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\begin{document}

\title{Evaluation of the short-term cessation and early initiation of
antithrombotic therapy in high-risk patients undergoing HoLEP procedure
for large prostates (\textgreater{} 100 mL): A critical evaluation}



\author[1]{Muhammed Ibis}%
\author[2]{Zafer Tokatli}%
\affil[1]{Affiliation not available}%
\affil[2]{Medicana International Ankara Hospital, Ankara, Turkey }%


\vspace{-1em}



  
  \date{June 13, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
\textbf{What is Known and Objective:} Currently, the safety and efficacy
of Holmium Laser Enucleation of Prostate (HoLEP) in patients with large
prostates (\textgreater{}100 ml) who are at high risk for Thromboembolic
Events (TE) and receiving Antithrombotic Therapy (AT) are controversial.
This study aims to characterise the safety and efficacy of the HoLEP in
patients with large prostates (\textgreater{}100ml) at high risk for TE
resuming AT in the early post-operative period.

\textbf{Methods:} We have \textbf{} reviewed retrospective data for 378
patients with large prostates treated with the HoLEP for symptomatic
benign prostatic hyperplasia between December 2016 and July 2020. One
hundred thirty-four of the patients had been receiving AT. Antiplatelet
(AP) therapy was maintained. Patients taking vitamin K antagonists and
new oral anticoagulants stopped taking the drug 5 and 2 days before the
HoLEP, respectively. Postoperatively, anticoagulants (AC) were resumed
within 24 hours. In patients receiving AT, we have determined
``pre-operative, peri-operative, and post-operative'' parameters,
functional outcome, and adverse events for the 3 months after the
operations. Subsequently, we have compared the results of 203 patients
without AT.

\textbf{Results and Discussion:} Patients receiving AC and AP were older
(p=0.015) and had a higher median ASA score (p\textless{}0.001).
Objective-voiding parameters (Qmax, PVR) and urinary symptoms (IPSS,
QoL) improved in the three groups (p\textless{}0.001). Median
enucleation and morcellation efficiencies were 1.58 (IQR:0.87-3.13) and
5 (IQR:1-8.08), median catheterisation and hospitalisation time was 2
days (IQR:2-3) and 3 days (IQR:3-4), respectively. The peri-operative
results were similar in the three groups. Overall, one patient in the AP
group required blood transfusion at 4 days postoperatively due to clot
retention and significant haemoglobin decrease (p=0.216). There was no
adverse TE in any patient within the 3-months postoperatively.

\textbf{What is new and Conclusion:} In cases with large-sized prostates
posing a high risk of bleeding as well as TE, the HoLEP procedure could
be applied without leaving AP agents in a safe and highly efficient
manner. Additionally, this procedure could be performed following the
cessation of AC treatment with the chance of a quite early initiation of
these agents to limit properly the potential risk of TE.%
\end{abstract}%



\sloppy






\textbf{Evaluation of the short-term cessation and early initiation of
antithrombotic therapy in high-risk patients undergoing HoLEP procedure
for large prostates (\textgreater{} 100 mL): A critical evaluation}



\textbf{WHAT IS KNOWN AND OBJECTIVE}

Benign Prostatic Hyperplasia (BPH) is one of the most common urological
diseases in elderly male patients. Associated lower urinary tract
symptoms (LUTS) are the primary cause of decreased health-related
Quality of Life (QoL) in these cases. \textsuperscript{1}{}

Several endoscopic surgical alternatives such as resection, ablation,
incision, vaporisation, and enucleation with mechanical morcellation
have been described and applied in the relief of LUTS secondary to
small-medium size BPH in patient's refractory to medical treatment or
those developing BPH-related complications. Despite that, endoscopic
management of large prostates (\textgreater{}100 ml) constituted a real
challenge for endo-urologists in this aspect. Especially, bleeding risk
may limit the endoscopic treatment alternatives use, particularly in
patients with large-volume prostates receiving antithrombotic
(antiplatelet-anticoagulant) therapy.\textsuperscript{2, 3}{}

