Journal of Clinical Anesthesia (2016) 34, 586–599
Review article
Risk stratification, perioperative and periprocedural management of the patient receiving anticoagulant therapy☆,☆☆,★,★★ Adriana D. Oprea MD (Assistant Professor of Anesthesiology)⁎, Christopher J. Noto MD (Assistant Professor of Anesthesiology), Thomas M. Halaszynski DMD, MD, MBA (Associate Professor of Anesthesiology) Yale University School of Medicine, New Haven, CT Received 7 January 2016; revised 2 June 2016; accepted 7 June 2016
Keywords: Anticoagulation; Bridging therapy; Perioperative period
Abstract As a result of the aging US population and the subsequent increase in the prevalence of coronary disease and atrial fibrillation, therapeutic use of anticoagulants has increased. Perioperative and periprocedural management of anticoagulated patients has become routine for anesthesiologists, who frequently mediate communication between the prescribing physician and the surgeon and assess the risks of both thromboembolic complications and hemorrhage. Data from randomized clinical trials on perioperative management of antithrombotic therapy are lacking. Therefore, clinical judgment is typically needed regarding decisions to continue, discontinue, bridge, or resume anticoagulation and regarding the time points when these events should occur in the perioperative period. In this review, we will discuss the most commonly used anticoagulants used in outpatient settings and discuss their management in the perioperative period. Special considerations for regional anesthesia and interventional pain procedures will also be reviewed. © 2016 Elsevier Inc. All rights reserved.
1. Introduction Use of prophylactic or therapeutic regimens of antithrombotics has increased because of the rise in prevalence of
☆
Disclaimers: none. Reprints: none applicable. ★ Financial support: none. ★★ Conflicts of interest: none. ⁎ Corresponding author at: Department of Anesthesiology, Yale University, 333 Cedar St, TMP 3, PO Box 208051, New Haven, CT 06520- 8051. Tel.: +1 203 785 2802; fax: +1 203 785 6664. E-mail address:
[email protected] (A.D. Oprea). ☆☆
http://dx.doi.org/10.1016/j.jclinane.2016.06.016 0952-8180/© 2016 Elsevier Inc. All rights reserved.
coronary artery disease, atrial fibrillation (AF), and other risk factors of the aging US population [1]. Perioperative and periprocedural management of anticoagulated patients has become routine for anesthesiologists, who frequently mediate communication between the prescribing physician and the surgeon and also assess risks of both thromboembolic and hemorrhagic complications. Data from randomized clinical trials on perioperative management of antithrombotic therapy are lacking. Therefore, clinical judgment is required regarding decisions to continue, discontinue, bridge, or resume anticoagulation and the time points when these events should occur in the perioperative period [2,3]. This review discusses the commonly used anticoagulants with emphasis on safe management and appropriate decision-making alternatives in the surgical
Perioperative management of anticoagulants setting. Special considerations for regional anesthesia and interventional pain procedures have also been reviewed.
2. Anticoagulants Unfractionated heparin (UFH) activates antithrombin III (ATIII) and accelerates the rate of inhibition of thrombin (factor IIa) and factor Xa. Therapeutic heparin levels are achieved by a 2- to 3-fold prolongation of the activated partial thromboplastin time (aPTT) or anti–factor Xa levels between 0.3 and 0.7 U/mL. Anticoagulation with heparin can be neutralized by protamine administration. Dosing protamine depends on both the route and time elapsed since the last heparin administration. For example, if 100 U of heparin is given subcutaneously, then 1-1.5 mg of protamine should be used for reversal. Similarly, if 100 U of heparin is administered intravenously, 1-1.5 mg of protamine should be used for reversal if heparin administration has occurred within the last 30 minutes; however, a smaller dose of protamine (0.25-0.375 mg) is required if N2 hours have elapsed since the last heparin administration. A potential complication of heparin administration is thrombocytopenia, the most serious form being heparininduced thrombocytopenia (HIT) thrombosis syndrome or HIT type II. HIT type I (non–immune mediated) can result in a mild decrease in platelet count but does not usually incur significant bleeding risks. However, patients with HIT type II (immune mediated) can have dangerously low platelet counts that occur 5-14 days after following initiation of heparin therapy [4]. There are also exceptions where HIT type II can occur either sooner or later than the time frame described above [4]. Low–molecular weight heparin (LMWH) has replaced UFH in many clinical situations and is typically administered subcutaneously. Enoxaparin (Lovenox, Sanofi) and dalteparin (Fragmin, Pfizer Inc) have several advantages over UFH such as dose-independent clearance, a more predictable anticoagulant response, improved bioavailability following subcutaneous injection, and lower risks of osteoporosis and HIT [5]. LMWH mechanism of action involves activating ATIII and subsequently inhibiting factor Xa, with little effect on thrombin inhibition. LMWH does not usually require monitoring of coagulation tests, but when necessary, anti–factor Xa levels should be measured, as LMWH has little effect on the aPTT. For LMWH prophylaxis, anti– factor Xa levels of 0.2-0.5 U/mL are desired, but levels should range between 0.5 and 1.2 U/mL for therapeutic anticoagulant effects [6]. Monitoring anti-Xa levels is indicated in patients with renal insufficiency who have received LMWH, but data do not support monitoring anti–factor Xa levels in obese patients [7]. Although protamine has been used to reverse effects from LMWH administration, it does not completely neutralize its anticoagulant activity because protamine only binds to the longer chains of LMWH.
587 Fondaparinux (Arixtra, GlaxoSmithKline) is indicated as an alternative to heparin or LMWH for initial treatment of venous thromboembolism (VTE) and for thromboprophylaxis in medical, surgical, and high-risk orthopedic patients. Fondaparinux exerts its effect through factor Xa inhibition and exhibits complete bioavailability following subcutaneous injection. Its plasma half-life is 17 hours, and because it does not bind to endothelial cells or plasma proteins, its clearance is dose independent [5]. In addition, fondaparinux is eliminated unchanged by the kidneys; therefore, it is contraindicated in patients with renal insufficiency. Warfarin (Coumadin, Bristol-Myers Squibb; Jantoven, Upsher-Smith Laboratories, Inc) interferes with the synthesis of vitamin K–dependent clotting proteins (factors II, VII, IX, and X). Because there is a delay in achieving antithrombotic effect with initiation of warfarin therapy, it is often combined with concomitant administration of a more rapidly acting parenteral anticoagulant such as heparin, LMWH, or fondaparinux. Warfarin is rapidly absorbed from the gastrointestinal tract, and its levels within plasma peak in approximately 90 minutes following administration; its plasma half-life is 36-42 hours [8]. Warfarin is metabolized in the liver by the cytochrome P 450 system, and agents that either induce or inhibit cytochrome P 450 can alter warfarin metabolism and its clinical effects. Monitoring warfarin treatment can be performed by measuring the prothrombin time (PT). The PT test measurement uses thromboplastin as its reagent, but because different thromboplastins have variable sensitivities to levels of vitamin K–dependent clotting factors, PT results can vary depending on the reagent used. Therefore, the international normalized ratio (INR) was introduced to monitor the effects of warfarin. For most clinical situations, warfarin is administered in doses to achieve a target INR of 2.0-3.0. The exceptions are in patients with mechanical mitral heart valves, older aortic mechanical valves (ball-in-cage, disk tilting), and newergeneration aortic mechanical valves in the presence of additional risk factors for thromboembolism (AF, previous thromboembolic event, left ventricular dysfunction, or hypercoagulable state), where a higher target INR (2.5-3.5) is recommended. The new oral anticoagulants (NOACs) available in the United States include dabigatran (direct thrombin inhibitor) and several anti-Xa agents (rivaroxaban, apixaban, and edoxaban) (Table 1). The NOACs have a rapid onset of action, with peak anticoagulant effects achieved within 1-4 hours, thereby reducing the need for temporary parenteral anticoagulation. Dabigatran (Pradaxa, Boehringer Ingelheim) is an oral direct thrombin inhibitor with a half-life of 12-14 hours and maximum anticoagulant effect achieved within 2-3 hours of ingestion. The predominant elimination pathway is by unchanged renal excretion; therefore, clearance can be longer in older adults and in those with reduced renal function. Monitoring of coagulation is not typically performed in patients taking dabigatran (INR should not be used to monitor therapy) [9].
