Hospital Practice
ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20
Perioperative Management of Target-Specific Oral Anticoagulants Brian Bergmark MD & Robert P. Giugliano MD, SM To cite this article: Brian Bergmark MD & Robert P. Giugliano MD, SM (2014) Perioperative Management of Target-Specific Oral Anticoagulants, Hospital Practice, 42:1, 38-45 To link to this article: http://dx.doi.org/10.3810/hp.2014.02.1090
Published online: 13 Mar 2015.
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Date: 05 November 2015, At: 15:45
C l i n i c a l F o c u s : H o s p i ta l A d m i s s i o n s , L at e s t P r o t o c o l s , P r e o p e r a t i v e M e d i c i n e , a n d T r a n s i t i o n s o f C a r e
Perioperative Management of Target-Specific Oral Anticoagulants
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DOI: 10.3810/hp.2014.02.1090
Brian Bergmark, MD 1 Robert P. Giugliano, MD, SM 2 1 Department of Medicine, Brigham and Women’s Hospital, Boston, MA; 2Department of Medicine, Cardiovascular Division, Brigham and Women’s Hospital; Harvard Medical School; Thrombolysis in Myocardial Infarction (TIMI) Study Group, Boston, MA
Abstract: Target-specific oral anticoagulants (TSOACs), which offer rapid onset and more predictable pharmacokinetics/dynamics compared with vitamin K antagonists, are rapidly growing in number and approved indications. At least 1 in 10 Americans receiving outpatient anticoagulant therapy requires interruption of anticoagulation for an invasive procedure annually, and management of these new agents in the perioperative setting is made challenging by difficulty measuring anticoagulant effect and the lack of effective reversal. Surgical planning must account for individual patient risks for bleeding and thrombosis, the type of procedure, and expected drug clearance. Based upon these considerations, a perioperative plan encompassing timing of TSOAC cessation and resumption, as well as bridging therapy, if needed, can be developed. Perioperative strategies remain largely predicated on extrapolations from pharmacokinetics and expert opinion, though a growing body of literature is providing greater guidance in this important area. Keywords: anticoagulation; surgery; perioperative management; bleeding; novel oral anticoagulant
Introduction
Correspondence: Robert P. Giugliano, MD, SM, Department of Medicine, Brigham and Women’s Hospital, TIMI Study Office, 350 Longwood Avenue, 1st Floor, Boston, MA 02115. Tel: 617-278-0145 Fax: 617-734-7329 E-mail: [email protected]
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Use of vitamin K antagonists (VKAs) has been the mainstay of oral anticoagulation for decades. Though effective, warfarin and related drugs are limited by numerous drug and food interactions, significant inter-individual and intra-individual variations in drug effect, slow time of onset, narrow therapeutic window, and required, continuous monitoring. These challenges prompted the search for alternative agents with rapid onset, predictable pharmacokinetics and pharmacodynamics, and a wide therapeutic window, obviating the need for monitoring of effect.1–3 The first of these target-specific oral anticoagulants (TSOACs) to reach the US market was dabigatran, a direct thrombin inhibitor, which was approved by the US Food and Drug Administration (FDA) for treatment of patients with nonvalvular atrial fibrillation (AF) in 2010.4 Rivaroxaban and apixaban, both oral factor Xa inhibitors, have subsequently been approved and the number of indications for each drug is expanding (Table 1). Edoxaban, a third factor Xa inhibitor, was recently found to be noninferior to warfarin for stroke prevention in patients with nonvalvular AF. Edoxaban therapy was associated with lower rates of patient bleeding and cardiovascular death.5 As use of the TSOACs has accelerated, clinicians have become familiar with their limitations, which are principally related to an inability to accurately measure drug effect and lack of effective reversal of anticoagulation. These issues manifest as uncertainty regarding whether a patient is taking the medication as prescribed and difficulty
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Perioperative Management of TSOACs
Table 1. Approved Indications for TSOACs Agent
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Dabigatran FDA EMA Rivaroxaban FDA EMA Apixaban FDA EMA Edoxaban
Table 2. Procedural Bleeding Risks8
AF
Prevent VTE
Treat VTE
ACS
2010 2011
-2008
RE-MEDY7 RE-SONATE7
--
2011 2011
2011 2008
2012 2011
-2013
2012 2012 ENGAGE AF-TIMI 485
-2011 2011 (Japan)
AMPLIFY18
--
HOKUSAI-VTE34 --
Abbreviations: ACS, acute coronary syndromes; AF, atrial fibrillation; AMPLIFY, Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy; EMA, European Medicine Agency; ENGAGE AF – TIMI 48, Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation—Thrombolysis in Myocardial Infarction 48; FDA, (US) Food and Drug Administration; HOKUSAI-VTE, Edoxaban Versus Warfarin for the Treatment of Symptomatic Venous Thomboembolism; PE, pulmonary embolism; RE-MEDY/ RE-SONATE, Extended Use of Dabigatran, Warfarin, or Placebo in Venous Thromboembolism (vs warfarin, RE-MEDY; vs placebo, RE-SONATE);VTE, venous thromboembolism.
