1

Holmium Laser Enucleation versus Transurethral
Resection in Patients with Benign Prostate Hyperplasia:

An Updated Systematic Review with Meta-Analysis and
Trial Sequential Analysis
Sheng Li1., Xian-Tao Zeng2., Xiao-Lan Ruan3, Hong Weng2, Tong-Zu Liu1, Xiao Wang1, Chao Zhang2,
Zhe Meng1, Xing-Huan Wang1*
1 Department of Urology, Zhongnan Hospital, Wuhan University, Wuhan, Peoples Republic of China, 2 Center for Evidence-based Medicine and Clinical Research, Taihe
Hospital, Hubei University of Medicine, Shiyan, Peoples Republic of China, 3 Department and Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong
University of Science and Technology, Wuhan, Peoples Republic of China
Abstract
Background: Holmium laser enucleation (HoLEP) in surgical treatment of benign prostate hyperplasia (BPH) potentially
offers advantages over transurethral resection of the prostate (TURP).
Methods: Published randomized controlled trials (RCTs) were identified from PubMed, EMBASE, Science Citation Index, and
the Cochrane Library up to October 10, 2013 (updated on February 5, 2014). After methodological quality assessment and
data extraction, meta-analysis was performed using STATA 12.0 and Trial Sequential Analysis (TSA) 0.9 software.
Results: Fifteen studies including 8 RCTs involving 855 patients met the criteria. The results of meta-analysis showed that: a)
efficacy indicators: there was no significant difference in quality of life between the two groups (P.0.05), but compared
with the TURP group, Qmax was better at 3 months and 12 months, PVR was less at 6, 12 months, and IPSS was lower at 12
months in the HoLEP, b) safety indicators: compared with the TURP, HoLEP had less blood transfusion (RR 0.17, 95% CI 0.06
to 0.47), but there was no significant difference in early and late postoperative complications (P.0.05), and c) perioperative
indicators: HoLEP was associated with longer operation time (WMD 14.19 min, 95% CI 6.30 to 22.08 min), shorter
catheterization time (WMD 219.97 h, 95% CI 224.24 to 215.70 h) and hospital stay (WMD 225.25 h, 95% CI 229.81 to 2
20.68 h).
Conclusions: In conventional meta-analyses, there is no clinically relevant difference in early and late postoperative
complications between the two techniques, but HoLEP is preferable due to advantage in the curative effect, less blood
transfusion rate, shorter catheterization duration time and hospital stay. However, trial sequential analysis does not allow us
to draw any solid conclusion in overall clinical benefit comparison between the two approaches. Further large, welldesigned, multicentre/international RCTs with long-term data and the comparison between the two approaches remain
open.
Citation: Li S, Zeng X-T, Ruan X-L, Weng H, Liu T-Z, et al. (2014) Holmium Laser Enucleation versus Transurethral Resection in Patients with Benign Prostate
Hyperplasia: An Updated Systematic Review with Meta-Analysis and Trial Sequential Analysis. PLoS ONE 9(7): e101615. doi:10.1371/journal.pone.0101615
Editor: Peter C. Black, University of British Columbia, Canada
Received March 12, 2014; Accepted June 8, 2014; Published July 8, 2014
Copyright: 2014 Li et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its
Supporting Information files.
Funding: The authors have no support or funding to report.
Competing Interests: The authors have declared that no competing interests exist.
* Email: [email protected]
. These authors contributed equally to this work.
enucleation of the prostate (HoLEP) [2]. Holmium laser

techniques have been introduced as a surgical intervention for
BPH more than 15 years. In 1997, Gilling et al [3] conducted the
first prospective randomized controlled trial (RCT) comparing
TURP with holmium laser resection of the prostate (HoLRP), the
result revealed HoLRP was associated with significantly longer
mean resection time (42.1 vs. 25.8 minutes) when compared to
TURP, while symptomatic and urodynamic improvement were
equivalent in both groups. Subsequently, HoLRP combined with
Introduction
The latest American Urological Associations (AUA) Guideline
defines transurethral resection of the prostate (TURP) as the gold
standard surgical treatment for benign prostate hyperplasia
(BPH) [1]. However, the latest guideline from the European
Association Urology (EAU) indicates that when the prostate
volume is larger than 80 ml, it is dangerous for BPH patients to be
treated with TURP, and EAU recommends holmium laser
PLOS ONE | www.plosone.org
July 2014 | Volume 9 | Issue 7 | e101615
Meta-Analysis of HoLEP versus TURP
Figure 1. Identification of eligible studies.