588 Table 1
A.D. Oprea et al. Oral anticoagulants: properties and indications
Drug
Mechanism
Half-life
Time to peak serum level
Metabolism
Indications
Warfarin
Vitamin K antagonist
36-42 h
90 min
Hepatic, oxidative metabolism
Rivaroxaban
Factor Xa inhibitor
7-11 h
2-4 h
33% renal (remainder metabolized to inactive molecules and eliminated in the feces and urine)
Apixaban
Factor Xa inhibitor
8-15 h
3-4 h
25% renal
DVT/PE treatment DVT prophylaxis AF (valvular and nonvalvular) DVT prophylaxis after knee/hip surgery DVT/PE treatment Nonvalvular AF DVT prophylaxis after knee/hip surgery DVT/PE treatment Nonvalvular AF DVT/PE treatment Nonvalvular AF DVT/PE treatment Nonvalvular AF
75% intestinal Edoxaban Dabigatran
Factor Xa inhibitor Direct thrombin inhibitor
9-10 h
1-2 h
12-14 h
2-3 h
Rivaroxaban (Xarelto, Bayer) is an oral direct factor Xa inhibitor with a bioavailability of 80%, reaching peak plasma concentration within 2-4 hours following administration. It has a half-life of 7-11 hours in patients with normal renal function, and it is not recommended in patients with renal insufficiency or those with significant hepatic impairment (because of a prolonged half-life) [8]. Apixaban (Eliquis, Bristol-Myers Squibb) is a direct and selective inhibitor of factor Xa that reaches peak plasma concentrations in approximately 3 hours and has a half-life of 815 hours. It is approved for use in AF and treatment of VTE. Apixaban is mostly eliminated through hepatic metabolism and the fecal route with about 25% excreted renally [10]. Edoxaban (Savaysa, Daiichi Sankyo) is another direct factor Xa inhibitor with a peak plasma concentration of 1-2 hours following administration and a half-life of 9-10 hours. It is indicated for extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5-10 days of initial therapy with another parenteral anticoagulant. Edoxaban is not recommended in patients with a creatinine clearance (Cr Cl) N 95 mL/min because of decreased effectiveness and increased risk of ischemic stroke in patients with nonvalvular AF when compared with warfarin. Approximately 50% of the drug is excreted by the kidneys, with the remainder eliminated through metabolism and biliary excretion [11].
3. Perioperative management of anticoagulants Clinicians must always assess the risks of thrombosis associated with discontinuing antithrombotic medications against risk of potential bleeding inherent to the proposed procedure. Management of patients on warfarin therapy differs significantly from those taking NOACs. Warfarin is typically discontinued 5-7 days before surgery to allow for INR normalization,
50% renal 50% metabolism and bile excretion 80% renal
but there may be a thrombotic risk during discontinuation, so clinicians must decide whether “bridging” therapy should be considered (ie, short-acting parenteral medications such as LMWH or UFH). However, given the short half-life of NOACs, these can be stopped within a shorter time period before any planned procedure or surgery without a need for bridging therapy under most clinical situations. Perioperative management of patients prescribed both vitamin K antagonists and NOACs should follow a stepwise approach described as: • Step 1: Assess bleeding risks (ie, does the anticoagulant need to be stopped for proposed procedure/surgery, or can the procedure be performed with patients continuing oral anticoagulants?) and also decide upon the duration of preoperative interruption of antithrombotic agent. • Step 2: Define thrombotic risks (ie, risk of a thromboembolic event due to perioperative interruption of anticoagulation). • Step 3: Consider bridging therapy, particularly for patients taking warfarin (patients at high risk of a thromboembolic event from perioperative interruption of anticoagulation should be considered for bridging therapy).
3.1. Management of patients on warfarin 3.1.1. Step 1: assessing bleeding risk(s) Assessment of risk involves an understanding of both patient comorbidities and the invasive nature of any proposed intervention. There are no clear or validated predictors for risk(s) of bleeding during the perioperative period, but there is evidence linking active cancer, thrombocytopenia (platelets b150 K), presence of a mechanical mitral valve, and a history of bleeding to an increased risk of perioperative/periprocedural bleeding [12].
Perioperative management of anticoagulants
Table 2
589
Bleeding risk based on the procedure (adapted with permission from Baron et al [16]
Procedure
Low bleeding risk (b1.5%)
High bleeding risk (1.5% or in vulnerable areas)
Anesthesiology Cardiac surgery Cardiovascular
Endotracheal intubation None Diagnostic coronary angiography (controversial)
Spinal and epidural anesthesia All Pacemaker or defibrillator placement (3.5% on warfarin therapy, 16% with bridging anticoagulation) Coronary intervention Electrophysiology testing and/or ablation Reconstructive procedures
Dental
Tooth extraction Endodontic procedures (root canal) Dermatology Minor skin procedures (excision of basal and squamous cell cancers, nevi, actinic keratoses, premalignant lesions) Gastroenterology Passage of endoscope for diagnostic purposes (including balloon enteroscopy) with or without mucosal biopsy Endoscopic retrograde cholangiopancreatography without sphincterotomy Endoscopic ultrasound without fine-needle aspiration Nonthermal (cold) snare removal of small polyps Lumenal self-expanding metal stent placement (controversial)
General surgery
Suture of superficial wounds
Gynecologic surgery
Diagnostic colposcopy Hysteroscopy Dilation and curettage Endometrial biopsy Insertion of intrauterine device Simple catheter exchange in well-formed, nonvascular tracts (eg, gastrostomy, nephrostomy, cholecystostomy tubes) Thoracentesis
Interventional radiology
Intravascular procedures Neurology
Neurosurgery Ophthalmology
Paracentesis Aspiration of abdominal or pelvic abscesses, placement of small-caliber drains Peripheral catheter placement, nontunneled catheter (peripherally inserted central catheter) placement Inferior vena cava filter placement Temporary dialysis catheter placement Venous access None
None Cataract surgery Intraocular injections (Avoid retrobulbar anesthesia; controversial)
Major procedures (wide excision of melanoma) Large polypectomy (N1 cm) Endoscopic mucosal and submucosal dissection Biliary or pancreatic sphincterotomy Percutaneous endoscopic gastrostomy Endoscopic ultrasound with fine-needle aspiration or needle biopsy Coagulation or ablation of tumors, vascular lesions Percutaneous liver biopsy Variceal band ligation (controversial) Major tissue injury Vascular organs (spleen, liver, kidney) Bowel resection Laparoscopy Laparoscopic surgery Bilateral tubal ligation Hysterectomy
Percutaneous transhepatic cholangiography or nephrostomy Percutaneous drainage of liver abscess or gallbladder Chest tube placement Aggressive manipulation of drains or dilation of tracts Biopsy of organs Hickman and tunneled dialysis catheter placement Arterial puncture Transvenous ablation Lumbar puncture Myelography Needle electromyography (controversial) Intracranial, spinal surgery Periorbital surgery Vitreoretinal surgery (continued on next page)
590
A.D. Oprea et al.
