atrial fibrillation undergoing catheter ablation to continued warfarin or discontinuation of warfarin with bridging [44]. In this trial, patients randomized to continue warfarin had a lower risk of stroke and less bleeding. We also agree with the EHRA position document statement that all patients undergoing catheter ablation for atrial fibrillation should receive full anticoagulation with heparin in addition to continuing their oral anticoagulant [40]. If a decision is made to discontinue the anticoagulant (eg, patient with impaired kidney function), bridging is reserved for those with a high to very high thromboembolic risk and not used for those with a moderate thromboembolic risk. (See 'Limited indications for bridging' below.) TIMING OF ANTICOAGULANT INTERRUPTION If a decision has been made to interrupt the anticoagulant for surgery with high or moderate bleeding risk, the agent should be stopped in sufficient time to allow anticoagulation to resolve. For some agents such as warfarin, laboratory testing is a reliable indicator that the https://www.uptodate.com/contents/perioperative-management-of-patients-receiving-anticoagulants/print 12/65 7/5/23, 10:17 AM Perioperative management of patients receiving anticoagulants - UpToDate anticoagulant effect has resolved after discontinuation; for direct oral anticoagulants (DOACs), well-validated and easily accessible testing is not always available. Data to guide the timing of anticoagulant interruption are evolving, especially for DOACs, and much of our practice is based on expert opinion and observational studies as we await results from ongoing trials [45]. Validated approaches have been developed to guide the timing of DOAC interruption. (See 'DOAC interruptions (overview)' below.) If a moderate or high bleeding risk surgery is required urgently or immediately, reversal of the anticoagulant may also be required. (See 'Urgent/emergency invasive procedure' below.) Risks of bleeding with neuraxial anesthesia and risks of thrombosis in patients with prosthetic heart valves are especially concerning; these issues are discussed in detail separately. (See "Neuraxial anesthesia/analgesia techniques in the patient receiving anticoagulant or antiplatelet medication" and "Antithrombotic therapy for mechanical heart valves".) Typical durations of anticoagulant interruption are illustrated by the RE-LY trial, which randomly assigned individuals with nonvalvular atrial fibrillation to warfarin or dabigatran for prevention of thromboembolism [9]. In this trial, nearly half of patients treated with dabigatran had surgery within 48 hours of stopping the drug, whereas only approximately 1 in 10 patients treated with warfarin had surgery within 48 hours of drug discontinuation. The incidence of thromboembolism was low (<1 percent), and bleeding rates were similar for those receiving warfarin or either dabigatran dose. Similar findings were reported in the PAUSE study, which focused on individuals with atrial fibrillation receiving a DOAC. (See 'Atrial fibrillation' above and 'DOAC interruptions (overview)' below.) Warfarin interruption Warfarin blocks a vitamin K-dependent step in clotting factor production; it impairs coagulation by interfering with the functions of factors II (prothrombin), VII, IX, and X. Resolution of warfarin effect is determined by measurement of the prothrombin time (PT), which is standardized across institutions using an international normalized ratio (INR). Discontinuation If warfarin discontinuation is appropriate, we typically omit warfarin for five days before an elective surgery (the last dose of warfarin is given on day minus 6); this duration of warfarin interruption should lead to normalization of the INR by the time of surgery and obviates the need for routine INR testing one to two days before the surgery [8,14,46,47]. This approach also appears to be safe, without exposing patients to an increased risk for perioperative bleeding [48,49]. When INR testing is not routinely done, routine use of vitamin K is avoided. https://www.uptodate.com/contents/perioperative-management-of-patients-receiving-anticoagulants/print 13/65 7/5/23, 10:17 AM Perioperative management of patients receiving anticoagulants - UpToDate There may be circumstances when preoperative INR testing is warranted, such as in patients who have a <5 day warfarin interruption or a recent high INR (>4.5). In such cases, we check the INR one to two days before the surgery, and, if the INR is >1.5, a low dose of oral vitamin K (eg, 1 to 2 mg) can be given for selected patients and/or procedures in which a normalized INR is required; this can be followed by re-checking an INR the following day. An INR in the normal (<1.3) or near-normal (1.3 to 1.4) range is important in patients undergoing surgery associated with a high bleeding risk (eg, intracranial, spinal, urologic) or if neuraxial