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CochraneDatabaseof SystematicReviews

Caregiver-mediated exercises for improvingoutcomesafter

stroke(Review)

Vloothuis JDM, MulderM, VeerbeekJM, Konijnenbelt M, Visser-MeilyJMA,Ket JCF, Kwakkel G,

van WegenEEH

Vloothuis JDM, Mulder M, Veerbeek JM, Konijnenbelt M, Visser-Meily JMA, KetJCF, KwakkelG, vanWegen EEH.

Caregiver-mediatedexercises for improving outcomes afterstroke.

CochraneDatabaseof SystematicReviews 2016, Issue12. Art.No.: CD011058.

DOI: 10.1002/14651858.CD011058.pub2.

www.cochranelibrary.com

Caregiver-mediated exercises for improvingoutcomesafterstroke(Review)

http://www.cochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .

7BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

22DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

25AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

26ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

26REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

54DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

59ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

63CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

63DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

63DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

64INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iCaregiver-mediated exercises for improving outcomes after stroke (Review)

[Intervention Review]

Caregiver-mediated exercises for improving outcomes after stroke

Judith DM Vloothuis1 , Marijn Mulder2, Janne M Veerbeek2,3, Manin Konijnenbelt1 , Johanna MA Visser-Meily4 , Johannes CF Ket 5, Gert Kwakkel6 , Erwin EH van Wegen7

1Department of Neurorehabilitation, Amsterdam Rehabilitation Research Centre, Reade, Amsterdam, Netherlands. 2Department of Re-

habilitation Medicine, MOVE Research Institute Amsterdam, VU University Medical Center, Amsterdam, Netherlands. 3Department

of Rehabilitation Medicine, Physical Therapy, VU University Medical Center, Amsterdam, Netherlands. 4Brain Center Rudolf Magnus,

University Medical Center Utrecht and De Hoogstraat, Utrecht, Netherlands. 5Medical Library, Vrije Universiteit Amsterdam, Amster-

dam, Netherlands. 6Department of Rehabilitation Medicine, MOVE Research Institute Amsterdam, Amsterdam Neurosciences, VU

University Medical Center, Amsterdam, Netherlands. 7 Department of Rehabilitation Medicine, MOVE Research Institute Amsterdam,

Amsterdam Neurosciences, VU University Medical Center, Amsterdam, Netherlands

Contact address: Judith DM Vloothuis, Department of Neurorehabilitation, Amsterdam Rehabilitation Research Centre, Reade,

Overtoom 283, PO Box 58271, Amsterdam, 1054 HW, Netherlands. [email protected].

Editorial group: Cochrane Stroke Group.

Publication status and date: New, published in Issue 12, 2016.

Citation: Vloothuis JDM, Mulder M, Veerbeek JM, Konijnenbelt M, Visser-Meily JMA, Ket JCF, Kwakkel G, van Wegen EEH.

Caregiver-mediated exercises for improving outcomes after stroke. Cochrane Database of Systematic Reviews 2016, Issue 12. Art. No.: CD011058. DOI: 10.1002/14651858.CD011058.pub2.

A B S T R A C T

Background

Stroke is a major cause of long-term disability in adults. Several systematic reviews have shown that a higher intensity of training can

lead to better functional outcomes after stroke. Currently, the resources in inpatient settings are not always sufficient and innovative

methods are necessary to meet these recommendations without increasing healthcare costs. A resource efficient method to augment

intensity of training could be to involve caregivers in exercise training. A caregiver-mediated exercise programme has the potential

to improve outcomes in terms of body function, activities, and participation in people with stroke. In addition, caregivers are more

actively involved in the rehabilitation process, which may increase feelings of empowerment with reduced levels of caregiver burden

and could facilitate the transition from rehabilitation facility (in hospital, rehabilitation centre, or nursing home) to home setting. As

a consequence, length of stay might be reduced and early supported discharge could be enhanced.

Objectives

To determine if caregiver-mediated exercises (CME) improve functional ability and health-related quality of life in people with stroke,

and to determine the effect on caregiver burden.

Search methods

We searched the Cochrane Stroke Group Trials Register (October 2015), CENTRAL (the Cochrane Library, 2015, Issue 10), MEDLINE

(1946 to October 2015), Embase (1980 to December 2015), CINAHL (1982 to December 2015), SPORTDiscus (1985 to December

2015), three additional databases (two in October 2015, one in December 2015), and six additional trial registers (October 2015). We

also screened reference lists of relevant publications and contacted authors in the field.

1Caregiver-mediated exercises for improving outcomes after stroke (Review)

mailto:[email protected]

Selection criteria

Randomised controlled trials comparing CME to usual care, no intervention, or another intervention as long as it was not caregiver-

mediated, aimed at improving motor function in people who have had a stroke.

Data collection and analysis

Two review authors independently selected trials. One review author extracted data, and assessed quality and risk of bias, and a second

review author cross-checked these data and assessed quality. We determined the quality of the evidence using GRADE. The small

number of included studies limited the pre-planned analyses.

Main results

We included nine trials about CME, of which six trials with 333 patient-caregiver couples were included in the meta-analysis. The

small number of studies, participants, and a variety of outcome measures rendered summarising and combining of data in meta-analysis

difficult. In addition, in some studies, CME was the only intervention (CME-core), whereas in other studies, caregivers provided

another, existing intervention, such as constraint-induced movement therapy. For trials in the latter category, it was difficult to separate

the effects of CME from the effects of the other intervention.

We found no significant effect of CME on basic ADL when pooling all trial data post intervention (4 studies; standardised mean

difference (SMD) 0.21, 95% confidence interval (CI) -0.02 to 0.44; P = 0.07; moderate-quality evidence) or at follow-up (2 studies;

mean difference (MD) 2.69, 95% CI -8.18 to 13.55; P = 0.63; low-quality evidence). In addition, we found no significant effects of

CME on extended ADL at post intervention (two studies; SMD 0.07, 95% CI -0.21 to 0.35; P = 0.64; low-quality evidence) or at

follow-up (2 studies; SMD 0.11, 95% CI -0.17 to 0.39; P = 0.45; low-quality evidence).

Caregiver burden did not increase at the end of the intervention (2 studies; SMD -0.04, 95% CI -0.45 to 0.37; P = 0.86; moderate-

quality evidence) or at follow-up (1 study; MD 0.60, 95% CI -0.71 to 1.91; P = 0.37; very low-quality evidence).

At the end of intervention, CME significantly improved the secondary outcomes of standing balance (3 studies; SMD 0.53, 95% CI

0.19 to 0.87; P = 0.002; low-quality evidence) and quality of life (1 study; physical functioning: MD 12.40, 95% CI 1.67 to 23.13; P =

0.02; mobility: MD 18.20, 95% CI 7.54 to 28.86; P = 0.0008; general recovery: MD 15.10, 95% CI 8.44 to 21.76; P < 0.00001; very

low-quality evidence). At follow-up, we found a significant effect in favour of CME for Six-Minute Walking Test distance (1 study;

MD 109.50 m, 95% CI 17.12 to 201.88; P = 0.02; very low-quality evidence). We also found a significant effect in favour of the

control group at the end of intervention, regarding performance time on the Wolf Motor Function test (2 studies; MD -1.72, 95%

CI -2.23 to -1.21; P < 0.00001; low-quality evidence). We found no significant effects for the other secondary outcomes (i.e. patient:

motor impairment, upper limb function, mood, fatigue, length of stay and adverse events; caregiver: mood and quality of life).

In contrast to the primary analysis, sensitivity analysis of CME-core showed a significant effect of CME on basic ADL post intervention

(2 studies; MD 9.45, 95% CI 2.11 to 16.78; P = 0.01; moderate-quality evidence).

The methodological quality of the included trials and variability in interventions (e.g. content, timing, and duration), affected the

validity and generalisability of these observed results.

Authors’ conclusions

There is very low- to moderate-quality evidence that CME may be a valuable intervention to augment the pallet of therapeutic options

for stroke rehabilitation. Included studies were small, heterogeneous, and some trials had an unclear or high risk of bias. Future high-

quality research should determine whether CME interventions are (cost-)effective.

P L A I N L A N G U A G E S U M M A R Y

Caregiver-mediated exercises for improving outcomes after stroke

Review question

What is the effect of performing exercises with a caregiver after stroke on outcome for people with stroke and burden for caregivers?

Background

2Caregiver-mediated exercises for improving outcomes after stroke (Review)

Stroke is a major cause of acquired adult disability. Research has shown that more time spent on exercise therapy in the first weeks to

months after stroke leads to better functioning. Due to lack of personnel and resources, in practice it is difficult to spend more time

on exercise therapy in this period. One method to increase this exercise time, is to involve caregivers in performing exercise training

together with a person with stroke. During this exercise training a therapist coaches patient and caregiver and an evaluation is planned

on a regular basis.

Study characteristics

We identified nine clinical trials to October 2015, which all investigated some form of caregiver-mediated exercises compared with

usual care, no treatment (intervention), or another intervention that was not caregiver-mediated.

Key results

We included 333 patient-caregiver couples in the review. We found trials in which caregiver-mediated exercises themselves were the

studied subject (called CME-core). In addition, we found trials in which the caregiver was the provider of another, already existing

intervention. In the latter category, it was difficult to separate the effect of caregiver-mediated exercises from the effect of the other

intervention.

We found evidence that caregiver-mediated exercises could have a positive effect on patients’ standing balance (low-quality evidence)

and quality of life (very low-quality evidence) directly after the intervention. In the long term, we found very low-quality evidence for

a positive effect on walking distance. For speed of use of the arm and hand, we found low-quality evidence in favour of the control

group.

We found no significant side effects or beneficial effects on caregiver strain; we judged the quality of this evidence as moderate (after

intervention) to very low (long term). Furthermore, we found no significant effects for basic activities of daily living, such as dressing and

bathing, after intervention (moderate-quality evidence) or follow-up (low-quality evidence). In addition, we found no significant effects

for extended activities of daily living, such as cooking and gardening, after intervention or at follow-up (both low-quality evidence).

In the CME-core analysis, we found moderate-quality evidence for a positive effect of caregiver-mediated exercises for basic activities

of daily living.

It can be concluded that caregiver-mediated exercises may be a promising form of therapy to add to usual care.

Quality of the evidence

The number of included trials was small and the level of evidence was of very low to moderate quality. Therefore, results should be

interpreted with caution.

3Caregiver-mediated exercises for improving outcomes after stroke (Review)

S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

Caregiver- mediated exercises compared with control intervention f or people with stroke

Patient or population: people w it h s t roke

Settings: inpat ient and out pat ient s et t ings

Intervention: c aregiver-m ediat ed exerc is es

Comparison: c ont rol, i.e. us ual c are, ot her int ervent ion, no int ervent ion

Outcomes Illustrative comparative risks* (9 5 % CI) Relative ef f ect

(9 5 % CI)

No of participants

(studies)

Quality of the evidence

(GRADE)

Comments

Assumed risk Corresponding risk

Control intervention Caregiver- mediated

intervention

Patient: ADL measures

Barthel Index. Sc ale 0 t o 100

(f ollow -up: 2 s t udies ; 3/

6 m ont hs )

FIM. Sc ale 7 t o 126 (no f ollow -up)

The m ean Bart hel Index

s c ore ranged ac ros s

c ont rol groups f rom 78

t o 84

1 s t udy: The m ean FIM

s c ore in t he c ont rol

group w as 65

The m ean Bart hel Index

s c ore in t he int erven-

t ion groups w as

5.09 higher (-2.88 t o 13.

07 higher)

1 s t udy: The m ean

FIM s c ore in t he int er-

vent ion group w as 11

higher (-1.59 t o 23.67

higher)

- Bart hel Index: 247

(3)

FIM : 48

(1)

Tot al: 295

⊕⊕⊕©

M oderat e

Higher s c ores are bet -

t er

M ore t han half of t he

s t udies at low ris k of

bias (3 low ris k of bias ,

1 at unc lear ris k of bias )

There w as c linic al het -

erogeneit y

SM D 0.21

(-0.02 t o 0.44)

Caregiver: measures of

mood, burden and QoL:

burden

Caregiver St rain Index

Sc ale. 0 t o 13

(f ollow -up 3 m ont hs )

Caregiver Burden

Sc ale. 22 t o 88

(no f ollow -up)

The m ean Caregiver

St rain Index s c ore in t he

c ont rol group w as

3.4

The m ean Caregiver

Burden Sc ale s c ore in

t he c ont rol group w as

46.6

The m ean Caregiver

St rain Index s c ore in t he

int ervent ion group w as

0.50 higher (-0.81 t o 1.

81 higher)

The m ean Caregiver

Burden Sc ale s c ore in

t he int ervent ion group

w as 1.30 low er (-4.88

t o 7.48 low er)

- Caregiver St rain Index:

(1)

Caregiver Burden Sc ale:

(1)

Tot al: 91

⊕⊕⊕©

M oderat e

Low er s c ores are bet t er

Bot h s t udies at low ris k

of bias

Sm all t ot al num ber of

part ic ipant s

SM D -0.04

(-0.45 t o 0.37)

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(R e v ie

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http://www.thecochranelibrary.com/view/0/SummaryFindings.html

Gait and gait- re-

lated measures: walk-

ing speed

in m / s

(f ollow -up: 1 s t udy, 9

m ont hs )

The m ean w alking

s peed ranged ac ros s

c ont rol groups f rom 0.

26 m / s t o 0.46 m / s

The m ean w alking

s peed in t he int erven-

t ion group w as 0.08 m /

s higher (-0.03 t o 0.18)

- 71

(2)

⊕©©©

Very low

Gait and gait- related

measures: walking dis-

tance measured with

the Six- M inute Walk

T est

in m et res w alked in 6

m inut es

(f ollow -up: 1 s t udy, 3

m ont hs )

The m ean dis t anc e

w alked ranged ac ros s

c ont rol groups f rom

157 m t o 166 m

The m ean dis t anc e

w alked in t he int erven-

t ion groups w as 30.98

m higher (-20.22 t o 82.

19 higher)

- 91

(2)

⊕⊕⊕©

m oderat e

Low er s c ores are bet t er

1 s t udy at unc lear ris k

of bias

Sm all t ot al num ber of

part ic ipant s

M D 0.04

(-0.10 t o 0.18)

M easures of mood and

QoL of the patient:

Stroke Impact Scale

St roke Im pac t Sc ale

m obilit y s c ale. Sc ale 9

t o 45.

(no f ollow -up)

The m ean St roke Im -

pac t Sc ale m obilit y

s c ore in t he c ont rol

group w as 66.8

The m ean St roke Im -

pac t Sc ale m obilit y

s c ore in t he int erven-

t ion group w as 18.2

higher (7.54 t o 28.86

higher)

- 51

(1)

⊕©©©

Very low

Higher s c ores are bet -

t er

1 s t udy at low ris k of

bias

Sm all t ot al num ber of

part ic ipant s

M D 18.2

(7.54 t o 28.86)

Length of stay: length

of stay in rehabilitation

unit

in days

The m ean lengt h of s t ay

in a rehabilit at ion unit in

t he c ont rol group w as

52.3 days

The m ean lengt h of s t ay

in a rehabilit at ion unit in

t he int ervent ion group

w as 12 days low er (-10.

88 t o 34.88)

- 20

(1)

⊕©©©

very low

Higher s c ores are bet -

t er

1 s t udy at low ris k of

bias and 1 at unc lear or

high ris k of bias

Sm all t ot al num ber of

part ic ipant s

There w as c linic al het -

erogeneit y

M D 0.08 m / s

(-0.03 t o 0.18)

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a fte

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k e

(R e v ie

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Adverse outcomes:

f alls

num ber of f alls / pat ient

(no f ollow -up)

1 s t udy: t he m ean num -

ber of f alls / pat ient in

t he c ont rol group w as

0.08

1 s t udy: t he m ean num -

ber of f alls / pat ient in

t he int ervent ion group

w as 0.04 low er (-0.10

t o 0.18 low er)

- 48

(1)

⊕©©©

Very low

Higher s c ores are bet -

t er

Bot h s t udies at low ris k

of bias

Sm all t ot al num ber of

part ic ipant s

M D 30.98 m

(-20.22 t o 82.19)

* The bas is f or t he assumed risk (e.g. t he m edian c ont rol group ris k ac ros s s t udies ) is provided in f oot not es . The corresponding risk (and it s 95% c onf idenc e int erval) is

bas ed on t he as s um ed ris k in t he c om paris on group and t he relative ef f ect of t he int ervent ion (and it s 95% CI).

ADL: ac t ivit ies of daily living; CI: c onf idenc e int erval; FIM : Func t ional Independenc e M eas ure; M D: m ean dif f erenc e; QoL: qualit y of lif e; RR: ris k rat io; SD: s t andard deviat ion;

SM D: s t andardis ed m ean dif f erenc e.

GRADE Working Group grades of evidenc e

High quality: Furt her res earc h is very unlikely t o c hange our c onf idenc e in t he es t im at e of ef f ec t .

M oderate quality: Furt her res earc h is likely t o have an im port ant im pac t on our c onf idenc e in t he es t im at e of ef f ec t and m ay c hange t he es t im at e.

Low quality: Furt her res earc h is very likely t o have an im port ant im pac t on our c onf idenc e in t he es t im at e of ef f ec t and is likely t o c hange t he es t im at e.

Very low quality: We are very unc ert ain about t he es t im at e.

6 C

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B A C K G R O U N D

Description of the condition

Stroke is a major cause of long-term disability in adults with ef-

fects on activities of daily living (ADL) and quality of life (QoL).

Although most people leave the rehabilitation setting with some

level of independent walking, many have residual walking disabil-

ities and it has been reported that following rehabilitation, only

7% of stroke survivors can walk at a level commensurate with

community participation (Ada 2009). Twelve months after stroke

about 28% of people with stroke remain dependent in their basic

ADLs, such as dressing, toileting, and indoor mobility (Ullberg

2015). Pettersen and colleagues reported that 32% of people with

stroke living at home after three years were inactive in extended

ADL (Pettersen 2002). Any treatment that improves functional

outcome can potentially reduce the burden of this illness for the

person, their caregivers, and society.

Description of the intervention

Several systematic reviews have shown that a higher intensity of

training in terms of time spent on exercise therapy can lead to bet-

ter functional outcome in people with stroke in terms of ADL and

functional performance (French 2010; Galvin 2008a; Kwakkel

2004; Kwakkel 2006; Langhorne 2011; Lohse 2014; Veerbeek

2011; Veerbeek 2014). One resource-efficient method to increase

intensity of training could be to involve caregivers in exercise train-

ing (De Weerdt 2002). We define caregiver-mediated exercises

(CME) as the person with stroke performing exercises together

with a caregiver under the auspices of a physical or occupational

therapist. “Under the auspices” means that the therapist is involved

as a coach by instructing both patient and caregiver on how to per-

form the exercises, and evaluating them on a regular basis. Hereby,

the exercises are aimed at improving ADL including mobility, such

as making transfers, standing, and walking.

How the intervention might work

Performing exercises together with a caregiver has the potential

to augment the intensity of practice without increasing healthcare

costs. This could improve outcomes in terms of body functions,

activities, and participation as well as cost effectiveness in people

with stroke.

In addition, caregivers are more actively involved in CME than

in the usually applied rehabilitation services, which may increase

feelings of empowerment with reduced levels of caregiver bur-

den (Brereton 2002; Smith 2004a). CME could lead to a reduced

length of inpatient stay or outpatient treatment in hospitals, re-

habilitation, and nursing settings, and may improve outcomes in

self-management, empowerment, and QoL of patients and care-

givers.

Why it is important to do this review

Several systematic reviews have indicated that additional exercise

therapy and repetitive task training have a significant, favourable

effect on functional outcome after stroke, and concluded that the

more time spent on exercise therapy (Galvin 2008a; Kwakkel

2004; Kwakkel 2006; Lohse 2014; Veerbeek 2011), and the higher

the number of repetitions, the better the outcome (French 2010;

Langhorne 2011; Veerbeek 2014). Therefore, clinical guidelines

recommend that people who are in a rehabilitation setting should

have the opportunity to train intensively (ESO 2008; NICE 2013;

SIGN 2010; Veerbeek 2014). For example, the stroke guideline in

the UK recommends a daily dose of 45 minutes of exercise therapy

(NICE 2013).

