Management of Antithrombotics for Gastrointestinal Procedures

Function

Bleeding Risk Associated with the Procedure

Various endoscopic procedures have different risks of associated bleeding.[2] Most data come from studies conducted in patients not receiving multiple antithrombotic agents; therefore, clinicians should interpret these risks with caution when applied to individual patients. Traditionally, endoscopic procedures associated with interventions have a higher bleeding risk than those without interventions. Other factors also influence this risk. For example, polypectomy, one of the most common interventions during endoscopy, carries a bleeding risk ranging from 0.3% to 10%, depending on polyp size, location, and type, as well as the resection or cautery technique used. Endoscopic submucosal dissection and endoscopic resection of large polyps (greater than 2 cm) are considered very high-risk procedures.[3]

Procedures with Lower Risk of Bleeding

• Diagnostic endoscopic procedures with or without biopsies
• Argon plasma coagulation
• Dilation of strictures
• Percutaneous endoscopic gastrostomy tube placement in patients on single antiplatelet therapy
• Biliary or pancreatic stenting
• Double-balloon enteroscopy without therapeutic intervention
• Esophageal, small bowel, or colonic stenting
• Endoscopic ultrasonography without tissue sampling or other interventions
• Radiofrequency ablation of Barrett esophagus
• Capsule endoscopy [2][5]

Procedures with Higher Risk of Bleeding

• Polypectomy
• Endoscopic interventions for bleeding
• Balloon-assisted enteroscopy for intervention
• Endoscopic mucosal resection or endoscopic submucosal dissection
• Endoscopic retrograde cholangiopancreatography with sphincterotomy
• Endoscopic ampullectomy
• Treatment of esophageal varices
• Percutaneous endoscopic jejunostomy tube placement
• Endoscopic ultrasonography with tissue sampling, cystogastrostomy, or other interventions
• Radiofrequency ablation of the esophagus or stomach

Thrombosis Risk Associated with Various Underlying Conditions

The underlying condition dictates the risk of thromboembolic episodes in these patients, especially when withholding the antithrombotic agent. Stroke prevention in nonvalvular atrial fibrillation is a very common indication for antiplatelet or anticoagulant therapy, and the risk of cerebral thromboembolism in these patients is predictable using the CHA₂DS₂-VASc index.[6][7] The score is used to determine whether the thrombosis risk is high enough to warrant preventive anticoagulant therapy. See Table 1 for the CHA₂DS₂-VASc scoring. In patients with coronary artery disease receiving antiplatelet therapy, a few important factors determine the risk of major adverse cardiac events. Placement of a drug-eluting coronary stent in the previous 12 months, placement of a bare-metal stent within 1 month, or occurrence of an acute coronary syndrome within 6 months is considered a high-risk condition requiring dual antiplatelet therapy. Patients receiving anticoagulation for venous thromboembolism or mechanical heart valves have different risk factors for thromboembolic episodes (see Image. Thromboembolic Episode Risks). The table shows that the patients were categorized into low-, medium-, and high-risk groups. See Table 2. [8] Coronary artery disease with stent placement is high-risk, while low-risk underlying conditions include ischemic heart disease without stent placement, previous placement of a bioprosthetic heart valve, peripheral vascular disease, and cerebrovascular disease. The implications of the CHA₂DS₂-VASc Score on antithrombotic therapy are discussed in the Clinical Significance section below. 

Table 1. CHA₂DS₂-VASc Score for Thromboembolic Stroke Risk in Nonvalvular Atrial Fibrillation

Table 2. Anticoagulation Recommendations Based on Total CHA₂DS₂-VASc Score

Clinical Significance

Interruption of Antithrombotic Therapy Before Endoscopy

Elective endoscopy: If the indication for antithrombotic therapy is short-term, elective procedures are best delayed until after that period. For patients receiving long-term or lifelong antithrombotic treatment, the decision to temporarily hold treatment for endoscopy should be made after discussion with the patient, the primary care clinician, and relevant specialists (eg, cardiologist, neurologist, hematologist, and gastroenterologist). In some high-risk patients, these agents cannot be interrupted, so the clinician and patient must weigh the risks and benefits of the procedure.