Accumulated data so far have shown that it has increased the incidence
of use of antithrombotic agents in cases at older ages and these
patients have multiple comorbidities, which may increase the risk of a
thromboembolic event (TE). Because of the high risk of TE,
antithrombotic therapy (AT) has always been continued during minor
surgeries and also AT was advised to be continued as soon as bleeding
control is achieved, if AT was planned to be discontinued. Regarding
this critical issue, guidelines state anti-platelet therapy should be
started again in high-risk patients as soon as possible (within 48 hours
if possible) after surgery. Similarly, coumadin should be restarted at
24 hours postoperatively in such patients (e.g., with prosthetic heart
valves).\textsuperscript{4}{}

HoLEP is a size-independent technique, enabling the complete removal of
enlarged adenomas through a safe and anatomic dissection made between
the adenoma(s) and surgical capsule associated with a lower risk of
intraoperative bleeding. Published data on this aspect showed that the
HoLEP procedure could reveal similar or better post-operative clinical
outcomes along with lower complication rates than open prostatectomy or
other endoscopic therapies. It has therefore become the new gold
standard technique to treat BPH/LUTS, especially in large-volume
prostates.\textsuperscript{5, 6} Long-term data have been emerging to
exhibit that this enucleation procedure has durable results with lower
retreatment rates.\textsuperscript{3, 7}{}

Last but not least, in the light of the clear risk of post-operative
bleeding after the treatment alternatives above coupled with the
increased risk of TE thanks to relatively longer cessation of
anticoagulant (AC) therapy, the HoLEP procedure may give the advantages
of the continuation of antiplatelet (AP) agents and immediate initiation
of AC agents if stopped, because of the effective and safe tissue
removal particularly in large-volume prostates.

This current study has aimed to evaluate the efficacy and safety of the
HoLEP procedure in cases with large prostates with a social emphasis on
the discontinuation besides the early initiation of AC and AP agents to
limit the risk of associated TE.

\textbf{~}

\textbf{METHODS}{}

This retrospective study included 378 patients presenting with LUTS and
large prostate. They underwent the HoLEP procedure between December 2016
and July 2020. Based on the use of AT agents, patients were divided into
three groups. While patients receiving acetylsalicylic acid and platelet
aggregation inhibitors were grouped as AP, patients receiving new oral
anticoagulants (NOAC) and Vitamin K antagonists were grouped as AC.
Afterwards, patients who did not receive AT were in the last one as the
non-treatment (NT) group. Patient characteristics, perioperative, and
postoperative outcomes were recorded properly in all cases.

For this study, we prepared a protocol as regards the use of
antithrombotic therapy in patients who underwent the HoLEP, after
detailed consultation with the responsible cardiologist. This protocol,
prepared in line with the ESC and EAU guidelines, aimed to reduce the
risk of TE reported during and after the HoLEP procedure in patients
with large prostates receiving AT therapy.\textsuperscript{4, 8}
Patients receiving vitamin K antagonists stopped taking the medication
for 5 days before the HoLEP and no alternative antithrombotic therapy
was initiated. However, in high-risk patients, such as patients with
mechanical prostatic heart valves or CHADS-VASc Score \textgreater{}3,
Vitamin K antagonists had been stopped 5 days ago and bridged with a
therapeutic dose of low molecular weight heparin (LMWH). Patients were
treated with a therapeutic dose of LMWH and a vitamin K antagonist
combination until the target INR value was reached immediately after the
surgery. Patients taking NOAC stopped taking medication 2 days before
surgery. The treatments of the patients who received vitamin K
antagonist and NOAC were resumed within 24 hours postoperatively. In the
AP group, the AP treatment of the patient who received single
antiplatelet therapy was not discontinued. However, the patients who
received both acetylsalicylic acid and P2Y12 inhibitors were operated
under acetylsalicylic acid treatment after the discontinuation of P2Y12
inhibitors. In these patients, P2Y12 inhibitors therapy was started
within 24 hours postoperatively. In patients who underwent surgery, INR
was \textless{}1.7. Pharmacological prophylaxis, such as LMWH, was not
applied to the patients in the NT group.