Currently, the resources in inpatient settings are not sufficient

to meet these recommendations. Most people admitted to stroke

units, rehabilitation wards, and nursing homes spend most of their

waking time during the working week inactive (Bernhardt 2004;

Smith 2008; West 2012), and on weekends, rehabilitation services

(including exercise therapy) in most hospital and rehabilitation

settings are not available (Otterman 2012). Therefore, it is impor-

tant to find innovative methods, such as CME, to enhance inten-

sity of training after stroke, without increasing costs.

However, the caregiver taking the role of a therapist (instead of

a family role) may burden the caregiver with yet another task

(Gordon 2004). Therefore, it is important to study the mood,

burden, and QoL of caregivers when involving them in CME

systematically. No systematic review has yet been conducted to

evaluate the effect of caregiver participation in exercise training on

functional outcome after stroke, or to evaluate the effect on mood

and burden of the caregiver when involved in CME.

O B J E C T I V E S

To determine if caregiver-mediated exercises (CME) improve

functional ability and health-related quality of life in people with

stroke, and to determine the effect on caregiver burden.

M E T H O D S

Criteria for considering studies for this review

Types of studies

7Caregiver-mediated exercises for improving outcomes after stroke (Review)

We included randomised controlled trials (RCTs), including clus-

ter-RCTs. One group of the trial must have received CME and we

considered this group as the experimental group for this review.

The other (control) group could have received usual treatment,

no treatment, or any other type of rehabilitation intervention or

attention-control as long as it was not caregiver-mediated. We ac-

cepted usual treatment when it was described as usual care in the

setting of the participant.

Types of participants

People, at least 18 years old, who had had a stroke. Stroke is

defined by the World Health Organization as “a clinical syndrome

typified by rapidly developing signs of focal or global disturbance

of cerebral functions, lasting more than 24 hours or leading to

death, with no apparent causes other than of vascular origin” (

WHO 1989). We included RCTs regardless of timing after stroke

and setting.

Types of interventions

One group of the RCT must have included CME, whereas the

caregiver involvement was not explicitly asked for in the other

group of the RCT. We included trials in which the patient and

their caregiver were trained or instructed together, as well as trials

in which the caregiver was trained or instructed alone. There was

no limit to the number of sessions or to the frequency of delivery.

We included all types of exercises as long as they were aimed at im-

proving patients’ abilities to perform daily activities. Therefore, we

excluded RCTs of speech, swallowing, or cognitive interventions

done together with a caregiver. We defined a caregiver or carer as

an unpaid or partially paid person who voluntarily helped an im-

paired person with his or her ADL. In other words, the mediated

services were not applied by a professional in health care but in

most cases, someone who was close to the patient and voluntarily

offered his or her services. This may have been a partner, family

member, or friend, but it can also have been a volunteer. We ar-

gued that this person was ’not a professional’ such as a ’therapy

assistant’. When a professional in health services applied the me-

diated exercises, we excluded the RCT. We included interventions

delivered at any location, for example at home, in hospital, or in

a rehabilitation setting. Because a caregiver can be the provider of

an intervention, we did not exclude trials that combined CME

with an existing intervention. However, we did differentiate be-

tween trials in which CME was the only intervention (CME-core)

and trials in which a caregiver was used to deliver another, exist-

ing intervention. We contacted trial authors when it was unclear

whether a trial met our definition.

Types of outcome measures

Primary outcomes

• Patient: basic ADL measures, such as the Barthel index (BI)

(Collin 1988; Mahoney 1965), Functional Independence

Measure (FIM) (Dodds 1993), modified Rankin Scale (mRS)

(De Haan 1995; Dromerick 2003); extended ADL measures,

such as the Nottingham Extended Activities of Daily Living

(NEADL) Index (Nouri 1987), or Frenchay Activities Index

(FAI) (Wade 1985). When found, we combined scales with the

same construct.

• Caregiver: measures of burden, for example Caregiver

Strain Index (CSI) (Robinson 1983). When found, we combined

scales with the same construct.

When possible we distinguished between caregivers who were fam-

ily or friends and other types of caregivers, such as volunteers, for

the above-mentioned measures of outcome.

Secondary outcomes

• Measures of motor impairment: Motricity Index (MI)

(Collin 1990), Fugl-Meyer Assessment (FMA) (Duncan 1983;

Sanford 1993; Shelton 2001).

• Gait and gait-related measures: walking speed, walking

distance, Timed-Up-and-Go test (TUG) (Collen 1990; Flansbjer

2005), Rivermead Mobility Index (RMI) (Collen 1991; Hsieh

2000; Hsueh 2003), Berg Balance Scale (BBS) (Berg 1992; Berg

1995; Mao 2002; Stevenson 2001).

• Measures of upper limb activities or function, for example,

Action Research Arm Test (ARAT) (Chen 2012; Hsieh 1998;

Platz 2005).

• Measures of mood and QoL of the patient, for example,

measured by the Stroke Impact Scale (SIS) (Duncan 1999;

Duncan 2002; Duncan 2003), and Hospital Anxiety and

Depression Scale (HADS) (Aben 2002; Bjelland 2002;

Herrmann 1997; Zigmond 1983).

• Measures of fatigue of the participant, for example,

measured by the Fatigue Severity Scale (FSS) (Valko 2008).

• Length of stay in hospital, rehabilitation centre, or nursing

home, or treatment in an outpatient clinic.

• Adverse outcomes, for example, pain, injury, or falls. When

possible, we compared the total number of falls between groups,

and the number of patients experiencing at least one fall between

groups.

• Caregiver: measures of mood and QoL, for example,

HADS (Aben 2002; Bjelland 2002; Herrmann 1997; Zigmond

1983), or CarerQoL (Brouwer 2006; Hoefman 2011).

When we found scales measuring the same construct, we combined

them. If studies reported outcome measures other than the ones

mentioned above, we verified if they measured the same construct.

If this was the case, we pooled them; if they did not measure the

same construct, we reported these outcomes separately.

8Caregiver-mediated exercises for improving outcomes after stroke (Review)

Search methods for identification of studies

See the ’Specialized register’ section in the Cochrane Stroke Group

module. We searched for trials in all languages and arranged trans-

lation of papers where necessary. Due to time limitations, we

were unable to perform the review within one year after the first

search (April 2014). Therefore, it was necessary to update our

search in October 2015. We used the same search strategy but due

to different availability of Information Specialists and providers

of databases, we adjusted the search strategies accordingly: Em-

base.com instead of Ovid/Embase, and EBSCO/AMED instead

of Ovid/AMED. We limited the update searches between 2014

and 2016.

Electronic searches

We searched the following databases and trials registers.

• Cochrane Stroke Group Trials Register (last searched

October 2015).

• Cochrane Central Register of Controlled Trials

(CENTRAL) (the Cochrane Library, 2015, Issue 10) (Appendix

1).

• Cochrane Database of Systematic Reviews (CDSR) (the

Cochrane Library, last searched October 2015) (Appendix 1).

• Cochrane Methodology Register (CMR) (the Cochrane

Library, last searched October 2015) (Appendix 1).

• Database of Abstracts of Reviews of Effects (DARE) (the

Cochrane Library, last searched October 2015) (Appendix 1). • Health Technology Assessment Database (HTA) (the

Cochrane Library, last searched October 2015) (Appendix 1).

• NHS Economic Evaluation Database (NHS EED) (the

Cochrane Library, last searched October 2015) (Appendix 1).

• MEDLINE (Ovid) (from 1946 to October 2015)

(Appendix 2).

• Embase (Ovid from 1980 to April 2014 and Embase.com

from 2014 to December 2015) (Appendix 3; Appendix 4).

• CINAHL (Cumulative Index of Nursing and Allied Health

Literature) (EBSCO) (from 1982 to December 2015) (Appendix

5).

• SPORTDiscus (EBSCO) (from 1985 to December 2015)

(Appendix 6).

• AMED (Alternative and Complementary Medicine) (Ovid

from 1985 to April 2014 and EBSCO from 1985 to December

2015) (Appendix 7; Appendix 8).

• Physiotherapy Evidence Database (PEDro) (from 1929 to

October 2015) (www.pedro.org.au/).

• REHABDATA (from 1956 to October 2015) (

www.naric.com/?q=en/REHABDATA).

• ClinicalTrials.gov (www.clinicaltrials.gov/).

• EU Clinical Trials Register (www.clinicaltrialsregister.eu).

• Stroke Trials Registry (www.strokecenter.org/trials/).

• Current Controlled Trials (www.controlled-trials.com).

• World Health Organization (WHO) International Clinical

Trials Registry Platform (www.who.int/ictrp/en/).

• Australian New Zealand Clinical Trials Registry (

www.anzctr.org.au/).

We developed the MEDLINE search strategy with the help of

the Cochrane Stroke Group Trials Search Co-ordinator (Brenda

Thomas) and adapted this for the other databases. Search strategies

for the main databases are included. For a complete overview of

the search, see Appendix 9.

Searching other resources

To identify further published, unpublished, and ongoing studies

we:

• searched the reference lists of all included articles;

• contacted experts and authors in the field;

• used Science Citation Index Cited Reference Search for

forward tracking of important articles.

Data collection and analysis

Selection of studies

Two review authors (JV, MM) independently screened the titles

of records obtained from the electronic searches and excluded ob-

viously irrelevant studies. Subsequently, we screened the remain-

ing abstracts and excluded those that were irrelevant. Finally, we

obtained the full-text articles for the remaining studies and the

same two review authors selected studies for inclusion in the re-

view based on the inclusion criteria described previously. We re-

solved any disagreement by discussion and, where necessary, in

consultation with a third review author (EvW).

Data extraction and management

Two review authors (JV, MM) conducted data extraction and re-

viewed risk of bias of the eligible trials. The review authors were

not blinded to study authors, journals, or outcomes. We resolved

any disagreement about risk of bias by discussion. If we could not

reach consensus, a third review author (EvW) made the final deci-

sion. One review author (JV) extracted data and a second review

author (MM) cross-checked the extracted data using a standard

checklist, including randomisation method, study population, in-

tervention methods and delivery, outcome measures, and follow-

up.

Assessment of risk of bias in included studies

We used the tool for assessing risk of bias in included RCTs as

described in Chapter 8 of the Cochrane Handbook for Systematic

9Caregiver-mediated exercises for improving outcomes after stroke (Review)

http://onlinelibrary.wiley.com/o/cochrane/clabout/articles/STROKE/frame.html

http://www.pedro.org.au/

http://www.naric.com/?q=en/REHABDATA

http://www.clinicaltrials.gov/

https://www.clinicaltrialsregister.eu

http://www.strokecenter.org/trials/

http://www.controlled-trials.com

http://www.who.int/ictrp/en/

http://www.anzctr.org.au/

Reviews of Interventions (Higgins 2011). We assessed allocation (se- lection bias), blinding (performance and detection bias), incom-

plete outcome data (attrition bias), selective reporting (reporting

bias), and other potential sources of bias, such as management of

dropouts (no intention-to-treat analysis). We presented the results

in ’Risk of bias’ tables. We provided our judgement (’low risk’,

’high risk’ or ’unclear risk’) for each entry, followed by a descrip-

tion of the judgement. We made our judgements transparent, and

used comments or quotes when necessary.

Measures of treatment effect

We extracted means and standard deviations (SDs) of postinter-

vention scores and follow-up scores. Where available, we also ex-

tracted means and SDs of change from baseline.

For continuous outcomes using similar measurement scales, we

used the mean difference (MD) with 95% confidence intervals

(CIs). If similar outcomes were measured on different scales, we

used Hedges’ g, calculated the 95% CI and standard mean differ-

ence (SMD).

We reported the direction of the effect for every scale to align

the treatment effects between outcome scales. For scales in which

a low score reflected a favourable outcome and a high score an

unfavourable outcome, we multiplied scores by -1.

We used Review Manager 5 for all quantitative analyses (RevMan

2014).

Unit of analysis issues

We took into account that studies can apply different randomisa-

tion methods, for example, at the level of a participant or at the

level of a group of participants (cluster randomisation).

In selected studies with multiple intervention groups, we made

multiple pair-wise comparisons between all possible pairs of inter-

vention groups. We made sure that participants were not double-

counted in the analysis.

Dealing with missing data

If data were missing or were not in a form suitable for quantita-

tive pooling, we contacted the trial authors to request additional

information.

Assessment of heterogeneity

We assessed the impact of heterogeneity in the meta-analysis for

each outcome with the I2 statistic (Higgins 2011). When there was

substantial statistical heterogeneity (I2 greater than 50%) we used

a random-effects model, otherwise we used a fixed-effect model

for meta-analysis.

Assessment of reporting biases

Because we identified fewer than 10 studies, we did not assess re-

porting bias by a funnel plot in which effect estimates and pre-

cision (standard error) of individual RCTs are plotted, as we had

planned.

Data synthesis

We performed a meta-analysis of the comparison CME versus con-

trol group (usual care, no intervention, or any other intervention)

where there were two or more RCTs with a low risk of bias in which

study population, intervention, and outcome measures were the

same. We determined the quality of evidence using GRADE levels

of evidence.

We included a ’Summary of findings’ table using the Cochrane

template, and included the following seven outcomes: ADL mea-

sures, burden of the caregiver, walking speed, walking distance,

mood of the patient, length of stay, and adverse events (falls) (see

Summary of findings for the main comparison). For each out-

come, we included the number of participants, the overall quality

of the evidence using GRADE levels of evidence, the magnitude

of the effect, a measure of burden of the outcome, and comments

(Guyatt 2008a; Guyatt 2008b).

In the text and tables, we have systematically described those stud-

ies that could not be included in the meta-analysis. In the same

way, we systematically reported other outcome measures that we

could not include in a meta-analysis because they did not measure

the same construct as our predefined outcome measures.

We used Review Manager 5 for the analyses (RevMan 2014).

Subgroup analysis and investigation of heterogeneity

Where two or more studies per subgroup were available, we per-

formed subgroup analysis for:

• interventions with a higher dose of training in the

intervention group than the control group versus interventions

with a same dose of training in intervention and control groups;

• interventions within six months after stroke and

interventions beyond six months after stroke;

• interventions aimed at the upper extremity and

interventions aimed at the lower extremity.

Sensitivity analysis

A caregiver could be a provider of an existing intervention, for

example constraint-induced movement therapy (CIMT). We in-

cluded trials investigating this form of CME. However, in these

trials, it was difficult to separate the effects of CME from the effects

of the intervention. In the other trials, CME itself was considered

as the only intervention under study. Therefore, we performed a

sensitivity analysis in which only these trials were included (CME-

core). A priori, we did not plan this sensitivity analysis, but decided

afterwards to include this analysis in light of the type of studies

10Caregiver-mediated exercises for improving outcomes after stroke (Review)

that we identified. In this sensitivity analysis, we also repeated the

subgroup analyses.

Where we applied a fixed-effect model, we subsequently applied a

random-effects model to assess the robustness of the results to the

method used.

R E S U L T S

Description of studies

See Characteristics of included studies, Characteristics of excluded

studies, and Characteristics of ongoing studies tables.

Results of the search

Through electronic searches we found 8107 citations. In addition,

one potentially relevant trial was already known to us, but not

found through electronic searches (Wall 1987). After removing

duplicates, we screened 5640 citations. Based on screening of titles,

we excluded 5201 obviously irrelevant studies and screened the

remaining 439 abstracts. Subsequently, we excluded 307 studies

based on the abstract. Finally, we assessed 132 full-text articles

or trial registry entries for eligibility. After an extensive search,

we still could not obtain full-text articles for four studies (“THE

DAYS AFTER”; “Family boosts results of poststroke therapy”; Liu

2012; Wang 2014). We identified 11 relevant systematic reviews,

which we screened for trials (Bakas 2014; Brereton 2007; Glasdam

2010; Klinke 2015; Lawler 2013; Legg 2011; Morris 2014; Parke

2015; Pollock 2014a; Pollock 2014b; Warner 2015). In total, we

identified 46 potentially relevant trials. The results of the search

are summarised in Figure 1. We were able to include nine trials for

final analysis (see Characteristics of included studies table), and we

included six trials in the meta-analysis (Abu Tariah 2010; Barzel

2015; Dai 2013; Galvin 2011; Wall 1987; Wang 2015).

11Caregiver-mediated exercises for improving outcomes after stroke (Review)

Figure 1. Study flow diagram.

12Caregiver-mediated exercises for improving outcomes after stroke (Review)

We excluded three trials from the meta-analysis because of poor

methodological quality (Agrawal 2013; Gómez 2014) or no re-

porting of required data (i.e. means or SDs, or both, of outcome

measures) (Agrawal 2013; Gómez 2014; Souza 2015), or both. We

had no success contacting the corresponding authors to request

the necessary data.

We excluded 37 trials, 35 with reasons given in the Characteristics

of excluded studies table. Two trials are ongoing (see

Characteristics of ongoing studies table).

Included studies

Participants

Characteristics

In the nine included studies, 456 stroke survivors and their care-

givers were randomised to CME or control interventions. A total

of 342 people with stroke-caregiver couples were included in the

six trials included in the meta-analysis. In these six trials, nine pa-

tient-caregiver couples were not analysed according to intention-

to-treat principles and no information about these withdrawals

was published. Therefore, we have presented information about

333 stroke survivors and their caregivers (ranging from 18 to 156

patient-caregiver couples per trial) in the meta-analysis.

The mean age in all studies was around 60 years. The mean time

since onset of symptoms ranged from 15 days to 10 years. One

trial did not report mean time since onset of symptoms (Gómez

2014).

Three studies defined inclusion or exclusion criteria for the care-

giver, for example “willing to participate”, “medically stable and

physically able” (Galvin 2011), “being defined as primary care-

givers” (Dai 2013), and “caregivers were excluded if they were in

poor physical health, had mental or behavioural disorders” (Wang

2015).

Four studies described an inclusion criterion for the patient about

the caregiver: “live with family caregiver at home” (Abu Tariah

2010), “patients with family support” (Gómez 2014), “had a care-

giver who was prepared to be a non-professional coach (e.g., fam-

ily member)” (Barzel 2015), and “availability of a family mem-

ber to supervise home exercises” (Souza 2015). Two studies gave

information about the caregiver: “about 50% of the caregivers

were nursing attendants” (Dai 2013), and “majority were patients’

spouse” (Wang 2015).

Sample size

Five trials included fewer than 50 participants: 20 participants

(Abu Tariah 2010; Wall 1987), 24 participants (Souza 2015), 30

participants (Agrawal 2013), and 40 participants (Galvin 2011).

Four trials included more than 50 participants: 51 participants

(Wang 2015), 55 participants (Dai 2013), 60 participants (Gómez

2014), and 156 participants (Barzel 2015).

Interventions

The content of the training and the timing was different between

trials. Details of each intervention are summarised in Table 1.

Two trials were aimed at the lower body (Galvin 2011; Wall 1987),

five at the upper body (Abu Tariah 2010; Agrawal 2013; Barzel

2015; Gómez 2014; Souza 2015), and two at both upper and

lower body (Dai 2013; Wang 2015). Four studies included patients

within six months after stroke (Agrawal 2013; Dai 2013; Galvin

2011; Gómez 2014), three studies included patients beyond six

months after stroke (Barzel 2015; Wall 1987; Wang 2015), one

study included patients from two months after stroke or later (Abu

Tariah 2010), one study included patients if they had a stroke

in the last 24 months (Souza 2015). The task of the caregiver

ranged across trials from supervision, guidance, encouragement,

to physical help. In four trials, usual care continued, so CME were

applied in addition to usual care (Agrawal 2013; Dai 2013; Galvin

2011; Gómez 2014). The frequency, duration, and programme

length differed between studies, with training frequencies ranging

from twice a week (Wall 1987; Wang 2015), to every day (Abu

Tariah 2010; Galvin 2011), with a duration per session ranging

from 30 minutes (Dai 2013), to three hours (Souza 2015), and

a programme length ranging from 14 days (Gómez 2014), to six

months (Wall 1987). In four trials, patients had weekly contact

with the supervising therapist (Agrawal 2013; Barzel 2015; Galvin

2011; Wang 2015). Two trials planned two to four sessions with a

therapist (Abu Tariah 2010; Dai 2013). One trial had 10 sessions

with a therapist in 22 days (Souza 2015). One trial consisted of

four groups, the amount of contact with the therapist differed

between trial groups (Wall 1987). The frequency and duration

of one trial was not clearly reported (Gómez 2014). Three trials

were carried out at home (Abu Tariah 2010; Barzel 2015; Wang

2015), one trial was carried out in an inpatient setting (Gómez

2014), three trials were carried out when patients were inpatient,

outpatient, or at home (Galvin 2011; Souza 2015; Wall 1987),

and two trials were unclear about the location of the intervention

(Agrawal 2013; Dai 2013).