doi:10.1371/journal.pone.0101615.g001
transurethral tissue morcellation evolved into HoLEP. Since then,

many studies on this issue have been conducted with different or
even contradictory results [46]. Therefore, whether HoLEP is
non-inferiority, equivalence, or superiority to TURP remains
unclear. An in depth reassessment of this question has important
clinical implications. Consequently, we performed this systematic
review with meta-analysis and trial sequential analysis (TSA) of all
the published RCTs in the hope of providing more precise
evidence.
Eligibility criteria
Studies were eligible for inclusion if they met the following
criteria: (1) study participants were clearly diagnosed as BPH and
needed surgical treatment (we excluded patients who had unstable
bladder, neurogenic bladder, preoperative urethral stricture,
history of bladder cancer, or previous history of bladder neck
cancer surgery); (2) randomized controlled studies which used
HoLEP and TURP as the intervention and control arms,
respectively; (3) at least reported one of the efficacy, safety or
perioperative outcomes, which consisted of the International
Prostate Symptom Score (IPSS), maximum flow rate (Qmax) (ml/
s), quality of life (QoL), postvoid residual volume (PVR) (ml), the
International Index of Erectile Function (IIEF), blood transfusion,
TUR syndrome, urethral stricture, bladder neck contracture,
secondary treatment, acute urinary retention (AUR), urinary tract
infection (UTI), and transient hematuria, operating time (min),
Methods
We reported this systematic review and meta-analysis based on
the methodology recommended by the Cochrane Collaboration
and according to the Preferred Reporting items for Systematic
Review and Meta-analysis (PRISMA) statement [7]. The protocol
(CRD42014007334) of this systematic review was published in the
PROSPERO register (www.crd.york.ac.uk/PROSPERO).

2014
Sun et al. [19]
82/82
40/40
15/15
50/50
52/48
100/100
31/30
61/59
Sample size
12
12
12
24
12
12
12
Follow-up,
mo
72.2/71.9
67.5/68.3
69.9/66.5
65.9/65.7
65.1/64.5
68.0/68.7
71.7/70.3
66.9/66.8
Age, yr
NA
62.4/58.5
36.5/36.3
57.9/59.8
70.3/56.2
53.5/49.9
77.8/70
44.3/44.6
Prostate size, g
24.4/24.6
23/25
22.5/21.4
23.4/23.3
NA
22.1/21.4
26.4/23.7
21.9/23
IPSS
4.6/4.6
NA
NA
NA
NA
NA
4.8/4.7
NA
QoL
5.3/5.7
8.4/8.1
5.8/6.9
5.2/4.5
NA
4.9/5.9
8.4/8.3
8.9/9.1
Qmax, ml/s
3
Low
Low
Mavuduru et al. [24]
Eltabey et al. [20]
Sun et al. [19]
doi:10.1371/journal.pone.0101615.t002
Unclear
Low
Gupta et al. [22]
Low
Unclear
Low
Tan/Gilling/Wilson et al. [26,29,32]
Montorsi/Rigatti/Briganti et al. [25,30,33]
Low
Gilling/Fraundorfer/Westenberg et al. [21,28,31]
Kuntz/Ahyai et al. [23,27]
Random sequence
generation
Trial
Unclear
Unclear
Unclear
Unclear
Unclear
Unclear
Low
Unclear
Allocation concealment
Table 2. Risk of bias assessment of the included randomized controlled trials (RCTs).
Low
Unclear
Unclear
Unclear
Unclear
Unclear
Low
Unclear
Blinding
Low
Low
Low
Low
Low
Low
Low
Low
Incomplete outcome
data
Low
Low
Low
Low
Low
Low
Low
Low
Selective outcome
reporting
115.8/108
130/105
91/103
112/84
NA
238/216
116.1/126.7
87.8/84.7
PVR, ml
Low
Low
Low
Low
Low
Low
Low
Low
Baseline imbalance
IPSS = International Prostate Symptom Score; QoL = quality of life; Qmax = maximum flow rate; PVR = postvoid residual volume; IIEF = International Index of Erectile Function; NA = not available.
doi:10.1371/journal.pone.0101615.t001
2010
Eltabey et al. [20]
2004; 2006; 2006
Montorsi/Rigatti/Briganti et al. [25,30,33]

