Comparison of the continuation and discontinuation of perioperative antiplatelet therapy in laparoscopic surgery for colorectal cancer: A retrospective, multicenter, observational study (YCOG 1603)

Abstract Aim The present study aimed to examine the effect of continuing antiplatelet therapy in the perioperative period for patients undergoing laparoscopic resection for colorectal cancer who had received preoperative antiplatelet therapy. Methods This retrospective, multicenter, observational study included patients who underwent laparoscopic surgery for colorectal cancer between January 2011 and May 2020. The study population was limited to patients who used antiplatelet therapy preoperatively. Results A total of 214 colorectal cancer patients who received antiplatelet therapy preoperatively were included in the present study. Eighty‐nine patients underwent surgery under the continuation of antiplatelet therapy, and 125 patients underwent surgery under the discontinuation of antiplatelet therapy before surgery. There were no significant differences between the two groups with regard to intraoperative blood loss (P = .889), intraoperative blood transfusion (P = 1.000), and conversion to laparotomy (P = 1.000). There were no significant differences between the two groups in the incidence of postoperative hemorrhagic complications (Clavien‐Dindo Grade ≥II, P = .453; Grade ≥III, P = .572) or three‐point major adverse cardiovascular events (P = .268). However, there were two cases of postoperative non‐fatal stroke in the discontinued antiplatelet therapy group. Conclusions The present study revealed that there were no significant differences in the surgical outcomes and postoperative complications between colorectal cancer patients who underwent laparoscopic resection with the continuation of antiplatelet therapy in the perioperative period and those in whom antiplatelet therapy was discontinued during the perioperative period. From the viewpoint of cardiovascular and cerebrovascular risk, it may be better for patients undergoing laparoscopic surgery for colorectal cancer to continue antiplatelet therapy. This study was registered with the Japanese Clinical Trials Registry as UMIN000038707 (http://www.umin.ac.jp/ctr/index.htm).


| INTRODUC TI ON
Antiplatelet therapy (APT) has been widely used for the secondary prevention of cardiovascular diseases, such as coronary artery disease and cerebrovascular disease, including cerebral infarction and transient ischemic attack. 1,2 In recent years, the effects of aspirin on the secondary prevention of these diseases have become clear, and the proportion of patients who receive APT at the time of surgery has been increasing. 3,4 Annually, 10% of patients receiving antithrombotic therapy (ATT), including APT and anticoagulation therapy (ACT), undergo surgery or other invasive procedures that require the temporary discontinuation of therapy. 3 However, excessive perioperative ATT withdrawal may put patients at risk for thromboembolism. 5 Regarding the continuation or discontinuation of APT in the perioperative period of non-cardiac surgery, the risks and benefits have been considered to differ depending on the background of the patient undergoing APT and the surgical procedure being performed. 6,7 However, there is limited information about the cardiovascular and/or cerebrovascular disease risk of each patient population and the bleeding risk associated with each surgical procedure. Thus, there has been no consensus on whether APT should be continued or discontinued during the perioperative period. 8,9 Laparoscopic surgery is now widely performed for colorectal cancer (CRC) 10 ; however, there is no consensus regarding the continuation or discontinuation of APT during these operations. Laparoscopic colorectal resection is generally considered to be associated with an intermediate risk of bleeding. 11 In recent years, there have been several reports about laparoscopic colorectal resection under continuous APT; however, the debate is still insufficient. 12  The present study aimed to examine the effect of continuing APT in the perioperative period for patients undergoing laparoscopic resection for CRC who had received preoperative APT. In this study, we targeted patients who were using aspirin, cilostazol, clopidogrel, ticlopidine, or prasugrel as APT before surgery.

