To elucidate the effect of antithrombotic therapy (ATT) on bleeding and thromboembolic complications during or after laparoscopic digestive surgery.

Published articles or internationally accepted abstracts between 2000 and 2017 were searched from PubMed, Cochrane Database, and Google Scholar, and studies involving laparoscopic digestive surgery and antiplatelet therapy (APT) and/or anticoagulation therapy (ACT) were included after careful review of each study. Data such as study design, type of surgical procedures, antithrombotic drugs used, and surgical outcome (both bleeding and thromboembolic complications) were extracted from each study.

Thirteen published articles and two internationally accepted abstracts were eligible for inclusion in the systematic review. Only one study concerning elective laparoscopic cholecystectomy in patients with perioperative heparin bridging for ACT showed that the risk of postoperative bleeding was higher compared with those without ACT. The remaining 14 studies reported no significant differences in the incidence of bleeding complications between the ATT group and the group without ATT. The risk of thromboembolic events (TE) associated with laparoscopic digestive surgery in patients receiving ATT was not significantly higher than those with no ATT or interrupted APT.

Laparoscopic digestive surgery in ATT-burdened patients for prevention of bleeding and TE showed satisfactory results. The risk of hemorrhagic complication during or after these procedures in patients with continued APT or heparin bridging was not significantly higher than in patients with no ATT or interrupted APT.

Following cancer, heart disease and cerebrovascular disease are the major causes of death worldwide. With the arrival of an aging society in recent years, the number of patients with heart disease and/or cerebrovascular disease who require non-cardiac surgery is increasing. For the purpose of preventing thromboembolic events (TE), most of them receive antithrombotic therapy (ATT), including antiplatelet therapy (APT) and anticoagulation therapy (ACT). Perioperative management of these patients is challenging for surgeons, and they are often at high risk of bleeding and thromboembolic complications[1-4].

Many digestive operations are currently performed laparoscopically. Several reports have shown advantages of laparoscopic digestive surgery, including early recovery of digestive function, reduction of body wall destruction, reduction of postoperative pain, less postoperative complications, and rapid return to daily life[5-9]. During laparoscopic surgery, minimizing surgical blood loss to maintain a dry operative field is exclusively important. Improvement of several techniques and new surgical devices, such as ultrasonic coagulating shears or saline-linked soft-coagulation system, led us to perform various types of advanced laparoscopic digestive operations including colorectal resection, esophagogastrectomy, and hepato-biliary-pancreas surgery. However, optimal management of patients receiving ATT during laparoscopic digestive surgery is still controversial.

The purpose of the current systematic review study is to elucidate the effect of ATT on bleeding and thromboembolic complications during or after laparoscopic digestive surgery.

Articles written in English and published between 2000 and 2017 were collected from PubMed, Cochrane Database and Google Scholar. We also used PubMed and Google Scholar to search internationally accepted English abstracts. The following key words were used for the search: Clopidogrel, aspirin, antiplatelet, anticoagulant, warfarin, bleeding, hemorrhage, gastrointestinal, gastroenterological, digestive and laparoscopic surgery. Articles or abstracts were included when published in peer reviewed journals or when accepted at internationally renowned medical conferences. Types of eligible studies included randomized clinical trials, prospective or retrospective cohort studies, or case-control studies; guidelines, review articles, or case series/reports were not included.

After removing duplicates, articles were systematically excluded by careful review of each study. The quality of each study was assessed depending on study design, and eligible articles and abstracts were determined. Complete data were extracted from each study, which included study design, year of publication, sample size, type of surgical procedures, type of antithrombotic drugs, and surgical outcome (both bleeding and thromboembolic complications).

To the best of our knowledge, this is the first systematic review that assesses the effect of ATT on bleeding and thromboembolic complications during and after laparoscopic digestive surgery. The present review summarized results of various types of laparoscopic digestive surgery in patients receiving ATT for the prevention of thromboembolism. The risk of hemorrhagic or thromboembolic complications during or after these procedures in patients with continued APT or heparin bridging was not significantly higher than in patients with no ATT or interrupted APT. There are some promising results for both basic and laparoscopic surgery. However, in terms of advanced laparoscopic surgery, such as colorectal resection or liver resection, there is scarce evidence.

ATT includes two types of medications, classified as antiplatelets and anticoagulants. Antiplatelets decrease platelet aggregation and prevent thrombus formation, and they are generally used for primary and secondary prevention of cardiovascular and cerebrovascular diseases, such as myocardial infarction or cerebral infarction. Antiplatelets include thienopyridine (e.g., clopidogrel, ticlopidine, or prasugrel), type III phosphodiesterase inhibitor (e.g., cilostazol), acetylsalicylic acid (aspirin), and other non-steroidal anti-inflammatory agents[10,26]. On the other hand, anticoagulants interfere with the native clotting cascade and prevent blood clotting, and they are generally used for atrial fibrillation, deep vein thrombosis, cardiac endoprostheses, and acute coronary syndrome. These include vitamin K antagonists (e.g., warfarin), heparin derivatives (e.g., fondaparinux), direct thrombin inhibitors (e.g., dabigatran), and factor Xa inhibitors (e.g., rivaroxaban, apixaban, edoxaban)[26,27]. The two latter types are now increasingly used and are referred to as direct-acting oral anticoagulants (DOACs) or non-vitamin K antagonist oral anticoagulants (NOACs). The types of antithrombotics, specific agents, and duration of action are summarized in Table 3.