anesthesia is to be used. (See 'Estimating procedural bleeding risk' above and 'Neuraxial anesthesia' below.) This timing of warfarin discontinuation is based on the biologic half-life of warfarin (36 to 42 hours) and the observed time for the PT/INR to return to normal after stopping warfarin (two to three days for the INR to fall to below 2; four to six days to normalize) [46]. Normalization of the INR may take longer in patients receiving higher-intensity anticoagulation (INR 2.5 to 3.5) and in older individuals [50]. Half-lives of other vitamin K antagonists also differ (eg, 8 to 11 hours for acenocoumarol; approximately four to six days for phenprocoumon [51]; approximately three days for fluindione). (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Warfarin administration'.) For a procedure that requires more rapid normalization of the INR, additional interventions may be needed to actively reverse the anticoagulant. (See 'Urgent/emergency invasive procedure' below.) This discontinuation schedule will produce a period of several days with subtherapeutic anticoagulation. As an example, it is estimated that if warfarin is withheld for five days before surgery and is restarted as soon as possible afterwards, patients would have a subtherapeutic INR for approximately eight days (four days before and four days after surgery) [14]. Thus, for patients at very high or high thromboembolic risk, bridging may be appropriate. Use of bridging preoperatively We generally reserve bridging for individuals considered at very high or high risk of thromboembolism (eg, recent [within the prior three months] stroke, mechanical heart valve, CHA DS -VASc score of 7 or 8 ( table 3) (calculator 1), 2 2 CHADS score of 5 or 6) if they require interruption of warfarin. In these cases, the bridging 2 agent (eg, therapeutic-dose subcutaneous low molecular weight [LMW] heparin) is started three days before surgery. (See 'Bridging anticoagulation' below.) A bridging agent may also be appropriate if there is a prolonged period during which the patient cannot take oral medications (eg, postoperative ileus) and in patients who have had https://www.uptodate.com/contents/perioperative-management-of-patients-receiving-anticoagulants/print 14/65 7/5/23, 10:17 AM Perioperative management of patients receiving anticoagulants - UpToDate a thromboembolic event during a prior episode of perioperative anticoagulant interruption. This practice is based on expert opinion and has not been formally evaluated in a clinical trial. Restarting warfarin and postoperative bridging We resume warfarin 12 to 24 hours after surgery, typically the evening of the day of surgery or the evening of the day after surgery, assuming there were no unexpected surgical issues that would increase bleeding risk and the patient is taking adequate oral fluids [8]. We use the same dose the patient was receiving preoperatively. After warfarin is restarted in the perioperative setting, it takes 5 to 10 days to attain a full anticoagulant effect as measured by an INR above 2. Thus, we generally treat individuals at very high risk and some individuals with a high risk of thromboembolism with a heparin bridging agent during this period. (See 'Bridging anticoagulation' below.) DOAC interruptions (overview) Individuals who interrupt therapy with a direct oral anticoagulant (DOAC) will have a shorter period without anticoagulation than those who interrupt therapy with warfarin, due to the rapid resolution of anticoagulant effect when a DOAC is discontinued preoperatively and the rapid resumption of effect when a DOAC is restarted postoperatively. The PAUSE (Perioperative Anticoagulation Use for Surgery Evaluation) study, which prospectively evaluated outcomes in 3007 individuals who were taking a DOAC for atrial fibrillation and underwent an elective surgery or procedure and followed a simple, standardized management approach for interruption of their anticoagulant [52]. There was no preoperative coagulation testing and no heparin bridging. Rates of thromboembolic and hemorrhagic complications associated with this management were low (major bleeding in <2 percent; ischemic stroke in <0.5 percent), thereby supporting the safety of this approach. In addition, there was approximately 94 percent adherence to the preoperative and postoperative DOAC interruption and resumption protocols, thereby supporting the generalizability of this approach. The PAUSE approach is illustrated in the figure ( figure 1) and summarized as follows: Low/moderate bleed risk For low/moderate bleeding risk surgery, omit the DOAC one day before and resume one day (approximately 24 hours) after the procedure, provided hemostasis is secure. The total duration of interruption is two days. High bleed risk For high bleeding risk surgery, omit the DOAC two days before and resume two days (approximately 48 hours) after