Parenteral anticoagulants (unfractionated heparin and low-molecular-weight heparin): Unfractionated heparin administered by continuous intravenous infusion can be discontinued 3 to 4 hours before endoscopic procedures, given its short half-life. Low-molecular-weight heparin (LMWH), including enoxaparin and dalteparin, should be discontinued 24 hours before the procedure, or longer if the procedure has a high risk of bleeding or if the patient has renal insufficiency. If the procedure is a diagnostic upper gastrointestinal tract endoscopy and biopsies are not planned, enoxaparin can be given the evening before the procedure, then restarted after the endoscopy.[9][10] Fondaparinux is a synthetic factor Xa inhibitor that requires discontinuation at least 36 hours preceding a high-risk procedure.

Warfarin: The therapeutic effect of warfarin is measured in terms of the international normalized ratio (INR). The INR decreases to less than 1.5 in more than 90% of patients when treatment is held for 5 days.[11] The overall risk of a thromboembolic event when warfarin is discontinued for 4 to 7 days is around 1%.[12] Therefore, some authorities recommend restarting warfarin within 4 to 7 days after initial discontinuation to minimize the risk of these events.[2] The American College of Gastroenterology and Canadian Association of Gastroenterology guidelines, however, recommend continuing warfarin in the elective setting.[2] The role of bridging therapy with unfractionated heparin or low-molecular-weight heparin in patients receiving warfarin across various indications has been studied. Based on current guidelines for patients with valvular atrial fibrillation receiving warfarin, bridging therapy is recommended for a CHA₂DS2-VASc score of 2 or higher. LMWH should be started 2 days after discontinuation of warfarin therapy, and the last dose should be administered at least 24 hours before the procedure.[9] Patients with a CHA₂DS2-VASc score of 0 or 1 do not require bridging therapy while withholding warfarin. Results from another study showed that bridging therapy for nonvalvular atrial fibrillation in the periprocedural period was associated with higher bleeding risk and no benefit in reducing thromboembolic episodes. However, clinicians should interpret these studies with caution in patients at higher risk of thrombosis.[13] In these patients, bridging therapy is always recommended, using an interprofessional approach with other clinicians who treat patients receiving anticoagulation therapy.

Direct oral anticoagulants: The use of direct oral anticoagulants (DOACs) has increased over the last decade. These agents include factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban) and the direct thrombin inhibitor dabigatran. Currently, no reliable laboratory assays can assess the anticoagulant effect of these agents. The duration before high-risk endoscopic procedures during which DOACs must be held depends on the patient's renal function. Factor Xa inhibitors should be held for 1 to 2 days if the creatinine clearance (CrCl) is 60 mL/min or more, for 3 days if the CrCl is between 30 mL/min and 59 mL/min, and for 4 days if the CrCl is less than 30 mL/min.[14] The recommendation for stopping dabigatran is 2 to 3 days before a high-risk procedure in patients with CrCl greater than 80 mL/min, 3 to 4 days before the procedure if CrCl is 30 to 49 mL/min, and 4 to 6 days before the procedure if CrCl is less than 30 mL/min.[15] Discontinuing factor Xa inhibitors before endoscopic procedures with a relatively low bleeding risk is safe without significant bleeding or thromboembolic complications.[16] While idarucizumab can reverse the effect of dabigatran, andexanet alfa can be given to patients receiving rivaroxaban or apixaban, the American College of Gastroenterology and Canadian Association of Gastroenterology guidelines do not support their use.[2]

Antiplatelet drugs: Aspirin and thienopyridines (clopidogrel, prasugrel, and ticagrelor) are the most commonly used antiplatelet agents. Aspirin irreversibly inhibits cyclooxygenase systems. Platelet function takes 7 to 9 days to return after discontinuing aspirin.[16] Thienopyridines inhibit platelet aggregation by binding to the P2Y12 component of the platelet adenosine diphosphate receptors. Clopidogrel and prasugrel must be stopped 5 to 7 days before normal platelet aggregation resumes. Ticagrelor, a reversible P2Y12 inhibitor, can be discontinued 3 to 5 days in advance.[17] In patients receiving dual antiplatelet therapy with aspirin and a thienopyridine, results from research showed that those who discontinued both had a much higher incidence of stent thrombosis than those who remained on aspirin alone.[18] Table 3 describes the management of antiplatelet drugs before endoscopic procedures.[4]

