JOURNAL PRESENTATION

Presented by-
vidisha adarsh
MPT (neurosciences)
Evaluator-
Dr. kritika sharma(PT)
Efficacy and safety of very early mobilisation within
24 h of stroke onset (AVERT): a randomised
controlled trial

 Prof. Julie Bernhardt, The Florey Institute of Neuroscience and Mental Health
(The Lancet 2015)
 Abstract:
1) Objective

 The author aimed to compare the effectiveness of frequent, higher dose, very early
mobilisation with usual care after stroke.

2) Method
The study was done in a parallel-group, single-blind, randomised controlled trial at 56 acute
stroke units in five countries. Patients (aged ≥18 years) with ischaemic or haemorrhagic
stroke, first or recurrent, who met physiological criteria were randomly assigned (1:1), via a
web-based computer generated block randomisation procedure (block size of six), to receive
usual stroke-unit care alone or very early mobilisation in addition to usual care.
 Contd…

Treatment with recombinant tissue plasminogen activator was allowed.

Randomisation was stratified by study site and stroke severity. Patients,
outcome assessors, and investigators involved in trial and data management
were masked to treatment allocation. The primary outcome was a favourable
outcome 3 months after stroke, defined as a modified Rankin Scale score of
0–2.
Procedure

Between July 18, 2006, and Oct 16, 2014, 2104 patients were
randomly assigned to receive either very early mobilisation (n=1054)
or usual care (n=1050); 2083 (99%) patients were included in the 3
month follow-up assessment. 965 (92%) patients were mobilised
within 24 h in the very early mobilisation group compared with 623
(59%) patients in the usual care group.
First mobilisation took place within 24 h for most patients in this
trial. The higher dose, very early mobilisation protocol was
associated with a reduction in the odds of a favourable outcome
at 3 months.
 Results

Early mobilisation after stroke is recommended in many clinical practice

guidelines worldwide, and our findings should affect clinical practice by
refining present guidelines; however, clinical recommendations should be
informed by future analyses of dose–response associations.
FUNDING

 National Health and Medical Research Council, Singapore Health,

Chest Heart and Stroke Scotland, Northern Ireland Chest Heart and
Stroke, UK Stroke Association, National Institute of Health Research.
 Introduction
 Early mobilisation after stroke, comprising out-of-bed sitting, standing, and walking, is
thought to contribute to the powerful effect of stroke-unit care and is recommended in many
guidelines however, it is poorly defined and not underpinned by strong evidence. The
biological rationale underlying the potential for early out-of-bed training centers around three
arguments: (1) that bed rest negatively affects the musculoskeletal, cardiovascular,
respiratory, and immune systems,4 and might slow recovery; (2) that immobility-related
complications are common early after stroke5 at a time when patients are very inactive;6 and
(3) that there might be a narrow window of opportunity for brain plasticity and repair,7 and
the optimum period for change could be early after stroke.8 Prompt start and more episodes
of out-of-bed activity might therefore improve outcome.
 Contd…

 However, early mobilisation also has a plausible potential for harm, particularly within the
first 24 h of stroke onset. Harms could include damage to the ischaemic penumbra
associated with reduced cerebral blood flow when the head position is raised or increased
blood pressure associated with activity that might also worsen outcome.
Method
 A single blind randomized controlled trial was done in 56 acute stroke units in 5
different countries. A total of 2014 patients were recruited meeting the exclusion and
inclusion criteria.
1. Inclusion criteria
a) Age- 18 years and above
b) Confirmed first or recurrent stroke.
c) Admission time within 24 hours to stroke unit.
 2) Exclusion criteria
a) Clinically significant premorbid level of disability (modified Rankin scale >2).
b) Early detoriation
c) Direct admission to the intensive care unit.
d) Documented palliative treatment.
e) Immediate surgery
f) Another serious medical illness or unstable coronary condition
g) No response to voice.
h) Systolic BP lower than 110 mm Hg or higher than 220 mm Hg
i) Oxygen saturation lower than 92% with oxygen supplementation.
j) Resting heart rate of less than 40 beats per min or more than 110 beats per min.
k) Temperature greater than 38.5C.
l) Patients with subarachnoid haemorrhage
Randomization and masking

