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Psychiatry and Clinical Neurosciences 2013; 67: 323331 doi:10.1111/pcn.

12066

Review Article

Atypical antipsychotics in the treatment of delirium


Hee Ryung Wang, MD, Young Sup Woo, MD, PhD and Won-Myong Bahk, MD, PhD*
Department of Psychiatry, Yeouido St. Marys Hospital, The Catholic University of Korea, Seoul, Korea

The aim of this study was to review the efficacy and effective and safe in treating delirium, even though
safety of atypical antipsychotics, comparing within there seemed to be no difference between each agent.
class, placebo, or compared to another active treat- In particular, comparison studies with haloperidol
ment for delirium. A literature search was conducted showed that the efficacy of atypical antipsychotics
using PubMed, EMBASE, and the Cochrane database was similar to that of low-dose haloperidol. It was
(1 January 19905 November 2012). Selection crite- concluded that atypical antipsychotics appear to be
ria for review were prospective, controlled studies effective and tolerable in the management of
(comparison studies), using validated delirium rating delirium, even though the evidence is limited.
scales as outcome measures. A total of six prospective,
randomized controlled studies were included in the Key words: atypical antipsychotic, delirium, efficacy,
review. It was found that atypical antipsychotics are safety, treatment.

ELIRIUM IS AN acute, confusional state that is delirium.4,5 Conservative management such as pre-
D characterized by consciousness disturbance,
changes in cognition and attention, and reduced
venting medical complications and providing
patients with a supportive environment is also very
awareness or perceptual disturbances that develop important. In terms of pharmacological interven-
acutely and have a fluctuating course.1 Delirium is tions, antipsychotic agents have been regarded as the
a common neuropsychiatric condition observed treatment of choice, because various antipsychotic
in medically ill patients. Lipowski reported that, agents have been shown to ameliorate a range of
among patients hospitalized for medical and surgi- delirium symptoms effectively in many previous
cal reasons, the incidence of delirium ranged from studies.68 Among antipsychotics, haloperidol has
10% to 18% and that the development of delirium been the most widely used because of its higher
is associated with a high mortality and morbidity.2 dopamine receptor potency, lower anticholinergic
The elderly are known to be at high risk for devel- effects, and the availability of various routes of use.9
oping delirium. According to Han and Kim, Side-effects, however, have been reported, especially
1040% of hospitalized elderly patients develop extrapyramidal effects.10 Due to the side-effects of
delirium during hospitalization.3 typical antipsychotics, the use of atypical antipsy-
For non-pharmacological interventions for chotics in the treatment of delirium has been
delirium, clinicians should correct and treat the increasing because of the lower incidence of extrapy-
underlying medical condition responsible for the ramidal symptoms with atypical compared to typical
antipsychotics.11,12
Despite the increasing usage of atypical antipsy-
chotics for delirium in clinical practice, limited
*Correspondence: Won-Myong Bahk, MD, PhD, Department of evidence is available on their efficacy and
Psychiatry, Yeouido St. Marys Hospital, College of Medicine, The
tolerability.11,12 Accordingly, the primary aim of this
Catholic University of Korea, 62 Yeouido-Dong, Youngdeungpo-Gu,
Seoul 150-713, Korea. Email: wmbahk@catholic.ac.kr
paper was to review the existing published literature
Received 18 January 2013; revised 5 April 2013; accepted 26 May on the role of atypical antipsychotics in the manage-
2013. ment of delirium.

2013 The Authors 323


Psychiatry and Clinical Neurosciences 2013 Japanese Society of Psychiatry and Neurology
324 H. R. Wang et al. Psychiatry and Clinical Neurosciences 2013; 67: 323331

