Redefining Clinically Significant Hematuria After Holmium Enucleation of the Prostate

Abstract

Introduction and Objective:

Holmium laser enucleation of the prostate (HoLEP) is often offered for symptomatic prostatic enlargement at high risk for bleeding. However, prior studies define clinically significant hematuria (CSH) narrowly as the need for blood transfusion or significant decrease in hemoglobin. We sought to evaluate risk factors contributing to a broader definition of CSH, which may contribute to alteration of clinical course.

Methods:

We analyzed 164 patients in a prospectively maintained database who underwent HoLEP at a single institution across two surgeons from November 2020 to April 2023. HoLEP was performed using Moses 2.0 (Boston Scientific) laser and the Piranha enucleation system (Richard Wolf). We defined CSH broadly as follows: clot retention, return to operating room, perioperative management variation due to hematuria, or continued gross hematuria past 1 month postoperatively. Univariable and multivariable ANOVAs were used. Multivariable analysis of CSH risk based on the use of antiplatelet (AP) agents or anticoagulants included correction for age, enucleation time (surrogate for case difficulty), and prostate volume.

Results:

17.7% (29/164) of our patients developed CSH after HoLEP. Longer enucleation time was a mild risk factor for developing CSH (multivariate odds ratio [OR] 1.01, p = 0.02). The strongest predictor of CSH was the use of anticoagulation or AP agents (OR 2.71 p < 0.02 on univariable analysis, OR 2.34 p < 0.02 on multivariable analysis), even when aspirin 81 mg was excluded.

Conclusion:

With a broadened definition, 18% of patients developed CSH following HoLEP, which impacted the clinical course. Our data suggest that the current definition of significant hematuria is too narrow and does not capture many patients whose clinical course is affected by hematuria. While safe, anticoagulants and APs significantly predicted an increased CSH risk, and patients should be counseled accordingly.

Introduction

The prevalence of benign prostatic hyperplasia (BPH) with lower urinary tract symptoms is estimated to be in ∼70% of men ages 60 to 69 and increases with age.¹ While transurethral resection of the prostate (TURP) has traditionally been the gold standard surgical intervention for symptomatic BPH, holmium laser enucleation of the prostate (HoLEP) is recommended by the American Urological Association (AUA) in patients at high risk for bleeding.² This is due to the favorable hemostatic properties of lasers compared with monopolar or bipolar energy. However, prior studies supporting the use of HoLEP in these patients define significant hematuria as either return to operating room or need for transfusion.^3

–6 These criteria exclude other clinically relevant complications of hematuria such as clot retention, perioperative management variation, office calls for hematuria, or prolonged postoperative hematuria.

As HoLEP is the recommended procedure for patients at high risk for bleeding, it is important to broaden the current understanding of their postoperative clinical course with respect to postoperative hematuria complications. Given the discrepancy between the current literature and our experience, we studied whether a broader definition of clinically significant hematuria (CSH) would more accurately reflect our patient experience after HoLEP.

Methods

Subjects

Subjects from an IRB approved prospectively maintained database of individuals who have undergone a HoLEP at a single institution beginning in November 2020 were included in this study. Individuals included between November 2020 and January 2021 were retrospectively included in the database. Individuals after February 2021 were consented and their data were prospectively collected. Inclusion criteria for this study were subjects undergoing a HoLEP between November 2020 and April 2023. Exclusion criteria were individuals who did not ultimately undergo a HoLEP, subjects who did not yet have 1 month of follow-up, or subjects with incomplete data for bleeding, use of anticoagulation (AC), or use of antiplatelet (AP) agents.

Procedure

Patients were on AC/APs for atrial fibrillation, coronary artery disease, history of deep vein thrombosis or pulmonary embolism, stroke history, and mechanical valves. Clopidogrel was held on average 5 days before surgery, while apixaban, enoxaparin, and rivaroxaban were held on average 3 days before surgery. Warfarin was held with a target nadir international normalized ratio 1.5 at day of surgery. There were few cases in which AC and/or AP were continued perioperatively if deemed unsafe by the prescribing provider to pause the medication. Aspirin 81 mg was not held before or following surgery. Clopidogrel, enoxaparin, rivaroxaban, and apixaban were targeted for restart on postoperative day 3 unless hematuria was poorly controlled. Warfarin was targeted for restart on postoperative day 1.