 Patients were randomly assigned (1:1), with a secure, remote, web-based computer-
generated block randomization procedure (block size of six), to receive usual stroke-unit
care alone or very early mobilization in addition to usual care. Randomization was
stratified by study site and stroke severity on the basis of baseline National Institutes of
Health Stroke Scale (NIHSS) score: mild (NIHSS 1–7), moderate (8–16), and severe
(>16).17 Intervention staff were masked to treatment allocation. To reduce the risk of
contamination of usual care intervention, staff were trained to conceal the mobilization
protocol and group allocation, patients were unaware of their treatment group, and
outcome assessors and investigators involved in trial and data management were masked
to group assignment.
 Procedure
 Components of usual care, including physical therapies, were at the discretion of individual
sites. The very early mobilisation intervention included three crucial elements: (1) begin
within 24 h of stroke onset; (2) focus on sitting, standing, and walking (ie, out-of-bed)
activity; and (3) result in at least three additional out-of-bed sessions to usual care. Patients
assigned to very early mobilisation were assisted by physiotherapy and nursing staff trained in
study procedures to continue out-of-bed activity at a dose guided by a detailed intervention
protocol. The task-specific intervention targeted recovery of standing and walking.
 Contd…

 Functional ability dictated intervention dose, with four levels specified, and
dose was adjusted in line with recovery (titrated). We applied a strict protocol
in the case of a patient’s first time out of bed, with mobilisation out of bed
only if the patient’s blood pressure did not drop by more than 30 mm Hg on
achievement of an upright position. The intervention period lasted 14 days or
until discharge from stroke-unit care, whichever was sooner. Therapy and
nursing input in both groups was recorded online.
 Outcome measure

The primary outcome was a favourable outcome at 3 months after stroke,

measured with the modified Rankin Scale.18 The modified Rankin Scale is an
ordinal scale ranging from 0 (no disability) to 5 (severe disability), with a score
of 6 allocated to those who die. They defined a favourable outcome as
modified Rankin Scale scores of 0–2 (no or minimum disability) and a poor
outcome as scores of 3–6 (moderate or severe disability, or death).
Stastistical analysis

 Statistical analysis plan was prespecified and STATA IC (version 13)was used for all
analyses.

 Primary efficacy analysis on an intention to treat basis was done with an assumption
for the main analysis that data were missing at random, this was done with the binary
logistic regression model, with treatment group as independent variables and 3 months
modified rankin scale as dependent variable

 Additional efficacy analysis of primary outcome included exploratory analysis of age;

stroke severity; stroke type; treatment with recombinant tissue plasminogen activator
and time to first mobilization.
Contd…

 Treatment effect of ordinal analysis of modified rankin scale at 3 months

was done with assumption free Wilcoxon-mann Whitney generalized odds
ratio approach.

 To examine the time taken to achieve unassisted walking 50m within 3

months of stroke a cox regression model was used with treatment group
as independent variable and time to assisted walking as dependent
variable keeping baseline NIHSS and age as covariants.

 The mortality outcome were analysed by binary logistic regression model.

 Results
 2014 patients were randomly assigned to receive either very early mobilization(1054) or usual
care(1050) with 2083 (99%) patients included in the 3 months follow up assessment. Baseline
characteristics were similar in both the groups.

 The three crucial elements of very early mobilization protocol were achieved. Patients in very
early mobilization group began mobilizing soon after randomization, at a median of 18.5
hours after stroke. In very early mobilization group 241 patients were mobilized wihin 12
hours and 965 patients within 24 hours and 1038 within 48 hours of which the corresponding
numbers in usual care were 148, 623 and 977 patients respectively.
Contd…

 Time to walking unassisted did not differ significantly between group.

