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Article of the week: The role of extended venous thromboembolism prophylaxis for major urological cancer operations

Every week, the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an editorial written by a prominent member of the urology community, a video prepared by the authors and a visual abstract; we invite you to use the comment tools at the bottom of each post to join the conversation. 

If you only have time to read one article this week, it should be this one.

The role of extended venous thromboembolism prophylaxis for major urological cancer operations

Rishi Naik*, Indrajeet Mandal*, Alexander Hampson, Tim Lane, Jim Adshead, Bhavan Prasad Rai and Nikhil Vasdev†§

*Faculty of Medical Sciences, UCL Medical School, University College London, London, Department of Urology, Lister Hospital, Stevenage, Department of Urology, Freeman Hospital, Newcastle upon Tyne and §School of Life and Medical Sciences, University of Hertfordshire, Hatfield, UK

Rishi Naik and Indrajeet Mandal are joint first authors.

Abstract

Objectives

Venous thromboembolism (VTE), consisting of both pulmonary embolism (PE) and deep vein thromboses (DVT), remains a well‐recognised complication of major urological cancer surgery. Several international guidelines recommend extended thromboprophylaxis (ETP) with LMWH, whereby the period of delivery is extended to the post‐discharge period, where the majority of VTE occurs. In this literature review we investigate whether ETP should be indicated for all patients undergoing major urological cancer surgery, as well as procedure specific data that may influence a clinician’s decision.

Methods

We performed a search of six databases (PubMed, Cochrane, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, and British Nursing Index (BNI)) from inception to June 2019, for studies looking at adult patients who received VTE prophylaxis after surgery for a major urological malignancy.

Results

Eighteen studies were analysed. VTE risk is highest in open and robotic Radical Cystectomy (RC) (2.6–11.6%) and ETP demonstrates a significant reduction in risk of VTE, but not a significant difference in Pulmonary Embolism (PE) or mortality. Risk of VTE in open Radical Prostatectomy (RP) (0.8–15.7%) is comparable to RC, but robotic RP (0.2–0.9%), open partial/radical nephrectomy (1.0–4.4%) and robotic partial/radical nephrectomy (0.7–3.9%) were lower risk. It has not been shown that ETP reduces VTE risk specifically for RP or nephrectomy.

Conclusion

The decision to use ETP is a fine balance between variables such as VTE incidence, bleeding risk and perioperative morbidity/mortality. This balance should be assessed for each specific procedure type. While ETP still remains of net benefit for open RP as well as open and robotic RC, the balance is closer for minimally invasive RP as well as radical and partial nephrectomy. Due to a lack of procedure specific evidence for the use of ETP, adherence with national guidelines remains poor. Therefore, we advocate further studies directly comparing ETP vs standard prophylaxis, for specific procedure types, in order to allow clinicians to make a more informed decision in future.

Editorial: How long is long enough for pharmacological thromboprophylaxis in urology?

Each year, millions of patients who undergo urological surgery incur the risk of deep vein thrombosis and pulmonary embolism, together referred to as venous thromboembolism (VTE), and major bleeding. Because pharmacological prophylaxis decreases the risk of VTE, but increases the risk of bleeding, and because knowledge of the magnitude of these risks remains uncertain, both clinical practice and guideline recommendations vary widely [1]. One of the uncertainties is the recommended duration of pharmacological thromboprophylaxis.

In this issue of the BJUI, Naik et al. [2] provide an up‐to‐date review that summarises the articles that examined extended thromboprophylaxis in patients with cancer who underwent radical prostatectomy (RP), radical cystectomy (RC) or nephrectomy. The outcomes on which they focussed include risks of VTE, bleeding, renal failure and mortality – all potentially influenced by whether or not patients receive extended prophylaxis.

After screening >3500 articles, the authors included 18 studies, none of them randomised controlled trials (RCTs) [2]. They found that VTE risk is highest in open and robot‐assisted RC, and that, based on observational studies, extended thromboprophylaxis significantly reduces the risk of VTE relative to shorter duration prophylaxis. Evidence suggested that robot‐assisted RP, as well as both open and robot‐assisted partial and radical nephrectomies, incur lower VTE risk than RCs or open RP. They did not find studies comparing extended prophylaxis to standard prophylaxis for RPs or nephrectomies [2].

