Introduction

Cardiovascular diseases (CVDs) include vascular and heart diseases, including atherosclerosis, peripheral vascular diseases, and cerebrovascular diseases. Cerebrovascular accidents (CVAs) include ischemic stroke, transient ischemic attack, and haemorrhagic stroke such as subarachnoid and intracerebral haemorrhages. CVDs are among the most common causes of adult death in the United States, with 1 in 3 adults dying each year1. CVA is the third leading cause of death in the United States, following heart disease and cancer2. The incidence rates of CVA and CVD increase with age1. Various treatments are available for patients with CVA and CVD, and those at risk, with the most common treatment being antithrombotic therapy3. As the CVA and CVD risk and incidence rates increase with age, the number of patients taking antithrombotics is also increasing; many of these patients have BPH that requires surgical treatment4. For this reason, urologists often perform BPH surgery in patients with CVA and CVD who are receiving antithrombotics5.

Benign prostatic hyperplasia (BPH) is one of the most common diseases in men aged >50 years, and its incidence increases with age >50 years6. For decades, the standard of surgical treatment for BPH was transurethral prostatectomy (TURP)7. However, TURP is known to be associated with high incidence rates of perioperative bleeding, transfusion, and delayed bleeding8. Bleeding-related problems can also occur, such as increased catheter maintenance duration, bladder irrigation time, and length of hospital stay, which can arise from TURP8,9,10. As an alternative to this problem, interests in minimally invasive surgery and less-invasive surgery have increased. The recent increasing interest in noninvasive surgery has led to the popularization of laser-assisted BPH surgery11. Holmium laser enucleation of the prostate (HoLEP) is one of the laser-assisted BPH surgeries.

Only few studies have included a large number of patients or have been conducted on Asian populations. The number of patients with risk factors of CVA or CVD is increasing because of the aging of society1. Therefore, we investigated the treatment efficacy and risks of CVA and CVD in patients who underwent HoLEP with antithrombotic therapy among Koreans.

Methods

This study reviewed a prospective cohort of patients who underwent HoLEP with LUTS/BPH. The BPH prospective cohort is part of the previous prospective SNUH-BPH Database Registry, which was approved by the Institutional Review Board of Seoul National University Hospital (IRB No. H-0810-027-260). We obtained informed consent from the patients. Study protocol and contents associated with this study followed the Declaration of Helsinki guidelines.

The inclusion criteria included patients aged ≥50 years who had a clinical diagnosis of BPH and received HoLEP. The exclusion criteria were patients with a history of genitourinary cancer and pelvic surgery, and neurogenic bladder dysfunction. Digital rectal examination, serum prostate specific antigen (PSA) level, international prostate symptom score (IPSS), overactive bladder symptom score (OABSS), 72-h voiding diary, cystourethroscopy, transrectal ultrasonography (TRUS), laboratory serum tests, and urine tests were used for baseline evaluation. Most of the antibiotics used were second-generation cephalosporins or ciprofloxacin for patients with hypersensitivity reactions. HoLEP was performed in the lithotomy position under general or spinal anaesthesia. Enucleation was performed with the three-lobe or early inverted V-shaped mucosal incision with anterior conjoining techniques12 using a holmium:YAG laser (Lumenis, The VersaPulse PowerSuite 100 W) with a 550-mm end laser fibre (Boston Scientific, AccuMax 550 Laser Fiber) and a laser setting of 80 W (2J × 40 Hz). The enucleated prostatic adenoma was morcellated with a morcellator (Lumenis, Versacut). After the operation, bladder irrigation was performed using normal saline. The intraoperative parameters included operative time, energy use, weight of enucleated prostate tissue, morcellation time, and intraoperative complications such as bladder injury and prostate capsule perforation. All the patients who were treated with antithrombotic therapy were instructed to resume their antithrombotic medications when haematuria was no longer visible.

Information on the use of antithrombotics and discontinuation methods during operation was collected. Postoperative parameters such as IPSS, OABSS, 72-h voiding diary, uroflowmetry, urine test, and PSA were evaluated. In addition, data regarding complications such as UTI, urgency, urinary incontinence, postoperative bleeding (which required transurethral coagulation or bladder irrigation), postoperative urinary retention, re-urethral catheterization, urethral stricture, bladder neck contracture, and cerebrovascular and cardiovascular events were collected. Follow-up was performed at 2 weeks, 3 months, and 6 months postoperatively.

The patients were categorized into two groups, a non-antithrombotic therapy group and an antithrombotic therapy group. The various clinical parameters, and the postoperative outcomes and complications associated with the use of antithrombotics were compared between the two groups.

All statistical analyses were performed using IBM SPSS Statistics version 22.0 (IBM, Armonk, NY, USA). Continuous variables were expressed as median and interquartile range (IQR), or mean and standard deviation (SD). Categorical variables were expressed using the ratio of events (%). Quantitative data were analysed using the Student t test. Binary variables were analysed when a chi-square test was applicable, but the Fisher exact test was performed if the distribution of the equation deviated significantly from normal. Multivariate analysis was performed using logistic regression. All statistical analyses were two-sided, and statistical significance was defined as a p value of ≤0.05.

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.

Table 1 Baseline patient characteristics of non- antithrombotic and antithrombotic groups.
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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 2 Type of oral antithrombic drug, indication and management during the operation of antithrombic group.
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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 difference in the duration of Foley catheter retention (p = 0.017), but the difference from that in clinical practice was not significant.

Table 3 Perioperative outcomes of non-antithrombic and antithrombic groups.
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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 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.

Table 4 Postoperative complications of non-antithrombic and antithrombic groups.
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Table 5 Clavien-Dindo classification of non-antithrombic and antithrombic groups.
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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 diseases13. Many of these patients need and receive oral antithrombotic treatment13. 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 transfusion14. 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 haemostasis15. 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 therapy4. In another study of 81 patients who underwent HoLEP, 14 patients maintained oral antithrombotics during surgery, but the transfusion rate was not significantly high16. When taking oral antithrombotics, HoLEP was recommended as a more suitable operation than TURP16. 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.

Marchion et al. reported acute cardiovascular events in 18 patients (1.9%) 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 tachycardia17. 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%, respectively18. Taylor et al. reported the occurrence of cardiovascular complications in 6 (9.2%) of 65 patients who discontinued antithrombotics before and after surgery19.

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 antithrombotics20.

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.