So far, there has been scarce evidence concerning the definite protocols or guidelines for each specific gastroenterological surgical procedure, including laparoscopic surgery. Thanks to the development of techniques and various energy devices, indication of laparoscopic digestive surgery is now expanded not only to basic procedures but also relatively advanced digestive operations[6,8,9]. During laparoscopic surgery, minimizing surgical blood loss to maintain a dry operative field is required, and thus, this procedure results in less surgical blood loss and a lower incidence of postoperative complications[16]. Although the optimal management of patients receiving ATT during laparoscopic digestive surgery is still controversial, rigorous antithrombotic management, such as continued aspirin monotherapy for APT or heparin bridging for ACT, is considered to be safe and feasible.

Using several recently updated guidelines concerning antithrombotics as references[26-30], the recommended protocol of perioperative management for patients undergoing ATT in the case of elective open or laparoscopic digestive surgery is shown in Figure 1. The management generally consists of three approaches according to types of ATT; APT, warfarin, and DOACs. In patients with thromboembolic risks, aspirin monotherapy is continued in patients with APT, and warfarin is substituted by heparin bridging 3-5 d before surgery. In the case of DOACs, ATT is stopped 1-2 d before surgery (with some modification needed if decreased renal function exists); if the thromboembolic risk is very high, heparin bridging might be considered. Postoperatively, every antithrombotic agent is reinstituted as soon as possible (POD1-2).

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Figure 1 Recommended perioperative management protocol for patients undergoing antithrombotic therapy in the case of elective laparoscopic digestive surgery. The management generally consists of three ways according to the types of antithrombotic therapy (ATT); antiplatelet therapy (APT), warfarin, and Direct-acting oral anticoagulants (DOACs). In patients with thromboembolic risks, aspirin monotherapy is continued in patients with APT, and/or warfarin was substituted by heparin bridging 3-5 d before surgery. In the case of DOACs, ATT is stopped 1-2 d before surgery (with some modification needed if decreased renal function exists); if the thromboembolic risk is very high, heparin bridging might be considered. Postoperatively, every antithrombotic agent is reinstituted as soon as possible (POD1-2). ATT: Antithrombotic therapy; APT: Antiplatelet therapy; TE: Thromboembolism; ACT: Anticoagulation therapy; DOAC: Direct-acting oral anticoagulant.

Recent updated guidelines concerning antithrombotic management during non-cardiac surgery[26,27,31-33] showed that the prevention of TE is more important than bleeding complications, as it might cause death or severe sequelae. Concerning implantation of a coronary stent, recent American College of Cardiology/American Heart Association (commonly known as ACC/AHA) and European Society of Cardiology (commonly known as ESC) guideline state that we should continue antiplatelet medications, at least aspirin monotherapy, in the perioperative period for patients with high risk of thromboembolism[30], but most institutions practically choose to discontinue APT in the case of major digestive surgery with bleeding risks. Discontinuing aspirin or clopidogrel may lead to an increased risk of acute myocardial infarction, cerebral infarction, and subsequent death[34,35]. Although some studies, including the POISE-2 study, have reported that a modest increase in bleeding risk was observed in continued APT patients during non-cardiac surgery[36,37], most studies have shown that there was no increase in significant bleeding events[38,39]. Thus, sufficient consideration and emphasis should be placed on the prevention of thromboembolism caused by cessation of antithrombotic drugs, rather than the risk of perioperative bleeding.

Concerning patients with ACT, heparin bridging is a common management for warfarin[40]. Recently, a large-scale randomized controlled trial (BRIDGE study) showed that heparin bridging was not recommended in the case of low bleeding risk surgery due to increased bleeding risks[25]. However, this study included relatively small numbers of major digestive surgery, and it could not conclude that heparin bridging is unnecessary in major general or abdominal surgery. In the current review, only one study concerning warfarin use and laparoscopic cholecystectomy showed an elevated risk of postoperative bleeding when heparin bridging was used[11]. The remaining studies demonstrated the safety of ACT bridging without an increase in severe bleeding complications. Especially in patients with high thromboembolic risks, heparin bridging might be considered to avoid critical thromboembolic complications.

In the present review, there was no report regarding patients who received DOACs during laparoscopic digestive surgery. Currently, DOACs are increasingly prescribed for the purpose of preventing arterial or venous thromboembolism. In large clinical trials, DOACs have been shown to have lower rates of intracranial hemorrhage compared to warfarin[41-44]. Furthermore, in cases of intracranial bleeding, there are reports that hematoma sizes were small in patients receiving DOACs compared to those with warfarin administration[45,46]. This difference is mainly due to the difference in mechanism of action in the blood clotting cascade. A sufficient understanding of these pharmacological characteristics, which is remarkably different from warfarin, is of paramount importance for surgeons. A recently published review and an ongoing prospective study[47,48] suggests safety and feasibility of perioperative management of DOACs during noncardiac surgery, which is rather simple compared with those of warfarin. Still, the detailed assessment of perioperative management protocol, such as the necessity of bridging anticoagulation, has not yet conducted and should be investigated further. In addition, these reports or reviews did not show results according to the procedure types. Safety of every surgical type, including laparoscopic digestive surgery, should be assessed in the future.