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Address correspondence to: Masashi Kubota, M.D., Department of Urology, Kobe City Medical Centre General Hospital, 2-1-1 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.
To assess the impact of continued perioperative anticoagulant drug administration on bleeding and complications in patients undergoing robot-assisted radical prostatectomy.
METHODS
Between January 2014 and January 2020, 620 patients with prostate cancer underwent robot-assisted radical prostatectomies and were retrospectively reviewed. Fourteen patients who discontinued antithrombotic therapy were excluded. Among the 606 included patients, 31 continued anticoagulant therapy during the perioperative phase (anticoagulant group). The anticoagulant group outcomes were compared with those of patients who continued clopidogrel and prasugrel (thienopyridine group = 13), aspirin monotherapy (aspirin group = 61), and no chronic antithrombotic agent (control group = 501). The primary outcome was the incidence of bleeding complications requiring transfusion, additional intervention, or readmission. Secondary outcomes were the incidence of thrombotic complications, estimated blood loss, and overall complication rates.
RESULTS
Among the 31 patients in the anticoagulant group, 20 (65%) used directed oral anticoagulants, 11 (35%) used warfarin, and 5 used combined aspirin. Only 1 (3%) patient in the anticoagulant group required postoperative transfusion, and none required additional interventions or readmission. No significant differences were detected between the anticoagulant and other groups (anticoagulant vs thienopyridine, aspirin, and control groups) regarding bleeding complications (3% vs 8%, P = .51; 0%, P = .34; 0.4%, P = .17, respectively), thrombotic complications (3% vs 0%, P = .70; 2%, P = .56; 0.2%, P = .11, respectively), estimated blood loss (200 vs 100 mL, P = .63; 175 mL, P = .64; 165 mL, P = .74, respectively), or other high-grade complications (6% vs 0%, P = .49; 2%, P = .26; 3%, P = .24, respectively).
CONCLUSION
Perioperative continuation of anticoagulant use is feasible for patients undergoing robot-assisted radical prostatectomy.
Recently, urologists have encountered an increasing number of prostate cancer patients with additional thrombotic comorbidities, such as stroke and heart disease. Most of these patients are prescribed antithrombotic agents, including anticoagulant and antiplatelet agents. This necessitates preoperative discussions to determine whether continuing antithrombotic therapy and the associated bleeding risk is preferable over discontinuing therapy and the risk of thrombotic complications.
As radical prostatectomy is classified as a hemorrhagic procedure,
patients with a high perioperative thromboembolism risk, such as poststroke patients and those with mechanical heart valves, are recommended to discontinue anticoagulant agents and/or receive bridging therapy with heparin derivatives.
Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines.
However, minimal information is available regarding the prophylactic efficacy of bridging therapy on preventing thromboembolism during urologic surgery; patients receiving bridging therapy during RARP have an increased risk of perioperative bleeding.
Radical prostatectomy with robot-assisted radical prostatectomy and laparoscopic radical prostatectomy under low-dose aspirin does not significantly increase blood loss.
Although these reports are limited by patient selection biases, they suggest that hemorrhagic complications following RARP are manageable, and that the perioperative continuation of aspirin use prevents thrombotic complications. However, to the best of our knowledge, the outcomes of continued perioperative anticoagulant therapy, including direct oral anticoagulant (DOAC) and warfarin during RARP, are unclear and lack evidence.
Our study, based on the minimally invasive RARP and its long-term learning curves, provides a potential third option: suppressing bleeding and thrombotic complications instead of discontinuing anticoagulant or bridging therapy.
Therefore, this study aimed to investigate the impact of continued anticoagulant (DOAC and warfarin) administration on bleeding and thrombotic complications during the perioperative period in patients undergoing RARP.