Two trials had more than one trial group. The study by Agrawal

2013, which was not included in meta-analysis, had two experi-

mental trial groups with different duration of intervention (60 and

90 minutes, five days a week) and one control group. Wall 1987

had two intervention groups (CME, CME plus physiotherapy)

and two control groups (physiotherapy, no intervention). We de-

cided to combine the intervention groups and the control groups

13Caregiver-mediated exercises for improving outcomes after stroke (Review)

into one comparison because of the small total number of partic-

ipants (20).

Compliance

Five studies recorded compliance: “frequency of training and tasks

completed was recorded” (Wang 2015), “the amount of training

was noted in a diary by patients’ families” (Abu Tariah 2010),

“compliance with therapy time was documented through the use of

an exercise diary, in which the number of exercises completed and

time taken to complete the exercises were recorded daily” (Galvin

2011), “a log sheet per participant to record the total number of

minutes completed per day” (Agrawal 2013), and “compliance was

assessed in all participants via a form (standard therapy group) or

a training diary (home CIMT group)” (Barzel 2015). Two trials

reported these outcomes in the results. Galvin 2011 reported that

245 minutes of additional exercise therapy was planned for each

participant and that a mean of 227 minutes was actually delivered.

Barzel 2015 reported a mean exercise time of 27.7 hours within

the four-week intervention. They also noted 12 cases of partici-

pants not adhering to the protocol. In Souza 2015, compliance

about wearing of the sling was reported in the results, but no in-

formation about compliance to the CME was provided. Agrawal

2013 mentioned “inability to monitor patient’s compliance with

the home exercise programme which might have influenced the

study”.

Comparisons

Interventions consisted of CME in addition to usual care (Agrawal

2013; Dai 2013; Galvin 2011; Gómez 2014), or instead of usual

care (Abu Tariah 2010; Barzel 2015; Souza 2015; Wall 1987; Wang

2015). Two studies included a control intervention (Abu Tariah

2010; Souza 2015), seven included usual care as control (Agrawal

2013; Barzel 2015; Dai 2013; Galvin 2011; Gómez 2014; Wall

1987; Wang 2015), one had no control intervention (Wall 1987).

Furthermore, there were different forms of interventions in terms

of type of exercise therapy, duration of the intervention, and timing

of the intervention.

Outcome measures

All trials reported outcome measures at the end of intervention.

Five trials reported outcome measures after three to six months’

follow-up (Abu Tariah 2010; Barzel 2015; Galvin 2011; Souza

2015; Wall 1987). Two trials reported outcome measures during

the intervention period (Dai 2013; Wall 1987). Some outcome

measures were not reported at baseline, but only at post interven-

tion and at follow-up. In some instances there were no SDs of

outcome measures given, for which we imputed other SDs from

the same study when possible (i.e. Galvin 2011: no SD at post

intervention for NEADL Index, CSI and Reintegration to Nor-

mal Living Index was available and follow-up SD was used; Abu

Tariah 2010: no SD at post intervention or follow-up for Wolf

Motor Function test - performance time was given and SD from

baseline was used). Walking speed was reported in different units

and were converted to metres/second. Where available, we also

extracted mean changes from baseline (Abu Tariah 2010; Barzel

2015; Galvin 2011; Wang 2015), and in those cases where postin-

tervention scores were not available, we used the mean change

from baseline. Abu Tariah 2010 and Wang 2015 gave no SDs, but

provided CIs. We calculated the SDs for these outcomes using the

Z-score.

One trial reported two outcome measures for extended ADL (

Galvin 2011). Based on that, the NEADL Index is developed for

people with stroke and widely used in stroke research, we restricted

to NEADL Index in the main analysis.

Insufficient information was available regarding the type of care-

giver, rendering it impossible to distinguish between caregivers

who were family or friends and other (voluntary) caregivers for the

different outcome measures. One study mentioned that “about

50% of the caregivers were nursing attendants” (Dai 2013), and

one study included four paid workers (Wang 2015). We did not

take this professional background into account during the analy-

ses.

The trials used a variety of outcome measures. Some outcome mea-

sures were identical, but most differed between trials. We com-

bined outcome measures when they appeared to measure the same

construct.

Excluded studies

We excluded 35 articles based on the full texts because they did

not meet the inclusion criteria (Adie 2014; Araujo 2015; Barzel

2009; Baskett 1999; Bertilsson 2014; Cameron 2015; Chang

2015; Chinchai 2010; El-Senousey 2012; Evans 1984; Forster

2013; Goldberg 1997; Grasel 2005; Harrington 2010; Harris

2009; Hebel 2014; Hirano 2012; Jones 2015; Kalra 2004; Koh

2015; Larson 2005; Lin 2004; Maeshima 2003; Marsden 2010;

McClellan 2004; Mudzi 2012; NCT00908479; Osawa 2010;

Parker 2012; Redzuan 2012; Schure 2006; Shyu 2010; Smith

2004b; Van de Port 2012; Walker 1996). See Characteristics of

excluded studies table.

The most common reasons for exclusion were: interventions

were educational for patient and caregiver but they performed

no, or minimal, exercises together (Chinchai 2010; El-Senousey

2012; Evans 1984; Forster 2013; Harrington 2010; Larson 2005;

Marsden 2010; Mudzi 2012; Parker 2012; Schure 2006; Shyu

2010; Smith 2004a); caregivers were involved and encouraged to

participate but caregiver participation was not mandatory (Adie

2014; Baskett 1999; Bertilsson 2014; Harris 2009; Jones 2015;

Lin 2004; McClellan 2004; NCT00908479; Van de Port 2012;

Walker 1996); and the intervention concerned ’skill training’

14Caregiver-mediated exercises for improving outcomes after stroke (Review)

https://archie.cochrane.org/sections/documents/view?version=z1610311627460202692183161311537%26format=REVMAN#STD-Chinchai-2010

https://archie.cochrane.org/sections/documents/view?version=z1610311627460202692183161311537%26format=REVMAN#STD-El_x002d_Senousey-2012

https://archie.cochrane.org/sections/documents/view?version=z1610311627460202692183161311537%26format=REVMAN#STD-Evans-1984

https://archie.cochrane.org/sections/documents/view?version=z1610311627460202692183161311537%26format=REVMAN#STD-Forster-2013

https://archie.cochrane.org/sections/documents/view?version=z1610311627460202692183161311537%26format=REVMAN#STD-Harrington-2010

https://archie.cochrane.org/sections/documents/view?version=z1610311627460202692183161311537%26format=REVMAN#STD-Larson-2005

https://archie.cochrane.org/sections/documents/view?version=z1610311627460202692183161311537%26format=REVMAN#STD-Marsden-2010

https://archie.cochrane.org/sections/documents/view?version=z1610311627460202692183161311537%26format=REVMAN#STD-Mudzi-2012

https://archie.cochrane.org/sections/documents/view?version=z1610311627460202692183161311537%26format=REVMAN#STD-Parker-2012

https://archie.cochrane.org/sections/documents/view?version=z1610311627460202692183161311537%26format=REVMAN#STD-Schure-2006

https://archie.cochrane.org/sections/documents/view?version=z1610311627460202692183161311537%26format=REVMAN#STD-Shyu-2010

https://archie.cochrane.org/sections/documents/view?version=z1610311627460202692183161311537%26format=REVMAN#STD-Smith-2004a

(Araujo 2015; Chang 2015; El-Senousey 2012; Forster 2013;

Grasel 2005; Hebel 2014; Kalra 2004; Mudzi 2012). Skill train-

ing is primarily aimed at training of the caregiver in performing

ADL and mobility together with the patient to improve function-

ing together in the home situation. Skill training is given to the

caregiver in a limited number of sessions by a professional, like a

therapist or a nurse, but it is not considered progressive training

to improve functioning of the patient.

Furthermore, there are some non-randomised studies about CME

(Barzel 2009; Hirano 2012; Maeshima 2003; Osawa 2010). Be-

cause of their relevance for the topic of this review they are listed

in Characteristics of excluded studies table. However, it is impor-

tant to note that our search was not aimed at identifying non-

randomised studies and, therefore, we may not be complete in

reporting these studies.

Risk of bias in included studies

Assessments for ’Risk of bias’ in individual studies are shown in

the Characteristics of included studies table. See also Figure 2 and

Figure 3 for a summary of the results.

Figure 2. Risk of bias graph: review authors’ judgements about each risk of bias item presented as

percentages across all included studies.

15Caregiver-mediated exercises for improving outcomes after stroke (Review)

Figure 3. Risk of bias summary: review authors’ judgements about each risk of bias item for each included

study.

16Caregiver-mediated exercises for improving outcomes after stroke (Review)

Allocation

All trials used random allocation to an intervention or control

group, of which four adequately described how the randomisation

procedure took place and provided sufficient information to de-

termine that the allocation procedure was concealed (Abu Tariah

2010; Barzel 2015; Galvin 2011; Wang 2015). One study was

unclear about the randomisation procedure, but did provide suffi-

cient information about allocation procedure (Souza 2015). The

other four studies did not describe the randomisation procedure

sufficiently (Agrawal 2013; Dai 2013; Gómez 2014; Wall 1987).

Blinding

Participant blinding

Due to the nature of the intervention, participants included in the

trials could not be blinded for treatment allocation.

Investigator blinding

Six studies blinded the outcome assessors to treatment allocation

(Abu Tariah 2010; Barzel 2015; Dai 2013; Galvin 2011; Souza

2015; Wang 2015). Three studies did not report anything about

an outcome assessor (Agrawal 2013; Gómez 2014; Wall 1987).

Five studies used participant-reported outcomes (questionnaires,

report of number of falls) (Barzel 2015; Dai 2013; Galvin 2011;

Souza 2015; Wang 2015). For these outcomes, the assessor (patient

or caregiver) was aware of the treatment allocation. This may have

biased the results.

Incomplete outcome data

Three studies had no withdrawals and, therefore, reported com-

plete outcome data (Agrawal 2013; Wall 1987; Wang 2015). Four

studies had withdrawals, but reasons were well described and com-

parable in the intervention and control group (Barzel 2015; Dai

2013; Galvin 2011; Souza 2015). One study reported only with-

drawals in the control group (Abu Tariah 2010). Reasons for with-

drawal were not documented by the participants, making the risk

of bias unclear. One trial did not describe withdrawals, making

the risk of bias unclear (Gómez 2014).

Selective reporting

For two included trials (Barzel 2015; Galvin 2011), we identified

a trial registry (NCT00666744) and published protocol (Barzel

2013; Galvin 2008b). Galvin 2011 reported no exclusion crite-

ria in the trial paper in contrast to the protocol paper (Galvin

2008b) and trial registration (NCT00666744). Not all outcome

measures that were reported in the protocol paper of Barzel 2013

were reported in the trial paper (Barzel 2015), such as the EQ-5D

and healthcare costs. There were an insufficient number of studies

(fewer than 10) to reliably examine the effects of risk of bias on

estimates of effect and thus we generated no funnel plots.

Other potential sources of bias

Three trials did not perform an intention-to-treat analysis. This

could be a potential source of bias (Abu Tariah 2010; Dai 2013;

Souza 2015). Three trials did not report means or SDs for (a

part of ) the study outcomes (Agrawal 2013; Galvin 2011; Souza

2015). In one trial, means and SDs for outcome measures were

not given, the included outcomes were insufficiently described,

and intervention and timing of measurements needed clarification

(Gómez 2014). We identified no other potential sources of bias

for the remaining trials (Barzel 2015; Wall 1987; Wang 2015).

Grading the quality of the evidence

We determined the quality of the evidence using GRADE levels

of evidence. We downgraded effects based on one trial by two

levels of evidence and effects based on a small total number of

participants (fewer than 200 participants) (BMJ Clinical Evidence

2012) by one level. When half, or more, of the included trials

for an outcome measure were of unclear or high risk of bias, we

downgraded the level of evidence by one level. When we found

substantial unexplained statistical heterogeneity or clinical hetero-

geneity, we also downgraded the level of evidence by one level.

In addition, when we found publication bias, we downgraded the

level of evidence by one level.

Effects of interventions

See: Summary of findings for the main comparison Caregiver-

mediated exercises compared with control intervention for people

with stroke

Caregiver-mediated exercises versus control

(Comparison 1 and 2): primary outcomes

Patient: activities of daily living measures

End of intervention

Three trials assessed the BI (100-point version) (Barzel 2015;

Galvin 2011; Wang 2015). We found no significant summary ef-

fect (mean difference (MD) 5.09, 95% CI -2.88 to 13.07; P =

17Caregiver-mediated exercises for improving outcomes after stroke (Review)

0.21; Table 2). One trial used the FIM (Dai 2013). The effect

of CME on the FIM was not significant (MD 11.04, 95% CI -

1.59 to 23.67; P = 0.09; Table 2). Overall, we found no signifi-

cant summary effect on basic ADL (standardised mean difference

(SMD) 0.21, 95% CI -0.02 to 0.44; P =0.07; Analysis 1.1). The

quality of evidence for effects on basic ADL was moderate; it was

downgraded one level due to clinical heterogeneity between stud-

ies.

Two trials assessed extended ADL (Barzel 2015; Galvin 2011).

We found no significant effects of CME on the NEADL Index

(MD 5.50, 95% CI -5.83 to 16.83; P = 0.34; Table 2) or on

the Instrumental Activities of Daily Living (IADL) (MD 0.02,

95% CI -0.72 to 0.76; P = 0.96; Table 2). Overall, we found no

significant summary effect on extended ADL (SMD 0.07, 95%

CI -0.21 to 0.35; P = 0.64; Analysis 1.2). This effect was based

on two trials with low risk of bias, but with clinical heterogeneity

between studies and a small total number of participants for this

outcome measure, resulting in a low quality of evidence.

Follow-up

Two trials assessed basic ADL and extended ADL at three months’

follow-up (Galvin 2011) and six months’ follow-up (Barzel 2015).

We found no significant summary effect of CME on basic ADL

(MD 2.69, 95% CI -8.18 to 13.55; P = 0.63; Analysis 2.1). This

effect was based on two trials with low risk of bias, but with clin-

ical heterogeneity between studies and a small total number of

participants for this outcome measure, resulting in a low quality

of evidence. The substantial statistical heterogeneity between tri-

als (I2 =69%), can be explained by different timing post stroke

(within six months versus beyond six months) and thus there was

no reason to downgrade the level of evidence further.

The effect of CME on extended ADL measured with the NEADL

Index (MD 9.50, 95% CI -1.83 to 20.83; P = 0.10; Table 2), or

measured with the IADL (MD 0.02, 95% CI -0.77 to 0.81; P =

0.96; Table 2) was not significant. Overall, there was no significant

summary effect of CME on extended ADL (SMD 0.11, 95% CI

-0.17 to 0.39; P = 0.45; Analysis 2.2). The quality of evidence

was low, based on two trials with low risk of bias, but with clinical

heterogeneity between studies and a small total number of partic-

ipants for this outcome measure.

Caregiver: measures of burden

End of intervention

One trial used the CSI to assess caregiver burden (Galvin 2011);

we found no significant effect (MD -0.50, 95% CI -1.81 to 0.81;

P = 0.46; Table 2). Another trial used the Caregiver Burden Scale

(Wang 2015), and again we found no significant effect (MD 1.30,

95% CI -4.88 to 7.48; P = 0.68; Table 2). Overall, we found no

significant summary effect of CME on caregiver strain (SMD -

0.04, 95% CI -0.45 to 0.37; P = 0.86; Analysis 1.3). These findings

were based on two trials with low risk of bias, but with a small

total number of participants for this outcome measure, resulting

in moderate quality of evidence.

Follow-up

One study reported follow-up of caregiver burden by using the

CSI, three months after termination of the intervention (Galvin

2011). We found no significant effect of CME on caregiver strain

compared with the control group (MD 0.60, 95% CI -0.71 to

1.91; P = 0.37; Analysis 2.3). The quality of the evidence for this

finding was very low, since it is based on only one trial with a small

number of participants.

Caregiver-mediated exercises versus control

(Comparison 1 and 2): secondary outcomes

Measures of motor impairment

One study assessed the FMA lower extremity score (Galvin 2011).

We found no significant effect after the intervention (MD 3.10,

95% CI -2.02 to 8.22; P = 0.24; Analysis 1.4) or at follow-up

(MD 3.40, 95% CI -1.74 to 8.54; P = 0.19; Analysis 2.4). These

findings were based on one trial with a small number of partici-

pants, resulting in a very low quality of evidence.

One study assessed the FMA upper extremity score (Abu Tariah

2010). We found no significant effect of CME at the end of in-

tervention (MD 4.43, 95% CI -2.09 to 10.95; P = 0.18; Analysis

1.5) or at follow-up (MD 2.75, 95% CI -8.24 to 13.74; P = 0.62;

Analysis 2.5). These findings were based on only one trial with a

small number of participants. Therefore, the quality of evidence

was very low.

Gait and gait-related measures

Balance

Two trials reported the BBS (Galvin 2011; Wang 2015). We found

a significant summary effect (MD 6.35, 95% CI 1.64 to 11.06;

P = 0.008; Table 2). One study assessed the Postural Assessment

Scale for Stroke Patients (Dai 2013), and found no significant

effect of CME (MD 3.50, 95% CI -0.52 to 7.52; P = 0.09;

Table 2). Overall, we found a significant summary effect of CME

on standing balance performance at the end of the intervention

(SMD 0.53, 95% CI 0.19 to 0.87; P = 0.002; Analysis 1.6). These

findings were based on a small total number of participants and

there was clinical heterogeneity between studies resulting in a low

quality of evidence. One trial was of unclear risk of bias (Dai 2013),

but more than half of the trials were of low risk of bias (Galvin

18Caregiver-mediated exercises for improving outcomes after stroke (Review)

2011; Wang 2015), and thus there was no reason to downgrade

the level of evidence further.

Only one trial assessed standing balance performance at three

months’ follow-up (Galvin 2011). There was no significant effect

(MD 8.40, 95% CI -1.04 to 17.84; P = 0.08; Analysis 2.6). This

effect was based on one trial with a small number of participants

resulting in a very low quality of evidence.

Walking distance

Two trials used the Six-Minute Walk Test to assess walking distance

(Galvin 2011; Wang 2015). We found no significant summary

effect of CME at the end of the intervention period (MD 30.98 m,

95% CI -20.22 to 82.19; P = 0.24; Analysis 1.7). These findings

were based on two trials with a low risk of bias, but with a small

total number of participants for this outcome measure, resulting

in a moderate quality of evidence.

Only one trial assessed the Six-Minute Walk Test at three months’

follow-up (Galvin 2011). There was a significant effect in favour

of CME (MD 109.50 m, 95% CI 17.12 to 201.88; P = 0.02;

Analysis 2.7). This finding was based on one trial with a small

number of participants, resulting in a very low quality of evidence.

Walking speed

Two trials reported comfortable walking speed (Wall 1987; Wang

2015). We found no significant summary effect of CME on walk-

ing speed (MD 0.08 m/s, 95% CI -0.03 to 0.18; P = 0.17; Analysis

1.8). This effect was based on one trial with low risk of bias (Wang

2015) and one trial with an unclear risk of bias (Wall 1987). In

addition, there was a small total number of participants. There-

fore, the quality of evidence was low.

Only Wall 1987 reported follow-up data three months after ter-

mination of the intervention. We found no significant effect of

CME on walking speed (MD 0.10 m/s, 95% CI -0.02 to 0.22; P =

0.10; Analysis 2.8). The quality of evidence was very low, because

the effect was based on only one trial of unclear risk of bias with

a small total number of participants.

Measures of upper limb activities or function

Two trials with low risk of bias used the Wolf Motor Function

test and the Motor Activity Log (Abu Tariah 2010; Barzel 2015).

However, there may be publication bias, because all studies ex-

cluded for meta-analysis were about upper limb training (Agrawal

2013; Gómez 2014; Souza 2015). In addition, there was a small

total number of participants for these outcome measures and we

detected substantial unexplained statistical heterogeneity between

trials. We graded the quality of the evidence as very low, except

the Wolf Motor Function test - performance time and the Motor

Activity Log - amount of use at the end of intervention, and the

Motor Activity Log - quality of movement at both end of interven-

tion and follow-up. We did not detect any substantial statistical

heterogeneity in these cases and, therefore, we graded the quality

of evidence as low.

