the perioperative management of anti thrombotic therapy - american college of chest physicians...
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DOI 10.1378/chest.08-0675 2008;133;299S-339SChest
Alex C. Spyropoulos, Richard C. Becker and Jack AnsellJames D. Douketis, Peter B. Berger, Andrew S. Dunn, Amir K. Jaffer, Practice Guidelines (8th Edition)
Clinicalof Chest Physicians Evidence-Based : American College*Antithrombotic Therapy
The Perioperative Management of
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The Perioperative Management ofAntithrombotic Therapy*American College of Chest PhysiciansEvidence-Based Clinical Practice Guidelines(8th Edition)
James D. Douketis, MD, FRCP(C); Peter B. Berger, MD, FACP;Andrew S. Dunn, MD, FACP; Amir K. Jaffer, MD;Alex C. Spyropoulos, MD, FACP, FCCP; Richard C. Becker, MD, FACP, FCCP;and Jack Ansell, MD, FACP, FCCP
This article discusses the perioperative management of antithrombotic therapy and is part of the AmericanCollege of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). The primary objectives ofthis article are the following: (1) to address the perioperative management of patients who are receiving vitaminK antagonists (VKAs) or antiplatelet drugs, such as aspirin and clopidogrel, and require an elective surgical orother invasive procedures; and (2) to address the perioperative use of bridging anticoagulation, typically withlow-molecular-weight heparin (LMWH) or unfractionated heparin (UFH). A secondary objective is to address theperioperative management of such patients who require urgent surgery. The recommendations in this articleincorporate the grading system that is discussed in this supplement (Guyatt G et al, CHEST 2008; 133:123S–131S).Briefly, Grade 1 recommendations are considered strong and indicate that the benefits do (or do not) outweighrisks, burden, and costs, whereas Grade 2 recommendations are referred to as suggestions and imply thatindividual patient values may lead to different management choices.The key recommendations in this article include the following: in patients with a mechanical heart valve or atrialfibrillation or venous thromboembolism (VTE) at high risk for thromboembolism, we recommend bridginganticoagulation with therapeutic-dose subcutaneous (SC) LMWH or IV UFH over no bridging during temporaryinterruption of VKA therapy (Grade 1C); in patients with a mechanical heart valve or atrial fibrillation or VTE atmoderate risk for thromboembolism, we suggest bridging anticoagulation with therapeutic-dose SC LMWH,therapeutic-dose IV UFH, or low-dose SC LMWH over no bridging during temporary interruption of VKAtherapy (Grade 2C); in patients with a mechanical heart valve or atrial fibrillation or VTE at low risk forthromboembolism, we suggest low-dose SC LMWH or no bridging over bridging with therapeutic-dose SCLMWH or IV UFH (Grade 2C).In patients with a bare metal coronary stent who require surgery within 6 weeks of stent placement, werecommend continuing aspirin and clopidogrel in the perioperative period (Grade 1C); in patients with adrug-eluting coronary stent who require surgery within 12 months of stent placement, we recommend continuingaspirin and clopidogrel in the perioperative period (Grade 1C).In patients who are undergoing minor dental procedures and are receiving VKAs, we recommend continuingVKAs around the time of the procedure and coadministering an oral prohemostatic agent (Grade 1B); in patientswho are undergoing minor dermatologic procedures and are receiving VKAs, we recommend continuing VKAsaround the time of the procedure (Grade 1C); in patients who are undergoing cataract removal and are receivingVKAs, we recommend continuing VKAs around the time of the procedure (Grade 1C).
(CHEST 2008; 133:299–339S)
Key words: arterial thromboembolism; aspirin; bleeding; bridging anticoagulation; clopidogrel; low-molecular-weightheparin; oral anticoagulant; perioperative; stroke; surgery; unfractionated heparin; venous thromboembolism; vitamin Kantagonist
Abbreviations: APTT � activated partial thromboplastin time; CABG � coronary artery bypass graft; CHADS2 � CongestiveHeart Failure-Hypertension-Age-Diabetes-Stroke; CI � confidence interval; DDAVP � 1-deamino-8-D-arginine vasopressin;INR � international normalized ratio; LMWH � low-molecular-weight heparin; NSAID � nonsteroidal antiinflammatory drug;OR � odds ratio; PCI � percutaneous coronary intervention; SC � subcutaneous; UFH � unfractionated heparin; VKA � vitaminK antagonist; VTE � venous thromboembolism
SupplementANTITHROMBOTIC AND THROMBOLYTIC THERAPY 8TH ED: ACCP GUIDELINES
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Summary of Recommendations
2.0 Perioperative Management of Patients Who AreReceiving VKAs
2.1. In patients who require temporary inter-ruption of a VKA before surgery or a procedureand require normalization of the INR for thesurgery or procedure, we recommend stoppingVKAs approximately 5 days before surgery overstopping VKAs within a shorter time intervalbefore surgery to allow adequate time for theINR to normalize (Grade 1B).2.2. In patients who have had temporary inter-ruption of a VKA before surgery or a proce-dure, we recommend resuming VKAs approxi-mately 12 to 24 h (the evening of or the nextmorning) after surgery and when there is ade-quate hemostasis over resumption of VKAscloser to surgery (Grade 1C).2.3. In patients who require temporary inter-ruption of a VKA before surgery or a procedureand whose INR is still elevated (ie, > 1.5) 1 to 2days before surgery, we suggest administeringlow-dose (ie, 1 to 2 mg) oral vitamin K tonormalize the INR instead of not administeringvitamin K (Grade 2C).2.4. In patients with a mechanical heart valve oratrial fibrillation or VTE at high risk for throm-boembolism, we recommend bridging anticoag-ulation with therapeutic-dose SC LMWH or IVUFH over no bridging during temporary inter-ruption of VKA therapy (Grade 1C); we suggesttherapeutic-dose SC LMWH over IV UFH(Grade 2C). In patients with a mechanical heartvalve or atrial fibrillation or VTE at moderaterisk for thromboembolism, we suggest bridginganticoagulation with therapeutic-dose SC LMWH,therapeutic-dose IV UFH, or low-dose SCLMWH over no bridging during temporaryinterruption of VKA therapy (Grade 2C); wesuggest therapeutic-dose SC LMWH over other
management options (Grade 2C). In patientswith a mechanical heart valve or atrial fibrilla-tion or VTE at low risk for thromboembolism,we suggest low-dose SC LMWH or no bridgingover bridging with therapeutic-dose SC LMWHor IV UFH (Grade 2C).Values and preferences: In patients at high ormoderate risk for thromboembolism, the recom-mendations reflect a relatively high value on pre-venting thromboembolism and a relatively lowvalue is on preventing bleeding; in patients at lowrisk for thromboembolism, the recommendationsreflect a relatively high value on preventing bleed-ing and a relatively low value on preventing throm-boembolism.
3.0 Perioperative Management of Patients Who AreReceiving Bridging Anticoagulation
3.1. In patients who require temporary inter-ruption of VKAs and are to receive bridginganticoagulation, from a cost-containment per-spective we recommend the use of SC LMWHadministered in an outpatient setting wherefeasible instead of inpatient administration ofIV UFH (Grade 1C).Values and preferences: This recommendation re-flects a consideration not only of the trade-off be-tween the advantages and disadvantages of SCLMWH and IV UFH as reflected in their effects onclinical outcomes (LMWH at least as good, possiblybetter), but also the implications in terms of resourceuse (costs) in a representative group of countries(substantially less resource use with LMWH).3.2. In patients who are receiving bridginganticoagulation with therapeutic-dose SCLMWH, we recommend administering the lastdose of LMWH 24 h before surgery or a proce-dure over administering LMWH closer to sur-gery (Grade 1C); for the last preoperative doseof LMWH, we recommend administering ap-proximately half the total daily dose instead of100% of the total daily dose (Grade 1C). Inpatients who are receiving bridging anticoagu-lation with therapeutic-dose IV UFH, we rec-ommend stopping UFH approximately 4 h be-fore surgery over stopping UFH closer tosurgery (Grade 1C).3.3. In patients undergoing a minor surgicalor other invasive procedure and who arereceiving bridging anticoagulation with ther-apeutic-dose LMWH, we recommend resum-ing this regimen approximately 24 h after (eg,the day after) the procedure when there isadequate hemostasis over a shorter (eg, < 12h) time interval (Grade 1C). In patients under-going major surgery or a high bleeding risk
*From McMaster University (Dr. Douketis), Hamilton, ON,Canada; Geisinger Clinic (Dr. Berger), Danville, PA; MountSinai School of Medicine (Dr. Dunn), New York, NY; Universityof Miami (Dr. Jaffer), Leonard M. Miller, School of Medicine,Miami, FL; Clinical Thrombosis Center (Dr. Spyropoulos),Lovelace Medical Center, Albuquerque, NM; Duke University(Dr. Becker), Durham, NC; and Boston University (Dr. Ansell),Boston, MA.Manuscript accepted December 20, 2007.Reproduction of this article is prohibited without written permissionfrom the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).Correspondence to: Jack E. Ansell, MD, FACP, FCCP, Depart-ment of Medicine, Boston University Medical Center, 88 EastNewton St, Boston, MA 02118; e-mail: [email protected]: 10.1378/chest.08-0675
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surgery/procedure and for whom postopera-tive therapeutic-dose LMWH/UFH is planned, werecommend either delaying the initiation oftherapeutic-dose LMWH/UFH for 48 to 72 h aftersurgery when hemostasis is secured, administer-ing low-dose LMWH/UFH after surgery whenhemostasis is secured, or completely avoidingLMWH or UFH after surgery over the adminis-tration of therapeutic-dose LMWH/UFH in closeproximity to surgery (Grade 1C). We recommendconsidering the anticipated bleeding risk and ad-equacy of postoperative hemostasis in individualpatients to determine the timing of LMWH orUFH resumption after surgery instead of resum-ing LMWH or UFH at a fixed time after surgeryin all patients (Grade 1C).3.4. In patients who are receiving bridging anti-coagulation with LMWH, we suggest against theroutine use of anti-factor Xa levels to monitor theanticoagulant effect of LMWHs (Grade 2C).
4.0 Perioperative Management of Patients Who AreReceiving Antiplatelet Therapy
4.2. In patients who require temporary inter-ruption of aspirin- or clopidogrel-containingdrugs before surgery or a procedure, we sug-gest stopping this treatment 7 to 10 days beforethe procedure over stopping this treatmentcloser to surgery (Grade 2C).4.3. In patients who have had temporary inter-ruption of aspirin therapy because of surgery ora procedure, we suggest resuming aspirin ap-proximately 24 h (or the next morning) aftersurgery when there is adequate hemostasis in-stead of resuming aspirin closer to surgery(Grade 2C). In patients who have had temporaryinterruption of clopidogrel because of surgeryor a procedure, we suggest resuming clopi-dogrel approximately 24 h (or the next morn-ing) after surgery when there is adequate he-mostasis instead of resuming clopidogrel closerto surgery (Grade 2C).4.4. In patients who are receiving antiplateletdrugs, we suggest against the routine use ofplatelet function assays to monitor the antithrom-botic effect of aspirin or clopidogrel (Grade 2C).4.5. For patients who are not at high risk forcardiac events, we recommend interruption ofantiplatelet drugs (Grade 1C). For patients athigh risk of cardiac events (exclusive of coro-nary stents) scheduled for noncardiac surgery,we suggest continuing aspirin up to and beyondthe time of surgery (Grade 2C); if patients arereceiving clopidogrel, we suggest interruptingclopidogrel at least 5 days and, preferably,within 10 days prior to surgery (Grade 2C). In
patients scheduled for CABG, we recommendcontinuing aspirin up to and beyond the time ofCABG (Grade 1C); if aspirin is interrupted, werecommend it be reinitiated between 6 h and48 h after CABG (Grade 1C). In patients sched-uled for CABG, we recommend interruptingclopidogrel at least 5 days and, preferably, 10days prior to surgery (Grade 1C). In patientsscheduled for PCI, we suggest continuing aspi-rin up to and beyond the time of the procedure;if clopidogrel is interrupted prior to PCI, wesuggest resuming clopidogrel after PCI with aloading dose of 300 to 600 mg (Grade 2C).4.6. In patients with a bare metal coronary stentwho require surgery within 6 weeks of stentplacement, we recommend continuing aspirinand clopidogrel in the perioperative period(Grade 1C). In patients with a drug-eluting coro-nary stent who require surgery within 12 monthsof stent placement, we recommend continuingaspirin and clopidogrel in the perioperative pe-riod (Grade 1C). In patients with a coronary stentwho have interruption of antiplatelet therapy be-fore surgery, we suggest against the routine use ofbridging therapy with UFH, LMWH, directthrombin inhibitors, or glycoprotein IIb/IIIa in-hibitors (Grade 2C).Values and preferences: These recommendations re-flect a relatively high value placed on preventing stent-related coronary thrombosis, a consideration of com-plexity and costs of administering bridging therapy inthe absence of efficacy and safety data in this clinicalsetting, and a relatively low value on avoiding theunknown but potentially large increase in bleeding riskassociated with the concomitant administration of aspi-rin and clopidogrel during surgery.
5.0 Perioperative Management of AntithromboticTherapy in Patients Who Require Dental, Dermato-logic, or Ophthalmologic Procedures
5.1. In patients who are undergoing minordental procedures and are receiving VKAs, werecommend continuing VKAs around the timeof the procedure and coadministering an oralprohemostatic agent (Grade 1B). In patientswho are undergoing minor dental procedures andare receiving aspirin, we recommend continuingaspirin around the time of the procedure (Grade1C). In patients who are undergoing minor dentalprocedures and are receiving clopidogrel, pleaserefer to the recommendations outlined in Section4.5 and Section 4.6.5.2. In patients who are undergoing minor der-matologic procedures and are receiving VKAs, werecommend continuing VKAs around the time ofthe procedure (Grade 1C). In patients who are
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undergoing minor dermatologic procedures andare receiving aspirin, we recommend continuingaspirin around the time of the procedure (Grade1C). In patients who are undergoing minor der-matologic procedures and are receiving clopi-dogrel, please refer to the recommendations out-lined in Section 4.5 and Section 4.6.5.3. In patients who are undergoing cataract re-moval and are receiving VKAs, we recommendcontinuing VKAs around the time of the proce-dure (Grade 1C). In patients who are undergoingcataract removal and are receiving aspirin, werecommend continuing aspirin around the timeof the procedure (Grade 1C). In patients who areundergoing cataract removal and are receivingclopidogrel, please refer to the recommendationsoutlined in Section 4.5 and Section 4.6.
6.0 Perioperative Management of AntithromboticTherapy Patients Who Require Urgent Surgical orOther Invasive Procedures
6.1. In patients who are receiving VKAs andrequire reversal of the anticoagulant effect for anurgent surgical or other invasive procedure, werecommend treatment with low-dose (2.5 to 5.0mg) IV or oral vitamin K (Grade 1C). For moreimmediate reversal of the anticoagulant effect,we suggest treatment with fresh-frozen plasma oranother prothrombin concentrate in addition tolow-dose IV or oral vitamin K (Grade 2C).6.2. For patients receiving aspirin, clopi-dogrel, or both, are undergoing surgery, andhave excessive or life-threatening periopera-tive bleeding, we suggest transfusion of plate-lets or administration of other prohemostaticagents (Grade 2C).
T he perioperative management of patients whorequire temporary interruption of vitamin K
antagonists (VKAs) or antiplatelet drugs because of asurgical or other noninvasive procedure is a commonand challenging clinical problem.1 Approximately250,000 such patients are being assessed annually inNorth America alone, which is based on an estimateof the prevalence of patients who are receivinglong-term treatment with a VKA, principally due toatrial fibrillation or a mechanical heart valve (�2.5million),2,3 and an estimate of the annual proportionof patients who are receiving a VKA and requiresurgery or an invasive procedure (�10%).4 Themanagement of these patients is challenging becausethe risk of a thromboemblic event during interrup-tion of VKA or antiplatelet therapy needs to bebalanced against the risk for bleeding when anti-thrombotic therapy is administered in close proxim-
ity to surgery or an invasive procedure. In assessingpatients who are receiving antithrombotic therapyand are undergoing a surgical or other procedure,two principal issues should be addressed:
Is interruption of antithrombotic therapy in theperioperative period needed? In patients who areundergoing a major surgical or invasive procedure,interruption of antithrombotic therapy is typicallyrequired to minimize the risk for perioperativebleeding. Continuation of VKA or aspirin therapy inthe perioperative period confers an increased risk forbleeding.5–9 On the other hand, in patients who areundergoing minor surgical or invasive procedures,such as dental, skin, or eye procedures, interruptionof antithrombotic therapy may not be required.
If antithrombotic therapy is interrupted, is bridg-ing anticoagulation needed? In the context of peri-operative anticoagulation, bridging anticoagulationmay be defined as the administration of a short-acting anticoagulant, such as subcutaneous (SC)low-molecular-weight heparin (LMWH) or IV un-fractionated heparin (UFH), administered typicallyas a therapeutic-dose regimen for approximately 8 to10 days during interruption of VKA therapy whenthe international normalized ratio (INR) is notwithin a therapeutic range. In patients who are re-ceiving antiplatelet drugs alone, bridging anticoagula-tion with LMWH or UFH is, typically, not adminis-tered. In general, the need for bridging anticoagulationis determined by patient risk for thromboembolismduring interruption of antithrombotic therapy. Thetherapeutic aim of bridging anticoagulation is tominimize the time patients are not receiving antico-agulant therapy, thereby minimizing the risk forthromboembolism, and to do this in a manner thatminimizes patients’ risk for perioperative bleeding.
The objective of this article is to provide treatmentrecommendations for patients who are receiving aVKA or antiplatelet drug and may require temporaryinterruption of treatment because of a surgical orother invasive procedure. Following a discussion ofgeneral management principles (Section 1), thisreview addresses the following patient groups as-sessed in clinical practice: patients who are receivingVKAs (Section 2); patients who are receiving bridg-ing anticoagulation after interruption of VKAs (Sec-tion 3); patients who are receiving antiplatelet drugs(Section 4); patients who are receiving VKAs orantiplatelet drugs and are undergoing minor surgicalor invasive procedures (Section 5); and patients whorequire urgent interruption of antithrombotic ther-apy (Section 6). The summary recommendationsfollow the format in Table 1, which frames thequestions this article addresses.