Table 2 (continued) Procedure
Low bleeding risk (b1.5%)
High bleeding risk (1.5% or in vulnerable areas)
Orthopedic surgery Otolaryngologic surgery
Arthrocentesis
Joint replacement Arthroscopy Any sinus surgery Biopsy or removal of nasal polyps Thyroidectomy Parotidectomy Septoplasty Turbinate cautery Reconstruction Tumor ablation (laser) Transbronchial biopsy Stricture dilation None Extracorporeal shock-wave lithotripsy Transurethral prostatectomy Bladder resection Tumor ablation Kidney biopsy Carotid endarterectomy Open or endovascular aneurysm repair Vascular bypass grafting
Plastic surgery Pulmonary
Rheumatology Urology
Vascular
Diagnostic fiberoptic laryngoscopy or nasopharyngoscopy Sinus endoscopy Fine-needle aspiration Vocal cord injection
Injection therapy Diagnostic bronchoscopy with or without bronchioalveolar lavage Endobronchial fine-needle aspirate (controversial) Airway stent placement (controversial) Arthrocentesis Circumcision Cystoscopy without biopsy
None
The HAS-BLED score was developed in nonoperative and nonprocedural settings to facilitate the decision of whether to initiate anticoagulation in patients with AF. Additionally, the HAS-BLED score has been found to be useful in assessing the bleeding risk when bridging therapy is being considered [13]. The score takes into account a history of Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition toward bleeding, Labile INR values, Elderly (N65 years), and concomitant use of Drugs/alcohol [14,15]. Current evidence supports that procedures with a low risk of bleeding (b1.5%) can be performed without interruption of warfarin (ie, an INR of 2.5 or less is accepted as safe) [16]. Minor dermatologic procedures such as removal of squamous or basal cell carcinomas and treatment for actinic keratosis can be safely performed with higher INR values (b3.5) [17]. Patients undergoing mild- to moderate-risk dental procedures (extractions, biopsies, and periodontal surgical procedures) may continue their warfarin therapy as long as the INR is b4 [18,19]. Cataract surgery and joint injections can also be performed without discontinuing warfarin therapy [20,21]. Endoscopic procedures (respiratory or gastroenterologic) are safe in those taking warfarin as long as there is no planned mucosal disruption [22,23]. Warfarin therapy should be discontinued for surgical procedures that carry an intermediate to high risk of bleeding (N1.5%), with treatment typically discontinued 5 days before the proposed procedure for the INR to normalize [20]
(Table 2). The rate of declining INR values following discontinuation is related to the initial INR value rather than the prescribed dose of warfarin [24]. Patients maintained at higher INR values (3-4), as well as the elderly patient population, often require a longer interruption period [25]. Normal hemostasis has been demonstrated with INR levels between 1 (100% clotting factor activity) and 2 (30% clotting factor activity). Despite that, an INR of b1.5 is currently accepted for most interventions [16,26]. However, patients scheduled for very high risk procedures (intracranial, neuraxial anesthesia) should have a normal INR documented on the day of surgery [27]. It is possible for the INR to be elevated despite holding warfarin for 5-7 days before scheduled intervention(s). If the INR is measured to be between 1.4 and 1.9 the day before the planned procedure, then administering a small oral dose of vitamin K (1-2.5 mg) may be helpful [28,29]. 3.1.1.1. Special considerations for high-risk bleeding procedures. For certain high-risk bleeding procedures (N1.5%), it has been recommended that warfarin therapy should be continued instead of initiating bridging therapy with LMWH because of an increased risk of bleeding with the latter. During AF ablation procedures, the recommendation is to continue warfarin administration (target INR between 2 and 3), instead of starting bridging therapy, to reduce the risks of both periprocedural stroke and bleeding that can be associated with LMWH [30,31]. Pacemaker and defibrillator implantation may also be performed without interruption of
Perioperative management of anticoagulants
591
warfarin administration, as bridging therapy can lead to a higher risk of implant pocket hematoma formation [32]. 3.1.2. Step 2: defining the thrombotic risk and considerations for bridging The 2012 American College of Chest Physicians EvidenceBased Clinical Practice Guidelines, 9th Edition, on perioperative management of antithrombotic therapy (2012 ACCP guidelines) provide a framework for managing patients taking anticoagulation medication and scheduled for elective surgery [20]. These guidelines stratify patients based on the indication for warfarin therapy (AF, presence of mechanical heart valves, and history of DVT or PE) and potential thrombotic risk (Table 3). Patients in the high-risk category have an annual risk of thrombosis of N10%, those within the moderate risk category have a 5%-10% risk, and patients in the low-risk category have b5% risk of thrombosis [2,20]. 3.1.2.1. Warfarin for treatment of AF. Atrial fibrillation is the most commonly encountered cardiac arrhythmia diagnosed in elderly patients, with a 5%-8% annual risk of stroke in the absence of anticoagulation. This risk can decrease to 1.6% in those treated with warfarin [33]. The risk of stroke during interruption of warfarin therapy can be estimated using the CHADS2 and CHA2DS2-VASc scores; however, these parameters have not been validated in the perioperative setting (Table 4). One attributing factor is that iatrogenic trauma from surgery induces a proinflammatory and prothrombotic state capable of resulting in an increased risk of stroke in the presence of AF [34,35]. The CHA2DS2-VASc is more discriminating than the CHADS2 score when identifying patients at low risk for thromboembolism (CHA2DS2-VASc of 0) vs at intermediate risk in the setting of AF [36]. Evidence indicates that CHA2DS2-VASc is superior in identifying which patients should receive anticoagulation. However, the CHADS2 score is more useful in determining whether bridging should be initiated. Based on the 2012 ACCP guidelines, patients with CHADS2 scores of 0-2 do not require bridging therapy, but patients with CHADS2 scores of 5-6 can benefit from such Table 3
Table 4 CHADS2 and CHA2DS2-VASc risk stratification scores for subjects with nonvalvular AF CHADS2 CHA2DS2 score VASc score C: Congestive heart failure H: Hypertension A: Age ≥ 75 y D: Diabetes S: Stroke/TIA V: Vascular disease (prior MI, PAD, or aortic plaque) A: Age 65-74 y S: Sex category (female sex) Maximum score
1 1 1 1 2
6
1 1 2 1 2 1 1 1 9
treatment. For those with intermediate CHADS2 scores of 34, the decision to start bridging therapy is at the discretion of the patient's cardiologist [20]. More recent literature suggests initiating bridging therapy for patients with AF and a CHA2DS2-VASc score of 2 or higher, but only the CHADS2 score was found helpful in predicting postoperative stroke [37]. Recent literature challenges the antithrombotic benefit of bridging. A meta-analysis involving 34 studies described a 13%-15% risk for perioperative bleeding and a 3%-4% increased risk of major bleeding, with no evidence of decreased risk for thrombosis, with bridging as compared with stopping warfarin alone [38]. Another study on 1884 patients with a mean CHADS2 score of 2.3, the BRIDGE trial, concluded that foregoing bridging therapy in patients requiring warfarin interruption decreased the risk of bleeding and was found to be noninferior in terms of stroke protection when compared with bridging therapy [39]. However, considerations from the BRIDGE trial cannot be universally applied because patients with a prior history of stroke and those with high CHADS2 scores (5-6) were underrepresented in the study. Therefore, it appears safe to discontinue anticoagulant therapy in patients treated with warfarin for AF, without bridging, if the CHADS2 score is b4 and/or if there is no history of a
Thromboembolic risk based on indication for warfarin (adapted with permission from Douketis et al [20]
Indication for warfarin Low risk
Moderate risk
CHA2DS2-VASc score of 2-3 or CHADS2 score of 0-2 (assuming no prior stroke or transient ischemic attack) Mechanical heart valve Bileaflet aortic valve prosthesis without AF or risk factors for stroke