2006
2004; 2007
Kuntz/Ahyai et al. [23,27]
2009
2003; 2006; 2012
Tan/Gilling/Wilson et al. [26,29,32]
Mavuduru et al. [24]
1999; 2001; 2004
Gilling/Fraundorfer/Westenberg et al. [21,28,31]
Gupta et al. [22]
Publication, yr
Trial
Table 1. Characteristics of the included randomized controlled trials (RCTs).
Low
Low
Low
Low
Low
Low
Low
Low
Other bias
NA
NA
NA
NA
22.3/21.4
NA
NA
NA
IIEF
Figure 2. Forest plot for International Prostate Symptom Score (IPSS) at 3 months, 6 months, and 12 months based on a random
effects model. WMD = weight mean difference; CI = confidence interval.
following trial characteristics: first authors name, publication year,

country, and the detailed information of PICOS (participant,
intervention, comparison, outcomes, and study design). For any
missing data, we contacted the corresponding authors. Two
authors independently selected study and extracted data, any
disagreement was resolved by discussion.
catheterization time (h), hospital stay (h), reduction of haemoglobin (g/dl) and serum sodium (mmol/L).
Search strategy
We searched PubMed, EMBASE, Science Citation Index, and
the Cochrane Library for relevant published studies up to October
10, 2013 (updated on February 5, 2014). The search strategy was
summarized in Appendix S1. The bibliographies of the included
studies and recent reviews were hand-searched. No language
restriction was applied.
Methodological quality assessment

The methodological quality of included studies was evaluated
using the Cochrane collaborations tool for assessing risk of bias
[8]. We mainly assessed the following six items: adequate sequence
generation, allocation concealment, blinding, incomplete outcome
data addressed, reporting bias, and other bias. Each item was
answered by Low (low risk of bias), Unclear (either lack of
information or uncertainty over the potential for bias), and High
(high risk of bias).
Study selection and data extraction

Our systematic search approach yielded titles and abstracts of
published articles according to the above eligibility criteria and we
excluded the clearly irrelevant results. The remaining trails were
evaluated in full text. Information of each included trial was
extracted using a pre-made data extraction form. We extracted the
Figure 3. Forest plot for maximum flow rate (Qmax) at 3 months, 6 months, and 12 months based on a fixed effects model.
WMD = weight mean difference; CI = confidence interval.
applied to determine if the trial should be terminated early under

the condition of an amply small P value [17]. In the same way,
trial sequential analysis can be applied to meta-analysis [10,14
15,18]. Trial sequential analysis depends on the quantification of
the required information size. We calculated the required
information size adjusted for diversity since the heterogeneity
adjustment with I2 underestimate the required information size
[16]. The trial sequential analysis was performed to maintain an
overall 5% risk of a type I error and 20% of the type II error (a
power of 80%) [16]. We anticipated an intervention effect of a
20% relative risk increase for the calculation of the required
information size [13]. We conducted post hoc trial sequential
analysis with 35% relative risk increase if the required information
size was very large. For the continuous outcomes of IPSS, Qmax,
PVR, duration of operation, catheterization time, hospital stay,
and reduction of haemoglobin, we estimated the required
information size to reject a reduction of 0.5, 3.0 ml/s, 5.0 ml,
5.0 min, 5 h, 5 h, 0.5 g/dl, respectively. We applied a constant
continuity correction of 1.0 in the no event trial. We used software
Trial Sequential Analysis (version 0.9, http://www.ctu.dk/tsa/)
and provided the 95% confidence intervals adjusted for sparse
data or repetitive testing.
Statistical analysis
All data were pooled using STATA version 12.0 (Stata Corp).
For binary outcomes, relative risks (RRs) and corresponding 95%
confidence intervals (CIs) were calculated; for continuous
outcomes, weighted mean differences (WMDs) and their 95%
CIs were calculated. The Cochran Q test was used to explore
statistical heterogeneity with P,0.1 for statistical significance; a
quantitative measure of heterogeneity across studies was also
investigated using the I2 statistic. Studies with I2 values of less than
40% were considered as having acceptable level of statistical
heterogeneity [9]. We used a fixed-effect analytical model to pool
the results of studies with acceptable or no heterogeneity.
Subgroup analysis was conducted to investigate potential source
of between-study heterogeneity. A two-side P value ,0.05 in the
Z-test was regarded as statistically significant.
Trial sequential analysis

