Journal of

Clinical Medicine

Review
Non-Pharmacological Interventions for Post-Stroke
Fatigue: Systematic Review and
Network Meta-Analysis
Ya Su 1 , Michiko Yuki 2, * and Mika Otsuki 2
1 Graduate School of Health Sciences, Hokkaido University, Sapporo, Hokkaido 060-0812, Japan;
[email protected]
2 Faculty of Health Sciences, Hokkaido University, Sapporo, Hokkaido 060-0812, Japan;
[email protected]
* Correspondence: [email protected]; Tel./Fax: +81-11-706-3592




Received: 20 December 2019; Accepted: 21 February 2020; Published: 25 February 2020


Abstract: Post-stroke fatigue (PSF) is one of the most serious sequelae, which often interferes with the
rehabilitation process and impairs the functional recovery of patients. Due to insufficient evidence,
it is unclear which specific pharmacological interventions should be recommended. Therefore, in this
paper, we compare the effectiveness of non-pharmacological interventions in PSF. A systematic
review and network meta-analysis of randomized controlled trials were performed using EMBASE,
MEDLINE, CINAHL, Cochrane library, ClinicalTrials.gov, CNKI, and CQVIP, from inception to
January 2018, in the English and Chinese languages. RCTs involving different non-pharmacological
interventions for PSF with an outcome of fatigue measured using the Fatigue Severity Scale were
included. Multiple intervention comparisons based on a Bayesian network are used to compare
the relative effects of all included interventions. Ten RCTs with eight PSF non-pharmacological
interventions were identified, comprising 777 participants. For effectiveness, most interventions did
not significantly differ from one another. The cumulative probabilities of the best non-pharmacological
intervention for fatigue reduction included Community Health Management (CHM), followed by
Traditional Chinese Medicine (TCM) and Cognitive Behavioral Therapy (CBT). Network meta-analysis
based on data from the selected RCTs indicated that the eight PSF non-pharmacological interventions
shared equivalent efficacy, but CHM, TCM, and CBT showed potentially better efficacy. In the future,
fatigue needs to be recognized and more accurate assessment methods for PSF are required for
diagnosis and to develop more effective clinical interventions.

Keywords: stroke; fatigue; nonpharmacological interventions; randomized controlled trials; network

meta-analysis

1. Introduction
Fatigue is a common and long-standing complication after stroke. The prevalence of post-stroke
fatigue (PSF) ranges from 25% to 85% [1]. The first report of fatigue after stroke, published in 1999,
stated that 40% of stroke patients reported fatigue as one of their most serious sequelae [2]. PSF often
limits the rehabilitation process and impairs the functional recovery of patients [3], and can also
indirectly affect patients’ psychological outcomes and quality of life. PSF has also been closely related
to prognosis and mortality [4]. As there is currently no specific measurement to identify fatigue and the
signs of fatigue are not always obvious to outsiders, it may be difficult to understand how a patient is
feeling. Thus, early detection and effective interventions are particularly important. Recently, PSF has
gained increasing attention from researchers. The Canadian Stroke Best Practice Recommendations,

J. Clin. Med. 2020, 9, 621; doi:10.3390/jcm9030621 www.mdpi.com/journal/jcm

J. Clin. Med. 2020, 9, 621 2 of 15

the first best practice recommendations for PSF, were published in 2015 [5]; further, in 2016, the top 10
published research priorities specific to stroke nursing identified managing fatigue as a top research
priority [6]. However, fatigue still does not receive enough attention in patients after stroke, making
the management of fatigue in patients after stroke difficult and directly affecting their prognosis.
Fatigue is a symptom commonly experienced in the general population. “Nonpathological fatigue”
describes a state of general tiredness if it lasts fewer than 3 months and has an identifiable cause,
which is related to lifestyle or overexertion and can be ameliorated by rest. In contrast, “pathological
fatigue” is experienced in many people with chronic illness, which has a longer duration, is difficult to
treat, and can cause severe impairments to an individual’s functional activity and quality of life [7].
Nonpathological fatigue is mostly acute, but pathological fatigue is chronic in nature. PSF is not like
typical tiredness, in that it does not always improve with rest. After a stroke, people may lack energy
or strength, feel constantly weary or tired, and may not feel in control of their recovery. Marleen H. de
Groot et al. defined PSF as a feeling of physical tiredness and lack of energy, described as pathologic,
abnormal, excessive, chronic, persistent, or problematic [8]. Joanna Lynch et al. defined PSF for
community and hospital patients. PSF in Community patients is defined as at least a 2-week period
over the past month when the patient has experienced fatigue, lack of energy, or an increased need to
rest every or nearly every day, leading to difficulty in taking part in everyday activities. In Hospital
patients, PSF is defined when the patient has experienced fatigue, a lack of energy, or an increased
need to rest every day or nearly every day since their stroke. Fatigue leads to difficulty in taking part
in everyday activities (for inpatients, this may include therapy and may include the need to terminate
an activity early due to fatigue) [9]. PSF is commonly measured using general fatigue scales, such as
the Fatigue Severity Scale (FSS) and Checklist of Individual Strength (CIS), as shown in Table 1 [10–21].
The prevalence of PSF ranges from 25% to 85%, and is likely reflected by different patient populations
as well as different measurement tools [1]. However, subjective general scales must be used, as there is
currently no objective method to identify PSF.
Pharmacological intervention has been reported to improve PSF, such as Tirilazad Mesylate, Modafinil,
and OSU6162. However, there is currently insufficient evidence to determine a specific pharmacological
intervention for PSF, and pharmacological management is far from satisfactory. Moreover, there is a lack
of systematic nursing management intervention for PSF [22]. Therefore, evidence-based medicine for
PSF patients is required to provide a theoretical basis for prevention, and treatment with targeted health
management programs are required to improve the quality of life of patients with fatigue after stroke.
In this study, we aim to compare the effectiveness of non-pharmacological interventions for PSF to provide
evidence for healthcare providers. Network meta-analyses (NMA), enabling the comparison of multiple
interventions to incorporate clinical evidence from both direct and indirect treatment comparisons in a
network of treatments and associated trials, is a valuable tool in comparative effectiveness research [23].
To the best of our knowledge, this is the first study using NMA for a multiple intervention comparison of
the currently available methods to determine the effectiveness of non-pharmacological interventions in
PSF. To provide effective support for stroke patients, it is necessary to first understand the effectiveness of
non-pharmacological interventions.
J. Clin. Med. 2020, 9, 621 3 of 15

