Abstract
Background/Aim: The aim of the study was to evaluate the risk of venous thromboembolism (VTE) after robot-assisted radical prostatectomy (RARP) and discuss whether a uniform prophylaxis for VTE after radical prostatectomy is also suitable for robotic surgery. On this context, we investigated the incidence and risk factors of VTE, including asymptomatic events, after RARP compared to transurethral resection of bladder tumor (TUR-BT). Patients and Methods: The participants were 209 patients with localized prostate cancer who underwent RARP, and 93 patients who underwent TUR-BT as controls. The incidence and risk factors of VTE, including deep vein thrombosis and pulmonary embolism, were systemically investigated seven days after surgery using contrast-enhanced computed tomography. Results: Of the 209 RARP patients, 5.7% (12/209) patients had VTE. All events were asymptomatic and the incidence of VTE was not significantly different between the two surgeries (p=0.90). In multivariate analyses, neoadjuvant androgen deprivation therapy (ADT) (p=0.006), D-dimer value on postoperative day 1 (p=0.001) and lymphocele formation (p=0.043) were significantly associated with VTE after RARP. Conclusion: The risk of VTE after RARP might not be so high and uniform prophylaxis might not be suitable for RARP because it might be the same as that after transurethral resection for bladder tumors. However, neoadjuvant ADT, high D-dimer levels after surgery and lymphocele formation should be noted as risk factors of VTE after RARP.
Robot-assisted radical prostatectomy (RARP) has become one of the most common surgical therapies for patients with localized prostate cancer and has recently been adopted worldwide (1-3). RARP has been previously reported to have lower invasiveness compared to open radical prostatectomy (ORP), in terms of lower risks of blood transfusion, less usage of perioperative analgesia, shorter duration of hospital stay and lower rates of surgery-associated complications (4, 5).
In the American Urological Association (AUA) best practice statement, radical prostatectomy for prostate cancer, including RARP, was considered to have a high risk or the highest risk for venous thromboembolism (VTE) (6). In this statement, in patients without a high bleeding risk, anticoagulant therapy (8-hourly subcutaneous administration of 5000 units heparin or daily subcutaneous administration of 40 mg enoxaparin) or combined use of intermittent pneumatic compression and anticoagulation therapy was recommended as prophylaxis for VTE (6). Moreover, prophylactic methods stratified according to the type of surgery, such as RARP, laparoscopic radical prostatectomy (LRP) or ORP, were not clearly described because of the lack of prospective data (6). However, previous reports have shown varying incidences of symptomatic VTE after RARP, LRP and ORP, ranging 0.2-1.8% (1, 7-9), 0.6-0.9% (9, 10) and 1.3-6.2% (11, 12), respectively. These data suggest that RARP might also be a less-invasive surgery in terms of the risk of VTE. However, the above data focused on symptomatic VTE, and not asymptomatic VTE.
Since postoperative asymptomatic VTE might increase the risk of mortality (13, 14), a detailed study including both symptomatic and asymptomatic VTE is needed to evaluate the precise incidence of VTE after RARP. However, to the best of our knowledge, thorough investigation of VTE, including deep venous thrombosis (DVT) and pulmonary embolism (PE), after RARP has never been conducted. In this research, we investigated the precise incidence and possible risk factors for VTE after RARP, as compared to transurethral resection of bladder tumor (TUR-BT). Moreover, we discussed whether uniform prophylaxis for VTE is required after RARP (6).
Patients and Methods
Study population and study design. At our Institution, from July 2019 to November 2020, 220 patients with clinical localized prostate cancer underwent RARP performed by one of six surgeons. Of these, 10 patients with renal dysfunction (eGFR <60 ml/min/1.73m2) and one patient who had VTE before surgery according to preoperative CECT were excluded from analyses. As a result, 209 patients who underwent RARP were prospectively enrolled in the study (Figure 1). As controls, 93 patients who underwent TUR-BT during the same period were also prospectively enrolled in this study, for comparison of differences in the incidence of VTE following RARP versus TUR-BT. In all patients, age, body mass index, medication with oral anticoagulants or antiplatelet agents, Charlson Comorbidity Index, neoadjuvant androgen deprivation therapy (ADT), lymph node dissection, surgical duration, estimated blood loss, D-dimer value on postoperative day (POD) 1, prostate volume and lymphocele formation after RARP were evaluated using multivariate analyses, as possible factors related to VTE after RARP. These variables were selected based on previous research reporting factors related to VTE after radical prostatectomy or from our clinical experience (8, 9, 15-17). The primary outcome measures were differences in the postoperative incidence of VTE (DVT and/or PE), DVT alone and PE alone after RARP and TUR-BT. The secondary outcome measures were risk factors for VTE after RARP. The study protocols were approved by the Ethics Committee of our Institution (clinical trial registration number 2019-093) and conformed to the ethical guidelines of the 1975 Declaration of Helsinki. Informed consent was obtained from all the study participants.