of atypical antipsychotics in preventing delirium in


METHODS high-risk patients were also excluded. Only studies
written in English were reviewed.
Search methods and selection criteria
To review the efficacy and tolerability of atypical
antipsychotics in treating delirium, we conducted a
RESULTS
literature search using PubMed, EMBASE, and the
Cochrane database (1 January 19905 November
Search results
2012) using the following search terms in various We initially identified 789 articles from PubMed,
combinations: delirium, antipsychotic agent, neu- 2627 from EMBASE, and 61 from the Cochrane data-
roleptic agent, olanzapine, risperidone, aripi- base. Among them, 552 articles overlapped. After we
prazole, quetiapine, ziprasidone, amisulpride, reviewed the abstracts of the 2925 articles identified,
zotepine, paliperidone. Prospective, randomized we retrieved 85 and reviewed them thoroughly.
controlled studies were selected for review. Specifi- Among these 85, six articles met the selection criteria
cally, studies were included that compared the effi- and were chosen for review by the two reviewers
cacy and tolerability of atypical antipsychotics either (WMB and HRW). The characteristics of the six
with placebo or another active treatment such as articles are listed in Table 1.
haloperidol, or that compared two or more atypical One study was a randomized, open prospective
antipsychotics to each other. The literature review study that compared amisulpride and quetiapine in
was also limited to studies that used standardized the treatment of delirium. Two studies were random-
diagnostic criteria for delirium and validated instru- ized controlled studies that investigated the efficacy
ments to rate delirium (e.g. Memorial Delirium and safety of olanzapine. One of these two was a
Assessment Scale [MDAS],13 Delirium Rating Scale comparative trial that compared olanzapine and
[DRS],14 Delirium Index [DI],15 or the revised version haloperidol. The other investigated the effectiveness
of DRS [DRS-R 98]16). Studies such as case series, or of olanzapine and risperidone compared to haloperi-
case reports, studies using retrospective design, dol. There was one randomized, placebo-controlled
studies of substance-associated delirium, and single- study that investigated the effectiveness of quetiap-
agent studies without an adequate control group ine. The remaining two articles were comparative
were excluded. Studies investigating the effectiveness trials of risperidone. Among these, one compared

Table 1. Studies of the clinical use of atypical antipsychotics in delirium

Sample Mean dose


Study Study setting size Medication (mg/day) Scale
Lee et al., 200517 Referred to the Psychiatric Consultation 40 Amisulpride 156.4 DRS-R-98
Service Quetiapine 113.0
Skrobik et al., 200418 Medical-surgical intensive care unit 73 Olanzapine 4.54 DI
Haloperidol 6.50
Grover et al., 201119 Referred to the consultation-liaison 74 Olanzapine 3.05 DRS-R-98
psychiatry Risperidone 0.95
Haloperidol 0.88
Tahir et al., 201020 Medical, surgical and orthopedic wards at 42 Quetiapine (placebo 40.0 DRS-R-98
a university hospital controlled)
Han and Kim, 20043 Medical wards, intensive care units, and 28 Risperidone 1.02 MDAS
oncology wards Haloperidol 1.71
Kim et al., 201021 Referred to the Psychiatric Consultation 32 Olanzapine 1.8 DRS-R-98
Risperidone 0.6
DI, Delirium Index; DRS-R-98, revised version of the Delirium Rating Scale; MDAS, Memorial Delirium Assessment
Scale.

2013 The Authors


Psychiatry and Clinical Neurosciences 2013 Japanese Society of Psychiatry and Neurology
Psychiatry and Clinical Neurosciences 2013; 67: 323331 Atypical antipsychotics in delirium 325