Table 1. General fatigue scales.

Scale Developed By Target Population Items

Profile of Mood States—fatigue subscale (POMS) McNair et al., 1971 [10] Psychiatric patients 65
Fatigue Severity Scale (FSS) Krupp et al., 1989 [11] MS, SLE 9
Fatigue Impact Scale (FIS) Fisk et al., 1994 [12] MS, CFS 40
Checklist of Individual Strength (CIS) Vercoulen et al., 1994 [13] CFS 24
SF-36 (Vitality subscale) Ware et al., 1994 [14] Chronic disease patients 4
Multidimensional Fatigue Inventory (MFI-20) Smets et al., 1995 [15] Cancer, CFS, General clinical populations 20
FACIT (Fatigue Scale) David Cella, et al., 1997 [16] Chronic Illness 13
Multidimensional Fatigue Symptom Inventory (MFIS) Stein et al., 1998 [17] Cancer-related fatigue 6
Brief Fatigue Inventory (BFI) Tito R et al., 1999 [18] Cancer-related fatigue 4
Fatigue Assessment Scale (FAS) Michielsen et al., 2003 [19] Workers 10
Neurological fatigue index-MS (NFI-MS) in stroke Mills et al., 2012 [20] MS 23
Detection List Fatigue (DLF) Nena Kruithof et al., 2016 [21] Post-stroke fatigue 9
MS: Multiple sclerosis; SLE: Systemic lupus erythematous; CFS: Chronic fatigue syndrome.
J. Clin. Med. 2020, 9, 621 4 of 15

2. Materials and Methods

This systematic review and network meta-analysis was conducted in accordance with the PRISMA
statement extension for NMA [24]. We followed a pre-specified protocol registered at PROSPERO
(CRD42018105983).

2.1. Inclusion and Exclusion Criteria

Only RCTs including outcome using fatigue score measured by FSS were used. We considered
that differences in the prevalence of PSF are likely reflected by different measurement tools, in order to
minimize the bias induced by the measurement of the outcome. Our inclusion criteria were any outcome
of fatigue measurement using FSS, as FSS is a widely accepted and used scale to measure fatigue in stroke
populations. We included any patients diagnosed with ischemic or hemorrhagic stroke, as diagnosed
by MRI or CT, and no age or gender limitations were considered. The control group was defined by
treatment as usual, including usual treatment, nursing, and rehabilitation, which we called “as usual”
(AU). The intervention group was defined as additional provided non-pharmacological interventions
based on usual treatment, where non-pharmacological intervention denotes the management of PSF
without medications. The outcome was the patient’s degree of fatigue pre- and post-intervention using
the FSS scale.

2.2. Data Search and Selection

We searched EMBASE, MEDLINE, CINAHL, Cochrane library, ClinicalTrials.gov, CNKI,
and CQVIP from inception to Jan. 2018, using the English and Chinese languages, and updated the
search to 2019. Our search terms are shown in Table A1. Two reviewers (Y.S. and M.O.) independently
read the titles and abstracts identified by the search, then screened the full text manuscripts of
potentially relevant references. Any eligibility disagreements were decided by discussing with a third
reviewer (M.Y.).

2.3. Data Extraction and Quality Assessment

Data extraction details included identification of the study, methods of study design, participant
characteristics, interventions, outcome measures, and results. Data from baseline and endpoint of
fatigue score were included in the results. If results included multiple post-intervention and follow-up
scores, we chose the last follow-up score as the endpoint score.
The risk of bias of the included RCTs was assessed based on the Cochrane tool using the
Review Manager version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen,
Denmark), with six assessment domains: Selection bias, performance bias, detection bias, attrition bias,
reporting bias, and other bias. For each study, the classification of “low risk” was shown in green,
“unclear risk” was shown in yellow, and “high risk” was shown in red.

