Perioperative Safety and Efficacy of Holmium Laser Enucleation of the Prostate in Patients Receiving Antithrombotic Therapy: A Prospective Cohort Study

We investigated the efficacy of and risk from holmium laser enucleation of the prostate (HoLEP) due to discontinuation of antithrombotics in patients with benign prostatic hyperplasia (BPH). Patients in the prospective SNUH-BPH Database Registry who underwent HoLEP between December 2010 and December 2017 were enrolled. Preoperative evaluation included symptom score questionnaires, laboratory tests, urine tests, prostate-specific antigens, urodynamic study, and transrectal ultrasonography. Postoperative evaluation was performed at 2 weeks, 3 months, and 6 months. Information regarding the types of antithrombotics and their use, underlying disease, and antithrombotic management during surgery was collected. The study included 55 patients. The mean age and preoperative prostate volume were 68.7 ± 6.4 years and 70.3 ± 32.2 mL, respectively. The mean preoperative hemoglobin level was 13.5 ± 2.6 g/dL in the patients receiving antithrombotics. Of the patients, 71% were taking aspirin. Seventy-five (66.5%) and 70 patients (28.2%) discontinued the antithrombotic therapy 5–7 days and <1 week preoperatively, respectively. Three patients (1.21%) were switched to low-molecular-weight heparin therapy, and 10 (4.03%) continued antithrombotic therapy. No significant differences were found in the incidence rates of postoperative transfusion (p = 0.894) or complications from antithrombotic use, thrombosis (p = 0.946), haemorrhage requiring bladder irrigation (p = 0.959), transurethral coagulation (p = 0.894), cardiovascular events (p = 0.845), and cerebrovascular events (p = 0.848). Efficacy and complications related to the short-term antithrombotic withdrawal before and after HoLEP also showed no significant differences. HoLEP may be a beneficial surgical technique for patients with BPH who are receiving antithrombotics.


Results
The data of 955 patients from a prospective database of patients who underwent HoLEP with BPH between December 2010 and December 2017 were analyzed. We found that 707 patients (74.0%) did not take antithrombotics before surgery and 248 (25.9%) took ≥1 antithrombotic before surgery. All the patients were followed up for 6 months. Table 1 summarizes the baseline characteristics of the patients. In both groups, the patients in the antithrombotic group were relatively older, had a higher body mass index, and had an underlying disease such as hypertension, diabetes, neurological disease, CVD, cerebrovascular disease, or chronic kidney disease. Both groups had normal hemoglobin levels, but the patients in the antithrombotic group had slightly lower hemoglobin levels.
Next, Table 2 summarizes the antithrombotic medications, indications or causes, and the treatment during surgery for patients in the antithrombotic group. Aspirin was the most commonly used drug, accounting for 71% of cases, followed by clopidogrel (22.9%). All other drugs were used in <3% of the patients. The most common cause of antithrombotic use was angina, accounting for 30% of the antithrombotic users. The next two leading causes of antithrombotic use were artery disease prevention (10.1%) and cerebrovascular disease (8.9%). During the operation, 95.7% of the patients discontinued antithrombotics, while 5.3% of the patients replaced the antithrombotic with LMWH or maintained the original antithrombotic. Table 3 compares the perioperative outcomes between the two groups. No significant differences in prostate volume and mean maximum urinary flow (Qmax) were found. The intraoperative parameters such as operation time, removed prostate weight, and complications were also not significantly different between the two groups. The immediate postoperative parameters showed no significant differences, particularly the number and duration of the additional continuous bladder irrigations and hospitalization duration. However, we found a significant www.nature.com/scientificreports www.nature.com/scientificreports/ difference in the duration of Foley catheter retention (p = 0.017), but the difference from that in clinical practice was not significant.
Furthermore, Tables 4 and 5 compares the incidence of postoperative complications between the two groups at 2 weeks, 3 months, and 6 months. Transfusion within 2 weeks after operation occurred in one case for both groups. No significant differences were found between the two groups in terms of the incidence of complications  www.nature.com/scientificreports www.nature.com/scientificreports/ related to blood clot and bleeding requiring transurethral coagulation (TUC) or continuous bladder irrigation. In addition, no significant differences in the incidence of complications were found between 3 and 6 months after operation. However, among the patients who temporarily discontinued antithrombotic therapy, one (0.4%) had an intracerebral infarction and another (0.4%) had a myocardial infarction.
The voiding parameters and symptom scores were not significantly different between the two groups before and after HoLEP. In both groups, the postoperative Qmax was increased and PVR was decreased significantly when compared with their preoperative values. After operation, positive changes were observed. No significant differences in the preoperative, 2-week, 3-month, and 6-month postoperative values of Qmax and PVR were found between the two groups. In the symptom scores, the IPSS improved in both groups as compared with the preoperative score, and no significant difference was found between the two groups.