risperidone and haloperidol, and the other compared


risperidone and olanzapine. Olanzapine
There have been a number of published studies
examining the effectiveness of olanzapine.18,19,21,2429
Atypical antipsychotics in delirium Three of those studies assessed the clinical efficacy
and safety of olanzapine using a prospective, ran-
Amisulpride domized controlled design.18,19,21
We reviewed two studies on the efficacy of amisul- Skrobik et al. compared the use of olanzapine
pride for the treatment of delirium.17,22 One was an and haloperidol over 5 days in the treatment of
uncontrolled study,22 so it was excluded from further delirium.18 This study was a prospective, randomized
review. One randomized, open prospective study controlled trial in a critical care unit setting. Subjects
investigating the effectiveness of amisulpride for were patients admitted to the medicalsurgical inten-
delirium met the selection criteria for this review.17 sive care unit and diagnosed with delirium based on
Lee et al. compared the effectiveness and safety DSM-IV criteria.30 The patients who had received any
of amisulpride and quetiapine in patients with antipsychotic agent within 10 days prior to admis-
delirium.17 They also compared the effect of each drug sion to hospital or intensive care unit, who had gas-
on sleep and recovery time. A total of 40 patients who trointestinal dysfunction, impeding oral/enteral drug
were referred for psychiatric consultation at a univer- treatment, and who had neurological status that
sity hospital were enrolled. The patients who had disturbed an adequate psychiatric evaluation were
taken antipsychotic agents, who seemed to resolve excluded. The subjects were randomly assigned to
spontaneously, and who had a prior history of psychi- either olanzapine or haloperidol on an even/odd day
atric disorder were excluded. The subjects were basis. Dosing titration depended on clinician judg-
randomized into either amisulpride or quetiapine ment. Benzodiazpine as adjuvant treatment and i.v.
groups. The dose was flexible depending on clinician haloperidol as rescue medication were allowed. The
decision. The instruments used for delirium ratings severity of delirium was measured using the DI. A
were the Clinical Global Impression-Severity (CGI-S) total of 73 patients were included in the analysis. The
scale,23 and the DRS-R 98. Sixteen subjects in the mean age of the study group was 63.26 11.66 years
amisulpride group and 15 subjects in the quetiapine for the haloperidol group and 67.50 6.04 years for
group completed the study. In the amisulpride the olanzapine group, respectively. The mean daily
group, subjects were prescribed a mean dose of doses were 6.5 mg (range, 128 mg) in the haloperi-
156.4 97.5 mg/day (range, 50800 mg/day). In the dol group and 4.54 mg in the olanzapine group
quetiapine group, subjects were prescribed a mean (range, 2.513.5 mg). In both group, DI scores were
daily dose of 113 85.5 mg/day (range, 50300 mg/ significantly reduced after 5 days of treatment with
day). Treatment was terminated when CGI-S reached each medication, but DI scores did not differ between
2. Benzodiazepine or other antipsychotics were not the two groups. Overall, DI scores in all patients went
allowed. In both groups, the DRS-R 98 score signifi- from 7.05 on day 1 to 5.05 on day 5. There were no
cantly decreased after treatment (from 10.5 4.1 to adverse effects reported in the olanzapine group,
3.5 1.4 for the amisulpride group, P < 0.001; from whereas six subjects in the haloperidol group experi-
10.1 4.1 to 3.5 2.6 for the quetiapine group, enced extrapyramidal symptoms. That study indi-
P = 0.001), but there was no significant group differ- cated that olanzapine has clinical utility and is
ence. The recovery time from delirium did not differ tolerable for the management of delirium in critically
between the two groups (6.3 4.4 days for the ill patients.18
amisulpride group and 7.4 4.1 days for the quetiap- Grover et al. examined the efficacy and tolerability
ine group). The percentage of patients who had >50% of olanzapine and risperidone compared to haloperi-
symptom reduction after treatment was 81.3% dol for delirium.19 That study had a prospective,
(n = 13) in the amisulpride group and 80% (n = 12) in single-blinded, randomized controlled design. Sub-
the quetiapine group. No serious adverse events were jects were patients who had been admitted to the
reported during the study period. That study thus medical and surgical ward and referred for psychiatric
demonstrated that both amisulpride and quetiapine consultation for delirium. Delirium was diagnosed
were effective in treating delirium and both were based on the DRS-R 98 and the Confusion Assess-
well-tolerated. ment Method Scale (CAM).31 Those who had alcohol

2013 The Authors


Psychiatry and Clinical Neurosciences 2013 Japanese Society of Psychiatry and Neurology
326 H. R. Wang et al. Psychiatry and Clinical Neurosciences 2013; 67: 323331