2.4. Statistical Analysis

First, a network plot for every intervention was drawn used using the STATA version 14.0
(StataCorp LP. College Station, TX, USA). Second, we conducted pair-wise meta-analyses with a
random effects model to synthesize studies comparing the intervention with control (AU). The results
were reported as pooled mean difference (MD) with the corresponding 95% confidence interval
(CI). Statistical heterogeneity across studies was assessed using a forest plot and the inconsistency
statistic (I2 ). Statistical significance was regarded as p < 0.05. All calculations were performed using
Review Manager version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen,
Denmark). Third, mixed comparisons were carried out on direct and indirect evidence. We conducted
Bayesian NMA using the Markov Chain Monte Carlo random effects model in Aggregate Data Drug
Information System (ADDIS) version 1.16.8 (Drugis, Groningen, NL). We networked the translated FSS
outcomes within studies and specified the relations among the MD across studies making different
different comparisons, as previously reported. This method combines direct and indirect evidence
for any given pair of interventions. We used p < 0.05 and 95% CI beyond the null value to assess
significance. We also calculated the inconsistency factor (IF) and 95% CI to evaluate the inconsistency
of each closed loop,
J. Clin. with
Med. 2020, the IF close to 0. In additional, the random effects variance and
9, 621 5 ofinconsistency
15

variance were roughly equal, which is considered to be less inconsistent. Furthermore, we assessed
the probability that each
comparisons, as intervention was This
previously reported. the most
methodefficacious, theand
combines direct second best,
indirect the third
evidence for anybest, and so
given pair of interventions. We used p < 0.05 and 95% CI beyond the null value
on, by calculating the MD of each treatment group, compared with arbitrary common controls, and to assess significance.
We also calculated the inconsistency factor (IF) and 95% CI to evaluate the inconsistency of each closed
counting theloop,
proportion of iterations of the Markov chain of the MD ranking in treatments.
with the IF close to 0. In additional, the random effects variance and inconsistency variance were
roughly equal, which is considered to be less inconsistent. Furthermore, we assessed the probability that
3. Results each intervention was the most efficacious, the second best, the third best, and so on, by calculating the
MD of each treatment group, compared with arbitrary common controls, and counting the proportion
Studiesofwere selected
iterations by following
of the Markov PRISMA
chain of the MD ranking guidelines [23]. Figure 1 presents a flow
in treatments. diagram
showing the searching and selection process for this systematic review. This systematic review
3. Results
identified 103 records and, ultimately, included 10 RCTs which compared non-pharmacological
Studies were selected by following PRISMA guidelines [23]. Figure 1 presents a flow diagram
interventions in the PSF population. A total of 777 patients from the 10 selected RCTs were included.
showing the searching and selection process for this systematic review. This systematic review identified
The population studyand,
103 records sizes variedincluded
ultimately, from 15 10 to 242,
RCTs median
which comparedagenon-pharmacological
ranged from 47 interventions
to 69 years,inand disease
the PSF population. A total of 777 patients from the
duration ranged from 2 weeks to 27 months. The studies were conducted 10 selected RCTs were included. The population
in Australia, the
study sizes varied from 15 to 242, median age ranged from 47 to 69 years, and disease duration ranged
Netherlands, and China, and the publication dates ranged from 2012 to 2018. We updated the search
from 2 weeks to 27 months. The studies were conducted in Australia, the Netherlands, and China,
to 2019 andand
found 4 pharmacological
the publication dates ranged from intervention trials
2012 to 2018. that were
We updated excluded.
the search to 2019The characteristics
and found 4 of
each trial are shown inintervention
pharmacological Table A2. Eight
trials non-pharmacological
that were interventions
excluded. The characteristics of each trial arewere
shown used
in for the
Table A2. Eight non-pharmacological interventions were used for the analyses, and the network plot
analyses, and the network plot for each intervention is shown in Figure 2.
for each intervention is shown in Figure 2.

Figure 1. Flow diagram. FSS = Fatigue Severity Scale; RCT = randomized controlled trails; AU = as
Figure 1. Flow diagram. FSS = Fatigue Severity Scale; RCT = randomized controlled trails; AU = as
usual (treatment, nursing, rehabilitation, education).
usual (treatment, nursing, rehabilitation, education).
 J. Clin. Med. 2020, 9, 621 6 of 15