MATERIALS AND METHODS
Study Cohorts and Design
This was a retrospective, descriptive study including prospectively maintained data from the institutional database approved by our institutional review board (IRB No. zn200601). Before the study, we obtained additional institutional review board approval to collect data from patients receiving anticoagulant and antiplatelet agents who were to undergo RARP while continuing their current drug therapy during the perioperative phase (IRB No. n170102). Therefore, only patients with prescriptions for daily anticoagulant or antiplatelet agents received an explanation regarding the study risks and safety; they provided consent before continuing their current drug therapy during the perioperative phase. In this study, all patients registered in the database diagnosed with clinical T1-4, N0-1, or M0 prostate cancer who underwent RARP between January 2014 and January 2020 were screened for possible retrospective analysis. Patients were excluded from the cohort if they stopped antithrombotic therapy preoperatively for any reason, such as the following: (1) they had already been ordered to discontinue their daily antithrombotic agents by their prescribing doctor; (2) had already interrupted their preoperative medication use; (3) did not have history of vascular or thrombotic disease; or (4) did not need to continue antithrombotic agents for primary prevention.
We divided the enrolled patients who continued their antithrombotic agents in the perioperative phase into 3 groups: continued use of any anticoagulant (anticoagulant group), antiplatelet therapy including any thienopyridine type (thienopyridine group), and acetylsalicylic acid monotherapy (aspirin group). Patients without recent antithrombotic therapy were assigned to the control group (control group). Surgical outcomes and complications of the anticoagulant group were compared with those of the thienopyridine, aspirin, and control groups.
Antithrombotic Agents and Thromboembolism Prevention
In this study, the anticoagulant agents used included warfarin potassium (warfarin) and DOAC (dabigatran etexilate mesylate, rivaroxaban, apixaban, and edoxaban tosylate hydrate); the antiplatelet agents used included acetylsalicylic acid and thienopyridine type antiplatelet agents (clopidogrel, prasugrel). Patients with a history of intervention for cardiovascular disease or stroke were preoperatively referred to a specialist for perioperative continuation of these drugs. All anticoagulant and antiplatelet agents were taken on the day of surgery and restarted on postoperative day 1. For patients who continued warfarin, the prothrombin time and international normalized ratio were monitored on the day before surgery to confirm that it was within the appropriate range (<3.0). To screen for deep vein thrombosis (DVT), preoperative venous ultrasonography of the lower extremities was performed in those with abnormally high D-dimer levels in preoperative systemic evaluation. Patients routinely wore elastic leg stockings or contraction pumps during surgery to prevent DVT. Patients in the control group received subcutaneous enoxaparin sodium (2000 IU, twice daily) injections from postoperative day 1 until discharge to prevent postoperative DVT. Except in the control group, postoperative enoxaparin sodium injections were contraindicated for use in addition to antithrombotic agents. Postoperative venous ultrasonography was performed in patients who developed symptoms suspected of DVT, such as lower extremities edema.
Surgical Procedure
Intraoperative procedures were standardized and not modified in any group. RARP was performed using a 4-arm da Vinci Si, X, Xi–system (Intuitive Surgical, Sunnyvale, CA). After May 2016, total anatomic reconstruction was introduced for urethral bladder anastomosis.
Total anatomical reconstruction during robot-assisted radical prostatectomy: focus on urinary continence recovery and related complications after 1000 procedures.
Withdrawal of the urethral catheter was scheduled on postoperative day 5. One expert surgeon who had performed >400 pure laparoscopic and RARPs supervised a team of 13 surgeons (certificated staff: 3, uncertificated staff: 4, and residents: 5) who performed the surgeries associated with this study.
Data Collection Regarding Clinical and Surgical Outcomes
The extracted patient data from the prospective database included disease histories requiring treatment with anticoagulant and antiplatelet agents and in-hospital medication records of the prescription of these drugs. In addition, age, body mass index, the Charlson Comorbidity Index, oncological background (initial prostate specific antigen, clinical T stage, Gleason score, and NCCN risk classification), and perioperative information (American Society of Anesthesiologists physical status [ASA PS], total operation time, estimated blood loss, transfusions, surgeon, neurovascular bundle preservation, extended lymph node dissection, length of hospital stay, readmission, in-hospital complications, and the Clavien-Dindo grade
Total anatomical reconstruction during robot-assisted radical prostatectomy: focus on urinary continence recovery and related complications after 1000 procedures.