the procedure, provided hemostasis is https://www.uptodate.com/contents/perioperative-management-of-patients-receiving-anticoagulants/print 15/65 7/5/23, 10:17 AM Perioperative management of patients receiving anticoagulants - UpToDate secure. The total duration of interruption is four days. Waiting an additional one day before resumption may be appropriate in some cases. Impaired kidney function For individuals with impaired kidney function (creatinine clearance [CrCl] <30 to 50 mL/min) who are taking dabigatran, there is an additional one day interruption before low/moderate bleeding risk procedures and an additional two days interruption before high bleeding risk procedures. Direct factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) do not require adjustments for kidney function. Using this approach, residual DOAC levels (not required in routine practice) were in a low range (<50 ng/mL) in most patients overall, and in 99 percent of patients having a high bleeding risk surgery [52]. This approach is outlined in more detail in the following sections. The population in the PAUSE study was exclusively individuals with atrial fibrillation. The perioperative management from PAUSE can also be applied to patients who are receiving DOAC therapy for venous thromboembolism (VTE) and require treatment interruption for an elective procedure ( algorithm 1). For individuals in whom the VTE was >30 days prior, management can be followed in the same manner as individuals with atrial fibrillation. For those who had a recent VTE (within the prior 30 days), perioperative management should be individualized and may include placement of a temporary inferior vena cava (IVC) filter or shorter periods of DOAC interruption. (See 'Temporary IVC filters' above.) Dabigatran Dabigatran is a direct thrombin inhibitor; it reversibly blocks the enzymatic function of thrombin in converting fibrinogen to fibrin. Discontinuation Dabigatran can be omitted for one day before a low/moderate bleeding risk surgical procedure and for two days before a high bleeding risk procedure, in individuals with normal or mildly impaired kidney function (CrCl >50 mL/min) ( figure 1). For those with impaired kidney function (CrCl 30 to 50 mL/min), dabigatran can be omitted for two days before a low/moderate bleeding risk procedure and four days before a high bleeding risk procedure. As an example, in a patient on dabigatran with a CrCl >50 mL/min undergoing a high bleeding risk procedure, the patient will skip four doses of dabigatran (no drug on surgical day minus 2 and day minus 1) and no drug on the day of surgery ( table 5). In dabigatran-treated patients with a CrCl 30 to 50 mL/min undergoing a high bleeding risk procedure such as neuraxial anesthesia, a longer interval for interruption is required. (See 'Neuraxial anesthesia' below.) https://www.uptodate.com/contents/perioperative-management-of-patients-receiving-anticoagulants/print 16/65 7/5/23, 10:17 AM Perioperative management of patients receiving anticoagulants - UpToDate The last preoperative day on which dabigatran is administered can be more closely estimated based on the elimination half-life of dabigatran, which varies according to kidney function (eg, 12 to 14 hours in patients with normal kidney function) [2,53-56]. A protocol incorporating bleeding risk and CrCl was tested in a prospective cohort of 541 dabigatran- treated patients undergoing surgery and was associated with low rates of bleeding and thrombotic complications [56]. Routine coagulation tests have not been validated for ensuring that dabigatran effect has resolved. A normal or near-normal activated partial thromboplastin time (aPTT) may be used in selected patients to evaluate whether dabigatran has been adequately cleared from the circulation prior to surgery (eg, patients at high risk of surgical bleeding) ( table 6). Importantly, the reliability of aPTT testing may depend on the specific assay used; if available, a diluted plasma thrombin time may be preferable [54,57,58]. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Dabigatran' and "Clinical use of coagulation tests".) Use of bridging In general, the rapid offset and onset of dabigatran activity makes bridging anticoagulation unnecessary. We reserve bridging anticoagulation for selected individuals who are at very high risk for postoperative thromboembolism and require extended interruption of dabigatran. Examples include postoperative bridging in patients who are unable to take oral medications postoperatively due to intestinal ileus from gastrointestinal surgery. (See 'Bridging anticoagulation' below.) Restarting dabigatran Dabigatran should be resumed postoperatively when hemostasis has been achieved, at the same dose the patient was receiving preoperatively. In general, dabigatran can be restarted one day (approximately 24 hours) after a low/moderate bleeding