Perioperative Management of Antithrombotic Therapy

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[ Education and Clinical Practice Guidelines and Consensus Statements ] 56

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Perioperative Management of 61
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Antithrombotic Therapy 63
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10 An American College of Chest Physicians Clinical Practice Guideline 65
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Q34 James D. Douketis, MD, FCCP; Alex C. Spyropoulos, MD, FCCP; M. Hassan Murad, MD, MPH; Juan I. Arcelus, MD;
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William E. Dager, PharmD; Andrew S. Dunn, MD, MPH; Ramiz A. Fargo, MD, FCCP; Jerrold H. Levy, MD;
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C. Marc Samama, MD; Sahrish H. Shah, MBBS; Matthew W. Sherwood, MD; Alfonso J. Tafur, MD; Liang V. Tang, MD;
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Q1 and Lisa K. Moores, MD, FCCP
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BACKGROUND: The American College of Chest Physicians Clinical Practice Guideline on the
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Perioperative Management of Antithrombotic Therapy addresses 43 Patients-Interventions-
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21 Comparators-Outcomes (PICO) questions related to the perioperative management of pa- 76
22 tients who are receiving long-term oral anticoagulant or antiplatelet therapy and require an 77
23 elective surgery/procedure. This guideline is separated into four broad categories, encom- 78
24 passing the management of patients who are receiving: (1) a vitamin K antagonist (VKA), 79
25 mainly warfarin; (2) if receiving a VKA, the use of perioperative heparin bridging, typically 80
26 with a low-molecular-weight heparin; (3) a direct oral anticoagulant (DOAC); and (4) an 81
27 antiplatelet drug. 82
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METHODS: Strong or conditional practice recommendations are generated based on high, mod-
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erate, low, and very low certainty of evidence using the Grading of Recommendations, Assess-
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31 ment, Development, and Evaluation (GRADE) methodology for clinical practice guidelines. 86
32 Q6 RESULTS: A multidisciplinary panel generated 44 guideline recommendations for the peri- 87
33 operative management of VKAs, heparin bridging, DOACs, and antiplatelet drugs, of which 88
34 two are strong recommendations: (1) against the use of heparin bridging in patients with 89
35 atrial fibrillation; and (2) continuation of VKA therapy in patients having a pacemaker or 90
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internal cardiac defibrillator implantation. There are separate recommendations on the
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perioperative management of patients who are undergoing minor procedures, comprising
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dental, dermatologic, ophthalmologic, pacemaker/internal cardiac defibrillator implantation,
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and GI (endoscopic) procedures.
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41 CONCLUSIONS: Substantial new evidence has emerged since the 2012 iteration of these 96
42 guidelines, especially to inform best practices for the perioperative management of patients 97
43 who are receiving a VKA and may require heparin bridging, for the perioperative manage- 98
44 ment of patients who are receiving a DOAC, and for patients who are receiving one or more 99
45 antiplatelet drugs. Despite this new knowledge, uncertainty remains as to best practices for 100
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the majority of perioperative management questions. CHEST 2022; -(-):---
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48 Q7 KEY WORDS: antithrombotic therapy; perioperative care; surgery; thrombosis 103
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50 ABBREVIATIONS: aptt = activated partial thromboplastin time; ASA = anticoagulant; GRADE = Grading of Recommendations, Assessment, 105
51 aspirin; ATE = arterial thromboembolism; CABG = coronary artery Development, and Evaluation; HR = hazard ratio; INR = international 106
bypass graft; CHADS2 = congestive heart failure, hypertension, age $ normalized ratio; LMWH = low-molecular-weight heparin; PICO =
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75 years, diabetes mellitus, prior stroke or transient ischemic attack; Patients-Interventions-Comparators-Outcomes; RR = relative risk;
53 CHA2DS2VASc = congestive heart failure, hypertension, age $ 75 UFH = unfractionated heparin; VKA = vitamin K antagonist 108
Q2
54 years, diabetes mellitus, prior stroke or transient ischemic attack, AFFILIATIONS: From the Department of Medicine (J. D. D.), St. 109
Q3
vascular disease history, age $ 65 years, female sex; COI = conflicts of Joseph’s Healthcare Hamilton and McMaster University, Hamilton,
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interest; CrCl = creatinine clearance; DOAC = direct oral
chestjournal.org e1
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Q8 Summary of Key Recommendations 15. In patients receiving VKA therapy who require 166
112 VKA interruption for a colonoscopy with 167
5. In patients receiving VKA therapy for a mechanical
113 168
heart valve who require VKA interruption for an anticipated polypectomy, we suggest against heparin
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elective surgery/procedure, we suggest against heparin bridging during the period of VKA interruption
115 170
bridging (Conditional Recommendation, Very Low (Conditional Recommendation, Very Low Certainty of
116 171
Certainty of Evidence). Evidence).
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6. In patients receiving VKA therapy for atrial 21. In patients receiving LMWH bridging for an
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fibrillation who require VKA interruption for an elective surgery/procedure, we suggest against
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elective surgery/procedure, we recommend against routine measurement of anti-factor Xa levels to
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heparin bridging (Strong Recommendation, Moderate guide perioperative LMWH management
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123 Certainty of Evidence). (Conditional Recommendation, Very Low Certainty of 178
124 Evidence). 179
7. In patients receiving VKA therapy for VTE as the
125 180
sole clinical indication who require VKA interruption 22. In patients receiving apixaban who require an
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for an elective surgery/procedure, we suggest against elective surgery/procedure, we suggest stopping
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heparin bridging (Conditional Recommendation, Very apixaban for 1 to 2 days before the surgery/procedure 183
129 Low Certainty of Evidence). over apixaban continuation (Conditional 184
130 Recommendation, Very Low Certainty of Evidence). 185
14. In patients receiving VKA therapy who require a
131 186
pacemaker or ICD implantation, we recommend 23. In patients receiving dabigatran who require an
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continuation of VKA over VKA interruption and elective surgery/procedure, we suggest stopping
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heparin bridging (Strong Recommendation, Moderate dabigatran for 1 to 4 days before the surgery/ 189
135 Certainty of Evidence). procedure over dabigatran continuation 190
136 (Conditional Recommendation, Very Low Certainty 191
137 of Evidence). 192
ON, Canada; Department of Medicine (A. C. S.), Northwell Health at
138 Lenox Hill Hospital, New York, NY; Donald and Barbara Zucker 193
139 School of Medicine at Hofstra/Northwell (A. C. S.), Hempstead, NY; 24. In patients receiving edoxaban who require an 194
140 Institute of Health Systems Science at The Feinstein Institutes for elective surgery/procedure, we suggest stopping 195
Medical Research (A. C. S.), Manhasset, NY; Mayo Clinic Evidence-
141 Based Practice Center (M. H. M. and S. H. S.), Rochester, MN;
edoxaban for 1 to 2 days before the surgery/procedure 196
142 Department of Surgery (J. I. A.), Facultad de Medicina, University of over edoxaban continuation (Conditional 197
143 Granada, Granada, Spain; Department of Pharmacy (W. E. D.), Uni- Recommendation, Very Low Certainty of Evidence). 198
versity of California-Davis, Sacramento, CA; Division of Hospital
144 Medicine (A. S. D.), Department of Medicine, Mt. Sinai Health System, 199
145 New York, NY; Department of Internal Medicine (R. A. F.), Loma 25. In patients receiving rivaroxaban who require an 200
146 Linda University Medical Center, Loma Linda, CA; Department of elective surgery/procedure, we suggest stopping 201
Internal Medicine (R. A. F.), Riverside University Health System
147 Medical Center, Moreno Valley, CA; Department of Anesthesiology, rivaroxaban for 1 to 2 days before the surgery/ 202
148 Critical Care, and Surgery (Cardiothoracic) (J. H. L.), Duke University procedure over rivaroxaban continuation 203
149 School of Medicine, Durham, NC; Department of Anaesthesia, 204
Intensive Care and Perioperative Medicine (C. M. S.), GHU AP-HP,
(Conditional Recommendation, Very Low Certainty of
150 Centre-Université Paris-Cité-Cochin Hospital, Paris, France; Inova Evidence). 205
151 Heart and Vascular Institute (M. W. S.), Falls Church, VA; Department 206
152 of Medicine (A. J. T.), Cardiovascular, NorthShore University 26. In patients who require DOAC interruption for an 207
HealthSystem, Evanston, IL; Institute of Hematology (L. V. T.), Union
153 Hospital, Tongji Medical College, Huazhong, University of Science and elective surgery/procedure, we suggest against 208
154 Technology, Wuhan, China; and the F. Edward Hébert School of perioperative heparin bridging (Conditional 209
155 Medicine (L. K. M.), Uniformed Services University of the Health 210
Sciences, Bethesda, MD. Recommendation, Very Low Certainty of Evidence).
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Q4 211
Drs Douketis and Spyropoulos served as co-primary authors.
157 27. In patients who had DOAC interruption for an 212
DISCLAIMER: American College of Chest Physician guidelines are
158 intended for general information only, are not medical advice, and do elective surgery/procedure, we suggest resuming 213
not replace professional medical care and physician advice, which al-
159 DOACs > 24 hours after a surgery/procedure over 214
ways should be sought for any medical condition. The complete
160 resuming DOACs within 24 hours (Conditional 215
disclaimer for this guideline can be accessed at https://www.chestnet.
161 org/Guidelines-and-Resources. 216
Recommendation, Very Low Certainty of Evidence).
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Q5 CORRESPONDENCE TO: James D. Douketis, MD; email: jdouket@ 217
163 mcmaster.ca 28. In patients who had DOAC interruption for an 218
Copyright Ó 2022 American College of Chest Physicians. Published by
164 elective surgery/procedure, we suggest against 219
Elsevier Inc. All rights reserved.
165 routine DOAC coagulation function testing to guide 220
DOI: https://doi.org/10.1016/j.chest.2022.07.025
e2 Guidelines and Consensus Statements [ -#- CHEST - 2022 ]

221 perioperative DOAC management (Conditional most common.3-7 Approximately 15% to 20% of 276
222 Recommendation, Very Low Certainty of Evidence). patients who are receiving anticoagulant therapy will 277
223 278
require a surgery/procedure annually,7-10 and 10% to
224 29a. In patients receiving ASA who are undergoing 279
15% of patients with coronary stents will require
225 elective non-cardiac surgery, we suggest ASA 280
surgery within 2 years of implantation.11,12
226 continuation over ASA interruption (Conditional 281
227 Recommendation, Moderate Certainty of Evidence). The current American College of Chest Physicians 282
228 283
34. In patients who are receiving ASA and (CHEST) guidelines on perioperative antithrombotic
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undergoing CABG surgery, we suggest continuation management have expanded from previous iterations to
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of ASA over interruption; in patients receiving a address 43 Patients-Interventions-Comparators-
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232 P2Y12 inhibitor drug, we suggest interruption of the Outcomes (PICO) questions. New domains that are 287
233 P2Y12 inhibitor over continuation perioperatively addressed include the perioperative management of 288
234 (Conditional Recommendation, Low Certainty of patients who are receiving DOACs (also referred to as 289
235 Evidence). non-vitamin K oral anticoagulants), P2Y12 inhibitor 290
236 antiplatelet drugs, and guidance on perioperative 291
237 36. In patients receiving antiplatelet drug therapy laboratory testing.13-15 The target audience for this 292
238 who are undergoing an elective surgery/procedure, guideline is the wide array of clinicians involved in 293
239 we suggest against the routine use of platelet perioperative patient care, but it is also relevant for 294
240 function testing prior to the surgery/procedure to researchers to identify areas of future study, for patients 295
241 guide perioperative antiplatelet management 296
to access a reliable information resource, and for clinical
242 (Conditional Recommendation, Very Low Certainty of 297
managers to facilitate the development of standardized
243 Evidence). 298
patient care paths.16,17 This guideline will be updated as
244 299
245 38. In patients receiving ASA and a P2Y12 inhibitor new evidence emerges in the field of perioperative 300
246 who had coronary stents placed within the last 3 to antithrombotic management in accordance with CHEST 301
247 12 months and are undergoing an elective surgery/ guideline policies.18 302
248 procedure, we suggest stopping the P2Y12 inhibitor 303
249
The aims of this practice guideline are: (1) to provide 304
prior to surgery over continuation of the P2Y12
250 evidence-based recommendations for the perioperative 305
inhibitor (Conditional Recommendation, Very Low
251 management of patients who are receiving 306
Certainty of Evidence).
252 antithrombotic therapy; and (2) to provide practical 307
253 39. In patients with coronary stents who require guidance to clinicians for managing such patients in the 308
254 interruption of antiplatelet drugs for an elective perioperative period. 309
255 surgery/procedure, we suggest against routine 310
256 bridging therapy with a glycoprotein IIb-IIIa The PICO questions and guideline statements are 311
257 inhibitor, cangrelor, or LMWH over routine use of separated into four broad categories to reflect the 312
258 dominant patient groups assessed in clinical practice: 313
bridging therapy (Conditional Recommendation, Low
259 314
Certainty of Evidence). Patients receiving a VKA, focused on warfarin.
260 315
261 Q9
Among patients receiving a VKA, the use of periop- 316
The perioperative management of antithrombotic erative heparin bridging.
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therapy encompasses patients who are receiving a Patients receiving a DOAC.
263 318
264
vitamin K antagonist (VKA), a direct oral Patients receiving an antiplatelet drug. 319
265 anticoagulant (DOAC), or an antiplatelet drug and 320
require surgery or an invasive procedure.1 The scope The PICO questions are further arranged to reflect
266 321
practical aspects of perioperative antithrombotic
267 of this problem is considerable because anticoagulant 322
management, which include:
268 and antiplatelet drugs are widely used for clinical 323
269 indications that include atrial fibrillation, VTE, Interruption and resumption of VKAs before and 324
Q10
270 mechanical heart valves, coronary artery disease, and after an elective surgery/procedure, and need for 325
271 peripheral arterial disease.2 Moreover, this clinical perioperative heparin bridging. 326
272 problem is likely to increase due to an aging For patients in whom heparin bridging is considered, 327
273 328
population in whom antithrombotic therapy is widely how to manage pre- and post-operative bridging
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used and in whom the need for a surgery/procedure is during VKA interruption.
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331 Interruption and resumption of DOACs before and factor IIa (thrombin) inhibitor dabigatran.20 As these 386
332 after an elective surgery/procedure. drugs differ in pharmacokinetic and pharmacodynamic 387
333 388
Perioperative management of antiplatelet therapy properties,21 recommendations that are specific for each
334 389
around non-cardiac surgery, coronary artery bypass DOAC will be made whenever possible based on
335 390
graft (CABG) surgery, and in patients with cardiac evidence from patients who are taking a specific DOAC.
336 391
stents. Where appropriate, recommendations will be made for
337 392
338
Management of VKAs, DOACs, and antiplatelet DOACs collectively. Q11
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339 drugs around minor procedures (dental, dermato- 394
logic, ophthalmologic, GI endoscopy, and cardiac Heparin Bridging
340 395
341 device implantation, the latter comprising pacemakers We define “heparin bridging” as the administration of a 396
342 and internal cardiac defibrillators [ICDs]). short-acting anticoagulant, typically a low-molecular- 397
343 weight heparin (LMWH) or, less often, unfractionated 398
344 Definitions of Patient Groups, Antithrombotic heparin (UFH), for an 8- to 10-day perioperative period 399
345 400
Agents, and Qualifying Remarks during interruption of a VKA when the international
346 401
The following definitions and qualifying remarks are normalized ratio (INR) is below the therapeutic range.14
347 402
aimed at facilitating an understanding of this practice We define a heparin bridging regimen as a therapeutic- Q12
348 403
guideline and the accompanying recommendations. dose (or full-dose) LMWH (eg, enoxaparin 1 mg/kg bid
349 404
or 1.5 mg/kg daily, dalteparin 100 IU/kg bid or 200 IU/
350 405
Patient Groups kg daily) or full-dose UFH (eg, to achieve a target
351 406
352 For patients who are receiving oral anticoagulant activated partial thromboplastin time [aPTT] of 1.5- to 407
353 therapy, the recommendations will pertain to those 2-times the control aPTT or a target anti-factor Xa level 408
354 patients who have one (or more) of the following of 0.35-0.70 IU/mL).22 Although there are intermediate- 409
355 clinical conditions: chronic atrial fibrillation; a dose LMWH regimens (eg, enoxaparin 40 mg bid) that 410
356 mechanical prosthetic heart valve; or VTE. Although have been referred to as “bridging,” our definition and 411
357 associated recommendations pertain to use of 412
there may be patients who are receiving anticoagulant
358 therapeutic-dose heparin bridging where the intent is to 413
therapy for other conditions (eg, dilated
359 414
cardiomyopathy), we focus on the most common prevent stroke and systemic embolism, referred to in this
360 415
indications for anticoagulant therapy. For patients who guideline as arterial thromboembolism (ATE);
361 416
are receiving antiplatelet therapy, the moreover, this is the bridging dose regimen that has
362 417
recommendations pertain mainly to patients who have been most widely studied.1,23 Heparin bridging should
363 418
364 coronary artery disease and require non-cardiac also be distinguished from perioperative use of low-dose 419
365 surgery, CABG surgery, or percutaneous coronary LMWH (eg, enoxaparin 40 mg daily, dalteparin 5,000 IU 420
366 interventions and, to a lesser extent, to patients daily) that is administered for prophylaxis against 421
367 receiving antiplatelet therapy for secondary prevention postoperative VTE rather than for the prevention of 422
368 of cardiovascular disease (eg, peripheral or ATE.24 423
369 cerebrovascular disease) who need non-cardiac 424
370 Other Definitions 425
surgery.
371 We define the “perioperative period” or the term 426
372 VKAs 427
“perioperatively” as the period before and after a
373 428
Although there are several VKAs available for clinical surgery/procedure that, in its entirety, spans from
374 429
375
use, including warfarin, acenocoumarol, fluindione, 1 week before until 4 weeks after a surgery/procedure.
430
376
phenprocoumon, and anisindione,19 the PICO questions This 5-week period is when most adverse thrombotic
431
377 and associated recommendations herein will refer to and bleeding outcomes may be attributed to 432
378 warfarin when the term VKA is used because most perioperative antithrombotic management.25 A 433
379 evidence has assessed warfarin-treated patients, with few “surgery” will refer to an intervention that requires 434
380 or no studies involving patients who are receiving other anesthesia (ie, general, neuraxial, regional block, local) 435
381 VKAs.13,14 and may take place with or without overnight 436
382 hospitalization, whereas a “procedure” will refer to a 437
383 DOACs diagnostic, therapeutic, or device-related intervention 438
384 DOACs that are in clinical use comprise the factor Xa that, typically, does not require overnight 439
385 440
inhibitors apixaban, edoxaban, and rivaroxaban, and the hospitalization.