HoLEPs were performed by two fellowship-trained endourologists at a single institution. Prostate enucleation was performed with a Boston Scientific MOSES holmium laser and morcellation was performed with a Wolf Piranha Morcellator. Hemostasis was addressed throughout the procedure. Bipolar transurethral resectoscope and laser fulguration were used at the surgeon's discretion to accomplish hemostasis, where hemostasis throughout enucleation was deemed inadequate. The surgical techniques and laser settings did not vary for patients on AC and/or AP therapy. Our enucleation settings were 2 J/50 Hz using MOSES enucleation and our fulguration settings were 1 J/20 Hz using long pulse width. Postoperatively, patients were observed for one night on continuous bladder irrigation and catheter was removed before discharge when possible. In this series, there were no catheter removals on the day of surgery.

Definition of CSH

“Clinically significant hematuria” was defined broadly with the aim to capture a variety of clinical scenarios requiring intervention. This variable included clot retention, return to the operating room, hospital admission for hematuria, deviation from standard perioperative management due to hematuria, or continued hematuria past 1 month postoperatively. Deviation from standard perioperative management included needing scheduled hand irrigations or prolonged continuous bladder irrigation for continued clot postoperatively, catheter traction, prolonged catheterization past postoperative day 1, and prolonged admission due to hematuria.

Statistical analysis

Univariable and multivariable ANOVAs were performed in R version 4.0.1. Predetermined variables included in multivariable analysis of predictors of CSH were as follows: use of AP agents or anticoagulants, prostate volume, age, and enucleation time (surrogate for case difficulty). A preplanned sensitivity analysis, including individuals only on 81 mg of aspirin in the no AP group instead of the AP group, was also performed with the same variables.

Results

Demographics

During the study period, 164 individuals underwent HoLEP and were included in the analysis. Median age was 70 years (interquartile range [IQR] 65–76) and median prostate size was 103 cc (IQR 82.8–138.0). Eighteen individuals were taking anticoagulant agents, 36 individuals were taking 81 mg of aspirin only, and 19 were taking other AP agents, including higher doses of aspirin. Mean enucleation time was 84 minutes and morcellation 16 minutes.

Any hematuria

Of the 164 subjects, 113 reported at least some gross hematuria at their 1 week follow-up visit, which is to be expected. Reported urine colors for these individuals ranged from clear pink to dark red with some clot material.

Clinically significant hematuria

Twenty-nine subjects (17.7%) experienced CSH. Symptoms and management are listed in Table 1. The strongest predictor of clinically significant gross hematuria was the use of anticoagulant or AP agents (p < 0.02 on univariable and multivariable analysis) (Table 2). This persisted even if the 81 mg dose of aspirin was excluded, indicating that the effect was primarily driven by the higher doses of AP agents (Table 3). The interactions between enucleation time and prostate volume, which are surrogates for case difficulty, are predictive on multivariable analysis (Tables 2 and 3).

Table 1.

Clinically Significant Hematuria

Symptoms	No. of subjects
Continuous bladder irrigation/hand irrigations outside of protocol	10 (34.5%)
Prolonged admission	10 (34.5%)
Clot retention	5 (17.2%)
Catheter traction	4 (13.8%)
Prolonged catheterization	4 (13.8%)
Significant gross hematuria at 1 month	4 (13.8%)
Readmission to hospital	2 (6.9%)
Return to operating room for clot evacuation	1 (3.4%)

Symptoms and management of subjects with clinically significant hematuria.

Table 2.

Predictors of Hematuria: Results of Preplanned Univariable and Multivariable Analysis Evaluating Expected Predictors of Gross Hematuria

	Univariable			Multivariable
	OR	95% CI	p	OR	95% CI	p
Age	1.01	0.96–1.06	0.70	1.00	0.94–1.05	0.88
Anticoagulants or antiplatelet agents	2.71	1.28–5.90	0.01^*	2.34	1.04–5.37	0.04^*
Volume	0.99	0.98–1.00	0.13	0.99	0.98–1.00	0.07
Enucleation time	1.01	0.99–1.02	0.05	1.01	1.00–1.02	0.02^*

Statistically significant.

CI = confidence interval; OR = odds ratio.

Table 3.