Overall, these findings are consistent with systematic reviews that estimated the procedure‐ and patient risk factor‐specific risks for 20 urological cancer procedures [3]. As these reviews suggested substantial procedure‐specific differences in the VTE risk estimates, the European Association of Urology (EAU) Guidelines provided separate recommendations for each procedure [4]. For urological (as well as gastrointestinal and gynaecological) patients, the National Institute for Health and Care Excellence (NICE) Guidelines suggest to ‘consider extending pharmacological VTE prophylaxis to 28 days postoperatively for people who have had major cancer surgery in the abdomen’ [5]. Because of variation in both bleeding and thrombosis risks across procedures, this advice is appropriate for some procedures and misguided for others. For instance, the procedure‐specific EAU Guidelines recommend extended VTE prophylaxis for open RC but not for robot‐assisted RP without lymphadenectomy [4].

The review by Naik et al. [2] identified the lack of urology‐specific studies comparing the in‐hospital‐only prophylaxis to extended prophylaxis. The few included studies were observational with considerable limitations (e.g. limited adjustment for possible confounders).

A recent update of a Cochrane review compared the impact of extended thromboprophylaxis with low‐molecular‐weight heparin (LMWH) for at least 14 days to in‐hospital‐only prophylaxis in abdominal or pelvic surgery procedures [6]. The authors identified seven RCTs (1728 participants) evaluating extended thromboprophylaxis with LMWH and generated pooled estimates for the incidence of any VTE (symptomatic or asymptomatic) after major abdominal or pelvic surgery of 13.2% in the control group compared with 5.3% in the patients receiving extended out‐of‐hospital LMWH (odds ratio [OR] 0.38, 95% CI 0.26–0.54).

Most events were asymptomatic, although the incidence of symptomatic VTE was also reduced from 1.0% in the in‐hospital‐only group to 0.1% in patients receiving extended thromboprophylaxis (OR 0.30, 95% CI 0.08–1.11). The authors reported no persuasive difference in the incidence of bleeding complications within 3 months of surgery (defined as major or minor bleeding according to the definition provided in the individual studies) between the in‐hospital‐only group (2.8%) and extended LMWH (3.4%) group (OR 1.10, 95% CI 0.67–1.81).

These findings are consistent with our own modelling study that demonstrated an approximately constant hazard of VTE up to 4 weeks after surgery [7]. That study also found that bleeding risk, by contrast, is concentrated in the first 4 days after surgery [7] (Fig.1). Using these findings, the EAU Guidelines suggest for patients in whom pharmacological prophylaxis is appropriate, extended pharmacological prophylaxis for 4 weeks [4]. Consistent with these recommendations, Naik et al. [2] found that 15 studies of 18 included in their review recommended extended prophylaxis.

Fig.1 Proportion of cumulative risk (%) of venous thromboembolism (VTE) and major bleeding by week since surgery during the first 4 postoperative weeks. Reproduced from: Tikkinen et al. [7].

(This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (https://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.)

 

Overall, as shown also by this review [2], the evidence base for urological thromboprophylaxis is limited. Although current evidence supports extended prophylaxis, definitively establishing the optimal duration of thromboprophylaxis will require large‐scale RCTs. Other unanswered key questions include: baseline risks of various procedures, timing of prophylaxis, patient risk stratification, as well as effectiveness of direct oral anticoagulants. In the meanwhile, suggesting extended duration to patients whose risk of VTE is sufficiently high constitutes a reasonable evidence‐based approach to VTE prophylaxis.

by Kari A.O. Tikkinen and Gordon H. Guyatt

 

References

  1. Violette PDCartwright RBriel MTikkinen KAGuyatt GH Guidelines of guidelines: thromboprophylaxis for urological surgery. BJU Int 2016118351– 8
  2. Naik RMandal IHampson A et al. The role of extended venous thromboembolism prophylaxis for major urological cancer operations. BJU Int 2019; 124: 935-44
  3. Tikkinen KACraigie SAgarwal A et al. Procedure‐specific risks of thrombosis and bleeding in urological cancer surgery: systematic reviews and meta‐analyses. Eur Urol 201873242– 51
  4. Tikkinen KACartwright RGould MK et al. EAU Guidelines on Thromboprophylaxis in Urological Surgery, 2017. European Association of Urology, 2018. Accessed November 2019
  5. National Institute for Health and Care Excellence (NICE)Venous Thromboembolism in over 16s: reducing the risk of hospital‐acquired deep vein thrombosis or pulmonary embolism. NICE guideline [NG89]. London: NICE, 2018. Accessed November 2019
  6. Felder SRasmussen MSKing R et al. Prolonged thromboprophylaxis with low molecular weight heparin for abdominal or pelvic surgery. Cochrane Database Syst Rev 20193CD004318
  7. Tikkinen KAAgarwal ACraigie S et al. Systematic reviews of observational studies of risk of thrombosis and bleeding in urological surgery (ROTBUS): introduction and methodology. Syst Rev 201423150. DOI: 10.1186/2046‐4053‐3‐150.