) were extracted. Regarding postdischarge complications, retrospective data was collected by reviewing outpatient medical records. Postdischarge patients were advised to visit our emergency department if they developed symptoms, and followed up as outpatients at 1 and 3 months after surgery. They were also asked about the development of complications and any treatment history at other hospitals.
The primary outcomes were as follows: the incidence of 90-day bleeding complications defined as any transfusion; any secondary surgical, endoscopic, or radiological procedure to treat hemorrhage; and readmission for hemorrhagic complications. High-grade complications were defined as Clavien-Dindo grade III or higher. The secondary outcomes were as follows: the incidence of 90-day thrombotic complications of Clavien-Dindo grade II or higher, intraoperative estimated blood loss, and the incidence of 90-day overall high-grade complications.
Statistical Analysis
A standard statistical software package (JMP, ver. 13; SAS Institute, Chicago, IL) was used to conduct the statistical analyses. The Mann-Whitney U and chi-square tests were used to determine the presence of significant between-group differences in the univariate analysis. A P value of <.05 was considered statistically significant.
RESULTS
The Study CONSORT (Consolidated Standards of Reporting Trials) flow diagram is shown in Figure 1. Among the 620 consecutive patients screened, 14 were excluded per the exclusion criterion of preoperative discontinuation of their antithrombotic agents. Eight of the 14 patients had no history of thrombotic disease who used aspirin only for primary prevention safely discontinued it. Three who were administered warfarin were recommended bridging therapy for unstable drug levels. One patient with a history of DVT safely completed anticoagulant therapy just before the surgery, after complete dissolution of the clot was confirmed. Two patients declined to continue their medications perioperatively. Six hundred and six patients were included in this study and were followed up until 90 days postoperatively, and all of them were available for data collection without missing value of parameters required. This included 105 patients who continued perioperative anticoagulant and/or antiplatelet agents for secondary disease prevention. The anticoagulant and antiplatelet agents used by the patients in each group are detailed in Table 1. A total of 31 patients used an anticoagulant agent; 11 (35%) used warfarin and 20 (65%) used a DOAC. Out of 31 patients, 5 continued warfarin and 100 mg of aspirin perioperatively. In the anticoagulant group, anticoagulant agents were used for the management and secondary prevention of cardiogenic embolus, postoperative cardiac valve surgery, and treatment of DVT. In contrast, aspirin and thienopyridines were mainly used for the treatment or secondary prevention of coronary artery disease and atherosclerotic cerebral infarction.
Figure 1The study CONSORT (Consolidated Standards of Reporting Trials) flow diagram. (Color version available online.)
Table 1List of continued anticoagulant and antiplatelet agents during the perioperative period of robot-assisted radical prostatectomy and comorbidities requiring antithrombotic therapy in all 4 patient groups
Parameter
Anticoagulant Group
Thienopyridine Group
Aspirin Group
Control Group
Patients, no.
31
13
61
501
Administered agents, n (%)
Anticoagulant agent
Warfarin
11 (35)
-
-
-
DOAC
20 (65)
-
-
-
Antiplatelet agent
Clopidogrel
-
11 (85)
-
-
Prasugrel
-
2 (15)
-
-
Aspirin combined (dual agents)
5 (16)
3 (23)
-
-
Aspirin monotherapy 100 mg
-
-
59 (97)
-
200 mg
-
-
2 (3)
-
History, n (%)
Cerebral infarction
5 (16)
6 (46)
13 (21)
2 (0.4)
Pulmonary embolism
3 (10)
0 (0)
0 (0)
0 (0)
Cardiac valve surgery
3 (10)
0 (0)
2 (3)
0 (0)
Deep vein thrombosis
11 (36)
1 (8)
0 (0)
0 (0)
Atrial fibrillation
14 (45)
0 (0)
5 (8)
7 (1)
Coronary artery disease
1 (3)
5 (38)
28 (46)
6 (1)
Carotid stenosis
0 (0)
2 (15)
8 (13)
0 (0)
AAA or ASO
0 (0)
0 (0)
9 (15)
3 (0.6)
AAA, aneurysm of the abdominal aorta; ASO, arteriosclerosis obliterans; DOAC, directed oral anticoagulants.