At this juncture, some qualifying and explanatoryremarks are warranted. First, research in periopera-
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Table 1—Perioperative Antithrombotic Therapy: Question Definition and Eligibility Criteria
Section PopulationIntervention or
Exposure/Comparison* OutcomesAvailable
MethodologyExclusionCriteria
2.0 Perioperative management of patients who are receiving VKAs2.1 Any patient receiving VKA and
having elective surgeryTiming of interruption of VKA before
surgeryHemostasis at time of
surgery (INR)Observational
studiesNone
2.2 Timing of resumption of VKA orLMWH after surgery
Hemostasis at time ofsurgery (bleed time)
Observationalstudies
None
2.3 INR testing to monitor anticoagulanteffect of VKAs before and aftersurgery vs no testing
Hemostasis at time ofsurgery (APTT,anti-factor Xa)
Observationalstudies
None
2.4.1 Patients with a mechanical heartvalve having elective surgery
Temporary interruption of VKA andbridging anticoagulation withLMWH/UFH vs no bridging
Stroke, other systemicembolism, majorhemorrhage
Observationalstudies
Not receivingVKA
2.4.2 Patients with chronic atrialfibrillation having electivesurgery
Temporary interruption of VKA andbridging anticoagulation withLMWH/UFH vs no bridging
Stroke, other systemicembolism, majorhemorrhage
Observationalstudies
Not receivingVKA
2.4.3 Patients with VTE havingelective surgery
Temporary interruption of VKA andbridging anticoagulation withLMWH/UFH vs no bridging
Stroke, other systemicembolism, majorhemorrhage
Observationalstudies
Not receivingVKA
3.0 Perioperative management of patients who are receiving bridging anticoagulation3.1 Costs of bridging anticoagulation Outpatient SC LMWH vs inpatient
IV UFHHealth-care system
costsObservational
studiesNone
3.2 Any patient receiving UFH orLMWH as bridginganticoagulation and havingelective surgery
Timing of interruption of LMWH orUFH before surgery
Major postoperativebleeding
Observationalstudies
None
3.3 Timing of resumption of LMWH orUFH after surgery
Major postoperativebleeding
Observationalstudies
None
3.4 APTT, and anti-factor Xa testing tomonitor anticoagulant effect ofLMWH and UFH before and aftersurgery
Major postoperativebleeding
Observationalstudies
None
4.0 Perioperative management of patients who are receiving antiplatelet therapy4.2 Any patient receiving an
antiplatelet drug and havingelective surgery
Timing of interruption of antiplateletdrugs before surgery
INR before and aftersurgery
Observationalstudies
None
4.3 Timing of resumption of antiplateletdrugs after surgery
Platelet function assaytesting before andafter surgery
Observationalstudies
None
4.4 Platelet function assay testing tomonitor antiplatelet effect ofantiplatelet drugs before and aftersurgery vs no testing
APTT and anti-factorXa before and aftersurgery
Observationalstudies
None
4.5 Any patient receiving antiplateletdrug and having noncardiacsurgery, cardiac surgery, orPCI
Temporary interruption vscontinuation of antiplatelet drugs
Myocardial ischemia,major hemorrhage
Randomizedcontrolled trials,observationalstudies
ReceivingVKA
4.6 Any patient with a coronary stentreceiving antiplatelet drug andhaving noncardiac surgery,cardiac surgery, or PCI
Temporary interruption vscontinuation of antiplatelet drugs
Myocardial ischemia,major hemorrhage
Randomizedcontrolled trials,observationalstudies
ReceivingVKA
5.0 Perioperative management of antithrombotic therapy in patients who require minor procedures5.1 Any patient receiving VKA or
antiplatelet drug and having aminor dental procedure
Temporary interruption vscontinuation of VKA or antiplatelettherapy
Arterial or VTE, majorhemorrhage
Randomizedcontrolled trials,observationalstudies
None
5.2 Any patient receiving VKA orantiplatelet drug and having aminor skin procedure
Temporary interruption vscontinuation of VKA or antiplatelettherapy
Arterial or VTE, majorhemorrhage
Randomizedcontrolled trials,observationalstudies
None
5.3 Any patient receiving VKA orantiplatelet drug and having aminor eye procedure
Temporary interruption vscontinuation of VKA or antiplatelettherapy
Arterial or VTE, majorhemorrhage
Randomizedcontrolled trials,observationalstudies
None
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tive antithrombotic therapy is an emerging field,with a relative paucity of randomized trials and apreponderance of observational studies assessingperioperative management strategies. Consequently,comparisons of certain management strategies (eg,bridging vs no bridging) are lacking whereas com-parisons of other strategies (eg, continuation vsinterruption of VKAs for minor procedures) arebetter developed. Second, as many of the pertinentobservational studies are based on small patientsamples, they may be underpowered to determine ifa management approach is efficacious (ie, associatedwith a low risk for thromboembolism) or safe (ie,associated with a low risk for bleeding). Such studiesshould, therefore, be interpreted with caution bothbecause of the observational study design and thesmall sample size. Third, it should be acknowledgedthat there is no standardized definition of “bridginganticoagulation.” Although it may be defined as theadministration of a therapeutic-dose regimen of SCLMWH or IV UFH during interruption of a VKA,bridging anticoagulation may also include a regimen oflow-dose SC LMWH. Ultimately, the perioperativeanticoagulant regimen used will depend, to a largeextent, on patient clinical characteristics and the type ofsurgery or procedure they are undergoing.
1.0 Perioperative Management ofAntithrombotic Therapy: General
Principles
1.1 Assessment of Thromboembolic Risk AfterInterruption of Antithrombotic Therapy
Interruption of antithrombotic therapy exposespatients to an increased risk for thromboembolicevents, such as stroke or mechanical valve thrombo-sis, with the risk varying depending on the indicationfor antithrombotic therapy and the presence of
comorbid conditions.10 These events can have dev-astating clinical consequences: embolic stroke, whichcan result in major disability or death in 70% ofpatients11,12; thrombosis of a mechanical heart valve,which is fatal in 15% of patients13; and perioperativemyocardial ischemia, which is associated with a two-fold- to fourfold-increased risk for death.14,15 Similarly,interruption of antiplatelet drugs in patients with asirolimus or paclitaxel drug-eluting coronary stent, es-pecially within 6 months of stent placement, signifi-cantly increases the risk for intracoronary stent throm-bosis and myocardial infarction.16,17
Stratifying patients according to their risk forperioperative thromboembolism is based on patients’clinical indication for antithrombotic therapy and thepresence of comorbidities. Although there is novalidated risk stratification of such patients, theapproach we have used in these guidelines is toseparate patients into a high-risk, moderate-risk, orlow-risk group according to their indication for anti-thrombotic therapy (Table 2).
1.2 Assessment of Bleeding Risk Associated WithSurgery or Other Invasive Procedures
The administration of antithrombotic therapy inthe perioperative period should be done in a way thatconsiders the risk for bleeding associated with thesurgery or procedure. Although bleeding is a treat-able perioperative complication, there is emergingevidence that the clinical impact of bleeding isconsiderable and, perhaps, greater than previouslyappreciated.18–20 Furthermore, postoperative bleed-ing delays the resumption of antithrombotic therapy,with the potential to further expose patients to anincreased risk for thromboembolism.21,22
Stratifying patients according to their risk forperioperative bleeding can be based on the risk forbleeding associated with the surgery or procedure
Table 1—Continued
Section Population Intervention or Exposure/Comparison OutcomesAvailable
MethodologyExclusionCriteria
6.0 Perioperative management of antithrombotic therapy patients who require urgent surgical or other invasive procedures6.1 Any patient receiving VKA and
having urgent surgeryVitamin K via different routes (IV vs
oral/SC) to reverse anticoagulanteffect of VKAs; blood products(FFP, PC) to reverse anticoagulanteffect of VKAs vs no bloodproducts
(1) Hemostasis at timeof surgery (INR)
Randomizedcontrolled trials,observationalstudies
None
(2) Major bleedingand surrogate
6.2 Any patient receiving anantiplatelet drug and havingurgent surgery
DDAVP/prohemostatic drugs andplatelet transfusion to reverseantiplatelet effect of antiplateletdrugs vs no DDAVP/prohemostaticdrugs and platelet transfusions
Myocardial ischemia,major hemorrhage
Observationalstudies
None
*FFP � fresh frozen plasma; PC � prothrombin concentrate.
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and should be coupled with an assessment of post-operative hemostasis.21–24 Although there is no vali-dated method that quantifies perioperative bleedingrisk, special attention is warranted for certain surgi-cal or other invasive procedures associated with ahigh risk for bleeding. In such patients, postoperativeantithrombotic therapy should be administered withcaution, especially therapeutic-dose LMWH or UFHwhen used as bridging anticoagulation. Surgical andother invasive procedures associated with a high bleed-ing risk include: coronary artery bypass or heart valvereplacement surgery25,26; intracranial or spinal sur-gery27; aortic aneurysm repair, peripheral artery bypass,and other major vascular surgery; major orthopedicsurgery, such as hip or knee replacement28; reconstruc-tive plastic surgery29; major cancer surgery; and pros-tate and bladder surgery.30,31
In addition, clinicians should note procedures that,on the surface, may appear to be associated with alow risk for bleeding but in which perioperativeanticoagulation should be undertaken with caution.Such procedures include: resection of colonic polyps,especially sessile polyps � 2 cm in diameter, inwhich bleeding may occur at the transected stalk32;biopsy of the prostate or kidney, in which thepresence of highly vascular tissue and endogenousurokinase may promote post-biopsy bleeding33; andcardiac pacemaker or defibrillator implantation, inwhich separation of the infraclavicular fascial layersand lack of cautery or suturing of unopposed tissueswithin the pacemaker or defibrillator pocket maypredispose to pocket hematoma development.34
1.3 Balancing Thromboembolic Risk and BleedingRisk
Inherent in perioperative antithrombotic manage-ment is the need for individualized patient manage-ment that balances individual risk for thromboem-bolism and bleeding. In patients classified as “highrisk for stroke or thromboembolism,” the need toprevent a thromboembolic event such as embolicstroke or intracoronary stent thrombosis will domi-nate perioperative antithrombotic management, ir-respective of bleeding risk. In such patients, thepotential clinical consequences of such events, whichmay be fatal or may cause permanent disability, will,in most patients, outweigh the potential clinicalconsequences of bleeding and will justify the needfor bridging anticoagulation or perioperative contin-uation of antithrombotic therapy. This approach, ifadopted, should nonetheless consider judicious useof postoperative bridging anticoagulation (ie, as out-lined in Section 3.0) and optimizing intraoperativehemostasis (ie, cautery and other local measures),with the intent of simultaneously minimizing thepotential for major surgical bleeding that wouldhave the undesired effect of delaying the resump-tion of or necessitating interruption of antithrom-botic therapy.
In patients classified as “moderate risk for throm-boembolism,” a single perioperative antithromboticstrategy will not be dominant and management willdepend more on an individual patient risk assess-ment. Thus, in patients at moderate risk for thrombo-
Table 2—Suggested Patient Risk Stratification for Perioperative Arterial or Venous Thromboembolism
Risk Stratum
Indication for VKA Therapy
Mechanical Heart Valve Atrial Fibrillation VTE
High Any mitral valve prosthesis CHADS2 score of 5 or 6 Recent (within 3 mo) VTEOlder (caged-ball or tilting disc)
aortic valve prosthesisRecent (within 3 mo) stroke or
transient ischemic attack,Severe thrombophilia (eg, deficiency
of protein C, protein S orantithrombin, antiphospholipidantibodies, or multipleabnormalities)
Recent (within 6 mo) stroke ortransient ischemic attack
Rheumatic valvular heartdisease
Moderate Bileaflet aortic valve prosthesis andone of the following: atrialfibrillation, prior stroke ortransient ischemic attack,hypertension, diabetes,congestive heart failure, age� 75 yr
CHADS2 score of 3 or 4 VTE within the past 3 to 12 moNonsevere thrombophilic conditions
(eg, heterozygous factor V Leidenmutation, heterozygous factor IImutation)
Recurrent VTEActive cancer (treated within 6 mo
or palliative)
Low Bileaflet aortic valve prosthesiswithout atrial fibrillation and noother risk factors for stroke
CHADS2 score of 0 to 2 (andno prior stroke or transientischemic attack)
Single VTE occurred � 12 mo agoand no other risk factors
*CHADS2 � Congestive heart failure-Hypertension-Age-Diabetes-Stroke.
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embolism, the need to prevent thromboembolism willhave less dominance than in “high-risk” patients andbridging anticoagulation may incorporate a modified,less aggressive, approach postoperatively in patientsundergoing surgery or a procedure associated with ahigh bleeding risk. In patients classified as “low risk forthromboembolism,” the need to prevent thromboem-bolism will have even less dominance and cliniciansmay avoid bridging anticoagulation altogether; if given,bridging should be curtailed postoperatively in suchpatients with a high bleeding risk.
1.4 Perioperative Antithrombotic Management:Practical Considerations
In managing antithrombotic therapy before andafter surgery or a procedure, clinicians should notethe following practical management considerations:
• For patients undergoing a major surgical or inva-sive procedure, if the intent is to eliminate anyeffect of antithrombotic therapy, it should bestopped at a time before the procedure (eg, approx-imately 5 days in patients receiving a VKA and 7 to10 days in patients receiving an antiplatelet drug)that leaves minimal or no residual antithromboticeffect at time of the procedure; doing so will mini-mize the risk for intraprocedural bleeding.
• The administration of a rapidly acting anticoagu-lant, such as LMWH or UFH, after surgery oranother invasive procedure increases the risk forbleeding. This risk is dependent on the dose ofanticoagulant (eg, therapeutic-dose more thanlow-dose) and the proximity to surgery that it isadministered (higher bleeding risk when adminis-tered closer to surgery). Delaying resumption of atherapeutic-dose LMWH or UFH regimen (for 48to 72 h after surgery), decreasing the dose ofLMWH or UFH (to a low-dose regimen), oravoiding its use altogether in the postoperativeperiod can mitigate the risk for bleeding.
• For perioperative anticoagulant dosing, althoughthere is evidence that low-dose (prophylactic-dose) LMWH or UFH (eg, dalteparin 5,000 IU qdor UFH 5,000 IU bid) is effective in preventingvenous thromboembolism (VTE), evidence is lack-ing that such low-dose treatment is effective inpreventing arterial thromboembolism.
• In resuming antithrombotic therapy after a surgi-cal or invasive procedure, it takes 2 to 3 days for ananticoagulant effect to begin after the start ofwarfarin,35 it takes 3 to 5 h for a peak anticoagulanteffect to be reached after the start of LMWH,36
whereas it takes minutes for an antiplatelet effectto begin after the start of aspirin37 and 3 to 7 days
for peak inhibition of platelet aggregation to bereached after the start of a (75 mg) maintenancedose of clopidogrel.38
• The majority of surgical or other invasive pro-cedures are being done without hospitalizationor with a short hospital stay; consequently,potential thromboembolic- or bleeding-relatedcomplications are likely to occur while the pa-tient is at home, especially during the initial 2weeks after a procedure.21,22,39,40 Close follow-up ofpatients during the early period after a procedure is,therefore, warranted to allow early detection andexpedited treatment of potential complications.
2.0 Perioperative Management of PatientsWho Are Receiving VKAs
Long-term VKA therapy is widely used for theprimary and secondary prevention of arterial thrombo-embolism and VTE for a wide spectrum of clinicalindications that include atrial fibrillation, mechanicalheart valve placement, VTE, coronary and peripheralartery disease, dilated cardiomyopathy, and primarypulmonary hypertension. In Section 2.0, we will focuson the perioperative anticoagulant management ofpatients with the most common clinical indications forlong-term VKA therapy: mechanical heart valve,chronic atrial fibrillation, and VTE.
2.1 Interruption of VKAs Before Surgery
In patients undergoing major surgery, interruptionof VKAs is generally required to minimize the riskfor perioperative bleeding,5–7 whereas in patientsundergoing certain minor surgical or other proce-dures, some of which are discussed in Section 5.0,interruption of VKAs may not be required. To ourknowledge, there are no randomized trials compar-ing interruption of VKAs vs no interruption or partialinterruption of VKAs before major surgery. Threeobservational studies have assessed continuation8,41
or partial interruption42 of VKAs in patients under-going surgery, with suggestive but not definitivefindings that continuation of VKAs increases the riskfor perioperative bleeding. In one retrospective co-hort study involving 603 VKA-treated patients whounderwent surgery, the majority of whom did nothave interruption of VKA therapy prior to surgery,the incidence of perioperative major bleeding was9.5% (95% confidence interval [CI]: 7.1–12.1),which is high; moreover, compared to patients withan INR � 2.0, patients with an INR � 3.0 appearedto be at higher risk for bleeding complications (oddsratio [OR], 1.6; 95% CI: 0.4–4.0).8 Another retro-spective study assessed 100 patients who underwentsurgery (58 had major surgery) and who had partial
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interruption of VKA, with a mean INR of 1.8 (range:1.2 to 4.9) on the day of surgery; in this study, onlytwo (2%) patients had major bleeding although 34(34%) patients required a blood transfusion.42
For patients who are receiving VKA therapy withwarfarin, which has a half-life of 36 to 42 h, treat-ment should be interrupted approximately 5 daysbefore surgery (corresponding approximately to 5half-lives of warfarin) to ensure there is no (orminimal) residual anticoagulant effect remaining bythe time of surgery.43,44 Previous prospective cohortstudies assessing standardized perioperative antico-agulation regimens interrupted warfarin 5 to 6 daysbefore surgery.21,22,39 In one of these studies,22 inwhich warfarin was stopped 5 days before surgeryand the INR was routinely measured on the daybefore surgery, only 15 of 224 (7%) patients had anelevated INR (� 1.5) on the day before surgery,which was corrected with low-dose (1 mg) oralvitamin K. A longer (eg, � 5 days) duration of VKAinterruption to attain a normalized INR by the timeof surgery may be required in patients with amechanical heart valve, who have a higher targetedINR range, which is typically 2.5 to 3.5.45 In addi-tion, advanced age may be associated with a prolon-gation in the decay of the anticoagulant effect ofwarfarin after its interruption. Thus, in a retrospec-tive cohort study of 633 patients who had excessiveanticoagulation (INR � 6.0), increasing age, in 10-year increments, conferred an increased likelihoodfor delayed normalization of the INR after warfarinwas stopped (hazard ratio, 1.18; CI: 1.01–1.38).46
For a minority of patients who are receiving VKAtherapy with phenprocoumon, in whom the VKA-related recommendations in this article would notapply, treatment should be interrupted approxi-mately 10 days before surgery based on the half-lifeof phenprocoumon of 96 to 140 h.47 Some investi-gators have suggested that, in selected patients,warfarin can be interrupted 2 to 3 days beforesurgery to aim for an INR of 1.5 to 1.9 at the time ofsurgery; however, the feasibility and safety of thisapproach remain uncertain.8,42,48
Recommendation
2.1. In patients who require temporary inter-ruption of a VKA before surgery or a proce-dure and require normalization of the INRfor the surgery or procedure, we recommendstopping VKAs approximately 5 days beforesurgery over a shorter time interval to allowadequate time for the INR to normalize(Grade 1B).
2.2 Resumption of VKAs After Surgery
When resuming VKAs after surgery, approxi-mately 48 h is required to attain a partial anticoag-ulant effect, with an INR � 1.5.43 Consequently, thepotential effect of VKAs to promote postoperativebleeding is likely to be mitigated by the delayedonset of their anticoagulant activity. It is reasonable,therefore, to resume VKA therapy on the evening ofthe day of surgery or the next day, with an antici-pated partial anticoagulant effect to occur 48 h later.In one study of 650 patients who resumed VKA afterbridging anticoagulation, with a dose correspondingto patients’ usual dose, the mean duration to achievea therapeutic INR was 5.1 days (SD: 1.1).21 Inanother study of 224 patients who resumed VKAafter bridging anticoagulation, with doubling of pa-tients’ usual dose for the initial 2 days after VKAresumption, the mean duration to achieve a thera-peutic INR was 4.6 days (range: 0 to 10).22 Oneretrospective cohort study involving 100 patientswho received bridging with LMWH found a longerthan expected time to attain a therapeutic INR aftersurgery, which was a median of 7.5 days (inter-quartile range: 4.3 to 13.0) after warfarin wasresumed postoperatively.49 The delay in attainingtherapeutic levels of anticoagulation in this studywas possibly related to suboptimal INR monitoringafter surgery.