managing unplanned and planned bleeding (ie, surgery and invasive procedures). Perioperative TSOAC management is a particularly common challenge. In the United States, approximately 10% of patients receiving anticoagulation therapy require drug interruption for an invasive procedure annually.6 Important issues in perioperative management of anticoagulation include balancing the risk of bleeding and risk of thrombosis, timing of TSOAC cessation preoperatively, reinitiation postoperatively, transitioning among anticoagulants when bridging therapy is used, and managing unplanned procedures. A nascent body of evidence has begun to provide guidance in this setting, though recommendations remain largely predicated on extrapolations from pharmacokinetic/dynamic data and expert opinion.7
Assessment of Risk
The first consideration in perioperative management is assessment of patient risk for bleeding and for thrombosis. The risk assessment includes the type of operation planned, the indication for anticoagulation, and patient-specific factors predisposing to either bleeding or thrombosis. The type of procedure can be classified as high-risk for bleeding, defined as a 2% to 4% 2-day risk of major bleed; or low-risk, with a 0 to 2% chance of patient bleeding in the first 2 days.8 Table 2 provides examples of high- and low-risk procedures. Patient-level risk of bleeding can be quantified in the outpatient setting using the HAS-BLED score (Table 3), which may be reasonable to consider perioperatively
High-Risk (2-day risk of major bleed 2%–4%) Heart valve replacement Coronary artery bypass surgery Abdominal aortic aneurysm repair Neurosurgical/urological/head and neck/abdominal/breast cancer surgery Bilateral knee arthroplasty Laminectomy Transurethral prostate resection Kidney biopsy Polypectomy, variceal treatment, biliary sphincterotomy, pneumatic dilatation PEG placement Endoscopically guided fine-needle aspiration Multiple tooth extractions (. 3) Vascular and general surgery Most major operations lasting . 45 minutes Spinal/epidural anesthesia (based on expert opinion) Low-Risk (2-day risk of major bleed 0%–2%) Abdominal hysterectomy Gastrointestinal endoscopy ± biopsy, enteroscopy, biliary/pancreatic stent without sphincterotomy, endosonography without fine-needle aspiration Pacemaker and cardiac defibrillator insertion and electrophysiologic testing Simple dental extractions Carpal tunnel repair Knee/hip arthroplasty and shoulder/foot/hand surgery and arthroscopy Dilatation and curettage Skin cancer excision Abdominal hernia repair Hemorrhoid surgery Axillary node dissection Hydrocele repair Cataract and non-cataract eye surgery Noncoronary angiography Bronchoscopy ± biopsy Central venous catheter removal Cutaneous and bladder/prostate/thyroid/breast/lymph node biopsies Abbreviation: PEG, percutaneous endoscopic gastrostomy. From Spyropoulos AC, Douketis JD. How I treat anticoagulated patients undergoing an elective procedure or surgery. Blood. 2012;120(15):2954–2962.8 © 2012, The American Society of Hematology. Used with permission.
as well.9 Omran et al9 found that a HAS-BLED score of $ 3 was highly predictive of perioperative hemorrhage among patients on long-term anticoagulation therapy who underwent a scheduled invasive procedure.9 Patient-specific risk for thrombosis varies with a number of factors, including the indication for anticoagulation, high CHADS2 or CHA2DS2-VASc score (Table 4) in AF, recent (# 3 months) venous thromboembolism (VTE), and active malignancy (summarized in Table 5). Once assessment of bleeding risk and thrombosis risk has been made, an anticoagulation strategy can be devised to address the timing of TSOAC cessation and resumption relative to surgery and whether or not bridging anticoagulation should be administered.