| Patient selection, antiplatelet therapy, and outcomes
Patients who received antiplatelet drugs other than the five abovementioned drugs were excluded from this study. The eligibility criteria of this study were as follows: (a) CRC patients >20 years of age (no upper age limit was applied), (b) who underwent laparoscopic surgery, (c) and who had received at least one of the five abovementioned APT drugs before surgery. The exclusion criteria of this study were as follows: (a) patients who underwent open or robotic surgery, (b) patients with multiple primary cancers, and (c) patients who underwent combined resection of other organs.
The decision whether to continue APT (c-APT group) or discontinue APT (d-APT group) during the perioperative period was made by the attending surgeon. In the c-APT group, the procedure for continuation of APT was as follows: (a) in patients receiving preoperative aspirin monotherapy, aspirin was continued; (b) in patients receiving preoperative drugs other than aspirin, the drug was substituted with aspirin; (c) patients who received preoperative dual antiplatelet therapy (DAPT) including aspirin continued APT with aspirin monotherapy; (d) patients who received preoperative DAPT without aspirin, it was selected to replace with aspirin and continue with aspirin only or continue with DAPT. In the c-APT group, aspirin was taken orally until the morning of surgery and was resumed from the day after surgery. For patients in the d-APT group, either (a) the discontinuation of APT or (b) preoperative heparin bridging were selected based on the judgment of the attending surgeon. The durations of the preoperative discontinuation of antiplatelet drugs were 3 days for cilostazol, 7 days for aspirin and ticlopidine, 14 days for clopidogrel and prasugrel. In the cases of bridge therapy, the bridging agent (aspirin or heparin) was started on the day that each APT agent was discontinued. In the d-APT group, postoperative APT was resumed at the discretion of the attending surgeon.
Antithrombotic therapy for preventing pulmonary embolism (PE) were not routinely performed after surgery in our institutions. ATT for colorectal cancer to continue antiplatelet therapy. This study was registered with the Japanese Clinical Trials Registry as UMIN000038707 (http://www.umin.ac.jp/ ctr/index.htm).

K E Y W O R D S
antiplatelet therapy, cardiovascular events, colorectal cancer, hemorrhagic complication, laparoscopic surgery was only performed when thrombotic complications including deep venous thrombosis (DVT) and PE were observed before and after surgery.
The primary outcome of this study was the incidence of intraoperative and postoperative hemorrhagic complications. The secondary outcomes of this study were the operation time, intraoperative blood loss, intraoperative blood transfusion rate, the rate of conversion to laparotomy, the length of postoperative hospital stay, all postoperative complications within 30 days (Clavien-Dindo classification [CD] grade ≥II), major adverse cardiovascular events (MACE), the exacerbation of postoperative heart failure, the reoperation rate, and in-hospital death.
In addition, the following preoperative clinical data were collected: age,

| Surgical procedure
Laparoscopic surgery for CRC was usually performed with five ports.
Lymph node dissection and colon or rectum mobilization, including central vascular ligation of the artery and vein, were all performed laparoscopically. Sigmoidectomy and rectal resection with anastomosis using the double stapling technique (DST) were performed with two 12-mm ports and three 5-mm ports, and statistical analyses colectomy with antiperistaltic side-to-side anastomosis (functional end-to-end anastomosis: FEEA) was performed with one 12-mm port and four 5-mm ports. DST reconstruction was performed intracorporeally using an ILS ™ (Ethicon Endo-Surgery) circular stapler. FEEA reconstruction was performed extracorporeally using an Echelon Flex™ (Ethicon Endo-Surgery), a Signia, or an i-Drive (Medtronic) stapler.