Recommendation
2.2. In patients who have had temporary inter-ruption of a VKA before surgery or a proce-dure, we recommend resuming VKAs approxi-mately 12 to 24 h (the evening of or the nextmorning) after surgery and when there is ade-quate hemostasis over resumption of VKAscloser to surgery (Grade 1C).
2.3 Laboratory Monitoring of VKA Therapy
Perioperative monitoring of the INR in patientswho are receiving VKA therapy is predicated onseveral factors, which include the feasibility of INRmonitoring prior to surgery and the time periodbetween interruption of VKAs and surgery. In thepreoperative period, it is reasonable to have INRtesting done at least once before surgery (preferably1 to 2 days before surgery) to confirm a normal ornear-normal INR and, in patients with an elevatedINR (eg, INR � 1.5), to administer low-dose vitaminK. Administration of vitamin K at this time will avoidthe need to administer plasma or other blood prod-ucts by ensuring the INR has normalized by the dayof surgery. In one retrospective cohort study involv-ing 43 patients who required temporary interruption
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of VKA and had an INR between 1.5 and 1.9 (mean:1.6) on the day before surgery, administering 1 mgoral vitamin K resulted in 91% of patients having anormal or near normal INR (ie, � 1.4) on the day ofsurgery.50 This study also suggested that preopera-tive administration of low-dose vitamin K does notappear to confer resistance to re-anticoagulationwhen a VKA is resumed after surgery. In the post-operative period, INR testing can be done to approx-imate when therapeutic anticoagulation is (or willbe) attained and, therefore, when LMWH or UFHcan be stopped for patients who have been receivingbridging anticoagulation.
Recommendation
2.3. In patients who require temporary inter-ruption of a VKA before surgery or a procedureand whose INR is still elevated (ie, > 1.5) 1 to 2days before surgery, we suggest administeringlow-dose (ie, 1 to 2 mg) oral vitamin K tonormalize the INR instead of not administeringvitamin K (Grade 2C).
2.4 Patient Risk Stratification and Assessing Needfor Bridging Anticoagulation
In assessing patients who are receiving VKAs forthe three principal indications, a mechanical heartvalve, chronic atrial fibrillation, or VTE, periopera-tive anticoagulant management (and need for bridg-ing) will be driven to a large extent by patients’ riskfor developing thromboembolism, either arterial orvenous, in the perioperative period. In this section,we have attempted to provide a reasonable, thoughlargely empiric, stratification of patients according totheir risk for thromboembolism (high, moderate,low) while acknowledging that comparative data onrisks for perioperative thromboembolism for theproposed risk strata are limited. This risk stratifica-tion scheme may be combined with individual pa-tient factors, which may include prior thromboem-bolism during VKA interruption or a prior embolicstroke, to determine the overall risk for thromboem-bolism (and need for bridging).
2.4.1 Patients With a Mechanical Prosthetic HeartValve
Risk Stratification: Patients with mechanical heartvalves are at increased risk for arterial thromboem-bolism, which includes stroke, systemic embolism,and valvular or intracardiac thrombosis. Risk strati-fication for patients with a mechanical heart valve isbased on studies that have assessed the risk forarterial thromboembolism during anticoagulant ther-apy and on older studies that assessed thromboem-
bolic risk while patients were receiving either noantithrombotic therapy or treatment that is currentlyconsidered suboptimal.51–53 What is lacking, how-ever, are estimates of the risk for thromboembolismin patients who have modern (bileaflet) prosthesesand have not received antithrombotic therapy overan extended time period. As trials that include suchpatients are lacking and are unlikely to be per-formed, clinicians can use the risk classificationproposed here as a general guide for patient man-agement.
Patients at high risk for arterial thromboembolism(� 10%/yr) may include those with one or more ofthe following: (1) a mitral valve prosthesis; (2) anolder-generation (caged-ball or tilting disk) aorticvalve prosthesis; and (3) a recent (within 6 months)stroke or transient ischemic attack. Patients at mod-erate risk for thromboembolism (4 to 10%/yr) mayinclude those with a bileaflet aortic valve prosthesisand one of the following: (1) atrial fibrillation; (2)prior stroke or transient ischemic attack; and (3)other stroke risk factors (hypertension, diabetes,congestive heart failure, age � 75 years). Patients atlow risk for thromboembolism (� 4%/yr) may in-clude those with a bileaflet aortic valve prosthesiswithout atrial fibrillation and who do not have otherrisk factors for stroke.
Assessing Need for Bridging Anticoagulation: In14 prospective cohort studies, bridging anticoagula-tion was assessed in approximately 1,300 patientswith a mechanical heart valve.7,21,22,40,54–64 As shownin Table 3, investigators studied predominantly ther-apeutic-dose LMWH regimens, although two studiesinvolving a total of 118 patients also assessed low-dose LMWH regimens.54,64 The issue of whether alow-dose anticoagulant regimen is efficacious for theprevention of arterial thromboembolism in patientswith a mechanical heart valve, as it is for preventingVTE,65 cannot be definitively addressed based on thelimited available evidence. It is probable that a moreintense, therapeutic-dose, anticoagulant regimenwould be required to prevent valve thrombosis andvalve-related systemic embolism during VKA inter-ruption and, until further evidence to the contrarybecomes available, is the preferred regimen. Theoverall crude risk for perioperative arterial thrombo-embolism was 0.83% (95% CI: 0.43–1.5). There wereno reported episodes of mechanical valve thrombosis.The interpretation of this finding is limited becausethere are no studies, to our knowledge, assessing therisk for arterial thromboembolism in (a comparatorgroup of) patients with a mechanical heart valve whohave VKA interruption for surgery but do not receivebridging anticoagulation.
Mathematical modeling can be used to estimate
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Tab
le3—
Non
rand
omiz
edP
rosp
ecti
veC
ohor
tSt
udi
esA
sses
sing
Bri
dgin
gA
ntic
oagu
lati
onA
fter
Inte
rru
ptio
nof
VK
AT
hera
py:
Cli
nica
lD
escr
ipti
onan
dR
esu
lts
(Sec
tion
2.4)
Stud
y/yr
Patie
nts
No.
and
Typ
eof
Proc
edur
e
Bri
dgin
gA
ntic
oagu
latio
nR
egim
enF
ollo
w-u
pA
fter
Proc
edur
e
Clin
ical
Out
com
es,%
No.
Indi
catio
nfo
rV
KA
The
rapy
Art
eria
lThr
ombo
embo
lism
inPa
tient
sW
ithM
echa
nica
lHea
rtV
alve
/A
rter
ialT
hrom
boem
bolis
m
Rec
urre
ntV
TE
inPa
tient
sW
ithV
TE
Dea
thM
ajor
Ble
ed
Kat
holi
etal
7 /197
823
5M
echa
nica
lhea
rtva
lve
(typ
eno
tsp
ecifi
ed)
25su
rgic
alU
FH
:int
erm
itten
tor
cont
inuo
usin
fusi
onN
otsp
ecifi
ed0
Not
appl
icab
le0
221
nons
urgi
cal
Span
dorf
eret
al60
/19
9920
12m
echa
nica
lhea
rtva
lve
(10
aort
ic,
2m
itral
)10
surg
ical
Eno
xapa
rin:
1m
g/kg
bid
1m
o0 0 0
Not
appl
icab
le0
1
4at
rial
fibri
llatio
n4
VT
EG
alla
and
Fuh
s54/
2000
8888
mec
hani
calh
eart
valv
e(2
7ao
rtic
,50
mitr
al,9
aort
ic�
mitr
al,2
tric
uspi
d)
Eno
xapa
rin:
30m
gbi
d1
mo
0N
otap
plic
able
03
Nut
escu
etal
237 /
2001
*23
21is
chem
icst
roke
�hy
perc
oagu
labl
est
ate
18su
rgic
al7
nons
urgi
cal
Dal
tepa
rin:
100
IU/k
gbi
d3
mo
0N
otap
plic
able
00
Tin
mou
thet
al61
/20
0124
12m
echa
nica
lhea
rtva
lve
(7ao
rtic
,5
mitr
al);
6at
rial
fibri
llatio
n;6
VT
E
9su
rgic
al17
nons
urgi
cal
Dal
tepa
rin:
200
IU/k
gqd
1m
o1 0 0
01 0 0
0
Wils
onet
al62
/200
147
7m
echa
nica
lhea
rtva
lve
(typ
eno
tsp
ecifi
ed)
11at
rial
fibri
llatio
n26
VT
E3
othe
r(c
ardi
omyo
path
y)
15su
rgic
al32
nons
urgi
cal
Dal
tepa
rin:
200
IU/k
gqd
or12
0IU
/kg
bid
(5,0
00IU
qdin
9pa
tient
s)
Not
spec
ified
0 0 1 0
00
0
Fer
reir
aet
al56
/200
382
82m
echa
nica
lhea
rtva
lve
(43
aort
ic,
39m
itral
)53
surg
ical
29no
nsur
gica
lE
noxa
pari
n:1
mg/
kgbi
d(d
ose
adju
sted
for
rena
lim
pair
men
t)
3m
o0
Not
appl
icab
leN
otav
aila
ble
1
Bau
doet
al72
/200
741
134
4m
echa
nica
lhea
rtva
lve
orat
rial
fibri
llatio
n67
VT
E
77su
rgic
al33
4no
nsur
gica
lV
ario
usth
erap
eutic
-do
se(2
2%)
orpr
ophy
lact
ic-d
ose
(78%
)re
gim
ens
Not
spec
ified
2(1
/1)
00
1 07
Dou
ketis
etal
21/
2004
†65
013
4m
echa
nica
lhea
rtva
lve
(52
aort
ic,5
2m
itral
,30
aort
ic�
mitr
al)
416
atri
alfib
rilla
tion
251
surg
ical
399
nons
urgi
cal
Dal
tepa
rin:
100
IU/k
gbi
d0.
5m
o1 3
Not
appl
icab
le4
6
Ham
mer
stin
glet
al58
/200
711
6M
echa
nica
lhea
rtva
lve
(76
aort
icva
lve,
31m
itral
valv
e,9
aort
ican
dm
itral
valv
es)
46su
rgic
al70
nons
urgi
cal
Eno
xapa
rin:
1m
g/kg
qdor
bid
1m
o0
00
1
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Tab
le3—
Con
tinu
ed
Stud
y/yr
Patie
nts
No.
and
Typ
eof
Proc
edur
e
Bri
dgin
gA
ntic
oagu
latio
nR
egim
enF
ollo
w-u
pA
fter
Proc
edur
e
Clin
ical
Out
com
es,%
No.
Indi
catio
nfo
rV
KA
The
rapy
Art
eria
lThr
ombo
embo
lism
inPa
tient
sW
ithM
echa
nica
lH
eart
Val
ve/A
rter
ial
Thr
ombo
embo
lism
Rec
urre
ntV
TE
inPa
tient
sW
ithV
TE
Dea
thM
ajor
Ble
ed
Kov
acs
etal
22/2
004‡
224
112
mec
hani
calh
eart
valv
e(t
ype
not
spec
ified
)11
2at
rial
fibri
llatio
n
67su
rgic
al15
7no
nsur
gica
lD
alte
pari
n:20
0IU
/kg
qd(5
,000
IUpo
stop
erat
ive
in35
patie
nts
athi
ghri
skfo
rbl
eedi
ng)
3m
o1 1
Not
appl
icab
le0
15
Con
stan
set
al64
/20
0798
30m
echa
nica
lhea
rtva
lve
(14
aort
ic,
16m
itral
)56
atri
alfib
rilla
tion
orar
teri
aldi
seas
e12
VT
E
98no
nsur
gica
lB
emip
arin
:3,5
00IU
qd3
mo
0 0 0
00
0
Tur
pie
and
Dou
ketis
40/2
004§
220
220
mec
hani
calh
eart
valv
e(1
65ao
rtic
,51
mitr
al,5
aort
ic�
mitr
al)
Not
spec
ified
Eno
xapa
rin:
1m
g/kg
bid
3m
o0
Not
appl
icab
le3
8
Jaff
eret
al57
/200
669
20m
echa
nica
lhea
rtva
lve
27at
rial
fibri
llatio
n18
VT
E4
othe
rar
teri
alin
dica
tions
18su
rgic
al47
nons
urgi
cal
Eno
xapa
rin:
1m
g/kg
bid
(30
mg
bid
post
oper
ativ
eaf
ter
surg
ical
proc
edur
es)
1m
o0 0
00
2
Spyr
opou
los
etal
55/
2006
901
246
mec
hani
calh
eart
valv
e34
9at
rial
fibri
llatio
n23
0V
TE
76ot
her
arte
rial
indi
catio
ns
394
surg
ical
507
nons
urgi
cal
The
rape
utic
-dos
e(7
5%)
and
prop
hyla
ctic
-dos
e(2
5%)
UF
Hor
LM
WH
regi
men
s
1m
o8�
2�6
31
Dun
net
al39
/200
626
017
6at
rial
fibri
llatio
n81
VT
E10
5su
rgic
al14
5no
nsur
gica
lE
noxa
pari
n:1.
5m
g/kg
qd1
mo
41
28
Mal
ato
etal
63/2
006
228
53m
echa
nica
lhea
rtva
lve
139
atri
alfib
rilla
tion
26V
TE
10ot
her
arte
rial
indi
catio
ns
101
surg
ical
127
nons
urgi
cal
The
rape
utic
-dos
e(4
0%)
orpr
ophy
lact
ic-d
ose
(60%
)L
MW
Hre
gim
ens
0 3 0
10
6
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the perioperative risk of arterial thromboembolism ifbridging anticoagulation is not given based on theprorated fraction of the annual risk of this out-come.66 Thus, the risk of thromboembolism in apatient with mechanical (mitral or aortic) heart valvewho is not treated with a VKA is estimated at 0.046%/d(ie, 17% annual risk67 � 365) or �0.4% for 8 days whenpatients are not therapeutically anticoagulated duringVKA interruption. The finding of a higher rate ofperioperative thromboembolism in studies of bridginganticoagulation compared to that derived from mathe-matical modeling suggests that the risk for thrombo-embolism is higher than expected. What remainsunclear is whether the administration of bridginganticoagulation decreases this rate further thanthat which would be observed if bridging had notbeen administered or whether bridging therapyhas no effect on the perioperative risk for arterialthromboembolism. This issue can only be ad-dressed through randomized trials comparing abridging vs no bridging strategy in patients with amechanical heart valve, which poses challenges interms of feasibility. In the meantime, cliniciansshould consider bridging anticoagulation in pa-tients with a mechanical prosthetic heart valvewho are at high or moderate risk for arterialthromboembolism (ie, stroke or valve thrombosis).
2.4.2 Patients With Chronic Atrial Fibrillation
Risk Stratification: Risk stratification in patientswith chronic atrial fibrillation is based on placebo-controlled randomized trials that assessed differentantithrombotic strategies in patients with nonvalvu-lar atrial fibrillation.68 Patients with rheumatic val-vular heart disease were not included in these trialsbut are considered to be at high risk for stroke.Bridging anticoagulation should be considered inselected patients with chronic atrial fibrillation whoare at high or moderate risk for arterial thromboem-bolism (ie, stroke or systemic embolism).3,69–71
Clinical prediction rules, such as the Congestive HeartFailure-Hypertension-Age-Diabetes-Stroke (CHADS2)score, may help to stratify patients with nonvalvularatrial fibrillation according to their risk for stroke.70
An administrative linked database study4 suggestedthat the CHADS2 score could be applied to theperioperative setting to estimate stroke risk in pa-tients with chronic atrial fibrillation who were un-dergoing surgery. The score ranges from 0 to 6 andis based on the whether any of five risk factors arepresent: congestive heart failure, hypertension, dia-betes, age � 75 years (1 point each); and prior strokeor transient ischemic attack (2 points). Patients athigh risk for arterial thromboembolism (ie, � 10%risk per year) may include those with one or more of
Tab
le3—
Con
tinu
ed
Stud
y/yr
Patie
nts
No.
and
Typ
eof
Proc
edur
e
Bri
dgin
gA
ntic
oagu
latio
nR
egim
enF
ollo
w-u
pA
fter
Proc
edur
e
Clin
ical
Out
com
es,%
No.
Indi
catio
nfo
rV
KA
The
rapy
Art
eria
lThr
ombo
embo
lism
inPa
tient
sW
ithM
echa
nica
lHea
rtV
alve
/A
rter
ialT
hrom
boem
bolis
m
Rec
urre
ntV
TE
inPa
tient
sW
ithV
TE
Dea
thM
ajor
Ble
ed
Hal
britt
eret
al81
/20
07¶
311
55m
echa
nica
lhea
rtva
lve
(29
aort
ic,
26m
itral
)12
4at
rial
fibri
llatio
n50
LV
dysf
unct
ion
59V
TE
23ot
her
(not
spec
ified
)
65su
rgic
al24
6no
nsur
gica
lT
hera
peut
ic-d
ose
LM
WH
orU
FH
in62
%of
mec
hani
cal
hear
tva
lve,
47%
ofat
rial
fibri
llatio
n,an
d55
%of
left
vent
ricu
lar
dysf
unct
ion
13
47
*Bri
dgin
gep
isod
esin
21pa
tient
s.†1
10pa
tient
sco
nsid
ered
high
risk
for
post
oper
ativ
ebl
eedi
ngdi
dno
tre
ceiv
epo
stop
erat
ive
LM
WH
.‡F
ive
patie
nts
had
intr
aope
rativ
eor
post
oper
ativ
em
yoca
rdia
linf
arct
ion
butw
ere
noti
nclu
ded
inT
able
3to
faci
litat
eac
ross
-stu
dyco
mpa
riso
ns,a
sot
her
stud
ies
did
notd
ocum
entp
erio
pera
tive
myo
card
ial
isch
emic
outc
omes
.§F
orty
patie
nts
cons
ider
edhi
ghri
skfo
rpo
stop
erat
ive
blee
ding
did
not
rece
ive
post
oper
ativ
eL
MW
H.
�Pat
ient
grou
p(a
ccor
ding
toin
dica
tion
for
VK
A)
that
outc
ome
even
tsoc
curr
edin
not
spec
ified
.¶3
11br
idgi
ngep
isod
esin
268
patie
nts.
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the following: (1) CHADS2 score of 5 or 6; (2) arecent (within 3 months) stroke or transient ischemicattack; or (3) rheumatic valvular heart disease. Pa-tients at moderate risk for thromboembolism (ie, 5 to10% risk per year) include those with a CHADS2score of 3 or 4, whereas patients at low risk forthromboembolism (ie, � 5% risk per year) includethose with a CHADS2 score of 0 to 2 who have nothad a prior stroke or transient ischemic attack.
Assessing Need for Bridging Anticoagulation:In 10 prospective cohort studies, bridging anti-coagulation has been assessed in approximately1,400 patients with chronic atrial fibrilla-tion.21,22,39,55,57,58,60–64 As outlined in Table 3, inves-tigators studied predominantly therapeutic-doseLMWH regimens, although low-dose LMWH regi-mens were also assessed in 4 studies involving ap-proximately 300 patients (exact number not discern-able from published data).56,63,64,72 As in patientswith a mechanical heart valve, the issue of whetherlow-dose anticoagulant regimens are efficacious toprevent arterial thromboembolism is also pertinentto patients with atrial fibrillation. Similar to patientswith a mechanical heart valve, there is inadequatedata to formulate definitive conclusions. It is proba-ble that a more intense, therapeutic-dose, anticoag-ulation regimen is more efficacious to prevent em-bolic stroke and systemic embolism than a low-doseregimen and, until evidence to the contrary is avail-able, it is the preferred management. The overallcrude risk for perioperative arterial thromboembo-lism in patients who received bridging anticoagula-tion was 0.57% (95% CI: 0.26–1.1). In studies thatdescribed the clinical characteristics of such patients,most patients had at least one additional risk factorfor stroke (ie, prior stroke, ventricular dysfunction,hypertension, diabetes, age � 75 years).