Respectively, the difference between the Haemoglobin (Hb) values
measured one day before the surgery and the values measured after 12
hours and 1 week the operation was defined as ``haemoglobin decrease
within 12 hours after surgery'' and ``haemoglobin decrease at 1-week
postoperatively''. As we started the AC treatment 24 hours after the
procedure and the drop in Hb levels could show the dilutional changes,
we thought that the effect of AC treatment might be quite limited for
the changes in Hb levels noted after 12 hours. To start the potential
effect of AC management on post-operative Hb changes, we focused on the
Hb levels detected 1-week after the procedures. The enucleation and
morcellation efficiency were calculated as the ratio of the removed
tissue volume to the enucleation-morcellation time. Functional data were
obtained from the post-op follow-up records of 337 patients referring to
our clinic for the 3\textsuperscript{rd}-month post-operative follow-up
evaluation. Because the data for 41 patients was not available, their
relevant recordings were excluded from the evaluation.

A single surgeon performed all the surgeries in the present study.
Prostate adenomas were enucleated as two or three lobes' techniques
depending on the prostate morphology (with/without a huge median lob).
The equipment included a 100W Holmium laser (Versapulse, Lumenis Inc.,
Santa Clara, CA, USA), 550-um end-firing flexible fibre, a 26fr
continuous flow laser resectoscope (Karl- Storz, Germany), 26fr
nephroscope, and morcellator (Versacut; LumenisInc). The standard laser
setting was adjusted as 1.2J and 50Hz.

We performed all statistical analyses with the SPSS 25.0.0.1 software
(IBM Corp., Armonk, NY, USA) with the Mann-Whitney U, Kruskal--Wallis
test, chi-squared test, and Wilcoxon signed-rank test. Normal
distribution assumption for continuous variables was analysed with the
Shapiro-Wilk test. A value of p\textless{}0.05 was considered
statistically significant.

\textbf{RESULTS}

Among the 337 patients included in the study, 24.6\% (n = 83) received
the AP, while 15.1\% (n = 51) received the AC therapy. The pre-operative
characteristics of the study patients were not statistically different
between groups except age (p=0.015) and the ASA score. Patients with the
AP and the AC showed more comorbidities (higher ASA status,
p\textless{}0.001) (Table 1). In the AP group, history showed coronary
heart disease in 56 patients (67.5\%); cerebrovascular accident in 8
(9.6\%); peripheral arterial occlusive disease in 9 (10.8\%); and other
reasons (primary prevention for coronary artery disease) in 10 (12.1\%).
Among the patients who received AC, 21 (41.2\%) of them had chronic
atrial fibrillation; 12 (23.5\%) had a cerebrovascular event; 8 (15.7\%)
had a prosthetic heart valve; 5 (9.8\%) had a pulmonary embolism; 3
(5.9\%) had a vascular prosthesis; 2 (3.9\%) had deep veined thrombosis.

Peri-operative outcomes did not differ significantly among the three
groups. The median time of enucleation and morcellation was 46 min
(IQR:15-120, p=0.548) and 15 min (IQR:4-60, p=0.168). Enucleation and
morcellation efficiency were 1.58 (IQR:0.87-3.13, p=0.115) and 5
(IQR:1-8.08, p=0.204), respectively. There was no difference between the
three groups as to haemoglobin decrease within 12 hours
(peri-operatively) and 1-week postoperatively (p=0.225 and p=0.545,
respectively) (Table 2). In the present study, all patients underwent
the HoLEP safely with no adverse TE within 3 months postoperatively.