441 Qualifying Remarks > 10%/year; intermediate risk: 4%-10%/year; low 496
442 risk: < 4%/year) and estimated risk for VTE (high risk: 497
This guideline pertains to patients who are receiving
443 498
anticoagulant or antiplatelet therapy and require an > 10%/month; intermediate risk: 4%-10%/month; low
444 499
elective, non-urgent, surgery/procedure and does not risk: < 2%/month); it is derived mainly from studies in a
445 500
address patients who require an urgent surgery/ non-perioperative setting that involved patients with
446 501
procedure, in whom the management paradigm differs atrial fibrillation,29-32 a mechanical heart valve,33-35 or
447 502
448 considerably from that of the elective clinical VTE36-38 who were not receiving anticoagulant therapy 503
449 setting.26-28 This guideline further pertains to patients (eg, placebo instead of a VKA in patients with atrial 504
450 who are receiving long-term, typically $ 3 months, fibrillation) or less effective antithrombotic therapy (eg, 505
451 antithrombotic therapy and focuses on VKAs (warfarin), ASA instead of a VKA in patients with a mechanical 506
452 DOACs (apixaban, dabigatran, edoxaban, rivaroxaban), heart valve).13,14,25 A perioperative risk classification for 507
453 patients with coronary artery disease, particularly if they 508
and antiplatelet drugs (aspirin [ASA], clopidogrel,
454 have coronary stents, is available elsewhere and is also 509
prasugrel, ticagrelor). This guideline does not address
455 empiric.39,40 510
the management of drugs with anticoagulant or
456 511
457
antiplatelet properties that are used infrequently (eg, The following qualifying remarks apply to this empiric 512
458 cilostazol, dipyridamole, pentoxifylline); that, in the case risk classification: 513
459 of DOACs, are used as low-dose regimens (eg, 514
rivaroxaban 2.5 mg bid); or that, typically, are used for The thromboembolic risk classification herein can
460 515
short periods (eg, nonsteroidal antiinflammatory be overridden based on individual patient charac-
461 516
462 drugs).13 Finally, this guideline does not address the teristics. For example, a “low-risk” patient with atrial 517
463 perioperative use of low-dose LWMHs, low-dose fibrillation and a CHA2DS2VASc score (congestive 518
464 DOACs, or other antithrombotic strategies that are heart failure, hypertension, age $ 75 years, diabetes 519
465 intended as prophylaxis against postoperative VTE.24 mellitus, prior stroke or transient ischemic attack, 520
466 vascular disease history, age $ 65 years, female 521
467 sex) # 4 or a CHADS2 score (congestive heart 522
468 Practical Aspects of Perioperative failure, hypertension, age $ 75 years, diabetes 523
469 Antithrombotic Management mellitus, prior stroke or transient ischemic 524
470 525
The management approach described below provides the attack) # 2 with a history of perioperative stroke
471 526
foundation upon which the guideline recommendations might be classified as “high-risk” and managed
472 527
have been applied. This perioperative antithrombotic accordingly.13,14
473 528
management approach aims to deliver individualized, The type of surgery can affect thromboembolic risk,
474 529
475 patient-centric care with the intent of minimizing especially for patients undergoing cardiovascular 530
476 perioperative thromboembolism and bleeding. surgery, such as CABG surgery or carotid endarter- 531
477 Perioperative antithrombotic management is anchored ectomy, in whom the risk for stroke or other 532
478 on the assessment of patients’ risk for thromboembolism thromboembolism may be higher irrespective of other 533
479 and surgery/procedure-related bleeding.1,13,14 The risk patient-related factors.41-43 534
480 classification schemes herein are empiric, requiring Patients’ thromboembolic risk may be less important 535
481 in certain perioperative circumstances. This can occur 536
prospective validation, but aim to provide individualized
482 in VKA- or DOAC-treated patients or those receiving 537
perioperative management, in particular to help
483 538
determine if perioperative anticoagulation interruption antiplatelet therapy who are undergoing a procedure
484 539
is needed and, if so, among VKA-treated patients, if that does not require anticoagulant or antiplatelet
485 540
heparin bridging is needed. interruption. Another situation is in patients who are
486 541
receiving DOAC therapy, irrespective of the clinical
487 542
Assessing Perioperative Risk for Thromboembolism indication (atrial fibrillation or VTE). Since the peri-
488 543
489 This involves estimating the risk for ATE, encompassing operative time period where such patients are not 544
490 stroke and systemic embolism for patients with atrial anticoagulated is short (1-3 days), this minimizes the 545
491 fibrillation or a mechanical heart valve, and the risk for risk for thromboembolism, irrespective of their 546
492 recurrent VTE for patients with a history of VTE with baseline risk, as reflected by the CHA2DS2VASc or 547
493 perioperative interruption of anticoagulant drugs. The CHADS2 score or proximity of recent VTE and, 548
494 risk classification in Table 1 is empiric and separates similarly, obviates the rationale for administering 549
495 heparin bridging. 550
patients according to estimated risk for ATE (high risk:
chestjournal.org e5

551 TABLE 1 ] Adapted American College of Chest Physicians (CHEST) Suggested Risk Stratification for Patient- Q28 606
552 Specific Periprocedural Thromboembolism13,14,25 607
553 Risk Category Mechanical Heart Valve Atrial Fibrillation VTE 608
554 609
High (> 10%/y Any mechanical mitral CHA2DS2VASc score $ 7 or Recent (< 3 mo and especially 1 mo) VTE
555 610
risk of ATE or > valve CHADS2 score of 5 or 6 Severe thrombophilia (deficiency of Q29
556 10%/mo risk of Caged ball or tilting-disc Recent (< 3 mo) stroke or protein C, protein S or antithrombin; 611
557 VTE) valve in mitral/aortic TIA homozygous factor V Leiden or 612
558 position Rheumatic valvular heart prothrombin gene mutation or double 613
Recent (< 3 mo) stroke or disease heterozygous for each mutation,
559 614
TIA multiple thrombophilias)
560 615
Antiphospholipid antibodies
561 Associated with vena cava filter 616
562 Active cancer associated with high VTE 617
563 riska 618
564 Moderate Bileaflet AVR with major CHA2DS2VASc score of 5 or VTE within past 3-12 mo 619
565 (4%-10%/y risk factors for strokeb 6 or CHADS2 score of 3 Recurrent VTE 620
risk of ATE or or 4 Non-severe thrombophilia (heterozygous
566 621
4%-10%/mo factor V Leiden or prothrombin gene
567 risk of VTE) mutation) 622
568 Active cancer or recent history of cancerc 623
569 Low (< 4%/y risk Bileaflet AVR without CHA2DS2VASc score of 1-4 VTE > 12 mos ago 624
570 of ATE or major risk factors for or CHADS2 score of 0-2 625
571 < 2%/mo risk strokeb (and no prior stroke or 626
572 of VTE) TIA) 627
573 628
This was an empiric risk classification, not prospectively validated. ATE ¼ arterial thromboembolism; AVR ¼ aortic valve replacement; CHADS2 ¼
574 congestive heart failure, hypertension, age $75 years, diabetes mellitus, prior stroke or transient ischemic attack; CHA2DS2VASc ¼ congestive heart 629
575 failure, hypertension, age $ 75 years, diabetes mellitus, prior stroke or transient ischemic attack, vascular disease history, age $ 65 years, female sex. 630
a
576 Includes pancreatic cancer, myeloproliferative disorders, primary brain cancer, gastric cancer, and esophageal cancer. 631
b
Atrial fibrillation, prior stroke or transient ischemic attack (TIA), hypertension, diabetes, congestive heart failure, and age > 75 years.
577 c
Within 5 years if history of cancer, excluding non-melanoma skin cancer.
632
578 633
579 634
580 Assessing Perioperative Risk for Surgery/ anticoagulant effect at the time of the surgery, and 635
581
Procedure-Related Bleeding delayed post-operative anticoagulant resumption, to 636
582 This involves an assessment of the surgery/procedure- account for the longer time required for surgical site 637
583 related bleed risk. The risk classification shown in hemostasis. Also included in this category are any 638
584 Table 2 separates patients into “high,” “low/moderate,” surgeries performed with neuraxial (spinal or 639
585 640
or “minimal” bleed risk categories and is based on the epidural) anesthesia or any other neuraxial (eg, pain
586 management) intervention due to concerns about the 641
expected 30-day post-operative risk of major bleeding
587 642
(high bleeding risk $ 2%, low/moderate bleeding risk risk for epidural hematoma, a rare but devastating
588 643
0%-2%, and minimal bleeding risk approximately complication that can result in lower limb
589 644
0%).1,25,44,45 paralysis.51,52
590 645
591 Minimal-bleed-risk procedures and selected surgeries The following qualifying remarks apply to this empiric 646
592 such as phacoemulsification (cataract) surgery are risk classification: 647
593 648
those in which anticoagulants may be continued Selected minimal-bleed-risk procedures may require 1
594 649
perioperatively without any or with minimal (ie, day to 2 days of anticoagulant interruption if there is concern
595 650
of procedure only) interruption.1,46-50 about bleeding: for example, a dental extraction may be
596 651
597
Low/moderate-bleed-risk surgeries/procedures more complex in a patient with poor dentition or
652
598
encompass a broad range of interventions in which compromised gingival integrity53; a screening colonos- 653
599 shorter periods of pre-operative anticoagulant inter- copy in patients with a history of polyps that may require 654
600 ruption and post-operative anticoagulant resumption resection54; and coronary angiography with a femoral 655
601 intervals are acceptable due to an overall lower bleed (instead of radial) artery access.48 656
602 risk.1 Surgical procedures (eg, an inguinal hernia repair55) 657
603 High-bleed-risk surgeries/procedures are those which may vary widely in complexity and might be 658
604 require sufficient pre-operative anticoagulant inter- justifiably categorized as low/moderate- or high- 659
605 ruption, so there is minimal-to-no residual bleed-risk. 660

661 TABLE 2 ] Suggested Risk Stratification for Procedural Bleed Risk, Based on ISTH Guidance Statements25 716
662 717
High-bleed-risk surgery/procedurea (30-d risk of Major surgery with extensive tissue injury
663 major bleed $ 2%) Cancer surgery, especially solid tumor resection (lung, esophagus, 718
664 gastric, colon, hepatobiliary, pancreatic) 719
665 Major orthopedic surgery, including shoulder replacement surgery 720
666 Reconstructive plastic surgery 721
Major thoracic surgery
667 722
Urologic or GI surgery, especially anastomosis surgery
668 Transurethral prostate resection, bladder resection, or tumor ablation 723
669 Nephrectomy, kidney biopsy 724
670 Colonic polyp resection 725
671 Bowel resection 726
Percutaneous endoscopic gastrostomy placement, endoscopic
672 727
retrograde cholangiopancreatography
673 Surgery in highly vascular organs (kidneys, liver, spleen) 728
674 Cardiac, intracranial, or spinal surgery 729
675 Any major operation (procedure duration > 45 minutes) 730
676 Neuraxial anesthesiab 731
Epidural injections
677 732
678 Low/moderate-bleed-risk surgery/procedurec Arthroscopy 733
(30-d risk of major bleed 0%-2%) Cutaneous/lymph node biopsies
679 734
Foot/hand surgery
680 Coronary angiographyd 735
681 GI endoscopy biopsy 736
682 Colonoscopy biopsy 737
683 Abdominal hysterectomy 738
Laparoscopic cholecystectomy
684 739
Abdominal hernia repair
685 Hemorrhoidal surgery 740
686 Bronchoscopy biopsy 741
687 e
Minimal-bleed-risk surgery/procedure (30-d risk Minor dermatologic procedures (excision of basal and squamous cell 742
688 of major bleed approximately 0%) skin cancers, actinic keratoses, and premalignant or cancerous skin 743
689 nevi) 744
690 Ophthalmologic (cataract) procedures 745
Minor dental procedures (dental extractions, restorations, prosthetics,
691 746
endodontics), dental cleanings, fillings
692 Pacemaker or cardioverter-defibrillator device implantation 747
693 748
694 ISTH ¼ International Society on Thrombosis and Haemostasis. 749
a
No residual anticoagulant effect at time of procedure (ie, four to five drug half-life interruptions pre-procedure). Q30
695 b 750
Includes spinal and epidural anesthesia or any other neuraxial (eg, pain management) intervention; consider not only absolute risk for major bleeding but
696 potentially devastating consequences of epidural bleeding and associated lower limb paralysis. 751
697 c
Some residual anticoagulant effect allowed (ie, two to three drug half-life interruptions pre-procedure). 752
d
698 Radial approach may be considered minimal bleed risk compared with femoral approach. 753
e
Procedure can be safely done under full-dose anticoagulation (may consider holding DOAC dose day of procedure to avoid peak anticoagulant effects).
699 754
700 755
701 Flexibility with the timing of post-operative DOAC therapeutic-dose IV UFH is another treatment option; 756
702 757
and LMWH resumption is warranted because a peak for example, in patients with severe renal insufficiency
703 758
anticoagulant effect occurs within 2 to 4 hours after or who are dialysis-dependent.14 Other types of hep-
704 759
administration21; this is especially pertinent if patients arin bridging may include intermediate-dose regi-
705 760
develop greater than expected post-operative mens (eg, enoxaparin 40 mg bid).14
706 761
707
bleeding. Heparin bridging should be administered in a manner 762
708 to minimize the risk for bleeding that would require 763
Practical Aspects of Heparin Bridging re-operation or another intervention (eg, wound
709 764
710 The following management points should be considered packing). Avoidance of major bleeding is important 765
711 when administering heparin bridging: because if it occurs, it typically requires a longer 766
712 Bridging is most often done with an LMWH, typically period of anticoagulant interruption that, in turn, 767
713 with a therapeutic-dose regimen (eg, enoxaparin exposes patients to an increased risk for thrombo- 768
714 1 mg/kg bid, dalteparin 100 IU/kg bid), administered embolism.56 Specifically, post-operative heparin 769
715 770
with the intent of preventing ATE. Bridging with bridging should be initiated when there is adequate
chestjournal.org e7

771 surgical/procedure-site hemostasis and the patient is tools (https://thrombosiscanada.ca, http://mapp.ipro. 826
772 at a relatively low risk for bleeding. Although sub- org, http://www.anticoagulationtoolkit.org/). At an 827
773 828
jective, this can be determined by assessing the institutional level, harmonization of perioperative
774 829
amount, type (serous, serosanguinous, bloody), and anticoagulant management care paths that encompass
775 830
progress (continuing, increasing, decreasing) of blood multiple specialties (eg, surgery, internal medicine,
776 831
collection in wound bandages or surgical drains. anesthesia) will facilitate standardization of patient
777 832
778
The administration of heparin bridging, particularly if management. 833
779 only used pre-operatively, does not preclude the 834
Standardized management is important because
780 administration of post-operative low-dose LMWH 835
unstructured usual care varies widely, based on
781 (eg, enoxaparin 40 mg daily); for example, in patients 836
surveys,61-63 with the potential for confusion among
782 at high risk for bleeding (eg, intracranial or spinal or 837
clinicians and patients as to the planned management. If
783 CABG surgery) in whom post-operative therapeutic- 838
784
anticoagulants are not managed with evidence-based 839
dose LMWH bridging might be avoided.
785 protocols or guidelines in the perioperative clinical 840
786 Role of Low-Dose LMWH as VTE Prophylaxis in setting, patients may be exposed to as much as a 0.5% to 841
787 Perioperative Management 1.0% excess risk for disabling stroke (based on a 842
788 In patients who require perioperative interruption of a benchmark risk # 0.5%) and a 3% to 6% excess risk for 843
789
VKA or a DOAC and are considered at high risk for serious bleeding (based on a benchmark risk # 1.5%), if 844
790 anticoagulant interruption is too short or too long or if 845
post-operative VTE, the need to administer low-dose
791 excessive heparin bridging is used.1,8,64,65 846
LMWH as VTE prophylaxis may be obviated once the
792 847
793
VKA or DOAC is resumed. However, there may be 848
794 circumstances when low-dose LMWH can be used in 849
patients at high VTE risk; for example, those having Methodology
795 850
796 abdominopelvic cancer surgery or hip or knee Selection of Panel Members and Conflicts of 851
797 replacement surgery.57,58 In such hospitalized patients, Interest Disclosure 852
798 low-dose LMWH would be started, typically, 12 to 24 853
The guideline panel was selected to comprise a
799 hours post-operatively and continued for 2 to 3 days 854
multidisciplinary group of clinicians that included
800 while the VKA takes effect or until resumption of 855
internists, thrombosis specialists, cardiologists,
801 DOAC therapy. In patients who resume antiplatelet 856
anesthesiologists, surgeons, intensivists, and
802 857
therapy after a surgery, the addition of low-dose pharmacists, who worked alongside methodologists
803 858
LMWH can be justified in high VTE risk situations from the Mayo Clinic Evidence Center.
804 859
but is empiric and should consider the risk of
805 860
bleeding. The CHEST Guidelines Oversight Committee and
806 861
Professional Standards Committee reviewed nominated
807 862
Communication and Standardization of panelists according to their qualifications and conflicts
808 863
Perioperative Management of interest (COI) before they were approved to join the
809 864
810 Perioperative antithrombotic management typically panel. Throughout the guideline process, panelists were 865
811 involves a team of health-care professionals, comprising required to update and disclose potential financial or 866
812 one or more of a surgeon/proceduralist, an internist/ intellectual COI according to each PICO question. COI 867
813 cardiologist/hematologist, an intensivist, a pharmacist, were reviewed and categorized as disqualifying, 868
814 an anesthesiologist, and a primary care physician, with manageable, or approved without management, per 869
815 CHEST policy (https://www.chestnet.org/-/media/ 870
multiple transitions of care. Consequently, it is
816 chesnetorg/About ACCP/Documents/ 871
important to have alignment of the proposed
817 872
management plan among the health-care team and that Guidelines_COI_Policy.ashx). Panelists with
818 873
it is communicated to and agreed upon by the surgeon/ manageable COI were required to abstain from voting
819 874
proceduralist, so as to avoid miscommunication that on PICO recommendations where such COI were
820 875
may lead to adverse outcomes or a delay of the surgery/ present but could participate in discussions, provided
821 876
822 procedure.17,59 This can be facilitated with perioperative they refrained from strong advocacy. A complete list of 877
823 antithrombotic clinics,16,59 which can be administered the panelists’ COI and their management is shown in 878
824 in-person or virtually,60 and with the support of online e-Appendix 1. 879
825 880