There are emerging data assessing the risk forarterial thromboembolism in patients with atrialfibrillation who do not receive bridging anticoag-ulation. In a community-based prospective cohortstudy (Anticoagulation Consortium to ImproveOutcomes Nationally [ACTION]) involving pa-tients who were receiving a VKA, 726 patients withatrial fibrillation had temporary interruption of aVKA and did not receive bridging.73 Four (0.6%)patients developed arterial thromboembolism (2strokes, 1 transient ischemic attack, 1 systemicembolism) during a 1-month follow-up periodafter surgery. In a retrospective cohort studyassessing 690 patients (�90% with atrial fibrilla-tion) who required temporary interruption of VKAtherapy prior to GI endoscopy, there were 11(1.6%) patients who developed a stroke within 1month of the procedure (A. Jaffer, submitted for
publication). Another study examined a linkedadministrative database of patients dischargedfrom hospital after surgery or an invasive proce-dure between 1996 and 2001, during a time periodwhen bridging was not routinely given.4 In thisstudy, the 30-day incidence of postoperative strokein patients with atrial fibrillation was 1.3%, whichwas more than fourfold higher than in patientswithout atrial fibrillation (OR, 4.6; 95% CI: 4.2–5.0). Taken together, these studies suggest that inpatients with atrial fibrillation who undergo sur-gery and do not receive bridging anticoagulation,the risk for perioperative arterial thromboembo-lism, consisting of stroke and transient ischemicattack, is approximately 1%. Furthermore, basedon an average annual risk of stroke of 5%(0.013%/d or �0.1% during 8 days of VKA inter-ruption), these studies suggest that the risk forarterial thromboembolism in the perioperativeperiod without bridging is higher than that pre-dicted based on mathematical modeling.74
2.4.3 Patients With Prior VTE
Risk Stratification: Compared to patients withatrial fibrillation or a mechanical heart valve, thereare several distinctions in the assessment of VKAinterruption and need for bridging anticoagulationin patients with prior VTE (ie, deep vein throm-bosis, pulmonary embolism). Whereas the first twogroups are at risk for stroke and other arterialthromboembolism, patients with VTE are at riskfor recurrent deep vein thrombosis or pulmonaryembolism. The consequences of these outcomesdiffer markedly. Embolic stroke is fatal or associ-ated with significant neurologic deficit in 70% ofpatients.11,12 On the other hand, recurrent VTE isfatal in approximately 4 to 9% of patients and isassociated with less morbidity.75,76 In addition,though low-dose anticoagulation has not beenproven to decrease the risk of arterial thrombo-embolic events, it has been shown in nonbridgingtrials to decrease the risk of postoperative VTE.65
Thus, although there is a lesser role for low-doseLMWH or UFH for patients with atrial fibrillationor mechanical heart valves, there is a strongerrationale for using these medications as bridgingtherapy for patients with prior VTE.
Risk stratification in patients with VTE is basedon an assessment of the risk for recurrent VTEafter the start of treatment,77 and risk factors forrecurrent disease after anticoagulant therapy hasbeen stopped.78,79 Patients at high risk for recur-rent disease may include those with: (1) recent(within 3 months) VTE; or (2) severe thrombo-philic conditions (deficiency of protein C, protein
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S or antithrombin, antiphospholipid antibodies, ormultiple thromobophilic abnormalities). Patientswho have had prior VTE after surgery might beconsidered high risk depending on the type ofsurgery they are undergoing (and the associatedthromboembolic risk) and perioperative anti-thrombotic management should be individualized.Risk stratification is less precise in other patientsand would be predicated on individualized factors.Patients at moderate risk for recurrent diseasemay include those with prior VTE within thepast 3 to 12 months, nonsevere thrombophilicconditions (heterozygous carrier of factor VLeiden mutation or factor II mutation), recurrentVTE, or active cancer (treated within 6 months orpalliative). Patients at low risk may includethose in whom VTE occurred � 12 months agoand do not have any of the above-mentioned riskfactors.
Assessing Need for Bridging Anticoagulation: Pro-spective cohort studies have evaluated bridging an-ticoagulation using therapeutic and low-dose regi-mens of various LMWHs in approximately 500patients with prior VTE39,55,57,59–64 (Table 3). Theoverall crude risk for recurrent symptomatic VTEwas 0.60% (95% CI: 0.13–1.7). However, the efficacyof low-dose LMWH or UFH as perioperative antico-agulation is unknown as data are lacking in regard tothe risk of recurrent VTE without bridging antico-agulation.
Recommendation
2.4. In patients with a mechanical heart valveor atrial fibrillation or VTE at high risk (Table2) for thromboembolism, we recommend bridg-ing anticoagulation with therapeutic-dose SCLMWH or IV UFH over no bridging during tem-porary interruption of VKA therapy (Grade 1C);we suggest therapeutic-dose SC LMWH over IVUFH (Grade 2C). In patients with a mechanicalheart valve or atrial fibrillation or VTE at moder-ate risk (Table 2) for thromboembolism, we sug-gest bridging anticoagulation with therapeutic-dose SC LMWH, therapeutic-dose IV UFH, orlow-dose SC LMWH over no bridging duringtemporary interruption of VKA therapy (Grade2C); we suggest therapeutic-dose SC LMWH overother management options (Grade 2C). In patientswith a mechanical heart valve or atrial fibrillationor VTE at low risk (Table 2) for thromboembo-lism, we suggest low-dose SC LMWH or no bridg-ing over bridging with therapeutic-dose SCLMWH or IV UFH (Grade 2C).
Values and preferences: In patients at high or moderaterisk for thromboembolism, the recommendations re-flect a relatively high value on preventing thromboem-bolism and a relatively low value is on preventingbleeding; in patients at low risk for thromboembolism,the recommendations reflect a relatively high value onpreventing bleeding and a relatively low value onpreventing thromboembolism.
3.0 Perioperative Management of PatientsWho Are Receiving Bridging
Anticoagulation
In patients who require temporary interruptionof VKAs and are to receive bridging anticoagula-tion, several treatment regimens have been as-sessed21,22,39,40,56,57,80,81 and are summarized in Table3. In total, � 4,000 patients who had temporary inter-ruption of a VKA and received bridging anticoagulationhave been studied to date, of whom approximately72% received therapeutic-dose LMWH, approximately20% received low-dose LMWH, and approximately 8%received therapeutic-dose UFH.
3.1 Perioperative Anticoagulation TreatmentRegimens
3.1.1 Therapeutic-Dose UFH
Therapeutic-dose IV UFH had been the most com-monly used bridging regimen7,82,83 but its use hasdeclined in recent years,84,85 likely because of theincreased inconvenience of IV drug administration andthe increase in the number of surgical procedures thatare being done without hospitalization.86 In studies thatassessed bridging anticoagulation with therapeutic-dose UFH, a dose-adjusted IV infusion was used,administered to achieve a target activated partialthromboplastin time (APTT) of 1.5 to 2.0 times thecontrol APTT value, with the infusion stopped approx-imately 4 h before surgery and resumed during theinitial 24 h after surgery.7,83 An emerging alternative toIV UFH is SC UFH, which is administered as a fixed,weight-based dose regimen (250 IU/kg bid) withoutAPTT monitoring and has shown to be efficacious andsafe for the treatment of acute VTE.87 The use offixed-dose SC UFH may provide a practical alternativeto IV UFH for bridging anticoagulation, though it hasonly been assessed in a small number of patients whorequired temporary interruption of warfarin for surgery.55
3.1.2 Therapeutic-Dose LMWH
Clinicians have, in recent years, increasinglyturned to therapeutic-dose SC LMWH in lieu ofUFH as bridging anticoagulation,84,85 likely because
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it can be easily administered outside of hospital andwithout laboratory monitoring.36 There is no stan-dardized bridging regimen with LMWH, and severaltherapeutic-dose regimens have been studied: dalte-parin 200 IU/kg qd; enoxaparin 1.5 mg/kg qd; tinza-parin 175 IU/kg qd; dalteparin 100 IU/kg bid; andenoxaparin 1 mg/kg bid.21,22,39,80
In the postoperative period, the use of therapeutic-dose LMWH administered can vary. The 3 principalmanagement approaches that have been studied are:(1) to administer therapeutic-dose LMWH within afixed time period after a procedure (within initial24 h); (2) to administer therapeutic-dose LMWHwithin a varied time period after a procedure (24 to72 h), with the initiation depending on the procedure-related bleeding risk and the adequacy of postopera-tive hemostasis; and (3) to replace therapeutic-doseLMWH with low-dose LMWH in select patientswho are undergoing a procedure associated with ahigh bleeding risk.
3.1.3 Low-Dose LMWH or UFH
Low-dose UFH (eg, UFH, 5,000 IU bid) orlow-dose LMWH (eg, enoxaparin, 30 mg bid, dalte-parin, 5,000 IU qd), which is typically used for theprevention of deep vein thrombosis in at-risk surgicaland medical patients, provides another bridging an-ticoagulation treatment option.65 This approach forperioperative anticoagulation has not been as widelystudied as therapeutic-dose regimens and has beenassessed mainly in lower-risk patients with atrialfibrillation or those with prior VTE. Though thisanticoagulant regimen has been used with the pre-sumed intent of providing some antithrombotic effi-cacy but at a lower risk for perioperative bleeding,data are very limited in regard to the efficacy oflow-dose UFH or LMWH to prevent arterial throm-boembolism in patients with a mechanical heartvalve or chronic atrial fibrillation.54,63,64,72 Indirectevidence from nonsurgical clinical settings involvingpatients with atrial fibrillation who received VKAsindicates that, compared to patients who were ther-apeutically anticoagulated, patients who had sub-therapeutic anticoagulation (INR � 2.0) were morelikely to develop a stroke and such strokes were moresevere and associated with greater mortality.88–90
Although, to our knowledge, there have been nostudies that have assessed the efficacy of low-doseLWMH or UFH to prevent arterial thromboembo-lism, a recent trial involving patients with chronicatrial fibrillation found that treatment with idrapa-rinux, a synthetic anti-Xa inhibitor, when adminis-tered in a therapeutic-dose regimen was as effica-cious as VKA therapy (INR range 2.0 to 3.0) for theprevention of stroke and systemic embolism.91 This
finding supports the premise that administration of atherapeutic-dose regimen of a non-VKA anticoagu-lant with properties similar to LMWHs is efficaciousfor the prevention of arterial thromboembolism.
Low-dose LMWH or UFH may be incorporatedinto a perioperative anticoagulation regimen in twopossible clinical scenarios. The first is as a “stand-alone” regimen in patients with prior VTE who arereceiving VKA therapy and are at moderate or lowrisk for recurrent disease in whom a therapeutic-dose anticoagulation regimen may not be consid-ered. In such patients, a low-dose LMWH or UFHregimen could be used during interruption of a VKAwith the intent of preventing recurrent venous (butnot arterial) thromboembolism. The rationale forthis approach is based on the established efficacy oflow-dose LMWH or UFH to prevent postoperativeVTE.65 The second scenario is in patients with anyclinical indication for VKA therapy who are under-going surgery that is associated with a high risk forbleeding (eg, cardiac, neurosurgical, urologic, majororthopedic). In such patients, administration oftherapeutic-dose LMWH or UFH during the initial48 to 72 h after surgery (or for the entire postoper-ative period) may confer an unacceptably high riskfor bleeding complications and a less intense antico-agulant regimen consisting of low-dose SC LMWHor UFH is likely to confer a lower risk for postoper-ative bleeding. Thus, in a registry involving 1,077patients who received bridging anticoagulation, post-operative low-dose LMWH or UFH was associatedwith a lower risk for minor bleeding compared tobridging anticoagulation with therapeutic-dose LMWHor UFH (OR � 0.46; CI: 0.20 –1.01).80 However,this registry was underpowered to detect potentialdifferences in major bleeding with low-dose ortherapeutic-dose anticoagulation.
To our knowledge, no prospective trials havecompared low-dose and therapeutic-dose LMWH orUFH as bridging anticoagulation to assess bothefficacy, in terms of preventing arterial thromboem-bolism, and safety, in terms of associated bleedingrisk. Although it is plausible that low-dose LMWH orUFH will confer a lower risk for bleeding complica-tions, one cannot exclude the possibility that suchtreatment will be less effective in preventing arterialthromboembolism than a therapeutic-dose regimen.This issue can only be resolved through well-designed randomized trials assessing different bridg-ing anticoagulation strategies.
3.1.4 Costs of Bridging Anticoagulation TreatmentRegimens
Recent studies have compared the costs of bridg-ing anticoagulation before and after surgery with
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in-hospital administered IV UFH and out-of-hospitalbridging anticoagulation SC LMWH.92–95 In a pro-spective cohort study assessing perioperative antico-agulation with patient-administered SC LMWH,nurse-administered SC LWMH, and in-hospital ad-ministered IV UFH, the anticoagulant-related costsfor patients undergoing an overnight surgical proce-dure were estimated at $672, $933, and $3,916 (allUSD), respectively.93 Another cohort study compar-ing costs in 26 patients who received in-hospital IVUFH and 40 patients who received out-of-hospitalSC LMWH and underwent elective surgery found asignificantly lower mean total health-care cost (by$13,114 USD) in patients who received periopera-tive LMWH.94 In a decision analysis study involvingpatients who required VKA interruption for GIendoscopy, similar findings were found in terms oflower costs associated with out-of-hospital use ofLMWH as bridging anticoagulation.96 Taken to-gether, these findings indicate that, compared toin-patient administration of IV UFH, there is con-siderable cost savings with the use of SC LMWHs,which can be administered in an outpatient setting,typically by the patient or by another health-careprovider.92–95 Additional studies are needed to assessthe feasibility and costs of unmonitored SC UFHas bridging anticoagulation for patients in whomLMWH may be contraindicated, such as those withsevere renal insufficiency or in whom LMWHs maybe unavailable or too costly.87
Recommendation
3.1. In patients who require temporary inter-ruption of VKAs and are to receive bridginganticoagulation, from a cost containment per-spective we recommend the use of SC LMWHadministered in an outpatient setting wherefeasible instead of inpatient administration ofIV UFH (Grade 1C).Values and preferences: This recommendation re-flects a consideration not only of the trade-off be-tween the advantages and disadvantages of SCLMWH and IV UFH as reflected in their effects onclinical outcomes (LMWH at least as good, possiblybetter), but also the implications in terms of resourceuse (costs) in a representative group of countries(substantially less resource use with LMWH).
3.2 Interruption of Bridging AnticoagulationBefore Surgery
Bridging anticoagulation with IV UFH, which hasa half-life of approximately 45 min, can be inter-rupted 4 h before planned surgery, a time intervalthat approximates 5 elimination half-lives of UFH,36
and is in accordance with the practice used inbridging anticoagulation studies.7,55 In patients whoare receiving bridging anticoagulation with SCLMWHs, which have elimination half-lives of 4 to5 h,36 the last dose should be administered 20 to 25 hbefore surgery (or on the morning of the day beforesurgery), a time interval that approximates 5 elimi-nation half-lives of LMWHs.36 There is evidencesuggesting that there will be a residual anticoagulanteffect if therapeutic-dose LMWH is given too closeto the time of the procedure. Thus, in a prospectivecohort study involving 73 patients who receivedtherapeutic-dose or low-dose LMWH as bridginganticoagulation, 30% (11 of 37) of patients whoreceived therapeutic-dose LMWH (qd or bid doseregimens) had a residual anticoagulant effect (de-fined as an anti-factor Xa � 0.10 IU/mL) at the timeof surgery whereas � 1% (1 of 36) of patients whoreceived low-dose LMWH had a residual anticoag-ulant effect at surgery.97 In another prospectivecohort study of 98 patients who received bridginganticoagulation with enoxaparin 1 mg/kg bid, withthe last dose given on the evening before surgery, adetectable residual anticoagulant effect (anti-factorXa � 0.10 IU/mL) was found in 100% (98 of 98) ofpatients.98 Furthermore, 34% of patients had ananticoagulant effect at the time of surgery that isconsidered within the therapeutic range (anti-factorXa � 0.50 IU/mL). Although there were no majorbleeds in the patients from both of these studies,most patients underwent low bleeding risk proce-dures and the potential for bleeding in patientshaving major surgical or other higher-risk invasiveprocedures cannot be excluded. Taken together,these findings suggest that the last preoperativedose of therapeutic-dose LMWH before surgeryshould be reduced to minimize the risk for aresidual anticoagulant effect at the time of sur-gery. Until prospective trials address this issuefurther, one management option, especially inpatients who are undergoing major surgery or arereceiving spinal/epidural anesthesia, is to adminis-ter only the morning dose of LMWH in patientsreceiving a twice-daily therapeutic-dose regimenand to reduce by 50% the total dose of LMWHgiven in patients who are receiving a once-dailytherapeutic-dose regimen.
Recommendation
3.2. In patients who are receiving bridginganticoagulation with therapeutic-dose SC LMWH,we recommend administering the last dose ofLMWH 24 h before surgery or a procedureover administering LMWH closer to surgery(Grade 1C); for the last preoperative dose of
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LMWH, we recommend administering ap-proximately half the total daily dose instead of100% of the total daily dose (Grade 1C). Inpatients who are receiving bridging anticoag-ulation with therapeutic-dose IV UFH, werecommend stopping UFH approximately 4 hbefore surgery over stopping UFH closer tosurgery (Grade 1C).
3.3 Resumption of Bridging Anticoagulation AfterSurgery
Following parenteral administration, LMWHs in-duce a rapid anticoagulant effect, with the potentialfor a detectable anticoagulant effect to occur within1 h and a peak anticoagulant effect to occur within 3to 5 h after administration.36 With UFH, though thetime to a peak anticoagulant effect varies, there is thepotential for this to also occur within 3 to 5 hfollowing an IV bolus and infusion.36 Consequently,clinicians should exercise caution when administer-ing these drugs in patients who have recently hadsurgery or other invasive procedures because of thepotential for bleeding at the surgical site, especiallywhen hemostasis is not secured. Three factors ap-pear to affect the risk for surgery-related bleeding:(1) the proximity to surgery that the anticoagulant isadministered; (2) the dose of anticoagulant adminis-tered; and (3) the type of surgery and its associatedbleeding risk. A superimposed consideration is thatbleeding can occur after any surgery or procedure,irrespective of the anticipated surgery-related riskfor bleeding and postoperative anticoagulant man-agement. Consequently, postoperative administra-tion of UFH and LMWHs should consider both theanticipated risk for bleeding, which is determinedpreoperatively, and the adequacy of surgical hemo-stasis, which is determined postoperatively.