In three groups, International Prostate Symptom Scores (IPSS),
post-voiding residual volume (PVR), and QoL score significantly
decreased and maximum flow rates (Qmax) significantly increased
postoperatively compared with the pre-operative values
(p\textless{}0.001) (Fig. 1A-D). Three months after surgery, these
functional results had improved significantly in all groups, with no
differences between the groups.

The post-operative complications were grouped based on the Clavien-Dindo
classification of surgical complications. No significant difference was
observed in the complications, except prolonged catheterisation (Table
3). The prolonged catheterisation associated with the need for prolonged
irrigation occurred in 36 (10.7\%) patients. Three groups were different
significantly from each other for prolonged catheterisation (p=0.028).
Also, the AP and AC groups were compared with the NT group in terms of
prolonged catheterisation (AP vs. NT; OR: 2.77, 95\% CI: 1.28-5.96,
p=0.007 and AC vs. NT; OR: 1.67, 95\% CI:0.61-4.55, p=0.391). In
general, one (1.2\%) patient in the AP group required blood transfusion
on 4 days postoperatively due to clot retention and significant
haemoglobin decrease (p = 0.216). The patient was catheterized, and the
clot was evacuated with no need for an operation. The AP and NT groups
were compared for blood transfusion and clot retention, no statistically
significant difference was observed (AP vs. NT; OR: 1.012, 95\% CI:
0.988--1.037, p=0.29). Also, there was no significant difference between
the groups according to urinary tract infection (UTI) and urethral
stricture/bladder neck contracture (Table 3). Consequently, there was no
adverse TE in any patient within 3-month postoperatively.{}

\textbf{DISCUSSION}

The published data demonstrated explicitly that the percentage of
elderly cases with co-morbid diseases (i.e., coronary artery disease,
cardiac valve disease, peripheric arterial disease, deep vein
thrombosis, and pulmonary emboli) is flourishing. The majority pose the
risk of TE requiring AT with certain agents such as acetylsalicylic
acid, P2Y12 inhibitors, NOAC, coumadin. Taking this along with the
increasing prevalence of elderly male patients with BPH under the
above-mentioned treatment into account, endoscopic surgical
interventions to remove the outlet obstruction in these cases carry the
increased risk of complications.\textsuperscript{9} Given the
procedure-related peri-operative bleeding risk and post-operative TE,
the AC treatment regimen needs to be well-balanced to limit the chance
of the above and occasionally life-threatening problems. ~

Several organisations have provided various recommendations on the
peri-operative management of AT agents in the urological field. For
patients undergoing elective HoLEP concerning the peri-operative
management of AP therapy, the EAU recommends stopping AP agents before
surgery and restarting when bleeding poses no longer a serious risk --
typically four days post-surgery--.\textsuperscript{8} On the other
hand, ESC suggests that AP agents can be discontinued before surgery and
continue taking aspirin after surgery should be based on an individual
decision that depends on the perioperative bleeding risk, weighed
against the risk of thrombotic complications.\textsuperscript{4} In a
study by Lotrionte et al., it was stated that the discontinuation of
aspirin in patients at risk of coronary artery disease increased the
risk of cardiovascular events threefold and that aspirin should be
maintained to provide surgery and the post-operative
period.\textsuperscript{10} Regarding the peri-operative management of
AC therapy, both EAU and ESC recommend the protocol applied in this
study. Similar to the management of AP agents, EAU recommends restarting
when bleeding is no longer a serious risk--typically four days
post-surgery. In our study, unlike the recommendations of these
guidelines, we had a shorter initiation time of postoperative AC therapy
and we practised the operations under AP monotherapy. A study published
as clinical practice recommendations on this topic suggested that laser
prostate surgery can be safely accomplished for the patient with a
therapeutic INR who is at significant risk for thrombosis without the
discontinuation of oral AC/AP \textsuperscript{11}. However, in the
light of current guidelines \textsuperscript{4, 8}, we used bridging
with vitamin K antagonist and DMWH in high-risk patients.