881 Selection of PICO Questions proportion was determined using the Freeman-Tukey 936
882 arcsine transformation method. All analyses were done 937
The PICO questions that anchor these guidelines were
883 938
based on those used with the last guideline iteration, using Open Meta-Analyst. Certainty of evidence was
884 939
supplemented by new PICOs proposed by the guideline categorized as high, moderate, low, or very low,
885 940
panel. All panelists voted on whether each PICO should reflecting the strengths and limitations of evidence that
886 941
Q13 be included in the guideline. For all PICOs, standardized were based on the study design, risk of bias, imprecision,
887 942
888 questions were developed using the population- inconsistency, indirectness of results, and likelihood of 943
889 intervention-comparator-outcome format. A listing of publication bias. Risk of bias in randomized trials was 944
890 all PICO questions is provided in e-Appendix 2. based on the Cochrane Collaboration’s Risk of Bias 2 945
891 tool,68 which considers the randomization process, 946
892 Data Sources deviations from intended interventions, missing 947
893 outcome data, outcome measurement, reported result 948
Multiple databases were searched using text words and
894 selection, and other sources of bias. Risk of bias in 949
controlled vocabulary as outlined in e-Appendix 2.
895 observational studies was based on the Newcastle- 950
896
This search was done in two parts: the first was the 951
systematic review of the literature from 1970 to Ottawa Scale, which considers the representativeness of
897 952
December 2011, used by the 9th Edition of the CHEST the exposed cohort, selection of the nonexposed cohort,
898 953
Perioperative Antithrombotic Therapy Practice ascertainment of exposure and outcomes, comparability
899 954
Guidelines; the second was an update of this search of cohorts, and adequacy of follow-up. Precision was
900 955
901 strategy to include studies up until end-July 2021. judged based on whether CIs crossed the null as a target 956
902 Searches were limited to English-language articles and of certainty. If there were few events (< 10), we 957
903 human subject studies, and by article type (clinical considered rating down by two to three levels unless the 958
904 trial, randomized clinical trial, systematic review). The sample size was large (> 2,000-4,000). An arbitrary RR 959
905 reduction threshold of 25% was used as a cutoff for 960
literature search was supplemented by conducting
906 lowering certainty in precision by two levels. Sample 961
Internet-based searches of relevant studies identified in
907 Evidence Tables that formed the basis of 962
ClinicalTrials.gov, meeting abstracts and conference
908 recommendations are shown in e-Appendix 3. 963
909
proceedings, asking content experts, and reference lists 964
910 of studies that satisfied inclusion criteria. Indirect Development of Recommendations 965
911 evidence was sought for questions that were not 966
supported by direct evidence. Panel members We used a modified Delphi technique to achieve
912 967
913 collaborated with the systematic review team to consensus on guideline statements.18,69 This method 968
914 identify and summarize indirect evidence. minimizes bias related to group interactions and 969
915 enables anonymity among panelists. Panelists without 970
916 Guideline Framework a primary COI voted on approving PICO-specific 971
917 guideline statements using a standardized online 972
The guideline followed the GRADE approach (Grading
918 survey tool (SurveyMonkey, Momentive Inc.). Each 973
of Recommendations, Assessment, Development and
919 panelist could also suggest edits to the guideline 974
Evaluation).66 For each PICO, the certainty of evidence
920 statement wording and could suggest additional 975
921
was rated using GRADE, and an evidence-to-decision 976
qualifying remarks or comments as to the
922 framework was developed using the GRADE evidence- 977
implementation of the guideline in clinical practice. To
923 to-decision criteria.67 Certainty of evidence was defined 978
achieve consensus and for inclusion in the final
924 as the extent to which our confidence in the effect 979
guideline, each guidance statement required at least
925 estimate was adequate to support a recommendation. 980
926
80% agreement among at least 75% of eligible panel 981
For each PICO, a recommendation was classified as a
members (without primary COI).
927 strong, referred to as “we recommend,” or conditional, 982
928 referred to as “we suggest.” For the 43 PICO questions and 44 associated 983
929 984
recommendations (two recommendations for PICO 29),
930 Evidence Synthesis 985
39 recommendations achieved consensus in the first
931 986
Outcomes from randomized trials and observational voting round, with the remainder achieving consensus
932 987
933
studies were expressed as a relative risk (RR) and in the second voting round. There were five guideline 988
934 associated 95% CI. Meta-analysis was conducted when statements (2, 6, 20, 28, and 34) in which one panel 989
935 feasible. For non-comparative studies, an overall member disagreed with either the strength or direction 990
chestjournal.org e9

991 of the recommendation, and one guideline statement Perioperative Interruption and Resumption of VKAs 1046
992 (29a) in which one panel member disagreed with both 1047
PICO 1: In patients requiring VKA interruption,
993 1048
the strength and direction of the recommendation. should VKA be interrupted $ 5 days vs < 5 days before
994 1049
995 an elective surgery/procedure? 1050
996 Evidence. No randomized trials compared a 5-day and 1051
Patients Who Are Receiving a VKA and
997 1052
Require an Elective Surgery or Procedure a < 5-day preoperative interruption of warfarin, and no
998 1053
study has compared the effect of a 5-day and > 5-day
999 Background: The timing of VKA interruption before a 1054
interruption on perioperative bleeding outcomes, relying
1000 surgery/procedure, decided upon with the intent of 1055
1001
instead on a surrogate outcome (ie, INR) at the time of 1056
achieving a normal or near-normal INR at the time of a
1002 surgery to determine the appropriateness of VKA 1057
surgery/procedure, is based on the elimination half-life
1003 interruption. In the non-perioperative setting, indirect 1058
of VKAs that are typically observed in patients without
1004 evidence supports a 5-day warfarin interruption period to 1059
major comorbidities (eg, impaired liver function),
1005 attain a normal or near-normal INR.78 In a prospective 1060
genetic polymorphisms, or drug-drug interactions that
1006 cohort study of 224 patients in whom warfarin was 1061
might affect VKA metabolism: 36 to 42 hours for
1007 stopped 5 days before a surgery/procedure and had INR 1062
warfarin, 8 to 11 hours for acenocoumarol, and 96 to
1008 testing the day before surgery, 15 (7%) patients had an 1063
1009
104 hours for phenprocoumon.70-73 For patients in 1064
INR > 1.5.56 In a randomized trial that compared a 5-day
1010 whom the intent is to normalize the INR after 1065
or 1-day pre-operative interruption of warfarin (with the
1011 interruption of warfarin, 5 days of interruption is needed 1066
1-day group receiving 1 mg oral vitamin K the day before
1012 for the anticoagulant effect to be eliminated or near- 1067
surgery), the mean INR was 1.2 at surgery in the 5-day
1013 eliminated; 6 or more days of interruption may be 1068
1014
interruption group.79 A subanalysis of a randomized trial 1069
needed in selected patients, such as elderly patients or in
1015 of DOAC vs warfarin therapy for atrial fibrillation that 1070
patients with genetic polymorphisms that may delay
1016 ssessed perioperative management found that longer 1071
warfarin metabolism,74,75 and in those with an elevated
1017 vs shorter ($ 3 days vs < 3 days) warfarin interruption 1072
INR (ie, > 3.5) when assessed. The resumption of a
1018 conferred a decrease risk for major bleeding (RR ¼ 0.29; 1073
VKA after a surgery/procedure implies that attainment
1019 95% CI: 0.15-0.55) without affecting ATE risk (RR ¼ 1074
of an anticoagulant effect is delayed after the initial two
1020 0.49; 95% CI: 0.19-1.3).80 Other observational studies 1075
to three doses are given and that a full anticoagulant
1021 support a longer ($ 5-day) interruption interval,81,82 1076
1022
effect (INR > 2.0) will occur 4 to 8 days after VKA 1077
as do uncontrolled studies of perioperative warfarin
1023 resumption.76 Given these considerations, routinely 1078
management in which $ 5-day interruption was
1024 measuring the INR in the immediate pre-operative (day 1079
associated with low rates of major bleeding
1025 before) and post-operative (1-2 days after) period during 1080
(approximately 2%) and
1026 a surgery/procedure would not be needed. There may be 1081
1027
ATE (< 0.5%).8,10,56,83-94 1082
circumstances, however, when such testing may be
1028 warranted; for example, in patients with a pre-operative 1083
1029 high (ie, > 3.5) INR, in patients who are known to have 1. In patients requiring VKA (warfarin) interruption 1084
1030 for an elective surgery/procedure, we suggest stopping 1085
delayed warfarin elimination, or if after post-operative
1031
VKA resumption there is unexpected bleeding. VKAs (warfarin) ‡ 5 days over an interruption of < 1086
1032 5 days before an elective surgery/procedure 1087
1033 For patients who require perioperative VKA interruption, (Conditional Recommendation, Low Certainty of 1088
1034 the premise of heparin bridging has been to shorten the 1089
Evidence).
1035 period before and after a surgery/procedure when patients 1090
1036 Guideline Implementation Considerations: 1091
are not therapeutically anticoagulated, with the aim of
1037 1092
mitigating the risk for perioperative ATE, primarily, as Providing a perioperative VKA management calendar
1038 1093
well as recurrent VTE. However, this premise can be that is distributed by paper or electronically to pa-
1039 1094
questioned given the multiplicity of factors that can lead tients and clinicians has the potential to minimize
1040 1095
1041
to perioperative thromboembolism,41,77 including the VKA dosing errors and optimize communication. 1096
1042 surgery/procedure itself,43 and the limited capacity of In selected patients, especially the elderly with 1097
1043 heparin bridging to affect these factors and associated comorbidities, patients with very low dose warfarin 1098
1044 pathophysiological pathways. requirements, and those with a higher target INR 1099
1045 1100

1101 range, a longer period of warfarin interruption may be patients’ usual dose vs doubling the warfarin dose for 1156
1102 needed. the first 2 post-operative days.97 By the fifth post- 1157
1103 1158
The interruption timing for non-warfarin VKAs will operative day, an INR $ 2.0 was attained in 13% of
1104 1159
differ, as it is shorter for acenocoumarol (2-3 days) the usual-dose group and 50% of the doubling dose
1105 1160
and longer for phenprocoumon (10-12 days). group (RR ¼ 0.27; 95% CI: 0.10 to 0.60); by the tenth
1106 1161
post-operative day, this occurred in 68% and 87% of
1107 PICO 2: In patients who interrupted warfarin before 1162
1108
these groups (RR ¼ 0.87; 95% CI: 0.65 to 1.00). In a 1163
an elective surgery/procedure, should warfarin be
1109 40-patient randomized trial that compared doubling 1164
resumed 12 to 24 hours after surgery (evening of, or
1110 vs usual-dose post-operative warfarin resumption, the 1165
next day) and when there is adequate hemostasis
1111 median number of days to reach an INR $ 2.0 was 1166
vs resuming warfarin further from the surgery/
1112 not significantly different in the two groups (7.8 1167
procedure?
1113 vs 9.0 days; 95% CI: –3.1 to 4.9).98 In observational 1168
1114 Evidence. There are no studies comparing early (12-24 studies that used post-operative VKA resumption with 1169
1115 hours) with delayed (> 24 hours) postoperative warfarin a double-dose or usual-dose regimen, the mean 1170
1116 1171
resumption. In uncontrolled observational studies, duration to attain an INR $ 2.0 was 4.6 and 5.1 days,
1117 1172
resuming warfarin within 24 hours after a surgery/ respectively.56,95
1118 1173
procedure was associated with rates of major bleeding
1119 1174
and ATE of 2.7% (95% CI: 1.6-3.9) and 0.1% (95% CI:
1120 3. In patients requiring VKA (warfarin) interruption 1175
0.1-1.8),56,83,87,90,91,95 whereas those that assessed
1121 for an elective surgery/procedure, we suggest 1176
delayed warfarin resumption reported rates of bleeding
1122 resuming the first post-operative VKA dose at the 1177
1123 and ATE of 8.6% (95% CI: 0-17.7) and 2.4% (95% CI: 0- 1178
patient’s usual dose over resuming VKA with double
1124 7.0), respectively.88,89,96 1179
the usual dose (Conditional Recommendation, Very
1125 1180
2. In patients requiring VKA (warfarin) interruption Low Certainty of Evidence).
1126 1181
for an elective surgery/procedure, we suggest Guideline Implementation Considerations:
1127 1182
1128
resuming VKA (warfarin) within 24 hours over a 1183
delay to > 24 hours after an elective surgery/procedure Although post-operative doubling of the warfarin
1129 1184
(Conditional Recommendation, Low Certainty of dose for 1 to 2 days may lead to a more rapid
1130 1185
1131 Evidence). attainment of an INR $ 2.0 in some patients, there 1186
1132
are concerns in applying this approach in practice; for 1187
Guideline Implementation Considerations: example, in patients with variable warfarin dose reg-
1133 1188
1134 For most patients, resuming VKAs within 24 hours imens and those expected to be hospitalized for > 1189
1135 implies resumption on the evening of the surgery/ 1 day. 1190
1136 procedure. 1191
1137
PICO 4: In patients who interrupted warfarin before a 1192
Implicit in the early (within 24 hours) resumption of a
1138 surgery/procedure and have an elevated INR (ie, > 1.5) 1193
VKA is that it takes, typically, 2 to 3 days for a partial
1139 1 to 2 days before surgery/procedure, should vitamin K 1194
anticoagulant effect and 5 to 6 days for a full anti-
1140 be administered vs not giving vitamin K? 1195
coagulant effect to occur.
1141 1196
VKA resumption may be delayed in certain post- Evidence. Among patients who have interrupted VKAs 5
1142 1197
operative circumstances, such as inadequate surgery/ to 6 days before a surgery/procedure, the practice of pre-
1143 1198
1144 procedure-site hemostasis, an anticipated need for operative INR measurement, typically on the day before 1199
1145 additional intervention, or patient inability to take or day of the surgery/procedure, may be done in selected 1200
1146 oral medications. patients; however, few studies have addressed the role of 1201
1147 vitamin K in this clinical setting. In an uncontrolled 1202
PICO 3: In patients who interrupted warfarin before a
1148 observational study of 43 VKA-treated patients who had 1203
surgery/procedure, should warfarin be resumed at
1149 an INR of 1.4 to 1.9 on the day before elective surgery 1204
1150
double the usual maintenance dose for 1 to 2 days 1205
and received 1 mg oral vitamin K, the INR was
1151 vs resuming warfarin with the usual maintenance dose? 1206
normalized (# 1.3) in 76.6% of patients on the day of
1152 Evidence. One randomized trial of 98 patients surgery.99 In another observational study of 82 VKA- 1207
1153 1208
compared post-operative resumption of warfarin at treated patients who received 1 mg IV vitamin K, on
1154 1209
1155 1210
chestjournal.org e11