3.3.1 Proximity to Surgery That Anticoagulants AreAdministered
In a pooled analysis of studies involving patientswho had major orthopedic surgery and receivedlow-dose fondaparinux (2.5 mg/d) 4 to 8 h postoper-atively or low-dose enoxaparin (40 to 60 mg/d) 12 to24 h postoperatively, the risk for major bleeding wassignificantly higher in fondaparinux-treated patients(2.7% vs 1.7%; p � 0.01).99 In another pooled anal-ysis that compared bleeding in patients who receivedlow-dose LMWH either within 6 h or 12 to 24 h aftermajor orthopedic surgery, the risk for bleeding washigher in patients who received LMWH closer tosurgery (6.3% [95% CI: 5–7] vs 2.5% [95% CI: 1–3]).100
In patients who received bridging anticoagulation,three prospective cohort studies suggest that delay-ing the postoperative initiation of therapeutic-dose
LMWH until hemostasis is secured and deferring (oravoiding altogether) postoperative therapeutic-doseLMWH are associated with a low risk for bleeding.In one study assessing 650 patients who underwent abroad spectrum of surgical and nonsurgical proce-dures and received therapeutic-dose bridging anti-coagulation, postoperative management, which in-cluded resumption of therapeutic-dose bridging withLMWH, depended on the anticipated bleeding riskand adequacy of postoperative hemostasis.21 Thus,patients who had procedures associated with a lowrisk for bleeding (eg, GI endoscopy, cardiac cathe-terization) resumed LMWH approximately 24 hafter the procedure (ie, day after procedure); pa-tients who had major surgery (eg, open abdominalsurgery) or in whom there was inadequate postoper-ative hemostasis resumed LMWH 48 to 72 h aftersurgery; and patients who had major surgery associ-ated with a high risk for bleeding (eg, cardiac,neurosurgical, urologic, major orthopedic) did notreceive any postoperative LMWH. With this ap-proach, the incidence of major bleeding was 1.0%during the first week after surgery, with no fatalbleeds. In another study involving 220 patients witha mechanical heart valve that used the same postop-erative anticoagulant management approach, the in-cidence of major bleeding was 2.3% during the firstweek after surgery, with no fatal bleeds.40 Anotherprospective cohort study involved 224 patients, inwhom once-daily therapeutic-dose LMWH or low-dose LMWH (in patients having surgery associatedwith a high bleeding risk) started on the day aftersurgery and administered only if postoperative he-mostasis was secured.22 The risk for bleeding duringthe first week after surgery in patients who receivedtherapeutic-dose LMWH was 2.9%, with no fatalbleeds. The risk for arterial thromboembolism withthe perioperative management approach used inthese studies is low (� 1%) and is discussed furtherin Section 2.4.
3.3.2 Dose of Anticoagulant Administered
A prospective multicenter registry evaluated 493patients who required interruption of a VKA andreceived bridging with LMWH or UFH or no bridg-ing (Jaffer A, submitted for publication). After ad-justment for surgical and patient-specific bleedingrisk factors, the administration of therapeutic-doseLMWH or UFH after the surgery or procedureconferred a greater than fourfold greater risk formajor bleeding (OR, 4.4; 95% CI: 1.5–14.7) com-pared to the postoperative administration of either alow-dose LMWH or UFH regimen or no bridging.
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3.3.3 Type of Surgery and Associated Bleeding Risk
A prospective bridging study39 of 260 patients inwhich all patients received therapeutic-dose once-daily LMWH perioperatively, with the first postop-erative dose administered 12 to 24 h after surgery,categorized surgeries or procedures as major (ex-pected duration � 1 h) or minor (expected duration� 1 h). This study39 found that major bleedingoccurred in 0.7% (1 of 148) of patients who had aninvasive procedure, in 0% (0 of 72) of patients whohad minor surgery, and in 20.0% (8 of 40) of patientswho had major surgery.
Taken together, these findings suggest that inpatients who receive bridging anticoagulation withtherapeutic-dose LMWH, this regimen should beadministered carefully in the postoperative period. Itappears that therapeutic-dose LMWH can be safelyresumed on the day after surgery in patients whohave had a minor surgical or other invasive proce-dure and in whom there is adequate hemostasis. Onthe other hand, administering therapeutic-doseLMWH within 24 h after major surgery appears toconfer an unacceptably high risk for bleeding com-plications.
In patients undergoing major surgery or a proce-dure (surgical or nonsurgical) associated with a highbleeding risk, management options that are prefera-ble over administering therapeutic-dose SC LMWHor IV UFH in close proximity to surgery (ie, within24 h) include: (1) delaying the resumption oftherapeutic-dose LMWH or UFH for 48 to 72 hafter the surgery/procedure; (2) administering onlylow-dose LMWH after the surgery/procedure; and(3) avoiding the use of LMWH altogether in thepostoperative period. The management option cho-sen is individualized and will depend on both thebleeding risk associated with the surgical or otherinvasive procedure and the adequacy of postopera-tive hemostasis. For example, in patients undergoingmajor surgery (eg, bowel resection), it may be rea-sonable to delay the resumption of therapeutic-doseLMWH or UFH. In patients undergoing a surgery(eg, radical prostatectomy) or procedure (eg, kidneybiopsy) associated with a high risk for bleeding, itmay be reasonable to not administer any LMWH orUFH after surgery and to simply resume VKAs.
Recommendation
3.3. In patients undergoing a minor surgical orother invasive procedure and who are receivingbridging anticoagulation with therapeutic-doseLMWH, we recommend resuming this regi-men approximately 24 h after (eg, the dayafter) the procedure when there is adequate
hemostasis over a shorter (eg, < 12 h) timeinterval (Grade 1C). In patients undergoingmajor surgery or a high bleeding risk surgery/procedure and for whom postoperativetherapeutic-dose LMWH/UFH is planned, werecommend either delaying the initiation oftherapeutic-dose LMWH/UFH for 48 to 72 h aftersurgery when hemostasis is secured, administer-ing low-dose LMWH/UFH after surgery whenhemostasis is secured, or completely avoidingLMWH or UFH after surgery over the adminis-tration of therapeutic-dose LMWH/UFH in closeproximity to surgery (Grade 1C). We recommendconsidering the anticipated bleeding risk and ad-equacy of postoperative hemostasis in individualpatients to determine the timing of LMWH orUFH resumption after surgery instead of resum-ing LMWH or UFH at a fixed time after surgeryin all patients (Grade 1C).
3.4 Laboratory Monitoring of BridgingAnticoagulation
In patients who are receiving IV UFH as bridginganticoagulation, clinicians can use the APTT to guidepreoperative and postoperative anticoagulation. How-ever, use of an UFH dosing nomogram, which wasnot designed for use in the perioperative setting, maybe misleading.39,101 For example, a dosing nomo-gram for IV UFH may result in excessive anticoag-ulation (ie, APTT � 150 s) for up to a 24-h periodwhile dose adjustments are being made. Althoughshort periods of excessive anticoagulation with UFHmay not increase the risk for bleeding in nonopera-tive clinical settings,102,103 such short periods ofover-anticoagulation might increase the risk for bleed-ing in a postoperative setting.
In patients who are receiving bridging anticoagu-lation with therapeutic-dose LMWH, there is noestablished role for routine perioperative monitoringof anti-factor Xa levels, as in certain nonoperativeclinical settings.36 In selected patient groups, such asthose with severe renal insufficiency (ie, calculatedcreatinine clearance � 30 mL/min or serum creati-nine � 178 mmol/L or � 2 g/dL) or at extremes ofbody weight, anti-factor Xa monitoring may be con-sidered to guide treatment as in nonoperative clinicalsettings.36
Recommendation
3.4. In patients who are receiving bridginganticoagulation with LMWH, we suggest againstthe routine use of anti-factor Xa levels to monitorthe anticoagulant effect of LMWHs (Grade 2C).
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4.0 Perioperative Management of PatientsWho Are Receiving Antiplatelet Therapy
An increasing number of patients are receiving anti-platelet drugs for the primary and secondary preven-tion of myocardial infarction or stroke and for theprevention of coronary stent thrombosis after place-ment of a bare metal or drug eluting stent.104,105 Theperioperative management of these patients is increas-ing in complexity because the spectrum of risk for acardiovascular event varies widely. In addition,these patients may be receiving treatment withone of several antiplatelet drug regimens, whichinclude: (1) aspirin alone; (2) clopidogrel alone; (3)aspirin combined with clopidogrel; (4) aspirincombined with dipyridamole; or (5) cilostozol,either alone or combined with either aspirin orclopidogrel. This section will focus on patientswho are receiving aspirin and/or clopidogrel.
4.1 Risk Stratification
Patients who are receiving antiplatelet therapyencompass a spectrum of risk for cardiovascularevents that depends, to a large extent, on the clinicalindication for antiplatelet therapy and whether pa-tients are receiving such treatment for the primary orsecondary prevention of cardiovascular disease. Cli-nicians should incorporate risk stratification in deci-sions concerning temporary interruption or continu-ation of antiplatelet therapy in the perioperativeperiod. There are no risk classification schemes, toour knowledge, that encompass the spectrum ofbenefit from antiplatelet agents. Nonetheless, pa-tients at low risk for perioperative cardiovascularevents in whom temporary interruption of antiplate-let drugs would not be expected to confer a substan-tial increased risk for cardiovascular events includethose who are receiving antiplatelet therapy (typi-cally aspirin) for the primary prevention of myocar-dial infarction or stroke.106 On the other hand,patients at high risk for cardiovascular events inwhom it may be preferable to continue antitplatelettherapy perioperatively include those who have hadrecent (within 3 to 6 months) placement of a baremetal or drug-eluting coronary stent, and to a lesserextent, who have suffered a myocardial infarctionwithin the past 3 months.107 The risk for cardiovas-cular events in these high-risk groups should beweighed against the risk and clinical impact ofbleeding with the operation planned when antiplate-let drugs are continued in the perioperative period.
4.2 Interruption of Antiplatelet Therapy BeforeSurgery
For patients who are receiving aspirin, whichirreversibly inhibits platelet function through cyclo-
oxygenase-1 inhibition, clinicians intending no anti-platelet effect at the time of surgery should interrupttherapy 7 to 10 days before surgery.108 Althoughaspirin has a half-life of 15 to 20 min, it irreversiblyinhibits platelet cyclooxygenase-1 and, therefore, itseffect persists for 7 to 10 days, which approximatesthe platelet lifespan.109,110 Consequently, 4 to 5 daysafter stopping aspirin will result in approximately50% of platelets having normal function, whereas 7to 10 days after stopping aspirin will result in � 90%of platelets having normal function. In patients whoare receiving clopidogrel, a thienopyridine derivativethat irreversibly inhibits adenosine diphosphate re-ceptor-mediated platelet activation and aggregationand has a half-life of 8 h, treatment should beinterrupted 7 to 10 days before surgery since it takesabout that many days to replace the platelet pool.111
This approach also applies to ticlopidine, anotherthienopyridine derivative which is used less fre-quently compared to clopidogrel, in part because ofan increased risk for drug-induced adverse effectssuch as neutropenia.112,113
Another antiplatelet agent that is used in combi-nation with aspirin is dipyridamole, a pyrimidopyri-midine derivative with antiplatelet and vasodilatorproperties that is indicated for secondary strokeprevention in patients with cerebrovascular dis-ease.114 Dipyridamole has reversible effects on plate-let function and has an elimination half-life of ap-proximately 10 h.115 However, since dipyridamole iscombined with aspirin (200 mg dipyridamole � 25mg aspirin), this drug would need to be interrupted7 to 10 days before elective surgery to allow elimi-nation of the antiplatelet effects of both drugs.
Cilostazol is a phosphodiesterase inhibitor withantiplatelet and vasodilatory properties that revers-ibly affects platelet function through cyclic adeno-sine monophosphate (cAMP) mediated inhibition ofplatelet activation and aggregation. Cilostazol may beused in patients with coronary artery disease, typi-cally if they have a coronary stent116 or peripheralarterial disease.117 The pharmacokinetics of cilosta-zol are dose-dependent, with an elimination half-lifeof approximately 10 h.118 Consequently, this drugwould need to be interrupted 2 to 3 days (corre-sponding to 5 elimination half-lives of cilostazol)before surgery to ensure elimination of its antiplate-let effect at the time of surgery.
For patients who are receiving a nonselectivenonsteroidal antiinflammatory drug (NSAID) or acyclyooxygenase-2 selective NSAID (ie, celecoxib),there is reversible inhibition of platelet-mediatedcyclooxygenase activity. To ensure there is no resid-ual antiplatelet effect at the time of surgery, theNSAID should be stopped at a time that correspondsto 5 elimination half-lives for that drug.119,120 For
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NSAIDs with a short, 2 to 6 h, half-life (eg, ibupro-fen, diclofenac, ketoprofen, indomethacin), thesedrugs should be stopped on the day before surgery.For NSAIDs with an intermediate, 7 to 15 h, half-life(eg, naproxen, sulindac, diflunisal, celecoxib), suchtreatment should be stopped 2 to 3 days beforesurgery. Finally, for NSAIDs with a long, � 20 hhalf-life (eg, meloxicam, nabumetone, piroxicam),these drugs should be stopped 10 days beforesurgery.
Recommendation
4.2. In patients who require temporary inter-ruption of aspirin- or clopidogrel-containingdrugs before surgery or a procedure, we sug-gest stopping this treatment 7 to 10 days beforethe procedure over stopping this treatmentcloser to surgery (Grade 2C).
4.3 Resumption of Antiplatelet Therapy AfterSurgery
In patients who have temporary interruption ofantiplatelet drugs before surgery, these agentsshould, in general, be resumed as soon as there isadequate postoperative hemostasis after surgery.Four studies assessed bridging anticoagulation inpatients with a mechanical heart valve, some of whomwere receiving both VKAs and aspirin.21,22,40,55 In thesestudies, aspirin was resumed on the same day as VKAs,starting with the usual maintenance dose of 81 mgdaily. Data are lacking in regard to the resumption ofclopidogrel or other antiplatelet drugs after surgery.One issue that warrants consideration is whetherresumption of treatment should be with a mainte-nance dose of clopidogrel (75 mg/d), which achievesmaximal platelet function inhibition 5 to 10 daysafter its administration,121–123 or with a loading dose(300 to 600 mg/d), which achieves maximal plateletfunction inhibition within 2 to 15 h after administra-tion.124–126 The dose of clopidogrel resumption willdepend largely on whether a patient has a coronarystent, the type of stent implanted, and how recentlythe stent was implanted.
Recommendation
4.3. In patients who have had temporary interrup-tion of aspirin therapy because of surgery or aprocedure, we suggest resuming aspirin approxi-mately 24 h (or the next morning) after surgerywhen there is adequate hemostasis instead ofresuming aspirin closer to surgery (Grade 2C). Inpatients who have had temporary interruption ofclopidogrel because of surgery or a procedure,
we suggest resuming clopidogrel approximately24 h (or the next morning) after surgery whenthere is adequate hemostasis instead of resumingclopidogrel closer to surgery (Grade 2C).
4.4 Laboratory Monitoring of Antiplatelet Therapy
Platelet function assays are available to measurethe antiplatelet activity of aspirin, clopidogrel and,potentially, other antiplatelet drugs, prior to sur-gery.127 However, these methods are not well stud-ied outside of a cardiac surgery or percutaneouscoronary intervention (PCI) setting.128 Furthermore,the clinical significance of the assay results is uncertainas they have not been shown to identify patients atincreased risk for perioperative bleeding.127 Additionalresearch is needed to identify the potential clinicalutility of platelet function assays.
Recommendation
4.4. In patients who are receiving antiplateletdrugs, we suggest against the routine use ofplatelet function assays to monitor the anti-thrombotic effect of aspirin or clopidogrel(Grade 2C).
4.5 Surgery in Patients Receiving AntiplateletTherapy
4.5.1 Noncardiac Surgery
In patients who are receiving antiplatelet drugtherapy and are undergoing noncardiac surgery,there are no randomized trials or prospective cohortstudies that compare the clinical benefits and risks ofcontinuing antiplatelet drugs with their temporaryinterruption. A randomized placebo-controlled trialinvolving patients undergoing hip fracture repair orjoint replacement surgery assessed de novo use ofaspirin compared to no aspirin use in the perioper-ative period and reported higher rates of majorbleeding in aspirin treated patients (2.9% vs 2.4%,p � 0.04).9
Studies in patients undergoing abdominal or pelvicsurgery are limited. A retrospective cohort study in52 patients found that perioperative continuation ofaspirin increases the risk for bleeding after prosta-tectomy.31 A retrospective cohort study involving 200patients who underwent intraabdominal surgeryfound that 12 of 55 (22%) patients with aspirin-associated abnormal platelet function had excessiveperioperative bleeding, whereas 7 of 97 (7%) withnormal platelet function had excessive bleeding.129
However, another study involving 52 patients whohad surgery found that perioperative aspirin use didnot confer an increased risk for bleeding.130
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Retrospective cohort studies have suggested in-creased rates of bleeding with perioperative contin-uation of clopidogrel.131,132 In addition, one prospec-tive cohort study in patients who underwentbronchoscopy found significantly higher incidencesof moderate or severe bleeding after biopsy inpatients who received clopidogrel (61%) or clopi-dogrel and aspirin (100%) compared to no antiplate-let drug (2%).133
4.5.2 CABG
Elective coronary artery bypass graft (CABG)surgery is frequently done in patients who are re-ceiving antiplatelet therapy with aspirin and/or clo-pidogrel.134 In addition, 10 to 15% of patients hos-pitalized with an acute coronary syndrome willrequire urgent CABG surgery during their hospital-ization and such patients are typically receivingantiplatelet therapy (aspirin alone or aspirin andclopidogrel) and anticoagulant therapy, the later withLMWH or UFH.135 Minimizing the risk for periop-erative bleeding in patients undergoing CABG sur-gery is important because of an increased risk fordeath and other adverse outcomes in patients whorequire a blood transfusion in the perioperativeperiod.136 In one study involving 11,963 patients whounderwent CABG, of whom 49% received transfu-sion of RBCs, transfusion was associated with signif-icant increases in mortality (OR, 1.77; CI: 1.67–1.87), renal failure (OR, 2.06; CI: 1.87–2.27), andneurologic events (OR, 1.37; CI: 1.30–1.44).137 Theperioperative management of anticoagulant therapyis comparable to that of noncardiac surgery, withinterruption of LMWH or UFH at a time prior toCABG surgery that will eliminate the anticoagulanteffect by the time of surgery. On the other hand, theperioperative management of antiplatelet therapy ismore problematic since 7 to 10 days after stoppingtreatment is required to eliminate an antiplateleteffect and urgent CABG is often required withoutadvance notice of 7 to 10 days.