Figure 2. Network plot for each intervention. The size of the nodes is proportional to the sample
Figure 2. Network plot for each intervention. The size of the nodes is proportional to the sample size
size of each intervention and the thickness of the lines proportional to the number of trails available.
of each intervention and the thickness of the lines proportional to the number of trails available. AU
AU = treatment, nursing, rehabilitation, education as usual; CBT = cognitive behavioral therapy;
= treatment, nursing, rehabilitation, education as usual; CBT = cognitive behavioral therapy; CHM =
CHM = community health management; CT = circuit training; HOT = hyperbaric oxygen therapy;
community health management; CT = circuit training; HOT = hyperbaric oxygen therapy; MT = music
MT = music therapy; RT = respiratory training; TCM = traditional Chinese medicine.
therapy; RT = respiratory training; TCM = traditional Chinese medicine.
3.1. Type of Intervention
3.1. Type of Intervention
3.1.1. Community Health Management (CHM)
3.1.1. Community Health Management (CHM)
One study assigned 90 patients to CHM and control (AU) groups at random [25]. The CHM
teamOne study assigned
consisted 90 patients
of 10 nurses, to CHM and
one neurology control
chief (AU) groups
physician, at random [25].
two rehabilitation The CHMand
physicians, team
one
consisted of 10 nurses, one neurology chief physician, two rehabilitation
psychological consultant. The CHM team assessed patients the day before discharge, provided physicians, and one
psychological consultant.manual
a stroke management The CHM team assessed
for patients, patients up
and followed the (by
daytelephone)
before discharge,
at 1, 2, provided
5, 8, and a12
stroke
weeksmanagement manual
after discharge. forpresent
In the patients, andthe
study, followed
health up (by telephone)
management at 1, patients
of stroke 2, 5, 8, and 12 weeks
included drug
after discharge. fatigue
management, In the education,
present study, the health
community management
activities, of stroke care.
and psychological patients included
After drug
implementing
management,
CHM, the FSSfatigue education,
of the CHM groupcommunity
were lower activities,
than thoseand psychological
of the control groupcare.
(AU)After implementing
and pre-intervention.
CHM, the FSS that
This indicates of the CHM group
conducting were lowerpost-stroke
community-based than thosehealth
of the control group
management (AU) andprevent
can effectively pre-
intervention.
the occurrenceThis
ofindicates thatthe
PSF, reduce conducting
incidence community-based
of PSF, and improve post-stroke
the qualityhealth
of life management can
in stroke patients.
effectively prevent the occurrence of PSF, reduce the incidence of PSF, and improve the quality of life
in3.1.2.
strokeTraditional
patients. Chinese Medicine (TCM)
Three studies showed that TCM intervention could improve fatigue after stroke [26–28]. The first
3.1.2. Traditional Chinese Medicine
study [26] used acupuncture (TCM)
at Baihui and Sishencong, using 200 rpm for 2 min per needle and leaving
theThree
needlestudies
for 30 min, once a day for five days a week
showed that TCM intervention for aimprove
could total of four weeks.
fatigue In stroke
after the second studyThe
[26–28]. [27],
moxibustion
first study [26] treatment was combined
used acupuncture at Baihuiwith
andintermediate
Sishencong,frequency
using 200electric
rpm foracupoint
2 min permassage
needle for
and15
days. Moxibustion
leaving the needle fortreatment
30 min, oncecombined with
a day for massage
five was performed
days a week once
for a total of per
four day, which
weeks. In the involved
second
selecting
study [27],acupoints
moxibustion(e.g., treatment
Baihui, Shenque, and Zusanli
was combined withacupoints) for moxibustion,
intermediate frequency using 3–5acupoint
electric acupoints
each time
massage for for 15–20Moxibustion
15 days. min per acupoint. Thecombined
treatment third study [28]
with investigated
massage transcutaneous
was performed acupoint
once per day,
electrical nerve stimulation targeting Zusanli, Neiguan, Guanyuan, Pishu, and Qihai
which involved selecting acupoints (e.g., Baihui, Shenque, and Zusanli acupoints) for moxibustion, acupoints using
Han’s acupoint stimulator for 30 min, once a day for a total of two weeks.
using 3–5 acupoints each time for 15–20 min per acupoint. The third study [28] investigated
transcutaneous acupoint electrical nerve stimulation targeting Zusanli, Neiguan, Guanyuan, Pishu,
3.1.3. Cognitive Behavioral Therapy (CBT)
and Qihai acupoints using Han’s acupoint stimulator for 30 min, once a day for a total of two weeks.
Two studies investigated CBT [29,30]. The intervention by Nguyen et al. [29] used a standardized
3.1.3.
CBT treatmentBehavioral
Cognitive Therapy (CBT)
manual comprised of six modules addressing fatigue over eight individual therapy
sessions. Treatment encompassed the psychoeducation
Two studies investigated CBT [29,30]. The intervention by CBT framework,
Nguyen reorganization
et al. [29] of daily
used a standardized
schedules, energy conservation, cognitive restructuring, sleep interventions, strategies
CBT treatment manual comprised of six modules addressing fatigue over eight individual therapy for physical and
mental fatigue,
sessions. and review
Treatment techniques
encompassed the for relapse prevention.
psychoeducation CBTThe second study
framework, [30] includedoffour
reorganization CBT
daily
schedules, energy conservation, cognitive restructuring, sleep interventions, strategies for physicalby
sessions based on problem solving methods, relaxation training, education, follow-up, and support
and mental fatigue, and review techniques for relapse prevention. The second study [30] included
four CBT sessions based on problem solving methods, relaxation training, education, follow-up, and
J. Clin. Med. 2020, 9, 621 7 of 15

telephone. The study concluded that cognitive behavioral intervention based on problem solving could
effectively improve fatigue after stroke, as well as medication compliance to help patients recover.

3.1.4. Respiratory Therapy (RT) and Music Therapy (MT)

Two studies investigated RT and MT [31,32]. The MT-based study [31] included 40 patients with
usual nursing and selected the appropriate music and volume, depending on the patient’s condition;
patients underwent MT for 30 min, once per day for five days a week, for a total of eight weeks.
After the intervention, fatigue scores were lower than the AU group and quality of life scores were
higher. The other one study [32] included 80 patients divided into four groups: MT, RT, RT + MT,
and AU. The RT group received rehabilitation using a breathing exercise for 15 min twice a day, for five
days a week; the MT group received rehabilitation using music therapy for 30 min once per day for
five days a week; the RT + MT group received both therapies five days a week. After eight weeks of
intervention, the RT + MT group had the lowest FSS scores and the AU control group had the highest
FSS scores.