 

Video: Role of extended venous thromboembolism prophylaxis for major urological cancer operations

The role of extended venous thromboembolism prophylaxis for major urological cancer operations

Read the full article

Abstract

Objectives

Venous thromboembolism (VTE), consisting of both pulmonary embolism (PE) and deep vein thromboses (DVT), remains a well‐recognised complication of major urological cancer surgery. Several international guidelines recommend extended thromboprophylaxis (ETP) with LMWH, whereby the period of delivery is extended to the post‐discharge period, where the majority of VTE occurs. In this literature review we investigate whether ETP should be indicated for all patients undergoing major urological cancer surgery, as well as procedure specific data that may influence a clinician’s decision.

Methods

We performed a search of six databases (PubMed, Cochrane, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, and British Nursing Index (BNI)) from inception to June 2019, for studies looking at adult patients who received VTE prophylaxis after surgery for a major urological malignancy.

Results

Eighteen studies were analysed. VTE risk is highest in open and robotic Radical Cystectomy (RC) (2.6–11.6%) and ETP demonstrates a significant reduction in risk of VTE, but not a significant difference in Pulmonary Embolism (PE) or mortality. Risk of VTE in open Radical Prostatectomy (RP) (0.8–15.7%) is comparable to RC, but robotic RP (0.2–0.9%), open partial/radical nephrectomy (1.0–4.4%) and robotic partial/radical nephrectomy (0.7–3.9%) were lower risk. It has not been shown that ETP reduces VTE risk specifically for RP or nephrectomy.

Conclusion

The decision to use ETP is a fine balance between variables such as VTE incidence, bleeding risk and perioperative morbidity/mortality. This balance should be assessed for each specific procedure type. While ETP still remains of net benefit for open RP as well as open and robotic RC, the balance is closer for minimally invasive RP as well as radical and partial nephrectomy. Due to a lack of procedure specific evidence for the use of ETP, adherence with national guidelines remains poor. Therefore, we advocate further studies directly comparing ETP vs standard prophylaxis, for specific procedure types, in order to allow clinicians to make a more informed decision in future.

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Visual abstract: The role of extended venous thromboembolism prophylaxis for major urological cancer operations

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Article of the Week: Risk Factors and Timing of VTE after RC

Every Week the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

Risk factors and timing of venous thromboembolism after radical cystectomy in routine clinical practice: a population-based study

R. Christopher Doiron*, Christopher M. Booth,,§, Xuejiao Wei§ and D. Robert Siemens*,,§

 

*Department of Urology, Queens University, Kingston, ON, Canada, Department of Oncology, Queens University, Department of Public Health Sciences, Queens University, and §Division of Cancer Care and Epidemiology, QueenUniversity Cancer Research Institute, Kingston, ON, Canada
Read the full article

Objective

To describe the risk factors and timing of perioperative venous thromboembolism (VTE) and its association with survival for patients undergoing radical cystectomy (RC) in routine clinical practice.

Patients and Methods

The population-based Ontario Cancer Registry was linked to electronic records of treatment to identify all patients who underwent RC between 1994 and 2008; VTE events were identified from hospital diagnostic codes. Multivariate logistic regression analysis was used to determine the factors associated with perioperative VTE. A Cox proportional hazards regression model explored the associations between VTE and survival.

novaotw3-results

Results

Of the 3 879 patients included in the study, 3.6% (141 patients) were diagnosed with VTE at ≤1 month of their surgical admission date. This increased to 4.7% (181) at ≤2 months and 5.4% (211) at ≤3 months. In all, 55% of VTE events presented after hospital discharge. In multivariate analysis, factors associated with VTE included higher surgeon volume (P = 0.004) and increased length of hospital stay (LOS; P< 0.001). Lymph node yield and adjuvant chemotherapy were not associated with VTE. VTE was associated with an inferior cancer-specific survival [hazard ratio (HR) 1.35, 95% confidence interval (CI) 1.13–1.62] and overall survival (HR 1.27, 95% CI 1.08–1.49).

Conclusions

Over half of VTE events in RC patients occur after hospital discharge, with a substantial incidence up to 3 months after surgery. Limited actionable risk factors for VTE were identified other than LOS. In this population-based cohort, VTE was associated with inferior long-term survival.

