Perioperative Management of Anticoagulant and Antiplatelet Therapy PDF

Published May 23, 2023 NEJM Evid 2023; 2 (6) DOI: 10.1056/EVIDra2200322 REVIEW ARTICLE Perioperative Management of Anticoagulant and Antiplatelet Therapy James D. Douketis, M.D.,1 and Alex C. Spyropoulos, M.D.2,3,4 Abstract The management of patients who are receiving an anticoagulant or antiplatelet drug and C. Corey Hardin, M.D., Ph.D., Editor require surgery or an invasive procedure is a common clinical problem encountered by a broad spectrum of health care professionals. This review provides an evidence-based but practical approach to common clinical scenarios involving patients who require an elective surgery/procedure and are receiving either a vitamin K antagonist, a direct oral anticoagulant, or single or dual antiplatelet therapy. This review also addresses the role of perioperative heparin bridging and the management of patients who are receiving an anticoagulant drug and need urgent surgery. Introduction T he management of patients who are receiving an anticoagulant or antiplatelet drug and require surgery or an invasive procedure is a common clinical problem1,2 that is increasing due to an aging population, with more patients likely to require a surgery/procedure.3-5 This review aims to inform the clinician managing patients who require surgery or a procedure and are receiving a vitamin K antagonist (VKA) and may need heparin bridging, a direct oral anticoagulant (DOAC), or single or dual antiplatelet therapy with acetylsalicylic acid (ASA) and/or a P2Y12 inhibitor. Foundational Concepts in Perioperative Antithrombotic Management For patients who need an elective surgery/procedure, perioperative antithrombotic management is anchored on an assessment of patient- and procedure-related risks for bleeding and thromboembolism (Tables 1 and 2), an understanding of pharmacologic properties of antithrombotic drugs pertinent to perioperative management (Tables S1 and S2 in the Supplementary Appendix), and ensuring adequate communication and management consensus among the health care team. The author afﬁliations are listed at the end of the article. Dr. Douketis can be contacted at [email protected] or at St. Joseph’s Healthcare Hamilton, Room F-544, 50 Charlton Ave. East, Hamilton, ON, Canada L8N 4A6. NEJM Evidence is produced by NEJM Group, a division of the Massachusetts Medical Society. Downloaded from evidence.nejm.org at HOSP UNIV DE TARRAGONA JOAN XXIII on June 26, 2023. For personal use only. No other uses without permission. Copyright © 2023 Massachusetts Medical Society. All rights reserved. For personal use only. No other uses without permission. Copyright © 2023 Massachusetts Medical Society. Table 1. Risk Classification for Surgery/Procedure-Related Bleeding.* High-bleed-risk surgery/procedure† (30-day risk of major bleed ‡2%) Major surgery with extensive tissue injury Cancer surgery, especially solid tumor resection (lung, esophagus, gastric, colon, hepatobiliary, pancreatic) Major orthopedic surgery, including shoulder replacement surgery Reconstructive plastic surgery Major thoracic surgery Urologic or gastrointestinal surgery, especially anastomosis surgery Transurethral prostate resection, bladder resection, or tumor ablation Nephrectomy, kidney biopsy Colonic polyp resection Bowel resection Percutaneous endoscopic gastrostomy placement, endoscopic retrograde cholangiopancreatography Surgery in highly vascular organs (kidneys, liver, spleen) Cardiac, intracranial, or spinal surgery Any major operation (procedure duration .45 minutes) Neuraxial anaesthesia¶ Epidural injections Low/moderate-bleed-risk surgery/procedure‡ (30-day risk of major bleed 0%–2%) Arthroscopy Cutaneous/lymph node biopsies Foot/hand surgery Coronary angiography by femoral artery approach Gastrointestinal endoscopy – biopsy§ Colonoscopy – biopsy§ Abdominal hysterectomy Laparoscopic cholecystectomy Abdominal hernia repair Hemorrhoidal surgery Bronchoscopy – biopsy Minimal-bleed-risk surgery/procedure§ (30-day risk of major bleed ~0%) Minor dermatologic procedures (excision of basal and squamous cell skin cancers, actinic keratoses, and premalignant or cancerous skin nevi) Ophthalmological (cataract) procedures Minor dental procedures (dental extractions, restorations, prosthetics, endodontics), dental cleanings, fillings Pacemaker or cardioverter-defibrillator device implantation Coronary angiography by radial artery approach Selected patients requiring screening gastrointestinal endoscopy and colonoscopy – biopsyk * Adapted from 2022 CHEST Guidelines. † No residual anticoagulant effect at the time of the procedure (i.e., four to five drug half-life interruption preprocedure). ‡ Some residual anticoagulant