Predictors of Hematuria if 81 mg Dose of Aspirin Is Excluded: Results of Preplanned Univariable and Multivariable Analysis Evaluating Expected Predictors of Gross Hematuria with 81 mg Aspirin Excluded

	Univariable			Multivariable
	OR	95% CI	p	OR	95% CI	p
Age	1.01	0.96–1.06	0.70	0.99	0.93–1.04	0.66
Anticoagulant or antiplatelet agents excluding 81 mg aspirin	2.72	1.18–6.17	0.02^*	3.02	1.20–7.68	0.02^*
Volume	0.99	0.98–1.00	0.13	0.99	0.98–0.99	0.03^*
Enucleation time	1.01	0.99–1.02	0.05	1.01	1.00–1.02	0.02^*

Statistically significant.

Discussion

In the early adoption of HoLEP, many studies discuss hematuria complications from a safety perspective. As a result, many define significant hematuria by their need for blood transfusion postoperatively^7,8 and hemoglobin loss.^7,9

–12 In using these definitions, the rate of significant hematuria in the literature is ∼0% to 5%.^9,13,14 We noted that none of our patients fits this narrowed hematuria definition postoperatively. With our broadened definition of CSH, 17.7% of patients met the criteria for significant hematuria postoperatively. Our most common CSH category was prolonged continuous bladder irrigation and hospital stay (n = 10), followed by prolonged catheterization, postoperative catheter traction, and hematuria for greater than 1 month postoperatively. Interestingly, one study demonstrated that 93.5% of patients expect hematuria to resolve after 30 days,¹⁴ targeting a potential area for improved counseling. While almost all patients expect some degree of hematuria postoperatively,¹⁴ counseling patients on realistic postoperative expectations is crucial for the patient–physician relationship.

As the leading cause of death in the United States, cardiovascular disease is also common, and the incidence of patients requiring AC and AP therapy due to cardiovascular disease has risen.^15,16 Thus, the number patients on AC or AP requiring surgical intervention for BPH is increasing. Furthermore, endourologists often need to continue AC or AP perioperatively due to cardiologic or neurologic recommendations, which worsens postoperative hematuria. Given an aging population with increased AP and anticoagulant use, it is important to delineate HoLEP postoperative complications of patients on AC or AP. While HoLEP is understood to have improved hemostatic properties for patients on AC/AP when compared with TURP,¹⁷ there may be increased risk for perioperative and postoperative hematuria complications.

In our study, the strongest predictor of clinically significant gross hematuria was the use of anticoagulant or AP agents, which persisted when excluding aspirin 81 mg (p < 0.02). This is consistent with the literature on perioperative AC/AP use in HoLEP. In two studies, patients on AC/AP had slightly prolonged hospital stays, length of continuous bladder irrigation, and catheterization postoperatively, but no difference in return to operating room or blood transfusion.^3,5,18,19 One study showed a blood transfusion rate of 7.7% in patients on antithrombotics.⁶ Other studies found that increased hospital stay and prolonged continuous bladder irrigation and catheterization times occurred in patients on AC but not on AP therapy.^18,19 Similarly, one study found preoperative anticoagulant, but not AP, use to be a risk factor for failed same-day void trial after HoLEP.²⁰

Lastly, one study found no significant difference in emergency room visits or Clavien grade ≥3 complications in patients on AC/AP after HoLEP.²¹ Overall, our data concur with the current literature that while HoLEP is a safe surgical technique in patients on AC/AP, they should be counseled carefully on their increased risk of CSH.

This new definition of CSH can be applied to other BPH surgical techniques as well. Although procedures such as photovaporization of the prostate (PVP) and HoLEP yield favorable hematuria parameters when compared with TURP, this patient population is not immune from clinical deviation with Clavien–Dindo grade ≤3 complications.²² PVP in anticoagulated patients demonstrates higher recatheterization rates, prolonged catheterization, prolonged bladder irrigations, and prolonged admission, although no transfusions when compared with controls.^23
–25

Even patients undergoing a procedure at lower risk for bleeding such as HoLEP and PVP should be counseled accordingly that there may be deviations of standard management.

When analyzing our data, we note that an increased enucleation time (odds ratio [OR] 1.01, p = 0.02) and prostate volume (OR 0.99, p = 0.03) predicted increased risk for CSH on multivariate analysis. We use these markers as a surrogate for overall case difficulty, which may explain this small but statistically significant risk.

One limitation of our study is that while we prospectively collected the data, it was retrospectively analyzed. We introduce a novel concept of CSH that seeks to broaden the definition to include Clavien–Dindo grade <3 complications, but this concept has no prior validation, which potentially limits the application of our findings. It is hard to conclude the meaning of our witnessed CSH rates as there is nothing to compare this composite outcome.