Read more articles of the week

Editorial: RC & VTE – Are We Doing Enough?

Using a large comprehensive population-based cohort from Canada, Doiron et al. [1] present an in-depth analysis of risk factors and timing of venous thromboembolism (VTE) after radical cystectomy (RC) for bladder cancer. This report reiterates what is already known, which is that VTE after RC occurs at a non-negligible rate (5.4%) and most VTEs occur after hospital discharge (55%). VTE is an established complication in patients undergoing major oncological surgery, with some guidelines recommending 4 weeks of VTE prophylaxis after major pelvic surgery. This significant incidence of VTE after discharge highlights the potential impact of extended VTE prophylaxis for up to 28 days. Level I evidence for such practice was published more than a decade ago [2]. Yet, the uptake of these data remains low, at least in urological oncology. A recent survey-based study of pelvic cancer centres from the UK showed that only two-thirds of centres use post-discharge prophylaxis [3]. Using highly granular data, Doiron et al. [1] provide a detailed timeline of VTE occurrence after RC. They found that among patients who were diagnosed with VTE after discharge, >60% of these events occurred at ≤4 weeks of discharge. Unfortunately, there were no data on whether VTE prophylaxis was used in the study population.

The authors identified greater surgeon volume and increased length of hospital stay as risk factors for postoperative VTE, while accounting for important disease-related covariates. As mentioned by the authors, surgeon volume is most likely a surrogate for another unmeasured confounder. Higher volume surgeons, who often practice in large/academic institutions, may have increased case complexity with patients at higher risk for VTE. Additionally, such institutions may be more prone to perform diagnostic testing in high-risk patients and identify VTEs that would have otherwise gone unnoticed. A report from France found that the rate of VTE after RC was 24% in a cohort of patients who all underwent complete lower limb ultrasound, yet the vast majority (92%) were asymptomatic [4]. In other words, if you are looking for a VTE, you are more likely to find one. However, the clinical relevance of these VTEs remains unclear.

As shown from prior studies, length of stay was also found to be a risk factor for VTEs. Why does an increase in length of stay lead to a higher rate of VTE? One explanation is that patients who stay in the hospital longer are more likely to be immobilised for longer. This may explain why patients undergoing RC have higher rates of VTE than those undergoing other urological oncology procedures. However, immobilisation is a difficult variable to define or to measure. If longer immobilisation leads to increased VTE incidence, recently implemented enhanced recovery after surgery (ERAS) protocols that lead to earlier mobilisation would be expected to be associated with fewer VTEs. It is important to mention that other previously associated factors with VTE, including operative time and body mass index, which may be related to immobilisation time are not recorded in this study.

The use of neoadjuvant chemotherapy (NACT) for muscle-invasive bladder cancer has been shown to improve overall survival and is being increasingly used in RC patients. This study examined NACT as a risk factor but did not find an association. Notably, they were limited by the few patients who had received NACT. The use of chemotherapy in patients with cancer is a well-recognised risk factor for VTE [5]. It will be important in the future to continue to examine the incidence of VTE in NACT patients as this population grows.

Taken together, patients undergoing major cancer surgery have a significant risk of postoperative VTE, with evidence showing that rates of VTE are increasing over time [6]. Although guidelines for VTE prophylaxis are not uniform, this study’s findings [1] that most VTEs occur after discharge is a reason for urological surgeons to strongly consider extended VTE prophylaxis in this high-risk population.

Read the full article
Nawar Hanna and Jacqueline M. Speed

 

Division of Urological Surgery and Center for Surgery and Public Health, Brigham and Womens Hospital/Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

 

References

 

 

2 Bergqvist D, Agnelli G, Cohen AT et al. Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. Engl J Med 2002; 346: 97580

 

3 Pridgeon S, Allchorne P, Turner B, Peters J, Green J. Venous thromboembolism (VTE) prophylaxis and urological pelvic cancer surgery: a UK national audit. BJU Int 2015; 115: 2239

 

 

5 Blom JW, Vanderschoot JPM, Oostindier MJ, Osanto S, van der Meer FJM, Rosendaal FR. Incidence of venous thrombosis in a large cohort of 66,329 cancer patients: results of a record linkage study. J Thromb Haemost 2006; 4: 52935

 

6 Trinh VQ, Karakiewicz PI, Sammon J et al. Venous thromboembolism after major cancer surgery: temporal trends and patterns of care. JAMA Surg 2014; 149: 439

 

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