or benzodiazepine withdrawal delirium, who had done and 2.4 1.7 mg/day for olanzapine. There
dementia, who were unresponsive to any physical or was significant improvement in DRS-R 98 scores
verbal stimulus, who suffered from a terminal illness, from baseline to day 7 in both groups, but the two
and who had psychotic or mood disorders were groups did not differ from each other. There was also
excluded from the study. Subjects who had profound no statistically significant difference in response rates
hearing or visual difficulty, aphasia, Parkinsons between the risperidone and olanzapine groups.
disease, prior history of neuroleptic malignant syn- Three patients in the olanzapine group and two in the
drome, and prolonged QTc interval (defined as risperidone group reported extrapyramidal symp-
>500 ms) were also excluded. Delirium severity was toms, but all were mild to moderate. This study indi-
assessed using the DRS-R 98. Seventy-four patients cates that both representative atypical antipsychotics
were randomly assigned to three medication groups: are similarly effective in the treatment of delirium.21
risperidone (n = 22), olanzapine (n = 26), or halo-
peridol (n = 26). Among these patients, 64 com-
pleted the study. The dosing schedule was based on Quetiapine
clinical judgment. The mean daily dose of each drug Since Schwartz and Masand reported the clinical effi-
was 0.88 0.98 mg/day for haloperidol, 3.05 cacy of quetiapine in the treatment of delirium in
1.44 mg/day for olanzapine, and 0.95 0.28 mg/ a retrospective chart review study,33 many studies
day for risperidone. All groups showed a significant have investigated the efficacy of quetiapine for
reduction from baseline in DRS-R 98 scores on days 3 delirium.17,3439 Most of these studies have been
and 6, but there were no significant differences uncontrolled, single-agent studies, but there have
among the three groups in terms of the degree of been three prospective, randomized controlled trials
reduction in DRS-R 98 scores. Four subjects in the that investigated the efficacy and safety of quetiapine
haloperidol group, six in the risperidone group and for delirium.17,20,39 Among the three studies, the
two in the olanzapine group reported some side- Devlin et al. study was excluded from review because
effects, but there was no group difference. This study the primary outcome measure was the time to first
showed that the two second-generation antipsychot- resolution of delirium, not the change of delirium
ics (olanzapine and risperidone) were similarly effec- severity measured on a validated delirium rating
tive and tolerable compared to haloperidol. scale.39 Among the remaining two randomized con-
Kim et al. conducted a 7-day, randomized con- trolled studies, one was a comparison study that
trolled trial to compare olanzapine and risperidone tested the effectiveness of amisulpride and quetiap-
for delirium treatment.21 Subjects were delirious ine, which has been described in the amisulpride
patients in three university hospitals who were section.17
referred for psychiatric consultation. The diagnosis of Tahir et al. assessed the clinical utility of quetiapine
delirium was based on DSM-IV criteria. Those who in the management of delirium.20 This was a double-
had dementia, and who had taken antipsychotics due blind, randomized controlled trial. The sample con-
to behavioral problems prior to referral were sisted of patients who were admitted to medical,
excluded. For efficacy, the DRS-R 98 was used to surgical, and orthopedic wards at a university hospi-
measure delirium severity. The Udvalg for Kliniske tal. Among these patients, those who met the DSM-IV
Undersogelser neurological side-effect scale32 was criteria for delirium and whose DRS-R 98 total score
used to assess neurological side-effects. The dosing was 15 were recruited. Those who had pre-existing
schedule was based on clinical judgment depending cognitive disturbances, pre-existing psychosis, sub-
on each patients medical condition over the 7 days. stance dependence, alcohol withdrawal, or who
Rescue medication such as a haloperidol or benzodi- took medication interacting with quetiapine were
azepine injection was allowed. Among the 32 excluded. Among the 372 patients screened, a total of
patients enrolled, 17 were randomized to risperidone 42 patients were recruited for this trial. The mean age
and 15 were randomized to olanzapine. Among of the subjects was 84.2 8.3 years (range, 5898
these, 12 subjects in the risperidone group and eight years). Twenty-nine patients completed the trial: 16
in the olanzapine group completed the trial. The patients in the quetiapine group and 13 patients in
mean initial doses were 0.6 0.2 mg/day for risperi- the placebo group. The DRS-R 98, Brief Psychiatric
done and 1.8 0.6 mg/day for olanzapine. The Rating Scale (BPRS),40 CGI, and Mini-Mental State
mean daily doses were 0.9 0.6 mg/day for risperi- Examination (MMSE)41 were used. The Abnormal

2013 The Authors


Psychiatry and Clinical Neurosciences 2013 Japanese Society of Psychiatry and Neurology
Psychiatry and Clinical Neurosciences 2013; 67: 323331 Atypical antipsychotics in delirium 327