~

In our opinion, the rational application of this protocol in cases with
large-volume prostates will limit the risk of bleeding and associated
complications. In parallel, the very early initiation of the AC agents
could be possible in this risk group of cases in which the complete
removal of enlarged adenomas. While the surgical procedure (HoLEP) could
be performed under AT in patients with small-sized prostates
\textsuperscript{12-14}, performing the procedure in large-sized
prostates made increase the risk of serious bleeding and related
problems think. Still, the results of our study suggest that this
concern is unfounded.

There were three groups in the study and no patient showed TE. In a
similar study, but with a smaller series, on Thulium Laser
Vapoenucleation of the Prostate (ThuVEP), Castellani et
al.\textsuperscript{15} pointed out two early admissions in the
intensive care unit and one late myocardial infarction. In our study and
the study of Castellani et al., the rate of patients with ASA[?]3 was
33.8\% and 71.6\%. The absence of TE in our study may be connected to
the slightly lower rate of this. Deuker et al.\textsuperscript{16} noted
that one patient died in their study in which they analysed the data of
268 HoLEP-treated patients. In this study, noteworthy that the treatment
of patients receiving coumadin was stopped 10 days before.{}

Bleeding in terms of Hb drop was evaluated with the post-operative Hb
values obtained at two different time intervals (post-operative 12 hours
and 1 week) after the procedure. Previously, Zheng et al. conducted a
meta-analysis and claimed that the hg change after HoLEP was comparable
in the AT and Non-AT groups.\textsuperscript{17} In this study, even
though the AP and AC groups had a higher risk of bleeding, remarkably,
the Hb drop after HoLEP was similar between the three groups. Our
results supported the results of studies conducted with similar
methodology.\textsuperscript{13, 14} Examination of our cases revealed
that although cases undergoing AP and AC treatment were older with
associated co-morbid diseases, the efficiency of enucleation and
morcellation procedures were similar in both groups. Our data were
compared with the results of previous studies.\textsuperscript{18, 19}
Recommendations for anatomical endoscopic enucleation of the prostate
(AEEP) in patients with BPH receiving AT therapy were observed by Netsch
et al.\textsuperscript{20} In the study in which all enucleation
procedures were discussed, it was noticed that patients under AP
treatment showed fewer bleeding-related complications compared to those
under AC treatment. Although patients receiving both AP and AC therapy
are associated with increased bleeding complications, most studies show
that AEEP is feasible in patients treated with AT and functional
outcomes are not different from patients receiving AT therapy. In
addition, Netsch et al noted that these findings were only for prostate
glands between 50 and 110 ml. In our study, HoLEP was an effective and
safe surgical procedure in AT-treated patients with a large prostate
(\textgreater{}100ml).

Regarding prolonged catheterisation issues in the three groups, the
results were found different (p = 0.028, 3x2 chi-square test). Also, in
case of patients undergoing AP treatment when compared with those with
no treatment, the AP and AC groups were compared with the NT group as to
prolonged catheterisation and our findings showed that catheterisation
time was significantly longer (AP vs NT; OR: 2.77, 95\% CI: 1.28-5.96,
p=0.007 and AC vs NT; OR: 1.67, 95\% CI:0.61-4.55, p=0.391, 2x2
chi-square test). It has been shown that antithrombotic therapies have a
significant effect on hospitalisation and catheterisation
time.\textsuperscript{21, 22} Likewise, Boeri et al. reported a
comparatively longer hospital stay and catheter maintenance, while they
did not see any difference concerning operation
time.\textsuperscript{23} HoLEP applied to 116 patients who received
continuous and intermittent AT treatment by EI Tayeb et
al.\textsuperscript{12} The transfusion rates were 3.5\% for AC patients
and 1.6\% for the non-AC group, which showed no significant difference.
Compared with the non-AC group, the length of hospitalisation and
duration of continuous bladder irrigation were longer in the AC group
(27.8 h vs. 24 h, 15 h vs. 13.5 h; p \textless{} 0.001, respectively).
Furthermore, there were no differences in enucleation time,
catheterization time, and transfusion rate between receiving AT patients
and the intermittent AT group. In addition, although not statistically
significant in our study, one case in the AP group required blood
transfusion with clot retention after the procedure (AP vs NT; OR:
1.012, 95\% CI: 0.988--1.037, p=0.29).