In patients who are receiving aspirin and requireCABG surgery, observational studies show that con-tinuing aspirin in the perioperative period appears toconfer an increased risk for mediastinal bleeding,blood transfusion, and reoperation,138,139 althoughthis finding was not found in all studies.140 Againstthese risks, aspirin use within 5 days prior to CABGwas shown in a large cohort study to confer a lowerrisk of postoperative mortality and without a con-comitant increase in reoperation for bleeding orneed for blood transfusion.26 Based on this benefit ofcontinued perioperative aspirin use in patients un-dergoing CABG, if aspirin therapy has been inter-rupted before surgery, it should be administered
early after surgery, always within 48 h after CABGand, preferably, within 6 h after surgery.141
In patients who are receiving clopidogrel andrequire CABG, there are no data to suggest benefitfrom the administration of clopidogrel in the periop-erative period whereas there are preliminary datasuggesting harm with this approach.142 In the CanRapid risk stratification of Unstable Angina PatientsSupress Adverse Outcomes With Early Implemen-tation of the American College of Cardiology/Amer-ican Heart Association guidelines (CRUSADE)study that included 2,855 patients with a non-STelevation myocardial infarction, 87% of patients un-derwent CABG within 5 days of prior clopidogrelexposure.143 Such patients had a 70% higher likeli-hood for a transfusion requirement of 4 U or more ofRBCs. The most compelling data about the risk ofbleeding among patients undergoing CABG who arereceiving clopidogrel come from the Clopidogrelin Unstable angina to prevent Recurrent Events(CURE) trial.144 In a postrandomization subgroupanalysis of this trial, exposure to clopidogrel within 5days prior to CABG was associated with an approx-imately 50% increase in major bleeding. Other ret-rospective studies have confirmed the increased riskfor bleeding with prior clopidogrel exposure in pa-tients undergoing CABG surgery.145–148 An in-creased risk of bleeding appears to occur even whenCABG is performed in an off-pump manner.149
Mitigating the risk for perioperative bleeding andtransfusion with antifibrinolytic drugs, such as apro-tinin, or platelet transfusion is problematic becauseboth treatments are associated with adverse effects.Although two randomized trials suggested a reduc-tion in the need for transfusion among patientstreated with aprotinin undergoing surgery while onclopidogrel without raising concerns of excessive riskof thrombosis, aprotinin appears to be associatedwith an increased risk for thrombotic and otheradverse effects,150,151 and is no longer available forclinical use in the United States. In one observationalstudy involving 4,374 patients undergoing CABGsurgery for ST-segment elevation myocardial infarc-tion, aprotinin use was associated with a 55% in-creased risk for myocardial infarction or congestiveheart failure and a 181% increased risk for stroke orencephalopathy.152 Similarly, pre-CABG platelettransfusion is associated with longer surgery and, par-adoxically, more bleeding and reoperation for bleedingcomplications.153 Alternative antifibrinolytic agents thatcan be used in lieu of aprotonin to reduce perioperativebleeding in patients undergoing cardiac surgery includeepsilon-aminocaproic acid and tranexamic acid, whichhave been shown to reduce transfusion require-ments.154,155 The efficacy of 1-deamino-8-D-arginine
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vasopressin (DDAVP) in patients undergoing cardiacsurgery who have been exposed to aspirin is lessclear.156
4.5.3 PCIs
Randomized trials have compared a 325-mg doseof aspirin to placebo among patients undergoing aballoon angioplasty type of PCI. The reduction inrisk associated with aspirin administration in thesestudies has led to the recommendation that aspirinbe administered in all patients prior to any PCIprocedure.17
Clopidogrel has been compared to placebo amongpatients with acute coronary syndromes and found toreduce the risk of procedure-related events.157,158 Inpostrandomization subgroup analyses of patients un-dergoing PCI in these trials, clopidogrel was partic-ularly beneficial among patients undergoing PCI andthe benefit seems to apply not only to patients whoreceived stents but to those undergoing balloonangioplasty and other types of PCI procedures aswell. Pretreatment with clopidogrel is recommendedbefore any type of PCI procedure whenever it can beaccomplished and such treatment should be contin-ued during the periprocedural period. Among pa-tients on long-term clopidogrel therapy, one studyshowed that periprocedural administration of a 600-mgloading dose of clopidogrel to such patients resulted ina greater inhibition of platelet aggregation than notreceiving a loading dose.159 Other studies have sug-gested that clinical outcomes are improved if PCI isperformed after a 600-mg loading dose of clopidogrelhas been administered; few patients in those studieswere receiving long-term clopidogrel and it is notknown whether chronically administered clopidogrelachieves the same effect.160–162
Recommendation
4.5. For patients who are not at high risk forcardiac events, we recommend interruption ofantiplatelet drugs (Grade 1C). For patients athigh risk of cardiac events (exclusive of coro-nary stents) scheduled for noncardiac surgery,we suggest continuing aspirin up to and beyondthe time of surgery (Grade 2C); if patients arereceiving clopidogrel, we suggest interruptingclopidogrel at least 5 days and, preferably,within 10 days prior to surgery (Grade 2C). Inpatients scheduled for CABG, we recommendcontinuing aspirin up to and beyond the time ofCABG (Grade 1C); if aspirin is interrupted, werecommend it be reinitiated between 6 h and48 h after CABG (Grade 1C). In patients sched-uled for CABG, we recommend interrupting
clopidogrel at least 5 days and, preferably, 10days prior to surgery (Grade 1C). In patientsscheduled for PCI, we suggest continuing aspi-rin up to and beyond the time of the procedure;if clopidogrel is interrupted prior to PCI, wesuggest resuming clopidogrel after PCI with aloading dose of 300 to 600 mg (Grade 2C).
4.6 Surgery in Patients With Coronary Stents
Patients who are receiving antiplatelet therapybecause of a bare metal or drug-eluting stent in thecoronary arteries deserve special consideration be-cause of the high thrombotic risk if antiplatelet drugtherapy is interrupted. In such patients who areundergoing noncardiac surgery, there is a markedlyincreased risk of coronary stent thrombosis in thepostoperative period, especially if surgery is under-taken in close proximity to stent placement.163–172
Furthermore, the clinical impact of stent thrombosisin this clinical setting is considerable, as it will befatal or associated with a large myocardial infarctionin � 50% of affected patients.107,163,173–175 A retro-spective cohort study assessed 40 consecutive pa-tients who had elective noncardiac surgery � 6weeks after coronary artery stenting.163 In this study,eight patients (20%) died postoperatively, in whomall but one had perioperative interruption of clopi-dogrel or aspirin.
To mitigate the risk for perioperative stentthrombosis, elective noncardiac surgery should beavoided during the period after stent placementwhen stent endothelialization is ongoing as this isthe time when coronary stents are most suscepti-ble to thrombosis. In patients with a bare metalstent, the aforementioned study suggested that therisk of thrombosis with surgery was higher inpatients who had surgery within 2 weeks of stent-ing compared to more than 2 weeks after stenting(p � 0.15).163 A larger study suggested that therisk of bare metal stent thrombosis and otheradverse events is increased if noncardiac surgery isperformed within 6 weeks of stent placement,164
which is consistent with the approximate timerequired for endothelialization around the baremetal stents.176,177
A relevant, but poorly studied, issue in the man-agement of patients with coronary stents who requiresurgery is whether bridging therapy is warranted forpatients in whom interruption of antiplatelet therapyis required because of a high bleeding risk associatedwith the planned surgery. In such patients, bridgingtherapy might consist of administering LMWH orUFH in a manner similar to that in patients whorequire temporary interruption of VKAs, though thisapproach has not been formally studied to assess
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efficacy and should be weighed against a potentialincreased risk for postoperative bleeding. An alter-native approach might be the use of bridging therapywith short-acting antiplatelet drugs such as the gly-coprotein IIb/IIIa antagonists tirofiban or eptifi-batide, which have been studied in patients under-going PCI.17 These agents have elimination half-livesof approximately 2 h and their interruption 10 hbefore surgery would allow restoration of plateletfunction by the time of surgery.108 Emerging short-acting antiplatelet drugs that target platelet P2 re-ceptors, such as cangrelor, may have clinical utility inthe perioperative setting because of rapid reversal ofantiplatelet activity after treatment is stopped.178
Studies are needed to assess the efficacy and safetyof bridging therapy in patients who are receivingantiplatelet drugs and, until relevant data are avail-able, clinical judgment and caution are urged inregard to the use of short-acting antithromboticagents in patients who require temporary interrup-tion of aspirin and/or clopidogrel.
Less is known about the timing of noncardiacsurgery in patients with a sirolimus- or paclitaxel-eluting coronary stent, in whom a longer time isrequired for coronary reendothelialization than pa-tients with a bare metal stent. There have beenseveral reports of thrombosis of such drug-elutingstents during the intraoperative and postoperativeperiod, in some cases even when surgery is per-formed years after stent placement.165–170 Thoughaspirin is recommended indefinitely after placementof a drug-eluting stent and clopidogrel is recom-mended for at least 3 months after placement of asirolimus-eluting stent and 6 months after placementof a paclitaxel-eluting stent, most patients are receiv-ing combined aspirin-clopidogrel therapy for at least12 months after placement of a drug-elutingstent.179,180 Consequently, elective surgery should bedelayed for 12 months after placement of a drug-eluting stent whenever possible.
Recommendation
4.6. In patients with a bare metal coronary stentwho require surgery within 6 weeks of stentplacement, we recommend continuing aspirinand clopidogrel in the perioperative period(Grade 1C). In patients with a drug-eluting cor-onary stent who require surgery within 12months of stent placement, we recommendcontinuing aspirin and clopidogrel in theperioperative period (Grade 1C). In patientswith a coronary stent who have interruptionof antiplatelet therapy before surgery, wesuggest against the routine use of bridgingtherapy with UFH, LMWH, direct thrombin
inhibitors, or glycoprotein IIb/IIIa inhibitors,(Grade 2C).Values and preferences: These recommendationsreflect a relatively high value placed on preventingstent-related coronary thrombosis, and a consider-ation of complexity and costs of administering bridgingtherapy in the absence of efficacy and safety data in thisclinical setting, and a relatively low value on avoidingthe unknown but potentially large increase in bleedingrisk associated with the concomitant administrationof aspirin and clopidogrel during surgery.
5.0 Perioperative Management ofAntithrombotic Therapy in Patients Who
Require Dental, Dermatologic, orOphthalmologic Procedures
Minor dental, dermatologic, and ophthalmologicprocedures can comprise up to 20% of all surgicaland nonsurgical procedures performed in patientswho are receiving antithrombotic therapy.21,55 Asthese procedures are typically associated with rela-tively little blood loss, a key question relates to thesafety of continuing antithrombotic therapy aroundthe time of the procedure and whether continuingtreatment confers an increased risk of clinicallyimportant bleeding. A practical issue that also relatesto the management of such patients is that most, ifnot all, minor procedures are undertaken in a clinicor other out-of-hospital setting. Consequently, bleed-ing that may occur after the procedure will occurwhile the patient is home and may generate concernand anxiety for the patient. Patients should, there-fore, be given instructions to deal with potentialbleeding, which usually requires prolonged localpressure over the site of a dental or dermatologicprocedure. In addition, patients should be advisedwhen bleeding is excessive and warrants medicalattention.
In our review of randomized and nonrandomizedprospective studies that assessed the risk of bleedingin patients who continue VKAs or antiplatelet drugsduring minor procedures, which are summarized inTables 4–8, we have focused on postproceduralbleeding. To distinguish bleeding that is clinicallyimportant and requires medical attention, frombleeding that does not require medical attention andis, typically, self-limiting, we classified bleeding intothree categories: (1) major bleeding, which refers tobleeding that requires transfusion of � 2 U packedRBCs181; (2) clinically relevant nonmajor bleeding,which refers to bleeding that is not major butrequires medical attention (eg, application of wounddressing or additional sutures); and (3) minor bleed-ing, which refers to bleeding that is self-limiting,
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Tab
le4
—R
ando
miz
edT
rial
sA
sses
sing
Con
tinu
atio
nof
Ant
ithr
omb
otic
The
rapy
inP
atie
nts
Und
ergo
ing
Den
tal
Pro
cedu
res:
Cli
nica
lD
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ipti
onan
dR
esu
lts
(Sec
tion
5.1)
*
Stud
y/yr
Patie
nts
Typ
eof
Proc
edur
e
Peri
proc
edur
alIn
terv
entio
n
Fol
low
-up
Clin
ical
Out
com
es,N
o./T
otal
No.
Typ
eof
Tre
atm
ent
Indi
catio
nfo
rA
TT
hera
pyN
o.G
roup
Thr
ombo
embo
lism
Eve
nts
Min
orB
leed
ing
Clin
ical
lyR
elev
ant
Non
maj
orB
leed
ing
Maj
orB
leed
Bor
ea etal
182 /
1993
30V
KA
MH
V,n
�30
Den
tale
xtra
ctio
ns15
Tre
atm
ent:
cont
inue
VK
A�
irrig
atio
n�
tran
exam
icac
id
10d
0T
reat
men
t:1/
15(6
.67%
)C
ontr
ol:0
/15
Tre
atm
ent:
1/15
(6.7
%)
Con
trol
:2/1
5(1
3.3%
)
Tre
atm
ent:
0/15
Con
trol
:0/1
5
15C
ontr
ol:s
top
VK
AE
vans et
al18
3 /20
02
109
VK
AN
otre
port
edD
enta
lext
ract
ions
57T
reat
men
t:co
ntin
ueV
KA
Not
spec
ified
0T
reat
men
t:13
/57
(22.
8%)
Tre
atm
ent:
2/57
(3.5
%)
Tre
atm
ent:
0/57
52C
ontr
ol:s
top
VK
Ada
y�
2C
ontr
ol:7
/52
(13.
5%)
Con
trol
:0/5
2C
ontr
ol:0
/52
Sacc
oet
al18
4 /20
06
131
VK
AV
TE
�16
,AF
�39
,M
HV
�59
,va
lvul
arhe
art
dise
ase
�13
Ora
lsur
geri
es(d
enta
lex
trac
tions
,fix
ture
inse
rtio
ns,e
xcis
ion
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stic
neof
orm
atio
ns)
65T
reat
men
t:V
KA
(ful
l-dos
e)�
tran
exam
icac
id�
spon
ge
10d
0T
reat
men
t:no
tre
port
edC
ontr
ol:n
otre
port
ed
Tre
atm
ent:
6/65
(9.2
%)
Con
trol
:10/
66(1
5.2%
)
Tre
atm
ent:
0/65
Con
trol
:0/6
6
66C
ontr
ol:V
KA
(red
uced
-dos
e)da
y�
3A
rdek
ian
etal
209 /
2000
39A
spir
inV
TE
�6,
AF
�1,
coro
nary
arte
rydi
seas
e�
20,
stro
ke�
10
Ora
lsur
gery
(sim
ple
and
com
poun
dde
ntal
extr
actio
ns,
and
mor
eco
mpl
expr
oced
ures
)
19T
reat
men
t:co
ntin
ueas
piri
nN
otsp
ecifi
ed0
Tre
atm
ent:
0/19
Tre
atm
ent:
4/19
(21.
1%)
Tre
atm
ent:
0/19
20C
ontr
ol:s
top
aspi
rin
day
�7
Con
trol
:0/2
0C
ontr
ol:2
/20
(10%
)C
ontr
ol:0
/20
*MH
V�
mec
hani
calh
eart
valv
e;A
T�
antit
hrom
botic
;AF
�at
rial
fibri
llatio
n.
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 323S
© 2008 American College of Chest Physicians by guest on October 19, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le5—
Ran
dom
ized
Tri
als
Ass
essi
ngP
rohe
mos
tati
cIn
terv
enti
ons
inP
atie
nts
Und
ergo
ing
Den
tal
Pro
cedu
res:
Cli
nica
lD
escr
ipti
onan
dR
esu
lts
(Sec
tion
5.1)
Stud
y/yr
Patie
nts
Typ
eof
Proc
edur
e
Peri
proc
edur
alIn
terv
entio
n
Fol
low
-up
Clin
ical
Out
com
es,N
o./T
otal
No.
Typ
eof
Tre
atm
ent
Indi
catio
nfo
rA
TT
hera
pyN
o.G
roup
Thr
ombo
embo
lism
Eve
nts
Min
orB
leed
ing
Clin
ical
lyR
elev
ant
Non
maj
orB
leed
ing
Maj
orB
leed
Al-B
elas
yan
dA
mer
185 /
2003
30V
KA
VT
E�
11,
AF
�7,
Den
tale
xtra
ctio
ns15
Tre
atm
ent:
surg
ical
glue
At
leas
t10
d0
Tre
atm
ent:
0/15
Tre
atm
ent:
0/15
Tre
atm
ent:
0/15
Stro
ke�
4,M
HV
�3,
VH
D�
5
15C
ontr
ol:g
elat
insp
onge
Con
trol
:0/1
5C
ontr
ol:5
/15
(33.
3%)
Con
trol
:0/1
5
Car
ter
and
Gos
s186 /
2003
85V
KA
VT
E�
20,
AF
�14
,C
AD
�10
,V
HD
�33
,st
roke
�1
Den
tale
xtra
ctio
ns43
Tre
atm
ent:
day
�2
tran
exam
icac
idN
otsp
ecifi
ed0
Tre
atm
ent:
0/43
Tre
atm
ent:
2/43
(4.6
%)
Tre
atm
ent:
0/43
52C
ontr
ol:d
ay�
5tr
anex
amic
acid
Con
trol
:0/5
2C
ontr
ol:1
/52
(1.9
%)
Con
trol
:0/5
2
Car
ter
etal
187 /
2003
49V
KA
VT
E�
8,A
F�
12,
CA
D�
5,st
roke
�5,
VH
D�
19
Den
tale
xtra
ctio
ns23
Tre
atm
ent:
surg
ical
glue
10d
0T
reat
men
t:0/
23T
reat
men
t:2/
23(8
.7%
)T
reat
men
t:0/
23
26C
ontr
ol:d
ay�
7tr
anex
amic
acid
Con
trol
:0/2
6C
ontr
ol:0
/26
Con
trol
:0/2
6
Hal
fpen
nyet
al18
8 /20
01
46V
KA
VT
E�
16,
AF
�12
,C
AD
�3,
stro
ke�
2,M
HV
�9,
VH
D�
3
Den
tale
xtra
ctio
ns20
Tre
atm
ent:
surg
ical
glue
(Ber
ipla
st)
Not
spec
ified
0T
reat
men
t:0/
20T
reat
men
t:2/
20(1
0%)
Tre
atm
ent:
0/20
26C
ontr
ol:s
urgi
cal
glue
(Sur
gice
l)C
ontr
ol:0
/26
Con
trol
:1/2
6(3
.8%
)C
ontr
ol:0
/26
Ram
strö
met
al18
9 /19
93
89V
KA
VT
E�
29,
AF
�9,
CA
D�
6,st
roke
�15
,M
HV
�29
,V
HD
�6
Ora
lsur
geri
es(d
enta
lex
trac
tions
,en
dodo
ntic
surg
ery)
44T
reat
men
t:tr
anex
amic
acid
Not
spec
ified
0T
reat
men
t:2/
44(4
.5%
)T
reat
men
t:0/
44T
reat
men
t:0/
44
45C
ontr
ol:s
alin
em
outh
was
hC
ontr
ol:2
/45
(4.4
%)
Con
trol
:10/
45(2
2.2%
)C
ontr
ol:0
/45
*VH
D�
valv
ular
hear
tdi
seas
e;C
AD
�co
rona
ryar
tery
dise
ase;
see
Tab
le4
for
expa
nsio
nof
abbr
evia
tions
.
324S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 19, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le6
—C
ohor
tSt
udi
esA
sses
sing
Con
tinu
atio
nof
Ant
ithr
omb
otic
The
rapy
inP
atie
nts
Und
ergo
ing
Den
tal
Pro
cedu
res:
Cli
nica
lD
escr
ipti
onan
dR
esu
lts
(Sec
tion
5.1)
*
Stud
y/yr
Patie
nts
Typ
eof
Proc
edur
e
Peri
proc
edur
alIn
terv
entio
n
Fol
low
-up
Clin
ical
Out
com
es,N
o./T
otal
No.
Typ
eof
Tre
atm
ent
Indi
catio
nfo
rA
TT
hera
pyN
o.G
roup
Thr
ombo
embo
lism
Eve
nts
Min
orB
leed
ing
Clin
ical
lyR
elev
ant
Non
maj
orB
leed
ing
Maj
orB
leed
Blin
der
etal
197/
2001
249
VK
AV
TE
�23
,AF
�53
,D
enta
lext
ract
ions
190
Tre
atm
ent:
INR
�2
Not
spec
ified
0T
reat
men
t:0/
190
Tre
atm
ent:
27/
190
(14.