We noticed in our practice that the patient expectations were not equal to the patient experience, evidenced by the percentage of patients who deviated from the standard protocol. However, while the investigation hinges on the patient experience, we did not include any validated patient-reported outcomes assessing the burden of additional hematuria episodes on their clinical experience. Our practice at the time of data collection included no same-day discharges or catheter removals, and all patients paused their AC and AP medications if deemed clinically safe by the prescribing provider. As our practice evolves to adopt more contemporary practices including continuing all anticoagulants and APs and same-day catheter removals, our observed rates of CSH may increase with the overall increased length of stay due to hematuria as seen in other studies.^26,27

The AUA guidelines recommend HoLEP for treating those at risk for bleeding, and so, our findings pose a challenge given that no better surgical option exists for this higher hematuria risk population. We propose that patients require better preoperative and postoperative counseling regarding the actual rates of CSH and more concrete descriptions of what they can expect. The postoperative course deviation literature focuses on Clavien–Dindo grade >3, but this does not capture most patients' concerns and mismatches of experience and expectations. Having well-informed patients on the variable postoperative hematuria course can decrease unnecessary phone calls and emergency room visits for gross hematuria after HoLEP. It is challenging to account for patient variability in their threshold to report hematuria, as different patients have different comfort levels with postoperative hematuria. Patients in this study are not reporting their level of hematuria based on a validated scale.²⁸

Our findings highlight the importance of both pre- and postoperative education for HoLEP patients on the variable postoperative hematuria course, and for actionable guidance on when to seek further medical attention based on a validated standardized visual scale.

Conclusions

We found that the current literature does not adequately capture CSH that commonly affects the postoperative clinical course for HoLEP patients. Using this broadened definition gives us a platform to better counsel patients on what to expect after HoLEP. Using this broadened definition, we identified that patients on AC and APs were at higher risk for developing clinically significant postoperative hematuria. While HoLEP is recommended by AUA guidelines in patients on AC/AP undergoing BPH surgery due to the laser's increased coagulative properties, patients must be adequately counseled on their increased risk of CSH. Our broadened definition allows clinicians to appropriate counsel their patients on possible variations from the expected clinical outcomes postoperatively. Our data suggest that the current definition of significant hematuria is too narrow and does not capture many patients whose clinical course is affected by hematuria.

Footnotes

Authors' Contributions

L.H.: Conceptualization, methodology, data curation, writing—original draft, writing—review and editing, and visualization. K.M.D.: Methodology, formal analysis, resources, data curation, writing—original draft, and writing—review and editing. M.N.: Writing—original draft and writing—review and editing. R.J.: Supervision, project administration, investigation, conceptualization, and writing—review and editing. S.O.Q.: Supervision, project administration, investigation, conceptualization, and writing—review and editing.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

Abbreviations Used

References

Wei

, Calhoun

, Jacobsen

. Urologic diseases in America project: Benign prostatic hyperplasia. J Urol, 2008; 179(5 Suppl):S75–S80.

Lerner

, McVary

, Barry

, et al. Management of lower urinary tract symptoms attributed to benign prostatic hyperplasia: AUA GUIDELINE PART II-surgical evaluation and treatment. J Urol, 2021; 206(4):818–826.

Rivera

, Krambeck

, Lingeman

. Holmium laser enucleation of the prostate in patients requiring anticoagulation. Curr Urol Rep, 2017; 18(10):77.

Ahyai

, Lehrich

, Kuntz

. Holmium laser enucleation versus transurethral resection of the prostate: 3-year follow-up results of a randomized clinical trial. Eur Urol, 2007; 52(5):1456–1463.

El Tayeb

, Jacob

, Bhojani

, et al. Holmium laser enucleation of the prostate in patients requiring anticoagulation. J Endourol, 2016; 30(7):805–809.

Bishop

, Liddell

, Ischia

, et al. Holmium laser enucleation of the prostate: Comparison of immediate postoperative outcomes in patients with and without antithrombotic therapy. Curr Urol, 2013; 7(1):28–33.

Jhanwar

, Sinha

, Bansal

, et al. Outcomes of transurethral resection and holmium laser enucleation in more than 60g of prostate: A prospective randomized study. Urol Ann, 2017; 9(1):45–50.

Zheng

, Peng

, Cao

, et al. Holmium laser enucleation of the prostate in benign prostate hyperplasia Patients with or without oral antithrombotic drugs: a meta-analysis. Int Urol Nephrol, 2019; 51(12):2127–2136.