Discussion
Haematuria is the most common complication of surgery for BPH. In some cases, transfusions may be necessary owing to persistent or late postoperative bleeding. These complications are related to the preoperative hypercoagulability state and present in many patients taking antithrombotics or coumarin derivatives relatively. Recently, aging and Western eating habits have increased the number of patients with thromboembolic diseases 13 . Many of these patients need and receive oral antithrombotic treatment 13 . However, prospective studies are lacking in patients who have been receiving long-term oral antithrombotic therapy prior to HoLEP.
Hochreiter et al. reported the benefits of HoLEP for patients taking antithrombotics first. In the study, 19 patients taking antithrombotics had undergone HoLEP and did not receive postoperative transfusion 14 . Bolton et al. reported that in a TURP study with coumarin-treated patients, 8% of the patients had long-term haematuria, 6% needed transfusion, and 2% required reoperation for haemostasis 15 . Descazeaud et al. reported their experience with 83 patients with high-risk bleeding tendency in a HoLEP study of patients taking oral antithrombotics. Of the 83 patients, 81 were taking oral antithrombotics and 2 had haemophilia. Of these patients, 33 discontinued taking oral antithrombotics before surgery, 34 shifted to low-molecular-weight heparin (LMWH), and 14 continued oral antithrombotic during operation. Transfusion was performed in 7 patients who discontinued oral antithrombotics, 5 with a LMWH replacement, and 7 who continued antithrombotic therapy 4 . In another study of 81 patients who underwent HoLEP, 14 patients maintained oral antithrombotics during surgery, but the transfusion rate was not significantly high 16 . When taking oral antithrombotics, HoLEP was recommended as a more suitable operation than TURP 16 . In the present study, 235 patients (95.7%) discontinued antithrombotic therapy. Three patients (1.2%) shifted to LMWH and 10 (4.1%) continued the use of the original antithrombotic. Transfusion was performed in 1 patient with LMWH replacement.    9%) who underwent GreenLight laser photoselective vaporization among 923 patients who were taking antithrombotics. The distribution of cardiovascular events was as follows: 4 patients with myocardial infarction, 7 with angina pectoris, 3 with venous thromboses, 1 with atrial fibrillation, 1 with hypotension, 1 with a vasovagal reflex episode, and 1 with supraventricular tachycardia 17 . In their study of 305 patients receiving antithrombotics before TURP, Raj et al. reported that cardiovascular and cerebrovascular events occurred at incidence rates of 0.98% and 0.65%, respectively 18 .    Table 5. Clavien-Dindo classification of non-antithrombic and antithrombic groups.
In the present study, the incidence of clot-related problem was 3.6%, the retention rate was 3.2%, the frequency of continuous bladder irrigation due to postoperative bladder bleeding was 2%, and the frequency of TUC in the antithrombotic group was 0.4%. The mean catheterization period was 1.4 days, and the mean length of hospital stay was 1 day. Of the patients, 95.2% were hospitalized for 1 day and only 4.8% were hospitalized for >1 day. Furthermore, among the patients who temporarily discontinued antithrombotic therapy, one (0.4%) had an intracerebral infarction and another (0.4%) had a myocardial infarction. No significant difference was found in the incidence of postoperative transfusion (p = 0.884) or complication with antithrombotic administration. Moreover, no significant difference was found in the incidence of haemorrhage (p = 0.959, p = 0.894) requiring thrombosis (p = 0.946), bladder washing, and transurethral coagulation. We found no significant differences in the incidence of complications between 2 weeks, 3 months, and 6 months after surgery.
Holmium laser does not penetrate deeply into the tissue, penetrating only at a depth of 0.4 mm. It achieves rapid vaporization and solidification of the tissue, and this is beneficial for regulating haemostasis in patients taking antithrombotics 20 .
This study analysed prospectively collected data, with an attempt to minimize bias. However, it still has limitations. The study cohort was followed up for 6 months, with limited results for long-term outcomes or complications occurring after 6 months. Future studies could examine patients several years postoperatively to provide better understanding and stronger implications regarding the efficacy of HoLEP as a surgical method for patients with BPH who are using antithrombotics in the long term.

Conclusion
This study suggests that HoLEP is an effective surgical method for patients with BPH who are taking antithrombotics. We observed a few cardiovascular and cerebrovascular complications related to short-term antithrombotic withdrawal before and after HoLEP in the patients with BPH who were receiving antithrombotic therapy.