2%)
Tre
atm
ent:
0/19
0C
ontr
ol:0
/59
CA
D�
27,
VH
D�
112
59C
ontr
ol:I
NR
,1.5
–2.0
Con
trol
:0/5
9C
ontr
ol:3
/59
(5.1
%)
Cam
pbel
let
al190/2
000
25V
KA
Not
repo
rted
Ora
lsur
geri
es(d
enta
lex
trac
tions
,sof
ttis
sue)
12T
reat
men
t:co
ntin
ueV
KA
1d
0T
reat
men
t:1/
12(8
.33%
)T
reat
men
t:0/
12T
reat
men
t:0/
12
13C
ontr
ol:s
top
VK
Ada
y�
3to
�4
Con
trol
:2/1
3(1
5.4%
)C
ontr
ol:0
/13
Con
trol
:0/1
3
Can
non
and
Dha
rmar
191/
2003
70V
KA
VT
E�
15,A
F�
10,
CA
D�
12,
stro
ke�
16,
MH
V�
8,V
HD
�9
Den
tale
xtra
ctio
ns35
Tre
atm
ent:
cont
inue
VK
A5
d0
Tre
atm
ent:
2/35
(5.7
)%T
reat
men
t:0/
35T
reat
men
t:0/
35
35C
ontr
ol:s
top
VK
Ada
y�
2;su
ture
s�
glue
Con
trol
:3/3
5(8
.6%
)C
ontr
ol:0
/35
Con
trol
:0/3
5
Del
laV
alle
etal
198/2
003
40V
KA
MH
V�
40D
enta
lext
ract
ions
40T
reat
men
t:st
opV
KA
;no
cont
rol
Not
spec
ified
0T
reat
men
t:16
/40
(40%
)T
reat
men
t:2/
40(5
.0%
)T
reat
men
t:0/
40
Dev
anie
tal
192/
1998
65V
KA
VT
E�
19,A
F�
12,
CA
D�
12,
stro
ke�
8,M
HV
�1,
VH
D�
16
Den
tale
xtra
ctio
ns33
Tre
atm
ent:
cont
inue
VK
A5
d0
Tre
atm
ent:
1/33
(3.0
%)
Tre
atm
ent:
0/33
Tre
atm
ent:
0/33
32C
ontr
ol:s
top
VK
Ada
y�
2C
ontr
ol:1
/32
(3.1
%)
Con
trol
:0/3
2C
ontr
ol:0
/32
Gas
par
etal
193/
1997
47V
KA
VT
E�
13,
Den
tale
xtra
ctio
ns32
Tre
atm
ent:
cont
inue
VK
A10
d0
Tre
atm
ent:
0/32
Tre
atm
ent:
2/32
(6.2
%)
Tre
atm
ent:
0/32
AF
�2,
MH
V�
23,
stro
ke�
4,V
HD
�2,
CA
D�
3
15C
ontr
ol:s
top
VK
Ada
y�
3C
ontr
ol:0
/15
Con
trol
:1/1
5(6
.7%
)C
ontr
ol:0
/15
Mad
anet
al210/
2005
51A
spir
inV
TE
�18
,CA
D�
6,st
roke
�4,
arte
rial
thro
mbo
embo
lism
�35
,PA
D�
5
Ora
lsur
geri
es(n
otsp
ecifi
ed)
51T
reat
men
t:co
ntin
ueas
piri
n;no
cont
rol
14d
0T
reat
men
t:1/
51(2
.0%
)T
reat
men
t:0/
51T
reat
men
t:0/
51
Mar
tinow
itzet
al199/1
990
40V
KA
VT
E�
7,M
HV
�18
,V
HD
�18
,C
AD
�6,
stro
ke�
4
Den
tale
xtra
ctio
ns40
Tre
atm
ent:
cont
inue
VK
A;n
oco
ntro
lN
otsp
ecifi
ed0
Tre
atm
ent:
1/40
(2.5
%)
Tre
atm
ent:
0/40
Tre
atm
ent:
0/40
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Tab
le6
—C
onti
nued
Stud
y/yr
Patie
nts
Typ
eof
Proc
edur
e
Peri
proc
edur
alIn
terv
entio
n
Fol
low
-up
Clin
ical
Out
com
es,N
o./T
otal
No.
Typ
eof
Tre
atm
ent
Indi
catio
nfo
rA
TT
hera
pyN
o.G
roup
Thr
ombo
embo
lism
Eve
nts
Min
orB
leed
ing
Clin
ical
lyR
elev
ant
Non
maj
orB
leed
ing
Maj
orB
leed
Ram
lian
dA
bdul
Rah
man
200/
2005
30V
KA
VT
E�
1,A
F�
9,V
HD
�20
Den
tale
xtra
ctio
ns30
Tre
atm
ent:
cont
inue
VK
A;n
oco
ntro
l10
d0
Tre
atm
ent:
3/30
(10%
)T
reat
men
t:1/
30(3
.3%
)T
reat
men
t:0/
30
Rus
soet
al201/
2000
104
VK
AM
HV
�10
4,A
F�
42D
enta
lpro
cedu
res
104
Tre
atm
ent:
stop
VK
Ada
y�
2;no
cont
rol
3m
o0
Tre
atm
ent:
0/10
4T
reat
men
t:2/
104
(1.9
%)
Tre
atm
ent:
0/10
4
Zano
net
al196/
2003
500
VK
AV
TE
�33
,AF
�59
,st
roke
�50
,M
HV
�39
,V
HD
�12
,C
AD
�78
,ot
her
�4
Den
tale
xtra
ctio
ns25
0T
reat
men
t:co
ntin
ueV
KA
Not
spec
ified
0T
reat
men
t:0/
250
Tre
atm
ent:
4/25
0(1
.6%
)T
reat
men
t:0/
250
250
Con
trol
:sto
pV
KA
Con
trol
:0/2
50C
ontr
ol:3
/250
(1.2
%)
Con
trol
:0/2
50
Zusm
anet
al202/
1992
23V
KA
AF
�5,
MH
V�
2,V
HD
�11
,M
I�
5
Den
tale
xtra
ctio
ns23
Tre
atm
ent:
cont
inue
VK
A;n
oco
ntro
lN
otsp
ecifi
ed0
Tre
atm
ent:
1/23
(4.3
%)
Tre
atm
ent:
3/23
(13%
)T
reat
men
t:0/
23
Bar
rero
etal
203/
2002
125
VK
AV
TE
�15
,AF
�57
,st
roke
�18
,M
HV
�10
,PA
D�
2,V
HD
�17
,C
AD
�2,
othe
r�
4
Den
tale
xtra
ctio
ns,
root
leve
rage
,os
teot
omy
125
Tre
atm
ent:
cont
inue
VK
A;n
oco
ntro
ltr
anex
amic
acid
,pr
essu
re,i
rrig
atio
n,su
rgic
al
Not
spec
ified
0T
reat
men
t:1/
229
(7.9
%)
Tre
atm
ent:
0/22
9T
reat
men
t:1/
229
(0.4
%)
Cie
slik
-Bie
leck
aet
al204/2
005
40V
KA
,asp
irin
AF
�3,
MH
V�
11,
CA
D�
6,V
HD
�3,
CA
D�
15,
othe
r�
5
Den
tale
xtra
ctio
ns,
othe
ror
alsu
rger
y40
Tre
atm
ent:
cont
inue
VK
A;n
oco
ntro
l;su
ture
s,sp
onge
Not
spec
ified
0T
reat
men
t:0/
40T
reat
men
t:2/
40(5
.0%
)T
reat
men
t:0/
40
Kei
aniM
otla
ghet
al205/2
003
40V
KA
AF
�6,
MH
V�
22,
VT
E�
12D
enta
lext
ract
ions
,ot
her
oral
surg
ery
40T
reat
men
t:co
ntin
ueV
KA
;no
cont
rol
tran
exam
icac
id†
14d
0T
reat
men
t:0/
40T
reat
men
t:0/
40T
reat
men
t:0/
40
Gar
cia-
Dar
enne
set
al206/2
003
96V
KA
MH
V�
56,4
0(V
TE
,C
AD
,str
oke)
Sing
lean
dm
ultip
lede
ntal
extr
actio
ns96
Tre
atm
ent:
cont
inue
VK
A;n
oco
ntro
ltr
anex
amic
acid
†,su
ture
s,gl
ue
Not
spec
ified
0T
reat
men
t:0/
96T
reat
men
t:3/
96(3
.1%
)T
reat
men
t:0/
96
Saou
ret
al194/
1994
396
VK
AA
F�
39,
MH
V�
396
Den
tale
xtra
ctio
ns15
6T
reat
men
t:co
ntin
ued
VK
AN
otsp
ecifi
ed0
Tre
atm
ent:
0/15
6T
reat
men
t:0/
156
Tre
atm
ent:
0/15
6
240
Con
trol
:dis
cont
inue
VK
Ada
y�
2C
ontr
ol:0
/240
Con
trol
:2/2
40(0
.8%
)C
ontr
ol:0
/240
Stre
etan
dL
eung
195/1
990
14V
KA
Den
tale
xtra
ctio
ns12
Tre
atm
ent:
cont
inue
VK
AN
otsp
ecifi
ed0
Tre
atm
ent:
0/12
Tre
atm
ent:
1/12
(8.3
%)
Tre
atm
ent:
0/12
2C
ontr
ol:s
top
VK
A�
tran
exam
icac
id�
sutu
res
Con
trol
:0/2
Con
trol
:0/2
Con
trol
:0/2
*See
Tab
les
4,5
for
expa
nsio
nof
abbr
evia
tions
.MI
�m
yoca
rdia
linf
arct
ion;
PAD
�pe
riph
eral
arte
rydi
seas
e.†M
outh
was
h.
326S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 19, 2011chestjournal.chestpubs.orgDownloaded from
usually with pressure at the bleeding site, and doesnot require medical attention.
5.1 Dental Procedures
Minor dental procedures assessed consist of singleor multiple tooth extractions and endodontic (rootcanal) procedures. The studies assessing periproce-dural antithrombotic therapy in patients having den-tal procedures are summarized in Tables 4–7.
5.1.1 Patients Who Are Receiving VKAs
Three randomized trials, summarized in Table 4,involving a total of 270 patients compared continuingVKA therapy with interrupting treatment prior to adental procedure.182–184 In these studies, there wereno episodes of thromboembolism or major bleedingwith either perioperative management strategy. Inone trial that compared continuing VKA vs stoppingtreatment 2 days before the procedure, there weremore clinically relevant nonmajor bleeds in patientswho continued VKA therapy (26.3% vs 13.5%).183 Inanother trial that compared continuing VKA therapyin conjunction with coadministered tranexamic acidmouthwash vs stopping VKA therapy 3 days beforethe procedure, there were fewer clinically relevantnonmajor bleeds in patients who continued VKAtherapy (9.2% vs 15.2%).184
Five randomized trials, summarized in Table 5,compared different prohemostatic drugs in a total of299 patients who continued VKA therapy around thetime of a dental procedure.185–189 In these studies,there were no episodes of thromboembolism ormajor bleeding. In one trial which compared tranex-amic acid mouthwash to saline mouthwash in pa-tients who continued VKA therapy, there were fewerclinically relevant nonmajor bleeds in patients whoreceived tranexamic acid (0% vs 22.2%).189 Anothertrial compared treatment with 2 or 5 days of tranex-amic acid mouthwash before the procedure.186 Inthis study, there was a lower incidence of clinicallyrelevant nonmajor bleeding in patients who received5 days of tranexamic acid (1.9% vs 4.6%). In theother trials, continuing VKA therapy while coadmin-istering a prohemostatic agent was associated with noepisodes of major bleeding although the incidence ofclinically relevant nonmajor bleeding varied acrossstudies.185,187,188
Seven prospective cohort studies, summarized inTable 6, assessed bleeding in patients who continuedVKA therapy during dental extraction and in acontrol group of patients who interrupted VKAtherapy before the procedure.190–196 In one studyinvolving 396 patients, of whom 156 continued VKAtherapy and 240 discontinued this treatment, therewere no major bleeds and the incidence of clinically
Tab
le7—
Coh
ort
Stu
dies
Ass
essi
ngP
rohe
mos
tati
cIn
terv
enti
ons
inP
atie
nts
Und
ergo
ing
Den
tal
Pro
cedu
res:
Cli
nica
lD
escr
ipti
onan
dR
esu
lts
(Sec
tion
5.1)
*
Stud
y
Patie
nts
Typ
eof
Proc
edur
e
Peri
proc
edur
alIn
terv
entio
n
Fol
low
-up,
d
Clin
ical
Out
com
es,N
o./T
otal
No.
Typ
eof
Tre
atm
ent
Indi
catio
nfo
rA
TT
hera
pyN
o.G
roup
Thr
ombo
embo
lism
Eve
nts
Min
orB
leed
ing
Clin
ical
lyR
elev
ant
Non
maj
orB
leed
ing
Maj
orB
leed
Blin
der
etal
207 /
1999
150
VK
AV
TE
�5,
AF
�26
,C
AD
�29
,V
HD
�70
Den
tale
xtra
ctio
ns50
Tre
atm
ent
1:tr
anex
amic
acid
100
Tre
atm
ent
1:4/
50(8
%)
Tre
atm
ent
1:2/
50(4
%)
Tre
atm
ent
1:0/
50
50T
reat
men
t2:
50co
ntro
l:su
rgic
algl
ue
Tre
atm
ent
2:2/
50(4
%)
Tre
atm
ent
2:2/
50(4
%)
Tre
atm
ent
2:0/
50
-ve
cont
rol0
/50
Con
trol
:3/5
0(6
%)
Con
trol
:0/5
0B
odne
ret
al20
8 /19
9869
VK
AV
TE
�14
,A
F�
23,
MH
V�
32
Den
tale
xtra
ctio
ns69
Tre
atm
ent:
cont
inue
VK
A;n
oco
ntro
l10
0T
reat
men
t:3/
69(4
%)
Tre
atm
ent:
0/69
Tre
atm
ent:
0/69
*PA
D�
peri
pher
alar
tery
dise
ase;
Tre
atm
ent�
trea
tmen
tgr
oup;
VH
D�
valv
ular
hear
tdi
seas
e;-v
eco
ntro
l�pa
tient
sno
tre
ceiv
ing
antit
hrom
botic
ther
apy.
See
Tab
les
4,5
for
expa
nsio
nof
abbr
evia
tions
..
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 327S
© 2008 American College of Chest Physicians by guest on October 19, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le8
—C
ohor
tSt
udi
esA
sses
sing
Con
tinu
atio
nof
Ant
ithr
omb
otic
The
rapy
inP
atie
nts
Und
ergo
ing
Der
mat
olog
icP
roce
dure
s:C
lini
cal
Des
crip
tion
and
Res
ult
s(S
ecti
on5.
2)*
Stud
y
Patie
nts
Typ
eof
Proc
edur
e
Peri
proc
edur
alIn
terv
entio
n
Fol
low
-up
Clin
ical
Out
com
es,N
o./T
otal
No.
Typ
eof
Tre
atm
ent
Indi
catio
nfo
rA
ntith
rom
botic
The
rapy
No.
Gro
upT
hrom
boem
bolis
mE
vent
s,%
Min
orB
leed
ing
Clin
ical
lyR
elev
ant
Non
maj
orB
leed
ing
Maj
orB
leed
Alc
alay
212 /
2001
93V
KA
AF
�10
,C
AD
�1,
MH
V�
3,ot
her
�2
Cut
aneo
ussu
rger
ies
16T
reat
men
t:co
ntin
ueV
KA
Not
spec
ified
0T
reat
men
t:0/
16T
reat
men
t:0/
16T
reat
men
t:0/
16
77-v
eco
ntro
lC
ontr
ol:0
/77
Con
trol
:0/7
7C
ontr
ol:0
/77
Bar
tlett
216 /
1999
171
Asp
irin
Not
repo
rted
Cut
aneo
ussu
rger
ies
52T
reat
men
t:co
ntin
ueas
piri
n5–
10d
0T
reat
men
t:1/
52(2
%)
Tre
atm
ent:
2/52
(3.8
%)
Tre
atm
ent:
0/52
119
-ve
cont
rol
Con
trol
:5/1
19(4
.2%
)C
ontr
ol:4
/119
(3.4
%)
Con
trol
:0/1
19
Bill
ings
ley
and
Mal
oney
213 /
1997
306
Not
repo
rted
Cut
aneo
ussu
rger
ies
81T
reat
men
t1:
cont
inue
aspi
rin
1d
0T
reat
men
t1:
17/8
1(2
1%)
Tre
atm
ent
1:1/
81(1
%)
Tre
atm
ent
1:0/
81
VK
A,
aspi
rin
12T
reat
men
t2:
cont
inue
VK
AT
reat
men
t2:
6/12
(50%
)T
reat
men
t2:
1/12
(8%
)T
reat
men
t2:
0/12
213
-ve
cont
rol
Con
trol
:28/
213
(13.
1%)
Con
trol
:1/2
13(0
.5%
)C
ontr
ol:0
/213
Kar
giet
al21
4 /20
0210
2N
otre
port
edC
utan
eous
surg
erie
s37
Tre
atm
ent
1:co
ntin
ueas
piri
n6–
10d
0T
reat
men
t1:
8/37
(21.
6%)
Tre
atm
ent
1:0/
37T
reat
men
t1:
0/37
VK
A,
aspi
rin
21T
reat
men
t2:
cont
inue
VK
AT
reat
men
t2:
7/21
(33.
3%)
Tre
atm
ent
2:5/
21(2
3.8%
)T
reat
men
t2:
0/21
44-v
eco
ntro
lC
ontr
ol:6
/44
(13.
6%)
Con
trol
:0/4
4C
ontr
ol:0
/44
Shal
oman
dW
ong21
7 /20
03
253
Asp
irin
Not
repo
rted
Cut
aneo
ussu
rger
ies
41T
reat
men
t�
cont
inue
das
piri
n3–
6m
o0
Tre
atm
ent-
0/41
Tre
atm
ent:
0/41
Tre
atm
ent:
0/41
212
-ve
cont
rol
Con
trol
:3/2
12(1
.4%
)C
ontr
ol:0
/212
Con
trol
:0/2
12
Syed
etal
215 /
2004
96V
KA
Not
repo
rted
Cut
aneo
ussu
rger
ies
47T
reat
men
t�
cont
inue
dV
KA
Not
spec
ified
0T
reat
men
t:0/
47T
reat
men
t:12
/47
(25.
5%)
Tre
atm
ent:
0/47
49-v
eco
ntro
lC
ontr
ol:0
/49
Con
trol
:3/4
9(6
.1%
)C
ontr
ol:0
/49
*See
Tab
les
4–7
for
expa
nsio
nof
abbr
evia
tions
.