CHA2DS2-VASc score of ≥6 or CHADS2 score of 5-6 Recent (within 3 mo) stroke or transient ischemic attack Bileaflet aortic valve prosthesis Any mitral valve prosthesis and AF, history of stroke or Any caged-ball or tilting-disk transient ischemic attack, or aortic valve prosthesis risk factors for stroke History of recent stroke, transient ischemic attack, or cardioembolic event (within 3 mo) VTE within previous 3-12 mo, VTE within previous 3 mo, severe thrombophilia, unprovoked VTE, or nonsevere thrombophilia, or active cancer (cancer diagnosed ≤6 mo or recurrent VTE patient undergoing cancer therapy)
AF
VTE
VTE N12 mo previously and no other risk factor (eg, provoked and transient)
CHA2DS2-VASc score of 4-5 or CHADS2 score of 3-4
High risk
592 prior stroke. For those with a history of recent stroke or CHADS2 scores of 5-6, bridging therapy should be considered. 3.1.2.2. Warfarin for treatment of DVT and PE. Patients with a history of a provoked DVT or PE (ie, due to recent surgery, estrogen treatment, pregnancy, lower extremity injury, flight time N8 hours) should be considered candidates for anticoagulation with warfarin for a 3-month period. Patients with unprovoked or recurrent DVT (unless confined to distal venous vessels) or PE are candidates for longer-term (indefinite) anticoagulation therapy [40]. Those with a history of provoked DVT or PE at an increased risk for recurrence are patients with active thrombophilic conditions such as ATIII deficiency, antiphospholipid antibody syndrome, or active cancer. These patients should be considered for long-term anticoagulation. The most important factor in the deciding to discontinue warfarin therapy for 5 days preoperatively vs bridging with LMWH is the time elapsed since the last incident of DVT/ PE. In patients with a documented very recent thrombotic event (within the previous 3 months), elective surgery should be postponed until the appropriate duration of anticoagulation has been achieved. For those patients with a recent DVT/PE (within 3 months) and requiring surgery that cannot be postponed, bridging therapy should be initiated because of a 50% risk of thrombosis recurrence in the absence of anticoagulation [20]. In patients at low risk of recurrence (DVT/PE history N12 months) and no additional apparent prothrombotic risk factors, warfarin can be discontinued for the recommended 5 days without bridging. For patients at a moderate thromboembolic risk (ie, history of DVT/PE between 3 and 12 months before elective surgery, active thrombophilia, or cancer), such a risk needs to be balanced against any periprocedural concern for bleeding in the event of initiating bridging therapy. This patient population can either forgo bridging or receive prophylaxic doses of LMWH when the intraor postoperative risk of bleeding is considered to be high [2,37]. 3.1.2.3. Warfarin for mechanical heart valves. There is an increased risk of a major embolic event (4 per 100 patientyears) for patients with mechanical cardiac valves in the absence of anticoagulation [41]. However, such risks can be decreased (1 per 100 patient-years) with warfarin therapy following prosthetic valve replacement surgery. The risk of embolism is estimated to be twice as high for those with mitral mechanical heart valves when compared with aortic valves [41]. Patients with bileaflet aortic valve prostheses, in the absence of a history of stroke or cardioembolic event, are considered low risk and could discontinue warfarin 5 days preoperatively [20]. Individuals with bileaflet mechanical aortic valves in the presence of AF are considered a moderate risk, whereas patients at high risk of thromboembolism in the absence of anticoagulation include those with mechanical valves in the mitral position, older aortic valves (ball-cage, tiltingdisk), multiple mechanical heart valves, and a history of cerebrovascular/cardioembolic events [20]. It has been suggested
A.D. Oprea et al. that patients in the high- and moderate-risk categories be considered for bridging therapy [2,42]. 3.1.3. Step 3: bridging therapy considerations Patients at high risk for thromboembolism should be considered for bridging therapy, but periprocedural bleeding must be weighed against antithrombotic benefit. Several trials have described increased bleeding risks and major bleeding events in those prescribed bridging therapy with no evidence of significant benefit toward thromboembolic events [38,39,43]. Therefore, until additional evidence becomes available, bridging with therapeutic doses of parenteral anticoagulants should only be considered in those with a high risk of thrombosis such as: - Patients with AF and a history of recent stroke or CHADS2 score 5-6, - Those with a recent DVT/PE event (within 3 months), - Individuals with mechanical mitral valves, and - Patients with older and/or bileaflet aortic valves along with a history of stroke or other cardioembolic event [2,44]. When bridging treatment is being considered in high-risk patients, therapeutic doses of either LMWH or UFH (LMWH is used more than UFH) should be administered. Both LMWH and UFH are recommended when bridging therapy is anticipated for individuals with AF and recent history of DVT/PE [45] (Table 5). However, for patients with mechanical heart valves, European and American bridging guidelines differ. The 2014 American College of Cardiology/American Heart Association Guidelines for Management of Patients With Valvular Heart Disease and the 2012 ACCP Guidelines on Perioperative Management of Antithrombotic Therapy recommend that both UFH and LMWH can be used in those with mechanical heart valves [20,42]. This is in contrast to the European Society of Cardiology guidelines where only UFH is approved for patients with mechanical heart valves because of a lack of studies assessing efficacy of LMWH in this patient population [46]. In patients prescribed warfarin for DVT/PE that occurred N3 months before the planned procedure and not categorized Table 5
Bridging regimens
Anticoagulant Therapeutic dose
Prophylactic dose
Enoxaparin
30 mg twice a day subcutaneously 40 mg daily subcutaneously 5000 U daily subcutaneously
Dalteparin
UFH
1 mg/kg twice a day subcutaneously 1.5 mg/kg daily subcutaneously 120 U/kg twice a day subcutaneously 200 U/kg daily subcutaneously Intravenous dose needed to achieve an aPTT 1.5-2 times the control aPTT
5000-7500 U twice/ three times a day subcutaneously
Perioperative management of anticoagulants Table 6
593
Recommendations for NOAC discontinuation before elective surgery
Guideline
Drug
Dabigatran High-risk bleeding
European Heart Rhythm Association
Cr Cl ≥ 80 mL/min Cr Cl 50-80 mL/min Cr Cl 30-50 mL/min Cr Cl 15-30 mL/min
≥48 h ≥72 h ≥96 h Not indicated Australasian Society Cr Cl ≥ 50 mL/min ≥72 h of Thrombosis and Cr Cl 30-49 mL/min ≥96-120 h Hemostasis Cr Cl not addressed ≥5 d Working Group on Perioperative Hemostasis and the French Study Group on Thrombosis and Hemostasis Manufacturer Cr Cl ≥ 50 mL/min ≥24-48 h recommendations Cr Cl b 50 mL/min ≥72-120 h
Rivaroxaban
Apixaban
Edoxaban
Low-risk High-risk Low-risk High-risk bleeding bleeding bleeding bleeding
Low-risk High-risk Low-risk bleeding bleeding bleeding
≥24 h ≥36 h ≥48 h Not indicated ≥48 h ≥72 h
≥48 h ≥48 h ≥48 h ≥48 h
≥24 h ≥24 h ≥24 h ≥36 h
≥48 h ≥48 h ≥48 h ≥48 h
≥24 h ≥24 h ≥24 h ≥36 h
≥48 h ≥48 h ≥48 h ≥48 h
≥72 h ≥72 h
≥24 h ≥24 h
≥72 h ≥96 h
≥24 h ≥72 h
Not addressed
≥24 h
≥5 d
≥24 h
≥5 d
≥24 h
Not addressed
as high risk for thromboembolism, prophylactic doses of LMWH or UFH can be used as bridging therapy. Such an approach would reduce thromboembolic risk and minimize concern for perioperative bleeding when compared with a therapeutic dose bridging model [20,44]. Bridging therapy with either LMWH or UFH can be started 24-48 hours following warfarin cessation (3 days before the planned surgery). Because UFH has the shorter half-life, the infusion should be stopped 4-6 hours before surgery, but when LMWH is used for bridging, the last dose should be administered 24 hours before the planned operation and at half the daily dose [16]. 3.1.4. Restarting warfarin therapy Warfarin is usually restarted within 12-24 hours following surgery provided adequate hemostasis has been established. When perioperative bridging was administered, LMWH can be restarted 24 hours after surgery for procedures with a low bleeding risk (HAS-BLED scoreb 3) and 48-72 hours following surgery for patients with a high bleeding risk (HAS-BLED scoreN 3). Perioperative bridging therapy can be discontinued after surgery as long as INR levels have been in the desired therapeutic range for at least 48 hours [37].