effect allowed (i.e., two to three drug half-life interruption preprocedure). § Procedure can be safely done under full-dose anticoagulation (may consider holding direct oral anticoagulant dose the day of the procedure to avoid peak anticoagulant effects). ¶ Includes spinal and epidural anesthesia or any other neuraxial (e.g., pain management) intervention; consider not only the absolute risk for major bleeding but potentially devastating consequences of epidural bleeding and associated lower limb paralysis. k Selected patients, especially if taking a vitamin K antagonist and in whom polypectomy is not anticipated, may be classified as minimal-bleed-risk; whether they are classified as low/moderate-bleed-risk (requiring anticoagulant interruption) or minimal-bleed-risk (not requiring anticoagulant interruption) should be based on individual patient characteristics and in discussion with the proceduralist. RISK ASSESSMENT FOR BLEEDING AND THROMBOEMBOLISM PHARMACOLOGIC PROPERTIES OF ANTICOAGULANT AND ANTIPLATELET DRUGS Given the heterogeneity in thromboembolic and bleed risk proﬁles of individual patients and various surgeries/ procedures,6-8 perioperative antithrombotic management adopts a patient-centric approach. Empiric risk classiﬁcation schemes for bleed risk (Table 1) and thromboembolic risk (Table 2)1,9,10 have been developed to guide management but may be overridden depending on individual patient circumstances and clinical judgment. In patients with coronary artery disease, risk classiﬁcation schemes are provided elsewhere but are also empiric.11-13 Knowledge of key pharmacokinetic and pharmacodynamic properties of anticoagulant and antiplatelet drugs, as shown in Tables S1 and S2, respectively, in the Supplementary Appendix, is important to minimize bleeding and thromboembolism risks.14,15 The timing of preoperative interruption of VKAs and DOACs is informed by the anticoagulant t1/2 (elimination half-life), whereas the timing of postoperative anticoagulant resumption is informed by the tmax (time to maximum anticoagulant activity).16 These properties also guide the use of heparin bridging, usually NEJM EVIDENCE NEJM Evidence is produced by NEJM Group, a division of the Massachusetts Medical Society. Downloaded from evidence.nejm.org at HOSP UNIV DE TARRAGONA JOAN XXIII on June 26, 2023. For personal use only. No other uses without permission. Copyright © 2023 Massachusetts Medical Society. All rights reserved. For personal use only. No other uses without permission. Copyright © 2023 Massachusetts Medical Society. 2 Table 2. Risk Classification for Thromboembolism.* Risk Category Mechanical Heart Valve Atrial Fibrillation Venous Thromboembolism High (.10%/year risk of ATE or .10%/month risk of VTE) Mechanical mitral valve with risk factors for stroke† Caged ball or tilting disc valve in mitral/aortic position Recent (,3 month) stroke or TIA CHA2DS2VASc score of 7 CHADS2 score of 5 or 6 Recent (,3 month) stroke or TIA Rheumatic valvular heart disease Recent (,3 months and especially 1 month) VTE Severe thrombophilia (deficiency of protein C, protein S or antithrombin; homozygous factor V Leiden or prothrombin gene mutation or double-heterozygous for each mutation, multiple thrombophilias) Antiphospholipid syndrome Active cancer associated with high VTE risk‡ Moderate (4%–10%/year risk of ATE or 4%–10%/month risk of VTE) Bileaflet AVR with major risk factors for stroke† CHA2DS2VASc score of 5 or 6 CHADS2 score of 3 or 4 VTE within the past 3–12 months Recurrent VTE Nonsevere thrombophilia (heterozygous factor V Leiden or prothrombin gene mutation) Active cancer or recent history of cancer§ Low (,4%/year risk of ATE or ,2%/month risk of VTE) Bileaflet AVR without major risk factors for stroke† CHA2DS2VASc score of 1–4 CHADS2 score of 0–2 (and no prior stroke or TIA) VTE more than 12 months ago * Adapted from 2022 CHEST Guidelines. ATE denotes arterial thromboembolism; AVR, aortic valve replacement; TIA, transient ischemic attack; and VTE, venous thromboembolism. † Includes atrial fibrillation, prior stroke or transient ischemic attack (including during perioperative period), prior valve thrombosis, rheumatic valvular heart disease, hypertension, diabetes, congestive heart failure, age .75 years. ‡ Includes pancreatic cancer, myeloproliferative disorders, primary brain cancer, gastric cancer, and esophageal cancer. § Within 5 years if history of cancer, excluding nonmelanoma skin cancer. with low-molecular-weight heparin (LMWH).17 Antiplatelet potency and platelet function reversibility also inform perioperative drug interruption and resumption.1,18 Patients Taking a VKA Although VKAs comprise warfarin, acenocoumarol, and phenprocoumon, most evidence