1211 average, 27 hours pre-operatively, a normalized INR for those who received perioperative bridging had an 1266
1212 surgery was achieved in 54.9% of patients.100 Other increased risk for major bleeding (RR ¼ 3.1; 95% CI: 1267
1213 1268
studies that have assessed vitamin K to normalize an 1.6-10.9).106 In a meta-analysis of non-randomized
1214 1269
elevated INR have been done in other clinical situations studies totaling 12,278 patients that compared
1215 1270
(eg, bleeding, urgent surgery) outside of the elective bridging vs no bridging in a mixed population of
1216 1271
perioperative setting.101-104 patients, of whom 24% had a mechanical heart valve,
1217 1272
1218
there was no significant difference in the risk of ATE 1273
4. In patients requiring VKA interruption for an
1219 in bridged and non-bridged groups (OR ¼ 0.80; 1274
elective surgery/procedure who have an elevated INR
1220 95% CI: 0.42-1.54), but bridging conferred an 1275
(ie, > 1.5) 1 to 2 days before the surgery/procedure, we
1221 increased risk of major bleeding (OR ¼ 3.60; 95% CI: 1276
suggest against routine use of pre-operative vitamin K
1222 1.52-8.50).23 In non-randomized studies in which all 1277
(Conditional Recommendation, Very Low Certainty of
1223 patients with a mechanical heart valve received 1278
1224
Evidence). 1279
perioperative therapeutic-dose heparin bridging, this
1225 Guideline Implementation Considerations: approach was associated with a pooled incidence of 1280
1226 1281
ATE and major bleeding of 0.9% (95% CI: 0.2-1.5)
1227 Uncertainty about routine pre-operative vitamin K 1282
and 2.8% (0.8-4.8), respectively.56,86-88,107-109
1228 administration relates to the dose of vitamin K, 1283
1229 limited availability of oral vitamin K formulations, 1284
5. In patients receiving VKA therapy for a mechanical
1230 and potential for resistance to post-operative re- 1285
heart valve who require VKA interruption for an
1231 anticoagulation. 1286
elective surgery/procedure, we suggest against heparin
1232 1287
1233
bridging (Conditional Recommendation, Very Low 1288
Bridging Anticoagulation During Interruption of
1234 VKA Therapy Certainty of Evidence). 1289
1235 1290
PICO 5: In patients with a mechanical prosthetic heart Guideline Implementation Considerations:
1236 1291
1237
valve, should bridging anticoagulation during In selected patients considered at high risk for 1292
1238
interruption of warfarin therapy be administered vs no thromboembolism (eg, those with [1] an older- 1293
1239 bridging? generation mechanical heart valve (ie, tilting-disc 1294
1240 valve); [2] a mechanical mitral valve with one or more 1295
Evidence. One randomized trial assessed the need for
1241 risk factors for thromboembolism; [3] a recent [within 1296
heparin bridging in patients with a mechanical
1242 1297
prosthetic heart valve. In the PERIOP-2 trial last 3 months] thromboembolic event; or [4] with
1243 1298
involving warfarin-treated patients who required an prior perioperative thromboembolism), pre- and
1244 1299
elective surgery/procedure, 20.7% (304 of 1,471) of post-operative heparin bridging is suggested (see
1245 1300
patients had a mechanical heart valve, of whom Guideline Statement 8).
1246 1301
1247 9.0% had a mitral valve and 11.7% had an aortic PICO 6: In patients with atrial fibrillation, should 1302
1248 valve prosthesis.105 This trial assessed the need for bridging anticoagulation be administered during 1303
1249 post-operative bridging, as all patients received pre- 1304
interruption of VKA therapy vs no bridging?
1250 operative bridging with open-label dalteparin, 200 1305
1251 IU/kg daily (100 IU/kg daily on the day before the Evidence. The BRIDGE trial assessed a heparin bridging 1306
1252 vs no bridging strategy in patients with atrial fibrillation 1307
surgery/procedure). Post-operatively, patients
1253 who required warfarin interruption for an elective 1308
received dalteparin 200 IU/kg daily (fixed-dose 5,000
1254 1309
IU daily in patients at high-bleed-risk) or placebo, in surgery/procedure.76 In a double-blind manner,
1255 1310
a double-blind manner, until the INR was $ 2.0; patients received bridging with therapeutic-dose
1256 1311
patient follow-up was for 12 weeks. In patients LMWH (dalteparin 100 IU/kg bid) for 3 days pre-
1257 1312
1258 with a mechanical heart valve, there was no operatively, with only the morning dose given on the 1313
1259 significant difference in the no bridging and bridging day before surgery/procedure, and for at least 5 days 1314
1260 groups for the outcomes of major thromboembolism post-operatively until the INR was $ 2.0. Patient 1315
1261 (0% vs 0.67%; P ¼ .67) and major bleeding follow-up was for 4 weeks post-operatively. This trial 1316
1262 (1.96% vs 0.67%; P ¼ .62). In an observational study showed that no bridging was noninferior to LMWH 1317
1263 assessing bridging vs no bridging management in bridging for the outcome of ATE (0.3% vs 0.4%; OR ¼ 1318
1264 VKA-treated patients with a mechanical heart valve, 0.80; 95% CI: 0.42-1.54), but bridging conferred a 1319
1265 1320

1321 threefold increased risk for major bleeding Evidence. In patients with a history of VTE, bridging 1376
1322 (3.2% vs 1.3%; OR ¼ 3.60; 95% CI: 1.52-8.50). In the anticoagulation has been used during VKA interruption 1377
1323 1378
PERIOP-2 trial, there was no significant difference for patients requiring an elective surgery/procedure,111
1324 1379
between the bridging (n ¼ 670) and no bridging (n ¼ but there are no randomized trials to address its efficacy
1325 1380
497) arms in the atrial fibrillation subgroup for the and safety. In an observational study of 755 patients that
1326 1381
outcomes of major thromboembolism (0.75% vs 1.41%) assessed a bridging (n ¼ 214) vs no bridging (n ¼ 514)
1327 1382
1328
and major bleeding (1.64% vs 2.62%).105 In a approach in VKA-treated patients with VTE who 1383
1329 subanalysis of a randomized trial of DOAC vs VKA required a surgery/procedure, there was no significant 1384
1330 therapy for atrial fibrillation that assessed perioperative difference in recurrent VTE or bleeding outcomes in the 1385
1331 management in 1,415 VKA-treated patients, those who two groups.112 Other observational studies found that 1386
1332 received heparin bridging compared with those not heparin bridging increased the risk for major bleeding 1387
1333 bridged were at increased risk for major bleeding with bridging,113,114 with no significant reduction in 1388
1334 (6.8% vs 1.6%; OR ¼ 4.4; 95% CI: 2.4-8.1).110 In an recurrent VTE.113,115,116 In a systematic review totaling 1389
1335 observational study of 2,200 patients with atrial 6,195 VKA-treated patients with VTE who required 1390
1336 1391
fibrillation who required perioperative VKA elective surgery, a heparin bridging vs no bridging
1337 1392
interruption, a multivariate analysis found that, approach was associated with a higher incidence of any
1338 1393
compared with no bridging, heparin bridging was bleeding (3.9% [95% CI: 2.0-7.4] vs 0.4% [95% CI: 0.1-
1339 1394
associated with higher rates of major bleeding 1.7]) and no effect on recurrent VTE (0.7% [95% CI: 0.4-
1340 1395
1341
(5.0% vs 1.3%; OR ¼ 3.84; 95% CI: 2.07-7.14) and 1.2] vs 0.5% [95% CI: 0.3-0.8]).117 1396
1342 cardiovascular events (13.0% vs 6.3%; OR ¼ 1.94; 1397
7. In patients receiving VKA therapy for VTE as the
1343 95% CI: 1.38-2.71).106 The aforementioned meta- 1398
sole clinical indication who require VKA interruption
1344 analysis found no significant difference in ATE but an 1399
for an elective surgery/procedure, we suggest against
1345 increased risk of bleeding for bridging vs no bridging in 1400
heparin bridging (Conditional Recommendation, Very
1346 a mixed population of patients, of whom 44% had atrial 1401
Low Certainty of Evidence).
1347 fibrillation.23 1402
1348 1403
Guideline Implementation Considerations:
1349 6. In patients receiving VKA therapy for atrial 1404
1350 fibrillation who require VKA interruption for an Suggesting against bridging with a therapeutic-dose 1405
1351 elective surgery/procedure, we recommend against heparin regimen does not preclude the use of a low- 1406
1352 heparin bridging (Strong Recommendation, Moderate dose heparin regimen, typically started within 24 1407
1353 Certainty of Evidence). hours after surgery and continued for up to 5 days 1408
1354 while VKA therapy is resumed, to decrease the risk 1409
for post-operative VTE.
1356 1411
In selected patients considered at high risk for In selected patients considered at high risk for VTE (eg,
1357 1412
thromboembolism (eg, those with a recent those with a recent [< 3 months] history of VTE36,118
1358 1413
[< 3 month] history of stroke or transient ischemic or other clinical situations associated with a high VTE
1359 1414
attack or with a CHA2DS2VASc score $ 7 or risk [Table 1]), pre- and post-operative heparin
1360 1415
1361
CHADS2 score of 5 or 6), pre- and post-operative bridging is suggested (see Guideline Statement 8). 1416
1362 heparin bridging is suggested (see Guideline 1417
PICO 8: In VKA-treated patients who are considered at
1363 Statement 8). 1418
high risk for thromboembolism (Table 1), should
1364 A perioperative VKA and heparin bridging calendar 1419
bridging anticoagulation be given during interruption
1365 (paper or electronic) that provides patients and cli- 1420
of VKA therapy vs no bridging?
1366 nicians an easy-to-use timetable for VKA interruption 1421
1367 and resumption alongside the heparin bridging PICO 9: In VKA-treated patients who are considered at 1422
1368 dosing regimen has the potential to minimize errors low-to-moderate risk for thromboembolism (Table 1), 1423
1369 should bridging anticoagulation be given during 1424
and optimize communication among caregivers.
1370 1425
interruption of VKA therapy vs no bridging?
1371Q14 PICO 7: In patients with VTE, should bridging 1426
1372 anticoagulation be administered during interruption of Evidence. Most studies assessing a bridging vs no 1427
1373 VKA therapy vs no bridging? bridging perioperative management strategy did not 1428
1374 1429
1375 1430

1431 separate patients according to thromboembolic risk; continued with a pro-hemostatic agent vs an 1486
1432 consequently, evidence to inform these related PICOs is alternative approach (interrupting VKA with or 1487
1433 1488
derived from studies referred to in the section entitled without heparin bridging or continuing VKA without
1434 1489
“Bridging Anticoagulation During Interruption of VKA pro-hemostatic agent or co-administering different pro-
1435 1490
Therapy,” supplemented by uncontrolled observational hemostatic agents)?
1436 1491
studies84,119,120 and meta-analyses23,121,122 that separated
1437 Evidence. Multiple randomized trials and prospective 1492
1438
patients and associated management according to 1493
cohort studies have evaluated perioperative
1439 thromboembolic risk. 1494
anticoagulant management for dental procedures.
1440 1495
8. In patients receiving VKA therapy who are Management strategies that have been assessed include:
1441 1496
classified as high risk for thromboembolism and who continuing VKAs, with or without co-administered pro-
1442 1497
require VKA interruption for an elective surgery/ hemostatic interventions that comprise antifibrinolytic
1443 1498
1444
procedure, we suggest heparin bridging over no drugs (eg, tranexamic acid) or local measures (eg, fibrin 1499
1445
heparin bridging (Conditional Recommendation, Very glue, topical hemostatic agents and sealants, sutures); 1500
1446 Low Certainty of Evidence). partial (2-3 days’ pre-procedure) VKA interruption; and 1501
1447 complete (5 days’ pre-procedure) VKA interruption.14 1502
1448 These studies had limitations, with one or more of the 1503
1449 Stratification of patients according to perioperative following: small (< 100 patients) study samples; variable 1504
1450 thromboembolic risk, as shown in Table 1, is empiric definitions of bleeding and other outcomes; and 1505
1451 as there are no clinical prediction models that have uncertain outcome capture during follow-up.123-148 1506
1452 been validated in this clinical setting. The type of Among four randomized trials comparing VKA 1507
1453 surgery may also affect thromboembolic risk; for 1508
continuation vs interruption, none showed a significant
1454 example, an anticipated higher risk in patients having 1509
increase in bleeding with VKA continuation.123,128,129,131
1455 1510
open cardiac or major vascular surgery. One meta-analysis (of two studies) comparing
1456 1511
1457 9. In patients receiving VKA therapy who are continuing vs interrupting VKAs found no significant 1512
1458 classified as low-to-moderate-risk for increased intra-procedural bleeding (RR ¼ 1.67; 95% CI: 1513
1459 thromboembolism and who require VKA interruption 0.97-2.89) or post-procedural bleeding (RR ¼ 1.44, 1514
1460 for an elective surgery/procedure, we suggest against 95% CI: 0.71-2.92) with VKA continuation.149 Taken 1515
1461 heparin bridging (Conditional Recommendation, Very together, these studies suggest that continuing VKAs is 1516
1462 Low Certainty of Evidence). associated with a low (approximately 5%) risk for any 1517
1463 bleeding, with such bleeding considered self-limiting. 1518
1464 Guideline Implementation Considerations: Another approach associated with a low risk for 1519
1465 1520
Although patients may be classified empirically as bleeding is partial interruption of the VKA for 2 to
1466 1521
low-to-moderate risk for thromboembolism, there 3 days before the dental procedure. In terms of
1467 1522
may be selected patients within this classification thromboembolic outcomes, these appeared rare
1468 1523
grouping (Table 1) in whom heparin bridging may be (< 0.1%), although it was uncertain if these outcomes
1469 1524
1470
considered; for example, patients with a history of were reliably identified during follow-up. If tranexamic 1525
1471 perioperative thromboembolism. acid is used, 10 mL of a 5% mouthwash solution can be 1526
1472 given just before the procedure and two to three times 1527
Management of Patients Who Are Receiving a VKA
1473 and Need Minor Procedures daily for 1 to 2 days’ post-procedure.123,150 1528
1474 1529
1475
Dental Procedures: Minor dental procedures include 10. In patients receiving VKA therapy who need a 1530
1476 single and multiple tooth extractions, and endodontic dental procedure, we suggest continuation of VKA 1531
1477 (root canal) procedures. over VKA interruption (Conditional Recommendation, 1532
1478 Low Certainty of Evidence). 1533
1479
PICO 10: In patients who are having minor dental 1534
1480 procedures and are receiving a VKA, should VKAs be Guideline Implementation Considerations: 1535
1481 continued vs stopped 5 to 6 days before the procedure? 1536
The risk for dental procedure-related bleeding may
1482 1537
PICO 11: In patients who are having minor dental vary, being lower with single tooth extractions and
1483 1538
procedures and are receiving a VKA, should VKAs be higher with multiple tooth extractions or in patients
1484 1539
1485 1540

1541 with poor gingival health; accordingly, VKA inter- Minor Ophthalmologic Procedures: Minor 1596
1542 ruption may be preferred in situations where oral ophthalmologic procedures include cataract surgery 1597
1543 1598
bleeding is expected to be considerable. (phacoemulsification), which is a largely avascular
1544 1599
11. In patients receiving VKA therapy who need a procedure, and surgery for glaucoma (iridotomy) and
1545 1600
dental procedure, we suggest using a pro-hemostatic diabetic retinopathy (panretinal photocoagulation,
1546 1601
vitrectomy). Whereas most eye surgery is done using
1547 agent with continuation of VKA over alternative 1602
1548 management options (eg, discontinuation of VKA sub-Tenon’s or topical anesthesia or a peribulbar 1603
1549 with or without heparin bridging) (Conditional (extraconal) block technique, retrobulbar (intraconal) 1604
1550 Recommendation, Low Certainty of Evidence). anesthesia poses a concern in anticoagulated patients 1605
1551 due to the potential complication of retrobulbar 1606
1552 Guideline Implementation Considerations: hematoma,155 which can lead to loss of vision. 1607
1553 1608
Pro-hemostatic options include pre- and post- PICO 13: In patients who are having a minor
1554 1609
procedure administration of oral tranexamic acid ophthalmologic procedure and are receiving a VKA,
1555 1610
mouthwash, two to three times daily, and should VKA be continued around the time of the
1556 1611
1557
intervention-specific measures (eg, extra sutures, procedure vs stopping the VKA 5 to 6 days before the 1612
1558 gauze soaked in tranexamic acid). procedure? 1613
1559 Minor Dermatologic Procedures: Minor skin 1614
Evidence. No randomized trials have assessed
1560 procedures include excision of basal and squamous cell 1615
1561
perioperative management with cataract surgery.156 In 1616
skin cancers, actinic keratoses, and premalignant or prospective cohort studies, the incidence of major and
1562 1617
cancerous skin nevi. non-major bleeding was < 3%.157-166 In a meta-analysis
1563 1618
1564 PICO 12: In patients who are having a minor of observational studies, patients who continued VKAs 1619
1565 dermatologic procedure and are receiving a VKA, around cataract surgery had an increased risk for 1620
1566 should VKA be continued around the time of the bleeding (OR ¼ 3.26; 95% CI: 1.73-6.16), with an 1621
1567 procedure vs stopping the VKA 5 to 6 days before the overall incidence of bleeding of 10% (95% CI: 5-19).46 1622
1568 However, almost all bleeds were self-limiting, 1623
procedure?
1569 consisting of dot hyphemas or subconjunctival bleeds, 1624
1570 Evidence. No randomized trials have assessed 1625
and no patient had compromised visual acuity related
1571 perioperative anticoagulant management. Prospective, 1626
to bleeding.
1572 controlled cohort studies reported a higher incidence of 1627
1573 bleeding in patients who continued VKAs compared 13. In patients receiving VKA therapy who require a 1628
1574 with patients with VKA interruption, with most bleeds minor ophthalmologic procedure, we suggest 1629
1575 1630
being self-limiting.151-154 The incidence of bleeding with continuation of VKA over VKA interruption
the continuation of VKAs appears to be low (< 5%),
1577 1632
although there was uncertainty as to the reliability that Evidence).
1578 1633
1579
events were identified. Guideline Implementation Considerations: 1634
1580 1635
12. In patients receiving VKA therapy who require a VKA interruption may be preferred in patients
1581 minor dermatologic procedure, we suggest 1636
considered at higher risk for bleeding; for example,
1582 1637
continuation of VKA over VKA interruption those having more complex retinal surgery or pa-
1583 1638
(Conditional Recommendation, Very Low Certainty of tients having surgery with retrobulbar anesthesia.
1584 1639
Evidence). Cataract surgery is done usually with topical anes-
1585 1640
1586 Guideline Implementation Considerations: thesia and, less commonly, with retrobulbar 1641
1587 anesthesia. 1642
1588 The risk for dermatologic procedure-related bleeding 1643
Cardiac Device Procedures: Commonly performed
1589 may vary, being lower with resections of small (1- 1644
cardiac device procedures include implantation of a
1590 2 cm) skin cancers and biopsies, and higher with re- 1645
permanent cardiac pacemaker or an ICD.
1591 sections of larger (> 3 cm) skin cancers, particularly if 1646
1592 skin grafting is required; accordingly, VKA interrup- PICO 14: In patients who are having a cardiac device 1647
1593 tion may be preferred in situations where site-related procedure and are receiving a VKA, should VKA be 1648
1594 bleeding is expected to be considerable or if lengthy continued around the time of the procedure vs stopping 1649
1595 1650
wound healing is expected (eg, skin graft). the VKA 5 to 6 days before the procedure?