3.2. Management of patients on fondaparinux Preoperative treatment with anticoagulants exposes patients undergoing surgery to higher risks of perioperative bleeding. There is limited information for perioperative management of those taking fondaparinux. Its effects last for 3-4 days (3-5 half-lives). Before elective surgery, patients prescribed fondaparinux should discontinue it for 72-96 hours
≥24 h (Cr Cl and bleeding risk not addressed)
≥48 h ≥24 h (Cr Cl not addressed)
≥24 h ≥24 h ≥24 h ≥36 h
≥24 h (Cr Cl and bleeding risk not addressed)
when treated with therapeutic doses (7.5 mg subcutaneously) and for 24 hours when on prophylactic doses (2.5 mg subcutaneously). The only clinical data for perioperative management of those on fondaparinux are for coronary artery bypass surgery patients, and findings support discontinuation 36 hours before such surgery [47].
3.3. Management of patients on NOACs The relatively short half-life of the NOAC class of medications permits discontinuation of these agents closer to the day of scheduled elective surgery. In addition, bridging therapy is not typically required, as thrombotic risks are not significantly increased when interrupting NOAC therapy but also because of concerns that bridging can increase periprocedural bleeding [48-50]. Data are emerging that certain surgical procedures can be performed without stopping warfarin, and the same may be applied to continuing perioperative NOAC treatment. For example, evidence from a registry involving 2179 patients taking NOACs and undergoing superficial skin surgical procedures, dental extractions, cataract surgery, and endoscopic procedures detected rare bleeding events (0.5%) when such procedures were conducted while patients continued NOAC therapy [51]. It has also been shown that dermatologic procedures can be safely performed on those taking NOACs [52]. Another retrospective study on patients undergoing pacemaker/AICD implantation while continuing dabigatran concluded that there are no risks of major bleeding and determined that it was safe to proceed with such surgery [53]. However, until additional studies assessing the safety of continuing perioperative NOAC therapy become available, it
594 Table 7
A.D. Oprea et al. Classification of pain procedures according to bleeding risk (adapted with permission from Narouze et al [65])
High risk
Intermediate risk
Low risk
Spinal cord stimulation trial and implant
Interlaminar and transforminal epidural steroid injections (all spinal levels) Facet medial branch nerve block and radiofrequency ablation Intradiscal procedures
Peripheral nerve block
Intrathecal catheter and pump implant Vertebral augmentation (kyphoplasty/vertebroplasty) Epiduroscopy/epidural decompression
Sympathetic blocks Paravertebral block Peripheral nerve stimulation and implant Pocket revision and IPG/ITP replacement
Peripheral joint and musculoskeletal injections Trigger point injections (including piriformis injection) Sacroiliac joint injection Sacral lateral branch blocks
IPG = implantable pulse generator; ITP = intrathecal pump.
may be prudent to stop these agents for most planned surgical procedures, except for those procedures with minimal bleeding risk (dental cleaning/fillings, cataract removal, minor skin procedures) [54,55]. Several guidelines exist for perioperative management of NOACs, and these recommendations are summarized in Table 6 [56-58]. Considerations for the guidelines have been based on patient renal function and potential bleeding risks. These guidelines classify surgical procedures with a 2day postoperative hemorrhagic risk of 2%-4% as high risk and include major cardiac, orthopedic, thoracic, vascular, abdominal, intracranial, head and neck, breast cancer, and urologic surgery; liver and kidney biopsy; or procedures lasting longer than 45 minutes (bleeding risk has been defined somewhat differently than in Table 2). In contrast, cholecystectomy, hysterectomy, endoscopy, arthroscopy, dilation and curettage, hernia repairs, and biopsies (bladder, prostate, thyroid, breast) are considered low– bleeding risk procedures (0%-2% two-day risk of major bleeding) [29].
3.4. Oral anticoagulation reversal therapies and urgent/emergent surgery Patients taking oral anticoagulants and presenting for emergency or trauma surgery should have these medications discontinued in addition to immediately instituting supportive measures protecting against hemorrhagic risks. The degree of anticoagulation for those prescribed warfarin can be assessed with INR levels, but effects from NOAC treatment cannot always be quantified with coagulation testing. As an example, an elevated PT would be expected in patients taking rivaroxaban, a prolonged aPTT in the presence of dabigatran, but PT measurements are insensitive in those on apixaban. In addition, INR, PT, and aPTT values do not correlate well with levels of NOAC medications found in the plasma; these tests merely confirm the presence of such agents in the patient's circulation.
Fresh frozen plasma (10-15 mL/kg) in addition to a slow infusion of vitamin K (5-10 mg) can reverse effects of warfarin. Warfarin can also be reversed with prothrombin complex concentrate (PCC) that has been found to be superior to fresh frozen plasma in reversing vitamin K antagonists. Advantages of PCC treatment are the rapid speed of infusion, lack of need for cross-matching, the small volume to be infused, and effectiveness of reversal, but there is also a higher risk of thromboembolism. A 4-factor PCC (K Centra, CSL Behring; contains factors II, VII, IX, and X) is currently Federal Drug Administration approved for warfarin reversal [8]. Risk assessment as to timing or urgency of a surgical procedure is warranted in patients taking NOACs, as discontinuing these agents for 24-48 hours usually results in a normal coagulation status. Dabigatran reversal can be achieved with hemodialysis in those scheduled for urgent procedures. Idarucizumab (Praxbind, Boehringer Ingelheim; administered in 2 consecutive infusions or boluses of 2.5 g each) has recently been Federal Drug Administration approved for dabigatran reversal but should be reserved for patients requiring truly emergent surgery. Idarucizumab is an antibody fragment that attaches to the thrombin-binding site of dabigatran, leading to complete reversal of anticoagulation effects within minutes [59]. No reversal agents are currently available for reversal of the anti-Xa inhibitors, but several drugs are in development. Therefore, in emergency situations, off-label administration of PCC and recombinant factor VII can be used in circumstances of life-threatening bleeding [8,60]. Andexanet alfa, a modified recombinant factor Xa, is being studied for reversal of all anti-Xa inhibitors (both oral and intravenous) and has been shown to be effective within minutes of administration [61] Aripazine (ciraparantag, PER 977) is a small molecule that interacts with anticoagulants through noncovalent hydrogen bonding and electrostatic interactions. This agent has entered phase II clinical trials and appears to inhibit nearly all anticoagulants with the exception of vitamin K antagonists and argatroban [60,62].
Perioperative management of anticoagulants Table 8
595
Periprocedural management of antithrombotics
Drug
Intravenous heparin
2015 Interventional Pain ASRA guidelines
2015 Update/2010 ASRA guidelines for neuraxial anesthesia
When to discontinue
When to restart
When to discontinue
When to restart
2h
2-6 h before to needle placement
1-4 h after nontraumatic needle placement 1 h after catheter removal
High and intermediate bleeding risk
Low bleeding risk
4h
4h
24 h if traumatic pass (eg, bloody)
Subcutaneous heparin
8-10 h
8-10 h
LMWH Prophylactic dosing Enoxaparin 30 mg twice a day Enoxaparin 40 mg daily Deltaparin 5000 U daily
12 h
12 h
2-4 h before catheter removal (normal aPTT documented) 2h No time restriction as to needle placement or catheter removal as long as the total dose of daily heparin is b10,000 U 4 h after a low-risk 10-12 h before needle Single daily dosing procedure placement First dose 6-8 h after needle placement 12-24 h after an 12 h before catheter removal Second dose 24 h intermediate- or after the first dose high-risk procedure At least 2 h after catheter removal Twice-daily dosing
LMWH 24 h 24 h Therapeutic dosing Enoxaparin 1.5 mg/kg daily or 1 mg/kg twice a day Dalteparin 120 U twice a day or 200 U daily Warfarin 5 d and normal Discontinuation INR may not be necessary if INR b3
Fondaparinux 2.5 mg daily
5 half-lives (3-4 d)
Dabigatran
4-5 d (normal renal function) 6 d (impaired renal function) 3d
Rivaroxaban
2 half lives
4 h after a low-risk 24 h procedure 12-24 h after an intermediate- or high-risk procedure
Not recommended with catheter in place At least 24 h after needle placement 2 h after catheter removal Epidural catheter contraindicated 2-4 h after catheter removal
24 h
4-5 d and normal INR
Remove catheter when INR is b1.5 Restart any time after catheter removal
24 h
36 h
12 h after catheter removal Epidural catheter not indicated
24 h
5 d before puncture, catheter 6 h after puncture, manipulation, or removal catheter manipulation, or removal
Shared assessment and risk stratification, a 2–half-life interval 24 h discontinuation may be considered
3 d before puncture, catheter 6 h after puncture, manipulation, or removal catheter manipulation, or removal
596
A.D. Oprea et al.