around perioperative management pertains to warfarin. PERIOPERATIVE VKA CONTINUATION There are several surgeries/procedures classiﬁed as having minimal bleed risk (Table 1) in which VKAs can be continued without interruption.19-25 Evidence from small, randomized trials and cohort studies supports the safety of continuing VKAs around minor dental and dermatologic procedures and cataract surgery, which is a mainly avascular procedure.1,9,10 There is emerging evidence as to the safety of continuing VKAs around gastrointestinal endoscopic procedures when done for screening purposes that require biopsies but where polypectomy is not anticipated.26 This approach is supported by practice guidelines but does not extend to DOACs due to lack of evidence for periendoscopic continuation. Table 1 classiﬁes bleed risk in common gastrointestinal procedures, which guides whether anticoagulants are interrupted or continued. Well-designed randomized trials, including BRUISE CONTROL-1,27 have shown that in patients with cardiac device implantation, a warfarin continuation approach is associated with less bleeding than warfarin interruption with heparin bridging.22,28 Preventing device pocket-site bleeding is important because its occurrence increases the risk for infection, which can have major clinical consequences.29,30 In patients in whom VKAs are continued, it is assumed that the degree of anticoagulation, as measured by the international normalized ratio (INR), will not be excessive, with an INR less than 3.0 at the time of the procedure. In certain dental or dermatologic procedures, patients may require adjunctive hemostatic measures such as oral tranexamic mouthwash or pressure dressings. For cataract surgery, it is assumed (as is the current practice in most patients) that topical instead of retrobulbar anesthesia will be used because the latter may increase the risk of retro-orbital bleeding. PERIOPERATIVE HEPARIN BRIDGING In a surgery/procedure that requires VKA interruption, heparin bridging may be considered, typically with a therapeutic-dose LMWH regimen (e.g., dalteparin, 100 IU/kg twice daily), which is the most widely studied and which NEJM EVIDENCE NEJM Evidence is produced by NEJM Group, a division of the Massachusetts Medical Society. Downloaded from evidence.nejm.org at HOSP UNIV DE TARRAGONA JOAN XXIII on June 26, 2023. For personal use only. No other uses without permission. Copyright © 2023 Massachusetts Medical Society. All rights reserved. For personal use only. No other uses without permission. Copyright © 2023 Massachusetts Medical Society. 3 usually (but not always) is administered before and after a surgery/procedure. The therapeutic premise of heparin bridging has been to shorten the period before and after a surgery/procedure so that patients are not fully anticoagulated while a VKA is interrupted and, in turn, to reduce the risk for perioperative stroke and other thromboembolism. The perioperative milieu, however, is one in which thromboembolism may occur through various mechanisms that would not be affected by perioperative heparin bridging.7 Large randomized controlled trials, including BRIDGE and PERIOP-2, and multiple observational studies provide consistent evidence that administering LMWH bridging during warfarin interruption in patients with atrial ﬁbrillation or mechanical heart valves does not affect the incidence of perioperative thromboembolism but increases the risk for major bleeding by threefold or higher.31-34 Moreover, the occurrence of perioperative bleeding, although typically treatable, has the consequence of delaying the resumption of anticoagulant therapy postprocedure, which then exposes patients to a downstream increased risk for thromboembolism.35 Recent practice guidelines recommend against routine heparin bridging in VKA-treated patients with atrial ﬁbrillation and advise against heparin bridging in patients with venous thromboembolism and in selected patients with a mechanical heart valve.1 Selected patients in whom heparin bridging may be warranted include those categorized as at high risk for thromboembolism (Table 2). The approach to warfarin interruption and bridging with an LMWH (Fig. 1) aims to minimize both the time patients are not fully anticoagulated and the bleeding risk. The rapid peak effect of LMWHs, occurring 3 to 4 hours after administration, prompts the need for ﬂexibility in the timing of postoperative resumption: approximately 24 hours for low/moderate-bleed-risk and 48 to 72 hours for high-bleed-risk surgery/procedures.36 With selected high-bleed-risk surgeries (e.g., cardiac or intracranial), the risks and consequences of bleeding may preclude the use of postoperative bridging with therapeutic-dose