We found no significant summary effect of CME on the Wolf

Motor Function test - functional ability (end of intervention: MD

0.02, 95% CI -0.52 to 0.55; P = 0.95; Analysis 1.9; follow-up four

to six months after termination: MD 0.08, 95% CI -0.46 to 0.61;

P = 0.77; Analysis 2.9), the Motor Activity Log - amount of use

(end of intervention: MD 0.01, 95% CI -0.36 to 0.38; P = 0.96;

Analysis 1.11; follow-up four to six months after termination: MD

0.21, 95% CI -0.65 to 1.08; P = 0.63; Analysis 2.11), and Motor

Activity Log - quality of movement (end of intervention: MD

0.08, 95% CI -0.26 to 0.42; P = 0.64; Analysis 1.12; follow-up

four to six months after termination: MD -0.03, 95% CI -0.43 to

0.37; P = 0.89; Analysis 2.12).

For the Wolf Motor Function test - performance time, we found

a significant summary effect in favour of the control group post

intervention (MD -1.72, 95% CI -2.23 to -1.21; P < 0.00001;

Analysis 1.10), but not at follow-up (MD 1.85, 95% CI -8.78 to

12.48; P = 0.73; Analysis 2.10).

One trial used the Nine Hole Peg test (Barzel 2015). We found no

significant effect post intervention (MD -0.04, 95% CI -0.11 to

0.03; P = 0.26; Analysis 1.13) or at follow-up (MD -0.05, 95% CI

-0.12 to 0.02; P = 0.17; Analysis 2.13). This evidence was based

on one trial with a small number of participants, resulting in a

very low quality of evidence.

Measures of mood and quality of life of the patient

One trial assessed QoL of the patients with the SIS 3.0 at the end

of the intervention (Wang 2015), and one trial assessed only SIS

hand function (Barzel 2015).

The effect of CME was significant for the composite physical scale

(MD 12.40, 95% CI 1.67 to 23.13; P = 0.02; Analysis 1.14),

mobility scale (MD 18.20, 95% CI 7.54 to 28.86; P = 0.0008;

Analysis 1.17), and general recovery scale (MD 15.10, 95% CI

8.44 to 21.76; P < 0.00001; Analysis 1.23).

For SIS hand function at follow-up (Barzel 2015), we found no

significant effect (MD -2.20, 95% CI -12.46 to 8.06; P = 0.67;

Analysis 2.14). These findings were based on one trial with a small

number of participants resulting in a very low quality of evidence.

The reported effects on SIS hand function were based on two

trials with low risk of bias, but with clinical heterogeneity between

studies, resulting in a moderate quality of evidence.

Measures of fatigue of the patient

None of the trials reported on effects of CME on fatigue of the

patient after intervention or at follow-up.

Length of stay

None of the included trials reported length of stay as an outcome

measure. However, Galvin 2011 did state that mean length of

19Caregiver-mediated exercises for improving outcomes after stroke (Review)

hospital stay for the intervention group was 35.7 days (SD 10.5)

and for the control group was 40.1 days (SD 15). Mean length

of stay in a rehabilitation unit was 40.3 days (SD 9.6) for the

intervention group and 52.3 days (SD 40) for the control group.

Patients were recruited in a hospital and a rehabilitation unit. We

found no significant differences for length of stay in a hospital

(MD 4.40 days, 95% CI -3.91 to 12.71; P = 0.30; Analysis 1.24)

or length of stay in a rehabilitation unit (MD 12.0 days, 95% CI -

10.88 to 34.88; P = 0.30; Analysis 1.25). These effects were based

on one trial, and length of stay was reported for a small number

of participants (n = 20). Therefore, we graded the quality of the

evidence as very low.

Adverse outcomes

One trial reported falls among participants (Dai 2013). We found

no significant effect of CME on the number of falls reported (MD

0.04, 95% CI -0.10 to 0.18; P = 0.57; Analysis 1.26). There was

no follow-up in this trial. This effect was based on one trial with

unclear risk of bias and a small number of participants, resulting

in a very low quality of evidence.

Caregiver: measures of mood and quality of life

None of the included trials reported measures of mood or QoL of

the caregiver.

Other outcomes

See Table 3.

Wall 1987 reported on gait parameters such as duration of single

support phase and asymmetry ratio. We did not summarise these

findings because they were beyond the scope of this review.

Dose of training

In three trials, the dose of training was comparable between the

intervention and control groups (Abu Tariah 2010; Souza 2015;

Wall 1987).

In six trials, the dose of training in the intervention group was

higher than the dose of training in the control group (Agrawal

2013; Barzel 2015; Dai 2013; Galvin 2011; Gómez 2014; Wang

2015). In four of these trials, there was as higher dose of training in

the intervention group because the intervention was additional to

usual care and the control group received only usual care (Agrawal

2013; Dai 2013; Galvin 2011; Gómez 2014). In one trial, the in-

tensity of training in the intervention group was higher due to the

differences between interventions in the intervention and control

groups (Wang 2015). The study compared a 90-minute visit of

a therapist and performing activities at least twice weekly, and if

possible, every day in the intervention group, with a weekly visit

or telephone call of the therapist and maintaining daily routines in

the control group. In one trial, daily CIMT, which is a high-inten-

sity training intervention, was compared with usual care (Barzel

2015). With that, the intensity of training in the intervention

group was higher than the dose of training in the control group.

We could not perform subgroup analysis for dose of training

(higher dose of training versus same dose of training). For most

outcome measures, all included trials had a higher dose of training

in the intervention group, so no comparison could be made. For

walking speed and upper arm function (Wolf Motor Function test

and Motor Activity Log), one included trial was in the higher dose

of training group and one included trial was in the same dose of

training group. Because there was only one study per subgroup for

these outcome measures, we did not perform a subgroup analysis.

Timing post stroke (Comparison 3)

We performed subgroup analyses for trials that included patients

within six months after stroke (Agrawal 2013; Dai 2013; Galvin

2011; Gómez 2014) versus trials that included patients beyond six

months after stroke (Barzel 2015; Wall 1987; Wang 2015). One

trial included patients from beyond two months after stroke (Abu

Tariah 2010), and another included patients directly after stroke

(Souza 2015); however, the reported mean time since stroke was

about nine months after stroke in the Abu Tariah 2010 study and

30 months after stroke in the Souza 2015 study. Therefore, we

included both trials in the chronic phase group.

Because of the low number of included trials, we could only per-

form a subgroup analysis for the outcome measure basic ADL at

the end of intervention. We found no difference between trials

that included participants within six months after stroke when

compared with trials that included patients beyond six months

after stroke (P = 0.21; Analysis 3.1). The quality of evidence for

this comparison was low, due to clinical heterogeneity between

studies and a small total number of participants per subgroup.

For all other outcome measures, the number of included trials per

subgroup was too low to test for subgroup differences.

Upper and lower extremity

Five trials were aimed at the upper extremity (Abu Tariah 2010;

Agrawal 2013; Barzel 2015; Gómez 2014; Souza 2015), and four

of these trials were about CIMT (Abu Tariah 2010; Barzel 2015;

Gómez 2014; Souza 2015). However, Agrawal 2013, Gómez

2014, and Souza 2015 were not included in meta-analysis.

Two trials were specifically aimed at the lower extremity (Galvin

2011; Wall 1987).

Basic and extended ADL were the only outcome measures in com-

mon when comparing upper and lower extremity trials. Due to

the low number of trials per subgroup, we could not perform a

subgroup analysis.

20Caregiver-mediated exercises for improving outcomes after stroke (Review)

Reported mean changes (Comparison 4)

Mean change from post intervention to follow-up

Galvin 2011 reported mean change at follow-up (three months

after termination of the intervention) from post intervention, us-

ing the outcome measures BI, CSI, NEADL Index, Reintegration

to Normal Living Index, FMA lower extremity score, BBS, Six-

Minute Walk Test, and the Motor Assessment Scale.

This study found a significant effect in favour of CME for the

Reintegration to Normal Living Index, CSI and the Six-Minute

Walk Test. The other mean changes were not significantly differ-

ent. This result was based on one trial with a small number of

participants, resulting in a very low quality of evidence.

Sensitivity analysis (Comparisons 5 and 6)

CME-core

In five trials, CME was the only intervention (CME-core)

(Agrawal 2013; Galvin 2011; Souza 2015; Wall 1987; Wang

2015). Four trials studied the effect of another, existing interven-

tion provided by the caregiver (Abu Tariah 2010; Barzel 2015; Dai

2013; Gómez 2014). In these four trials, it was difficult to sepa-

rate the effects of CME from the effects of the other intervention

(e.g. CIMT). Therefore, we performed a sensitivity analysis that

included only CME-core trials

Three CME-core trials were suitable for meta-analyses (Galvin

2011; Wall 1987; Wang 2015). We found a significant summary

effect for basic ADL post intervention in favour of CME (2 studies;

MD 9.45, 95% CI 2.11 to 16.78; P = 0.01; Analysis 5.1). This

effect was based on two studies with low risk of bias, but with

a small total number of participants for this outcome measure,

resulting in a moderate quality of evidence.

We found no significant effect at follow-up (1 study; MD 9.00,

95% CI -1.29 to 19.29; P = 0.09; Analysis 6.1). This effect was

based on one study with a small number of participants, resulting

in a very low quality of evidence.

For extended ADL, we found no significant summary effect post

intervention (1 study; MD 5.50, 95% CI -5.83 to 16.83; P =

0.34; Analysis 5.2) or at follow-up (1 study; MD 9.50, 95% CI

-1.83 to 20.83; P = 0.10; Analysis 6.2). These effects were based

on one study with a small number of participants resulting in a

very low quality of evidence. For outcome measures relating to

caregiver burden, we found no significant differences between the

CME and control groups (see Analysis 1.3; moderate quality of

evidence; and Analysis 2.3: very low quality of evidence).

For the secondary outcome measures, we found significant effects

in favour of CME post intervention for standing balance (2 stud-

ies; MD 6.35, 95% CI 1.64 to 11.06; P = 0.008; Analysis 5.3;

moderate quality of evidence) and QoL, concerning the compos-

ite physical subscale (1 study; MD 12.40, 95% CI 1.67 to 23.13;

P = 0.02; Analysis 1.14; very low quality of evidence), mobility

subscale (1 study; MD 18.20, 95% CI 7.54 to 28.86; P = 0.0008;

Analysis 1.17; very low quality of evidence), and general recovery

subscale of the SIS (1 study; MD 15.10, 95% CI 8.44 to 21.76;

P < 0.00001; Analysis 1.23; very low quality of evidence). We

found a significant effect in favour of CME for walking distance

at follow-up (1 study; MD 109.50 m, 95% CI 17.12 to 201.88;

P = 0.02; Analysis 2.7; very low quality of evidence).

The included trials did not report the outcome measures FMA

upper extremity, upper limb activities or function, length of stay,

and adverse outcome for this sensitivity analysis.

The total number of included trials per subgroup within this sen-

sitivity analysis was too small to test for subgroup differences.

Robustness of the results

In all analyses where we applied a fixed-effect model, we subse-

quently applied a random-effects model. This did not affect the

overall results.

For one study, we combined two intervention groups (CME; CME

plus physiotherapy) and two control groups (physiotherapy; no

intervention) (Wall 1987). When we made separate comparisons

of each intervention group versus each control group, we found

no differences in the results (Comparison 7).

One study reported two outcome measures for extended ADL:

the NEADL Index and the Reintegration to Normal Living Index

(Galvin 2011). To prevent double counting this trial in our meta-

analysis, we included the NEADL Index in our primary analy-

sis. We performed a sensitivity analysis in which we replaced the

NEADL Index with the Reintegration to Normal Living Index

(Comparison 8). Changing the outcome measure did not affect

the direction or magnitude of the effect, neither did it affect the

significance level of the meta-analysis.

Qualitative synthesis

We could not include three trials in meta-analyses: the various

reasons are described in the Results of the search section (Agrawal

2013; Gómez 2014; Souza 2015).

All three trials were aimed at the upper extremity, with two trials

applying CIMT (Gómez 2014; Souza 2015). For details of these

trials, see the Characteristics of included studies table.

Agrawal 2013 comprised exercise training for the upper extrem-

ity in addition to usual care for two months. The three groups

included a total of 30 participants. The results of each group are

separately summarised in Table 4.

Gómez 2014 studied CIMT with a caregiver in addition to usual

care compared with usual care alone. The trial included a total of

60 participants and the intervention lasted 14 days. The goal of

this trial was to determine if family support could increase eligi-

bility for CIMT and to study the influence of social and family

support. Reported outcomes were a description of the included

21Caregiver-mediated exercises for improving outcomes after stroke (Review)

participants and their level of social and family support. Further-

more, correlations were calculated between ADL, cognitive func-

tioning, and level of social and family support, and were all found

to be significant. Means and SDs were not reported. Gómez 2014

concluded that family can play a crucial role in delivering a CIMT

protocol and that social and family support has a positive influence

on functional outcome of the patient.

Souza 2015 studied CIMT (partly) performed together with a

caregiver versus CIMT performed with a therapist. The trial in-

cluded a total of 24 participants and had a follow-up of six months.

The study authors published effectiveness indexes for the out-

come measures Motor Activity Log - quality of movement, FMA

upper extremity scale, and Stroke Specific Quality of Life Scale

(SSQoL). There were no differences between experimental and

control groups and the authors concluded that CIMT therapy

(partly) together with a caregiver is equally effective as CIMT ther-

apy with a therapist, but less expensive.

D I S C U S S I O N

Summary of main results

For an overview of the results, see the Summary of findings for the

main comparison.

Effects on outcome measures

This review aimed to determine the effectiveness of CME versus

control in people with stroke. We included nine out of 46 po-

tentially relevant trials. The meta-analyses included 333 patient-

caregiver couples. Four trials assessed the primary outcome mea-

sure of ADL. We found no significant summary effect on basic

ADL at the end of intervention (Analysis 1.1; moderate quality of

evidence) or at follow-up (Analysis 2.1; low quality of evidence).

For extended ADL, there were two trials, in which we found no

significant summary effect at the end of intervention (Analysis 1.2;

low quality of evidence) or follow-up (Analysis 2.2; low quality

of evidence). Two trials assessed the primary outcome measure of

caregiver burden at the end of intervention and one trial at fol-

low-up. For both time points, we found no significant summary

effects of CME (at the end of intervention: Analysis 1.3; moderate

quality of evidence; at follow-up: Analysis 2.3; very low quality of

evidence).

With regard to secondary outcome measures, we found a signifi-

cant effect in favour of CME at the end of intervention for stand-

ing balance (three studies; Analysis 1.6; low quality of evidence)

and QoL (one study: composite physical (Analysis 1.14), mobil-

ity (Analysis 1.17), and general recovery (Analysis 1.23) subscales;

very low quality of evidence). The composite physical scale is a sum

score of the scales strength, hand function, mobility, and ADL/

IADL. We found a significant effect on walking distance at follow-

up (one study; Analysis 2.7; very low quality of evidence). On the

Wolf Motor Function test - performance time at the end of inter-

vention there was a significant effect in favour of the control group

(two studies; Analysis 1.10; low quality of evidence). We found

no significant effects for walking distance post intervention or for

standing balance at follow-up, and QoL was not reported at fol-

low-up. We found no significant effects for FMA upper and lower

extremity scores, walking speed, measures of upper limb activities

or function, length of hospital stay, and adverse events (falls) at

both post intervention and at follow-up (where assessed). None of

the included trials reported on measures of fatigue of the patient

or mood and QoL of the caregiver.

Unfortunately, due to the small number of included trials, we

could not apply subgroup analyses with respect to the dose of

training and focus of CME training aimed at the upper or lower

extremity. In the subgroup analysis regarding timing since stroke

onset (within six months after stroke versus beyond six months

after stroke), we could only make a comparison for basic ADL

at the end of intervention. For the other outcome measures, the

number of included studies per subgroup was too small. Timing

since stroke did not have an effect on basic ADL at the end of

intervention (Analysis 3.1; low quality of evidence).

One trial reported mean changes from post intervention to follow-

up. Most reported mean changes were in favour of CME. The

mean change of caregiver burden from post intervention to follow-

up was significantly in favour of the CME group (Analysis 4.4;

very low quality of evidence).

CME-core

We included all trials of CME in the primary analysis. However,

several trials used CME as the only intervention (CME-core),

where in others a caregiver provided an existing intervention, for

example CIMT. In the latter trials, it is difficult to separate the

effects of CME from the effects of the other intervention.

Sensitivity analysis with the three trials investigating CME-core

showed one important difference compared with the primary anal-

ysis. We found a significant effect in favour of CME-core on ba-

sic ADL post intervention (Analysis 5.1; moderate quality of evi-

dence). On secondary outcome measures, we found the same sig-

nificant effects in favour of CME as in the primary analysis at the

end of intervention for standing balance (Analysis 5.3; moderate

quality of evidence) and QoL (composite physical: Analysis 1.14;

mobility: Analysis 1.17; general recovery scale: Analysis 1.23; all

very low quality of evidence), and at follow-up for walking dis-

tance (Analysis 2.7; very low quality of evidence). We could not

perform subgroup analysis.

It is important to note that in the CME-core analysis only lower

extremity trials could be included. An ADL outcome, such as the

BI, is more sensitive to lower extremity improvement than to upper

extremity improvement (Kwakkel 2004).

22Caregiver-mediated exercises for improving outcomes after stroke (Review)

These positive effects of CME-core on basic ADL and standing

balance may suggest improved and earlier independence, similar

to early supported discharge interventions.

Importance of the CME-core analysis

There are a limited number of trials and outcome measures in-

cluded in this meta-analysis. Due to the number of participants

in the trial of Barzel (n = 156), this trial has a large effect on the

results (Barzel 2015). The main affected outcome measures are

basic ADL, extended ADL, and measures of upper limb activities

or function (Wolf Motor Function test and Motor Activity Log).

In this trial, CIMT provided by a caregiver was compared with

standard therapy; therefore, this trial is one of the trials in which

the effects of CME are difficult to separate from the effects of

the other intervention (CIMT). Therefore, we believe that the

sensitivity analysis, in which only CME-core trials are included, is

especially important. The effects found in the analysis of CME-

core are probably the most robust to answer the objective of this

review.

Activities of daily living

We found no significant effects on basic or extended ADL in the

primary analyses. These results were not robust because CME

had a significant positive effect on basic ADL at the end of the

intervention in the sensitivity analysis of CME-core. There was no

positive effect on basic ADL at follow-up. This may be attributed

to the ceiling effect of outcome measures of basic ADL (Quinn

2011). Therefore, it is important that measures of extended ADL

are included in studies investigating CME.

CME has the potential to increase intensity of training. In most

included trials in this review, CME did increase intensity of train-

ing (Agrawal 2013; Barzel 2015; Dai 2013; Galvin 2011; Gómez

2014; Wang 2015). Several systematic reviews have shown that a

higher intensity of training can lead to better outcome in people

with stroke in terms of ADL (French 2010; Galvin 2008a; Kwakkel

2004; Kwakkel 2006; Langhorne 2011; Lohse 2014; Veerbeek

2011; Veerbeek 2014), and, therefore, one may expect favourable

outcomes in terms of ADL. However, based on the low number of

proof-of-concept trials and moderate-quality evidence, our results

are not conclusive yet and more trials assessing ADL are needed.

Caregiver burden

CME are yet another task for the caregiver and, therefore, one

could hypothesise that CME will lead to an increase in caregiver

burden. However, several authors have argued that caregiver bur-

den could actually decrease during CME, due to concurrent edu-

cation of both patient and caregiver and increased caregiver sup-

port, by providing caregivers with more knowledge about the ca-

pabilities of the person with stroke and themselves (Galvin 2011;

Kalra 2004; Wang 2015). This may potentially increase feelings of

self-efficacy and control of the caregiver (van den Heuvel 2001).

When combining data in this review from two trials that assessed

caregiver burden, we found no significant effects, that is, there was

no increase or decrease in caregiver burden (Galvin 2011; Wang

2015). Quality of the evidence was moderate. Reported mean

change on the CSI from post intervention to follow-up was in

favour of CME (Galvin 2011).