Table 8 (continued) Drug
2015 Interventional Pain ASRA guidelines
2015 Update/2010 ASRA guidelines for neuraxial anesthesia
When to discontinue
When to restart
When to discontinue
When to restart
24 h
3 d before puncture, catheter manipulation, or removal
6 h after puncture, catheter manipulation, or removal
High and intermediate bleeding risk Apixaban
Low bleeding risk
3-5 d
4. Periprocedural management of patients on anticoagulants (interventional pain, regional and neuraxial procedures) A major consideration for anticoagulated patients undergoing regional anesthesia or interventional pain medicine procedures within the neuraxial space is dealing with the potential development of a spinal or epidural hematoma. This complication can result in permanent neurologic damage and paralysis [27] Peripheral and soft tissue injections in anticoagulated patients can also lead to hematoma formation, with an increased concern when planning deep peripheral nerve blockade (PNB) where manual vessel compression could be difficult. Such a compromising hematoma could result in a “compartment syndrome” or neurologic compromise and nerve injury from mechanical compression [63,64]. The scope of interventional pain procedures is multifaceted, including PNBs, vertebral augmentation, joint injections, and cancer pain interventions, along with soft tissue procedures and trigger point injections. Bleeding complications from these techniques include hematoma formation, hemarthroses, and subcutaneous ecchymoses. The American Society of Regional Anesthesia and Pain Medicine (ASRA) and several European societies have issued guidelines for management of patients taking antiplatelet, anticoagulant, and antifibrinolytic medications and subsequently planning either neuraxial anesthesia or interventional pain procedures [27,65-67]. The 2015 Interventional Pain ASRA guidelines classify bleeding risk following interventional spine and pain procedures [65] (Table 7). Several of the published recommendations for moderate- and high-risk pain procedures are similar to the 2010 ASRA advisory third edition and its 2015 update for patients on antithrombotics undergoing regional anesthesia (2010 ASRA guidelines for neuraxial anesthesia) [27]. However, additional distinctions do exist, as the 2015 Interventional Pain ASRA guidelines indicate that, when performing low-risk pain procedures, less stringent criteria would be acceptable [27,65]. In contrast, for certain pain interventions in those on anticoagulants, the 2015 Interventional Pain ASRA guidelines suggest more stringent criteria than identified in the 2010 ASRA guidelines for neuraxial anesthesia. For example, in patients who have significantly
altered vertebral anatomy (ie, spondylosis) or are to undergo procedures with large-gauge needles and stiff sytletted leads such as spinal cord stimulation, risk of bleeding may be higher than when performing neuraxial techniques for anesthesia in the operating room. Also, longer time intervals to restart some anticoagulants following pain procedures are recommended [65]. Regardless of which published guidelines are consulted, it remains important to follow a formal risk assessment with management decisions performed in conjunction with the physician managing a patient's anticoagulation therapy when necessary. A thorough discussion of all published guidelines is beyond the scope of this review (please see www.asra.com), but current recommendations for neuraxial anesthesia and interventional pain procedures are summarized in Table 8. In addition to the timing of the procedure in relation to the anticoagulant administration, a few comments and caveats are necessary.
1. Intravenous heparin - All patients receiving heparin longer than 4 days should have platelet count checked before neuraxial blockade or removal of an epidural catheter to exclude thrombocytopenia that may suggest HIT [27,65]. - Intravenous heparin can be used intraoperatively following neuraxial procedures; however, dilute concentrations of local anesthetics should be used, and close postoperative monitoring remains necessary to detect evidence of a developing hematoma [27]. - In situations of traumatic neuraxial needle placement (ie, bloody tap or requiring multiple needle passes) during neuraxial procedures performed before surgical procedures where intraoperative heparin administration is planned (ie, vascular surgery), the risk of hematoma formation is unknown, and proceeding with surgery should be considered on an individual basis [27]. - Risk of developing a compromising hematoma from full heparin anticoagulation during cardiac bypass surgery also remains unknown [27]. 2. Subcutaneous UFH - For patients receiving subcutaneous UFH N10,000 U daily or more than twice-daily dosing, insufficient data
Perioperative management of anticoagulants are available for ASRA to make formal recommendations. There are reports that thrice-daily heparin dosing can increase bleeding risks; however, epidural catheters have been maintained in patients on thrice-daily heparin at several institutions [27,68-70]. 3. Warfarin - In patients receiving preoperative warfarin (typically the night before neuraxial manipulation), an INR should be checked before performing neuraxial blockade if the first dose was given N24 hours before placement of the block or if a second warfarin dose was administered [27]. - All patients receiving warfarin in conjunction with neuraxial or deep PNB catheters should have daily INR monitoring. Both motor and sensory function should be assessed, and dilute concentrations of local anesthetics should be used to facilitate neurological evaluation [27]. - Concurrent medications affecting hemostatic mechanisms such as antiplatelet agents (aspirin, nonsteroidal anti-inflammatory drugs) should be avoided [27]. - Removal or manipulation of neuraxial and deep PNB catheters should occur when the INR is b1.5 (correlates with clotting factor levels of at least 40%), and neurologic evaluation should be continued for 24 hours following catheter removal. - With an INR between 1.5 and 3, caution should be used when removing neuraxial and deep PNB catheters, along with a review of patient medical records to determine if other agents affecting hemostasis (including those with no effect on INR) are present. In this situation, routine neurologic evaluation should occur before catheter removal and until INR has reached the desired level. - There are no recommendations regarding management of patients receiving therapeutic levels of warfarin in conjunction with neuraxial or deep PNB catheters. For patients with an INR N3, warfarin should be held or reduced in the presence of indwelling neuraxial or deep PNB catheters [27] (Table 8). 4. Fondaparinux - Placing indwelling catheters in patients on fondaparinux is not recommended by ASRA [27]. - The German Society of Anesthesiology and Intensive Care Medicine recommends a delay of 36-42 hours after the last dose of fondaparinux before needle puncture. These considerations apply only to patients treated with prophylactic doses of fondaparinux (2.5 mg subcutaneously daily). - Neuraxial procedures should not be performed for patients on therapeutic doses of fondaparinux (5-10 mg subcutaneously daily) given the increased risk of spinal or epidural hematoma [67]. 5. NOACs (dabigatran, rivaroxaban, apixaban) - For patients on edoxaban, there are no guidelines for performing neuraxial interventions or pain procedures. However, its half-life is similar to that of rivaroxaban and apixaban. Therefore, stopping the agent 3 days
597
-
-
-
-
before neuraxial procedures and resuming 6 hours postintervention may be appropriate. When performing low-risk interventional pain procedures, a 2–half-life discontinuation interval should be considered for patients taking NOACs, a shared risk decision that should be made in conjunction with the prescribing physicians. When performing moderate- and high-risk interventional pain procedures on these patients, a 5–half-life period of discontinuation of the agent is recommended. In clinical situations with a high risk of VTE, it is recommended to use an LMWH bridge that will be discontinued 24 hours before performing any interventional pain procedure and to have a 24-hour delay before resuming these agents following the intervention [65]. In those with very high risks of VTE, half the usual dose of the oral anticoagulant can be initiated 12 hours after performing interventional pain procedures (Table 8) [27,65,71–75].
5. Conclusions Management of anticoagulation therapy in the perioperative period should be based on patient-specific conditions (renal, hepatic, cardiac) and surgery-related (trauma, cancer) issues to safely proceed with surgery and anesthetic care. Perioperative management can differ depending on whether the patient is receiving a prophylactic or a therapeutic anticoagulant regimen. Therefore, understanding the complexity of anticoagulation management is essential, and decisions about proceeding with surgery, regional procedures, and interventional techniques in patients receiving such therapy need to be made on an individual basis. It should also be recognized that the risk of hematoma formation, thrombosis, or bleeding will not be completely eliminated even when preventative strategies and existing guidelines are followed. Alternative anesthetic and analgesic planning may be required for patients at unacceptable risk.