LMWH, and in such patients, a prophylactic (low-dose) LWMH regimen (e.g., dalteparin, 5000 IU daily) can be given for 3 to 5 days while the VKA is resumed. Avoidance of postoperative heparin bridging is also advised in patients when surgical hemostasis is inadequate. Finally, routinely measuring antifactor Xa levels during perioperative bridging has not been studied31-33 and is unlikely to have clinical utility. TIMING OF VKA INTERRUPTION AND RESUMPTION Stopping warfarin (36- to 42-hour half-life) 5 days before the day of the surgery/procedure is sufﬁcient to ensure that more than 90% of such patients will have a normal (<1.3) or near-normal (1.3 to 1.4) INR at the time of the surgery, thereby obviating the need for routine preoperative INR testing.35,37 Shorter (2 to 3 days) and longer (7 to 10 days) interruptions are needed for acenocoumarol and phenprocoumon, respectively. Warfarin can be resumed Minimal-bleed-risk Warfarin Low/moderate-bleed-risk Warfarin* Warfarin LMWH** High-bleed-risk LMWH** Warfarin* Warfarin LMWH** –7 –6 –5 –4 –3 –2 LMWH**† –1 0 1 2 3 4 5 Day of Surgery/Procedure Figure 1. Perioperative Management of Vitamin K Antagonists (Warfarin), Adapted from the 2022 ACCP Guidelines. * Warfarin can be resumed on the evening of the procedure (day 0) for most patients or the day after the procedure (i.e., day 1) at the patient’s usual maintenance dose. ** Bridging suggested for high thrombotic risk populations with full-dose, subcutaneous low-molecular-weight heparin (LMWH; e.g., enoxaparin, 1 mg/kg twice a day or 1.5 mg/kg daily or dalteparin, 100 IU/kg twice a day or 200 IU/kg daily), with the last dose given the morning of the day prior to the procedure (i.e., day 21) at half the total daily dose. † Low-dose LMWH (e.g., enoxaparin, 40 mg daily or dalteparin, 5000 IU daily) can be used for venous thromboembolism prophylaxis for the ﬁrst 24 to 72 hours postprocedure, with full-dose LMWH resumed 2 to 3 days postprocedure. NEJM EVIDENCE NEJM Evidence is produced by NEJM Group, a division of the Massachusetts Medical Society. Downloaded from evidence.nejm.org at HOSP UNIV DE TARRAGONA JOAN XXIII on June 26, 2023. For personal use only. No other uses without permission. Copyright © 2023 Massachusetts Medical Society. All rights reserved. For personal use only. No other uses without permission. Copyright © 2023 Massachusetts Medical Society. 4 within 24 hours of, and often on the evening of, the surgery/procedure. Although doubling the ﬁrst postoperative dose of warfarin, as compared with resuming the usual warfarin dose, has been supported by some studies,38 the beneﬁt in terms of time to reach a therapeutic INR is limited (~1 day faster).35,39,40 An interruption of longer than 5 days may be required in patients who have delayed warfarin elimination due to advanced age or interacting drugs that interfere with warfarin metabolism and in patients with a recent high (>3.5) INR or with a higher target INR (i.e., 2.5 to 3.5).41,42 Patients Taking a DOAC In patients taking DOACs (apixaban, dabigatran, edoxaban, or rivaroxaban), perioperative management is anchored on their 10- to 14-hour elimination half-lives (18 to 24 hours for dabigatran in patients with impaired renal function), which informs preoperative interruption, and their rapid onset of action that occurs 2 to 3 hours after intake, which informs postoperative resumption.43 Key pharmacokinetic properties of DOACs relevant for perioperative management are shown in Table S1. This rapid offset and onset of action obviate the need for heparin bridging. Subanalyses and a meta-analysis of randomized trials comparing DOAC versus warfarin therapy in patients with atrial ﬁbrillation who required an elective surgery found that patients who received heparin bridging during DOAC interruption had an approximately threefold higher risk of major bleeding with no effect on thromboembolism.44-47 PERIOPERATIVE DOAC CONTINUATION Most studies assessing DOACs involve patients with a cardiac device implant. These studies suggest that DOACs can be safely continued around pacemaker or internal cardiac deﬁbrillator implantation48 and in patients having an atrioventricular node ablation procedure.49-51 A randomized trial comparing the continuation of dabigatran versus 1 to 2 days of interruption found no signiﬁcant difference in rates of pocket hematoma (2.1% vs. 2.1%).52 A subanalysis of randomized trials comparing DOACs versus warfarin use in patients with atrial ﬁbrillation found less bleeding with periprocedural continuation of DOACs than with warfarin continuation.47 For minor dental and skin procedures and cataract surgery, DOAC continuation appears to be safe,53-55 preferably with a delayed dose (for once-daily