 The overall case fatality rate was 8% in 3 months. 7% patient died in usual care group
and8% died in very early mobilization group. The main cause being the stroke
progression, pneumonia and recurrent stroke.
Discussion.

 The very early mobilisation protocol was effectively delivered, leading to an earlier,
more frequent, and higher dose of out-of-bed sitting, standing, and walking activity
than usual care. The very early mobilisation intervention significantly reduced the
odds of a favourable outcome 3 months after stroke compared with lower dose usual
care starting, on average, 5 h later. This outcome of very early mobilisation was
recorded against a background of favourable overall prognosis, with almost 50% of
patients having a favourable outcome and fewer than 8% dying at 3 months, despite
more than 25% of participants being older than 80 years, and more than 45% having
had a moderate or severe stroke.
Contd…

 Although the case-fatality rate at 3 months was higher in the very early mobilisation
group, no significant difference was recorded between groups. The prespecified
subgroup analyses of efficacy might provide a signal that patients with severe stroke
and those with intracerebral haemorrhage had reduced odds of a favourable outcome
by 3 months if treated with the very early mobilisation protocol.
CRITICAL ANALYSIS
TITLE OF THE STUDY- Title of the study is appropriate but the study
design has not been mentioned.

 ABSTRACT :-

POSITIVE POINTS- NEGATIVE POINTS-

Objective/ Purpose mentioned Design of the study has not

been mentioned.

Methods have been described Sampling method has not been

descriptively. described.
Outcome measures have been Risks and the harmful effects
given. (if any ) of the intervention has
not been given.

Results and conclusions have Protocol of treatment is not

been mentioned clearly. mentioned

Funding and information about

the funders IS given.
 INTRODUCTION-
POSITIVE POINTS NEGATIVE POINTS

Background about the condition given No mention of the precautions of

along with background of the study. training.

Harmful effects of treatment given No mention about the consent from

patient or caregivers.

Background of the intervention to be

administered given.

Purpose of the study mentioned.

 METHODOLOGY-

 POSITIVE POINTS-

1) Inclusion and exclusion Criteria have been stated clearly.

2) Details about the training of both the experimental and control group have
been given descriptively.

3) Outcome measures have been described well.

4) Recruitment of subjects (acute) mentioned.

5) Type of randomisation mentioned.

 NEGATIVE POINTS-

1) Ethical approval/ clearance not mentioned.

2) Patient education about the procedure not mentioned.

3) No follow up.
 STATISTICAL ANALYSIS-

 POSITIVE POINTS-

1) Software used mentioned

2) Individual components analysed and mentioned about the

models used.

3) Independent and dependent variables mentioned.

4) Registry trail institution and Registration number mentioned.

 RESULTS-

 POSITIVE POINTS-

1) Results given in a proper tabular form.

2) Results described under different outcome measures.

 NEGATIVE POINTS-

1) Total no of patients included, randomization mentioned and

follow up not given in flow chart.

2) Definite effect of intervention not mentioned clearly.

3) Analysed missing data (assumed as 0 from training time) also

included.
 DISCUSSION-
 POSITIVE POINTS-

1) Point wise discussion of the results were done from outcome

measures.

2) Feedback on the same point wise were proposed.

3) Conclusion have been stated.

 NEGATIVE POINTS-

1) An over-all impact of the study was not established descriptively.

2) Recommendation and limitation no mentioned.

3) Scope for further studies not mentioned.