Cumulative meta-analyses of trials are at risk of yielding random
errors because of sparse data and repetitive testing of accumulated
data [1016]. In the single trial, trial sequential analysis (TSA) is
similar to interim analysis that may increase the risk of type I
errors. In order to minimize this risk, monitoring boundaries were
Figure 4. Forest plot for postvoid residual volume (PVR) at 6 months and 12 months based on a random effects model.
WMD = weight mean difference; CI = confidence interval.
Meta-analysis of 3-month and 6-month IPSS showed no

significant differences (3 months: WMD 0.47, 95% CI, 20.98 to
1.92, heterogeneity I2 = 0.0%, TSA adjusted 95% CI, 25.46 to
6.40; 6 months: WMD 20.61, 95% CI, 21.36 to 0.14,
heterogeneity I2 = 66.4%, TSA adjusted 95% CI, 23.6 to 2.46)
(Fig. 2). However, at 12 months, treatment of HoLEP led to a
significant decrease in IPSS based on a random effects model
(WMD 21.17, 95% CI, 21.99 to 20.34, heterogeneity
I2 = 81.1%, TSA adjusted 95% CI 24.54 to 2.21) (Fig. 2). Trial
sequential analysis of trials data obtained at 12 months showed
that there was insufficient evidence to show a reduction of 0.5 in
IPSS, the cumulative Z-curve surpassed the futility boundary, but
it did not cross the trial sequential monitoring boundary (Fig. S1).
Qmax. The Qmax data including 855 BPH patients were
acquired from eight trials [1926]. Of them, two [21,26] reported
Qmax at 3 months, seven [2026] at 6 months, and seven [19
23,2526] reported data at 12 months. There was no significant
difference in Qmax at 6 months (WMD 0.62 ml/s, 95% CI 20.70
to 1.94 ml/s, heterogeneity I2 = 21.5%, TSA adjusted 95% CI, 2
0.62 to 2.02 ml/s). But the results showed significant differences
favoring HoLEP at 3 and 12 months based on a random effects
model (3 months: WMD 3.49 ml/s, 95% CI, 0.64 to 6.35 ml/s,
heterogeneity I2 = 0.0%, TSA adjusted 95% CI, 22.45 to
9.64 ml/s; 12 months: WMD 1.47 ml/s, 95% CI, 0.40 to
2.54 ml/s, heterogeneity I2 = 0.0%, TSA adjusted 95% CI, 2
Results
Characteristics of included studies
Our initial search yielded 1065 potential publications and finally
8 trials [1926] were included (Fig. 1). The eight trials [1926],
which were referring to fifteen publications [1933] based on the
different durations of follow-up period. Our meta-analysis
included data of 855 participants. All trials were published in
English. Table 1 shows the baseline characteristics of the included
RCTs. The max follow-up duration ranged from 9 months to 24
months.
Bias risk assessment

The risk of bias could be fully assessed in only one trial [26] and
it was judged to be of low risk of bias in all items. Two trials
[22,25] did not report the method of randomization. Method of
blinding was given in two trials, of which one [19] blinded the
study participants and outcome assessors and another [26] blind
the outcome assessors only. Table 2 illustrates the risk of bias
assessment results.
Efficacy
IPSS. The IPSS data were acquired from seven trials [1926].
Of them, two [21,26] reported IPSS at 3 months, seven [2026] at
6 months, and seven [1923,2526] reported data at 12 months.
Figure 5. Forest plot for intraoperative complications. RR = relative risk; CI = confidence interval.
respectively. Trial sequential analysis of trials data obtained at 6