DOACs) until after a procedure (or omitting the morning dose for twice-daily DOACs) to avoid a peak anticoagulant effect during the procedure. DOAC INTERRUPTION AND RESUMPTION In patients in whom DOAC interruption is required, evidence for recommended management (Fig. 2) is derived mainly from the PAUSE trial, in which 3007 patients with atrial ﬁbrillation who were taking a DOAC (1257 on apixaban, 668 on dabigatran, and 1082 on rivaroxaban) received standardized perioperative management based on pharmacokinetic principles.56 This approach was associated with low 30-day perioperative rates of thromboembolism (0.16% to 0.60%) and major bleeding (0.9% to 1.85%), depending on the DOAC. In patients having a low/moderate-bleed-risk surgery/ procedure, which encompasses most day surgeries that typically last less than 1 hour and most ambulatory procedures, PAUSE-based management requires 1 day off the DOAC before the surgery/procedure, which corresponds to a 30- to 36-hour interruption interval (or two to three DOAC half-lives) between the last dose and the procedure. In patients having a high-bleed-risk surgery/ procedure, which comprises most surgeries lasting 1 hour or more or any neuraxial (epidural or spinal) anesthesia, PAUSE-based management requires 2 days off the DOAC before the surgery/procedure, which corresponds to a 60to 68-hour interruption interval (or four to ﬁve DOAC half-lives) between the last dose and the procedure. In high-bleed-risk patients, this management was associated with rates of major bleeding of 0.9% to 3.0%, depending on the DOAC patients were receiving. Although laboratory testing did not inform DOAC interruption, 98.8% of such patients had a DOAC level less than 50 ng/ml at the time of surgery, and depending on the DOAC 86% to 98% had a DOAC level less than 30 ng/ml. Another study of nonstandardized perioperative DOAC management in 422 patients found that a 48- to 72-hour interruption interval was optimal, associated with 95% of patients having a preoperative DOAC level of 30 ng/ml or less,57,58 thereby supporting the PAUSEbased management. After the surgery/procedure, DOAC resumption is ﬂexible to allow variability in surgery/procedure site hemostasis, whereby DOACs can be resumed approximately 24 hours after a low/moderate-bleed-risk procedure and approximately 48 to 72 hours after a high-bleed-risk procedure. In cases where postoperative resumption of oral medications is delayed, prophylactic (low-dose) LMWH can be given in surgeries associated with a high venous thromboembolism (VTE) risk.1 Of note, some anesthesia societies recommend an empiric-based DOAC interruption interval of NEJM EVIDENCE NEJM Evidence is produced by NEJM Group, a division of the Massachusetts Medical Society. Downloaded from evidence.nejm.org at HOSP UNIV DE TARRAGONA JOAN XXIII on June 26, 2023. For personal use only. No other uses without permission. Copyright © 2023 Massachusetts Medical Society. All rights reserved. For personal use only. No other uses without permission. Copyright © 2023 Massachusetts Medical Society. 5 Direct Oral Anticoagulant Procedure Bleeding Risk Postprocedure Resumption* Preprocedure DOAC Interruption Day –6 Day –5 Day –4 Day –3 Day –2 Day –1 Day +1 Day +2 Day +3 Day +4 High Apixaban Dabigatran (CrCl ≥ 50 ml/min) Dabigatran (CrCl < 50 ml/min) High Low/Mod High Low/Mod Surgery/Procedure (Day 0) Low/Mod High Edoxaban Low/Mod High Rivaroxaban Low/Mod No DOAC administered that day Figure 2. Perioperative Management of Direct Oral Anticoagulants, Adapted from 2022 ACCP Guidelines. * Direct oral anticoagulant (DOAC) can be resumed approximately 24 hours after low/moderate-bleed-risk procedures and 48 to 72 hours after high-bleed-risk procedures. In selected patients at high risk for venous thromboembolism, low-dose anticoagulants (i.e., enoxaparin, 40 mg daily or dalteparin, 5000 IU daily) can be given for the ﬁrst 48 to 72 hours postprocedure. 3 days or more or 72 hours before neuraxial (spinal/epidural) anesthesia or a procedure (e.g., nerve root block),59,60 which is slightly longer than the 60- to 68-hour interval assessed in PAUSE We suggest preoperative consultation with the treating anesthesiologist if there is uncertainty as to DOAC interruption. PREOPERATIVE MEASUREMENT OF DOAC LEVELS To measure the anticoagulant effect of DOACs, antifactor Xa levels can be used for apixaban, edoxaban, and rivaroxaban, and the dilute thrombin time for dabigatran.61-63 However, these tests are not widely and rapidly accessible, and even if the tests are available there is no consensus as to the DOAC level that would enable a surgery/procedure to proceed safely.64,65 Some have advocated that a level less than 50 ng/ml is a safe threshold to