| Statistical analysis
Categorical variables were expressed as the frequency and proportion (%), and numerical data were presented as the median and interquartile range (IQR). All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan 13 ), which is a graphical user interface for R (The R Foundation for Statistical Computing). The Mann-Whitney U test, the Fisher's exact test, and Pearson's chi-squared test were performed for comparisons between independent groups when appropriate. P values of <.05 were considered to indicate statistical significance. The surgical outcomes are summarized in Table 3. There were no significant differences between the two groups in intraoperative blood loss (c-APT 10 mL   The postoperative complications are presented in Table 4. The

| D ISCUSS I ON
This retrospective multicenter study revealed that there was no significant difference in the surgical outcomes or postoperative complications between patients who underwent laparoscopic surgery for CRC with the continuation of APT in the perioperative period and those in whom APT was discontinued in the perioperative period.
There was no significant difference in the incidence of intraoperative and postoperative hemorrhagic complications between the two groups. However, although the incidence did not differ to a statistically significant extent, there were two cases of postoperative nonfatal stroke in patients in whom APT was discontinued during the perioperative period.
Several previous studies have shown that APT with agents such as aspirin is useful for the secondary prevention of cardiovascular and/or cerebrovascular disease. 1,2 Previously, aspirin was also prescribed for the primary prevention of CVE; however, in recent years there has been some skepticism regarding the use of aspirin for primary prevention. 14   abdominal open surgery or laparoscopic surgery. 11 Although some guidelines have been published, there is still no complete consensus on whether or not to continue APT. 15 Some previous studies have reported that perioperative APT during surgery in various areas was not associated with an increase in hemorrhagic complications. [16][17][18] Another study suggested that the continuation of APT reduced the incidence of MACE after surgery. 19 However, these studies targeted the heterogeneous patient populations who were treated with several different surgical procedures, not a single procedure. Even though these procedures were in the same intermediate risk group, they could not be said to have the same bleeding risk. In addition, other previous studies on whether or not APT should be continued have often used preoperative APT-free patients as a control group for the APT continuation group. 20,21 This was thought to be due to the limited number of patients who received APT. However, the preoperative administration of APT was considered to be associated with a high-risk postoperative CVE, and the risk postoperative bleeding and CVE in the above setting was potentially different.
Thus, we only included patients who had received APT preoperatively in this study. Few studies have compared the presence or absence of APT in a population limited to patients who were using APT preoperatively prior to laparoscopic colorectal resection. In this study, all patients who had received APT for primary prevention were included in the d-APT group. Indeed, patients used for primary prevention may potentially have fewer serious comorbidities and serious past medical history. However, we considered that patients who had received primary prevention have been prescribed for the presence of some comorbidities with cardiovascular and/or cerebrovascular event (CVE) risk, and it was considered that patients with preoperative APT had a higher CVE risk than patients who were not prescribed APT. For that reason, we considered that patients with extremely low CVE risk were not included in this study.
The results of our study did not show a significant increase in in- Stroke is a profoundly serious and potentially fatal complication that can leave sequelae. The overall incidence of stroke in this study  22 American Society of Regional Anesthesia and Pain Medicine also treats aspirin separately from other antiplatelet drugs. 23 If these were accepted more widely, the influence of continuing aspirin on the presence or absence of epidural anesthesia may disappear.
The present study was associated with some limitations. First, this study was retrospective in nature and had a limited sample size.
Second, non-clinical hemorrhagic complications and CVE might have gone undetected because contrast-enhanced CT was not routinely performed after surgery. Another limitation was the relatively small number of postoperative events. Therefore, further randomized prospective trials with a larger study population are needed to validate the efficacy of the continuation of APT. However, the authors believe that the findings of this study will provide a firm foundation for future studies.
In conclusion, we revealed that there was no significant difference in the surgical outcomes or postoperative complications between patients who underwent laparoscopic surgery for CRC with the continuation of APT in the perioperative period and those in whom APT was discontinued in the perioperative period. However, two patients in the d-APT group developed non-fatal stroke after surgery, while no patients who continued to receive APT experienced this complication. Non-fatal stroke is a significant non-negligible complication. Thus, it may be better to continue APT in laparoscopic surgery for CRC. Cardiovascular death a 0 (0.0) 1 (0.8)
a Within 30 d after surgery. b Cases requiring additional treatment for heart failure.