HaEmaturia After Transurethral resection of bladder Tumour (HEATT): A multicentre,regional collaborative analysis of factors associated with emergency re-admission with haematuria following TURBT

Abstract

Objective:

To calculate the re-admission rate with haematuria within 30 days of elective transurethral resection of bladder tumour (TURBT), and identify factors associated with this.

Materials and Methods:

This was a multicentre, retrospective audit, identifying all adult patients over the age of 16 who underwent elective TURBT between 1 September and 30 November 2019. Data were collected from medical records and operation notes on patient demographics, intra-operative factors and post-operative management. Primary outcome measure was the proportion of patients emergently re-admitted with haematuria. Secondary outcome measures were the re-operation rate for haematuria, and the rate of new acute thrombotic event (TE). Fisher’s exact test was used to calculate p values within subgroups for re-admission rates.

Results:

443 patients from 12 hospitals were included. Median age was 75 years (17–99). 15 patients (3.4%) were re-admitted with haematuria. Subgroup analysis demonstrated higher rate of re-admission for pre-existing antithrombotic agents (ATAs) (2.0% vs. 6.1%, p = 0.046), increased for non-Aspirin ATAs (10.5%, p = 0.0015). 52% of non-Aspirin ATAs were restarted within 48 hours of surgery; post-operative plan for restarting was not documented in 22.1%. One patient (0.23%) developed acute TE (pulmonary embolus).

Conclusion:

Pre-existing use of non-Aspirin ATAs is associated with increased risk of post-TURBT haematuria, with variable practice in post-operative recommencement.

Level of evidence:

Level 3

Keywords

Bladder cancer emergency urology haematuria anticoagulation transurethral resection of bladder tumour

Introduction

Transurethral resection of bladder tumour (TURBT) is an index procedure for urological trainees in the United Kingdom¹; in England alone in 2017–2018, 19,387 such operations were carried out.² This is primarily for bladder cancer (BCa), of which the predominant histological type in developed countries is urothelial cell carcinoma (UCC).³ Tobacco smoking is the single greatest risk factor for BCa.⁴ As a result, many patients with BCa are current or previous smokers, and are therefore likely to have co-existing cardiovascular disease, treatment for which may include antithrombotic agents (ATAs) in the form of antiplatelet agents (AP) or oral anticoagulants (AC).

All such medications are known to increase the risk of bleeding, and following the increase in use of factor Xa inhibitors (e.g. Apixaban and Edoxaban), the European Association of Urology (EAU) published guidelines on ‘Thromboprophylaxis in Urological Surgery’ in 2017. These guidelines offered clear advice when to withhold each drug class pre-operatively;⁵ however, guidance for recommencing ATAs post-operatively is less clear. We therefore sought to identify potential patient, tumour and operative features associated with emergency re-admission(s) with haematuria following TURBT, and whether regional variations in practice may contribute to re-admission rates.

Materials and methods

Study design and ethics approval

HaEmaturia after Transurethral resection of bladder Tumour (HEATT) was a retrospective, multicentre regional clinical audit designed and led by the West Midlands Urology Research Collaborative. It was registered at each participating Trust’s Clinical Audit/Research and Development departments.

Data collection

Data collection was carried out over a 3-month period from the 1 September to the 30 November 2019. All patients (age over 16 years) undergoing elective TURBT for either primary or recurrent bladder tumour(s), were identified from operative theatre diaries at each participating Trust.

Data collected included patient demographics (age; gender; pre-existing ATA; previous intravesical therapy; previous pelvic radiotherapy); tumour demographics (primary or recurrent; solitary or multifocal; size in millimetres (mm)); operative factors (level of primary surgeon; energy source used; tumour resection technique; energy source used; inclusion of detrusor muscle in histological specimen; recognised intra-operative bladder perforation); and extra-operative management variables (timing of pre-operative cessation and post-operative restarting of ATA; need for blood transfusion; length of stay; need for further surgery for post-operative haematuria within index admission).