allow surgery to proceed, whereas others have suggested a level less than 30 ng/ml, which is the limit of DOAC level detection of some assays.66,67 A subanalysis of the PAUSE study suggests that DOAC levels less than 30 ng/ml or 30 to 50 ng/ml are not associated with an increased risk for perioperative bleeding.68,69 Based on this uncertainty, DOAC level testing is not recommended for routine use perioperatively in patients having an elective surgery/procedure.1 Patients Receiving Antiplatelet Therapy Antiplatelet drugs, comprising ASA and the P2Y12 inhibitors clopidogrel and prasugrel, irreversibly inhibit platelet function so that 7 to 10 days (i.e., platelet lifespan) of preoperative interruption is needed to fully restore platelet function,18 whereas with the P2Y12 inhibitor ticagrelor, which reversibly inhibits platelet function, 2 to 4 days of interruption are needed to restore platelet function (Tables S1 and S2).70 With postoperative management, a maximal antiplatelet effect occurs within minutes after resuming ASA, within 2 hours after resuming ticagrelor, at approximately 3 days after resuming prasugrel, and at 4 to 5 days after resuming clopidogrel at a 75-mg maintenance dose.71-73 An overall approach to perioperative antiplatelet management is shown in Figure 3. NONCARDIAC SURGERY ASA interruption may be favored in patients with stable coronary artery disease who have not had prior coronary revascularization and are undergoing a high-bleed-risk NEJM EVIDENCE NEJM Evidence is produced by NEJM Group, a division of the Massachusetts Medical Society. Downloaded from evidence.nejm.org at HOSP UNIV DE TARRAGONA JOAN XXIII on June 26, 2023. For personal use only. No other uses without permission. Copyright © 2023 Massachusetts Medical Society. All rights reserved. For personal use only. No other uses without permission. Copyright © 2023 Massachusetts Medical Society. 6 ASA continued* Cangrelor** Cangrelor** Ticagrelor† P2Y12 inhibitors*** Clopidogrel†† Prasugrel§ –9 –8 –7 –6 –5 –4 –3 –2 –1 –1–6 h 0 +4–6 h Day +1 Day of Surgery/Procedure Figure 3. Perioperative Management of Antiplatelet Drugs, Adapted from 2022 ACCP Guidelines. * Based on surgery/procedure bleed-risk assessment. ** Routine use is not suggested. If used, initiate within 72 hours from P2Y12 inhibitor discontinuation at a dose of 0.75 mgkg21min21; resume within 6 hours postprocedure for a minimum of 48 hours and a maximum of 7 days total. Very-low-quality data for antiplatelet bridging with glycoprotein IIb/IIIa inhibitors (e.g., eptiﬁbatide, tiroﬁban). *** P2Y12 inhibitors can be resumed within 24 hours postprocedure at a maintenance dose. † For ticagrelor, 3- to 5-day interruption. †† For clopidogrel, 5-day interruption. § For prasugrel, 7- to 10-day interruption. ASA denotes acetylsalicylic acid. surgery, whereas ASA continuation may be favored in patients undergoing vascular procedures (e.g., carotid endarterectomy) or in those with a recent (1 year or less) myocardial infarction or with prior coronary revascularization. Randomized trials have assessed whether to continue or interrupt ASA for noncardiac surgery.74 These studies, of which the PEP and POISE-2 trials are the largest, suggest that continuing ASA does not appear to reduce the incidence of myocardial ischemic events or overall mortality but confers an approximately 1% increased risk for major bleeding.75,76 A limitation of these trials was that there was no comparison, except in subgroups, of ASA continuation versus 7- to 10-day ASA interruption that would reﬂect management options in clinical practice. In POISE-2, the increase in bleeding with perioperative ASA use occurred in patients who were prior nonusers and initiated ASA before surgery but not in ASA users who continued ASA perioperatively. Overall, perioperative ASA use is associated with a decrease in the risk for major (venous and arterial) thromboembolism (relative risk [RR], 0.74; 95% conﬁdence interval [CI], 0.58 to 0.94) while increasing the risk for major bleeding (RR, 1.31; 95% CI, 1.15 to 1.50).77 Practice guidelines suggest that nonusers of ASA should not initiate ASA perioperatively, whereas users of ASA should continue ASA perioperatively.1,78,79 An important caveat mentioned in these guidelines is that perioperative ASA interruption can be justiﬁed in many patients, such as those undergoing a high-bleed-risk surgery. BEFORE CORONARY ARTERY BYPASS GRAFTING SURGERY Large observational studies have supported perioperative ASA use around coronary artery bypass grafting (CABG) surgery by demonstrating a reduction in cardiovascular events without increasing bleeding.80 In the ATACAS trial, patients received ASA (100 mg) starting 1 to 2 hours before CABG (prior