.66) UK (-4.02, -1.14) Favours VEM Favours usual care Time to first mobilisation (hours) Subgroup Age < >80 Stroke Severity Mild Mod Severe Stroke Type Infarct Haemorrhage 258 rtpa treated No Yes Time to first mobilisation <12h 12-24h >24h Recruitment Region ASIA AUST/NZ UK No. pts n Effect (95% CI) ES 95% CI 4.50 (3.55, 5.45) 3.50 (2.53, 4.47) 2.50 (1.54, 3.46) 4.00 (3.05, 4.95) 3.00 (2.04, 3.96) 2.00 (1.10, 2.90) 4.00 (3.06, 4.94) 3.00 (2.01, 3.99) 4.00 (3.06, 4.94) 3.00 (2.04, 3.96) 3.50 (2.46, 4.54) 3.50 (2.53, 4.47) 1.50 (0.18, 2.82) 4.00 (2.50, 5.50) 3.50 (2.54, 4.46) 3.00 (2.04, 3.96) Favours usual care Favours VEM Frequency, median daily sessions of out of bed activity The Lancet online - supplement

44 No. Therapy delivered Subgroup pts n ES 95% CI Effect (95% CI) Subgroup No. n pts ES 95% CI Effect (95% CI) Age Age < (24.50, 31.50) < (125.69, ) (17.05, 22.95) (127.84, ) > (11.51, 17.49) > (83.60, ) Stroke Severity Stroke Severity Mild (23.04, 26.96) Mild (118.98, ) Mod (18.96, 25.04) Mod (120.70, ) Severe (7.45, 17.55) Severe (38.51, ) Stroke Type Stroke Type Infarct (21.02, 22.98) Infarct (120.99, ) Haemorrhage (15.52, 24.48) Haemorrhage (104.38, ) rtpa treated rtpa treated No (20.03, 22.97) No (124.00, ) Yes (15.98, 24.02) Yes (100.48, ) Time to first mobilisation Time to first mobilisation <12h (14.76, 24.24) <12h (103.40, ) 12-24h (20.95, 25.05) 12-24h (131.66, ) >24h (5.66, 16.34) >24h (54.62, ) Recruitment Region Recruitment Region ASIA (23.48, 33.52) ASIA (150.25, ) AUST/NZ (21.02, 24.98) AUST/NZ (129.97, ) UK (12.54, 17.46) UK (63.59, ) -25 Favours usual care Favours VEM Daily amount, median mins per day in out of bed activity Favours usual care Favours VEM Total amount, mins over the intervention period The Lancet online - supplement

45 Non-efficacy External validity Time to mobilisation 18.2 hours Fidelity Contamination Power Sample size calculation based on estimated 7% difference Time to mobilisation 22.4 hours

46 Bernhardt IJS 2015 SAP So how do we unpack this? 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) Regression models: eg. Efficacy 3 dose characteristics as independent variables, 3 months mrs outcome (dichotomized mrs 0-2 favourable outcome vs mrs 3-6 as poor outcome) as the dependent variable, adjusted for baseline NIHSS and age Classification and regression tree CART analyses

47 Unpublished data

48 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. Better outcomes seen with short, frequent mobilisations in the early phase after stroke (more likely to regain independence) 3. We need to characterise the optimal patterns of mobilisation for these patients

49 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. Exploration whether short, frequent mobilisations in the early phase after stroke increase the chance of regaining to regain independence) 3. We need to characterise the optimal patterns of mobilisation for these patients

50 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. Exploration whether short, frequent mobilisations in the early phase after stroke increase the chance of regaining to regain independence) 3. We need to characterise the optimal patterns of mobilisation for these patients Watch this space

51 Favourable outcome (mrs 0-2) rtpa cohort n OR (95%CI) Country Number of patients Australia 261 New Zealand 34 Singapore 6 Malaysia 6 All UK 200

52 Conclusions (3) 1. Patients who had been treated with rtpa did not incur any additional hazard from early mobilisation. 2. Better outcomes seen with short, frequent mobilisations in the early phase after stroke (more likely to regain independence) 3. We need to characterise the optimal patterns of mobilisation for these patients

53 Large, slow, pragmatic trials Babies born to investigators baby: 20 patients recruited

54 A Very Effective Reproductive Treatment

55 Thank you all very much! AVERT Collaboration