3.1.5. Circuit Training (CT)

One study involved 250 patients undergoing CT [33]. The intervention included a 90 min graded
task-oriented CT program twice a week over 12-weeks (24 sessions). It included four stages: Warm up
(15 min), CT (60 min), evaluation and a short break (10 min), and a group game (15 min). The study
found that CT improved walking speed, stair walking, and walking distance, but showed no significant
effects in fatigue after stroke; possibly because the patients had low average baseline fatigue and
depression levels.

3.1.6. Hyperbaric Oxygen Therapy (HOT)

One study of 62 patients undergoing HOT was found [34]. Patients absorbed pure oxygen once a
day for 20 min through a mask, and the procedure was repeated three times with a rest time of 5 min
in between. The study showed that, after a four-week intervention, the AU group showed aggravation
of PSF; however, the HOT group showed no significant difference in FSS scores.

3.2. Assessment of Risk of Bias

We summarize the results of our assessment of the risk of bias for the included studies in Figure 3.
All study designs were RCTs, and a high risk of bias was not found in the design of any studies.
However, concealment of allocation was difficult to assess in eight studies, due to poor reporting.
There were 10 (100%) RCTs with a low risk of bias in random sequence generation and 9 (90%) with a
low risk of bias in selective reporting. One RCT showed low risk and high risk of bias in participants
and outcome assessment, respectively. Blinding of outcome assessment was difficult to assess in six
studies, due to poor reporting. As for incomplete outcomes, five studies had a low risk of bias.
J. Clin. Med. 2020, 9, 621 8 of 15

Figure 3. Forest plots and assessment of risk of bias. Horizontal lines correspond to study-specific MD
Figure
and 95%3.CI.
Forest plotsofand
The area the assessment of risk
square reflects of bias. Horizontal
study-specific lines
weight. The correspond
diamond to study-specific
represents MD
pooled results
and 95% CI. The area of the square reflects study-specific weight. The diamond represents
of MD and 95% CI. (1.1.1) Articles in English and (1.1.2) Articles in Chinese. For each study, the selection pooled
results
bias, of MD andbias,
performance 95%detection
CI. (1.1.1) Articles
bias, in English
attrition and (1.1.2)
bias, reporting bias,Articles in Chinese.
and other biases wereFor assessed
each study,
at
the selection
“low bias, performance
risk” if shown bias, detection
in green, “unclear bias, attrition
risk” if shown bias,
in yellow, andreporting bias,
“high risk” if and
shownother biases were
in red.
assessed at “low risk” if shown in green, “unclear risk” if shown in yellow, and “high risk” if shown
3.3. Pair-Wise
in red. Meta-Analysis
Figure 3 summarizes the outcomes, showing that CBT, CHM, HOT, MT, RT, and MT + RT
3.4. Network Meta-Analyses
interventions for Interventions
were significantly better than the control treatment (AU). TCM with transcutaneous
acupoint electrical nerve
We established stimulation
a network and moxibustion interventions
for non-pharmacological combined with intermediate
in PSF. frequency
Table 2 summarizes
electric acupoint massage were also significantly better than the control treatment.
the results of the network meta-analysis regarding the reduction of fatigue after stroke by However,
FSS. The
TCM with
results showacupuncture
that TCM, CT,at Baihui and Sishencong
CBT, CHM, HOT, MT, RT,acupoints
MT + RT, wasandnot significantly
eight different from
PSF non-pharmacological
AU (−0.40 (−1.07,
interventions were0.27)). Direct meta-analysis
not statistically different inof
MDthefor
English articles’ scores.
FSS reduction subgroup showed significant
heterogeneity
We checkedbetween trials (I = 78%,
2
for inconsistency, degrees
where the IFofwas
freedom = 1,and,
(df)0.66
0.00 and p = 0.03). The close
thus, was Chinese
to 0articles
(Figure
subgroup showed the
significant 2 = 95%, df = 7, p < 0.00001).
A1). In addition, randomheterogeneity between
effects variance trials (I
(1.28 (0.63, 2.55)) and the inconsistency variance (1.27
(0.64, 2.55)) were roughly equal, which is considered to be less inconsistent.
3.4. Network Meta-Analyses for Interventions
We established a network Table
for2.non-pharmacological
Network meta-analysis for interventions.
interventions in PSF. Table 2 summarizes
theTCMresults of the network meta-analysis regarding the reduction of fatigue after stroke by FSS.
The– results show that TCM, CT, CBT, CHM, HOT, MT, RT, MT + RT, and eight PSF non-pharmacological
1.40ppppp
interventions
(-3.15,
were not statistically different in MD for FSS reduction scores.
AU
We checked for inconsistency, where the IF was 0.00 and 0.66 and, thus, was close to 0 (Figure A1).
0.35)
In–addition, the random effects variance (1.28 (0.63, 2.55)) and the inconsistency variance (1.27 (0.64,
1.13ppppp
0.27ppppp
2.55)) were roughly
(-3.05,
(–1.05, equal,
CBTwhich is considered to be less inconsistent.
3.42)
2.61)
0.46ppppp 1.86ppppp 0.71ppppp
(–3.02, (–1.08, (–3.09, CHM
3.87) 4.87) 4.44)
– – – –
1.61ppppp 0.21ppppp 1.34ppppp 2.07ppppp
CT
(–5.19, (–3.23, (–5.20, (-6.35,
1.83) 2.81) 2.24) 2.08)
– – – –
0.05ppppp
1.54ppppp 0.16ppppp 1.29ppppp 1.99ppppp
(–4.24, HOT
(–5.03, (–3.20, (–5.09, (–6.32,
4.32)
1.83) 2.85) 2.42) 2.15)
J. Clin. Med. 2020, 9, 621 9 of 15

Table 2. Network meta-analysis for interventions.