Flow chart of selection of patients who underwent RARP. Ten patients with renal dysfunction (eGFR <60 ml/min/1.73 m2) and one patient who had VTE before surgery, diagnosed by preoperative CECT, were excluded. The remaining 209 patients were included in the present study. RARP, Robot-assisted radical prostatectomy; VTE, venous thromboembolism; CECT, contrast-enhanced computed tomography.
Methods of evaluating VTE. In the present study, to detect not only DVT, but also PE, whole-body contrast-enhanced CT (CECT), including CT angiography and venography, with a CT slice thickness of 5.0 mm was used. All diagnoses of VTE were dependent on radiographic image interpretation by radiologists. The time point of detection of VTE was decided based on the results of a previous multi-institutional cohort study including 5,951 participants, which reported that the median times from surgery to development of symptomatic VTE after LRP or RARP were within 10 and 11 days, respectively (9). Hence, CECT was performed 7 days after RARP and TUR-BT in this study. Representative images of DVT and PE on CECT are shown in Figure 2a and b, respectively.
Representative cases of DVT (a) and PE (b) in this study. The yellow dotted circles show DVT (a) and PE (b) in representative cases in this study. DVT, Deep venous thrombosis; PE, pulmonary embolism.
Surgical procedures of RARP and TUR-BT. RARP was performed via a transperitoneal approach in the lithotomy with Trendelenburg position. In all the patients, sequential compression devices and compression stockings were placed on their lower limbs before surgery for VTE prophylaxis. The above placements were maintained until full ambulation. In this study, low-molecular-weight heparin for prophylaxis of VTE was not used postoperatively, in order to avoid increasing the risk of postoperative bleeding. TUR-BT was performed in the lithotomy without Trendelenburg position. All TUR-BT patients received VTE prophylaxis in the same manner as patients who underwent RARP. The preoperative rest period of the anticoagulant or antiplatelet agent varied from 1 to 7 days, and the time point of resumption it was mostly POD 2 or 3 for both patients who underwent RARP and TUR-BT. Several of the patients with prostate cancer had received neoadjuvant ADT that was prescribed before the patient initial visit at our Institution. Therefore, the types of neoadjuvant ADT were diverse, including anti-androgen therapy, gonadotropin-releasing hormone agonist or antagonist therapy, and combined therapy, and therapy duration also varied.
Statistical analysis. The Pearson’s Chi-square test and the Mann-Whitney U-test were used for univariate analyses, and logistic regression analysis was used for multivariate analyses. The receiver operating characteristic (ROC) curve was created using the Youden index method to investigate cut-off values. All statistical analyses were performed using the SPSS software package version 26 (SPSS, Chicago, IL, USA). p<0.05 was considered statistically significant. All data were collected from the electronic health record system of our institution.
Results
Table I shows a comparison of patient characteristics between patients who underwent RARP and TUR-BT. Age (p<0.001), medication with oral anticoagulant or antiplatelet agents (p=0.012), and surgical duration (p<0.001) were significantly different between RARP and TUR-BT groups. As the primary outcome measures, we investigated the incidence of VTE, DVT and PE after RARP and TUR-BT. Of the patients who underwent RARP, 5.7% (12/209), 2.9% (6/209) and 3.8% (8/209) had VTE (DVT and/or PE), only DVT and only PE, respectively (Figure 3a). Of the patients who underwent TUR-BT, 5.4% (5/93), 3.2% (3/93) and 3.2% (3/93) had VTE (DVT and/or PE), only DVT and only PE, respectively (Figure 3b). The incidence of VTE, DVT and PE were not significantly different between the RARP and TUR-BT groups (p=0.90, 0.87 and 0.80, respectively) (Table II). All VTE events were asymptomatic, but all patients with VTE were treated with oral anticoagulant therapy (without low-molecular-weight heparin). None of the asymptomatic VTE events led to a severe condition or fatality during the follow-up period of 11-36 months (mean=23.1 months).
Characteristics between patients who underwent robot-assisted radical prostatectomy (RARP) and transurethral resection of bladder tumor (TUR-BT).