and 12 months all showed that there was insufficient evidence to
show a reduction of 5.0 ml in PVR, the cumulative Z-curves
surpassed the futility boundary, but they did not cross the trial
sequential monitoring boundary (Fig. S4, Fig. S5).
IEFF. Only one trial [25] reported IEFF data at 6 months
(WMD 0.10, 95% CI, 21.29 to 1.49), 12 months (WMD 20.30,
95% CI, 21.73 to 1.13), and 24 months (WMD 20.30, 95% CI,
222.68 to 22.08). They were all showed no significant difference
between HoLEP and TURP.
0.75 to 3.91 ml/s) (Fig. 3). Trial sequential analysis of trials data
obtained at 12 months showed that there was insufficient evidence
to show a reduction of 3.0 ml/s in Qmax, the cumulative Z-curve
surpassed the futility boundary, but it did not cross the trial
sequential monitoring boundary (Fig. S2).
QoL. The QoL data were obtained from four trials including
445 BPH patients. Two trials [21,26] reported QoL at 3 months,
three [21,2526] at 6 months, and four [19,21,2526] at 12
months. Meta-analysis of 3 months (WMD 20.19, 95% CI, 20.68
to 0.30, heterogeneity I2 = 0.0%), 6 months (WMD 0.06, 95% CI,
20.48 to 0.60, heterogeneity I2 = 77.3%) and 12 months (WMD
20.09, 95% CI, 20.65 to 0.47, heterogeneity I2 = 82.6%) all
showed no significant difference between HoLEP and TURP
based on a random effects model (Fig. S3).
PVR. The PVR data were obtained from four trials including
514 BPH patients. Three trials [20,2324] reporting PVR at 6
months and three [1920,23] at 12 months were pooled with
random effects model. The results presented significant differences
favoring HoLEP (6 months: WMD 28.90 ml, 95% CI, 215.15 to
22.64 ml, heterogeneity I2 = 66.1%; 12 months: WMD 2
15.98 ml, 95% CI, 222.50 to 29.47 ml, heterogeneity
I2 = 46.6%) (Fig. 4). Trial sequential adjusted 95% CI, of 6 and
12 months were 234.43 to 16.63 ml, 242.58 to 10.61 ml,
Safety
Intraoperative complications. Seven trials [1924,26] reported blood transfusion involving 755 BPH patients and the
result of analysis (Fig. 5) showed a significant difference between
HoLEP and TURP (RR 0.17, 95% CI, 0.06 to 0.47, heterogeneity
I2 = 0.0%). Application of a constant continuity correction of 1.0
in the zero event trial did not change the result. TSA showed that
14.8% (755) of the required information size of 5112 patients were
accrued to detect or reject a 35% reduction in relative risk, the
cumulative Z-curve surpassed the futility boundary, but it did not
cross the trial sequential monitoring boundary (Fig. S6). The TSA
adjusted 95% CI was 0.00 to 11.89.
7
Figure 6. Forest plot for early postoperative complications. RR = relative risk; CI = confidence interval.
and crossed the trial sequential monitoring boundary (Fig. 9). TSA
adjusted 95% CI was 2.18 to 21.99 min.
Catheterization time. The catheterization time data obtained from eight trials [1926] and the meta-analysis result
showed a significant difference between intervention groups
(WMD 219.97 h, 95% CI, 224.24 to 215.70; heterogeneity
I2 = 53.4%; Fig. 8) based on a random effects model. TSA showed
that there was sufficient evidence to show a reduction of 5 h, with
crossing of the trial sequential monitoring boundary for favoring
HoLEP (Fig. 10). TSA adjusted 95% CI was 226.88 to 212.69 h.
Hospital stay. Six trials [1921,23,2526] reported hospital
stay data. The duration of hospital stay was shorter in HoLEP
(WMD 225.25 h, 95% CI, 229.81 to 220.68 h, heterogeneity
I2 = 27.6%; Fig. 8) based on a random effects model. TSA showed
that sufficient evidence was available to show a reduction of 5 h,
with crossing of the trial sequential monitoring boundary for
favoring HoLEP (Fig. 11). TSA adjusted 95% CI was 235.37 to 2
12.13 h.
Reduction of hemoglobin and serum sodium. Four trials
[1920,23,25] reported reduction of hemoglobin and the pooled
result showed no significant difference between HoLEP and
TURP (WMD 20.59 g/dl, 95% CI, 21.20 to 0.01 g/dl;
heterogeneity I2 = 62.9%; Fig. 8). TSA showed that there was
Only one trial [25] reported TUR syndrome and one [24]
reported injury of mucosa. They were both showed no significance
between HoLEP and TURP (Fig. 5).
Early postoperative complications. Six trials [2126]
reported acute urinary retention, three trials [2122,26] reported
urinary tract infection, and one trial [24] reported transient
hematuria. They all showed no significant difference between
HoLEP and TURP (Fig. 6)
Late postoperative complications. Seven trials [1923,25
26] reported urinary stricture, five trials [20,2225] reported
urinary incontinence, four trials [2123,26] reported secondary
treatment, three trials [22,2425] reported transient dysuria, and
one trial [23] reported the bladder neck stenosis. They all showed
no significant difference between HoLEP and TURP (Fig. 7).
Perioperative indicators
Duration of operation. Eight trials reported the duration of
operation [1926] and the pooled result showed a significant
difference favoring TURP (WMD 14.19 min, 95% CI, 6.30 to
22.08 min, heterogeneity I2 = 92.1%; Fig. 8) based on a random
effects model. TSA showed that sufficient evidence was established
to show even a small reduction of 5.0 min in duration of
operation, the cumulative Z-curves surpassed the futility boundary
Figure 7. Forest plot for late postoperative complications. RR = relative risk; CI = confidence interval.
groups in QoL, while lower IPSS at 12 months, higher Qmax