Further data were collected on emergency re-admissions (classified as admission onto a surgical admissions/assessment unit, or surgical ward, with or without an overnight stay in hospital) following discharge within 30 days of TURBT, with haematuria or a new acute thromboembolic event (TE) (defined as deep vein thrombosis; pulmonary embolism; non-haemorrhagic stroke; or acute coronary syndrome), and the need for further surgery for haematuria during re-admission.

Outcome measures

The primary outcome measure was the proportion of patients undergoing elective TURBT who were re-admitted as an emergency with haematuria within 30 days. Secondary outcome measures were the re-operation rate for haematuria within 30 days of TURBT, and the rate of new acute TE within 30 days of TURBT.

Statistical analysis

The rates for the primary and secondary outcomes were calculated, and then subgroup analysis for each variable collected was carried out with the proportion of emergency re-admission with haematuria within each subgroup calculated. Fisher’s exact test was used to calculate p values within subgroups for re-admission rates (p value < 0.05 significant), and for those subgroups which demonstrated this level of p value or less, relative risk (RR) and odds ratio (OR) for emergency re-admission were calculated. Statistical analysis was carried out using online calculators at www.scistat.com.

Results

Data were available for 443 patients undergoing elective TURBT at 12 hospitals within the West Midlands. Patient demographics are shown in Table 1. The majority of patients were male (79.5%), with an age range of 17–99 years (median 75). Table 2 summarises ATA use within our cohort, and their perioperative management. 147 patients (33.2%) were on ATAs prior to surgery, 61 of whom were taking Aspirin.

Table 1.

Patient demographics.

Age (years)
Median	75
Range	17–99
Gender	N (%)
Male	352 (79.5)
Female	91 (20.5)
Previous treatment	N (%)
Radiotherapy (pelvic)	16 (3.6)
Intravesical treatment	73 (16.5)
Mitomycin	23
BCG (Bacillus Calmette-Guerin)	44
Mitomycin and BCG	6
None	354 (79.9)

Table 2.

Pre-operative ATAs and perioperative management.

Patients not taking ATAs	296 (66.8%)
Patients taking ATAs	147 (33.2%)
Warfarin	18
Direct oral anticoagulants	36
Low molecular weight heparin	1
Aspirin	61
Clopidogrel	30
Pre-operative cessation time for non-Aspirin ATAs (days)
0	4
1	2
2	23
3	13
4	1
5	10
6	3
7	20
8 or more	2
Not documented	8
Post-operative restarting time for non-Aspirin ATAs (days)
0	2
1	24
2	21
3	8
4	0
5	2
6	0
7	3
8 or more	7
Not documented	19

ATAs: antithrombotic agents.

Tumour, surgical and perioperative management factors are shown in Table 3; most TURBTs were for primary (62.1%); solitary (63.9%); and <30 mm (66.3%) tumours. More specimens contained detrusor muscle than not (60.5% vs. 37.9%, respectively), and registrars were primary operators for most cases (53.7%). Only five patients (1.1%) required a post-operative blood transfusion, and the median length of post-operative hospital stay was 1 day.

Table 3.

Tumour, surgical and post-operative characteristics.

Intra-operative
Tumour characteristics	N (%)
Primary or recurrent tumour
Primary	275 (62.1)
Recurrent	167 (37.7)
Not documented	1 (0.2)
Number of tumours
Solitary	283 (63.9)
Multifocal	158 (35.7)
Not documented	2 (0.4)
Tumour size
<30 mm	294 (66.3)
⩾30 mm	147 (33.1)
Not recorded	2 (0.6)
Resection technique
Fractionated	443 (100)
Energy source used
Monopolar diathermy	401 (90.5)
Bipolar diathermy	42 (9.5)
Inclusion of detrusor muscle in specimen
Muscle present	268 (60.5)
No muscle present	168 (37.9)
Not documented	7 (1.6)
Recognised bladder perforation at time of TURBT
Level of primary operating surgeon	N (%)
Present	7 (1.6)
Not present	436 (98.4)
Consultant	166 (37.5)
Registrar	238 (53.7)
Consultant and registrar	34 (7.7)
Not specified	5 (1.1)
Post-operative
Blood transfusion required	N (%)
Yes	5 (1.1)
No	438 (98.9)
Length of stay	0–67 days Median 1 day

TURBT: transurethral resection of bladder tumour.