Venn diagrams indicating the rates of VTE, DVT and PE after (a) RARP and (b)TUR-BT. (a) The rates of VTE, DVT and PE after RARP were 5.7% (12/209), 2.9% (6/209) and 3.8% (8/209), respectively. (b) The rates of VTE, DVT and PE after TUR-BT were 5.4% (5/93), 3.2% (3/93) and 3.2% (3/93), respectively. VTE, Venous thromboembolism; DVT, deep venous thrombosis; PE, pulmonary embolism; RARP, robot-assisted radical prostatectomy; TUR-BT, transurethral resection of bladder tumor.
Comparison of the incidence of postoperative venous thromboembolism (VTE) including deep venous thrombosis (DVT) and pulmonary embolism (PE), and PE between patients who underwent robot-assisted radical prostatectomy (RARP) and transurethral resection of bladder tumor (TUR-BT).
For the secondary outcome measures, we investigated the risk factors of VTE after RARP. Table III and Table IV show a comparison of patient characteristics, preoperative clinical parameters and perioperative parameters between patients with and without VTE after RARP. In this study, none of the patients had a past history of VTE. In univariate analyses, neoadjuvant ADT (p=0.009), D-dimer level on POD1 (p=0.001) and prostate volume (p=0.031) were statistically significantly associated with VTE after RARP (Table III and Table IV). In multivariate analyses, as shown in Table V, neoadjuvant ADT [odds ratio (OR)=11.676; 95% confidence interval (CI)=2.022-67.411; p=0.006], D-dimer level on POD1 (OR=1.319; CI=1.125-1.548; p=0.001) and lymphocele formation (OR=16.130; CI=1.098-236.953; p=0.043) were significantly associated with VTE after RARP.
Patient characteristics and preoperative clinical parameters of patients with and without venous thromboembolism (VTE) after robot-assisted radical prostatectomy (RARP).
Perioperative parameters of patients with and without venous thromboembolism (VTE) after robot-assisted radical prostatectomy (RARP).
Multivariate analyses of predictive factors of venous thromboembolism (VTE) after robot-assisted radical prostatectomy (RARP).
ROC analysis, performed to elucidate the optimal cut-off values of D-dimer on POD1 for predicting VTE after RARP, indicated that a cut-off value of 4.2 μg/ml (p=0.001) yielded the best accuracy for predicting VTE after RARP (Figure 4).
Receiver operating characteristic curve for calculating the cut-off value of D-dimer on postoperative day 1 for predicting VTE after RARP. The area under curve, sensitivity, and specificity of the cutoff D-dimer value of 4.2 μg/ml (black arrow) for predicting VTE were 0.78, 0.75 and 0.76, respectively. VTE, Venous thromboembolism; RARP, robot-assisted radical prostatectomy.
Discussion
In the present study, we investigated the incidence of VTE after RARP. Of patients who underwent RARP, 5.7% (12/209), 2.9% (6/209) and 3.8% (8/209) had postoperative VTE, DVT and PE, respectively. All the VTE events were asymptomatic and did not lead to a severe condition or fatality during the follow-up period, and the incidences of VTE, DVT and PE were not significantly different between RARP and TUR-BT. In multivariate analyses, neoadjuvant ADT, D-dimer level on POD1 and lymphocele formation after RARP were significantly associated with VTE after RARP.
Several previous studies have reported the incidence of DVT and PE after RARP as 0.1-1.2% and 0.2-0.5%, respectively (1, 7-9). However, these studies only focused on symptomatic VTE (1, 7-9), and no study reported the precise incidence of VTE, including asymptomatic events, after RARP. The incidence of VTE in the present study was higher than in the above-mentioned studies (1, 7-9). The reason for the higher detection rate of VTE in our study compared to other reports might be that we used CECT to thoroughly detect small, asymptomatic blood clots. Fortunately, none of the asymptomatic VTE events in our study led to severe condition or fatality during the observation period. One of the reasons for this could be that oral anticoagulant therapy was commenced immediately after detecting the small blood clots.
In this study, the incidence of VTE, DVT and PE was not significantly different between RARP and TUR-BT groups, although RARP was classified as having a higher risk for causing VTE in the AUA best practice statement (6). Comparison of the common patient variates in the two surgical groups showed that patients in the RARP group were significantly younger and the rate of preoperative oral anticoagulant or antiplatelet administration was lower, while their surgical duration was significantly prolonged. In previous reports, age and surgical duration were reported as risk factors for VTE after RARP (8, 17), while medication with oral anticoagulant or antiplatelet agents was not reported. Hence, in this study, age and the rate of oral anticoagulant or antiplatelet medication could be confounders that decreased the incidence of VTE after RARP or increased the incidence of VTE after TUR-BT. Therefore, further research with more participants and aligning these background factors between patients who underwent RARP and TUR-BT is needed.