As shown in Table 2, the patients in the anticoagulant group were older (P = .007), had higher ASA PS scores (P <.001), and more severe comorbidities (P = .043) than those in the control group. Furthermore, the rate of a Charlson Comorbidity Index of 5 or more in the anticoagulant group was significantly higher than that in the aspirin group. However, there were no significant between-group differences regarding other baseline patient characteristics or surgical procedures, except for the rate of neurovascular bundle preservation in patients in the control group.
Table 2Comparison of the patient backgrounds and surgical procedures among the Anticoagulant, Thienopyridine, Aspirin, and Control groups
Parameter
Anticoagulant Group
vs
Thienopyridine Group
P
Aspirin Group
P
Control Group
P
Patients, no.
31
13
61
501
Age, median (IQR)
71 (66-76)
72 (68-76)
.85
72 (69-75)
.86
68 (65-73)
.007
ASA PS ≧3, n (%)
14 (45)
6 (46)
.65
13 (21)
.018
11 (2)
<.001
Charlson comorbidity index ≧5, n (%)
2 (6)
2 (15)
.34
4 (7)
.66
4 (0.8)
.043
BMI ≧25, median (IQR)
12 (39)
5 (38)
.63
16 (26)
.16
158 (32)
.26
NCCN high risk group, n (%)
18 (58)
7 (54)
.72
34 (56)
.51
213 (43)
.066
Expert surgeon, n (%)
9 (29)
5 (38)
.39
15 (25)
.41
126 (25)
.38
Neurovascular bundle preservation, n (%)
2 (6)
2 (15)
.34
7 (11)
.36
113 (23)
.021
Extended lymph node dissection, n (%)
9 (29)
3 (23)
.50
28 (47)
.08
201 (40)
.15
ASA PS, American Society of Anesthesiologists physical status classification; BMI, body mass index; IQR, interquartile range; NCCN, National Comprehensive Cancer Network.
The perioperative outcomes and postoperative complications observed in all groups and the comparison of those between the anticoagulant group and other groups are shown in Table 3. All patients who used anticoagulant and/or antiplatelet agents could take their drugs orally on postoperative day 1. The primary outcome (the incidence of bleeding complications) in the anticoagulant group was 3% (1 out of 31 patients), and was not significantly different compared to that in the thienopyridine, aspirin, and control groups (vs 8%, P = .51; 0%, P = .34; 0.4%, P = .17, respectively). Importantly, no patient had bleeding complications of Clavien-Dindo grade III or more and needed secondary interventions due to postoperative bleeding. Postoperative thrombotic events included acute myocardial infarction (1 patient, anticoagulant group), lung infarction (1 patient, aspirin group), and cerebral infarction (1 patient, control group). No other patients developed thrombotic complications, and there were no significant differences between the anticoagulant and other groups regarding the incidence of thrombotic complications (3% vs 0%, P = .70; 2%, P = .56; 0.2%, P = .11, respectively). Moreover, there were no significant between-group differences in estimated blood loss (200 vs 100 mL, P = .63; 175 mL, P = .64; 165 mL, P = .74, respectively), or 90-day rates of high-grade overall complications (6% vs 0%, P = .49; 2%, P = .26; 3%, P = .24, respectively), despite the patients in the anticoagulant group being older and having a higher ASA PS. Although only 1 patient needed postoperative transfusion in the anticoagulant group due to a decrease in the hemoglobin level, they did not have any hemorrhage or bleeding source when examined using contrast-enhanced computed tomography. However, this patient discontinued his DOAC until the hemoglobin level recovered. The other patient with high-grade complication in the anticoagulant group needed emergency operation for postoperative port site hernia. As a result of these complications, only 1 patient in the anticoagulant group required a temporary postoperative interruption in antithrombotic therapy.