Veerbeek 2014 did show a significant homogeneous positive sig-

nificant effect size on caregiver strain in its meta-analysis of trials

about CME. The difference with our analysis is that they included

Kalra 2004, which we excluded because we implemented a differ-

ent definition of CME. Kalra 2004 applied skill training of the

caregiver, which strictly speaking is not the same as CME as it is

not a progressive training intervention. However, as skill training

and CME may be closely related, the current results on the effect

of CME on caregiver burden are not robust. So, results on care-

giver burden are inconclusive and more trials assessing caregiver

burden in CME are needed.

Adherence to safety

Adherence to safety is essential in CME. Only one included trial

assessed adverse events in terms of number of falls, and there were

no differences between the intervention and control groups. These

findings suggest that, at the least, CME are equally safe as usual

care. However, the quality of the evidence was very low. Since a

caregiver is not a professional therapist, specific screening, training,

and instruction are needed to address safety risks (e.g. falling).

Therefore, an important part of each CME protocol should be

addressing safety during CME.

Dose of training

Veerbeek 2014 found strong evidence in favour of physiotherapy

interventions with intensive, high repetitive, task-oriented, and

task-specific training in all phases post stroke. This is in line with

several other meta-analyses that showed that intensity of training

and repetitive task training are crucial aspects of stroke rehabilita-

tion, suggesting that more exercise therapy is better (French 2010;

Galvin 2008a; Kwakkel 2004; Kwakkel 2006; Langhorne 2011;

Lohse 2014; Pollock 2014a; Veerbeek 2011; Veerbeek 2014). Pol-

lock and colleagues suggested that a dose of 30 to 60 minutes per

day, delivered five to seven days per week, has a surplus value in

terms of activities. However, no conclusions could be drawn re-

garding to the total duration of the intervention due to substantial

heterogeneity in the analyses (Pollock 2014a).

All trials included in the high-intensity training group had a dose

of at least 30 to 60 minutes per day delivered five to seven days

per week. In all trials, except for Dai 2013, the intervention group

received at least 16 hours of exercise treatment compared with

the control group (Kwakkel 2004; Veerbeek 2011). In one trial,

23Caregiver-mediated exercises for improving outcomes after stroke (Review)

the intervention group received an extra 10 hours of treatment

compared with the control group (Dai 2013).

Unfortunately, in the present review, we could not perform a sub-

group analysis of the augmented dose of training compared to

dose-matched trials.

Timing post stroke

The first two months after stroke are considered the optimal time

for recovery of function (Cramer 2008; Hankey 2007; Jørgensen

1995; Jørgensen 1999; Kwakkel 2003; van Kordelaar 2014).

Pollock 2014a found evidence of greater benefit of an interven-

tion associated with a shorter time since stroke onset. Therefore,

increasing intensity of training with CME seems especially mean-

ingful in the first months after stroke. We could only perform one

subgroup analysis (basic ADL post intervention), and we found

no difference between participants who started the intervention

in the first six months after stroke and participants who started

the intervention beyond six months after stroke. However, it is

not possible to conclude if there are any differences in effect of

CME at different time points after stroke due to the low number

of included trials in subgroup analyses.

Upper versus lower extremity

Five of the nine included trials were aimed at the upper extremity

(Abu Tariah 2010; Agrawal 2013; Barzel 2015; Gómez 2014;

Souza 2015), and four of these trials were about CIMT (Abu

Tariah 2010; Barzel 2015; Gómez 2014; Souza 2015). CIMT

has proven to be an effective therapy (Nijland 2011). However,

CIMT can be a time-consuming therapy and asking for the help

of a caregiver can decrease the time spent by a therapist, so the

intervention is still enforceable. Souza and colleagues performed

an important trial by comparing CIMT therapy (partly) together

with a caregiver to CIMT therapy done with a therapist. They

found no differences between experimental and control groups

and concluded that these forms of therapy provision are equally

effective, but that training with a caregiver is less expensive when

compared to training with a therapist (Souza 2015).

In our primary analysis, we found a significant effect in favour

of the control intervention on the performance time of the Wolf

Motor Function test at post intervention, but not at follow-up.

This result is largely determined by a single study with a large

number of participants (Barzel 2015), and should, therefore, be

considered with caution.

Only two included trials were specifically aimed at the lower ex-

tremity (Galvin 2011; Wall 1987). A disadvantage of interventions

aimed at the lower extremity is the safety aspect. The risk of ad-

verse events (e.g. tripping or falling) is much higher when standing

or walking is practiced compared with practicing the use of the

upper extremity. However, evidence for intensity trials focused on

the lower limb showed them to be more effective than those aimed

at the upper paretic limb after stroke. This latter finding makes

focusing CME on gait and gait-related activities meaningful.

Overall completeness and applicability of evidence

We found a limited number of trials (nine) with substantial varia-

tion in type of CME, duration, timing of training (i.e. within six

months or beyond six months after stroke), and outcome measures,

which hampered summarising and combining data in a meta-anal-

ysis. However, for both primary outcome measures we found two

or more trials of relative good quality.

Due to the limited number of included studies, not enough good

quality trials were available to perform subgroup analyses, with the

exception of timing post stroke (i.e. within six months or beyond

six months) for the outcome basic ADL.

Two studies included paid as well as unpaid caregivers, which could

not be separated in the results (Dai 2013; Wang 2015). Therefore,

this review could not compare the effect of paid and unpaid care-

givers. The effects of exercising with a paid caregiver may be differ-

ent compared with exercising with an unpaid caregiver, especially

when there is a difference in the relationship between patient and

caregiver.

There may be cultural, ethnic, and societal differences between re-

gions and countries that can influence the applicability and effec-

tiveness of CME interventions. Where ethnicity in itself may not

be a limitation for individualised CME programmes after stroke,

potential facilitators and barriers may be present that relate to the

capacity of the professional to navigate cultural and ethnic differ-

ences effectively (Norris 2014).

In addition, involving caregivers during the rehabilitation process

can be more or less easy to implement and may be more or less

accepted as self-evident in certain cultures for several reasons. In

some countries, rehabilitation services are not readily available and

communities are required to help, so-called ’community-based

rehabilitation’ (WHO CBR). One of the excluded trials performed

CME in both groups (Redzuan 2012). When contacted, the study

author explained that caregivers (or paid workers) are often asked

to help in Malaysia. Conversely, caregivers in Western cultures,

with advanced healthcare systems and different social practices

may be more inclined to leave healthcare services to professionals.

However, due to constant changes and budget cuts in Western

health care, more pressure is put on the family to provide care.

Therefore, CME could have very different implications in different

cultures.

Quality of the evidence

The risk of bias of the nine included trials was generally low or

unclear (Characteristics of included studies table). Unfortunately,

there was insufficient data (fewer than 10 trials) to examine the

24Caregiver-mediated exercises for improving outcomes after stroke (Review)

effects of risk of bias on the calculated estimates of effect reliably

by funnel plots.

The overall quality of evidence was very low to moderate. De-

tails of GRADE levels of evidence are presented in the Effects of

interventions section. The meta-analysis could include only six

trials and these included trials were small, considering the number

of included participants per trial. Therefore, we downgraded most

of the evidence one level due to a small total number of partici-

pants (fewer than 200 participants). For some outcome measures

(mainly aimed at upper extremity functioning), there was substan-

tial unexplained statistical heterogeneity and we downgraded the

level of evidence one level. For other outcome measures, there was

substantial clinical heterogeneity. There is substantial variation be-

tween type of exercises performed with a caregiver between trials.

We differentiated between CIMT trials (Abu Tariah 2010; Barzel

2015), trials with mobility exercises (Galvin 2011; Wall 1987;

Wang 2015), and other trials (Dai 2013). When these trials were

combined, we downgraded the level of evidence because there was

clinical heterogeneity. In addition, there may be publication bias

in the comparisons about upper extremity functioning, because all

trials not included in meta-analyses were aimed at upper extremity

functioning, and, therefore, we downgraded the level of evidence

for these outcome measures.

For an overview of the quality of evidence per outcome measure

see Summary of findings for the main comparison.

Potential biases in the review process

In some countries, CME appears to be more necessary or is more

accepted, or both, in daily practice due to lack of formal rehabil-

itation services or because of cultural attitudes. Although specu-

lative, the implementation of CME could, therefore, be different

across countries, suggesting that compliance should be systemat-

ically measured in CME trials. As we did not identify any com-

pleted trials from, for example, Africa, Asia, and South America,

information on such cultural differences remains elusive.

In the current review, we made a distinction between CME and

skill training of the caregiver, whereby we excluded trials about

skill training as skill training does not pertain specifically to a

couple performing exercises together. There could potentially be

some overlap between these two forms of training. By excluding

trials about skill training, potentially useful information from these

trials may have been missed. However, we are confident that our

current results do adequately reflect the effects of CME.

Regarding the data-analysis, we employed imputation or extrap-

olation procedures where SDs were not reported or could not be

obtained from the study authors. In four analyses, the SDs from

the same trial were used, for example from baseline. For mean

changes, we used 95% CI and the Z-score to calculate SDs. Al-

though this could be a potential source of bias, it is unlikely that

results were impacted in a major way.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

Currently, there is evidence of very low to moderate quality that

caregiver-mediated exercises (CME) can improve patients’ func-

tional performance in terms of standing balance and quality of

life (QoL) at the end of intervention and walking distance at the

end of follow-up, with no significant increase or decrease effect on

caregiver burden and no significant effects on (extended) activities

of daily living (ADL). Separate analyses of only CME-core trials

suggest favourable effects in terms of basic ADL at the end of inter-

vention. However, the results should be interpreted with caution

since the included phase II trials were small, had potential bias,

and had methodological shortcomings including multiple testing.

In addition, one outcome measure was in favour of the control

group (Wolf Motor function test - performance time), although

this result was mainly influenced by one study with a relatively

large number of participants.

The findings in this review suggest that CME may be a valuable

and resource-efficient intervention to augment intensity of reha-

bilitation services after stroke. The effect of CME may be explained

by, at least in part, an increase in intensity of training. However,

due to the small number of included trials, we could not confirm

or reject this hypothesis. In addition, CME can be a treatment

option when an increase in intensity of training is useful, for ex-

ample in constraint-induced movement therapy (CIMT). To im-

plement CME, it is essential that study protocols are published

explaining in detail the type, intensity, and content of exercises as

well as safety instructions. Finally, CME can be used in inpatient

settings as well as in outpatient settings and may be used in acute,

subacute, and chronic phase after stroke.

Implications for research

Further studies are needed to get a more complete overview of the

different aspects of CME such as timing, duration, and frequency,

to assess the most suitable target audience, and to assess (long-

term) effects. In addition, it is important to study caregiver burden

in relation to CME further, and to assess self-efficacy and study

empowerment of people with stroke and their caregivers, which

may allow stroke patients to return earlier to the community and

stay independently at home (van Vliet 2015). At the moment,

only nine trials have been published that use different outcome

measures and measurement tools, making it difficult to summarise

and combine outcome measures.

In addition, studies about cost-effectiveness are needed. CME have

the potential to achieve a higher intensity of training, resulting

in better functional outcome, without increasing healthcare costs.

One included trial recorded length of stay and showed a positive

trend (Galvin 2011). However, more studies are needed to de-

termine if CME can be cost-effective by reducing length of stay,

25Caregiver-mediated exercises for improving outcomes after stroke (Review)

supporting early supported discharge, improving outcomes, and

therewith reducing direct and indirect healthcare costs.

To visualise exercises, measure compliance, or keep contact with a

supporting therapist, the use of e-health appears promising. This

could also be a cost-effective method. E-health in combination

with CME has not been studied to date, but two similar clinical

trials conducted in different countries (i.e. Adelaide, Australia and

Amsterdam, the Netherlands) are currently ongoing (Care4Stroke

trial 2014). In particular, because of the impact of availability of

community-based stroke services as well as cultural differences

with respect to the role of the caregiver as a co-therapist, CME

cannot be implemented around the world in the same way. Due to

these cross-cultural differences, exercising with a caregiver will be

interpreted and implemented differently and so it will be necessary

to identify these differences before implementation.

In conclusion, future trials should obey the current CON-

SORT statements for reporting randomised controlled trials

(CONSORT 2010). In addition, they should be powered in a

more robust way by including more participants and provide larger

treatment contrasts of additional (caregiver-mediated) exercises

when compared with the control group as suggested in several

meta-analyses with respect to intensity of exercise therapy, include

a long-term follow-up, use a consensus-based set of clinical out-

come measures (particularly with respect to primary outcomes

such as basic ADL and extended ADL), as well as perceived bur-

den of the caregiver. Preferably, these trials should include an eco-

nomical evaluation alongside to investigate the cost-effectiveness

of these services.

A C K N O W L E D G E M E N T S

We acknowledge the support of Brenda Thomas and Hazel Fraser

from the Cochrane Stroke Group, Remke Albers from Amsterdam

Rehabilitation Research Centre Reade and the Dutch Cochrane

Centre for their help in preparing the protocol and the assistance

in developing the search strategies. In addition, we wish to ac-

knowledge all external peer reviewers, with special thanks to the

consumer reviewer Marion Foreman.

R E F E R E N C E S

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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Abu Tariah 2010

Methods Design: randomised trial of CIMT training vs NDT training Study duration: 6 months (2 months’ intervention and 4 months’ follow-up) Randomisation: 20 participants were randomly numbered from 1 to 20; odd numbers participated in the CIMT group, even numbers in the NDT group

Allocation concealment: not applicable: all participants were randomised at the same time Blinding: assessors blind for group allocation ITT: no

Participants Randomised: 20 participants Withdrawals: 2 participants dropped out of the NDT group at an early stage. There were no reasons given by the participants

Intervention: 10 participants; 8 men and 2 women; mean age 54.8 years (SD 10.9); mean time since stroke 9.2 months (SD 5.79)

Control: 8 participants; 4 men and 4 women; mean age 60.6 years (SD 4.9); mean time since stroke 9.6 months (SD 4)

Inclusion criteria: stroke > 2 months ago; aged 40 to 75 years; live with family caregivers at their homes; no balance problem that might risk safety

Exclusion criteria: recurrent, bilateral or brain stem stroke; inability to actively extend 10° at metacarpophalangeal and interphalangeal joints, and 20° at wrist; substantial use

of the involved upper extremity in their life situation: Motor Activity Log - amount of

use scale > 2.5; major cognitive deficits (score < 24 points on the Folstein Mini-Mental

State Examination); excessive spasticity and pain, as determined by clinical judgement

Interventions Intervention: CIMT: intensive training of the affected arm 2 hours/day, while restraining the unaffected hand with a resting splint, 7 days/week, for 2 months; 2 trained occupa-

tional therapists educated and trained stroke survivors and their caregivers at home in

3 or 4 sessions; detailed information about the training activities to be carried out were

given; importance of caregiver commitment was discussed; training activities focuses

on patient’s ADL/IADL/leisure activities; amount of training was noted in a diary by

patients’ family

Control: NDT: training consisted of weight bearing and facilitation of arm movement based on conventional NDT procedures; 2 hours/day during weekdays in outpatient

clinic and a home programme of 2 hours during the weekend for 2 months; once a week

a home visit and follow-up telephone calls

Setting: outpatient clinic of a large hospital; intervention done at home

Outcomes Included outcomes: Wolf Motor Function test, Motor Activity Log, Fugl-Meyer Assess- ment upper extremity

Measurements: baseline assessment, post intervention after 2 months, follow-up 4 months after end of the treatment

Notes

Risk of bias

34Caregiver-mediated exercises for improving outcomes after stroke (Review)

Abu Tariah 2010 (Continued)

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk The 20 participants were randomly num-

bered from 1 to 20; odd numbers in CIMT

group, even numbers in NDT group

Allocation concealment (selection bias) Low risk All participants were randomised at the

same time.

Blinding of participants and personnel

(performance bias)

All outcomes

High risk Participants and personnel cannot be blind

for the intervention

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk Investigators were blind to the allocation

of the group, they provided the evaluation.

The investigators were not the therapists

who treated the participants

Incomplete outcome data (attrition bias)

All outcomes

Unclear risk 2 withdrawals in the control NDT group,

there were no reasons given by the par-

ticipants. No withdrawals in intervention

group. The effect of withdrawal from the

control group was unclear

Selective reporting (reporting bias) Unclear risk No trial registry; nothing stated. Outcomes

were described in results

Other bias Unclear risk Small sample size; no ITT analysis

Agrawal 2013

Methods Design: randomised trial of exercise training of upper extremity in addition to usual care vs usual care; 3 groups: 90 minutes’ exercise training, 60 minutes’ exercise training,

control

Study duration: 4 weeks Randomisation: ’randomly assigned’, not described how Allocation concealment: not described Blinding: not described ITT: yes

Participants Randomised: 30 participants Withdrawals: 0 Intervention: Group A (+ 90 minutes): 10 participants; 7 men and 3 women; mean age 55.80 years

(SD 4.10); mean time since stroke 3.50 months (SD 1.08)

Group B (+ 60 minutes): 10 participants; 5 men and 5 women; mean age 55.70 years

(SD 6.24); mean time since stroke 3.70 months (SD 1.34)

Group C (control): 10 participants; 7 men and 3 women; mean age 55.20 years (SD 6.

35Caregiver-mediated exercises for improving outcomes after stroke (Review)

Agrawal 2013 (Continued)

12); mean time since stroke 3.50 months (SD 1.08)

Inclusion criteria: subacute median carotid artery stroke diagnosed by neuro-physician on CT or MRI scan; Fugl-Meyer Assessment upper extremity scale score between 10

and 57; aged 45 to 65 years

Exclusion criteria: Mini-Mental Status Examination score < 20; visual/auditory impair- ments; presence of any other neurological diagnosis other than stroke or any other major

comorbidity; unstable cardiovascular status; non-co-operative patients

Interventions Intervention: GRASP (Graded Repetitive Arm Supplementary Program) protocol: self- administered upper-limb exercise programme aimed at improving upper-limb recovery;

exercise book and kit tailored according to the motor impairment level; exercise book

contained written and pictorial instructions; kit contained inexpensive equipment to

complete the exercises; each exercise was graded by varying repetitions to meet each

participant’s need; exercises included strengthening of the arm, range of motion, and

gross and fine motor skills. Repetitive goal and tasks-oriented activities were designed

to simulate partial or whole skill sets required for ADL; 5 days/week, 90 minutes/day

(group A) or 60 minutes/day (group B); help of 1 caregiver; weekly meeting with the

therapist; plus the education programme: information on stroke recovery and general

health

Control: education programme (information on stroke recovery and general health) and conventional physiotherapy (not described)

Setting: rehabilitation unit of a hospital

Outcomes Included outcomes: Fugl-Meyer Assessment upper extremity scale, Chedoke Arm and Hand Activity Inventory

Measurements: baseline assessment, post intervention assessment after 4 weeks

Notes In results section, SDs were not noted.

Contact with authors was unsuccessful.

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk “Randomly assigned”; but not described

how.

Allocation concealment (selection bias) Unclear risk Not described

Blinding of participants and personnel

(performance bias)

All outcomes

High risk Participants and personnel cannot be blind

for the intervention

Blinding of outcome assessment (detection

bias)

All outcomes

Unclear risk Not described

Incomplete outcome data (attrition bias)

All outcomes

Low risk No withdrawals

36Caregiver-mediated exercises for improving outcomes after stroke (Review)

Agrawal 2013 (Continued)

Selective reporting (reporting bias) Unclear risk No trial registry; nothing stated

Other bias Unclear risk None of the SDs in the result section were

noted.