risk surgery/procedure and two days (approximately 48 hours) after a high bleeding risk surgery/procedure. Since dabigatran has a rapid onset of action, with peak effects occurring two to three hours after intake, caution should be used in patients who have had major surgery or other procedures associated with a high bleeding risk. In cases where the resumption of dabigatran is delayed for two to three days and there is concern about patients being exposed to an increased risk for VTE, we usually administer a low- dose LMW heparin regimen (eg, enoxaparin 40 mg daily) until the DOAC is resumed. If this schedule is used, most patients will omit dabigatran for two total days for a low/moderate bleeding risk procedure and four total days for a high bleeding risk procedure. An additional one to two days of dabigatran interruption is done in patients with moderately impaired kidney function (CrCl 30 to 50 mL/min). https://www.uptodate.com/contents/perioperative-management-of-patients-receiving-anticoagulants/print 17/65 7/5/23, 10:17 AM Perioperative management of patients receiving anticoagulants - UpToDate Rivaroxaban Rivaroxaban is a direct factor Xa inhibitor; it reversibly blocks the enzymatic function of factor Xa in converting prothrombin to thrombin. Discontinuation Rivaroxaban can be omitted for one day in patients who are having a low/moderate bleeding risk surgical procedure and for two days before a high bleeding risk procedure ( figure 1). Thus, for low/moderate bleeding risk procedures, the patient will omit one dose of rivaroxaban on the one day before the procedure; for high bleeding risk procedures, the patient will omit two doses of rivaroxaban on the two days before the procedure. These intervals are based on an elimination half-life of 7 to 11 hours and apply to individuals with normal kidney function or mildly impaired kidney function (CrCl >50 mL/min), who are likely to be receiving the 20 mg once daily dose; and to those with moderately reduced kidney function (CrCl 30 to 50 mL/min), who are likely to be receiving the 15 mg once daily dose. Longer intervals for interruption may be required for situations in which the bleeding risk is very high, such as neuraxial anesthesia. (See 'Neuraxial anesthesia' below.) Rivaroxaban interacts with dual inhibitors of CYP-3A4 and P-glycoprotein (eg, systemic ketoconazole, ritonavir); dose adjustment or substitution of heparin may be appropriate if these dual CYP-3A4 and P-glycoprotein inhibitors are used perioperatively. Interactions with drugs that inhibit only one of these enzymes do not seem to alter rivaroxaban anticoagulant effect. Routine coagulation tests have not been validated for ensuring that the rivaroxaban anticoagulant effect has resolved. A normal or near-normal anti-factor Xa activity level may be used in selected patients to evaluate whether rivaroxaban has been adequately cleared from the circulation prior to surgery (eg, patients at high risk of surgical bleeding) ( table 6) [2]. The reliability of anti-factor Xa activity testing may depend on the specific assay used, and clinicians are advised to speak with their clinical laboratory to determine whether this assay is available at their institution and whether it has been validated for direct factor Xa inhibitors. Use of bridging In general, the rapid offset and onset of rivaroxaban makes bridging anticoagulation unnecessary. In rare cases bridging may be required, such as the use of postoperative bridging in individuals who have a very high thromboembolic risk and are unable to take oral medications postoperatively due to intestinal ileus from gastrointestinal surgery. (See 'Bridging anticoagulation' below.) Restarting rivaroxaban Rivaroxaban can be resumed postoperatively when hemostasis has been achieved, at the same dose the patient was receiving preoperatively. In general, https://www.uptodate.com/contents/perioperative-management-of-patients-receiving-anticoagulants/print 18/65 7/5/23, 10:17 AM Perioperative management of patients receiving anticoagulants - UpToDate rivaroxaban can be restarted one day after a low/moderate bleeding risk procedure and two days after a high bleeding risk procedure. Since rivaroxaban has a rapid onset of action, caution should be used in patients who have had major surgery or other procedures associated with a high bleeding risk. We generally restart rivaroxaban one day after low bleeding risk surgery and two to three days after high bleeding risk surgery. In cases where the resumption of rivaroxaban is delayed for two to three days and there is concern about patients being exposed to an increased risk for VTE, we usually administer a low-dose LMW heparin regimen (eg, enoxaparin 40 mg daily) until the DOAC is resumed. If this schedule is used, most patients will omit rivaroxaban for two total days for a low/moderate bleeding risk procedure and four total