Table 3. Management of Patients Receiving P2Y12 Receptor Antagonist Antiplatelet Drugs Before Endoscopic Procedures

Emergent Endoscopy

The most common indication for emergent endoscopic procedures is gastrointestinal tract bleeding. The common etiologies of acute upper gastrointestinal tract bleeding are peptic ulcer disease, variceal bleeding, and gastritis or esophagitis, whereas lower gastrointestinal tract bleeding is most commonly diverticular in origin. The decision to discontinue antithrombotic therapy and reverse anticoagulation must be weighed against the risk of causing a thromboembolic event. Correction of the INR to between 1.5 and 2.5 is adequate for diagnostic and interventional purposes and is comparable to that in patients who are not anticoagulated. Therapeutic measures to achieve hemostasis in patients with gastrointestinal tract bleeding are effective even with a moderately elevated INR.[19][20] Therefore, delaying the procedure until the INR normalizes is not advisable. In patients with acute bleeding, warfarin should be held, and anticoagulation reversal is most rapidly achieved with 4-factor prothrombin complex concentrate. Fresh-frozen plasma has a slower onset in reversing warfarin and requires a larger volume of infusion, so this therapy is only used when prothrombin complex concentrate is unavailable.[21] Vitamin K, 5 to 10 mg, can be administered intravenously as adjunctive therapy. In patients with mechanical heart valves who require reversal of anticoagulation, fresh frozen plasma or prothrombin complex concentrate is an option.[22] High-dose vitamin K therapy is generally not preferred in these patients, as it can prolong coagulability.

If urgent reversal of anticoagulation is necessary for patients receiving UFH, a slow infusion of protamine sulfate can be administered. The dose is calculated based on the administered heparin dose and the duration of therapy. The anticoagulant effect of dabigatran is reversible with idarucizumab. Idarucizumab is approved for life-threatening bleeding or before emergent surgical procedures.[23] Because idarucizumab is primarily excreted by the kidneys, hemodialysis is also a viable option in these patients. For patients receiving antiplatelet therapy who present with acute major bleeding, options include stopping the agent or reversing it with platelet transfusion, with consideration of the thrombotic risk in the individual patient.

Resumption of Antithrombotic Therapy After Endoscopy

Anticoagulation should generally be resumed upon completion of the procedure unless a continued risk of major bleeding remains.[2][10] This approach is based on studies of warfarin and unfractionated heparin (UFH), with limited literature on the resumption of DOACs. For patients receiving warfarin who have a high risk of thromboembolism and receive bridging therapy, LMWH should be restarted 48 hours after completion of the procedure. In the setting of endoscopic sphincterotomy, UFH should be started 1 to 2 days after the procedure and continued until the INR reaches a therapeutic level with warfarin. Warfarin should be restarted 3 days after endoscopic sphincterotomy, and DOAC reinitiation should be delayed for 5 days. For patients at lower risk of thromboembolism, warfarin should be restarted on the day of the procedure or within 24 hours, and a DOAC should be restarted no sooner than 24 hours after the procedure. Because of the shorter duration of DOACs, if treatment with these agents cannot resume within 24 hours of a high-risk procedure, bridging therapy should be considered with UFH or LMWH in patients with a high risk of thrombosis.[24] In patients receiving DOACs for stroke prophylaxis in atrial fibrillation, these agents can safely be resumed 1 day after low-risk procedures and 2 to 3 days after high-risk procedures without the need for bridging.[25] All antiplatelet agents should be resumed shortly after hemostasis is achieved.

Enhancing Healthcare Team Outcomes

Healthcare professionals must educate patients on the importance of holding antithrombotic medications for a specific duration before endoscopic procedures and of resuming them promptly. Patient education may include direct counseling, printed materials, and technology-based reminders. The interprofessional team must discuss the potential risks and benefits of this strategy with patients. In addition to the specialists, proceduralists, and other clinicians, nurses monitor the patient following the procedure. A board-certified pharmacotherapy pharmacist can consult with clinicians to stop and resume anticoagulation therapy in the context of the procedure. A patient-centered interprofessional team consisting of the primary care clinician, gastroenterologists, cardiologists, hematologists, pharmacists, and nurses must be involved in guiding patients through medication regimen changes, monitoring for bleeding, titrating therapy, and recognizing complications early, should they occur. This interprofessional team approach improves patient outcomes.