Barzel 2015

Methods Design: cluster-randomised trial of home CIMT vs standard therapy Study duration: 4 weeks Randomisation: practices were stratified by region and randomly allocated by an external biometrician (1:1, block size of 4) using a computer-generated sequence

Allocation concealment: yes, by the computer-generated sequence. Randomisation was per practice and further allocation concealment was not necessary. Furthermore, patients

were included in the study before randomisation of practices to minimise differential

self-selection

Blinding: assessors blind for group allocation; statistician was also masked ITT: yes

Participants Randomised: 156 participants Withdrawals: 5 withdrawals in the intervention group because of death, poor health, and not wanting to continue; 4 withdrawals in the control group because of moving, death,

and poor health

Intervention: Home CIMT: 85 participants; 51 men and 34 women; mean age 62.55 years (SD 13.73); mean time since stroke 56.57 months (SD 47.36)

Standard therapy: 71 participants; 43 men and 28 women; mean age 65.30 years (SD

12.63); mean time since stroke 45.65 months (SD 57.69)

Inclusion criteria: physical and occupational therapy practices: treating adults with upper limb dysfunction after stroke unless they already offered CIMT, with 1 therapist with

a professional qualification or at least 2 years of experience in treatment of chronic im-

pairment caused by stroke; patients: > 6 months after stroke, mild-to-moderate impair-

ment of arm function and minimal residual hand function (minimum 10° active wrist

extension, 10° active thumb abduction or extension, and 10° extension of 2 additional

fingers), had a referral for physical or occupational therapy, > 18 years, had a caregiver

who was prepared to be a non-professional coach (e.g. family member)

Exclusion criteria: severely impaired verbal communication, inability to give consent, se- vere neurocognitive deficits (score < 23 in the Mini-Mental State Examination), terminal

illness, or life-threatening comorbidities, or previously received CIMT

Interventions Intervention: home CIMT: patients were instructed to train in their home environment for 2 hours each day, accompanied by a coach. Additionally, patients were asked to wear

a resting glove during exercises and ADL to immobilise their non-affected hand. The

therapists guided the coach on how to document the time or repetitions per time for

each exercise and to assist the patient in keeping a training diary. Therapists used the

first of 5 home visits to instruct the patient and the coach in the principles of home

CIMT, set individually tailored goals, and work through the first 2 to 3 exercises, focusing

on everyday practice. During subsequent weekly home visits, therapists supervised the

training, set up new exercises, and applied behavioural techniques. Professional therapy

time was not used to practise exercises

37Caregiver-mediated exercises for improving outcomes after stroke (Review)

Barzel 2015 (Continued)

Control: conventional physical or occupational therapy, but additional home training was not obligatory. Standard therapy could consist of various therapeutic techniques

typical of stroke therapy. The standard therapy group therapists reported details of pro-

fessional treatment delivery and any agreements (e.g. homework) made with patients via

a standardised documentation sheet

Setting: intervention group - home; control group - therapy practice

Outcomes Included outcomes: Motor Activity Log - quality of movement, Wolf Motor Function test - performance time, Motor Activity Log - amount of use, Wolf Motor Function test -

functional ability, Nine Hole Peg Test, SIS hand function, Barthel index, IADL

Measurements: baseline assessment, post intervention assessment after 4 weeks, follow- up assessment at 6 months. Interim interview (Motor Activity Log) at 3-month follow-

Notes For mean changes of outcomes means and 95% confidence intervals were given. To

calculate SDs, we used the Z-score (1.96)

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk Practices were stratified and randomly al-

located by an external biometrician using a

computer-generated sequence

Allocation concealment (selection bias) Low risk By computer-generated sequence. Further-

more, patients were included in the study

before randomisation of practices to min-

imise differential self-selection

Blinding of participants and personnel

(performance bias)

All outcomes

High risk Participants and personnel cannot be blind

for the intervention

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk Outcome assessors and the statistician were

masked.

Incomplete outcome data (attrition bias)

All outcomes

Low risk 5 withdrawals in intervention group and 4

in the control group; well described and for

similar same reasons

Missing data were imputed using correct

methods; analyses were by ITT and in case

of missing values, a last observation carried

forward imputation was performed

Selective reporting (reporting bias) Low risk The study protocol is available and pres-

elected outcomes are in the review. There

are some minor differences: EQ-5D, costs

38Caregiver-mediated exercises for improving outcomes after stroke (Review)

Barzel 2015 (Continued)

and SIS are not described in this paper

Other bias Low risk

Dai 2013

Methods Design: randomised trial of VR plus conventional rehabilitation vs conventional rehabil- itation

Study duration: 4 weeks Randomisation: the wards of the same hospital were randomly assigned to the intervention or control group

Allocation concealment: not described Blinding: assessors blind for group allocation ITT: no

Participants Randomised: 55 participants Withdrawals: 3 withdrawals in the intervention group because of depression, upper gastrointestinal bleeding, and transfer to another hospital, 4 withdrawals in the control

group because of declination (2), asthma attack (1), and transfer to another hospital (1)

Intervention: 24 participants; 16 men and 8 women; mean age 57.21 years (SD 12.23); time since stroke 56.88 days (SD 38.93)

Control: 24 participants; 12 men and 12 women; mean age 65.54 years (SD 14,67); time since stroke 73.88 days (SD 37.86)

Inclusion criteria: for the stroke patients: being diagnosed by physicians by CT or MRI scan of the brain as having experienced a right hemispheric stroke, including haemor-

rhagic or ischaemic strokes, and first-time stroke with a duration < 6 months from the

stroke onset; meeting the conditions for neglect on any of the 2 scales within the Be-

havioral Inattention Test Conventional subtest; capable of communicating in Mandarin

Chinese or Taiwanese, and understanding instructions; for the primary caregivers: be-

ing defined as primary caregivers by patients during inpatient rehabilitation, including

family members, friends, employed nursing aides, and foreign caregivers; willing to par-

ticipate in supervising and guiding the patients’ VR training; capable of communicating

in Mandarin Chinese or Taiwanese

Exclusion criteria: recurrent stroke with duration > 6 months from stroke onset; < 2 subtests of diagnosed neglect; incapability to communicate; lack of primary caregivers

Interventions Intervention: VR plus conventional rehabilitation (see control); VR: 1. with their eyes open, the patients moved their head up and down for 20 times or for 1 minute. They

also moved their head from side to side for 20 times or for 1 minute, 2. with their eyes

closed, the patients moved their head up and down for 20 times or for 1 minute. They

also moved their head from side to side for 20 times or for 1 minute, 3. the polypropylene

corrugated board was placed on the trainers’ thighs. The target was at the same height

as the patients’ eyes. The patients gazed at the target while moving their head up and

down and from side to side for 20 times, 4. the patients rested as necessary. The patients

performed steps 1 to 3 repeatedly, and the entire process took approximately 30 minutes;

patients were seated in their wheelchairs and their heads and bodies were in the middle

position. The instructors verbally reminded the patients to maintain their heads and

bodies in the middle position; first and second week a registered trained nurse trained

the patients in VR; third and fourth week: patients were guided and supervised by their

39Caregiver-mediated exercises for improving outcomes after stroke (Review)

Dai 2013 (Continued)

primary caregivers (the nurse taught the caregivers how to do this in sessions of 5 to 10

minutes, 2 to 4 in total); training once a day for 30 minutes; total of 10 sessions in 2

weeks

Control: conventional rehabilitation: the exercise training for the physiotherapy included passive exercises, active exercises, resistive exercises, ambulation training, and so on. The

occupational therapy included maintaining or improving physiological functions such

as endurance, balance, and training; to improve ADL, such as dressing, using the toilet,

sanitation, home care, and others; 5 days/week for 2 hours

Setting: rehabilitation wards of 2 medical centres

Outcomes Included outcomes: Rivermead Behavioral Inattention Test, Functional Independence Measure, Postural Assessment Scale for people with stroke, falls/person

Measurements: baseline assessment, assessment at day 14, and assessment at day 28

Notes “In the Taiwanese health care system, informal caregivers typically assist patients in their

activities of daily living”

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk The wards were randomly assigned, but

method not described.

Allocation concealment (selection bias) Unclear risk The wards were randomly assigned, but

method not described.

Blinding of participants and personnel

(performance bias)

All outcomes

High risk Participants and personnel cannot be blind

for the intervention

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk Assessors were blinded.

Incomplete outcome data (attrition bias)

All outcomes

Low risk 7 withdrawals: 4 in control group and 3

in intervention group. Reasons were well

described and about the same

Selective reporting (reporting bias) Unclear risk No trial registry; nothing stated

Other bias Unclear risk No ITT analysis

40Caregiver-mediated exercises for improving outcomes after stroke (Review)

Galvin 2011

Methods Design: randomised trial of exercise therapy (FAME (Fitness And Mobility Exercise) programme) plus ’routine’ physiotherapy vs ’routine’ physiotherapy

Study duration: 5 months (8 weeks’ intervention and 3 months’ follow-up) Randomisation: computer-generated random numbers placed in sealed envelopes. The envelopes were opened by an independent person by enrolment of a participant

Allocation concealment: yes, by the sealed envelopes Blinding: assessor blind for group allocation ITT: yes

Participants Randomised: 40 participants Withdrawals: 2 participants in the intervention group withdrew because of second stroke and myocardial infarction. 1 participant in the control group withdrew because of med-

ically unwell

Intervention: 20 participants; 13 men and 7 women; mean age 63.15 years (SD 13.3); time since stroke 18.9 days (SD 2.9)

Control: 20 participants; 7 men and 13 women; mean age 69.95 years (SD 11.69); time since stroke 19.7 days (SD 3)

Inclusion criteria: for the people with stroke: first unilateral stroke (MRI or CT); no impairment of cognition (> 23 of 30 on the Mini-Mental State Examination); aged

≥ 18 years; participating in a physiotherapy programme; a family member willing to

participate in the programme; 3.2 to 5.2 on the Orpington Prognostic Scale (to control

for heterogeneity); for the caregivers: willing to participate in the programme; nominated

by the person with stroke as the person that he or she would most like to assist him or

her in the performance of the exercises; medically stable and physically able to assist in

the delivery of exercises

Exclusion criteria (only described in protocol): hemiplegia of a non-vascular origin; dis- charge < 2 weeks following stroke; pre-existing neurological disorder resulting in a motor

deficit in addition to that resulting from the stroke; present with any lower extremity

orthopaedic condition such as recent fractured femur or amputation; have receptive/

expressive dysphasia

Suitability was determined after consultation with the individual, their family, and the

physiotherapist in charge of the patient’s routine care

Interventions Intervention: FAME programme plus ’routine’ physiotherapy (see control); FAME pro- gramme: doing exercises together with a nominated family member; daily, 35 minutes,

inpatient or at home; weekly were treatment goals set and instructions given by a treating

therapist; individual treatment protocol except for the time component; emphasis of

the programme was on achieving stability and improving gait velocity and lower limb

strength based on patterns derived from findings reported in a systematic review of 151

intervention studies on stroke rehabilitation; a second family member could be involved;

compliance was documented with an exercise diary

Control: ’routine’ physiotherapy: inpatient or outpatient in either hospital or rehabilita- tion unit; duration was not recorded; given by staff not linked to the project

Setting: 6 (acute) hospital stroke units or rehabilitation units, or both, in the same hospital or linked to the hospital; inpatient and (if possible) outpatient

Outcomes Included outcomes: lower limb section of the Fugl-Meyer Assessment, Motor Assessment scale, Berg Balance Scale, Six-Minute Walk Test, 100-point original Barthel Index, Rein-

tegration to Normal Living Index, Nottingham Extended Activities of Daily Living In-

dex, Caregiver Strain Index

41Caregiver-mediated exercises for improving outcomes after stroke (Review)

Galvin 2011 (Continued)

Measurements: baseline, post intervention (8 weeks) and follow-up 3 months after postin- tervention assessment

Notes No SDs were available for Caregiver Strain Index, Nottingham Extended Activities of

Daily Living Index and Reintegration to Normal Living Index at post intervention

Contact with authors was unsuccessful.

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk Computer-generated random numbers in

sealed envelopes, which were opened by an

independent person

Allocation concealment (selection bias) Low risk Random numbers in sealed envelopes

Blinding of participants and personnel

(performance bias)

All outcomes

High risk Participants and personnel cannot be blind

for the intervention

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk Outcome assessor was not involved in care

and unaware of group allocation

Incomplete outcome data (attrition bias)

All outcomes

Low risk 2 withdrawals in intervention group and

1 in the control group; well described and

for similar reasons. Missing data were im-

puted using correct methods; analyses were

by ITT and a last measurement carried for-

ward method was used to account for attri-

tion

Selective reporting (reporting bias) Low risk Study protocol was available and all the pre-

selected outcomes were in the review

Other bias Unclear risk No SDs were available for Caregiver Strain

Index, Nottingham Extended Activities of

Daily Living Index and Reintegration to

Normal Living Index at post intervention.

SDs from follow-up were imputed

42Caregiver-mediated exercises for improving outcomes after stroke (Review)

Gómez 2014

Methods Design: randomised trial of CIMT in addition to usual care with help of a caregiver vs usual care

Study duration: 14 days Randomisation: simple alternating randomisation Allocation concealment: no Blinding: no information about the assessor of the measurements ITT: not clear: withdrawals were not described. Different numbers were given in the outcome tables

Participants Randomised: 60 participants Withdrawals: not described Intervention: 30 participants; 20 men and 10 women; mean age 68.03 years (SD 12.43) ; time since stroke not described

Control: 30 participants; 20 men and 10 women; mean age 68.33 years (SD 12.78); time since stroke not described

Inclusion criteria: 20 grades extension in the wrist and 10 grades extension in metacarpal joints, subacute phase after stroke, people in wheelchairs or with severe balance problems,

people with mild cognitive impairment, people with family support

Exclusion criteria: excessive spasticity, behavioural problems

Interventions Intervention: CIMT therapy with a restriction of 75% of the non-affected arm with a mitt (4 hours free), forced use of the affected arm: daily 1.5 hours with an occupational

therapist, 2 hours and ADL monitored by personnel and family and 2 hours of manual

activities proposed by the occupational therapist and supervised by family (for 14 days

every day?)

Patients wore the sling for 14 days. Before the start there was a meeting with the family

in which the exercises were explained and a log sheet with activities to be completed

every day during the 14 days of the therapy was given

Control: usual care: traditional occupational therapy Setting: a chronic care and long-stay facility in Spain, inpatient rehabilitation setting

Outcomes Included outcomes: Barthel Index, Index of Lawton and Brody (version 8), Purdue Peg- board, Dynamometer Test, Cognitive Mini Mental Examination of Lobo, modified scale

of Socio-family Gijon; outcomes that needed clarification: cancellation, Nlesulam

Measurements: baseline and post intervention (14 days?)

Notes Article in Spanish. No means and SDs for outcome measures were given, included

outcomes were not all clear, intervention and timing of measurements needed some

clarification. However, contact with the authors was unsuccessful

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk Randomisation by simply alternating.

However, it was not described which

method was used

43Caregiver-mediated exercises for improving outcomes after stroke (Review)

Gómez 2014 (Continued)

Allocation concealment (selection bias) Unclear risk It was not described which randomisation

method was used. Therefore, allocation

concealment was unknown

Blinding of participants and personnel

(performance bias)

All outcomes

High risk Participants and personnel cannot be blind

for the intervention

Blinding of outcome assessment (detection

bias)

All outcomes

Unclear risk Not described

Incomplete outcome data (attrition bias)

All outcomes

Unclear risk Withdrawals were not described.

Selective reporting (reporting bias) Unclear risk No trial registry, nothing stated

Other bias Unclear risk No means and SDs were described.

Souza 2015

Methods Design: randomised trial of CIMT partly supervised by a caregiver vs CIMT supervised by a therapist

Study duration: 6 months (22 days’ intervention and 6 months’ follow-up) Randomisation: patients were randomised by a staff member not involved in the study. Randomisation information was stored in sealed envelopes that were kept in a cabinet

accessible solely to the principal investigator

Allocation concealment: yes, by the sealed envelopes Blinding: assessor blinded for group allocation ITT: no

Participants Randomised: 24 participants Withdrawals: 3 participants in the intervention group withdrew because of fatal recur- rent stroke, moving away, and financial limitations; 2 participants in the control group

withdrew because of returning to work and finding the exercises too difficult

Intervention: 9 participants; 6 men and 3 women; mean age 61.7 years (SD 12.7); time since stroke 27.6 months (20.9)

Control: 10 participants; 9 men and 1 women; mean age 59.5 years (SD 9.1); time since stroke 35.3 months (SD 33.8)

Inclusion criteria: aged > 18 years; history of ischaemic or haemorrhagic stroke leading to upper limb paresis in the previous 24 months; minimal active range of motion of 10°

for wrist extension, 10° for abduction/extension of the thumb and at least 2 additional

digits, 90° for shoulder flexion and abduction, 45° for shoulder external rotation, 30°

for elbow extension, 45° for forearm supination and pronation (from neutral position)

, wrist extension (from neutral), and finger extension of all digits; amount-of-use score

on the Motor Activity Log > 2.5; balance and stability to move using a glove in the

unaffected hand; safe and independent transfer to toilet; ability to stand for 2 minutes

with and without the glove (with support of upper limbs, if necessary); availability of a

44Caregiver-mediated exercises for improving outcomes after stroke (Review)

Souza 2015 (Continued)

family member to supervise home exercises

Exclusion criteria: medical problems or cognitive deficit (Mini-Mental State Examination score < 24) that could interfere with study completion; aphasia or hemi-neglect; intended

or actual participation in any other study; significant pain (≥ 4 on a visual analogue scale)

in any joint; upper limb treatment with antispasticity drugs in the previous 6 months;

and severe upper limb spasticity (≥ 3 in the Modified Ashworth Scale)

Interventions Intervention: in the CIMT1.5h direct group, patients performed exercises with the paretic upper limb for 1.5 hours at an outpatient facility and home exercises, supervised by a

caregiver or family member, for additional 1.5 hours. 2 days before treatment started, the

caregiver was trained for 1 hour by the researcher providing CIMT on how to supervise

the prescribed exercises performed by the patient at home. Each caregiver was instructed

to make notes in a log book about the exercises performed, the number of repetitions, and

difficulties experienced by the patient. At the beginning of each session, the homework

was discussed and when necessary, the level of difficulty was increased or new tasks were

prescribed. The CIMT1.5h direct group received written assignment of practice at home

Control: in the CIMT3h direct group, patients performed exercises under direct super- vision of a therapist, at the outpatient facility,

In both groups , training was provided in an individual basis and consisted of shaping prin- ciples and task-specific practice. Shaping exercises comprised a battery of tasks including

grasping and releasing objects of different shapes, playing cards and board games, clay ac-

tivities, drawing, and painting. Tasks were tailored to needs of each patient. Task-specific

practice for both groups involved preparing a snack (sandwiches and juice), including

arranging dishes and cutlery on a table, washing and drying them, and putting them

in a cupboard. Treatment regimens were designed to ensure that both groups received

the same amount of task practice and shaping. Furthermore, in both groups, patients

were required to use a padded mitt in the unaffected hand at home, as much as possible

during waking hours. The mitt prevented use of the unaffected hand to perform fine

motor activities and was used during ADL and household activities. All patients were

instructed to record the use time of the mitt and any difficulties perceived at home, in

log books. At the beginning of each outpatient session the notes were discussed and, if

necessary, problem-solving strategies were applied

Setting: at home and an outpatient clinic

Outcomes Included outcomes: Motor Activity Log - quality of movement, Fugl-Meyer Assessment upper extremity scale, Stroke Specific Quality of Life Scale

Measurements: baseline, post intervention 2 days after stop of the intervention, and follow-up 6 months after post intervention assessment

Notes No means and SDs were published of post intervention or follow-up scores, but ef-

fectiveness indexes were. However, contact with the authors was unsuccessful. Stroke

leading to upper limb paresis in the previous 24 months was named as an inclusion

criterion. However, mean time after stroke was 27 months in the intervention group and

35 months in the control group

Risk of bias

Bias Authors’ judgement Support for judgement

45Caregiver-mediated exercises for improving outcomes after stroke (Review)

Souza 2015 (Continued)

Random sequence generation (selection

bias)

Unclear risk “Patients were randomised by a staff mem-

ber not involved in the study”. But not de-

scribed how

Allocation concealment (selection bias) Low risk Used sealed envelopes

Blinding of participants and personnel

(performance bias)

All outcomes

High risk Participants and personnel cannot be blind

for the intervention

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk Assessor blinded for group allocation

Incomplete outcome data (attrition bias)

All outcomes

Low risk 5 withdrawals: 2 in control group and 3

in intervention group. Reasons were well

described and similar

Selective reporting (reporting bias) Unclear risk No trial registry; nothing stated

Other bias Unclear risk No ITT

No means and SDs were described

Wall 1987

Methods Design: randomised trial about exercise therapy; 4 groups: home exercise programme alone, outpatient physiotherapy alone, home exercises + physiotherapy, no intervention

Study duration: 9 months (6 months’ intervention, 3 months’ follow-up) Randomisation: ’randomly assigned’ is stated in article. No further information Allocation concealment: not described Blinding: not described ITT: yes, no withdrawals

Participants Randomised: 20 participants Withdrawals: 0 Intervention and control: 4 interventions; 5 participants per intervention; no information about participants per intervention; in general: aged 45 to 70 years; men and women;

time since stroke between 18 months and 10 years

Inclusion criteria: not clearly stated (capable of walking with or without a walking stick) Exclusion criteria: negative prognosticators such as serious or unstable medical condi- tions, major central sensory disorders, homonymous hemianopia, marked cognitive dis-

turbances, intractable pain, motivation defects, incontinence of bowel or bladder

Interventions Intervention: Group B: home exercise programme: 10 exercises over 1 hour. They were designed

hierarchically in terms of complexion. Each exercise lasted 5 minutes with the same

distribution of exercise and rest. After the fifth and the eighth exercise there was a 5-

minute rest. After 1 month, the most basic exercise was dropped and an additional,

46Caregiver-mediated exercises for improving outcomes after stroke (Review)

Wall 1987 (Continued)

more demanding, exercise was added. The exercises were done twice a week. A booklet

describing the exercises, duration, and sequence was provided. The programme was

undertaken in the person’s home with supervision of their spouse or companion. Twice a

week for 1 hour. The physiotherapist monitored the programme. Instructional videotapes

were available to demonstrate the correct way to do the exercise. These were shown to

patients and caregivers when they came for assessment

Group C: outpatient physiotherapy + home exercise programme: exercise programme

(as Group B); once a week for 1 hour outpatient physiotherapy and once a week for 1

hour home exercise programme

Control: Group A: outpatient physiotherapy alone; the exercises were taught by a physiotherapist.