days for a high bleeding risk procedure. Adjustments are not made routinely for patients with moderately impaired kidney function (CrCl 30 to 50 mL/min). Apixaban Apixaban is a direct factor Xa inhibitor; it reversibly blocks the enzymatic function of factor Xa in converting prothrombin to thrombin. Discontinuation Apixaban can be omitted for one day before a low/moderate bleeding risk procedure and for two days before a high bleeding risk procedure ( figure 1). Thus, for low/moderate bleeding risk procedures, the patient will omit two dose of apixaban on the one day before the procedure; for high bleeding risk procedures, the patient will omit four doses of apixaban on the two days before the procedure. These intervals are based on an apixaban elimination half-life of 8 to 12 hours. These intervals apply to individuals with normal kidney function or mildly impaired kidney function (CrCl >50 mL/min), who are likely to be receiving the 5 mg twice daily dose; and to those with moderate to severe kidney insufficiency (CrCl 30 to 50 mL/min), who are likely to be receiving the 2.5 mg twice daily dose. Longer intervals for interruption may be required for situations in which the bleeding risk is very high, such as neuraxial anesthesia. (See 'Neuraxial anesthesia' below.) Routine coagulation tests have not been validated for ensuring that apixaban effect has resolved. A normal or near-normal anti-factor Xa activity level may be used in selected patients to evaluate whether apixaban has been adequately cleared from the circulation prior to surgery (eg, patients at high risk of surgical bleeding) ( table 6). The reliability of anti-factor Xa activity testing may depend on the specific assay used, and clinicians are advised to speak with their clinical laboratory to determine whether this assay is available at their institution and whether it has been validated for direct factor Xa inhibitors. https://www.uptodate.com/contents/perioperative-management-of-patients-receiving-anticoagulants/print 19/65 7/5/23, 10:17 AM Perioperative management of patients receiving anticoagulants - UpToDate Use of bridging In general, the rapid offset and onset of apixaban makes bridging anticoagulation unnecessary. In rare cases, bridging may be required, such as the use of postoperative bridging in individuals who have a very high thromboembolic risk and are unable to take oral medications postoperatively due to intestinal ileus from gastrointestinal surgery. (See 'Bridging anticoagulation' below.) Restarting apixaban Apixaban can be resumed postoperatively when hemostasis has been achieved, at the same dose the patient was receiving preoperatively. In general, apixaban can be restarted one day after a low/moderate bleeding risk procedure and two days after a high bleeding risk procedure. Since apixaban has a rapid onset of action, caution should be used in patients who have had major surgery or other procedures associated with a high bleeding risk. We generally restart apixaban one day after low/moderate bleeding risk surgery and two days after a high bleeding risk surgery. In cases where the resumption of apixaban is delayed for two to three days and there is concern about patients being exposed to an increased risk for VTE, we usually administer a low-dose LMW heparin regimen (eg, enoxaparin 40 mg daily) until the DOAC is resumed. If this schedule is used, most patients will omit apixaban for two total days for a low/moderate bleeding risk procedure and four total days for a high bleeding risk procedure. Adjustments are not made routinely for patients with moderately impaired kidney function (CrCl 30 to 50 mL/min). Edoxaban Edoxaban is a direct factor Xa inhibitor; it reversibly blocks the enzymatic function of factor Xa in converting prothrombin to thrombin. Discontinuation Edoxaban can be omitted for one day before a low/moderate bleeding risk procedure and for two days before a high bleeding risk procedure ( figure 1). Thus, for low/moderate bleeding risk procedures, the patient will omit one dose of edoxaban on the one day before the procedure; for high bleeding risk procedures, the patient will omit two doses of edoxaban on the two days before the procedure. These intervals are based on an edoxaban elimination half-life of 10 to 14 hours. These intervals apply to individuals with normal kidney function or mildly impaired kidney function(CrCl >50 mL/min) and those with moderately impaired kidney function (CrCl 30 to 50 mL/min), who are likely to be receiving the 60 mg once daily or the 30 mg once daily doses, respectively. Longer intervals for interruption may be considered for those undergoing major surgery, neuraxial anesthesia or manipulation, or other situations in which complete hemostatic function may be required. (See 'Neuraxial anesthesia' below.) https://www.uptodate.com/contents/perioperative-management-of-patients-receiving-anticoagulants/print 