users stopped ASA 4 days before surgery) or placebo, with resumption within 24 hours after CABG.81 The trial found no signiﬁcant effect of ASA use on 30-day postoperative rates of myocardial infarction (13.8% vs. 15.8%; RR, 0.87; 95% CI, 0.71 to 1.07), death, or other cardiovascular outcomes, and ASA use did not increase the risk for reoperation related to bleeding (1.8% vs. 2.1%; RR, 0.87; 95% CI, 0.47 to 1.6). The generalizability of results may be questioned because interrupting ASA and restarting it 1 to 2 hours before CABG (representing the ASA continuation group) is not a widespread practice. Among patients who are receiving ASA and a P2Y12 inhibitor, subanalyses of randomized trials involving patients with acute coronary syndromes, of whom a subgroup required CABG surgery, suggested that interrupting clopidogrel or ticagrelor approximately 5 days before surgery minimized bleeding and did not affect cardiovascular event risk. Practice guidelines generally suggest interrupting the P2Y12 inhibitor at 3 to 5 days (ticagrelor), 5 days (clopidogrel), or 7 to 10 days (prasugrel) before CABG surgery.1,13 In patients who developed an acute coronary syndrome, were treated with percutaneous coronary intervention and NEJM EVIDENCE NEJM Evidence is produced by NEJM Group, a division of the Massachusetts Medical Society. Downloaded from evidence.nejm.org at HOSP UNIV DE TARRAGONA JOAN XXIII on June 26, 2023. For personal use only. No other uses without permission. Copyright © 2023 Massachusetts Medical Society. All rights reserved. For personal use only. No other uses without permission. Copyright © 2023 Massachusetts Medical Society. 7 dual antiplatelet therapy, and require urgent CABG surgery, one management option is to wait at 3 to 5 days to allow the antiplatelet effect of the P2Y12 inhibitor to recede sufﬁciently. If urgent CABG surgery is needed, transfusing platelets with the intent of providing fully functional platelets may seem sensible,82 but this approach may only provide hemostatic beneﬁt if antiplatelet drugs are not circulating in plasma, leading to inhibition of newly transfused platelets.83,84 PATIENTS WITH CORONARY STENTS About 10% to 15% of patients with coronary stents will require surgery within 2 years of stenting.85,86 Perioperative management can vary depending on the timing of stent placement, the stent type (drug-eluting or bare metal), the stent location, whether the stent is in a dominant or nondominant coronary artery and the number and length of stents.87,88 Management options vary from stopping both antiplatelet drugs and bridging with a glycoprotein IIb/IIIa inhibitor or cangrelor to continuing both drugs without interruption.89,90 The interval between coronary stenting and the surgery will also affect management because the risk for cardiovascular events is highest within 4 to 6 weeks after stenting but may persist for 6 to 12 months.91,92 In a subanalysis of the POISE-2 trial that assessed 470 patients with a coronary stent who required major noncardiac surgery,93,94 those who continued ASA were at lower risk for developing myocardial infarction than patients who did not receive perioperative ASA (5.1% vs. 11.0%; hazard ratio, 0.44; 95% CI, 0.22 to 0.87), although ASA use increased major bleeding (4.6% vs. 3.8%; hazard ratio, 1.22; 95% CI, 1.01 to 1.48). Practice guidelines recommend an approach of continuing ASA while interrupting the P2Y12 inhibitor 3 to 10 days before the planned surgery, depending on the antiplatelet drug,1,12 and recommend continuing ASA perioperatively in patients with coronary stents who require elective noncardiac surgery.1,79,95 Bridging with short-acting tiroﬁban, eptiﬁbatide (glycoprotein IIb/IIIa inhibitors), or cangrelor, although not routinely recommended, may be considered in highrisk situations such as surgery within 2 to 4 weeks of coronary stenting.1 Consultation with a cardiologist and surgeon is advisable in these situations. Patients Who Need an Emergency or Urgent Surgery In patients who are receiving an anticoagulant and need surgery, 2% to 3% will need emergency surgery (within 6 hours) or urgent surgery (within 24 hours). They are at high risk for bleeding (17% to 23%), thromboembolism (7% to 16%), and death (2% to 6%).96,97 VKA REVERSAL FOR URGENT SURGERY Management is anchored on the INR: If it is less than 2.0, no further intervention may be needed, whereas if the INR is 2.0 to 3.0 or higher anticoagulant reversal is warranted in many clinical circumstances. In randomized trials, prothrombin complex concentrates (PCCs) containing factors II, VII, IX, and X in reliable quantities provide faster INR normalization compared with fresh frozen plasma, which contains clotting factors in variable