TCM
−1.40
AU
(−3.15, 0.35)
−0.27 1.13
CBT
(−3.05, 2.61) (−1.05, 3.42)
0.46 1.86 0.71
CHM
(−3.02, 3.87) (−1.08, 4.87) (−3.09, 4.44)
−1.61 −0.21 −1.34 −2.07
CT
(−5.19, 1.83) (−3.23, 2.81) (−5.20, 2.24) (−6.35, 2.08)
−1.54 −0.16 −1.29 −1.99 0.05
HOT
(−5.03, 1.83) (−3.20, 2.85) (−5.09, 2.42) (−6.32, 2.15) (−4.24, 4.32)
−0.59 0.80 −0.32 −1.05 1.01 0.96
MT
(−3.28, 2.16) (−1.30, 2.95) (−3.46, 2.73) (−4.64, 2.68) (−2.62, 4.69) (−2.65, 4.80)
−0.39 1.02 −0.08 −0.82 1.23 1.17 0.20
MT + RT
(−3.64, 2.96) (−1.83, 3.94) (−3.94, 3.45) (−5.06, 3.27) (−2.95, 5.38) (−2.92, 5.37) (−2.66, 3.03)
−0.61 0.78 −0.35 −1.08 0.99 0.92 −0.03 −0.24
RT
(−3.87, 2.71) (−2.00, 3.63) (−3.98, 3.25) (−5.16, 3.15) (−3.09, 5.13) (−3.17, 5.10) (−2.85, 2.80) (−3.29, 2.79)
The direct and indirect evidence were mixed comparisons. When the entire 95% confidence interval does not contain 1, the MD is statistically significant. TCM: traditional Chinese
medicine; AU: as usual (treatment, nursing, rehabilitation, education); CBT: cognitive behavioral therapy; CHM: community health management; CT: circuit training; HOT: hyperbaric
oxygen therapy; MT: music therapy; RT: respiratory training.
 (–3.87, (–3.98, (–5.16, (–2.85, (–3.29,
3.63) 5.13) 5.10)
2.71) 3.25) 3.15) 2.80) 2.79)
The direct and indirect evidence were mixed comparisons. When the entire 95% confidence interval
does not contain 1, the MD is statistically significant. TCM: traditional Chinese medicine; AU: as usual
(treatment, nursing, rehabilitation, education); CBT: cognitive behavioral therapy; CHM: community
health
J. Clin. Med. management;
2020, 9, 621 CT: circuit training; HOT: hyperbaric oxygen therapy; MT: music therapy; RT: 10 of 15
respiratory training.

3.5.
3.5.Rank
RankProbability
ProbabilityofofInterventions
Interventions
Figure
Figure4 4shows
showsthe theranking,
ranking,indicating
indicatingthe theprobability
probabilityofofbeing
beingthe
thebest
bestintervention
interventiontotoreduce
reduce
fatigue after stroke, followed by the second best, third best, and so on, among all interventions.
fatigue after stroke, followed by the second best, third best, and so on, among all interventions. As As lower
fatigue
lower is better,isRank
fatigue 1 isRank
better, the worst
1 is theand the and
worst higher
thecumulative probabilities
higher cumulative in Rank in
probabilities 9 indicates better
Rank 9 indicates
intervention effectiveness. Thus, Rank 9 (in which the cumulative probabilities
better intervention effectiveness. Thus, Rank 9 (in which the cumulative probabilities indicated indicated the best
the
non-pharmacological intervention) was CHM (0.41), rank 8 was TCM (0.23), and rank
best non-pharmacological intervention) was CHM (0.41), rank 8 was TCM (0.23), and rank 7 was CBT 7 was CBT (0.17).
The worst
(0.17). intervention
The was rankwas
worst intervention 1, CT (0.35).
rank 1, CT (0.35).