20/65 7/5/23, 10:17 AM Perioperative management of patients receiving anticoagulants - UpToDate Routine coagulation tests have not been validated for ensuring that edoxaban effect has resolved. A normal or near-normal anti-factor Xa activity level may be used in selected patients to evaluate whether edoxaban has been adequately cleared from the circulation prior to surgery (eg, patients at high risk of surgical bleeding) ( table 6). The reliability of anti-factor Xa activity testing may depend on the specific assay used, and clinicians are advised to speak with their clinical laboratory to determine whether this assay is available at their institution and whether it has been validated for direct factor Xa inhibitors. Use of bridging In general, the rapid offset and onset of edoxaban makes bridging anticoagulation unnecessary. In rare cases, bridging may be required, such as the use of postoperative bridging in individuals who have a very high thromboembolic risk and are unable to take oral medications postoperatively due to intestinal ileus from gastrointestinal surgery. (See 'Bridging anticoagulation' below.) Restarting edoxaban Edoxaban can be resumed postoperatively when hemostasis has been achieved, at the same dose the patient was receiving preoperatively. In general, edoxaban can be restarted one day after a low/moderate bleeding risk procedure and two days after a high bleeding risk procedure. Since edoxaban has a rapid onset of action, caution should be used in patients who have had major surgery or other procedures associated with a high bleeding risk. We generally restart edoxaban one day after low bleeding risk surgery and two to three days after high bleeding risk surgery. In cases where the resumption of edoxaban is delayed for two to three days and there is concern about patients being exposed to an increased risk for VTE, we usually administer a low- dose LMW heparin regimen (eg, enoxaparin 40 mg daily) until the DOAC is resumed. If this schedule is used, most patients will omit edoxaban for two total days for a low/moderate bleeding risk procedure and four total days for a high bleeding risk procedure. BRIDGING ANTICOAGULATION Bridging anticoagulation involves the administration of a short-acting anticoagulant, typically a low molecular weight (LMW) heparin, during the interruption of a longer-acting agent, typically warfarin. Limited indications for bridging The intent of bridging is to minimize the time the patient is not anticoagulated, thereby minimizing the risk for perioperative thromboembolism. However, this needs to be balanced with the importance of mitigating the risk of postoperative bleeding. Accumulating evidence suggests that in the vast majority of patients, bridging does not provide a benefit in lowering thromboembolic risk, whereas most data show a consistent increase in https://www.uptodate.com/contents/perioperative-management-of-patients-receiving-anticoagulants/print 21/65 7/5/23, 10:17 AM Perioperative management of patients receiving anticoagulants - UpToDate bleeding risk. Our approach to the use of bridging is depicted in the algorithm ( algorithm 1) and summarized as follows: Avoid bridging in individuals who have low thromboembolic risk with anticoagulant interruption [59]: Individuals receiving a direct oral anticoagulant (DOAC), unless they have a high thromboembolic risk and a prolonged period during which they cannot take the DOAC postoperatively (eg, due to intestinal ileus) Routine prophylactic anticoagulation in atrial fibrillation Secondary prophylaxis following venous thromboembolism (VTE) (more than three months prior) Bridging may be appropriate during warfarin discontinuation in the following individuals, shown below; however, it may also be considered in other individuals in whom the clinician deems bridging appropriate based on individual patient characteristics and the type of surgery or procedure [1,59]: Mechanical mitral valve (exceptions may include those with newer-generation On-X valves or without any additional stroke risk factors) (see "Antithrombotic therapy for mechanical heart valves", section on 'Lower INR target for On-X aortic valve') Mechanical aortic valve with major additional stroke risk factors (eg, prior stroke or TIA) Embolic stroke within the previous three months or very high stroke risk (eg, CHADS 2 score of 5 or 6) VTE within the previous three months (except those with a calf deep vein thrombosis (DVT) and no evidence of DVT on repeat ultrasound, who may not require bridging) Possibly in selected individuals with recent coronary stenting (eg, within the previous three months) (see "Periprocedural management of antithrombotic therapy in patients receiving long-term oral anticoagulation and undergoing percutaneous coronary intervention") Previous thromboembolism during interruption of chronic anticoagulation (based on presumed increased risk; not addressed in clinical trials) Individuals with valvular atrial fibrillation (or associated with mitral valvular heart disease) have not been included in large trials, and there may be cases in which the clinician who best knows https://www.uptodate.com/contents/perioperative-management-of-patients-receiving-anticoagulants/print 22/65 7/5/23, 10:17 AM Perioperative management of patients receiving anticoagulants - UpToDate the patient may have greater concerns about thrombosis and may decide that bridging is appropriate. We feel more strongly about avoiding bridging the lower the patient's baseline thromboembolic risk (eg, lower CHADS or CHA DS -VASc score ( table 3)) and the higher the 2 2 2 risk of bleeding. Evidence to support the limited use of bridging to selected individuals with very high thromboembolic risk comes from several meta-analyses. As an example, a 2020 meta-analysis that included six randomized trials and 12 cohort studies found that bridging was associated with an increased risk of bleeding (relative risk [RR] 2.83; 95% CI 2.00-4.01) with no statistical reduction in thromboembolic risk (RR 1.26; 95% CI 0.61-2.58) [60]. Supporting evidence for the practice of avoiding bridging in most individuals with atrial fibrillation includes the following: In the BRIDGE trial (Bridging Anticoagulation in Patients who Require Temporary Interruption of Warfarin Therapy for an Elective Invasive Procedure or Surgery), which randomly assigned 1884 patients with atrial fibrillation who required interruption of warfarin for an invasive procedure to receive bridging anticoagulation with the LMW heparin dalteparin versus placebo, the incidence of arterial thromboembolic events 30 days after the procedure was similar in those who received dalteparin or placebo (0.3 versus 0.4 percent) [48]. The incidence of major bleeding (a secondary outcome) was higher in those who received dalteparin (3.2 versus 1.3 percent), although none of the bleeds were fatal. Patients were excluded from the trial if they had a mechanical heart valve or a recent (within previous 12 weeks) stroke, embolism, or transient ischemic attack. The PERIOP-2 trial assessed 1471 patients with atrial fibrillation or a mechanical heart valve who required warfarin interruption for an elective surgery/procedure [49]. A mechanical heart valve was present in 21 percent (mitral in 9 percent; aortic in 12 percent). Before the surgery/procedure, all patients received bridging with the LMW heparin dalteparin, 200 IU/kg daily (100 IU/kg daily on the day before the surgery/procedure). After the surgery/procedure, patients were randomly assigned to receive dalteparin 200 IU/kg daily (fixed-dose 5,000 IU daily in patients at high-bleed-risk) or placebo until the INR was 2.0 and were followed for 12 weeks. There was no significant difference in the risk of major thromboembolism (for atrial fibrillation, 1.41 versus 0.75 percent, p = 0.27; for mechanical valves, 0 versus 0.67 percent, p = 0.49) or for major bleeding (for atrial fibrillation, 2.62 versus 1.64 percent, p = 0.25; for mechanical valves, 1.96 versus 0.67 percent, p = 0.62). Bridging versus no bridging did not affect major outcomes in patients who required a major procedure during participation in large anticoagulation trials for atrial fibrillation, https://www.uptodate.com/contents/perioperative-management-of-patients-receiving-anticoagulants/print 23/65 7/5/23, 10:17 AM Perioperative management of patients receiving anticoagulants - UpToDate including the RE-LY (warfarin versus dabigatran), ROCKET-AF (warfarin versus rivaroxaban), and ARISTOTLE (warfarin versus apixaban) trials [9-11]. In the RE-LY trial, patients receiving warfarin had more thromboembolic events associated with bridging than with non-use of bridging (1.8 versus 0.3 percent); patients who received bridging also had a higher risk of major bleeding (warfarin: 6.8 percent with bridging, 1.6 percent without; dabigatran: 6.5 percent with bridging, 1.8 percent without) [61]. Additional real world data come from the ORBIT-AF and Dresden registries. ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) is a community-based registry of outpatients with atrial fibrillation receiving any oral anticoagulant; in this study, 2200 of 7372 individuals (30 percent) had interruption of anticoagulation for a procedure [62]. Bridging was used in 24 percent of these interruptions, especially in patients with a history of stroke or a mechanical heart valve and/or receiving warfarin; bleeding events were more common in individuals who received bridging compared with those who did not receive bridging (5 versus 1.3 percent). A composite endpoint that included major bleeding, myocardial infarction, stroke, systemic embolism, hospitalization, or death within 30 days was also higher in those who received bridging (13 versus 6.3 