References [1] Bracey AW. Perioperative management of antithrombotic and antiplatelet therapy. Tex Heart Inst J 2015;42:239-42. [2] van Veen JJ, Makris M. Management of peri-operative anti-thrombotic therapy. Anaesthesia 2015(70 Suppl. 1):58-67 [e21–3]. [3] Eisele R, Melzer N, Bramlage P. Perioperative management of anticoagulation. Chirurg 2014;85:513-9. [4] Greinacher A. Heparin-induced thrombocytopenia. N Engl J Med 2015; 373:252-61. [5] Tapson VF, Shirvanian S. Venous thromboembolism: identifying patients at risk and establishing prophylaxis. Curr Med Res Opin 2015:1-64. [6] Hirsh J, Levine MN. Low molecular weight heparin. Blood 1992;79: 1-17. [7] Egan G, Ensom MH. Measuring anti-factor Xa activity to monitor low– molecular-weight heparin in obesity: a critical review. Can J Hosp Pharm 2015;68:33-47.
598 [8] Daniels PR. Peri-procedural management of patients taking oral anticoagulants. BMJ 2015;351, h2391. [9] Levy JH, Faraoni D, Spring JL, Douketis JD, Samama CM. Managing new oral anticoagulants in the perioperative and intensive care unit setting. Anesthesiology 2013;118:1466-74. [10] Mandernach MW, Beyth RJ, Rajasekhar A. Apixaban for the prophylaxis and treatment of deep vein thrombosis and pulmonary embolism: an evidence-based review. Ther Clin Risk Manag 2015;11:1273-82. [11] Minor C, Tellor KB, Armbruster AL. Edoxaban, a novel oral factor Xa inhibitor. Ann Pharmacother 2015;49:843-50. [12] Tafur AJ, McBane R, Wysokinski WE, Litin S, Daniels P, Slusser J, et al. Predictors of major bleeding in peri-procedural anticoagulation management. J Thromb Haemost 2012;10:261-7. [13] Omran H, Bauersachs R, Rübenacker S, Goss F, Hammerstingl C. The HAS-BLED score predicts bleedings during bridging of chronic oral anticoagulation. Results from the national multicentre BNK online bRiDging REgistRy (BORDER). Thromb Haemost 2012;108:65-73. [14] Roldán V, Marín F, Manzano-Fernández S, Gallego P, Vílchez JA, Valdés M, et al. The HAS-BLED score has better prediction accuracy for major bleeding than CHADS2 or CHA2DS2-VASc scores in anticoagulated patients with atrial fibrillation. J Am Coll Cardiol 2013;62:2199-204. [15] Apostolakis S, Lane DA, Buller H, Lip GY. Comparison of the CHADS2, CHA2DS2-VASc and HAS-BLED scores for the prediction of clinically relevant bleeding in anticoagulated patients with atrial fibrillation: the AMADEUS trial. Thromb Haemost 2013;110:1074-9. [16] Baron TH, Kamath PS, McBane RD. Management of antithrombotic therapy in patients undergoing invasive procedures. N Engl J Med 2013;368:2113-24. [17] Palamaras I, Semkova K. Perioperative management of and recommendations for antithrombotic medications in dermatological surgery. Br J Dermatol 2015;172:597-605. [18] Pototski M, Amenábar JM. Dental management of patients receiving anticoagulation or antiplatelet treatment. J Oral Sci 2007;49:253-8. [19] Perry DJ, Noakes TJ, Helliwell PS, Society BD. Guidelines for the management of patients on oral anticoagulants requiring dental surgery. Br Dent J 2007;203:389-93. [20] Douketis JD, Spyropoulos AC, Spencer FA, Mayr M, Jaffer AK, Eckman MH, et al. Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141:e326S-50S. [21] Jamula E, Anderson J, Douketis JD. Safety of continuing warfarin therapy during cataract surgery: a systematic review and meta-analysis. Thromb Res 2009;124:292-9. [22] Anderson MA, Ben-Menachem T, Gan SI, Appalaneni V, Banerjee S, Cash BD, et al. Management of antithrombotic agents for endoscopic procedures. Gastrointest Endosc 2009;70:1060-70. [23] Veitch AM, Baglin TP, Gershlick AH, Harnden SM, Tighe R, Cairns S, et al. Guidelines for the management of anticoagulant and antiplatelet therapy in patients undergoing endoscopic procedures. Gut 2008;57: 1322-9. [24] Kearon C, Hirsh J. Management of anticoagulation before and after elective surgery. N Engl J Med 1997;336:1506-11. [25] Hylek EM, Regan S, Go AS, Hughes RA, Singer DE, Skates SJ. Clinical predictors of prolonged delay in return of the international normalized ratio to within the therapeutic range after excessive anticoagulation with warfarin. Ann Intern Med 2001;135:393-400. [26] Dzik WS. Reversal of drug-induced anticoagulation: old solutions and new problems. Transfusion 2012;52(Suppl. 1):45S-55S. [27] Horlocker TT, Wedel DJ, Rowlingson JC, Enneking FK, Kopp SL, Benzon HT, et al. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine evidence-based guidelines (third edition). Reg Anesth Pain Med 2010;35:64-101. [28] Woods K, Douketis JD, Kathirgamanathan K, Yi Q, Crowther MA. Low-dose oral vitamin K to normalize the international normalized ratio
A.D. Oprea et al.
[29] [30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
prior to surgery in patients who require temporary interruption of warfarin. J Thromb Thrombolysis 2007;24:93-7. Spyropoulos AC, Douketis JD. How I treat anticoagulated patients undergoing an elective procedure or surgery. Blood 2012;120:2954-62. Sticherling C, Marin F, Birnie D, Boriani G, Calkins H, Dan GA, et al. Antithrombotic management in patients undergoing electrophysiological procedures: a European Heart Rhythm Association (EHRA) position document endorsed by the ESC working group thrombosis, Heart Rhythm Society (HRS), and Asia Pacific Heart Rhythm Society (APHRS). Europace 2015;17:1197-214. Di Biase L, Burkhardt JD, Santangeli P, Mohanty P, Sanchez JE, Horton R, et al. Periprocedural stroke and bleeding complications in patients undergoing catheter ablation of atrial fibrillation with different anticoagulation management: results from the role of coumadin in preventing thromboembolism in atrial fibrillation (AF) patients undergoing catheter ablation (COMPARE) randomized trial. Circulation 2014;129: 2638-44. Birnie DH, Healey JS, Wells GA, Verma A, Tang AS, Krahn AD, et al. Pacemaker or defibrillator surgery without interruption of anticoagulation. N Engl J Med 2013;368:2084-93. Agarwal S, Hachamovitch R, Menon V. Current trial-associated outcomes with warfarin in prevention of stroke in patients with nonvalvular atrial fibrillation: a meta-analysis. Arch Intern Med 2012;172: 623-31. Yun AJ, Lee PY, Bazar KA. Can thromboembolism be the result, rather than the inciting cause, of acute vascular events such as stroke, pulmonary embolism, mesenteric ischemia, and venous thrombosis? A maladaptation of the prehistoric trauma response. Med Hypotheses 2005;64: 706-16. Kaatz S, Douketis JD, Zhou H, Gage BF, White RH. Risk of stroke after surgery in patients with and without chronic atrial fibrillation. J Thromb Haemost 2010;8:884-90. Olesen JB, Torp-Pedersen C, Hansen ML, Lip GY. The value of the CHA2DS2-VASc score for refining stroke risk stratification in patients with atrial fibrillation with a CHADS2 score 0-1: a nationwide cohort study. Thromb Haemost 2012;107:1172-9. Williams LA, Hunter JM, Marques MB, Vetter TR. Periprocedural management of patients on anticoagulants. Clin Lab Med 2014;34: 595-611. Siegal D, Yudin J, Kaatz S, Douketis JD, Lim W, Spyropoulos AC. Periprocedural heparin bridging in patients receiving vitamin K antagonists: systematic review and meta-analysis of bleeding and thromboembolic rates. Circulation 2012;126:1630-9. Douketis JD, Spyropoulos AC, Kaatz S, Becker RC, Caprini JA, Dunn AS, et al. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med 2015;373:823-33. Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141: e419S-94S. Cannegieter SC, Rosendaal FR, Briët E. Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses. Circulation 1994;89:635-41. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP, Guyton RA, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. J Am Coll Cardiol 2014;63:e57-185. Haighton M, Kempen DH, Wolterbeek N, Marting LN, van Dijk M, Veen RM. Bridging therapy for oral anticoagulation increases the risk for bleeding-related complications in total joint arthroplasty. J Orthop Surg Res 2015;10:145. Keeling D, Baglin T, Tait C, Watson H, Perry D, Baglin C, et al. Guidelines on oral anticoagulation with warfarin—fourth edition. Br J Haematol 2011;154:311-24.