1651 Evidence. The BRUISE CONTROL trial assessed a higher in the VKA interruption-heparin bridging group 1706
1652 warfarin interruption-bridging vs warfarin than in the VKA continuation group (12.0% [95% CI: 1707
1653 1708
continuation-no bridging strategy in patients with atrial 5.0-19.1] vs 4.7% [95% CI: 0.2-9.2]); this difference was
1654 1709
fibrillation or a mechanical heart valve who required not statistically significant.
1655 1710
implantation of a pacemaker or ICD.167 In the warfarin
1656 15. In patients receiving VKA therapy who require 1711
interruption-bridging group, patients received
1657 VKA interruption for a colonoscopy with anticipated 1712
1658
therapeutic-dose LMWH (89% of patients) or IV UFH 1713
polypectomy, we suggest against heparin bridging
1659 (11% of patients) pre-procedure for 3 days. Post- 1714
during the period of VKA interruption (Conditional
1660 procedure, bridging was resumed within 24 hours. The 1715
1661 primary outcome of clinically significant pocket 1716
1662 hematoma occurred in 3.5% (12 of 343) of patients in 1717
1663 the warfarin continuation group, and in 16.0% (54 of
Perioperative Management of Patients Who 1718
1664 338) of patients in the warfarin interruption-bridging Are Receiving Heparin Bridging 1719
1665 group (RR ¼ 0.19; 95% CI: 0.10-0.36). Meta-analyses of Background: The perioperative management of patients 1720
1666 who receive heparin bridging is informed by an 1721
observational studies where VKAs were continued
1667 understanding of the basic pharmacologic properties of 1722
around the time of pacemaker/ICD implantation
1668 bridging agents, LMWH and UFH.22 LMWHs have an 1723
demonstrated similar low (approximately 2%-6%) rates
1669 1724
of pacemaker pocket hematomas.50,168,169 Smaller elimination half-life of 3 to 5 hours, which informs pre-
1670 1725
randomized trials also reported higher bleeding with operative interruption timing, and a peak action
1671 1726
VKA interruption and bridging compared with VKA occurring 3 to 4 hours after administration, which
1672 1727
1673 continuation around pacemaker implantation,170-172 informs post-operative initiation timing.22 UFH has a 1728
1674 whereas a 467-patient retrospective cohort study dose-dependent elimination half-life that is 1729
1675 reported a 1.6% incidence of major pocket hematomas approximately 90 minutes but can vary from 30 to 120 1730
1676 in patients who did not interrupt warfarin for minutes depending on the level of anticoagulation (as 1731
1677 pacemaker implantation.173 reflected by the aPTT or anti-factor Xa levels) at the time 1732
1678 of interruption.22 1733
1679 14 In patients receiving VKA therapy who require a 1734
1680 pacemaker or ICD implantation, we recommend Perioperative Use of IV UFH as Bridging 1735
1681 continuation of VKA over VKA interruption and Anticoagulation 1736
1682 heparin bridging (Strong Recommendation, Moderate PICO 16: In patients who are receiving bridging 1737
1683 Certainty of Evidence). anticoagulation with therapeutic-dose IV UFH, should 1738
1684 UFH be stopped 4 to 6 hours before surgery vs stopping 1739
UFH closer to surgery?
1686 1741
Continuation of VKAs around cardiac device pro-
1687 PICO 17: In patients who are receiving bridging 1742
cedures is based on the premise that the patient’s INR
1688 anticoagulation with therapeutic-dose IV UFH, should 1743
at the time of the procedure is < 3.0.
1689 UFH be resumed > 24 hours after a surgery/procedure 1744
1690 PICO 15: In patients receiving VKA therapy who vs within 24 hours after a surgery/procedure? 1745
1691 require VKA interruption for a colonoscopy with 1746
1692 anticipated polypectomy, should heparin bridging be Evidence. There are no studies assessing the timing of IV 1747
1693 given vs no heparin bridging? UFH interruption and resumption around the time of a 1748
1694 surgery/procedure. Based on the elimination half-life, an 1749
1695 Evidence. The management of patients undergoing infusion of UFH can be stopped 4 to 6 hours before 1750
1696 polypectomy poses specific challenges because of the surgery to eliminate any residual anticoagulant effect.22 1751
1697 potential for post-procedure bleeding, which can be Resumption of IV UFH after surgery follows the 1752
1698 delayed when the scar formed over the polyp stalk is approach used for LMWH in terms of the timing of 1753
1699 dislodged with potential exposure of friable, vascular 1754
post-operative resumption, and with IV UFH resumed
1700 1755
tissue.54 One randomized trial compared continuing at the same infusion rate as that used pre-
1701 1756
VKAs with cold snare polypectomy vs VKA interruption operatively.175,176
1702 1757
and heparin bridging with hot snare polypectomy in 184
1703 16. In patients receiving therapeutic-dose IV UFH 1758
1704
patients who needed colonic polyp resection.174 The 1759
bridging for an elective surgery/procedure, we suggest
1705 incidence of polypectomy-related major bleeding was 1760
stopping UFH ‡ 4 hours before a surgery/procedure

1761 over stopping IV UFH < 4 hours before a surgery/ risk surgery, should therapeutic-dose LMWH be 1816
1762 procedure (Conditional Recommendation, Very Low resumed within 24 hours after surgery vs resuming 1817
1763 1818
Certainty of Evidence). LMWH > 24 hours after surgery?
1764 1819
1765 17. In patients receiving therapeutic-dose IV UFH Evidence. No randomized trials have compared an early 1820
1766 bridging for an elective surgery/procedure, we suggest (within 24 hours) or delayed (> 24 hours) resumption of 1821
1767 resuming UFH ‡ 24 hours after a surgery/procedure therapeutic-dose LMWH after a surgery/procedure, 1822
1768 over resuming UFH within 24 hours after a surgery/ irrespective of the type of surgery. The BRIDGE trial 1823
1769 procedure (Conditional Recommendation, Very Low used a standardized post-operative heparin resumption 1824
1770
Certainty of Evidence). regimen where LMWH was resumed 24 hours after a 1825
1771 1826
low/moderate-bleed-risk surgery/procedure and 48 to 72
hours after a high-bleed-risk surgery/procedure was
1773 1828
When resuming UFH post-operatively, we suggest associated with a 3.2% incidence of major bleeding.76 In 1829
1774
avoiding a bolus dose and commencing with a lower- a subanalysis of the RE-LY trial, which compared
1775 1830
1776
intensity infusion that is associated with a lower target warfarin and dabigatran for stroke prevention in atrial 1831
1777 aPTT than that used for initiation of full-dose UFH fibrillation, patients who were receiving (open-label) 1832
1778 administration. warfarin and received perioperative LMWH bridging 1833
1779 without a standardized bridging regimen had a 1834
Perioperative Use of LMWH as Bridging
1780
Anticoagulation
6.8% incidence of major bleeding.110 An observational Q16 1835
1781 study in which all patients received LMWH bridging 1836
1782 PICO 18: In patients who are receiving LWMH with enoxaparin 1.5 mg/kg daily, started 12 to 24 hours 1837
1783 bridging, should the last pre-operative dose of LMWH after all types of surgery, patients who had major (>1 1838
1784 be given 24 hours before surgery vs 12 hours before 1839
hour duration) surgery had a 20% (8 of 40) incidence of
1785 surgery? 1840
major bleeding, whereas major bleeding occurred in
1786 1841
1787 Evidence. There are no studies assessing the timing of 0.7% (1 of 148) of patients who had a minor (< 1 hour 1842
1788 LMWH bridging interruption before a surgery/ duration) surgery or procedure.179 Other observational Q17 1843
1789 procedure and its effect on bleeding or other clinical studies that allowed a flexible post-operative bridging 1844
1790 outcomes. In observational studies assessing LMWH regimen in high-bleeding risk patients, with either 1845
1791 bridging, there were no apparent higher bleeding rates delayed resumption of therapeutic-dose LMWH or 1846
1792 (compared with non-bridged controls from other substitution of a low-dose regimen, found a low (< 5%) 1847
1793 studies) if the last dose of LMWH was given incidence of major bleeding.84,87,88,92,107,120,180,181 Taken 1848
1794 together, these studies support flexible postoperative 1849
approximately 12 hours (evening) before surgery or
1795 resumption timing of LMWH bridging, to occur after 24 1850
approximately 24 hours before a surgery/procedure.56,95
1796
In studies assessing a surrogate marker for bleeding hours or after 48 to 72 hours depending on the surgery/ 1851
1797 1852
1798
(anti-factor Xa levels), > 90% of patients who received procedure-related bleed risk, and when there is adequate
1853
their last LMWH dose approximately 12 hours before a surgical site hemostasis.
1799 1854
1800 surgery/procedure had a detectable anticoagulant effect 1855
1801 at surgery, with 34% of patients having an elevated 19. In patients receiving LMWH bridging for an 1856
1802 (therapeutic level) anticoagulant effect (ie, anti-factor Xa elective surgery/procedure, we suggest administering 1857
1803 level $ 0.50 IU/mL) at the time of surgery.177,178 the first post-operative LMWH bridging dose at 1858
1804 1859
least 24 hours after a surgery/procedure over
1805 18. In patients receiving LMWH bridging for an 1860
administering it less than 24 hours after a surgery/
1806 elective surgery/procedure, we suggest administering 1861
1807
procedure (Conditional Recommendation, Very Low 1862
the last pre-operative LMWH bridging dose at
1808
Certainty of Evidence). 1863
approximately 24 hours over administering the last
1809 dose 10 to 12 hours before a surgery/procedure Guideline Implementation Considerations: 1864
1811 We suggest waiting at least 24 hours before resuming 1866
Evidence).
1812 LMWH bridging in patients having a low-to- 1867
1813 Q15 PICO 19: In patients who are receiving bridging with moderate-bleed-risk surgery/procedure and waiting at 1868
1814 therapeutic-dose LMWH and are having high bleeding- least 48 to 72 hours before resuming LMWH bridging 1869
1815 1870

1871 in patients having a high-bleed-risk surgery/proced- did not incorporate anti-factor Xa measurements as part 1926
1872 ure (Table 2). of perioperative management.23,76,105 1927
1873 1928
For patients in whom the management plan is to
1874 21. In patients receiving LMWH bridging for an 1929
delay resumption of LMWH bridging for 48 to 72
1875 elective surgery/procedure, we suggest against routine 1930
hours and who are considered at high risk for post-
1876 measurement of anti-factor Xa levels to guide 1931
operative VTE, low-dose LMWH can be administered
1877 perioperative LMWH management (Conditional 1932
1878
for the initial 2 to 3 days before the transition to 1933
1879 LMWH bridging. 1934
PICO 20: In patients receiving LMWH bridging,
1881 1936
should half the total daily dose of LMWH be given on There may be select patients undergoing high-bleed-
1882 1937
the day before the surgery/procedure vs administering risk surgeries/procedures (ie, intracranial, spinal) or
1883 1938
the full dose of LMWH? patients who require an urgent (nonelective) surgery/
1884 1939
1885
procedure where anti-factor Xa measurement may be 1940
Evidence. The evidence for administering half the total considered.
1886 1941
dose of LMWH bridging on the day before the surgery/
1887 1942
procedure incorporates the evidence used for Guideline
1888 1943
1889
Statement 18, shown above.56,95,177,178 In addition, in the Patients Who Are Receiving a DOAC and 1944
1890 BRIDGE and PERIOP-2 trials, which gave half the total Require an Elective Surgery/Procedure 1945
1891 daily LMWH bridging dose on the day before the 1946
Background: The interruption of DOACs before an
1892 surgery/procedure in patients who received pre- elective surgery/procedure can follow a 1947
1893 operative bridging, this approach was associated with 1948
pharmacokinetic-based approach, as used with the
1894 low rates of perioperative major bleeding (3.2%, 1949
perioperative management of other anticoagulants,
1895 1.6%).76,105 1950
whereby the pre-operative interruption interval
1896 1951
1897
corresponds to four to five elimination half-lives of each 1952
20. In patients receiving LMWH bridging for an
1898 DOAC.182,183 Given the DOAC half-lives of 9 to 14 1953
elective surgery/procedure, we suggest administering
1899 hours, withholding DOACs for 2 full days before a 1954
half the total daily dose of LMWH the day prior to the
1900 surgery/procedure, which corresponds more precisely to 1955
surgery/procedure over administering the full dose of
1901 a 60- to 68-hour interval (or four to five half-lives) from 1956
LMWH the day prior (Conditional Recommendation,
1902 the last DOAC dose until the surgery, should result in 1957
Very Low Certainty of Evidence).
1903 minimal to no residual anticoagulant effect at the time of 1958
1904 Guideline Implementation Considerations: surgery.184 This approach can be used for patients 1959
1905 having a high-bleed-risk surgery/procedure, whereas for 1960
This guidance may apply more to patients having a
1906 1961
high-bleed-risk surgery, including patients having patients having a low/moderate-bleed-risk surgery/
1907 1962
neuraxial (spinal or epidural) anesthesia, rather than procedure, withholding DOACs for 1 full day before the
1908 1963
in patients having a low-to-moderate-bleed-risk sur- procedure, which corresponds to a 30- to 36-hour
1909 1964
1910 gery/procedure (Table 2). interruption interval (or approximately three DOAC 1965
1911 Administering half the total daily dose of LMWH can half-lives), should result in a residual anticoagulant 1966
1912 be done by giving, on the morning of the day before effect which is acceptable clinically for lower bleed risk 1967
1913 the surgery/procedure, only the morning dose of a procedures. In all patients, no DOAC is taken on the day 1968
1914 twice-daily LMWH regimen or approximately 50% of of the surgery/procedure. 1969
1915 the dose of a once-daily LWMH regimen. 1970
1916
There are two important qualifying remarks to this 1971
1917 PICO 21: In patients receiving LMWH bridging, pharmacokinetic-based DOAC interruption 1972
1918 should measurement of anti-factor Xa levels be management strategy: 1973
1919 routinely done vs no anti-factor Xa measurements? In dabigatran-treated patients with impaired renal 1974
1920 1975
Evidence. There are no studies that have compared a function (creatinine clearance [CrCl] < 50 mL/min),
1921 1976
perioperative LMWH bridging strategy with and interruption for 3 to 4 full days is required to allow for
1922 1977
without pre-operative anti-factor Xa measurements. the longer time required for drug clearance as 75% to
1923 1978
1924 Large randomized trials and prospective cohort studies 80% of dabigatran clearance is by the kidney.21,185 1979
1925 1980