values at 3 and 12 months, less PVR at 6, 12 months were all
noted in HoLEP group (P,0.05), but results of trial sequential
analysis suggested evidence was not sufficient enough for the effect.
Hence, we were only able to infer that HoLEP had the potential
advantage in the curative effect.
In the outcome of blood transfusion, HoLEP approach was
obviously better than TURP and it might be associated with better
laser coagulation technology; however, trial sequential analysis did
not allow us to draw any solid conclusion on safety. Only one trial
reported there were no significant difference of TUR syndrome
and injury of mucosa rate between HoLEP and TURP. For early
and late postoperative complications, we found no significant
difference in AUR/re-catheterization, UTI, transient hematuria,
urethral stricture, urinary incontinence, re-operation, transient
dysuria, or bladder neck stenosis. In perioperative indicators,
HoLEP was associated with longer operation time. This may be
insufficient evidence to show a reduction of 0.5 g/dl in reduction

of haemoglobin, the cumulative Z-curve did not cross the trial
sequential monitoring boundary (Fig. S7). TSA adjusted 95% CI
was 23.07 to 1.89 g/dl.
The reporting of reduction of serum sodium was infrequent,
and only two trials [19,23] showed no significant difference
between two groups (WMD 21.21 mmol/L, 95% CI, 22.63 to
0.22 mmol/L; Fig. 8).
Discussion
Major findings
This systematic review included a total of 8 RCTs enrolling 855
patients, all trials were assessed to be of low to moderate risk of
bias. The main finding of this systematic review was that both
HoLEP and TURP could significantly improve symptoms in BPH
patients. There was no statistical difference between the two
Figure 8. Forest plot for perioperative indicators. WMD = weight mean difference; CI = confidence interval.
incomplete study identification, which indicates lower level of

efficiency in literature search and a serious risk of publication bias;
(2) these published meta-analyses used Jadad Scale for assessing
risk of bias, which lacks in consideration of allocation concealment
and it is not recommended for use by the Cochrane Collaboration
[8]; (3) small sample sizes. In addition, their studies were not
registered, and the main results of effectiveness evaluation (Qmax)
were different [3435].
Another earlier review/meta-analysis [36] showed the most
commonly minimally invasive surgical therapy (MIST) for BPH at
that time. But only 4 included trials compared HoLEP with
TURP, and the authors did not explore HoLEP vs. TURP in
due to the fact that morcellation in HoLEP requires a much longer

time than traditional TURP. However, Holmium laser technique
is significantly advantageous in terms of catheterization time and
hospital stay. Trial sequential analysis provided firm evidence of
shorter catheterization time and hospital stay associated with the
treatment of HoLEP as compared to TURP.
Results in relation to other studies and reviews

A relevant meta-analysis involving 4 RCTs by Tan et al [34]
and a recent updated meta-analysis involving 6 RCTs by Yin et al
[35] both reported some of the major outcomes. However, they
are both associated with various weaknesses as follows: (1)
10
Figure 9. Trial sequential analysis of operation time. The required information size for operation time was calculated based on a two side
a = 5%, b = 20% (power 80%), a minimal relevant difference of 5.0 min, a standard deviation of 29.2 min, and D2 = 63% as estimated in a random
effects model.
the available evidence with comprehensive analyses of the risk of bias

using subgroup analyses with test for subgroup differences and also
applied the new method that called trial sequential analysis to
identify whether the outcomes reach a conclusive conclusion [10
11,15,37]. To our knowledge, this is the first application trial
sequential analysis in Urology. And we added results of sexual
function.
Our study has some limitations that should be demonstrated.
We contacted corresponding authors of all trials to clarify
methodological details and obtain relevant outcomes, but only a
few authors responded. Therefore, firstly, the precise methodological quality of the included studies remains unclear. Secondly,
since most of the included RCTs lacked long-term data (.12
months), we were unable to provide any long-term evidence.
Thirdly, data were sparse for sexual function. Fourthly, the
included studies do not provide enough information as to prostate
size and anti-coagulated patients for in-depth subgroup analysis.
Lastly, the overall sample size was still small.
greater depth. Other shortcomings of this study included a lack of

the methodological quality assessment tool for the included RCTs,
and there were no subgroup analyses of effective outcomes
according to follow-up time. In addition, there was no information
on perioperative outcomes such as hospital stay.
Strengths and limitations