Feedback and correction was given by this therapist. Twice a week for 1 hour

Group D: control group: no therapy

Setting: outpatient

Outcomes Included outcomes: walking speed Other outcomes: measurements of duration of the single support phase of the affected side, measures of the degree of temporal symmetry; asymmetry ratio

Measurements: baseline assessment, 1 month interval during treatment, after treatment, and follow-up after 3 months

Notes Inclusion criteria were not clearly stated. There was information about the participants:

all participants had residual hemiplegia due to stroke experienced between 18 months

and 10 years previously. They all had undergone rehabilitation and were discharged

from this. All participants were capable of walking and showed (subjectively) a reduced

support phased time of the affected limb

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk “Randomly assigned”, but not stated how.

Allocation concealment (selection bias) Unclear risk Not described

Blinding of participants and personnel

(performance bias)

All outcomes

High risk Participants and personnel cannot be blind

for the intervention

Blinding of outcome assessment (detection

bias)

All outcomes

Unclear risk Not described

Incomplete outcome data (attrition bias)

All outcomes

Low risk No withdrawals

Selective reporting (reporting bias) Unclear risk No trial registry; nothing stated

47Caregiver-mediated exercises for improving outcomes after stroke (Review)

Wall 1987 (Continued)

Other bias Low risk

Wang 2015

Methods Design: randomised trial of a caregiver-mediated home-based intervention vs usual care Study duration: 12 weeks Randomisation: with computer-generated numbers, each approved patient drew a folded piece of paper with 1 of these numbers from a bag

Allocation concealment: yes, folded pieces of paper in a bag Blinding: assessor blind for group allocation ITT: yes, no withdrawals

Participants Randomised: 51 participants Withdrawals: 0 Intervention: 25 participants; 13 men and 12 women; mean age 62.0 years (SD 9.5); time since stroke 18.0 months (SD 15.2)

Control: 26 participants; 17 men and 9 women; mean age 65.4 years (SD 10.6); time since stroke 18.5 months (SD 17.1)

Inclusion criteria: single ischaemic or haemorrhagic stroke in the cerebral hemisphere, as determined through CT or MRI; > 6 months post onset; mild-to-moderate disability

(Brunstrom 3 to 5); undergoing rehabilitation activities ≤ 2 times a week; home dwelling;

had family members, friends, or paid workers as caregivers; still required assistance to

accomplish everyday activities

Definition caregiver: a person who was most responsible for person’s daily care and who

lived with the person

Exclusion criteria: patient: required use of nasogastric feeding, urine tube, tracheal tube; exhibit 1 of the following conditions: recurring stroke, dementia, global or receptive

aphasia, severe orthopaedic disability, unstable medical condition; caregiver: poor phys-

ical health; mental or behavioural disorders; unable to provide the person at least 2 x 60-

to 90-minute sessions of rehabilitation training per week

Interventions Intervention: caregiver-mediated home-based intervention (CHI): CHI programme con- sisted of 3 phases: phase 1 (weeks 1 to 4) to improve person’s body functions and struc-

tural components; phase 2 (weeks 5 to 8) to improve person’s ability to undertake every-

day activities within their living environments using task-specific restorative and com-

pensatory training methods; and phase 3 (weeks 9 to 12) to help the person reintegrate

into the society by participating in restorative outdoor leisure activities; a physiothera-

pist outlined a personalised weekly training schedule according to the CHI programme;

weekly visit of the physiotherapist of about 90 minutes: tasks were explained, demon-

strated, practiced, and evaluated; individualised training guidelines or illustrations were

written; frequency of training and tasks completed was recorded; caregiver was asked

to encourage and help if necessary the patient to perform the planned activities twice

weekly and if possible every day

Control: usual care: patients maintained their everyday routines; received weekly visits or telephone calls by the therapist to talk about rehabilitation progress, daily activities,

and general health; no specific instructions or guidance related to rehabilitation skills

Setting: rehabilitation and neurology departments of teaching hospitals

48Caregiver-mediated exercises for improving outcomes after stroke (Review)

Wang 2015 (Continued)

Outcomes Included outcomes: Barthel Index, Caregiver Burden Scale, Berg Balance Scale, Six-Minute Walk Test, walking speed, SIS

Measurements: baseline assessment, post intervention assessment (12 weeks)

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk “Computer-generated numbers on folded

pieces of paper in a bag: each approved pa-

tient draw a folded paper”

Allocation concealment (selection bias) Low risk “Folded pieces of paper in a bag”

Blinding of participants and personnel

(performance bias)

All outcomes

High risk Participants and personnel cannot be blind

for the intervention

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk “All outcome measurements were evalu-

ated by an independent physical therapist”

Incomplete outcome data (attrition bias)

All outcomes

Low risk No withdrawals, no missing outcomes

Selective reporting (reporting bias) Unclear risk No trial registry; nothing stated

Other bias Low risk

ADL: activities of daily living; CIMT: constraint-induced movement therapy; CT: computerised tomography; IADL: instrumental

activities of daily living; ITT: intention-to-treat; MRI: magnetic resonance imaging; NDT: neurodevelopmental treatment; SD:

standard deviation; SIS: Stroke Impact Score; VR: vestibular rehabilitation.

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Adie 2014 No CME intervention. Caregivers were involved in the intervention, but were not obliged

Araujo 2015 No CME intervention, but skill training and a bit educational intervention

Barzel 2009 CME, not RCT

49Caregiver-mediated exercises for improving outcomes after stroke (Review)

(Continued)

Baskett 1999 No CME intervention. Family and caregivers were encouraged to participate during therapy

Bertilsson 2014 No CME intervention. Caregivers were asked to be involved in the intervention, but were not obliged

Cameron 2015 No CME intervention. Intervention about how and at which moment to support caregivers

Chang 2015 No CME intervention. Part of the intervention was skill training. Another part was an intervention for the

patient. The 2 interventions could not be separated

Chinchai 2010 No CME intervention. Educational intervention for the caregiver, with a small part consisting of skill training

El-Senousey 2012 No CME intervention but skill training and educational intervention for the caregivers

Evans 1984 No CME intervention. Educational intervention for patient and caregiver

Forster 2013 No CME intervention but skill training and educational intervention for the caregivers

Goldberg 1997 No CME intervention. Intervention consists of a support programme for patient and caregivers at home

Grasel 2005 Not an RCT, no CME but skill training for the caregivers.

Harrington 2010 No CME intervention. Group community education programme where caregivers were invited to also participate

Harris 2009 No CME intervention. Family and caregivers were encouraged to participate during therapy. 1 article reported

specifically about the role of caregiver involvement in this treatment

Hebel 2014 No CME intervention, but skill training intervention

Hirano 2012 CME, not RCT

Jones 2015 No CME intervention. “Optional caregiver inclusion”

Kalra 2004 No CME intervention but skill training and educational intervention for the caregivers

Koh 2015 No CME intervention. Caregivers were included to provide safety, but the exercises were done by the patient

him- or herself

Larson 2005 No CME intervention. Educational intervention by nurse for caregiver

Lin 2004 No CME intervention. Family and caregivers were encouraged to participate during therapy

Maeshima 2003 CME, not RCT

Marsden 2010 No CME intervention. Exercises for patient, educational intervention for both patient and caregiver

McClellan 2004 No CME intervention. Family and caregivers were encouraged to participate during therapy

50Caregiver-mediated exercises for improving outcomes after stroke (Review)

(Continued)

Mudzi 2012 No CME intervention but skill training and educational intervention for the caregivers

NCT00908479 No CME intervention. Family and caregivers were encouraged to participate during therapy. Only trial infor-

mation was found

Osawa 2010 CME, not RCT

Parker 2012 No CME intervention. Educational intervention for the caregiver, with a small part consisting of skill training

Redzuan 2012 Comparison of 2 caregiver-mediated interventions. Studied intervention was video therapy, not CME

Schure 2006 No CME intervention. Educational intervention for the caregiver, with a small part consisting of skill training

Shyu 2010 No CME intervention. Educational intervention for the caregiver, with a small part consisting of skill training

Smith 2004b No CME intervention. Educational intervention for patient and caregiver

Van de Port 2012 No CME intervention. Family and caregivers were encouraged to participate during therapy

Walker 1996 No CME intervention. Intervention aimed at dressing. Family and caregivers were encouraged to participate

during therapy

CME: caregiver-mediated exercise; RCT: randomised controlled trial.

Characteristics of ongoing studies [ordered by study ID]

ATTEND trial 2013

Trial name or title ATTEND trial

Methods RCT

Participants People with stroke, recent ischaemia (< 1 month), residual disability, aged 18 to 99 years, able to identify a

nominated caregiver

Interventions Intervention: trained family-led caregiver-delivered, home-based rehabilitation programme: patient is advised to undergo therapy twice a day for 6 months. Caregiver training is given for approximately 60 minutes/day

for up to 3 days. Components: information, joint goal setting, task-orientated training, discharge planning,

exercises. Detailed instructions for exercises will be used from www.physiotherapyexercises.com/

Control: usual care

Outcomes Primary outcome: modified Rankin Scale

Secondary outcomes: Barthel Index, Caregiver Burden Scale, health-related quality of life: WHO Quality of

Life - BREF and EuroQoL, patient and caregiver mood: Hospital Anxiety and Depression Scale, Nottingham

Extended Activities of Daily Living Index, costs. On 3 and 6 months

51Caregiver-mediated exercises for improving outcomes after stroke (Review)

http://www.physiotherapyexercises.com/

ATTEND trial 2013 (Continued)

Starting date 1 August 2013

Study duration: 4.5 years

Sample size: “1200”

Information authors: first results are expected in 2016

Contact information [email protected]

[email protected]

Notes CTRI/2013/04/003557

Care4Stroke trial 2014

Trial name or title Care4Stroke program: caregiver mediated exercises with e-health support for early supported discharge after

stroke

Methods RCT

Participants People with stroke, aged > 18 years, in the early rehabilitation phase (24 hours to 3 months), knowing and

able to appoint a caregiver who he/she wants to participate in the programme, living independently before the

stroke, planned to be discharged home, being able to follow instructions (a Mini-Mental State Examination

score > 23 points), Functional Ambulation Score < 5, score of < 11 on Hospital Anxiety and Depression Scale,

motivated for CME, no serious comorbidity

Caregivers: aged > 18 years, sufficiently motivated for CME, score of < 11 on the Hospital Anxiety and

Depression Scale, medically stable and physically able to perform the exercises with the patient, no significant

caregiver strain (< 4 points on Caregiver Strain Index), no serious comorbidity

To determine suitability of both patient and partner, an intake exercise session together with a trained therapist

will be scheduled prior to inclusion. The therapist will check the inclusion/exclusion criteria and judge if the

exercises can be done adequately and safely

Interventions Intervention: the Care4Stroke programme consists of 8 weeks of complementary exercise therapy done with a caregiver, alongside usual therapy. 31 standardised exercises are available that can be customised per individual

situation. The exercises are presented in a smart phone/ tablet app with videos and voiceover. The patient and

their caregiver are asked to do the exercises minimally 5 times/week for 30 minutes on at least both weekend

days or the equivalent dosage with an adopted schedule. Patients and their caregiver will have a weekly session

with a trained therapist. In this session, the participating couple will be instructed as to which exercises should

be performed safely during the next week and evaluate the exercises done last week. All patients and caregivers

will be supported by a handbook with instructions. The programme starts when the patient is admitted. When

the discharge date of the patient is earlier than the finishing of the programme, the programme continues at

home with monitoring from the treating therapist

Control: patients will receive usual care according to the Dutch guidelines for people with stroke and the Royal Dutch Guidelines of Physical Therapy

Outcomes Primary outcomes: length of stay and the mobility part of the Stroke Impact Scale 3.0

Secondary outcomes: other domains of Stroke Impact Scale 3.0, Fugl-Meyer Assessment lower extremity

Scale, Motricity Index Lower Extremity, Six-Minute Walk Test, walking speed, Timed-Up-and-Go Test, Berg

Balance Scale, Rivermead Mobility Index, Barthel Index, Nottingham Extended Activities of Daily Living

Index, modified Rankin Scale, personal opinion questionnaire for empowerment, EuroQol, amount of daily

activity

52Caregiver-mediated exercises for improving outcomes after stroke (Review)

http://mailto:[email protected]

Care4Stroke trial 2014 (Continued)

For the caregiver: Expanded Caregiver Strain Index, Carer Quality of Life Scale

For both patient and caregiver: Hospital Anxiety and Depression Scale, General Self-efficacy Scale, Fatigue

Severity Scale, and (cost) diaries

Measurements at baseline, post intervention (8 weeks after randomisation), and follow-up (12 weeks after

randomisation)

Starting date 1 April 2014

Study duration: 2 years

Sample size: “66”

Contact information [email protected]

[email protected]

Notes www.trialregister.nl/trialreg/admin/rctview.asp?TC=4300

In Australia, a study with the same objective, inclusion and exclusion criteria has been done. Analyses are

currently been done. This study is part of the Care4Stroke trial

CME: caregiver-mediated exercises; RCT: randomised controlled trial.

53Caregiver-mediated exercises for improving outcomes after stroke (Review)

http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4300

D A T A A N D A N A L Y S E S

Comparison 1. Caregiver-mediated exercises versus control - end of intervention

Outcome or subgroup title No. of

studies

No. of

participants Statistical method Effect size

1 Patient: activities of daily living

(ADL) measures: combined

4 295 Std. Mean Difference (IV, Fixed, 95% CI) 0.21 [-0.02, 0.44]

1.1 Barthel Index 3 247 Std. Mean Difference (IV, Fixed, 95% CI) 0.16 [-0.09, 0.41]

1.2 Functional Independence

Measure

1 48 Std. Mean Difference (IV, Fixed, 95% CI) 0.49 [-0.09, 1.06]

2 Patient: ADL measures: extended

ADL: combined

2 196 Std. Mean Difference (IV, Fixed, 95% CI) 0.07 [-0.21, 0.35]

2.1 Nottingham Extended

Activities of Daily Living Index

1 40 Std. Mean Difference (IV, Fixed, 95% CI) 0.29 [-0.33, 0.92]

2.2 Instrumental Activities of

Daily Living (IADL)

1 156 Std. Mean Difference (IV, Fixed, 95% CI) 0.01 [-0.31, 0.32]

3 Caregiver: burden: combined 2 91 Std. Mean Difference (IV, Fixed, 95% CI) -0.04 [-0.45, 0.37]

3.1 Caregiver Strain Index 1 40 Std. Mean Difference (IV, Fixed, 95% CI) -0.23 [-0.85, 0.39]

3.2 Caregiver Burden Scale 1 51 Std. Mean Difference (IV, Fixed, 95% CI) 0.11 [-0.44, 0.66]

4 Measures of motor impairment:

Fugl-Meyer Assessment lower

extremity

1 40 Mean Difference (IV, Fixed, 95% CI) 3.10 [-2.02, 8.22]

5 Measures of motor impairment:

Fugl-Meyer Assessment upper

extremity

1 18 Mean Difference (IV, Fixed, 95% CI) 4.43 [-2.09, 10.95]

6 Gait and gait-related measures:

balance: combined

3 139 Std. Mean Difference (IV, Fixed, 95% CI) 0.53 [0.19, 0.87]

6.1 Berg Balance Scale 2 91 Std. Mean Difference (IV, Fixed, 95% CI) 0.56 [0.14, 0.98]

6.2 Postural Assessment Scale

for Stroke Patients

1 48 Std. Mean Difference (IV, Fixed, 95% CI) 0.48 [-0.09, 1.06]

7 Gait and gait-related measures:

Six-Minute Walk Test

2 91 Mean Difference (IV, Fixed, 95% CI) 30.98 [-20.22, 82.

19]

8 Gait and gait-related measures:

walking speed

2 71 Mean Difference (IV, Fixed, 95% CI) 0.08 [-0.03, 0.18]

9 Measures of upper limb activities

or function: Wolf Motor

Function test - functional

ability

2 174 Mean Difference (IV, Random, 95% CI) 0.02 [-0.52, 0.55]

10 Measures of upper limb

activities or function: Wolf

Motor Function Test -

performance time

2 174 Mean Difference (IV, Fixed, 95% CI) -1.72 [-2.23, -1.21]

11 Measures of upper limb

activities or function: Motor

Activity Log (MAL) - amount

of use

2 174 Mean Difference (IV, Fixed, 95% CI) 0.01 [-0.36, 0.38]

54Caregiver-mediated exercises for improving outcomes after stroke (Review)

12 Measures of upper limb

activities or function: MAL -

quality of movement

2 174 Mean Difference (IV, Fixed, 95% CI) 0.08 [-0.26, 0.42]

13 Measures of upper limb

activities or function: Nine

Hole Peg test

1 156 Mean Difference (IV, Fixed, 95% CI) -0.04 [-0.11, 0.03]

14 Measures of mood and quality

of life (QoL) of the patient:

Stroke Impact Scale (SIS) -

composite physical

1 51 Mean Difference (IV, Fixed, 95% CI) 12.40 [1.67, 23.13]

15 Measures of mood and QoL of

the patient: SIS - strength

1 51 Mean Difference (IV, Fixed, 95% CI) 12.20 [-0.08, 24.48]

16 Measures of mood and QoL of

the patient: SIS - ADL/IADL

1 51 Mean Difference (IV, Fixed, 95% CI) 11.4 [-1.11, 23.91]

17 Measures of mood and QoL of

the patient: SIS - mobility

1 51 Mean Difference (IV, Fixed, 95% CI) 18.20 [7.54, 28.86]

18 Measures of mood and QoL of

the patient: SIS - hand function

2 207 Mean Difference (IV, Fixed, 95% CI) 2.64 [-5.87, 11.15]

19 Measures of mood and QoL of

the patient: SIS - memory

1 51 Mean Difference (IV, Fixed, 95% CI) 6.30 [-1.65, 14.25]

20 Measures of mood and

QoL of the patient: SIS -

communication

1 51 Mean Difference (IV, Fixed, 95% CI) 3.0 [-2.34, 8.34]

21 Measures of mood and QoL of

the patient: SIS - emotion

1 51 Mean Difference (IV, Fixed, 95% CI) 2.10 [-4.35, 8.55]

22 Measures of mood and QoL

of the patient: SIS - social

participation

1 51 Mean Difference (IV, Fixed, 95% CI) 6.70 [-1.69, 15.09]

23 Measures of mood and QoL

of the patient: SIS - general

recovery

1 51 Mean Difference (IV, Fixed, 95% CI) 15.10 [8.44, 21.76]

24 Length of stay - hospital 1 37 Mean Difference (IV, Fixed, 95% CI) 4.40 [-3.91, 12.71]

25 Length of stay - rehabilitation

unit

1 20 Mean Difference (IV, Fixed, 95% CI) 12.0 [-10.88, 34.88]

26 Adverse outcomes: falls 1 48 Mean Difference (IV, Fixed, 95% CI) 0.04 [-0.10, 0.18]

Comparison 2. Caregiver-mediated exercises versus control - end of follow-up

Outcome or subgroup title No. of

studies

No. of

participants Statistical method Effect size

1 Patient: activities of daily living

(ADL) measures: ADL

2 196 Mean Difference (IV, Random, 95% CI) 2.69 [-8.18, 13.55]

1.1 Barthel Index 2 196 Mean Difference (IV, Random, 95% CI) 2.69 [-8.18, 13.55]

2 Patient: ADL measures: extended

ADL: combined

2 196 Std. Mean Difference (IV, Fixed, 95% CI) 0.11 [-0.17, 0.39]

2.1 Nottingham Extended

Activities of Daily Living Index

1 40 Std. Mean Difference (IV, Fixed, 95% CI) 0.51 [-0.12, 1.14]

2.2 IADL 1 156 Std. Mean Difference (IV, Fixed, 95% CI) 0.01 [-0.31, 0.32]

55Caregiver-mediated exercises for improving outcomes after stroke (Review)

3 Caregiver: burden 1 40 Mean Difference (IV, Fixed, 95% CI) 0.60 [-0.71, 1.91]

3.1 Caregiver Strain Index 1 40 Mean Difference (IV, Fixed, 95% CI) 0.60 [-0.71, 1.91]

4 Measures of motor impairment:

Fugl-Meyer Assessment lower

extremity

1 40 Mean Difference (IV, Fixed, 95% CI) 3.40 [-1.74, 8.54]

5 Measures of motor impairment:

Fugl-Meyer Assessment upper

extremity

1 18 Mean Difference (IV, Fixed, 95% CI) 2.75 [-8.24, 13.74]

6 Gait and gait-related measures:

balance

1 40 Mean Difference (IV, Fixed, 95% CI) 8.40 [-1.04, 17.84]

6.1 Berg Balance Scale 1 40 Mean Difference (IV, Fixed, 95% CI) 8.40 [-1.04, 17.84]

7 Gait and gait-related measures:

Six-Minute Walking Test

1 40 Mean Difference (IV, Fixed, 95% CI) 109.50 [17.12, 201.