Involuntary Movements Scale (AIMS)42 and a clinical sample consisted of patients who were referred for
examination were used to assess side-effects of que- psychiatric consultation at a university hospital and
tiapine. Subjects were evaluated on days 1, 2, 3, 4, 7 diagnosed with delirium based on the Structured
and 10 after randomization and followed up on day Clinical Interview for DSM-III-R (SCID).45 Those who
30. Forty-two subjects were randomly assigned to had any type of dementia or other psychiatric disor-
either quetiapine or placebo with a flexible dose. The ders identified using the SCID were excluded. A total
starting dose for quetiapine was 25 mg once daily. of 28 patients were randomized to receive risperi-
The dose was increased by 25 mg per day to a done or haloperidol with flexible doses. The starting
maximum dose of 175 mg if the DRS-R 98 score did dose was 1.5 mg for haloperidol and 1.0 mg for ris-
not improve after treatment. If symptoms of delirium peridone. The dose could be increased based on clini-
were resolved as based on the DRS-R 98, the dose was cal judgment during the 7 days of the study period.
decreased. The highest mean daily dose of quetiapine Two subjects in the haloperidol group and two in the
was 40 mg on day 4 (25 mg/day on day 1, and risperidone group dropped out. The mean daily doses
37.50 mg/day on day 10). The quetiapine group were 1.71 0.84 mg for haloperidol and 1.02
showed more rapid improvement in DRS-R 98 scores 0.41 mg for risperidone. The MDAS was used to
than the placebo group. Additionally, the quetiapine measure delirium severity. The initial DRS score for
compared to the placebo group showed faster all patients was 22.76 4.30, with no significant dif-
improvement on the non-cognitive subscale of the ference between groups. Both groups had a signifi-
DRS-R 98 (items 18) but not on the cognitive sub- cant decrease in MDAS scores from screening to day
scale (items 913). There were no differences in the 7, but the two groups did not differ. There was also
MMSE, BPRS, and CGI scores between the two no significant difference between the groups in
groups. Seven subjects died within 30 days after response rate, defined as MDAS <13 (risperidone
entering the trial (four in the quetiapine group and group 42%; haloperidol group 75%). No side-effects
three in the placebo group). One subject was with- were reported by subjects in either group. The results
drawn from quetiapine because of sedation. Abnor- of that study indicate that risperidone has similar
mal involuntary movements were reported in both efficacy and tolerability to haloperidol.3
groups (4.8% of the quetiapine group and 14.3% of
the placebo group). Even though the study was ter- Ziprasidone
minated early due to concerns of the Food and Drug There have been no prospective, randomized, con-
Administration regarding the usage of an antipsy- trolled studies of the effectiveness and tolerability
chotic agent in the elderly, that study demonstrated of ziprasidone using validated instruments to assess
the potential of quetiapine for a more rapid reduc- delirium. There have been several case reports4951
tion in the severity of non-cognitive symptoms of and one randomized, placebo-controlled trial.52 The
delirium.20 only randomized controlled trial on the use of
ziprasidone, performed by Girard et al.,52 was
Risperidone excluded from the present review because validated
instruments were not used for primary outcome
A number of studies have tested the use of risperi- measures.
done in the management of delirium.14,31,4348
There have been three prospective trials on the use
Aripiprazole
of risperidone in the treatment of delirium.3,19,21
Among them, one study examined the efficacy and Only case reports,28,53 uncontrolled studies54,55 and
tolerability of olanzapine and risperidone compared one non-randomized study56 have reported regarding
to haloperidol.19 Another was a 7-day, randomized the use of aripiprazole for delirium. There have been
controlled trial that compared olanzapine and ris- no prospective, randomized controlled studies that
peridone.21 Both studies are reviewed in the olanza- have examined aripiprazoles effectiveness and toler-
pine section. We discuss the remaining study in this ability using validated instruments to assess delirium.
section.3
Han and Kim conducted a double-blind, random- Other atypical antipsychotics
ized controlled trial to compare risperidone and There is a prospective open-label trial that examined
haloperidol for the treatment of delirium.3 The the efficacy of paliperidone in the treatment of