15 patients (3.4%) were re-admitted as emergencies with haematuria within 30 days of TURBT, of which nine patients were on ATAs. Five were direct oral anticoagulants (DOACs) that were restarted within 72 hours of surgery (two cases with no documented restart time in the operation notes), and the other cases were Warfarin (two patients), low molecular weight heparin (one patient) and Clopidogrel (one patient).

None of the patients out of the entire cohort re-admitted required surgical intervention for haematuria, although one patient required return to theatre for bleeding during their initial elective admission. All re-admitted patients were managed at a ward-based level with management including observation, blood transfusion or catheterisation requiring irrigation. One patient in the entire cohort (0.23%) developed an acute thrombotic event (pulmonary embolism) within 30 days of TURBT; this particular individual was already on Warfarin, with their international normalised ratio (INR) found to be sub-therapeutic on re-admission despite having restarted Warfarin the day after surgery as instructed.

Figure 1 shows subgroup analysis for patient, tumour and surgical characteristics. Factors associated with a higher rate of (emergency) re-admission with haematuria were male gender; pre-existing ATA use; previous intravesical therapy; multifocal tumours; tumour size greater than 3 cm; use of monopolar diathermy; and presence of detrusor muscle in the histological specimen. When Fisher’s exact test was applied to these variables (Table 4), only the subgroup for ATAs produced a p value of <0.05 (p = 0.046; RR 3.02, 95% CI 1.09–8.32; OR 3.15, 95% CI 1.00–9.03); when those patients taking Aspirin as their only ATA was excluded from this subgroup, the p value reduced to 0.0015 (RR 5.16, 95% CI 1.89–14.10; OR 5.65, 95% CI 1.95–16.36).

Table 4.

Subgroup analysis of pre-, intra- and post-operative characteristics and their association with emergency re-admission rates with haematuria within 30 days of TURBT.

Characteristic	Number of patients within each subgroup re-admitted with haematuria	p value (Fisher’s exact test)
Gender
Male (n = 352)	14	0.32
Female (n = 91)	1
Antithrombotic agents (ATAs)
Not taking any ATAs (n = 296)	6
All ATAs (n = 147)	9	0.046^a
ATAs excluding Aspirin (n = 86)	9	0.0015^a
Previous intravesical therapy
Yes (n = 73)	4	0.30
No (n = 370)	11
Primary or recurrent tumour
Primary (n = 275)	9	1
Recurrent (n = 167)	6
Tumour size
<30 mm	12	0.40
⩾30 mm	3
Number of tumours
Solitary (n = 283)	8	0.42
Multifocal (n = 158)	7
Energy source used
Monopolar diathermy	12	0.17
Bipolar diathermy	3
Inclusion of detrusor muscle in specimen
Included (n = 268)	10	0.79
Not included (n = 168)	5
Level of primary surgeon
Consultant (n = 166)	5	1
Registrar (n = 238)	7

TURBT: transurethral resection of bladder tumour; ATAs: antithrombotic agents.

Comparison for each of these subgroups was performed against patients not taking any ATAs.