Figure 4. Rank probability of Figure 4. Rank probability

interventions. of interventions.
TCM: traditional Chinese medicine; AU: as usual
(treatment, nursing, rehabilitation, education); CBT: cognitive behavioral therapy; CHM: community
TCM: traditional
health ChineseCT:
management; medicine; AU: as usual
circuit training; (treatment,
HOT: nursing,
hyperbaric oxygenrehabilitation,
therapy; MT:education); CBT:RT:
music therapy; cognitive
behavioral therapy;
respiratory CHM: community health management; CT: circuit training; HOT: hyperbaric oxygen
training.
therapy; MT: music therapy; RT: respiratory training.
4. Discussion
4. Discussion
Despite the fact that most interventions did not significantly differ in effectiveness from one
another in thisthe
Despite review, themost
fact that cumulative probabilities
interventions did notindicate that the
significantly best
differ in non-pharmacological
effectiveness from one
intervention for fatigue
another in this review,reduction was CHM,
the cumulative followedindicate
probabilities by TCMthatandthe
CBT.bestThe Canadian Stroke
non-pharmacological
Best Practice Recommendations updated the best practice recommendations
intervention for fatigue reduction was CHM, followed by TCM and CBT. The Canadian for PSF in Stroke
2019 [35].
Best
Although there is insufficient evidence to recommend pharmacological or non-pharmacological
interventions, stroke survivors who experience PSF should be screened and assessed. First, stroke
survivors should be routinely asked about PSF during healthcare visits, following return to the
community and at transition points. Second, prior to discharge from a hospital, stroke unit, or emergency
department, stroke survivors, their families, and informal caregivers should be provided with basic
information regarding the frequency and experience of PSF. Third, stroke survivors who experience
PSF should be screened for common and treatable post-stroke comorbidities, as well as medications
that are associated with and/or exacerbate fatigue. The results also highlight the importance of CHM.
In this review, many interventions could not be included, as there was no control group.
One such intervention was COGRAT, an RCT that compares group cognitive therapy (CO) with
a new treatment combining cognitive therapy (CO) with graded activity training (GRAT), called
COGRAT [36]. Both treatment groups demonstrated significant improvements in fatigue, but a
greater proportion of COGRAT participants achieved clinical improvement. As the COGRAT trial
J. Clin. Med. 2020, 9, 621 11 of 15

had no AU control group, we could not perform network meta-analysis as it was unclear whether
the reduction in fatigue was a result of the physical training or a combined effect with CBT. However,
we included studies using CBT without supervised exercise therapy, which showed that CBT may
be sufficient for clinically significant and sustained improvements in fatigue for at least two months
post-treatment [29]. Another study which was excluded as there was no AU control group investigated
group therapy versus individual task training [37], where no significant differences between groups
were found for improvement of fatigue. We also excluded one study which compared fatigue
management (FM) with group stroke education (GSE) [38]. FM was comprised of six psychoeducation
sessions aimed at alleviating fatigue, which included an overview and introduction to fatigue, fatigue
management, sleep/relaxation, exercise and nutrition, mood, and future focus. Although they reported
that FM greatly reduced FSS scores, compared with the GSE group, we could not perform network
meta-analysis due to the absence of control intervention. We also found another study that used
GSE intervention but could not include it, as the design was a quasi-experiment, not RCT [39]. A
previous Cochrane review providing a comprehensive review of PSF intervention [40] showed results
that were somewhat similar to ours. It included two non-pharmacological interventions, a fatigue
education program, and a mindfulness-based stress reduction program; the results indicated that
there was no statistically significant benefit of non-pharmacological intervention and that there was
insufficient evidence to show the efficacy of any intervention to treat or prevent PSF. Despite the
fact systematic reviews and meta-analyses of randomized trials have long been important synthesis
tools for guiding evidence-based medicine, to our knowledge, this is the first network meta-analysis
enabling the comparison of multiple non-pharmacological interventions for PSF to incorporate clinical
evidence. It could provide evidence for healthcare providers to select effective interventions to improve
the health management and quality of life of stroke patients.
This review had several limitations: First, article selection was limited to studies in the English and
Chinese languages, which may have introduced a language bias and Ethnic heterogeneity; moreover,
the studies were conducted in Australia, the Netherlands, and China, and differences in the prevalence
and intervention effectiveness of PSF may be reflected in different countries. However, this study
showed good consistency, and more studies are needed to identify the differences among different
countries. Second, the sample size and limited data regarding follow-up measurements among the
included articles led to an increased heterogeneity between trials. Only two studies had follow-up data,
which made a great difference in the result of the endpoint follow-up. However, most previous studies
have shown no significant difference in fatigue scores at all time points [41,42]. Third, methodologically,
we assessed the risk of bias based on the Cochrane tool, and most trials in this review were judged to
be at an unclear or high risk of bias. Thus, we recommend that the results of this study be interpreted
with caution. Fourth, we failed to evaluate some important clinical outcomes and comorbidities in PSF
patients. In further studies, comorbidities should be considered and assessed. Furthermore, in order to
minimize the bias induced by the measurement, we only included FSS and may have missed other
interventions. Therefore, future large-sample-sized RCTs based on detailed clinical outcomes may
optimize the network and multiple-treatment comparison.

5. Conclusions
In conclusion, this network meta-analysis showed no significant differences among fatigue scores in
eight PSF non-pharmacological interventions. The cumulative probabilities of best non-pharmacological
intervention highlighted CHM followed by TCM and CBT. Despite the high prevalence of fatigue
and its great impact on the quality of life in stroke patients, the development of treatment remains
compromised due to a lack of understanding by health professionals. Thus, there is an urgent need
to recognize PSF, and more accurate assessment methods for PSF need to be developed in order to
improve our understanding of its etiology and to develop more effective clinical interventions.
 pharmacological intervention highlighted CHM followed by TCM and CBT. Despite the high
prevalence of fatigue and its great impact on the quality of life in stroke patients, the development of
treatment remains compromised due to a lack of understanding by health professionals. Thus, there
is an urgent need to recognize PSF, and more accurate assessment methods for PSF need to be
developed in order to improve our understanding of its etiology and to develop more effective
J. Clin. Med. 2020, 9, 621 12 of 15
clinical interventions.
Author Contributions: Design of the study, M.Y. and Y.S.; data selection and extraction, all authors; statistical
Author Contributions: Design of the study, M.Y. and Y.S.; data selection and extraction, all authors; statistical
analysis, M.Y. and Y.S.; writing—original draft preparation, Y.S.; writing—review and editing: M.Y. and M.O.;
analysis, M.Y. and Y.S.; writing—original draft preparation, Y.S.; writing—review and editing: M.Y. and M.O.;
supervision:M.Y.;
supervision: M.Y.;All
all authors
authorshave
reviewed the manuscript
read and and
agreed to the approved
published the final
version version.
of the manuscript.
Funding:This
Funding: Thisresearch
researchreceived
receivedno
noexternal
externalfunding.
funding.