In the AUA best practice statement, TUR-BT was considered minor surgery with a low to moderate risk of VTE, while RARP was included in the high- or highest-risk group (6). In this statement, VTE prophylaxis in the low- or moderate-risk group included early ambulation or anticoagulation therapy (i.e., 12-h subcutaneous administration of 5,000 units heparin or daily subcutaneous administration of 40 mg enoxaparin) (6). In the present study, however, the VTE prophylaxis method after RARP was different from the methods used for all the risk categories described in the AUA statement: intermittent pneumatic compression was performed for all the subjects, irrespective of whether they underwent RARP or TUR-BT, and anticoagulation therapy was not administered, to minimize the risk of postoperative bleeding. Actually, in Japan, pharmacological prophylaxis for VTE after RARP is infrequent compared to other countries (18). Yet, lack of a significant difference in the incidence of VTE between after RARP and after TUR-BT with the same VTE prophylaxis suggests that the risk classification of RARP can be downgraded, and a uniform VTE prophylaxis strategy for all patients undergoing radical prostatectomy might not be suitable for those undergoing RARP.
Regarding the risk factors of VTE after RARP, to the best of our knowledge, no study has reported neoadjuvant ADT as a risk factor for postoperative VTE. However, in several studies, ADT itself has been reported to increase the risk of VTE (19-21) by a mechanism involving alteration of serum lipoproteins and promotion of obesity and increased arterial stiffness (22). Moreover, other studies have reported that the androgen receptor on megakaryocytic cells regulates platelet activation and androgen inhibits arterial thrombosis (23, 24). In the present study, therefore, neoadjuvant ADT might have altered some metabolism mechanisms of patients as the above to be prone to get VTE, and subsequently surgery might be a trigger of VTE appearance.
D-dimer levels have been used to rule out a diagnosis of VTE (25, 26), and high D-dimer values are reported to be associated with VTE events (27). Our study showed that a D-dimer value on POD1 of more than 4.2 μg/ml was a predictive factor of VTE after RARP.
Lymphocele formation was previously reported to be associated with VTE after radical prostatectomy by impairing pelvic venous flow (15). In the present study as well, lymphocele formation after RARP was associated with the risk of VTE. Thus, although lymph node dissection was not associated with VTE after RARP in this analysis, the results suggest that attention might be needed in patients who undergo pelvic lymph node dissection to assess the development of lymphocele.
Previously, several risk factors of VTE after RARP other than the above factors have been reported: e.g., body mass index, blood transfusion and surgical duration (8). Moreover, as a recent topic, COVID19 was also a risk factor of VTE (28). Anyway, including the risk factors in this study and others, patients with risk factors should be carefully observed about VTE after RARP.
Our study has several limitations. First, the sample size was relatively small. Second, it is unclear whether the time point of CT examination in this study was appropriate. Since there are no reports about the precise time from surgery to development of asymptomatic VTE, we selected the time point of 7 days after surgery with reference to a multi-institutional cohort study that focused on symptomatic VTE (9). Finally, the type and duration of preoperative ADT, and type and duration of discontinuation of oral anticoagulant or antiplatelet therapy varied in the present study. Therefore, their effect on VTE could not be precisely evaluated.
This systemic investigation of VTE after RARP using CECT showed that all the VTE events were asymptomatic and the incidence of VTE after RARP was not significantly different from that of VTE after TUR-BT, which is considered a minor surgery with a low risk of VTE. Therefore, the risk of VTE after RARP might not be so high, and uniform prophylaxis of VTE after radical prostatectomy according to the AUA best practice statement might not be suitable for RARP. However, neoadjuvant ADT, high D-dimer levels after surgery and lymphocele formation should be noted as risk factors of VTE after RARP.
Acknowledgements
The Authors would like to thank to the following individuals for supporting our research: Hiroshi Kameoka and Masato Kobayashi.
Footnotes
Authors’ Contributions
Masao Kataoka, Yu Endo, Kei Yaginuma, Akihisa Hasegawa, Syunta Makabe, Yuki Harigane, Kanako Matsuoka, Seiji Hoshi, Junya Hata, Yuichi Sato, Hidenori Akaihata, Soichiro Ogawa, Ishii Shirou and Hiroshi Ito collected, evaluated, and analyzed the clinical data. Satoru Meguro drafted the manuscript. Supervision, project administration, Nobuhiro Haga and Yoshiyuki Kojima.
Conflicts of Interest
The Authors declare no conflicts of interest.
- Received June 26, 2022.
- Revision received July 29, 2022.
- Accepted August 6, 2022.
- Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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