Discussion

Thromboprophylaxis in adult surgical patients is pursued vigorously, with wide circulation of pre-operative risk assessments and guidelines.^6,7 While patients may be at high risk of acute thrombosis from significant pre-existing cardiovascular disease and risk factors, those on established ATAs would be considered at high risk of bleeding. The last 10 years has seen the frequent use of many new ATAs in place of Warfarin, especially DOACs such as Apixaban, Edoxaban and Rivaroxaban.⁸ These novel agents have standard doses, do not require regular monitoring with international normalised ratio (INR) and have a faster onset of action.⁹ However, the capability for monitoring their effects on coagulation has limited availability,¹⁰ and reversal agents for their effects are limited (and expensive) compared to Warfarin.¹¹

Surgeons are responsible for balancing the risk between post-operative bleeding and TEs. Decision-making is difficult and occurs on a case-by-case basis due to less experience of newer ATAs, and a high percentage of patients undergoing TURBT with previous history of TE already on ATAs. Assessing perioperative ATA use risk is particularly important with TURBT as the area operated on does not permit tamponade or packing. Tranexamic acid, a urokinase inhibitor, has helped haematuria in patients with polycystic kidney disease,^12,13 but with less clear benefit in post-TURBT haematuria.^14,15 TXA inhibits urokinase which activates plasminogen into plasmin, in turn degrading fibrin and leading to clot dissolution.¹⁶ However, in haematuria such clot persists and requires evacuation to prevent the complications of retention and infection.

Encouragingly, the 3.4% emergency re-admission rate for haematuria of our cohort for post-TURBT was comparable to previous studies,^17,18 with a much lower re-operation rate for haematuria compared to known literature, including approximately 40% for patients on Clopidogrel.¹⁹ There was also a favourable rate compared to Getting It Right First Time (GIRFT) Hospital Episode Statistics (HES) data, although these specific rates included all reasons for re-admission post-TURBT instead of haematuria only.² Only one patient in our cohort developed post-operative acute TE. There was a demonstrable increase in hospital re-admission for haematuria for patients on ATAs compared to non-ATAs (2.0% vs. 6.1%, respectively). The risk of post-TURBT haematuria with non-Aspirin ATAs increased to 10.5%, comparable to previous studies evaluating non-Aspirin anticoagulation in haematuria¹⁷ and in patients undergoing TURBT.¹⁸ Overall, the proportion of patients we observed requiring re-admission with haematuria was similar to previous studies with appropriate pre-operative anticoagulation suspension, but unsurprisingly, much lower than post-operative hospital re-admission rates for haematuria (19–21%) where anticoagulation was not withheld.^20–22

Despite minimal regional variability in pre-operative practice regarding management of ATAs, there were differences in post-operative documentation on restarting. The EAU (thromboprophylaxis) guidelines recommend ‘restarting when bleeding is no longer a serious risk, typically four days post-surgery, rather than withholding for longer periods’.⁵ In our cohort, 54.7% of patients on non-Aspirin ATAs had them restarted within 48 hours of surgery; there was no documented plan for restarting in 22.1%. Some centres use bridging therapy with low molecular weight or intravenous unfractionated heparin before reintroduction of oral anticoagulants²³; this was not evident for any patient in our cohort. Our findings, if representative of wider UK practice, emphasise the need for clear national, and international, guidance on post-operative ATA prescription.

Despite the multicentre nature of our study and some statistically significant findings, there were insufficient numbers of some patient, tumour or surgical factors to allow meaningful statistical analyses. Although we were able to identify the energy source used for resection, the vast majority of TURBTs were carried out using monopolar diathermy (87.8%), and all were performed using fractionated resection. In contrast, bipolar resection and en-bloc resection are thought to be associated with reduced post-operative haematuria (our cohort had paradoxical findings regarding bipolar resection but the numbers for this were very small),^24,25 but our results reflected surgical practice within the region. We were unable to identify which patients received low molecular weight heparin (LMWH) thromboprophylaxis post-operatively, and therefore whether it was a contributory or causal factor to post-operative haematuria or re-admission.

Some cases lacked documentation of post-op reintroduction of ATAs. It is difficult to assess how these missing data may have impacted our findings. Finally, when this study was conceived it was intended to be performed prospectively, but this was in the period just before the global COVID-19 pandemic which forced many elective surgeries in the National Health Service (NHS) to be cancelled including TURBT.^26,27 Given the different challenges met by our participating centres, a retrospective review of practice was felt more feasible.