Table 3Comparison of the complications and surgical outcomes among the Anticoagulant, Thienopyridine, Aspirin, and Control groups
Parameter
Anticoagulant Group
vs
ThienopyridineGroup
P
Aspirin Group
P
Control Group
P
Patients, no.
31
13
61
501
Bleeding complication, n (%)
1 (3)
1 (8)
.51
0 (0)
.34
2 (0.4)
.17
Transfusion, n (%)
1 (3)
1 (8)
.51
0 (0)
.34
2 (0.4)
.17
Secondary procedure, n (%)
0 (0)
0 (0)
1.00
0 (0)
1.00
0 (0)
1.00
Readmission for hemorrhage, n (%)
0 (0)
0 (0)
1.00
0 (0)
1.00
0 (0)
1.00
Thrombotic complication, n (%)
1 (3)
0 (0)
.70
1 (2)
.56
1 (0.2)
.11
Overall complications, n (%)
9 (29)
4 (31)
.69
11 (18)
.17
88 (18)
.09
High-grade complications, n (%)
2 (6)
0 (0)
.49
1 (2)
.26
14 (3)
.24
Operation time, median, min (IQR)
267 (194-317)
260 (219-357)
.77
297 (235-349)
.11
295 (245-356)
.10
Estimated blood loss, median, mL (IQR)
200 (50-450)
100 (90-350)
.63
175 (50-351)
.64
165 (50-400)
.74
Hemoglobin deficit, median, mg/dL (IQR)
2.1 (1.7-2.7)
2.2 (1.9-3.1)
.67
2.1 (1.5-2.5)
.68
2.2 (1.6-2.8)
.85
Postoperative discontinuation of antithrombotic therapy, n (%)
In this study, patients who continued anticoagulant therapies during the perioperative period did not experience high-grade hemorrhagic complications that needed a secondary procedure, or readmission due to bleeding complications; only 1 patient needed a postoperative transfusion. One patient experienced a thrombotic complication in the anticoagulant group. Moreover, these patients did not demonstrate any significant differences in the incidence of bleeding or thrombotic outcomes when compared to patients using antiplatelet agents or no antithrombotic agents.
To our knowledge, this is the first study investigating perioperative continuation of anticoagulant agents during RARP. The purpose of perioperative continued anticoagulant agent use is to avoid the incidence of fatal thrombosis including cerebral, myocardial, and lung infarctions caused by instability of the coagulation fibrinolytic system. However, the current recommended heparin bridging therapy is associated with increased bleeding,
instability of drug concentration due to switching, hypercoagulability during intraoperative withdrawal, and the stress of injection pain and hospital access. Although aspirin is widely indicated and used for secondary prevention of noncardiogenic cerebral infarction (eg, lacunar infarction, atherothrombotic infarction), as well as primary and secondary prevention of acute coronary syndromes (eg, postoperative percutaneous coronary intervention),
anticoagulant agents are recommended alone or in combination with antiplatelet agents in patients with cardiogenic cerebral infarction, acute coronary syndromes with high risk of thrombosis (eg, paroxysmal and chronic atrial fibrillation, myocardial infarction with left atrial or ventricular thrombus, cases complicated by pulmonary thromboembolism, prosthetic valves), and treatment of DVT.
AHA/ACCF Secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation.
As patients who are administered anticoagulant agents are considered to be at higher risk of perioperative embolism than those taking aspirin alone, all included patients needed to be stratified and compared according to the type of continued antithrombotic agents in this study. In robot-assisted partial nephrectomy, although perioperative continuation of aspirin is considered safe, clopidogrel increases the risk of bleeding.
The present study also consistent for the result for the safety of the perioperative continuation of aspirin in patients undergoing RARP.