328S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 19, 2011chestjournal.chestpubs.orgDownloaded from
relevant nonmajor or minor bleeding was low inpatients who continued and interrupted VKA ther-apy, at 0% and 0.8%, respectively.194 In anotherstudy that assessed bleeding in 250 patients whounderwent dental extractions during VKA therapyand a control group of 250 patients who had dentalextractions but were not receiving a VKA, there wereno major bleeds reported, and the incidence ofclinically relevant nonmajor bleeding was similar inthe VKA and no VKA groups, of 1.6% and 1.2%,respectively.196 Five additional smaller studies in-volving between 14 and 249 patients provided similarresults, with no major bleeds reported. However,these studies reported incidences of minor bleedingof 0 to 8.3%. In 11 prospective cohort studies,summarized in Table 6, that assessed continuation ofVKA therapy but without a control group, there wereno major bleeds reported.196–206 Two other cohortstudies with a total of 211 patients, summarized inTable 7, assessed different prohemostatic agents inpatients undergoing dental extraction and receiving aVKA.207,208 There were no major bleeds reported,and the incidence of clinically relevant nonmajor andminor bleeding was 0 to 8%.
Taken together, these studies indicate that con-tinuing VKA therapy around the time of a minordental procedure does not confer an increase inclinically important major bleeding. However, thesestudies were not adequately powered to exclude thepossibility that undertaking dental procedures dur-ing VKA therapy confers an increased risk for clini-cally relevant nonmajor or minor bleeding. Untilsuch studies are undertaken, it is reasonable toconsider coadministration of a local prohemostaticagent, which appears to decrease the risk for clini-cally relevant nonmajor and minor bleeding.
5.1.2 Patients Who Are Receiving AntiplateletDrugs
In one small randomized trial of 39 patients thatcompared continuing or interrupting aspirin before adental procedure, there were no major bleeds inboth treatment arms but the incidence of clinicallyrelevant nonmajor bleeding was higher in patientswho continued aspirin therapy (21% vs 10%).209 In acohort study involving 51 patients who continuedaspirin therapy around the time of a dental procedure,there were no major bleeds and clinically relevantnonmajor bleeding occurred in one patient.210
Studies are lacking in regard to patients who arereceiving clopidogrel and require a dental proce-dure, although it is probable that the continuation ofclopidogrel and aspirin in patients undergoing dentalprocedures will increase the risk of bleeding abovethat seen with aspirin alone.211 In high-risk patients
with a coronary stent implanted within the past year,or perhaps at any time in the past in the case of adrug-eluting stent, the risk of stent thrombosis withclopidogrel interruption probably outweighs the riskof procedure-related bleeding associated with con-tinuation of treatment. In lower-risk patients withouta coronary stent, periprocedural management isuncertain, although it is probably reasonable tointerrupt clopidogrel therapy and to continue aspiringiven that combined antiplatelet treatment will in-crease bleeding risk above that of the risk with eitherdrug alone.
Recommendation
5.1. In patients who are undergoing minordental procedures and are receiving VKAs, werecommend continuing VKAs around the timeof the procedure and coadministering an oralprohemostatic agent (Grade 1B). In patientswho are undergoing minor dental proceduresand are receiving aspirin, we recommendcontinuing aspirin around the time of theprocedure (Grade 1C). In patients who areundergoing minor dental procedures and arereceiving clopidogrel, please refer to the rec-ommendations outlined in Section 4.5 andSection 4.6.
5.2 Dermatologic Procedures
Minor dermatologic procedures assessed includeexcisions of basal and squamous cell carcinomas,actinic keratoses, and malignant or premalignantnevi. Studies of periprocedural antithrombotic man-agement are summarized in Table 8.
5.2.1 Patients Who Are Receiving VKAs
Four cohort studies assessed continuing VKA ther-apy around the time of a dermatologic procedure ina total of 96 patients.212–215 In one study that as-sessed 47 patients who continued VKA therapy (and49 control patients who were not receiving VKAtherapy at the time of procedure), there were nomajor bleeds but the incidence of clinically rele-vant nonmajor bleeding was higher in patientswho continued VKA therapy (25.5% vs 6.1%).215
There were similar findings in two other cohortstudies,213,214 whereas no bleeds were reported ina third study involving 16 patients who continuedVKA therapy.212
5.2.2 Patients Who Are Receiving AntiplateletDrugs
Four cohort studies assessed continuing aspirintherapy around the time of a dermatologic procedure
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 329S
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in a total of 211 patients.213,214,216,217 There were nomajor bleeds associated with continuing aspirin. Intwo studies, minor bleeding was more frequent inpatients who continued aspirin around the time of theprocedure compared to patients who were not receiv-ing aspirin (21% vs 13%, respectively; 21.6% vs 13.6%,respectively).213,214 However, in two other cohort stud-ies the incidence of minor bleeding appeared compa-rable in patients who received or who did not receiveaspirin around the time of the procedure (1.9% vs4.2%, respectively; 0% vs 1.4%, respectively).216,217
Data for patients who are receiving clopidogreland require dermatologic procedures are limited tocase reports of patients who developed thromboem-bolic events during antiplatelet therapy interrup-tion.218 Periprocedural management in such patientscan follow that in patients undergoing dental orother minor procedures.
Recommendation
5.2. In patients who are undergoing minor der-matologic procedures and are receiving VKAs, werecommend continuing VKAs around the time ofthe procedure (Grade 1C). In patients who areundergoing minor dermatologic procedures andare receiving aspirin, we recommend continuingaspirin around the time of the procedure (Grade1C). In patients who are undergoing minor der-matologic procedures and are receiving clopi-dogrel, please refer to the recommendations out-lined in Section 4.5 and Section 4.6.
5.3 Ophthalmologic Procedures
Minor ophthalmologic procedures assessed aredominated by cataract extraction, which was under-taken in � 90% of patients studied. A small minorityof patients studied had vitreoretinal or other oph-thalmologic procedures. Our recommendations,therefore, pertain to patients undergoing cataractextraction. These studies are summarized in Table 9.
5.3.1 Patients Who Are Receiving VKAs
Six prospective cohort studies assessed bleeding inpatients who continued VKA therapy during oph-thalmologic surgery and in a control group of pa-tients who were either not receiving VKA therapy orwho interrupted VKA therapy before surgery.219–224
Two other prospective cohort studies assessed bleed-ing in patients who continued VKA therapy duringophthalmologic surgery but did not have a controlgroup.225,226 In one prospective cohort study assess-ing patients who had cataract surgery, there was noapparent increase in arterial thromboembolic events
in 208 patients who discontinued VKAs compared to526 patients who continued VKAs and the incidenceof such events appeared higher in patients whocontinued VKAs (1.14% vs 0.48%).221 In these pa-tients, there were no major or clinically relevantnonmajor bleeds. In another cohort study involving639 patients who continued VKAs and 1,203 controlswho were not taking VKAs around the time ofcataract surgery, there were no arterial thromboem-bolic events.219 There appeared to be a higherincidence of clinically relevant nonmajor bleeding(0.16% vs 0.08%) and minor bleeding (1.41% vs0.67%) in patients who continued VKAs althoughthere were no major bleeds reported. While othersmaller cohort studies demonstrated similar re-sults,225,226 one cohort study involving 125 patientswho had cataract surgery reported a high rate ofmajor bleeding (8.7%).224
5.3.2 Patients Who Are Receiving AntiplateletDrugs
A prospective cohort study assessing patients whounderwent cataract surgery found no important in-crease in arterial thromboembolic events in 977patients who interrupted aspirin compared to 3,363patients who continued aspirin (0.20% vs 0.65%).221
In these patients, there were no major or clinicallyrelevant nonmajor bleeds and marginally higherclinically relevant nonmajor bleeds in patients whocontinued aspirin (0.06% vs 0%). Other studiesreported similar results in patients undergoing cata-ract or vitreoretinal surgery.222,223
There are few data in regard to the safety ofcontinuing clopidogrel in patients undergoing oph-thalmologic surgery. One study of patients undergo-ing cataract surgery found that although subconjunc-tival hemorrhage was more common in patients whowere receiving either clopidogrel or warfarin thanaspirin or no antithrombotic drugs, there were nosight-threatening bleeding complications.227 Onestudy described a patient who was receiving aspirinand clopidogrel and underwent an intracapsularextraction and anterior vitrectomy in whom thepostoperative course was complicated by extensivehyphema and vitreous hemorrhage that clearedwithin 3 months.228 As with other minor procedures,perioperative management will be driven by throm-boembolic risk.
Recommendation
5.3. In patients who are undergoing cataractremoval and are receiving VKAs, we recom-mend continuing VKAs around the time of theprocedure (Grade 1C). In patients who are un-
330S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 19, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le9
—C
ohor
tSt
udi
esA
sses
sing
Con
tinu
atio
nof
Ant
ithr
omb
otic
The
rapy
inP
atie
nts
Und
ergo
ing
Oph
thal
mol
ogic
Surg
ery:
Cli
nica
lD
escr
ipti
onan
dR
esu
lts
(Sec
tion
5.3)
*
Stud
y
Patie
nts
Typ
eof
Proc
edur
e
Peri
proc
edur
alIn
terv
entio
n
Fol
low
-up
Clin
ical
Out
com
es,N
o./T
otal
(%)
No.
Typ
eof
Tre
atm
ent
Indi
catio
nfo
rA
ntith
rom
botic
The
rapy
No.
Gro
upT
hrom
boem
bolis
mE
vent
sM
inor
Ble
edin
g
Clin
ical
lyR
elev
ant
Non
maj
orB
leed
ing
Maj
orB
leed
Hir
schm
anan
dM
orby
219/2
006
1,84
2V
KA
Not
repo
rted
Cat
arac
tsu
rger
y63
9T
reat
men
t:co
ntin
ueV
KA
10d
0T
reat
men
t-9/
639
�1.
4%T
reat
men
t:1/
63(0
.16%
)T
reat
men
t:0/
639
1,20
3-v
eco
ntro
lC
ontr
ol:8
/120
3(0
.7%
)C
ontr
ol:1
/120
3(0
.08%
)C
ontr
ol:0
/120
3
Kal
lioet
al220/
2000
1,16
7V
KA
,asp
irin
Not
repo
rted
Cat
arac
tsu
rger
y(�
80%
)
482
Tre
atm
ent
1:st
opas
piri
nda
y�
3ltr
eatm
ent
2:st
opV
KA
day
�2
Not
spec
ified
0T
reat
men
t1:
18/
482
(3.7
%);
trea
tmen
t2:
3/76
(3.9
%)
Tre
atm
ent
1:0/
482;
trea
tmen
t2:
0/76
Tre
atm
ent
1:0/
482;
trea
tmen
t2:
0/76
76-v
eco
ntro
lC
ontr
ol:2
5/60
9(4
.1%
)C
ontr
ol:0
/609
Con
trol
:0/6
09
Kat
z etal
221/
2003
37,6
11V
KA
,asp
irin
VT
E�
206,
CA
D�
793,
stro
ke�
738,
VH
D�
248,
CA
D�
2,04
0,ot
her
�16
9
Cat
arac
tsu
rger
y3,
363
Tre
atm
ent
1:co
ntin
ueas
piri
n10
dT
reat
men
t1:
22/
3,36
3(0
.65%
)T
reat
men
t1:
0/3,
363
Tre
atm
ent
1:2/
3,36
3(0
.06%
)T
reat
men
t1:
0/3,
363
977
Tre
atm
ent
2:st
opas
piri
nT
reat
men
t2:
2/97
7(0
.20%
)T
reat
men
t2:
0/97
7T
reat
men
t2:
0/97
7T
reat
men
t2:
0/97
714
,322
-ve
cont
rola
spir
inC
ontr
olas
piri
n:33
/14,
322
(0.2
3%)
Con
trol
aspi
rin:
3/14
,322
(0.0
2%)
Con
trol
aspi
rin:
5/14
,322
(0.0
3%)
Con
trol
aspi
rin:
0/14
,322
526
Tre
atm
ent
3:co
ntin
ueV
KA
Tre
atm
ent
4:6/
526
(1.1
4%)
Tre
atm
ent
4:0/
526
Tre
atm
ent
4:0/
526
Tre
atm
ent
4:0/
526
208
Tre
atm
ent
4:st
opV
KA
Tre
atm
ent
5:1/
208
(0.4
8%)
Tre
atm
ent
5:0/
208
Tre
atm
ent
5:0/
208
Tre
atm
ent
5:0/
208
18,2
15-v
eco
ntro
lVK
AC
ontr
olV
KA
:52/
18,2
15(0
.29%
)C
ontr
olV
KA
:3/
18,2
15(0
.02%
)C
ontr
olV
KA
:7/
18,2
15(0
.04%
)C
ontr
olV
KA
:0/
18,2
15L
umm
ean
dL
aatik
aine
n222/
1994
351
VK
A,a
spir
inN
otre
port
edC
atar
act
surg
ery
54T
reat
men
t1:
cont
inue
aspi
rin
At
leas
t3
d0
Tre
atm
ent
1:6/
54(1
1.1%
)T
reat
men
t1:
0/54
Tre
atm
ent
1-0/
54
17T
reat
men
t2:
stop
VK
AT
reat
men
t2:
0/17
Tre
atm
ent
2:3/
17(1
7.6%
)T
reat
men
t2-
0/17
208
-ve
cont
rol
Con
trol
:21/
208
(10.
1%)
Con
trol
:0/2
08C
ontr
ol-
0/20
8
Nar
endr
anan
dW
illia
mso
n223/
2003
541
VK
A,a
spir
inV
TE
�1,
Vitr
eore
tinal
surg
ery
60T
reat
men
t1:
cont
inue
aspi
rin
Not
spec
ified
0T
reat
men
t1:
0/60
Tre
atm
ent
1:2/
60(3
.3%
)T
reat
men
t1-
0/60
AF
�2,
7T
reat
men
t2:
stop
VK
AT
reat
men
t2:
1/7
(14.
3%)
Tre
atm
ent
2:1/
7(1
4.3%
)T
reat
men
t2-
1/7
�14
.3%
MH
V�
3,O
ther
�1
474
-ve
cont
rol
Con
trol
:10/
474
(2.1
%)
Con
trol
:0/4
74C
ontr
ol:0
/474
Rob
erts
etal
225/
1991
31V
KA
,asp
irin
,di
pyri
dam
ole,
sulfi
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dergoing cataract removal and are receivingaspirin, we recommend continuing aspirinaround the time of the procedure (Grade 1C). Inpatients who are undergoing cataract removaland are receiving clopidogrel, please refer tothe recommendations outlined in Section 4.5and Section 4.6.
6.0 Perioperative Management ofAntithrombotic Therapy Patients Who
Require Urgent Surgical or OtherInvasive Procedures
6.1 Patients Who Are Receiving VKAs
In the nonbleeding patient who requires rapid(within 12 h) reversal of the anticoagulant effect ofVKAs because of an urgent surgical or other invasiveprocedure, treatment options that have been as-sessed in observational studies include fresh-frozenplasma, prothrombin concentrates, and recombinantfactor VIIa.229 No randomized trials, to date and toour knowledge, have compared these treatments inpatients who require urgent reversal of anticoagula-tion.230 In addition to these treatment options, allpatients should receive vitamin K, at a dose of 2.5 to5.0 mg po or by slow IV infusion.231 Administeringfresh-frozen plasma, prothrombin concentrates, orrecombinant factor VIIa alone will temporarily over-ride but will not eliminate the anticoagulant effect ofVKAs, which persist until VKAs are endogenouslymetabolized or neutralized by vitamin K. For exam-ple, as fresh-frozen plasma has an elimination half-life of 4 to 6 h, not administering vitamin K will leadto reemergence of a VKA-associated anticoagulanteffect within 12 to 24 h. If surgery is urgent but canbe delayed for 18 to 24 h, the anticoagulant effect ofVKAs is likely to be neutralized by IV vitamin K, ata dose of 2.5 to 5.0 mg without the need for bloodproduct or recombinant factor VII administra-tion.230,232
Recommendation
6.1. In patients who are receiving VKAs andrequire reversal of the anticoagulant effect foran urgent surgical or other invasive procedure,we suggest treatment with low-dose (2.5 to 5.0mg) IV or oral vitamin K (Grade 1C). For moreimmediate reversal of the anticoagulant effect,we suggest treatment with fresh-frozen plasmaor another prothrombin concentrate in additionto low-dose IV or oral vitamin K (Grade 2C).
6.2 Patients Who Are Receiving Antiplatelet Drugs
There is no pharmacologic agent that can reversethe antithrombotic effect of aspirin, clopidogrel, or
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ticlopidine, which irreversibly inhibit platelet func-tion. Consequently, patients who require an urgentsurgical or other invasive procedure that requiresnormalized platelet function may receive transfusedplatelets, which would not be affected by prioradministration of antiplatelet drugs.233 However, theefficacy and safety of platelet transfusion in patientswho are not thrombocytopenic and who require anurgent surgical or other invasive procedure are notknown. One randomized trial in 11 healthy volun-teers who received aspirin (325 mg loading dose, 81mg maintenance dose) and clopidogrel (300-mg or600-mg loading dose, 75-mg maintenance dose)found that subsequent transfusion of 12.5 U plateletsled to normalized platelet function as determined byplatelet function assays.234 However, studies to as-sess the efficacy and safety of a platelet transfusion toneutralize the antiplatelet effects of aspirin or clopi-dogrel in the perioperative setting are lacking. Untilsuch studies are done, it is reasonable to limitplatelet transfusion to those patients who have ex-cessive or life-threatening bleeding in the perioper-ative period.
Potential alternatives to platelet transfusion inpatients who have been exposed to antiplateletdrugs are prohemostatic agents. These includeε-aminocaproic acid and tranexamic acid, which areantifibrinolytic agents, and 1-deamino-8-D-argininevasopressin, which increases plasma levels of vonWillebrand factor and associated coagulation factorVIII. These agents may improve platelet function inpatients who have been exposed to antiplateletdrugs.235 However, outside of the setting of cardiacsurgery, these drugs have not been widely stud-ied113,236 and should be limited to patients who haveexcessive or life-threatening perioperative bleedingbecause of potential prothrombotic effects.
Recommendation
6.2. For patients receiving aspirin, clopidogrel,or both, are undergoing surgery and have ex-cessive or life-threatening perioperative bleed-ing, we suggest transfusion of platelets or ad-ministration of other prohemostatic agents(Grade 2C).
Conflict of Interest Disclosures
Dr. Ansell discloses that he has received consultant fees fromBristol-Myers Squibb, Roche Diagnostics, and InternationalTechnidyne Corporation. He is also on the speakers bureau forRoche Diagnostic Corporation and Sanofi-Aventis, and is the pastpresident of the Anticoagulation Forum.
Dr. Douketis reveals no real or potential conflicts of interestor commitment.
Dr. Dunn discloses that he received grant monies from and ison the speakers bureau for Sanofi-Aventis. He has also served onadvisory committees for Sanofi-Aventis, Eisai, and Roche Diag-nostics.
Dr. Jaffer discloses that he has received consultant fees fromSanofi-Aventis and AstraZeneca, and that he is on the speakersbureau for Sanofi-Aventis.
Dr. Becker reveals no real or potential conflicts of interest orcommitment.
Dr. Spyropoulos discloses that he has received consultantfees from Boehringer Ingelheim, and has served on the speakersbureau for Sanofi-Aventis and Eisai.
Dr. Berger discloses that he has spoken at Council on MedicalEducation-approved scientific symposia supported by Bristol-Myers Squibb, Sanofi-Aventis, the Medicines Company, Astra-Zeneca, Medtronic, Schering-Plough, Lilly, and Daiichi Sankyo.He has served as a consultant for PlaCor, Lilly, Daiichi Sankyo,Molecular Insight Pharmaceuticals, and CV Therapeutics. Dr.Berger also owns equity in Lumen, Inc (a company that isdeveloping an embolic protection device).
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