Finally, assessment of the efficiency in the removal of obstruction
during a three-month evaluation period in all groups in terms of
pre-operative and post-operative Qmax, PVR, IPSS, and QoL parameters
revealed no significant difference between the three groups. These
findings again indicated the successful removal of the obstruction with
the HoLEP procedure in all group cases. In other words, our findings
revealed the efficiency and performance of a successful HoLEP in cases
with large-sized prostates with or without AP medication.

Our study has some potential limitations. First of all, the
retrospective nature of our study method may be a major limitation.
Second, performing all procedures by an experienced surgeon may have had
a positive effect on the outcomes. Besides, the use of the ASA score
instead of the Charlson co-morbidity index may make up another
limitation. Last but not least, the limited duration of irrigation time
could be the final possible limitation. Still, despite these possible
limitations, we believe that considering the highly limited data
published in the literature focusing on the possibility of early
initiation of AC management, particularly following the surgical
intervention for large prostates; Our findings could contribute to the
existing information with reliable clinical implications.

\textbf{WHAT IS NEW AND CONCLUSION}

Our results reveal that the HoLEP procedure could be applied without
leaving AP in a safe and highly efficient manner in cases with
large-sized prostates carrying a high risk of bleeding besides
thromboembolic events. Additionally, this procedure could be conducted
following the cessation of AC treatment with the chance of very early
initiation of these agents to limit well the potential risk of
thromboembolic events. However, we noted that this approach may prolong
the duration of catheterization after the procedure, which may cause
necessary precautions.

\textbf{~}

\textbf{CONFLICT OF INTEREST}

None declared.

\textbf{~}

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22.~~~~~~~~ Branchu B, Léon P, Fournier R, et al. Impact des
anticoagulants et antiagrégants sur complications hémorragiques chez les
patients traités par HoLEP. Progrès en Urologie. 2020;30(12):639-45.

23.~~~~~~~~ Boeri L, Capogrosso P, Ventimiglia E, et al. Clinical
comparison of holmium laser enucleation of the prostate and bipolar
transurethral enucleation of the prostate in patients under either
anticoagulation or antiplatelet therapy. European urology focus.
2020;6(4):720-8.





\textbf{FIGURE LEGENDS}

\textbf{Figure 1.} Comparison of functional results preoperative and
postoperative 3rd month. (A) Qmax (Maximum flow rate), (B) IPSS
(International prostate symptoms score), (C) PVR (Postvoiding residual
volume), and (D) QoL (Quality of life). *p \textless{} 0.001. NT:
Non-Treatment, AP: Antiplatelet therapy, AC: Anticoagulation therapy.\selectlanguage{english}
\begin{figure}[H]
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\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

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\textbf{Hosted file}

\verb`Table 1.docx`  available at \url{https://authorea.com/users/410688/articles/538360-evaluation-of-the-short-term-cessation-and-early-initiation-of-antithrombotic-therapy-in-high-risk-patients-undergoing-holep-procedure-for-large-prostates-100-ml-a-critical-evaluation}

\textbf{Hosted file}

\verb`Table 2.docx`  available at \url{https://authorea.com/users/410688/articles/538360-evaluation-of-the-short-term-cessation-and-early-initiation-of-antithrombotic-therapy-in-high-risk-patients-undergoing-holep-procedure-for-large-prostates-100-ml-a-critical-evaluation}

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