The difficulty of assessing the individual patient risk–benefit balance between preventing post-operative haematuria and acute TE is the overall question that arises from our study. The number of post-operative TEs in our cohort was very low, and much less frequent than post-operative haematuria. However, post-operative bleeding is typically associated with less morbidity than TE and can potentially be managed much readily with bladder irrigation, blood transfusion or even re-operation. Pre-operative individual risk stratification depending on previous thrombotic history, tumour size and likely operative time should be performed. Where patients are deemed high-risk patients for bleeding or for venous thromboembolism (VTE), specialist anticoagulation management advice from Haematology should be sought.

Conclusion

Use of non-Aspirin ATAs is associated with a significantly increased risk of haematuria following TURBT requiring emergency re-admission. Further larger and prospective studies are required to investigate perioperative ATA management patients undergoing endourological procedures, to best inform national and international guidelines.

Footnotes

Acknowledgements

The authors acknowledge Timothy Moorby, Consultant Haematologist at University Hospitals Coventry & Warwickshire NHS Trust, for haematological input into this manuscript regarding the perioperative management of ATAs; and Keunhwi Ahn, George Delves, Mohammed El-Hadi, Anil Krishan, Mahmoud Nosseir, Lahiru Siriwardena and Raghav Varma for collection of further data for final analysis.

Conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship and/or publication of this article.

Ethical approval

This study was performed as part of a multicentre Clinical Audit project and therefore did not require Research Ethics Committee approval as per the guidance outlined by the NHS Health Research Authority.

Informed consent

None required.

Guarantor

P.B.S.

Contributorship

P.B.S. researched literature, conceived the study, developed the protocol and wrote the first draft of the manuscript. All authors were involved in data collection, reviewed and edited the manuscript, and approved the final version of the manuscript.

ORCID iDs

Piyush B Sarmah

Abi Kanthabalan

Donald Nyanhongo

References

The Intercollegiate Surgical Curriculum Programme. Urology curriculum. The intercollegiate surgical curriculum programme, https://www.iscp.ac.uk/media/1112/urology-curriculum-aug-2021-approved-oct-20v2.pdf (2021, accessed 28 February 2022).

Gray

Day

Briggs

TWR

, et al. Transurethral resection of bladder tumour as day-case surgery: Evidence of effectiveness from the UK Getting it Right First Time (GIRFT) programme. J Clin Urol 2020; 13(3): 221–227.

Wong

MCS

Fung

FDH

Leung

, et al. The global epidemiology of bladder cancer: A joinpoint regression analysis of its incidence and mortality trends and projection. Sci Rep 2018; 8(1): 1–12.

Lenis

Lec

Chamie

, et al. Bladder cancer: A review. JAMA 2020; 324(19): 1980–1991.

Tikkinen

Cartwright

Gould

, et al. EAU guidelines on thromboprophylaxis in urological surgery. Arhnem: European Association of Urology, 2020.

Bartlett

Mauck

Stephenson

, et al. Perioperative venous thromboembolism prophylaxis. Mayo Clin Proc 2020; 95(12): 2775–2798.

Laymon

Harraz

Elshal

, et al. Venous thromboembolism after radical cystectomy and urinary diversion: A single-center experience with 1737 consecutive patients. Scand J Urol 2019; 53(6): 392–397.

Vinogradova

Coupland

Hill

, et al. Risks and benefits of direct oral anticoagulants versus warfarin in a real world setting: Cohort study in primary care. BMJ 2018; 362: k2505.

Lip

GYH

. Atrial fibrillation in 2011: Stroke prevention in AF. Nat Rev Cardiol 2011; 9(2): 71–73.

10.