Compared with previous meta-analyses, our systematic review has
several strengths. First, we based it on a published protocol with rigid
inclusion criteria for randomized clinical trials (http://www.crd.york.
ac.uk/PROSPERO/display_record.asp?ID = CRD42014007334).
Second, our study included 8 RCTs and considered more outcomes,
which can provide a more comprehensive view on the efficacy and
safety. Third, our study followed the recommended Cochrane
collaborations tool for assessing risk of bias. The previous metaanalyses [3435] used the Jadad Scale, which lacks in consideration
of allocation concealment and is not recommended by the Cochrane
Handbook for Systematic Reviews of Interventions [8]. Therefore,
results of the methodological quality assessment of our study are
more robust. Fourth, our search strategy was devised rigorously with
a more precise focus and we placed no restrictions on the type of
outcomes reported in the trials (Appendix S1); therefore, we found
more eligible RCTs. Fifth, we attempted to evaluate the strength of
Implication for research and practice

Our meta-analysis may also have some implications for further
researches and clinical practice. Future researches should clarify
the effectiveness, safety, potential advantages and disadvantages of
11
Figure 10. Trial sequential analysis of catheterization time. The required information size for operation time was calculated based on a two
side a = 5%, b = 20% (power 80%), a minimal relevant difference of 5.0 min, a standard deviation of 26.8 min, and D2 = 60% as estimated in a random
effects model.
HoLEP compared with TURP in large, high-quality RCTs, which

also evaluate long-term outcomes and sexual functions relevant
outcomes and focus more on prostate size, anti-coagulated patients
and so on. In clinical practice, surgeons should not be limited to
only conventional TURP as a treatment option for BPH. Although
conventional TURP is still regarded as gold-standard in clinical
guidelines, our findings have illustrated several advantages of
HoLEP including a more favorable procedural safety profile,
shorter catheterization duration time and hospital stay. We would
thus like to highlight to clinicians that HoLEP presents as a viable
treatment option for BPH. It is potentially a better treatment
strategy, especially for elderly patients, those with large volume of
prostate or high risk patients.
After TSA adjustment for sparse data and multiple updating in

cumulative meta-analysis, it seems unsure that HoLEP provides
overall clinical benefit for BPH patients. Considering our main
limitations, data from large, well-conducted international/multicentre RCTs with long-term data (follow-up duration.12 months)
are necessary; sexual function-analysis and cost-analysis are still
needed, and the comparison between the two approaches remains
open.
Supporting Information
Figure S1 Trial sequential analysis of International
Prostate Symptom Score (IPSS) at 12 months. The
required information size for IPSS at 12 months was calculated
based on a two side a = 5%, b = 20% (power 80%), a minimal
relevant difference of 0.5, a standard deviation of 3.5, and
D2 = 77% as estimated in a random effects model.
(TIF)
Conclusions
In summary, our study provided the strongest available
evidence and showed that there were no clinically relevant
differences in early and late postoperative complications between
the two techniques. Although the operative time favored TURP,
HoLEP was more preferable due to its more favorable profile,
defined by the clinically relevant differences detected regarding
curative effect and less blood transfusion. Additionally, catheterization time and hospital stay were significantly shorter in HoLEP.
Figure S2 Trial sequential analysis of maximum flow

rate (Qmax) at 3 months. The required information size for
Qmax at 3 months was calculated based on a two side a = 5%,
b = 20% (power 80%), a minimal relevant difference of 3.0 ml/s, a
12
Figure 11. Trial sequential analysis of hospital stay. The required information size for operation time was calculated based on a two side
a = 5%, b = 20% (power 80%), a minimal relevant difference of 5.0 min, a standard deviation of 34.1 min, and D2 = 54% as estimated in a random
effects model.
standard deviation of 13.8 ml/s, and D2 = 0% as estimated in a

fixed effects model.
(TIF)
Figure S6 Trial sequential analysis of blood transfusion. A diversity adjusted information size of 5112 patients was
calculated using a two side a = 5%, b = 20% (power 80%),
D2 = 0%, an anticipated relative risk increase of 35% and an
event proportion of 4% in the control arm. Trials with no events
were included in the study with a constant continuity correction of
1. The blue cumulative Z-curve was constructed using a fixed
effects model.
(TIF)
Figure S3 Forest plot for quality of life (QoL) at 3