1981 There may be selected patients in whom a longer CrCl < 30 mL/min if taking dabigatran or rivaroxaban). 2036
1982 duration of pre-operative DOAC interruption may be DOACs were interrupted for 1 day before and 1 day 2037
1983 2038
required, irrespective of the DOAC used. This may after (2 days total) a low/moderate-bleed-risk surgery/
1984 2039
include patients with severely impaired renal function procedure and for 2 days before and 2 days after (4 days
1985 2040
(CrCl < 30 mL/min) or hepatic function, and in those total) a high-bleed-risk surgery/procedure. An exception
1986 2041
who are taking drugs that, through inhibition of to this management occurred in a small proportion of
1987 2042
1988
CYP3A4 or P-glycoprotein pathways, may interfere patients (2.7% [80 of 3,007]) who were receiving 2043
1989 with DOAC clearance.186-188 dabigatran and had a CrCl < 50 mL/min in whom the 2044
1990 interruption interval was extended by 1 or 2 days 2045
An alternative pre-operative management strategy
1991 depending on the surgery/procedure bleed risk. With 2046
includes measurement of DOAC levels before the
1992 this overall management approach, 30-day post- 2047
surgery/procedure,189,190 which may be considered in
1993 operative incidences of ATE and major bleeding, 2048
patients who require an urgent (ie, within 24 hours)
1994 respectively, were: 0.16% (95% CI: 0-0.48) and 2049
1995
surgery, such as hip fracture repair.191 A practical issue 2050
1.35% (95% CI: 0-2.0) in the apixaban cohort (n ¼
1996 with this approach is that routine coagulation function 2051
1,257); 0.60% (95% CI: 0-1.33) and 0.9% (95% CI: 0-
1997 tests such as the INR or aPTT may be insensitive to 2052
1.73) in the dabigatran cohort (n ¼ 668); and
1998 exclude a residual preoperative DOAC effect,192 thereby 2053
0.37% (95% CI: 0-0.82) and 1.85% (95% CI: 0-2.65) in
1999 necessitating the need to measure DOAC levels with 2054
the rivaroxaban cohort (n ¼ 1,082).
2000
Q18 more sensitive but less widely available tests. These tests 2055
2001 consist of DOAC-calibrated anti-Xa levels for apixaban, Retrospective subanalyses of the major randomized 2056
2002 edoxaban, and rivaroxaban, and the dilute thrombin trials assessing DOACs vs warfarin in atrial fibrillation 2057
2003 time or ecarin clotting time for dabigatran; however, 2058
were done to assess perioperative DOAC management
2004 2059
questions remain as to their clinical utility.193-195 but, in general, such management was not standardized
2005 2060
as the timing of DOAC interruption and resumption
2006 2061
Perioperative Interruption and Resumption of varied and 15% to 20% of patients received heparin
2007 2062
DOACs and Heparin Bridging bridging.8,10,80,85,197 A meta-analysis of > 19,000
2008 2063
2009 PICOs 22-25: In patients who are receiving a DOAC patients who underwent a procedure in the randomized 2064
2010 (apixaban, dabigatran, edoxaban, or rivaroxaban) and trials comparing DOACs vs warfarin in atrial fibrillation 2065
2011 require an elective surgery/procedure, should DOACs was reported as well.198 Taken together, these studies 2066
2012 be interrupted for 1 to 2 days (1-4 days for dabigatran) reported rates of perioperative ATE of 0.5% to 1.0% and 2067
2013 before a surgery/procedure vs interrupting DOACs rates of major bleeding of 2% to 5%, which are 2068
2014 earlier? comparable to rates observed in patients who receive 2069
2015 non-standardized VKA interruption and 2070
2016 Evidence. Two prospective studies assessed a 2071
resumption.23,198
2017 standardized perioperative DOAC management, with 2072
2018 standardized DOAC interruption. The first was a Additional evidence relating to pre-operative DOAC 2073
2019 prospective management study of 541 dabigatran- management involves patients undergoing catheter 2074
2020 treated patients with atrial fibrillation who required an ablation for atrial fibrillation. An observational study 2075
2021 elective surgery/procedure; 24- and 48-hour DOAC reported an increase in bleeding with periprocedural 2076
2022 2077
interruption intervals were adopted for low- and high- DOAC continuation199 while another reported no
2023 2078
bleed-risk surgeries/procedures, respectively.185 This difference in bleeding outcomes.200 A 306-patient
2024 2079
approach was associated with low 30-day post-operative randomized trial that compared 1-day DOAC
2025 2080
rates of ATE (0.2%; 95% CI: 0-0.5) and major bleeding interruption vs no interruption found no significant
2026 2081
2027
(1.8%; 95% CI: 0.7-3.0). The second study, PAUSE, was difference in bleeding outcomes (11.3% vs 9.7%; risk 2082
2028 a prospective management study of 3,007 patients with difference ¼ 1.7%; 95% CI –5.5 to 8.8).201 An 2083
2029 atrial fibrillation taking a DOAC (apixaban, dabigatran, observational study assessing pacemaker/ICD 2084
2030 or rivaroxaban) who required an elective surgery/ implantation and minimal DOAC interruption (ie, 2085
2031 procedure and received standardized perioperative skipping or delaying the immediate pre-procedure dose) 2086
2032 management196; patients with severe renal insufficiency, reported a low rate (1.6%) of major pocket 2087
2033 in whom DOAC therapy was not clinically indicated, hematomas.173 A 25-patient observational study 2088
2034 were excluded (CrCl < 25 mL/min if taking apixaban or assessing DOAC continuation in patients having 2089
2035 2090

2091 cataract surgery identified no bleeding events.202 An o 4 days off for high-bleed-risk if CrCl < 50 mL/min 2146
2092 observational study comparing perioperative DOAC (this extended duration of interruption of > 2 days 2147
2093 2148
interruption and continuation in patients undergoing reflects the unique management of patients who are
2094 2149
low bleeding risk procedures reported lower rates of receiving dabigatran and have a CrCl < 50 mL/
2095 2150
overall bleeding (OR ¼ 0.59; 95% CI: 0.39 to 0.91) and min).
2096 2151
minor bleeding (OR ¼ 0.59; 95% CI: 0.37 to 0.93) with This management may be applied irrespective of
2097 2152
2098
DOAC interruption, a finding that persisted after whether patients are receiving dabigatran for atrial 2153
2099 adjustment for confounders (OR ¼ 0.62; 95% CI: 0.41 fibrillation or VTE. 2154
2100 to 0.95).203 2155
2101 24. In patients receiving edoxaban who require an 2156
It is noteworthy that almost all evidence pertaining to elective surgery/procedure, we suggest stopping
2102 2157
perioperative DOAC management involves patients with edoxaban for 1 to 2 days before the surgery/procedure
2103 2158
2104
atrial fibrillation. Few studies, limited to retrospective over edoxaban continuation (Conditional 2159
2105 case series, have assessed perioperative DOAC Recommendation, Very Low Certainty of Evidence). 2160
2106 management in patients with VTE.204,205 There are no 2161
2107 studies assessing perioperative management in patients Guideline Implementation Considerations: 2162
2108 who are receiving low-dose DOAC therapy (rivaroxaban The total duration of perioperative edoxaban inter- 2163
2109 2.5 mg bid) and ASA for stable coronary or peripheral ruption will depend on the bleed risk associated with 2164
2110 arterial disease.206 the surgery/procedure: 2165
2111 2166
o 1 day off before low/moderate-bleed-risk;
2112 22. In patients receiving apixaban who require an 2167
o 2 days off before high-bleed-risk.
2113 elective surgery/procedure, we suggest stopping 2168
2114 This management may be applied irrespective of 2169
apixaban for 1 to 2 days before the surgery/procedure
2115 whether patients are receiving edoxaban for atrial 2170
over apixaban continuation (Conditional
2116 fibrillation or VTE. 2171
2117 2172
2118
25. In patients receiving rivaroxaban who require an 2173
2120 The total duration of perioperative apixaban inter- rivaroxaban for 1 to 2 days before the surgery/ 2175
2121 ruption will depend on the bleed risk associated with procedure over rivaroxaban continuation (Conditional 2176
2122 the surgery/procedure: Recommendation, Very Low Certainty of Evidence). 2177
2123 o 1 day off before low/moderate-bleed-risk; 2178
2124 o 2 days off before high-bleed-risk. Guideline Implementation Considerations: 2179
2125
This management may be applied irrespective of The total duration of perioperative rivaroxaban 2180
2126 interruption will depend on the bleed risk associated 2181
whether patients are receiving apixaban for atrial
2127 with the surgery/procedure: 2182
2128
fibrillation or VTE. 2183
o 1 day off before low/moderate-bleed-risk;
2129 23. In patients receiving dabigatran who require an 2184
o 2 days off before high-bleed-risk.
2131 This management may be applied irrespective of 2186
dabigatran for 1 to 4 days before the surgery/
2132 whether patients are receiving rivaroxaban for atrial 2187
procedure over dabigatran continuation (Conditional
2133 fibrillation or VTE. 2188
2134 2189
2135 Guideline Implementation Considerations: PICO 26: In patients who require DOAC interruption 2190
2136 for an elective surgery/procedure, should perioperative 2191
2137
The total duration of perioperative dabigatran inter- 2192
bridging be given vs no bridging?
2138 ruption will depend on the bleed risk associated with 2193
2139 the surgery/procedure and patient renal function: Evidence. In a subanalysis of the RE-LY trial that 2194
2140 o 1 day off before low/moderate-bleed-risk if CrCl $ assessed patients with AF who were receiving open- 2195
2141 50 mL/min; label dabigatran (or warfarin) and required treatment 2196
2142 o 2 days off before low/moderate-bleed-risk if CrCl < interruption for an elective surgery/procedure, those 2197
2143 50 mL/min; who received perioperative LMWH bridging were at 2198
2144 o 2 days off before high-bleed risk if CrCl $ 50 mL/ higher risk for major bleeding than those who did 2199
2145 2200
min; not receive bridging (6.5% vs 1.8%; P < .001), and

2201 use of bridging had no significant effect on stroke/ resuming DOACs within 24 hours (Conditional 2256
2202 systemic embolism outcomes (0.5% vs 0.3%; P ¼ Recommendation, Very Low Certainty of Evidence). 2257
2203 2258
.46).110 In a prospective patient registry of 901
DOAC-treated patients who required an elective
2205 2260
surgery, perioperative LMWH bridging was The resumption of DOACs post-operatively will
2206 2261
associated with an increased risk for major bleeding depend on the bleed risk associated with the surgery/
2207 2262
2208
(OR ¼ 4.6; 95% CI: 1.1-9.9) with no significant effect procedure:
2263
2209 on thromboembolic outcomes (OR ¼ 1.9; 95% CI: o at least 24 hours after low/moderate-bleed-risk;
2264
2210 0.7-5.4).207 In the aforementioned DOAC meta- o 48-72 hours after high-bleed-risk. 2265
2211 analysis, perioperative LMWH bridging was DOACs have a rapid onset of action, with a peak 2266
2212 associated with a threefold higher incidence of major effect occurring 1 to 3 hours after intake, thereby 2267
2213 bleeding compared with the non-bridged group requiring cautious administration after a surgery/ 2268
2214 (4.8% [95% CI: 3.4-6.2] vs 1.6% [95% CI: 1.2-2.0%]), 2269
procedure.
2215 with no differences in the pooled rates of stroke/ 2270
2216 Perioperative Laboratory Measurement of DOAC 2271
systemic embolism.198
2217 Therapy 2272
2218 26. In patients who require DOAC interruption for an Background: The role of measuring DOAC levels 2273
2219 2274
elective surgery/procedure, we suggest against before a surgery/procedure, akin to a pre-operative
2220 2275
perioperative heparin bridging (Conditional measurement of the INR in VKA-treated patients, is
2221 2276
Recommendation, Very Low Certainty of Evidence). uncertain.45,209,210 Unlike with an INR measurement
2222 2277
2223
where a level < 1.5 is considered safe to allow most 2278
2224 surgery/procedures to proceed,51 such a threshold 2279
2225 The rapid offset and rapid onset of action of DOACs with DOACs is uncertain as levels of < 30 ng/mL 2280
2226 obviate the need for heparin bridging with short- (the lower limit of detection of DOAC levels for some 2281
2227 acting anticoagulants such as UFH or LMWH in a assays) or < 50 ng/mL have been suggested.211,212 2282
2228 perioperative setting. Although a subanalysis of the PAUSE study suggested 2283
2229
PICO 27: In patients who had DOAC interruption for that pre-operative DOAC levels < 30 ng/mL or 30 to 2284
2230 50 ng/mL were not associated with an increased risk for 2285
an elective surgery/procedure, should DOACs be
2231 perioperative bleeding, this study was underpowered to 2286
2232
resumed > 24 hours after a surgery/procedure 2287
vs resuming DOACs within 24 hours? assess such an association, and additional research is
2233 2288
needed to define safe pre-operative DOAC levels
2234 2289
Evidence. One randomized trial of 662 DOAC-treated according to the surgery/procedure-related risk for
2235 2290
2236
patients who required a pacemaker/ICD implantation bleeding.213,214 2291
compared perioperative DOAC continuation (median
2237 Potential barriers for the clinical use of DOAC assays, 2292
2238
interval between pre- and post-procedure DOAC doses: 2293
including relatively high costs and limited availability,
2239 12 hours) and DOAC interruption (median interval: 72 2294
can be mitigated if laboratories are configured to run
2240 hours) found no significant difference in pacemaker/ 2295
these assays with similar 20- to 30-minute turnaround
2241 ICD pocket hematomas (OR ¼ 1.02; 95% CI: 0.36- 2296
times as with the INR and aPTT, and provide the
2242 2.87).208 Evidence from the PAUSE study, as discussed 2297
2243
requisite quality control measures.215,216 2298
above, informs the incidence of major bleeding and ATE
2244 when DOACs are resumed > 24 hours after a surgery/ PICO 28: In patients who interrupted a DOAC before a
2299
2245 procedure. Other evidence regarding post-operative 2300
2246
surgery/procedure, should the anticoagulant effect of 2301
DOAC resumption timing is derived from the PAUSE DOACs routinely be measured with coagulation
2247 2302
trial in which resumption was standardized at function tests vs not measuring the anticoagulant effect
2248 2303
approximately 24 hours (for a low/moderate-bleed-risk of DOACs?
2249 2304
surgery/procedure) and 48 to 72 hours (for a high-bleed-
2250 2305
risk surgery/procedure). Evidence. Although DOAC-level testing has been
2251 2306
assessed in various clinical settings,217-221 no studies
2252 2307
2253
27. In patients who had DOAC interruption for an have assessed the clinical utility of measuring the 2308
2254 elective surgery/procedure, we suggest resuming residual anticoagulant effect of a DOAC after its 2309
2255 DOACs > 24 hours after a surgery/procedure over interruption before a surgery/procedure. Specifically, no 2310

2311 study has compared the safety of a perioperative DOAC with administration of blood products or DOAC- 2366
2312 testing-driven strategy with a strategy that does not specific reversal agents. 2367
2313 2368
involve DOAC-level testing.184 One prospective registry
2314 2369
2315
assessed 422 patients who interrupted DOACs with Perioperative Management of Patients Who 2370
non-standardized intervals (ranging from 1 to 218 Are Receiving Antiplatelet Drugs
2316 2371
hours), according to physician discretion, and had Background: Knowledge of basic pharmacologic
2317 2372
2318
DOAC levels measured just before the surgery. In properties of antiplatelet drugs will inform the timing of 2373
2319 patients with a 49- to 72-hour interruption interval, only perioperative interruption and resumption. When 2374
2320 5% had a residual DOAC level > 30 ng/mL, and none interrupting ASA and the P2Y12 inhibitors clopidogrel 2375
2321 had a level > 50 ng/mL.222 A receiver-operator curve and prasugrel, since these drugs irreversibly inhibit 2376
2322 analysis identified a DOAC interruption interval 2377
platelet function, 7 to 10 days (ie, platelet life span) of
2323 of 54 hours to best predict a residual anticoagulant 2378
interruption is needed to restore platelet function.223-225
2324 level # 30 ng/mL. In the PAUSE study, 85% (n ¼ 2,541) When interrupting the P2Y12 inhibitor ticagrelor, which
2379
2325 of patients had a DOAC level measured just before the 2380
2326
reversibly inhibits platelet function, at least 2 to 3 days of 2381
surgery/procedure, but this was not available for interruption is needed to restore platelet function.226,227
2327 2382
clinical use and did not affect the DOAC interruption When resuming antiplatelet drugs post-operatively, a
2328 2383
protocol.196 In the overall study population, maximal antiplatelet effect occurs within minutes after
2329 2384
encompassing patients having a low/moderate-bleed- taking ASA, within 2 hours after taking ticagrelor, and
2330 2385
2331
risk and high-bleed-risk surgery/procedure, the occurs 4 to 5 days after resuming clopidogrel with a 2386
2332 proportion of patients on apixaban (n ¼ 1,129), (75 mg) maintenance dose only, and after 3 days after 2387
2333 dabigatran (n ¼ 563), and rivaroxaban (n ¼ 965) with resuming prasugrel.226,228,229 If a loading dose of 2388
2334 a pre-operative DOAC level < 50 ng/mL was 90.5%, clopidogrel is used, the maximal antiplatelet effect 2389
2335 95.1%, and 96.8%, respectively. Patients having a 2390
occurs between 2 and 6 hours.230,231 Less commonly
2336 high-bleed-risk surgery/procedure or any neuraxial 2391
used reversible inhibitors of platelet function include
2337 anesthesia, in whom the interval between the last 2392
cilostazol, dipyridamole, and pentoxifylline, with half-
2338 DOAC dose and DOAC-level testing (just before the 2393
2339
lives of 2 to 10 hours,232-234 and vorapaxar, which has a 2394
surgery/procedure) was approximately 60 to 68 prolonged, 3- to 15-day antiplatelet effect.235 Nonsteroidal
2340 2395
hours (corresponding to 2 full days off before the antiinflammatory drugs have reversible antiplatelet
2341 2396
surgery/procedure [4 days off if on dabigatran and properties with half-lives that vary from 2 to 6 hours
2342 2397
CrCl < 50 mL/min]), were considered separately (ibuprofen, ketoprofen, indomethacin), to 7 to 15 hours
2343 2398
2344
given a heightened concern about bleeding in the (celecoxib, naproxen, diflunisal), to approximately 20 2399
2345 event of a significant residual DOAC level at surgery. hours (meloxicam, nabumetone, piroxicam).236 2400
2346 In this subgroup, the proportion of patients on 2401
2347 apixaban (n ¼ 335), dabigatran (n ¼ 183), and Patients Having Non-cardiac Surgery 2402
2348 rivaroxaban (n ¼ 314) with a DOAC level < 50 ng/mL 2403
PICOs 29-32: In patients receiving antiplatelet drugs
2349 was 97.9%, 99.4%, and 99.3%, respectively; the 2404
who require non-cardiac surgery, should antiplatelet
2350 proportion with a DOAC level < 30 ng/mL was 93.1%, 2405
2351 drugs be continued perioperatively vs stopping 7 to 2406
98.9%, and 85.3%, respectively.
2352 10 days before surgery? 2407
2353 2408
28. In patients who had DOAC interruption for an Evidence. One 80-patient trial compared 4 to 5 days
2354 2409
elective surgery/procedure, we suggest against routine vs 10 days of ASA interruption before surgery, with
2355 2410
DOAC coagulation function testing to guide too few cardiovascular (n ¼ 1) or bleeding (n ¼ 0)
2356 2411
2357 perioperative DOAC management (Conditional events for adequate interruption.237 The PEP trial 2412
2358 Recommendation, Very Low Certainty of Evidence). involved 17,444 patients who required hip fracture 2413
2359 repair or hip/knee joint replacement with patients 2414
2360 randomized to receive ASA or placebo started pre- 2415
2361 DOAC-level testing may be considered, on a case-by- operatively and continued for 35 days.238 ASA use was 2416
2362 case basis, in nonelective perioperative clinical situa- associated with a decreased risk for VTE (RR ¼ 0.71; 2417
2363 tions; for example, in patients who require an urgent/ 95% CI: 0.54-0.94) and did not affect the risk for 2418
2364 emergency surgery/procedure in whom DOAC-level clinically overt myocardial ischemia (RR ¼ 1.57; 2419
2365 2420
testing may inform the need for active DOAC reversal 95% CI: 0.93-2.65) or stroke (RR ¼ 1.13; 95% CI:

2421 0.69-1.85) but conferred an increased risk for major 29b. In patients receiving ASA therapy who are 2476
2422 bleeding (2.9% vs 2.4%; P ¼ .04). In a randomized undergoing elective non-cardiac surgery and require 2477
2423 2478
trial of 220 patients who were at high cardiovascular ASA interruption, we suggest stopping ASA £ 7 days
2424 2479
risk and were undergoing surgery, ASA (or placebo) instead of 7 to 10 days before the surgery (Conditional
2425 2480
was started 7 days before surgery and continued for Recommendation, Very Low Certainty of Evidence).
2426 2481
30 days.239 Patients in the ASA group had a lower
2428
risk for major cardiovascular events (1.8% vs 9.0%; 2483
2429 7.2% absolute risk reduction; 95% CI: 1.3-13.0), but This suggestion may be modified on a case-by-case 2484
2430 the study was underpowered to detect a difference in basis, depending on individual patient circumstance; 2485
2431 bleeding. POISE-2 was a randomized, placebo- for example, surgery-related bleeding risk. 2486
2432 controlled trial that assessed immediate pre-operative 2487
30. In patients receiving clopidogrel who are
2433 ASA initiation (200 mg) or ASA continuation in 2488
undergoing an elective non-cardiac surgery, we
2434 10,010 patients with known or at risk for coronary 2489
suggest stopping clopidogrel 5 days instead of 7 to
2435 artery disease who were having major non-cardiac 2490
2436
10 days before the surgery (Conditional 2491
surgery.240 Perioperative ASA initiation/continuation Recommendation, Very Low Certainty of Evidence).
2437 2492
did not reduce the risk for non-fatal myocardial
2438 2493
infarction or death (7.0% vs 7.1%; RR ¼ 0.99; 95% CI: Guideline Implementation Considerations:
2439 2494
0.86-1.2), a finding observed in both initiation and This suggestion may be modified on a case-by-case
2440 2495
2441
continuation strata, but increased the risk for major basis, depending on individual patient circumstances; 2496
2442 bleeding (4.6% vs 3.8%; RR ¼ 1.2; 95% CI: 1.01-1.50). The for example, surgery-related bleeding risk. 2497
2443 interpretation of these results involves consideration 2498
that post-operative nonsteroidal antiinflammatory drug 31. In patients receiving ticagrelor who are
2444 2499
2445 use occurred in 37% of patients, which may have undergoing an elective non-cardiac surgery, we 2500
2446 impaired the cardioprotective effects of ASA241; suggest stopping ticagrelor 3 to 5 days instead of 7 to 2501
2447 moreover, major bleeding was increased in the ASA 10 days before the surgery (Conditional 2502
2448 initiation stratum (4.6% vs 3.5%; hazard ratio [HR] ¼ Recommendation, Very Low Certainty of Evidence). 2503
2449 2504
1.34; 95% CI: 1.03-1.74) but not the ASA continuation Guideline Implementation Considerations:
2450 2505
stratum (4.6% vs 4.1%; HR ¼ 1.11; 95% CI: 0.84-
2451 This suggestion may be modified on a case-by-case 2506
1.48). Smaller, likely underpowered, trials assessing
2452 basis, depending on individual patient circumstances; 2507
perioperative ASA interruption vs continuation or
2453 for example, surgery-related bleeding risk. 2508
2454
single-dose pre-operative ASA administration reported 2509
2455 no significant difference in thromboembolic or 32: In patients receiving prasugrel who are 2510
2456 bleeding events.242-245 undergoing an elective non-cardiac surgery, we 2511
2457 suggest stopping prasugrel 7 days instead of 7 to 2512
No prospective studies have assessed perioperative
2458 10 days before the surgery (Conditional 2513
management of clopidogrel, prasugrel, or ticagrelor in
2459 Recommendation, Very Low Certainty of Evidence). 2514
2460
non-cardiac surgery. Retrospective cohort studies of 2515
2461 clopidogrel suggest an increased risk of bleeding with Guideline Implementation Considerations: 2516
2462 perioperative clopidogrel continuation.246-248 2517
This suggestion may be modified on a case-by-case
2463 2518
29a. In patients receiving ASA who are basis, depending on individual patient circumstances;
2464 2519
undergoing elective non-cardiac surgery, we for example, surgery-related bleeding risk.
2465 2520
2466
suggest ASA continuation over ASA interruption PICO 33: In patients receiving antiplatelet drugs who 2521
2467 (Conditional Recommendation, Moderate Certainty require non-cardiac surgery, should antiplatelet drugs 2522
2468 of Evidence). be resumed # 24 hours or > 24 hours after surgery? 2523
2469 2524
Guideline Implementation Considerations: 33. In patients who require antiplatelet drug Q19
2470 2525
2471 This guidance may be modified on a case-by-case interruption for an elective surgery/procedure, we 2526
2472 basis. For example, in select patients undergoing a suggest to resume antiplatelet drugs £ 24 hours 2527
2473 non-cardiac surgery associated with a high bleeding instead of > 24 hours after the surgery/procedure 2528
2474 risk (eg, intracranial, spinal); if ASA interruption is (Conditional Recommendation, Very Low Certainty of 2529
2475 2530
adopted, we suggest interruption for # 7 days. Evidence).

2531 Patients Having Coronary Artery Bypass Graft of bleeding were similar in patients stopping 2586
2532 Surgery clopidogrel 7 days before surgery and those stopping 2587
2533 2588
PICO 34: In patients receiving antiplatelet drugs who ticagrelor 24 to 72 hours before surgery.256 A meta-
2534 2589
require CABG surgery, should antiplatelet drugs be analysis of four randomized trials and one observational
2535 2590
continued perioperatively vs stopping antiplatelet drugs study totaling 2,632 patients undergoing CABG surgery
2536 2591
7 to 10 days before CABG surgery? that compared > 5 days vs < 5 days interruption of
2537 2592
2538
clopidogrel found patients with a longer interruption 2593
PICO 35: In patients receiving antiplatelet drugs who had a lower incidence of re-operation (1.8% vs 3.2%;
2539 2594
require CABG surgery, should antiplatelet drugs be OR ¼ 0.47; 95% CI: 0.25-0.91) and major bleeding
2540 2595
resumed within 24 hours or $ 24 hours after CABG (19.7% vs 30.2%; OR ¼ 0.71; 95% CI: 0.51-0.98) and
2541 2596
2542
surgery? cardiovascular events.257 2597
2543 Evidence. Determining whether to continue or stop 2598
2544
There are no randomized trials or trial subanalyses that 2599
antiplatelet drugs before CABG surgery is important address the resumption of antiplatelet drugs post-
2545 2600
because of the need to minimize surgical-site bleeding, operatively. One 100-patient observational study
2546 2601
which can cause life-threatening pericardial tamponade. compared resuming ASA 1 hour or 6 hours’ post-CABG
2547 2602
2548
In a > 8,000-patient cohort study, ASA use within surgery and reported no significant difference in 2603
2549 5 days prior to CABG was associated with a reduction in bleeding or transfusion requirement outcomes.258 2604
2550 overall mortality without a concomitant increased risk 2605
2551 for re-operation for pericardial bleeding or need for 34. In patients who are receiving ASA and undergoing 2606
2552 blood transfusion.249 ATACAS was a randomized, CABG surgery, we suggest continuation of ASA over 2607
2553 placebo-controlled trial assessing perioperative ASA use interruption; in patients receiving a P2Y12 inhibitor 2608
2554 in patients who required CABG surgery where patients drug, we suggest interruption of the P2Y12 inhibitor 2609
2555 received ASA 100 mg, starting 1 to 2 hours’ pre-CABG 2610
over continuation perioperatively (Conditional
2556 (prior ASA users stopped it 4 days’ pre-surgery), or 2611
Recommendation, Low Certainty of Evidence).
2557 2612
placebo, with resumption within 24 hours’ post-
CABG.250 After 30 days of follow-up, there was no
2559 2614
significant effect of ASA on the outcomes of myocardial For pre-operative P2Y12 interruption, we suggest:
2560 2615
2561
infarction (13.8% vs 15.8%; RR ¼ 0.87; 95% CI: 0.71- o 7 days for prasugrel; 2616
2562 1.07), death, and other cardiovascular outcomes; ASA o 5 days for clopidogrel; 2617
2563 use was not associated with an increased risk for re- o 3 to 5 days for ticagrelor. 2618
2564 operation related to bleeding (1.8% vs 2.1%; RR ¼ 0.87; 2619
35. In patients receiving ASA or a P2Y12 inhibitor
2565 95% CI: 0.47-1.6). Stopping ASA in prior users for at 2620
who are undergoing CABG surgery, we suggest
2566 least 4 days and restarting it just before surgery may 2621
resuming the ASA or P2Y12 inhibitor within 24 hours
2567 question the generalizability of the study results, whereas 2622
after surgery compared to ‡ 24 hours after surgery
2568 continuing ASA perioperatively without interruption (as 2623
2569
(Conditional Recommendation, Low Certainty of 2624
in one of the treatment arms) may have better reflected
2570 Evidence). 2625
what is done in clinical practice.
2572 In patients who also are receiving the P2Y12 inhibitor 2627
2573 clopidogrel, subanalyses of large trials involving Resumption of antiplatelet therapy may be delayed in 2628
2574 patients with acute coronary syndromes who patients who develop post-CABG thrombocytopenia 2629
2575 subsequently required CABG reported a 50% higher (platelet count < 50,000 109/L), typically occurring 2630
2576 with on-pump surgery. 2631
risk for major bleeding and a 70% higher need for
2577 2632
transfusion requirements in patients who received Perioperative Measurement of Antiplatelet Therapy
2578 2633
clopidogrel within 5 days before CABG.251,252
2579 PICO 36: In patients who are receiving antiplatelet 2634
2580
Observational studies have also found increased 2635
therapy, should platelet function assays be routinely
2581 bleeding in patients who received clopidogrel within 2636
used to measure antiplatelet effect vs no routine use of
2582 5 days of CABG surgery.253-255 In a subanalysis of the 2637
antiplatelet function testing?
2583 PLATO trial, which compared ticagrelor with 2638
2584 clopidogrel in ASA-treated patients with an acute Evidence. Several platelet function assays have been 2639
2585 coronary syndrome who needed CABG surgery, rates assessed mostly in patients having cardiac surgery or 2640

2641 percutaneous coronary interventions.259,260 One and reported no observable pattern of adverse outcome 2696
2642 observational study (n ¼ 107) assessed platelet function incidence using a given management strategy.273 2697
2643 2698
in patients who received or did not receive ASA around
2644 The timing of surgery after coronary stenting balances 2699
the time of a colorectal surgery and found that impaired
2645 the urgency of an elective surgery (eg, cancer 2700
platelet function observed with ASA continuation did
2646 resection) and the cardiovascular risk relating to the 2701
not affect the incidence of blood transfusion.261 Other
2647 time interval since stenting. Observational studies of 2702
2648
studies have not shown a correlation between platelet 2703
patients with coronary stents who required surgery
2649 function assay results and clinical outcomes.262,263 2704
provide evidence to inform this issue. In a
2650 2705
36. In patients receiving antiplatelet drug therapy who retrospective study of 20,590 patients with coronary
2651 2706
are undergoing an elective surgery/procedure, we stents who underwent surgery, the risk for adverse
2652 2707
suggest against the routine use of platelet function cardiovascular outcomes appeared highest in the initial
2653 2708
2654 testing prior to the surgery/procedure to guide 6 weeks after stent placement (8%-10%) but appeared 2709
2655 perioperative antiplatelet management (Conditional to plateau at 6 months (1%-2%) and remain stable at 2710
2656 Recommendation, Very Low Certainty of Evidence). 24 months.274 In a linked administrative database 2711
2657 study comparing post-operative rates of adverse 2712
2658
Guideline Implementation Considerations: cardiovascular outcomes in 4,303 patients with and 2713
2659 Platelet function testing could be used with a possible 20,232 patients without recent (within 1 year) drug- 2714
2660 small benefit and little harm in certain scenarios such eluting coronary stent placement, stented patients had 2715
2661 as patients undergoing CABG surgery who have a higher risk for myocardial infarction (1.6% vs 0.2%; 2716
2662 OR ¼ 4.82; 95% CI: 3.25-7.16) and cardiac death 2717
recently started taking a P2Y12 inhibitor. Costs would
2663 2718
be moderate for implementation. (1.0% vs 0.2%; OR ¼ 5.87; 95% CI: 3.60-9.58), and
2664 2719
this increased risk was statistically significant only if
2665 Patients With Coronary Stents Having Surgery 2720
surgery was done within 1 month of stenting.275
2666 2721
2667
PICOs 37-40: In patients who require surgery within 2722
Bridging therapy during antiplatelet drug interruption
2668 6 weeks of placement of a bare-metal coronary stent or 2723
has been assessed with multiple strategies and
2669 within 12 months of placement of a drug-eluting 2724
agents.276 One randomized trial assessed IV cangrelor,
2670 coronary stent, should ASA and clopidogrel be 2725
a reversible ultra-short-acting P2Y12 inhibitor
2671 continued vs stopping antiplatelet drugs 7 to 10 days 2726
(elimination half-life of 3-6 minutes), as a bridging
2672 before surgery? 2727
agent in patients who were receiving and interrupted
2673 2728
2674
Evidence. Perioperative antiplatelet management aims to P2Y12 inhibitor therapy prior to CABG surgery277,278; 2729
2675 minimize the risk for stent thrombosis, which occurs in this 198-patient study reported no effect of bridging 2730
2676 2% to 5% of patients and is associated with mortality as on CABG-related bleeding (OR ¼ 1.15; 95% CI: 0.47- 2731
2677 high as 50%.264-269 A subanalysis of the POISE-2 trial 2.79) or other adverse events (7.8% vs 5.2%; P ¼ .45). 2732
2678 assessed 470 patients with a coronary stent who required Observational studies have investigated bridging with 2733
2679 major non-cardiac surgery, with patients who were IV UFH279 or subcutaneous LMWH,280 and bridging 2734
2680 allocated to continue ASA perioperatively exhibiting a with short-acting IV glycoprotein IIb/IIIa inhibitors 2735
2681 decrease in the incidence of myocardial infarction (tirofiban, eptifibatide) or cangrelor, with no clear 2736
2682 benefits of these approaches.281-285 2737
(5.1% vs 11.0%; HR ¼ 0.44; 95% CI: 0.22-0.87) and a
2683 2738
small increase in major bleeding (4.6% vs 3.8%; HR ¼
2684 We were unable to address management and outcomes 2739
1.22; 95% CI: 1.01-1.48).270 In observational studies,
2685 in these studies according to the stent type, whether 2740
perioperative antiplatelet therapy interruption for
2686 drug-eluting or bare-metal; consequently, the guideline 2741
2687
> 5 days was a predictor of major adverse 2742
statements do not specify management according to
2688 cardiovascular events (OR ¼ 2.11; 95% CI: 1.23-3.63),271 2743
stent type. However, coronary stents implanted in
2689 as was no perioperative antiplatelet therapy (OR ¼ 3.73; 2744
current practice are of the drug-eluting type.
2690 95% CI: 1.26-11.07).272 A systematic review of patients 2745
2691 with coronary stents who required surgery found one 37. In patients receiving ASA and a P2Y12 inhibitor 2746
2692 randomized trial and 15 observational studies assessing with coronary stents placed within the last 6 to 2747
2693 at least six different perioperative antiplatelet 12 weeks who are undergoing an elective surgery/ 2748
2694 management strategies with variable rates of adverse procedure, we suggest either continuation of both 2749
2695 2750
cardiovascular events (0%-21%) and bleeding (0%-22%), antiplatelet agents or stopping one antiplatelet agent