Romero-Otero

, García-González

, García-Gómez

, et al. Factors influencing intraoperative blood loss in patients undergoing holmium laser enucleation of the prostate (HoLEP) for benign prostatic hyperplasia: A large multicenter analysis. Urology, 2019; 132:177–182.

10.

Gloger

, Schueller

, Paulics

, et al. Aquablation with subsequent selective bipolar cauterization versus holmium laser enucleation of the prostate (HoLEP) with regard to perioperative bleeding. Can J Urol, 2021; 28(3):10685–10690.

11.

Elzayat

, Habib

, Elhilali

. Holmium laser enucleation of the prostate in patients on anticoagulant therapy or with bleeding disorders. J Urol, 2006; 175(4):1428–1432.

12.

Westhofen

, Schott

, Keller

, et al. Superiority of holmium laser enucleation of the prostate over transurethral resection of the prostate in a matched-pair analysis of bleeding complications under various antithrombotic regimens. J Endourol, 2021; 35(3):328–334.

13.

Montorsi

, Naspro

, Salonia

, et al. Holmium laser enucleation versus transurethral resection of the prostate: results from a 2-center prospective randomized trial in patients with obstructive benign prostatic hyperplasia. J Urol, 2008; 179(5 Suppl):S87–S90.

14.

Assmus

, Lee

, Large

, et al. Understanding holmium laser enucleation of the prostate (HoLEP) recovery: Assessing patient expectations and understanding. Can Urol Assoc J, 2022; 16(1):E25–E31.

15.

Lund

, Saunders

, Edwards

, et al. Anticoagulation trends in adults aged 65years and over with atrial fibrillation: A cohort study. Open Heart, 2021; 8(2):e001737.

16.

Jourdi

, Godier

, Lordkipanidze

, et al. Antiplatelet therapy for atherothrombotic disease in 2022—From population to patient-centered approaches. Front Cardiovasc Med, 2022; 9:805525.

17.

Mavuduru

, Mandal

, Singh

, et al. Comparison of HoLEP and TURP in terms of efficacy in the early postoperative period and perioperative morbidity. Urol Int, 2009; 82(2):130–135.

18.

Neuville

, Codas

, Ravier

, et al. [Anticoagulation impact on bleeding risk during HoLEP: Monocentric study of 156 patients]. Prog Urol, 2018; 28(2):128–134.

19.

Branchu

, Léon

, Fournier

, et al. [Impact of antiplatelet and anticoagulant treatments on bleeding complications in patients treated with HoLEP]. Prog Urol, 2020; 30(12):639–645.

20.

Cooley

, Assmus

, Ganesh

, et al. Predictors of failed same-day catheter removal after holmium laser enucleation of the prostate. Urology, 2022; 170:168–173.

21.

Agarwal

, Large

, Stoughton

, et al. Real-world experience of holmium laser enucleation of the prostate with patients on anticoagulation therapy. J Endourol, 2021; 35(7):1036–1041.

22.

Kumar

, Vasudeva

, Kumar

, et al. A prospective randomized comparative study of monopolar and bipolar transurethral resection of the prostate and photoselective vaporization of the prostate in patients who present with benign prostatic obstruction: a single center experience. J Endourol, 2013; 27(10):1245–1253.

23.

Knapp

, Chalasani

, Woo

. Perioperative adverse events in patients on continued anticoagulation undergoing photoselective vaporisation of the prostate with the 180-W Greenlight lithium triborate laser. BJU Int, 2017; 119 Suppl 5:33–38.

24.

Woo

, Hossack

. Photoselective vaporization of the prostate with the 120-W lithium triborate laser in men taking coumadin. Urology, 2011; 78(1):142–145.

25.

Pawan

, Anup

, Niraj

, et al. Safety and efficacy of photoselective vaporization of prostate in patients receiving anticoagulants. Minerva Urol Nefrol, 2013; 65(3):189–195.

26.

Becker

, Netsch

, Hansen

, et al. Perioperative safety in patient under oral anticoagulation during holmium laser enucleation of the prostate. J Endourol, 2019; 33(3):219–224.

27.

Deuker

, Rührup

, Karakiewicz

, et al. Holmium laser enucleation of the prostate: efficacy, safety and preoperative management in patients presenting with anticoagulation therapy. World J Urol, 2021; 39(4):1219–1226.

28.

Stout

, Borofsky

, Soubra

. A visual scale for improving communication when describing gross hematuria. Urology, 2021; 148:32–36.