Acknowledgments:We
Acknowledgments: Wethank
thankall
allthe
theresearchers
researcherswho
whokindly
kindlyprovided
providedthe
thedata
datafor
forthe
thenetwork
networkmeta-analysis.
meta-analysis.
Conflicts Interest:The
ConflictsofofInterest: Theauthors
authorsdeclare
declareno
noconflict
conflictofofinterest.
interest.

Appendix A
Appendix A

Figure A1.Inconsistency
FigureA1. Inconsistencytest.
test.

Table A1. MEDLINE search terms.

Table A1. MEDLINE search terms.
TI stroke or cerebrovascular accident or cva or cerebral vascular event or
S1 S1TI stroke or cerebrovascular accident or cva or cerebral vascular event or cve or transient 89,99489,994
cve or transient ischemic attack or tia
S2ischemic TI fatigue
attack or tiaor exhaustion or tiredness or lethargy 24,958
S3 TI fatigue after stroke OR TI post stroke fatigue 99
S2 TI fatigue or exhaustion or tiredness or lethargy 24,958
S4 S1 AND S2 195
S3 S5TI fatigueAB
after stroke ORorTIintervention
treatment post stroke fatigue
or therapy or management or rehabilitation99 7,697,803
S4 TI controlled clinical trial or randomized controlled trail or randomized or
S6S1 AND S2 195 478,666
placebo or randomly or trial or groups
S5 S7AB treatment
S3 ORor S4
intervention or therapy or management or rehabilitation 7,697,803
195
S6 S8TI controlled
S5 AND S6 AND S7
clinical trial or randomized controlled trail or randomized or placebo or 478,666 7

randomly or trial or groups

S7 S3 OR S4 195

S8 S5 AND S6 AND S7 7

Table A2. Characteristics of all involved studies.

J. Clin. Med. 2020, 9, 621 13 of 15

Table A2. Characteristics of all involved studies.

Type of N Mean Age (Years) Time p-Value

Author/Year Country Intervention
Stroke Gender Post-Incident Baseline Baseline vs.
Intervention Control Intervention Control Endpoint
(Male) Stroke vs. Post Follow-Up
Ingrid G L van de Ischemic and
Netherlands CT 162 CT = 125 AU = 117 56 58 N/A 24 weeks >0.05 >0.05
Port, 2012 Haemorrhagic
Sylvia Nguyen, Ischemic and
Australia CBT 11 CBT = 9 AU = 6 47 51 27 months 16 weeks <0.05 <0.05
2017 Haemorrhagic
Ischemic and
Lv Huila, 2017 China MT 24 MT = 20 AU = 20 62 62 2.28 months 8 weeks <0.05 N/A
Haemorrhagic
Ischemic and
Yin Hongna, 2016 China TCM 33 AT = 30 AU = 30 62 62 2.95 months 4 weeks <0.05 N/A
Haemorrhagic
Wang Rongyun, Ischemic and
China TCM 45 AT = 38 AU = 39 67 67 2 weeks 2 weeks <0.05 N/A
2017 Haemorrhagic
Ischemic and 27days-
Li Lanhua, 2014 China TCM 51 AT = 46 AU = 45 51 51 4 weeks <0.05 N/A
Haemorrhagic 20 months
Ischemic and
Liu Vanjin, 2018 China CBT N/A CBT = 30 AU = 30 N/A N/A N/A 8 weeks <0.05 N/A
Haemorrhagic
MT MT = 20
Li Qianfeng, 2017 China Ischemic RT 47 RT = 20 AU = 20 57 57 N/A 8 weeks <0.05 N/A
MT+RT MT + RT = 20
Ischemic and
Liu Fengli, 2017 China CHM 43 CHM = 45 AU = 45 47 49 N/A 12 weeks <0.05 N/A
Haemorrhagic
Ischemic and
Zhang Libo, 2014 China HOT N/A HOT = 31 AU = 31 N/A N/A N/A 4 weeks <0.05 N/A
Haemorrhagic
FSS: Fatigue Severity Scale; CT: circuit training; AU: treatment, nursing, rehabilitation as usual; CBT: cognitive behavioral therapy; MT: music therapy; TCM: Traditional Chinese Medicine;
RT: respiratory training; CHM: community health management; HOT: hyperbaric oxygen therapy; N/A: not available; there are two p values in the table, the first is FSS scores of baseline vs
post and the second is FSS scores of baseline vs follow-up, and only two studies had follow-up data.
J. Clin. Med. 2020, 9, 621 14 of 15

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