88]

8 Gait and gait-related measures:

walking speed

1 20 Mean Difference (IV, Fixed, 95% CI) 0.10 [-0.02, 0.22]

9 Measures of upper limb activities

or function: Wolf Motor

Function test - functional

ability

2 174 Mean Difference (IV, Random, 95% CI) 0.08 [-0.46, 0.61]

10 Measures of upper limb

activities or function: Wolf

Motor Function test -

performance time

2 174 Mean Difference (IV, Random, 95% CI) 1.85 [-8.78, 12.48]

11 Measures of upper limb

activities or function: Motor

Activity Log - amount of use

2 174 Mean Difference (IV, Random, 95% CI) 0.21 [-0.65, 1.08]

12 Measures of upper limb

activities or function: Motor

Activity Log - quality of

movement

2 174 Mean Difference (IV, Fixed, 95% CI) -0.03 [-0.43, 0.37]

13 Measures of upper limb

activities or function: Nine

Hole Peg test

1 156 Mean Difference (IV, Fixed, 95% CI) -0.05 [-0.12, 0.02]

14 Measures of mood and quality

of life of the patient: Stroke

Impact Scale (SIS) - hand

function

1 156 Mean Difference (IV, Fixed, 95% CI) -2.20 [-12.46, 8.06]

Comparison 3. Timing post stroke - end of intervention

Outcome or subgroup title No. of

studies

No. of

participants Statistical method Effect size

1 Patient: activities of daily living

measures: combined

4 295 Std. Mean Difference (IV, Fixed, 95% CI) 0.21 [-0.02, 0.44]

1.1 < 6 months 2 88 Std. Mean Difference (IV, Fixed, 95% CI) 0.44 [0.01, 0.86]

1.2 > 6 months 2 207 Std. Mean Difference (IV, Fixed, 95% CI) 0.12 [-0.16, 0.39]

56Caregiver-mediated exercises for improving outcomes after stroke (Review)

Comparison 4. Mean change from post intervention - end of follow-up

Outcome or subgroup title No. of

studies

No. of

participants Statistical method Effect size

1 Patient: activities of daily living

(ADL) measures: Barthel Index

1 40 Mean Difference (IV, Fixed, 95% CI) 2.3 [-3.95, 8.55]

2 Patient: ADL measures: extended

ADL - Nottingham Extended

Activities of Daily Living Index

1 40 Mean Difference (IV, Fixed, 95% CI) 4.00 [-0.99, 8.99]

3 Patient: ADL measures: extended

ADL - reintegration to normal

living index

1 40 Mean Difference (IV, Fixed, 95% CI) 4.3 [2.03, 6.57]

4 Caregiver: Caregiver Strain

Index

1 40 Mean Difference (IV, Fixed, 95% CI) 1.1 [0.45, 1.75]

5 Measures of motor impairment:

Fugl-Meyer Assessment lower

extremity

1 40 Mean Difference (IV, Fixed, 95% CI) 0.30 [-2.21, 2.81]

6 Gait and gait-related measures:

balance: Berg Balance Scale

1 40 Mean Difference (IV, Fixed, 95% CI) -0.9 [-4.78, 2.98]

7 Gait and gait-related measures:

Six-Minute Walking Test

1 40 Mean Difference (IV, Fixed, 95% CI) 43.3 [15.11, 71.49]

8 Other outcomes: Motor

Assessment Scale

1 40 Mean Difference (IV, Fixed, 95% CI) 1.1 [-0.92, 3.12]

Comparison 5. Sensitivity analysis - caregiver-mediated exercise (CME)-core - end of intervention

Outcome or subgroup title No. of

studies

No. of

participants Statistical method Effect size

1 Patient: activities of daily living

(ADL) measures: Barthel Index

2 91 Mean Difference (IV, Fixed, 95% CI) 9.45 [2.11, 16.78]

2 Patient: ADL measures: extended

ADL - Nottingham Extended

Activities of Daily Living Index

1 40 Mean Difference (IV, Fixed, 95% CI) 5.5 [-5.83, 16.83]

3 Gait and gait-related measures:

balance: Berg Balance Scale

2 91 Mean Difference (IV, Fixed, 95% CI) 6.35 [1.64, 11.06]

57Caregiver-mediated exercises for improving outcomes after stroke (Review)

Comparison 6. Sensitivity analysis - caregiver-mediated exercise (CME)-core - end of follow-up

Outcome or subgroup title No. of

studies

No. of

participants Statistical method Effect size

1 Patient: activities of daily living

(ADL) measures: Barthel Index

1 40 Mean Difference (IV, Fixed, 95% CI) 9.0 [-1.29, 19.29]

2 Patient: ADL measures: extended

ADL - Nottingham Extended

Activities of Daily Living Index

1 40 Mean Difference (IV, Fixed, 95% CI) 9.5 [-1.83, 20.83]

Comparison 7. Walking speed, different possibilities study of Wall

Outcome or subgroup title No. of

studies

No. of

participants Statistical method Effect size

1 Walking speed - caregiver-

mediated exercises (CME)

vs physiotherapy - end of

intervention

2 61 Mean Difference (IV, Fixed, 95% CI) 0.06 [-0.07, 0.20]

2 Walking speed - CME vs

physiotherapy - end of follow-

1 10 Mean Difference (IV, Fixed, 95% CI) 0.11 [-0.04, 0.26]

3 Walking speed - CME vs

no intervention - end of

intervention

2 61 Mean Difference (IV, Fixed, 95% CI) 0.06 [-0.08, 0.19]

4 Walking speed - CME vs no

intervention - end of follow-up

1 10 Mean Difference (IV, Fixed, 95% CI) 0.10 [-0.04, 0.24]

5 Walking speed - CME and

physiotherapy vs physiotherapy

- end of intervention

2 61 Mean Difference (IV, Fixed, 95% CI) 0.07 [-0.06, 0.21]

6 Walking speed - CME and

physiotherapy vs physiotherapy

- end of follow-up

1 10 Mean Difference (IV, Fixed, 95% CI) 0.10 [-0.11, 0.31]

7 Walking speed - CME

and physiotherapy vs

no intervention - end of

intervention

2 61 Mean Difference (IV, Fixed, 95% CI) 0.07 [-0.07, 0.20]

8 Walking speed - CME

and physiotherapy vs no

intervention - end of follow-up

1 10 Mean Difference (IV, Fixed, 95% CI) 0.09 [-0.11, 0.29]

58Caregiver-mediated exercises for improving outcomes after stroke (Review)

Comparison 8. Extended activities of daily living (ADL) - analyses with Reintegration to Normal Living Index

(RNLI)

Outcome or subgroup title No. of

studies

No. of

participants Statistical method Effect size

1 Patient: ADL measures: extended

ADL - combined - end of

intervention

2 196 Std. Mean Difference (IV, Fixed, 95% CI) 0.01 [-0.27, 0.29]

1.1 RNLI 1 40 Std. Mean Difference (IV, Fixed, 95% CI) 0.03 [-0.59, 0.65]

1.2 Instrumental Activities of

Daily Living (IADL)

1 156 Std. Mean Difference (IV, Fixed, 95% CI) 0.01 [-0.31, 0.32]

2 Patient: ADL measures: extended

ADL - combined - end of

follow-up

2 196 Std. Mean Difference (IV, Random, 95% CI) 0.29 [-0.37, 0.95]

2.1 RNLI 1 40 Std. Mean Difference (IV, Random, 95% CI) 0.69 [0.05, 1.33]

2.2 IADL 1 156 Std. Mean Difference (IV, Random, 95% CI) 0.01 [-0.31, 0.32]

A D D I T I O N A L T A B L E S

Table 1. Outline of included studies

Study ID Form of

training

Upper or

lower

body

Tim-

ing since

stroke

Task care-

giver

Routine

care con-

tinued

Control

group

Pro-

gramme

(length -

fre-

quency-

duration)

Contact

with ther-

apist

Place

Abu Tariah

2010

CIMT Upper > 2 months Carried

out the in-

tervention

with

support of

therapists

No Neurode-

velopmen-

tal train-

ing, same

intensity

2 months -

daily - 2

hours

3 or 4 ses-

sions

Home

Agrawal

2013

Exercise

therapy

Upper “Sub-acute

stroke”

Encour-

age-

ment, par-

ticipating,

and help

Yes Usual care 4 weeks -5

days/week

- 60 to 90

minutes

Weekly Inpatient?

Barzel

2015

CIMT Upper > 6 months Supervi-

sion, help,

and main-

tain-

ing train-

ing diary

No Usual care,

frequency

of seeing a

therapist

was the

same

4 weeks -

Every

weekday

(not week-

end) - 2

hours

5 x 60 min-

utes

Home

59Caregiver-mediated exercises for improving outcomes after stroke (Review)

Table 1. Outline of included studies (Continued)

Dai 2013 Vestibu-

lar rehabil-

itation

Both < 6 months Guidance

and super-

vision

(in third

and fourth

week)

Yes Usual care 4 weeks -

10 sessions

per 2 weeks

- 30 min-

utes

2 to 4 ses-

sions

in first 2

weeks

Inpatient?

Galvin

2011

Exercise

therapy

Lower As-

sessment 2

weeks after

stroke on-

set

Encour-

agement

and help

Yes Usual care 8 weeks -

every day -

35 minutes

Weekly Inpatient

or at home

Gómez

2014

CIMT Upper < 6 months Monitor-

ing and su-

pervising

Yes Usual care 14

days - ev-

ery day* -

5.5 hours*

1.5 hours

per day*

Inpatient

Souza

2015

CIMT: 1.5

hours with

therapist

and 1.5

hours with

caregiver

Upper < 24

months**

Super-

vision and

making

notes

No CIMT: 3

hours with

therapist

22 days -

10 sessions

- 3 hours

10 x 90

minutes

Outpa-

tient and

home

Wall 1987 Exercise

therapy

Lower After dis-

charge

of rehabili-

tation

Supervi-

sion

No No inter-

vention

6 months

- twice a

week - 1

hour

1 group:

twice a

week

1 group:

once a

week

1 group:

’monitor-

ing’

Outpa-

tient or at

home

Wang

2015

Ex-

ercise pro-

gramme

aimed at

body func-

tions,

activities,

and partic-

ipation

Both > 6 months Encour-

agement

and help

No Usual care 12 weeks -

min-

imal twice

a week, if

pos-

sible every

day - min-

imal 50 to

60 minutes

Weekly 90

minutes

Home

CIMT: constraint-induced movement therapy.

* Details of the intervention are not completely clear, contact with the authors was not successful.

** But mean time since stroke was 27 and 35 months since stroke, unclear why.

60Caregiver-mediated exercises for improving outcomes after stroke (Review)

Table 2. (Standard) Mean differences which are not reported in section ’data and analysis’

Outcome Outcome mea-

sure

Fixed-ef-

fect or random-

effects model

Mean difference Confidence in-

terval

Heterogeneity P value

1.1 Patient: ADL

measures -

Combined

1.1.1 Barthel In-

dex

Random-effects 5.09 -2.88 to 13.07 58% 0.21

1.1.2 Functional

Independence

Measure

Fixed-effect 11.04 -1.59 to 23.67 - 0.09

1.2 Patient: ADL

measures - ex-

tended ADL

1.2.1 Notting-

ham Extended

Activities of

Daily Living In-

dex

Fixed-effect 5.50 -5.83 to 16.83 - 0.34

1.2.2 IADL Fixed-effect 0.02 -0.72 to 0.76 - 0.96

1.3 Caregiver:

burden

1.3.1 Caregiver

Strain Index

Fixed-effect -0.50 -1.81 to 0.81 - 0.46

1.3.2 Caregiver

Burden Scale

Fixed-effect 1.30 -4.88 to 7.48 - 0.68

1.6 Gait and

gait-related

measures:

balance

1.6.1 Berg Bal-

ance Scale

Fixed-effect 6.35 1.64 to 11.06 0% 0.008

1.6.2 Postural

Assessment

for Stroke pa-

tients

Fixed-effect 3.50 -0.52 to 7.52 - 0.09

2.2 Patient: ADL

measures -

extended ADL

2.2.1

Nottingham Ex-

tended

Activities of

Daily Living In-

dex

Fixed-effect 9.50 -1.83 to 20.83 - 0.10

2.2.2 IADL Fixed-effect 0.02 -0.77 to 0.81 - 0.96

3.1 Patient: ADL

measures - com-

bined

3.1.1 < 6 months Fixed-effect 0.44* 0.01 to 0.86 0% 0.04

3.1.2 > 6 months Random-effects 4.90 -7.56 to 17.36 77% 0.44

8.1 Patient ADL

measures - ex-

tended ADL -

end of interven-

tion

8.1.1 Reintegra-

tion to normal

living Index

Fixed-effect 0.20 -3.76 to 4.16 - 0.92

61Caregiver-mediated exercises for improving outcomes after stroke (Review)

Table 2. (Standard) Mean differences which are not reported in section ’data and analysis’ (Continued)

8.1.2 IADL Fixed-effect 0.02 -0.72 to 0.76 - 0.96

8.2 Patient ADL

measures - ex-

tended ADL -

end of follow-up

8.2.1 Reintegra-

tion to normal

living Index

Fixed-effect 4.50 0.54 to 8.46 - 0.03

8.2.2 IADL Fixed-effect 0.02 -0.77 to 0.81 - 0.96

ADL: activities of daily living; IADL: instrumental activities of daily living.

*Standardised mean difference.

Table 3. Results ’other outcomes’ (not included in meta-analysis)

Outcome Control group

(mean (SD))

Intervention group

(mean (SD))

Baseline Post

intervention

Follow-up Baseline Post intervention Follow-up

Behavioural

Inattention Test

Conventional (

Dai 2013)

48.79 (44.64) 68.83 (44.72) - 49.71 (39.63) 88.71 (44.56) -

Motor

Assessment Scale

(Galvin 2011)

29.7 (12.9) 34.5 (11.6) 35.2 (10.8) 24.3 (11.1) 36.1 (10.2) 37.9 (9.7)

SD: standard deviation.

Table 4. Results Agrawal 2013 (study not included in meta-analysis)

Outcome Control group

(mean scores)

GRASP 60 group

(mean scores)

GRASP 90 group

(mean scores)

Baseline Post

intervention

Baseline Post

intervention

Baseline Post

intervention

Fugl-Meyer As-

sessment upper

extremity

31.3 37.0 32.9 44.0 34.7 48.2

Chedoke Arm

and Hand Activ-

ities Inventory

20.3 26.8 21.0 30.0 24.4 37.0

62Caregiver-mediated exercises for improving outcomes after stroke (Review)

C O N T R I B U T I O N S O F A U T H O R S

Judith Vloothuis wrote the protocol with the support of the other authors who directed protocol focus and quality, and commented

on the protocol.

Johannes Ket helped to develop search strategies.

Marijn Mulder and Judith Vloothuis screened the references, with the help of Janne Veerbeek.

Erwin van Wegen helped resolving questions and disagreements.

Judith Vloothuis extracted the data and Marijn Mulder cross-checked these data.

Judith Vloothuis entered data in RevMan and performed analyses.

All authors interpreted the analysis.

Judith Vloothuis drafted the review.

All authors gave input, read, revised, and approved the final version.

D E C L A R A T I O N S O F I N T E R E S T

Judith DM Vloothuis: none known.

Marijn Mulder: none known.

Janne M Veerbeek: none known.

Manin Konijnenbelt: none known.

Johanna MA Visser-Meily: none known.

Johannes CF Ket: none known.

Gert Kwakkel: none known.

Erwin EH van Wegen: none known.

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

• The second review author who also did the search and cross-checked data extraction changed from Janne Veerbeek to Marijn

Mulder.

• Added Johannes Ket to the review team.

• Updated ’Description of the intervention’ section. Whereby we made clearer that we included interventions which were aimed at

improving activities of daily living including mobility (review: ’Hereby, the exercises are aimed at improving activities of daily living

including mobility, such as making transfers, standing and walking’), instead of only interventions to improve function (protocol:

’main aim to improve motor function’).

• Described the definition of ’caregiver’ in more detail in the ’Types of interventions’ section: a caregiver or carer as an unpaid or partially paid person who voluntarily helps an impaired individual with his or her activities of daily living. In other words, the

mediated services were not applied by a professional in health care but in most cases, someone who was close to the patient and

voluntarily offered his or her services. This may have been a partner, family member, or friend, but it could have also have been a

volunteer. We argued that this person is ’not a professional’ such as a ’therapy assistant’.

• Included trials that combined caregiver-mediated exercises (CME) with another intervention in contrary to our description in

the protocol (’Types of interventions’). We included these trials because during search and data analysis two forms of CME came

forward: trials in which CME was the only intervention (CME-core) and trials in which caregivers provided an existing intervention.

We differentiated between those trials in a sensitivity analysis (’CME-core’).

63Caregiver-mediated exercises for improving outcomes after stroke (Review)

• Changed primary outcome measure ’Caregiver: measures of mood, burden and quality of life’ to ’Caregiver: measures of burden.

Our primary objective was to learn the effect of CME on caregiver burden. Especially because one can argue that CME gives a

caregiver influence and knowledge and, therefore, can lessen caregiver burden, but one can also argue that CME are yet another task

for the caregiver in these stressful times and will increase caregiver burden. Moved mood and quality of life to secondary outcomes.

• Changed the order of the secondary outcome measures to a more logical order (from impairment to participation).

• Renamed the secondary outcome measure ’measures of upper limb activities of function’ to ’measures of upper limb activities or function’

• Added a sentence under ’Selection of studies’ about the screening of abstracts, after the screening of titles.

• In the protocol, we proposed under ’Subgroup analysis and investigation of heterogeneity’ to do a subgroup analysis of

interventions in addition to usual care versus control and interventions instead of usual care versus control. We did not do this

subgroup analysis, but a subgroup analysis of interventions with a higher dose of training in the intervention group than the control

group versus interventions with a same dose of training in intervention and control group. We changed this because we experienced

the importance of difference of dose of training. We noticed that in the group ’interventions instead of usual care’ dose of training

could still be higher.

I N D E X T E R M S Medical Subject Headings (MeSH)

∗Caregivers; ∗Postural Balance; ∗Quality of Life; Activities of Daily Living; Exercise Therapy [∗methods]; Randomized Controlled

Trials as Topic; Stroke Rehabilitation [∗methods]; Walking

MeSH check words

Adult; Humans

64Caregiver-mediated exercises for improving outcomes after stroke (Review)