months, 6 months, and 12 months based on a random
effects model. WMD = weight mean difference; CI = confidence interval.
(TIF)
Figure S4 Trial sequential analysis of postvoid residual
volume (PVR) at 6 months. The required information size for
PVR at 6 months was calculated based on a two side a = 5%,
b = 20% (power 80%), a minimal relevant difference of 5.0 ml, a
standard deviation of 20.7 ml, and D2 = 73% as estimated in a
random effects model.
(TIF)
Figure S7 Trial sequential analysis of hemoglobin

decrease. The required information size for operation time
was calculated based on a two side a = 5%, b = 20% (power 80%),
a minimal relevant difference of 0.5 g/dl, a standard deviation of
2.3 g/dl, and D2 = 79% as estimated in a random effects model.
(TIF)
Appendix S1 Search strategy protocols used for each
electronic database.
(DOC)
Trial sequential analysis of postvoid residual

volume (PVR) at 12 months. The required information size
for PVR at 6 months was calculated based on a two side a = 5%,
b = 20% (power 80%), a minimal relevant difference of 5.0 ml, a
standard deviation of 36.7 ml, and D2 = 0% as estimated in a
random effects model.
(TIF)
Figure S5
Checklist S1 PRISMA checklist.
(DOC)
13
XTZ. Contributed reagents/materials/analysis tools: XHW XTZ CZ.

Contributed to the writing of the manuscript: SL XTZ XLR.
Author Contributions
Conceived and designed the experiments: XHW SL. Performed the
experiments: SL XW HW XTZ ZM TZL ZM. Analyzed the data: SL TZL
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14
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Holmium Laser Enucleation versus Transurethral

Resection in Patients with Benign Prostate Hyperplasia:

enucleation of the prostate (HoLEP) [2]. Holmium laser

PLOS ONE | www.plosone.org

July 2014 | Volume 9 | Issue 7 | e101615

Meta-Analysis of HoLEP versus TURP

Figure 1. Identification of eligible studies.

transurethral tissue morcellation evolved into HoLEP. Since then,

July 2014 | Volume 9 | Issue 7 | e101615

PLOS ONE | www.plosone.org

Sun et al. [19]

Mavuduru et al. [24]

Eltabey et al. [20]

Sun et al. [19]

Gupta et al. [22]

Tan/Gilling/Wilson et al. [26,29,32]

Montorsi/Rigatti/Briganti et al. [25,30,33]

Gilling/Fraundorfer/Westenberg et al. [21,28,31]

Kuntz/Ahyai et al. [23,27]

Eltabey et al. [20]

2004; 2006; 2006

Montorsi/Rigatti/Briganti et al. [25,30,33]

Kuntz/Ahyai et al. [23,27]

2003; 2006; 2012

Tan/Gilling/Wilson et al. [26,29,32]

Mavuduru et al. [24]

1999; 2001; 2004

Gilling/Fraundorfer/Westenberg et al. [21,28,31]

Gupta et al. [22]

Table 1. Characteristics of the included randomized controlled trials (RCTs).

Meta-Analysis of HoLEP versus TURP

July 2014 | Volume 9 | Issue 7 | e101615

Meta-Analysis of HoLEP versus TURP

following trial characteristics: first authors name, publication year,

Methodological quality assessment

Study selection and data extraction

July 2014 | Volume 9 | Issue 7 | e101615

Meta-Analysis of HoLEP versus TURP

applied to determine if the trial should be terminated early under

Trial sequential analysis

PLOS ONE | www.plosone.org

July 2014 | Volume 9 | Issue 7 | e101615

Meta-Analysis of HoLEP versus TURP

Meta-analysis of 3-month and 6-month IPSS showed no

Bias risk assessment

July 2014 | Volume 9 | Issue 7 | e101615

Meta-Analysis of HoLEP versus TURP

respectively. Trial sequential analysis of trials data obtained at 6

July 2014 | Volume 9 | Issue 7 | e101615

Meta-Analysis of HoLEP versus TURP

PLOS ONE | www.plosone.org

July 2014 | Volume 9 | Issue 7 | e101615

Meta-Analysis of HoLEP versus TURP

groups in QoL, while lower IPSS at 12 months, higher Qmax

insufficient evidence to show a reduction of 0.5 g/dl in reduction

July 2014 | Volume 9 | Issue 7 | e101615

Meta-Analysis of HoLEP versus TURP

incomplete study identification, which indicates lower level of

due to the fact that morcellation in HoLEP requires a much longer

Results in relation to other studies and reviews