 CONSORT 2010 CHECKLIST-

TITLE AND ABSTRACT

1a) Identification as a randomized trial in the title – YES
1b) Structured summary of trial design, methods, results, and
conclusions – YES
INTRODUCTION
 Background and objectives:
2a) Scientific background and explanation of rationale - YES
2b) Specific objectives or hypothesis - NO
 METHODS

 Trial design :

3a) Description of trial design including allocation ratio – YES

3b) Important changes to methods after trial commencement (such

as eligibility criteria), with reasons - No

Participants :

4a) Eligibility criteria for participants - YES

4b) Settings and locations where the data were collected- YES
 INTERVENTIONS :
5a) The interventions for each group with sufficient details to allow
replication, including how and when they were actually
administered- YES.
OUTCOMES:
6a) Completely defined pre-specified primary and secondary
outcome measures, including how and when they were assessed -
YES
6b) Any changes to trial outcomes after the trial commenced with
reasons- NONE
SAMPLE SIZE:

7a) How sample size was determined- NO

7b) When applicable, explanation of any interim analyses and

stopping guidelines- NO

RANDOMISATION:

8a)Method used to generate the random allocation sequence- YES

8b )Type of randomization; details of any restriction (such as

blocking and block size)- YES
 ALLOCATION CONCEALMENT MECHANISM:
 9) Mechanism used to implement the random allocation sequence
(such as sequentially numbered containers), describing any steps
taken to conceal the sequence until interventions were assigned-
YES
IMPLEMENTATION:
 10) Who generated the random allocation sequence, who enrolled
participants, and who assigned participants to interventions- NO
BLINDING:
11a) If done, who was blinded after assignment to interventions (for
example, participants, care providers, those assessing outcomes) –
NO

STATISTICAL METHODS :

 12a) Statistical methods used to compare groups for primary and

secondary outcomes - YES

 12b) Methods for additional analyses, such as subgroup analyses

and adjusted analyses - YES
RECRUITMENT :

14a) Dates defining the periods of recruitment and follow-up - YES

14b) Why the trial ended or was stopped - TRIAL WAS

COMPLETED

BASELINE DATA:

15) A table showing baseline demographic and clinical

characteristics for each group - YES
NUMBERS ANALYSED:

16)For each group, number of participants included in each analysis

and whether the analysis was by original assigned groups – YES

OUTCOMES AND ESTIMATION:

 17a) For each primary and secondary outcome, results for each
group, and the estimated effect size and its precision (such as
95% confidence interval) - NO
 ANCILLARY ANALYSES:

18) Results of any other analyses performed, including subgroup

analyses and adjusted analyses, distinguishing pre-specified from
exploratory- YES

 HARMS:

19) All important harms or unintended effects in each group - YES

 DISCUSSION

Limitations:

 20) Trial limitations, addressing sources of potential bias,

imprecision, and, if relevant, multiplicity of analyses - YES

Generalisability:

 21) Generalisability (external validity, applicability) of the trial

findings - NO
Interpretation:

 22) Interpretation consistent with results, balancing benefits and

harms, and considering other relevant evidence - YES
 OTHER INFORMATION

Registration:

 23) Registration number and name of trial registry - YES

Protocol:

 24) Where the full trial protocol can be accessed, if available - YES

Funding:

 25) Sources of funding and other support (such as supply of drugs),

role of funders - YES
 PEDro Scale-

1. Eligibility criteria were specified: Y/N.

2. Subjects were randomly allocated to groups (in a crossover

study, subjects were randomly allocated an order in which
treatments were received): Y/N

3. Allocation was concealed: Y/N

4. The groups were similar at baseline regarding the most

important prognostic indicators: Y/N
5. There was blinding of all subjects: Y/N.

6. There was blinding of all therapists who administered the

therapy: Y/N

7. There was blinding of all assessors who measured at least one

key outcome: Y/N

8. Measures of at least one key outcome were obtained from more

than 85% of the subjects initially allocated to groups: Y/N
9. All subjects for whom outcome measures were available received
the treatment or control condition as allocated or, where this was
not the case, data for at least one key outcome was analysed by
“intention to treat: Y/N

10. The results of between-group statistical comparisons are

reported for at least one key outcome: Y/N

11. The study provides both point measures and measures of

variability for at least one key outcome: Y/N
ANY QUESTIONS???