2751 within 7 to 10 days of surgery (Conditional 40. In patients with coronary stents who require 2806
2752 Recommendation, Very Low Certainty of Evidence). continued dual antiplatelet therapy, we suggest 2807
2753 2808
delaying an elective surgery/procedure over not
delaying the surgery/procedure (Conditional
2755 2810
Either approach is reasonable depending on the Recommendation, Very Low Certainty of Evidence).
2756 2811
bleeding risk associated with the surgery/procedure if
antiplatelet therapy is continued and risk for acute
2758 2813
2759
coronary syndrome/coronary stent thrombosis if an- The duration of surgery/procedure delay is addressed 2814
2760 tiplatelet therapy is interrupted. on a case-by-case basis and should consider the ur- 2815
2761 Several factors will weigh in the decision about gency of the surgery/procedure, the time elapsed since 2816
2762 whether to continue dual antiplatelet therapy or coronary stenting, and the risk profile of the coronary 2817
2763 interrupt one agent including: the timing of stent stenting (eg, critical location, multiple stents). 2818
2764 placement (whether closer to 6 weeks or 12 weeks); With regard to timing of cessation of P2Y12 inhibitors Q21 2819
2765 the type of stent (drug-eluting or bare-metal); the or ASA, we refer to Guideline Statements 29a/b 2820
2766 location of the stent (whether at a dominant coronary through 33. 2821
2767 2822
artery or not); and the number and length of stents
2768 Patients Having a Minor Dental, Dermatologic, or 2823
implanted.
2769 Ophthalmologic Procedure 2824
2770 38. In patients receiving ASA and a P2Y12 inhibitor 2825
2771
PICOs 41-43: In patients who are receiving antiplatelet 2826
who had coronary stents placed within the last 3 to
2772 drugs and require a minor dental, dermatologic, or 2827
12 months and are undergoing an elective surgery/
2773 ophthalmologic procedure, should antiplatelet drugs be 2828
procedure, we suggest stopping the P2Y12 inhibitor
2774 continued vs stopping antiplatelet drugs 7 to 10 days 2829
prior to surgery over continuation of the P2Y12
2775
inhibitor (Conditional Recommendation, Very Low before the procedure? 2830
2776 2831
Certainty of Evidence). Evidence. In patients having minor dental procedures,
2777 2832
2778 Guideline Implementation Considerations: small (< 100 patients) randomized trials and cohort 2833
2779 studies suggest no increase in major bleeding with 2834
2780
This guidance is based on indirect evidence and ASA continuation.146,286-290 In patients having minor 2835
2781 expert-based consensus that stopping P2Y12 in- skin procedures, prospective cohort studies totaling 2836
2782 hibitors in patients with stents > 3 months’ post- about 200 patients suggest a low (< 1%) risk for 2837
2783 implantation is likely safe. major bleeding with continuation of ASA.291,292 In 2838
2784 Several factors will weigh in the decision about patients having phacoemulsification (cataract) surgery, 2839
2785 whether to continue or interrupt the P2Y12 inhibitor, prospective cohort studies have suggested a low 2840
2786 including: the timing of stent placement (whether 2841
(< 1%) incidence of major bleeding with perioperative
2787 closer to 3 months or 12 months); the type of stent 2842
ASA continuation.159,160,293 In patients having eyelid
2788 (drug-eluting or bare-metal); the location of the stent 2843
surgery, one 42-patient randomized trial compared
2789 2844
(whether at a dominant coronary artery or not); and ASA continuation with no perioperative ASA use and
2790 2845
the number and length of stents implanted. reported no significant effect on bleeding or
2791 2846
2792
Q20 39. In patients with coronary stents who require thromboembolic outcomes.294 In patients having skin 2847
2793 interruption of antiplatelet drugs for an elective procedures, one meta-analysis of two randomized 2848
2794 surgery/procedure, we suggest against routine trials and 28 observational studies totaling > 14,000 2849
2795 bridging therapy with a glycoprotein IIb-IIIa patients found no significant increase in bleeding with 2850
2796
inhibitor, cangrelor, or LMWH over routine use of perioperative ASA continuation.295 No studies have 2851
2797 assessed the management of patients who are receiving 2852
bridging therapy (Conditional Recommendation, Low
2798 P2Y12 inhibitors alone and require minor dental, skin, 2853
Certainty of Evidence).
2799 2854
or eye procedures.
2801 41. In patients receiving an antiplatelet drug (ASA or 2856
2802
A bridging approach may be considered in selected 2857
P2Y12 inhibitor) who are undergoing a minor dental
2803 high-risk patients; for example, in those with a recent 2858
procedure, we suggest continuing the antiplatelet
2804 (within 3 months) coronary stent in a critical location. 2859
drug (ASA or the P2Y12 inhibitor) over stopping the
2805 2860

2861 antiplatelet agent before the procedure (Conditional (Conditional Recommendation, Low Certainty of 2916
2862 Recommendation, Very Low Certainty of Evidence). Evidence). 2917
2863 2918
2864 Guideline Implementation Considerations: Guideline Implementation Considerations: 2919
2865 2920
Patients who are receiving dual antiplatelet therapy Patients who are receiving dual antiplatelet therapy
2866 2921
with ASA and a P2Y12 inhibitor can continue ASA with ASA and a P2Y12 inhibitor can continue ASA
2867 2922
and interrupt the P2Y12 inhibitor. and interrupt the P2Y12 inhibitor.
2868 2923
2869 2924
42. In patients receiving an antiplatelet drug (ASA or
2870 2925
2871
P2Y12 inhibitor) who are undergoing a minor Perioperative Antithrombotic Patient Care 2926
dermatologic procedure, we suggest continuing the Pathways
2872 2927
2873
antiplatelet drug (ASA or P2Y12 inhibitor) over Based on the evidence presented, perioperative 2928
2874 stopping the antiplatelet drug before the procedure antithrombotic patient care pathways are shown in 2929
2875 (Conditional Recommendation, Very Low Certainty of Figure 1, Figure 2, and Figure 3. These pathways can be 2930
2876 Evidence). used to inform individual patient management and to 2931
2877 develop standardized care paths for clinics or 2932
2878 2933
institutions. Figure 1 pertains to patients receiving a
2879 Patients who are receiving dual antiplatelet therapy 2934
VKA and provides guidance on whether to interrupt
2880 with ASA and a P2Y12 inhibitor can continue ASA 2935
VKA therapy perioperatively (if interruption is needed),
2881 and interrupt the P2Y12 inhibitor. 2936
2882
how to interrupt VKA pre-operatively, whether to use 2937
2883 43. In patients receiving an antiplatelet drug (ASA heparin bridging therapy and how to bridge, and how to 2938
2884 or P2Y12 inhibitor) undergoing a minor restart VKA and bridging therapy (if used) post- 2939
2885 ophthalmologic procedure, we suggest continuing the operatively. Figure 2 pertains to patients receiving a 2940
2886 antiplatelet drug (ASA or P2Y12 inhibitor) DOAC and provides guidance on whether to interrupt 2941
2887 throughout the ophthalmologic procedure over DOAC therapy perioperatively, and if interruption is 2942
2888 stopping the antiplatelet agent before the procedure needed, how to interrupt DOAC therapy based on 2943
2889 2944
2890 2945
2891 2946
2892 Minimal-bleed-risk Warfarin 2947
2893 2948
2894 Low/moderate-bleed-risk Warfarin Warfarin* 2949
2895 2950
LMWH** LMWH**
2896 2951
2897 2952
High-bleed-risk Warfarin Warfarin*
2898 2953
2899 LMWH** LMWH**† 2954
2900 2955
2901 2956
2902 2957
2903 2958
2904 2959
–7 –6 –5 –4 –3 –2 –1 0 1 2 3 4 5
2905 2960
2906 2961
Day of Surgery/Procedure
2907 2962
2908 Legend 2963
2909 *Warfarin can be resumed on the evening of procedure (D0) for most patients, or the day after procedure (i.e., D1) at the 2964
2910 patient’s usual maintenance dose. 2965
2911 **Bridging suggested for high thrombotic risk populations with full-dose, subcutaneous LMWH (e.g., enoxaparin, 1 mg/kg bid or 2966
1.5 mg/kg daily or dalteparin, 100 IU/kg bid or 200 IU/kg daily), with the last dose given the AM of the day prior to the procedure
2912 2967
(i.e., D-1) at half the total daily dose.
2913 †Low-dose LMWH (e.g., enoxaparin, 40 mg daily or dalteparin 5,000 IU daily) can be used for VTE prophylaxis for first 24-72 hours 2968
2914 post-procedure, with full dose LMWH resumed 2-3 days post-procedure. 2969
2915 2970
Q35 Figure 1 – Perioperative management of vitamin K antagonists (warfarin). LMWH ¼ low-molecular-weight heparin. Q31
Q32

2971 3026
Direct Oral Procedure Pre-Procedure DOAC Interruption Post-Procedure Resumption*
2972 Anticoagulant Bleeding 3027
2973 Risk Day -6 Day -5 Day -4 Day -3 Day -2 Day -1 Day +1 Day +2 Day +3 Day +4 3028
2974 3029
Surgery/Procedure (Day 0)
2975 High 3030
Apixaban
2976 Low/Mod 3031
2977 Dabigatran High 3032
2978 (CrCl ≥ 50 3033
ml/min) Low/Mod
2979 3034
Dabigatran High
2980 (CrCl < 50 3035
2981 ml/min) Low/Mod 3036
2982 High 3037
Edoxaban
2983 Low/Mod 3038
2984 High 3039
2985 Rivaroxaban 3040
Low/Mod
2986 3041
2987 No DOAC administered that day 3042
2988 3043
*DOAC can be resumed ~24 hours after low/moderate-bleed-risk procedures, and 48-72 hours after high-bleed-risk
2989 3044
procedures. In selected patients at high risk for VTE, low-dose anticoagulants (i.e., enoxaparin, 40 mg daily or
2990 dalteparin, 5,000 IU daily) can be given for the first 48-72 hours post-procedure. 3045
2991 3046
Figure 2 – Perioperative management of direct oral anticoagulants (DOACs). CrCl ¼ creatinine clearance.
2992 3047
2993 3048
2994 surgical/procedural bleed risk in the pre- and post- the timing of peri-operative interruption based on the 3049
2995 operative period. Figure 3 pertains to patients who are type of antiplatelet agent (ie, aspirin, clopidogrel, 3050
2996 receiving antiplatelet therapy and provides guidance on prasugrel, ticagrelor). 3051
2997 3052
2998 3053
2999 3054
3000 ASA continued* 3055
3001 3056
3002 3057
Cangrelor** Cangrelor**
3003 3058
3004 3059
3005 Ticagrelor† 3060
P2Y12 inhibitors***
3006 3061
3007 Clopidogrel†† 3062
3008 3063
3009 3064
Prasugrel§
3010 3065
3011 3066
3012 3067
3013 –9 –8 –7 –6 –5 –4 –3 –2 –1 –1–6 h 0 +4–6h Day +1 3068
3014 3069
3015 3070
3016 Day of Surgery/Procedure 3071
3017 3072
Legend:
3018 *Based on surgery/procedure bleed risk assessment. 3073
3019 **Routine use not suggested. If used, initiate within 72 hours from P2Y12 inhibitor discontinuation at dose of 0.75 mg/kg/min; 3074
3020 resume within 6 hours post-procedure for minimum of 48 hours and maximum of 7 days total. Very low quality data for 3075
3021 antiplatelet bridging with glycoprotein IIb/IIIa inhibitors (e.g., eptifibatide, tirofiban). 3076
***P2Y12 inhibitors can be resumed within 24 hours post-procedure at a maintenance dose.
3022 3077
†For ticagrelor, 3-5 day interruption
3023 ††For clopidogrel, 5 day interruption 3078
3024 §For prasugrel, 7-10 day interruption. 3079
3025 3080
Figure 3 – Perioperative management of antiplatelet drugs. ASA ¼ aspirin.

3081 Future Research References 3136
3082 3137
Although there have been important advances in the 1. Spyropoulos AC, Al-Badri A, Sherwood MW, Douketis JD.
3083 Periprocedural management of patients receiving a vitamin K 3138
perioperative management of anticoagulant and antagonist or a direct oral anticoagulant requiring an elective
3084 3139
antiplatelet therapy, much work remains to bridge procedure or surgery. J Thromb Haemost. 2016;14(5):875-885.
3085 3140
gaps in knowledge. In VKA-treated patients with a 2. Colacci M, Tseng EK, Sacks CA, Fralick M. Oral anticoagulant
3086 utilization in the United States and United Kingdom. J Gen Intern 3141
3087 mechanical heart valve, there is a need for a well- Med. 2020;35(8):2505-2507. 3142
3088 designed randomized trial to determine whether any 3. Omling E, Jarnheimer A, Rose J, Bjork J, Meara JG, Hagander L. 3143
perioperative heparin bridging is needed during Population-based incidence rate of inpatient and outpatient
3089 surgical procedures in a high-income country. Br J Surg. 3144
3090 perioperative VKA interruption. In DOAC-treated 2018;105(1):86-95. 3145
3091 patients, there is a need for additional research 4. Gao L, Tadrous M, Knowles S, et al. Prior authorization and 3146
3092 Canadian public utilization of direct-acting oral anticoagulants. 3147
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3093 interruption intervals before neuraxial anesthesia or 3148
5. Proietti M, Laroche C, Opolski G, et al. ‘Real-world’ atrial
3094 regional nerve block procedures, and for patients with fibrillation management in Europe: observations from the 2-year 3149
3095 follow-up of the EURObservational Research Programme-Atrial 3150
severe chronic kidney disease, with a CrCl < 30 mL/ Fibrillation General Registry Pilot Phase. Europace. 2017;19(5):
3096 722-733. 3151
min. Further research is also needed as to the
3097 6. Steinberg BA, Gao H, Shrader P, et al. International trends in 3152
perioperative management of patients who are
3098 clinical characteristics and oral anticoagulation treatment for 3153
3099
receiving low-dose DOAC regimens, whether in patients with atrial fibrillation: results from the GARFIELD-AF, 3154
combination with ASA for chronic coronary or ORBIT-AF I, and ORBIT-AF II registries. Am Heart J. 2017;194:
3100 132-140. 3155
3101 peripheral arterial disease or for the secondary 7. Williams BA, Honushefsky AM, Berger PB. Temporal trends in the 3156
3102 prevention of VTE and those who are receiving incidence, prevalence, and survival of patients with atrial 3157
fibrillation from 2004 to 2016. Am J Cardiol. 2017;120(11):
3103 antiplatelet monotherapy with a P2Y12 inhibitor. A 1961-1965. 3158
3104 challenging area of research is the perioperative 8. Healey JS, Eikelboom J, Douketis J, et al. Periprocedural bleeding 3159
3105 management of antiplatelet drugs, especially those and thromboembolic events with dabigatran compared with 3160
warfarin: results from the Randomized Evaluation of Long-Term
3106 with coronary stents who are receiving ASA and a 3161
Anticoagulation Therapy (RE-LY) randomized trial. Circulation.
3107 P2Y12 inhibitor, as there are multiple factors (timing 2012;126(3):343-348. 3162
3108 9. Zulkifly H, Lip GYH, Lane DA. Epidemiology of atrial fibrillation. 3163
of stent placement, type of surgery, type of antiplatelet
3109 Int J Clin Pract. 2018;72(3):e13070. 3164
therapy) that make it difficult to undertake well- 10. Sherwood MW, Douketis JD, Patel MR, et al. Outcomes of
3110 3165
designed randomized trials. In all patient groups, the temporary interruption of rivaroxaban compared with warfarin in
3111 patients with nonvalvular atrial fibrillation: results from the 3166
3112
role of perioperative laboratory testing that includes rivaroxaban once daily, oral, direct factor Xa inhibition compared 3167
3113 anti-factor Xa levels during heparin bridging, DOAC with vitamin K antagonism for prevention of stroke and embolism
3168
trial in atrial fibrillation (ROCKET AF). Circulation. 2014;129(18):
3114 anti-factor Xa levels and dilute thrombin time testing, 1850-1859. 3169
3115 antiplatelet function testing, and viscoelastic testing, 11. Kristensen SD, Knuuti J, Saraste A, et al. 2014 ESC/ESA guidelines 3170
3116 remains uncertain. Research is also needed to inform on non-cardiac surgery: cardiovascular assessment and 3171
management: the Joint Task Force on non-cardiac surgery:
3117 perioperative anticoagulant management of special cardiovascular assessment and management of the European 3172
3118 patient populations (eg, those who are dialysis- Society of Cardiology (ESC) and the European Society of 3173
Anaesthesiology (ESA). Eur Heart J. 2014;35(35):2383-2431.
3119 dependent). Finally, although beyond the scope of this 3174
12. Cruden NL, Harding SA, Flapan AD, et al. Previous coronary stent
3120 guideline, research is needed in patients who require 3175
implantation and cardiac events in patients undergoing noncardiac
3121 surgery. Circ Cardiovasc Interv. 2010;3(3):236-242. 3176
an urgent/emergency surgery to inform best practices,
3122 13. Douketis JD, Berger PB, Dunn AS, et al. The perioperative 3177
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3123
assays to measure DOAC levels, and the role of Physicians Evidence-Based Clinical Practice Guidelines (8th
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3125
anticoagulant and antiplatelet reversal strategies. 3180
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3182
3128Q33 Q23 Funding/support: The authors have reported to CHEST that no 2012;141(suppl 2):e326S-e350S. 3183
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3130Q24 Financial/nonfinancial disclosure: None declared. nomenclature for oral anticoagulants: communication from the 3185
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as Jennifer Cookingham, Andrew Dominello, Laura Hyppolite, and
3133 Thromb Res. 2019;182:167-174. 3188
Ariana McGinn for their assistance with the tables and figures.
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Perioperative Management of Antithrombotic Therapy

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[ Education and Clinical Practice Guidelines and Consensus Statements ] 56

PGL 5.6.0 DTD CHEST5181_proof 23 September 2022 6:11 pm EO: CHEST-22-1202

e2 Guidelines and Consensus Statements [ -#- CHEST - 2022 ]

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e22 Guidelines and Consensus Statements [ -#- CHEST - 2022 ]

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e24 Guidelines and Consensus Statements [ -#- CHEST - 2022 ]

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e26 Guidelines and Consensus Statements [ -#- CHEST - 2022 ]

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e28 Guidelines and Consensus Statements [ -#- CHEST - 2022 ]

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e30 Guidelines and Consensus Statements [ -#- CHEST - 2022 ]

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e32 Guidelines and Consensus Statements [ -#- CHEST - 2022 ]

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e34 Guidelines and Consensus Statements [ -#- CHEST - 2022 ]

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e36 Guidelines and Consensus Statements [ -#- CHEST - 2022 ]

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