quantities.98,99 Such patients also should receive vitamin K, 2.5 to 5 mg orally or intravenously, to enable in vivo replenishing of vitamin K–dependent factors II, VII, IX, and X. Practice guidelines support the administration of PCCs as ﬁrst-line agents for VKA reversal.97 Compared with fresh frozen plasma, PCCs offer the advantage of targeted clotting factor replacement, rapid administration without the need for blood-group cross-matching or thawing, and low volume of infusion but with a drawback of higher cost. DOAC REVERSAL FOR URGENT SURGERY Patient management depends on whether the surgery is emergent (i.e., <6 hours), such as an aneurysm rupture; urgent (i.e., 6 to 24 hours), such as hip fracture repair; or semi-urgent (>24 hours), such as cholecystectomy. DOAC level measurement is limited because such tests, comprising antifactor Xa levels for apixaban, edoxaban, and rivaroxaban and the dilute thrombin time or ecarin clotting time for dabigatran, are not widely available and may be difﬁcult to interpret. If available, a DOAC level less than 50 ng/ml reﬂects a low level of residual anticoagulation and would allow many surgeries to proceed without the need for reversal.100,101 If rapid DOAC testing is not available or if a DOAC level is greater than 50 ng/ml, DOAC-speciﬁc reversal agents such as andexanet-a for oral factor Xa inhibitors (apixaban or rivaroxaban) and idarucizumab for dabigatran have been shown in nonrandomized trials to rapidly reduce or normalize DOAC levels.102-105 If DOAC reversal agents are not available, PCCs can be administered as agents to overwhelm the anticoagulant effect of circulating DOACs, but they do not actively remove the DOAC.106 Anticoagulant reversal options are shown in Table 3. Future Directions Although pivotal clinical trials have provided important evidence to better inform perioperative antithrombotic NEJM EVIDENCE NEJM Evidence is produced by NEJM Group, a division of the Massachusetts Medical Society. Downloaded from evidence.nejm.org at HOSP UNIV DE TARRAGONA JOAN XXIII on June 26, 2023. For personal use only. No other uses without permission. Copyright © 2023 Massachusetts Medical Society. All rights reserved. For personal use only. No other uses without permission. Copyright © 2023 Massachusetts Medical Society. 8 Table 3. Anticoagulant Reversal Agents and Dosing.* DOACs VKAs (Warfarin, Acenocoumarol, Phenprocoumon) Reversal Agent Options Anti-Xa Inhibitors (Apixaban, Edoxaban, Rivaroxaban) Anti-IIa Inhibitor (Dabigatran) Plasma Fresh frozen plasma, 2–6 units (depending on INR) PCCs Four-factor PCC, 30 IU/kg (maximum 3000 units)† Four-factor PCC, 30 IU/kg (maximum 3000 units) Four-factor PCC, 30 IU/kg (maximum 3000 units) or FEIBA (factor VIII inhibitor bypass activity), 50 IU/kg (maximum 2000 units) Specific reversal n/a Andexanet-a Low dose: 400 mg IV bolus, 30 mg/min, followed by 2-hour IV infusion at 4 mg/min‡ High dose: 800 mg IV bolus, 30 mg/min, followed by 2-hour IV infusion at 8 mg/min§ Idarucizumab 2.5 g (50 ml) IV bolus for 2 doses, 15 minutes apart * DOAC denotes direct oral anticoagulant; INR, international normalized ratio; IV, intravenous; n/a, not applicable; PCCs, prothrombin complex concentrates; and VKA, vitamin K antagonist. † Preferred over fresh frozen plasma. ‡ Dosing if last dose of DOAC given more than 8 hours before. § Dosing if last dose of DOAC given within 8 hours or unknown. management, additional research is needed to further assess LMWH bridging in VKA-treated patients with mechanical heart valves to assess interruption intervals in DOAC-treated patients who need a neuraxial procedure and to compare management strategies for patients with coronary stents who are receiving dual antiplatelet therapy, especially for patients who need surgery within close proximity of stenting. Finally, additional research is needed on the management of anticoagulated patients who need urgent surgery. Chest Physicians Clinical Practice Guideline. Chest 2022;162: e207-e243. DOI: 10.1016/j.chest.2022.07.025. 2. Spyropoulos AC, Al-Badri A, Sherwood MW, Douketis JD. Periprocedural management of patients receiving a vitamin K antagonist or a direct oral anticoagulant requiring an elective procedure or surgery. J Thromb Haemost 2016;14:875-885. DOI: 10.1111/jth. 13305. 3. Williams BA, Honushefsky AM, Berger PB. Temporal trends in the incidence, prevalence, and survival of patients with atrial ﬁbrillation from 2004 to 2016. Am J Cardiol 2017;120:1961-1965. DOI: 10.1016/j.amjcard.2017.08.014. Disclosures Author disclosures and other supplementary materials are available at evidence.nejm.org. Author Affiliations 4. Steinberg BA, Gao H, Shrader P, et al. 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