Alfirevic

Downing

Daras

, et al. Has the introduction of direct oral anticoagulants (DOACs) in England increased emergency admissions for bleeding conditions? A longitudinal ecological study. BMJ Open 2020; 10(5): e033357.

11.

Holster

Valkhoff

Kuipers

, et al. New oral anticoagulants increase risk for gastrointestinal bleeding: A systematic review and meta-analysis. Gastroenterology 2013; 145(1): 105–112.

12.

Peces

Aguilar

Vega

, et al. Medical therapy with tranexamic acid in autosomal dominant polycystic kidney disease patients with severe haematuria. Nefrologia 2012; 32(2): 160–165.

13.

Yao

Zhou

, et al. Treatment of persistent gross hematuria with tranexamic acid in autosomal dominant polycystic kidney disease. Kidney Blood Press Res 2017; 42(1): 156–164.

14.

Jendoubi

Malouch

Bouzouita

, et al. Safety and efficacy of intravenous tranexamic acid in endoscopic transurethral resections in urology: Prospective randomized trial. Prog Urol 2017; 27(16): 1036–1042.

15.

Moharamzadeh

Ojaghihaghighi

Amjadi

, et al. Effect of tranexamic acid on gross hematuria: A pilot randomized clinical trial study. Am J Emerg Med 2017; 35(12): 1922–1925.

16.

Mazzitelli

Quek

, et al. Tranexamic acid is an active site inhibitor of urokinase plasminogen activator. Blood Adv 2019; 3(5): 729–733.

17.

Ghali

Moses

Raffin

, et al. What factors are associated with unplanned return following transurethral resection of bladder tumor? An analysis of a large single institution’s experience. Scand J Urol 2016; 50(5): 370–373.

18.

Nieder

Meinbach

Kim

, et al. Transurethral bladder tumor resection: Intraoperative and postoperative complications in a residency setting. J Urol 2005; 174(6): 2307–2309.

19.

Prader

De Broca

Chevallier

, et al. Outcome of transurethral resection of bladder tumor: Does antiplatelet therapy really matter? Analysis of a retrospective series. J Endourol 2017; 31(12): 1284–1288.

20.

Fukuhara

Kakizaki

Kaneko

, et al. Safety and efficacy of continuous administration of antithrombotic drugs during transurethral resection of bladder tumors. Nihon Hinyokika Gakkai Zasshi 2017; 108(1): 17–23.

21.

Konishi

Washino

Nakamura

, et al. Risks and complications of transurethral resection of bladder tumors in patients receiving antiplatelet and/or anticoagulant therapy: A retrospective cohort study. BMC Urol 2017; 17(1): 1–7.

22.

Wada

Okazaki

Kobayashi

, et al. Perioperative complications of transurethral resection of bladder tumor in patients receiving antithrombotic therapy. Hinyokika Kiyo 2014; 60(11): 531–535.

23.

Chakravarti

MacDermott

Transurethral resection of the prostate in the anticoagulated patient. Br J Urol 1998; 81(4): 520–522.

24.

D’souza

Verma

Holmium laser transurethral resection of bladder tumor: Our experience. Urol Ann 2016; 8(4): 439–443.

25.

Zhang

Wang

Mao

, et al. Transurethral en bloc resection with bipolar button electrode for non-muscle invasive bladder cancer. Int Urol Nephrol 2018; 50(4): 619–623.

26.

NHS,England NHS and Improvement. Letter to chief executives of all NHS trusts and foundation trusts, CCG accountable officers, GP practices and primary care networks, and providers of community health services, 2020, https://www.england.nhs.uk/coronavirus/wp-content/uploads/sites/52/2020/04/second-phase-of-nhs-response-to-covid-19-letter-to-chief-execs-29-april-2020.pdf

27.

BBC News. Coronavirus: Trust stops non-urgent operations amid second wave fears. BBC News, 18th November 2020, www.bbc.co.uk/news/uk-england-leicestershire-54989890 (accessed 28 February 2022).