In our study, all screened patients were routinely considered to continue using their anticoagulant and antiplatelet agents. As a result, among the 110 patients who used these drugs for secondary prevention of thrombotic diseases, 105 (95.5%) could continue using them during the perioperative phase. Among them, 31 patients in the anticoagulant group demonstrated only 3% transfusion rate and did not need secondary procedure for bleeding. Based on these outcomes, we hypothesized that RARP on continued anticoagulation is feasible with adequate control of bleeding complications; this study becomes the first step in proposing a novel option, instead of discontinuing anticoagulants, bridging therapy should be considered in perioperative management of prostate cancer patients with thrombotic diseases.
The incidence of perioperative thrombosis in the control group was excellent, with the benefits of screening and prevention (1 of 501 [0.2%] patients). However, 1 patient in the anticoagulant group had a postoperative myocardial infarction; he was on both aspirin and warfarin because of prior cardiac valve surgery and coronary artery bypass grafting. The occurrence of a myocardial infarction, despite continued antithrombotic therapy, suggests that the risk of thrombosis due to perioperative discontinuation of antithrombotic agents in a part this patient group, surpasses the risk of hemorrhage due to the continuation of antithrombotic agents. Additionally, in such patients with a risk of high thrombosis, the antithrombotic therapy should be preoperatively reconfirmed as sufficient to prevent postoperative thrombotic complications. In particular, it should be noted that management of antiplatelet agents is also necessary to prevent acute coronary syndromes.
Our study has several limitations. First, this retrospective designed descriptive study involved a small population at a single institution, and lacked a power sample size calculation to detail what cohort size is needed to detect the expected differences. Because the incidence of hemorrhagic complications due to perioperative continuation of antithrombotic agent use was extremely low, performing a multivariate analysis for adjustment for covariates using the incidence of bleeding complications as the objective variable was difficult. Therefore, it should be noted that this study design was insufficient to statistically clarify the safety of continuing anticoagulant therapy compared to each of the other groups. Moreover, this observational design study is limited by selection bias. That is, only patients who choose surgical treatment were included in this study cohort, while patients at higher risk for complications could choose other treatment options.
In addition, the anticoagulant group involved patients using both DOAC and warfarin. As these drugs can be interchangeable in patients with the same disease backgrounds and indications, it was considered appropriate to include them in the same group for analysis. The priority was to clarify that this group did not have an increased risk of perioperative bleeding. For the next step of the analysis of embolism prevention, patients in this group should have been divided according to drug indication into acute coronary syndromes, stroke, and DVT, amongst others. A larger sample size is needed to determine the incidence of complications in each of these subgroups. Moreover, although no patient in the thienopyridine group experienced any high-grade bleeding complications, a larger cohort is needed to accurately evaluate this group.
To establish the safety of perioperative continuation of anticoagulant agent use, the most ideal study design is a randomized control trial that compares patient groups continuing vs discontinuing anticoagulant therapy (or using heparin infusion bridging therapy). Such a trial design requires establishing a confidence interval and noninferior margin as part of a noninferiority trial. Estimating an appropriate sample size and appropriate noninferior margin prior to the start of the present study, was difficult because of the paucity of relevant existing articles. However, our results may benefit future trials of this nature.
CONCLUSION
Despite several limitations, the present study showed that RARP can be safely performed in patients who continue with perioperative use of anticoagulant agents. Such continued anticoagulant therapy does not increase perioperative blood loss or the rate of high-grade bleeding complications. Further verification of our results in multicenter randomized control trials is required to improve the safe perioperative management of patients undergoing RARP.
Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines.
Radical prostatectomy with robot-assisted radical prostatectomy and laparoscopic radical prostatectomy under low-dose aspirin does not significantly increase blood loss.
Total anatomical reconstruction during robot-assisted radical prostatectomy: focus on urinary continence recovery and related complications after 1000 procedures.
AHA/ACCF Secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation.
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