2013 The Authors


Psychiatry and Clinical Neurosciences 2013 Japanese Society of Psychiatry and Neurology
328 H. R. Wang et al. Psychiatry and Clinical Neurosciences 2013; 67: 323331

delirium,57 but there have been no randomized Three studies were comparison studies that directly
controlled studies on the efficacy of paliperidone for compared two antipsychotics to each other.17,19,21
delirium. One study used haloperidol as an active compara-
To our knowledge, there have been no clinical tor.19 All three comparison studies showed improve-
studies to have tested the efficacy and tolerability of ments in delirium symptoms after use of atypical
zotepine for the treatment of delirium. antipsychotics, and there were no between-group dif-
ferences in efficacy and tolerability.
The other two studies were haloperidol-controlled
DISCUSSION studies that examined the effectiveness of olanzapine
In this review, we discussed studies that tested the and risperidone.3,18 Both studies reported similar effi-
efficacy and safety of atypical antipsychotics in the cacy of each atypical antipsychotic agent compared to
treatment of delirium. Since their introduction, atypi- haloperidol, suggesting the potential use of each
cal antipsychotics have replaced typical antipsychot- atypical antipsychotic agent as a safe alternative to
ics in various clinical uses because of their favorable haloperidol.
side-effect profiles.58 For the same reasons, the use of Across the six studies, extrapyramidal symptoms
second-generation antipsychotics in the management were one of the most common adverse events
of delirium has increased, which reflects a change in reported, while the metabolic side-effects were much
prescription patterns. Since one of the first studies of less frequently reported. That might be because the
the use of atypical antipsychotics for delirium,48 there treatment duration for delirium in these studies was
have been numerous published reports regarding relatively shorter than the duration for other major
their clinical efficacy and tolerability; but when we psychiatric disorders, such as affective disorders or
consider that many etiologies are known to cause psychotic disorders.
delirium and that delirium has a fluctuating nature, it While reviewing the extant literature, we identified
is difficult to affirm that the significant improvement several concerns and methodological limitations.
in delirium symptoms observed in many previous First, most studies had small sample sizes. The
clinical trials after the use of atypical antipsychotics is sample sizes across the six studies were between 20
purely due to the effect of atypical antipsychotics. and 80, which is too small a sample to generalize the
Thus, we selected only well-controlled studies to results. Second, there was significant heterogeneity
separate the influence of atypical antipsychotics on across studies in terms of the characteristics of the
delirium symptoms from other variables that could study groups and the etiology of delirium. Partici-
influence the treatment response and course of pants across the six studies presented with delirium
delirium. symptomatology at admission to medical or surgical
We conducted a literature search and found a total wards or developed delirium while undergoing treat-
of six randomized controlled, prospective clinical ment in intensive care units. The underlying etiology
trials that tested the utility of atypical antipsychotics of delirium for each participant also varied, and
in delirium. included etiologies such as malignant tumors, ortho-
Among the six studies reviewed, only one was a pedic problems, pneumonia, neurosurgical condi-
placebo-controlled study.20 The rest were comparison tions, and other medical and surgical conditions.
studies, some of which compared the efficacy of Third, no study reported controlling for these hetero-
atypical antipsychotics to haloperidol,3,18,19 and the geneous differences in their analyses or controlling
others compared different atypical antipsychotics to for any treatment (including non-specific, non-
each other.17,19,21 pharmacological treatments) given to patients to
The only placebo-controlled study examined the manage an underlying medical/surgical condition.
efficacy of quetiapine among general hospital inpa- Because these can be confounding variables, future
tients whose DRS-R 98 total scores were 15.20 studies should describe and explain these variables in
Although the quetiapine and placebo groups did not their assessment and analyses. Fourth, we found that
differ in their delirium severity at any time point, the there were few studies that investigated the tolerabil-
quetiapine group had a more rapid improvement in ity systematically. There were no validated assess-
symptoms. But because that study was prematurely ment tools for drug side-effects used in the six
discontinued, we are unable to draw any definitive studies except the scales assessing the extrapyramidal
conclusions. symptoms.

2013 The Authors


Psychiatry and Clinical Neurosciences 2013 Japanese Society of Psychiatry and Neurology
Psychiatry and Clinical Neurosciences 2013; 67: 323331 Atypical antipsychotics in delirium 329

There are some limitations to the present review. of atypical antipsychotics for the treatment of
First, we included only randomized controlled, pro- delirium according to the motor subtypes or various
spective studies that were written in English. We may delirium etiologies.
have excluded important studies written in other lan-
guages or with uncontrolled, naturalistic, or retro-
spective designs, which can also provide valuable ACKNOWLEDGMENT
information about the utility of atypical antipsychot- The authors have no conflict of interest to declare.
ics. Second, we included only studies that used
validated delirium rating scales as efficacy outcome
measures. Thus, we excluded some trials that REFERENCES
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