Perioperative management of anticoagulants [45] Spyropoulos AC, Turpie AG, Dunn AS, Spandorfer J, Douketis J, Jacobson A, et al. Clinical outcomes with unfractionated heparin or low–molecular-weight heparin as bridging therapy in patients on longterm oral anticoagulants: the REGIMEN registry. J Thromb Haemost 2006;4:1246-52. [46] Hamm CW, Bassand JP, Agewall S, Bax J, Boersma E, Bueno H, et al. ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: the task force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2011;32:2999-3054. [47] Landenhed M, Johansson M, Erlinge D, Olsson ML, Bjursten H. Fondaparinux or enoxaparin: a comparative study of postoperative bleeding in coronary artery bypass grafting surgery. Scand Cardiovasc J 2010;44:100-6. [48] Healey JS, Brambatti M. Periprocedural management of oral anticoagulation in patients with atrial fibrillation: approach in the era of new oral anticoagulants. Can J Cardiol 2013;29:S54-9. [49] Ortel TL. Perioperative management of patients on chronic antithrombotic therapy. Blood 2012;120:4699-705. [50] Vanassche T, Lauw MN, Connolly SJ, Eikelboom JW. Heparin bridging in peri-procedural management of new oral anticoagulant: a bridge too far? Eur Heart J 2014;35:1831-3. [51] Beyer-Westendorf J, Gelbricht V, Förster K, Ebertz F, Köhler C, Werth S, et al. Peri-interventional management of novel oral anticoagulants in daily care: results from the prospective Dresden NOAC registry. Eur Heart J 2014;35:1888-96. [52] Callahan S, Goldsberry A, Kim G, Yoo S. The management of antithrombotic medication in skin surgery. Dermatol Surg 2012;38:1417-26. [53] Rowley CP, Bernard ML, Brabham WW, Netzler PC, Sidney DS, Cuoco F, et al. Safety of continuous anticoagulation with dabigatran during implantation of cardiac rhythm devices. Am J Cardiol 2013;111:1165-8. [54] Ferrandis R, Castillo J, de Andrés J, Gomar C, Gómez-Luque A, Hidalgo F, et al. The perioperative management of new direct oral anticoagulants: a question without answers. Thromb Haemost 2013;110:515-22. [55] Douketis J, Bell AD, Eikelboom J, Liew A. Approach to the new oral anticoagulants in family practice: part 2: addressing frequently asked questions. Can Fam Physician 2014;60:997-1001. [56] Heidbuchel H, Verhamme P, Alings M, Antz M, Diener HC, Hacke W, et al. Updated European Heart Rhythm Association practical guide on the use of non–vitamin K antagonist anticoagulants in patients with nonvalvular atrial fibrillation. Europace 2015;17:1467-507. [57] Sié P, Samama CM, Godier A, Rosencher N, Steib A, Llau JV, et al. Surgery and invasive procedures in patients on long-term treatment with direct oral anticoagulants: thrombin or factor-Xa inhibitors. Recommendations of the working group on perioperative haemostasis and the French study group on thrombosis and haemostasis. Arch Cardiovasc Dis 2011;104:669-76. [58] Tran H, Joseph J, Young L, McRae S, Curnow J, Nandurkar H, et al. New oral anticoagulants: a practical guide on prescription, laboratory testing and peri-procedural/bleeding management. Australasian Society of Thrombosis and Haemostasis. Intern Med J 2014;44:525-36. [59] Pollack CV, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015; 373:511-20. [60] Crowther M, Crowther MA. Antidotes for novel oral anticoagulants: current status and future potential. Arterioscler Thromb Vasc Biol 2015;35: 1736-45.
599 [61] Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med 2015;373:2413-24. [62] Greinacher A, Thiele T, Selleng K. Reversal of anticoagulants: an overview of current developments. Thromb Haemost 2015;113:931-42. [63] Jeng CL, Torrillo TM, Rosenblatt MA. Complications of peripheral nerve blocks. Br J Anaesth 2010;105(Suppl. 1):i97-107. [64] Horlocker TT. Regional anaesthesia in the patient receiving antithrombotic and antiplatelet therapy. Br J Anaesth 2011;107(Suppl. 1): i96-106. [65] Narouze S, Benzon HT, Provenzano DA, Buvanendran A, De Andres J, Deer TR, et al. Interventional spine and pain procedures in patients on antiplatelet and anticoagulant medications: guidelines from the American Society of Regional Anesthesia and Pain Medicine, the European Society of Regional Anaesthesia and Pain Therapy, the American Academy of Pain Medicine, the International Neuromodulation Society, the North American Neuromodulation Society, and the World Institute of Pain. Reg Anesth Pain Med 2015;40:182-212. [66] Breivik H, Bang U, Jalonen J, Vigfússon G, Alahuhta S, Lagerkranser M. Nordic guidelines for neuraxial blocks in disturbed haemostasis from the Scandinavian Society of Anaesthesiology and Intensive Care Medicine. Acta Anaesthesiol Scand 2010;54:16-41. [67] Gogarten W, Vandermeulen E, Van Aken H, Kozek S, Llau JV, Samama CM, et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol 2010;27:999-1015. [68] King CS, Holley AB, Jackson JL, Shorr AF, Moores LK. Twice vs three times daily heparin dosing for thromboembolism prophylaxis in the general medical population: a metaanalysis. Chest 2007;131:507-16. [69] Leonardi MJ, McGory ML, Ko CY. The rate of bleeding complications after pharmacologic deep venous thrombosis prophylaxis: a systematic review of 33 randomized controlled trials. Arch Surg 2006;141:790-7. [70] Davis JJ, Bankhead BR, Eckman EJ, Wallace A, Strunk J. Three-timesdaily subcutaneous unfractionated heparin and neuraxial anesthesia: a retrospective review of 928 cases. Reg Anesth Pain Med 2012;37: 623-6. [71] Li J, Halaszynski T. Neuraxial and peripheral nerve blocks in patients taking anticoagulant or thromboprophylactic drugs: challenges and solutions. Local Reg Anesth 2015;8:21-32. [72] Conway R, O'Shea FD, Cunnane G, Doran MF. Safety of joint and soft tissue injections in patients on warfarin anticoagulation. Clin Rheumatol 2013;32:1811-4. [73] Ahmed I, Gertner E. Safety of arthrocentesis and joint injection in patients receiving anticoagulation at therapeutic levels. Am J Med 2012; 125:265-9. [74] Singelyn FJ, Verheyen CC, Piovella F, Van Aken HK, Rosencher N, Investigators ES. The safety and efficacy of extended thromboprophylaxis with fondaparinux after major orthopedic surgery of the lower limb with or without a neuraxial or deep peripheral nerve catheter: the EXPERT study. Anesth Analg 2007;105:1540-7. [75] American Society of Regional Anesthesia and Pain Medicine. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine evidence-based guidelines (interim update 2015); 2015 [http://www.asra.com/advisory-guidelines/article/1/anticoagulation-3rdedition. Accessed May 9, 2016].