percent). In the Dresden NOAC registry, over 800 patients who were receiving dabigatran, rivaroxaban, or apixaban for any indication and underwent an invasive procedure had similar rates of major cardiovascular events if they received bridging, no bridging, or no anticoagulant discontinuation [63]. Bridging was not an independent risk factor for major bleeding; however, individuals undergoing major procedures were more likely to receive bridging and to have major bleeding. Supporting evidence for the practice of avoiding bridging in other groups includes the following: VTE In a systematic review from 2019 that evaluated patients who were receiving a vitamin K antagonist to treat venous thromboembolism (VTE; 28 cohort studies that included nearly 7000 procedures), the pooled incidence of recurrent VTE was similar with and without bridging [64]. The risk of bleeding was generally higher when bridging was used. Any indication for anticoagulation In a large systematic review and meta-analysis involving 34 studies (33 observational and one randomized) in patients receiving a vitamin K antagonist for any indication who were undergoing elective surgery or procedures. there was no significant difference in the rate of thromboembolism in patients who received bridging compared with patients who did not (odds ratio [OR] 0.80; 95% CI 0.42-1.54) [65]. https://www.uptodate.com/contents/perioperative-management-of-patients-receiving-anticoagulants/print 24/65 7/5/23, 10:17 AM Perioperative management of patients receiving anticoagulants - UpToDate Bridging was associated with a threefold increase in major bleeding compared with no bridging (OR 3.60; 95% CI 1.52-8.50); full-dose heparin was associated with an increase in overall bleeding compared with lower heparin doses (OR 2.28; 95% CI 1.27-4.08). (See 'Heparin product and dose' below.) A potential role for bridging in reducing the risk of "rebound hypercoagulability" has also been proposed; however, this premise is not supported by data from the BRIDGE trial discussed above [48]. Heparin product and dose Typically, LMW heparins are used for bridging, as they have similar efficacy compared with unfractionated heparin, are more convenient to use, and generally do not require monitoring. Intravenous unfractionated heparin is less costly and can be reversed more rapidly than subcutaneous LMW heparin; it may be a reasonable alternative in some individuals. We prefer LMW heparin for bridging anticoagulation in individuals with a very high risk of arterial thromboembolism (eg, rheumatic heart disease, atrial fibrillation with recent embolic stroke, high-risk mechanical heart valve) and those with a moderate risk of thromboembolism (eg, active cancer) [27,28,66]. Perioperative anticoagulation management in individuals with prosthetic heart valves is discussed in detail separately. (See "Anticoagulation for prosthetic heart valves: Management of bleeding and invasive procedures", section on 'Planning for invasive procedures'.) For individuals with impaired kidney function and/or those requiring hemodialysis, intravenous or subcutaneous unfractionated heparin can be used more easily because dosing is unaffected by kidney function [67]. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'LMW heparin standard dosing'.) There are no data on using the direct oral anticoagulants (DOACs) as bridging agents. We do not use any of the DOACs for bridging. Heparins can be dosed at prophylactic doses, therapeutic doses, or doses intermediate between the two. The term "therapeutic dose" refers to doses typically used for treatment of thromboembolic disease, despite the fact that in this case it is being used prophylactically (to prevent thromboembolism). There are no clinical trial data or practice standards to guide dosing, and clinical judgment is required to determine the appropriate dose for each patient [65,68,69]. https://www.uptodate.com/contents/perioperative-management-of-patients-receiving-anticoagulants/print 25/65 7/5/23, 10:17 AM Perioperative management of patients receiving anticoagulants - UpToDate Therapeutic dosing Therapeutic dosing (also called "full dose") is appropriate for bridging anticoagulation for individuals with a potential arterial thromboembolic source (eg, atrial fibrillation, mechanical heart valve) or VTE within the preceding month. Typical regimens include enoxaparin, 1 mg/kg subcutaneously twice daily or dalteparin, 100 units/kg subcutaneously twice daily. Intermediate dosing Intermediate-dose anticoagulation may be appropriate for individuals with atrial fibrillation or VTE within the preceding month when bridging is needed but concerns about bleeding are greater. Typical regimens include enoxaparin, 40 mg twice daily, or dalteparin, 5000 units subcutaneously twice daily. Prophylactic dosing Prophylactic-dose anticoagulation (also called "low dose") generally