© Hospital Practice, Volume 42, Issue 1, February 2014, ISSN – 2154-8331 39 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.
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Table 3. The HAS-BLED Score30,31
H A S B L E D
Risk Factor
Points
Score
Bleeds/100 Patient-Years for Patients with AF
Annual Bleeding Risk for Patients with AF, %
Hypertension (. 160 mm Hg SBP) Abnormal renal and/or liver function Stroke Bleeding history or diathesis
+1 +1 or +2 +1 +1 +1 +1 +1 or +2 0–9
1 2 3 4 5
1.02 1.88 3.74 8.70 12.50
3.4 4.1 5.8 8.9 9.1
$6
$ 12.50
$ 9.1
Labile INR (TTR , 60%) Elderly (aged . 65 years) Drugs/Alcohol (1 point each) Total
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Abbreviations: AF, atrial fibrillation; INR, international normalized ratio; SBP, systolic blood pressure; TTR, time in therapeutic range.
Timing of Preoperative Cessation
Timing of preoperative anticoagulant cessation needs to take into account operative bleeding risk, desired level of anticoagulation at the time of surgery, and expected clearance of the agent. For dabigatran, which has a half-life of 14 to 17 hours and is 80% renally cleared, the length of effect after cessation varies inversely with creatinine clearance.10 For a patient with normal renal function, drug interruption 48 hours prior to procedure is expected to allow return of physiologic hemostasis.7,10 Expert opinion suggests that for interventions with low bleeding risk (for instance, procedures in which an international normalized ratio [INR] of 1.5 in a warfarin-treated patient would be safe), holding dabigatran for only 24 hours preoperatively is reasonable.7 Minor dental procedures, such as extraction of 1 to 3 teeth, are considered low risk by expert opinion.11,12 In the setting of renal dysfunction, a longer interval should be allowed between dabigatran interruption and surgery, as shown in Table 6.
An analysis of the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, which demonstrated a lower ischemic stroke rate with use of dabigatran 150 mg twice daily compared with warfarin in patients with nonvalvular AF,13 examined the outcomes of patients who underwent planned or urgent invasive procedures during the trial period.6 A total of 4591 patients were included in the analysis. Major perioperative bleeding occurred in 3% to 5% of patients with no significant difference among the dabigatran-110 mg-, dabigatran-150 mg-, and warfarintreated groups.6 Dabigatran use was interrupted on average 49 hours preoperatively, whereas warfarin was held an average of 114 hours pre-procedure.6 Among patients undergoing urgent surgery, rates of major bleeding were higher in the cohort as a whole (17%–21%), but similar among the 3 trial groups.6 The RE-LY analysis suggests that dabigatran provides comparable perioperative patient safety to warfarin and supports the relevance of a 48-hour pre-procedural duration of drug interruption.
Table 4. The CHADS2 and CHA2DS2-VASc Scores32,33 Risk Factor
CHADS2 Points
CHA2DS2-VASc Points
CHA2DS2-VASc Score
Annual Stroke Risk, %
C H A
Congestive heart failure Hypertension ($ 140/90 mm Hg) Age
+1 +1 +1 ($ 75 years)
1 2 3
1.3 2.2 3.2
D S V S
Diabetes Mellitus Stroke/TIA/Thromboembolism Vascular disease Sex
+1 +2 -
4 5 6
4.0 6.7 9.8
$7
$ 9.5
Total
0–6
+1 +1 +1 ($ 65 years) or +2 ($ 75 years) +1 +2 +1 +0 (Men) or +1 (Women) 0–9
Abbreviation: TIA, transient ischemic attack.
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Perioperative Management of TSOACs
Table 5. Risk Stratification for Perioperative Thromboembolism12 Risk category
MHV
Atrial Fibrillation
VTE
High (. 10%/y risk of ATE or . 10%/mo risk of VTE)
Any mechanical mitral valve
CHADS2 score of 5 or 6
Recent (, 3 mo) VTE
Caged-ball or tilting disc valve in mitral/aortic position
Recent (, 3 mo) stroke or TIA
Severe thrombophilia
Intermediate (4%–10%/y risk of ATE or 4%–10%/mo risk of VTE)
Rheumatic valvular heart disease
Bileaflet AVR with major risk factors for stroke
CHADS2 score of 3 or 4
Recurrent VTE Nonsevere thrombophilia Active cancer VTE . 12 mo ago
CHADS2 score of 0–2 (and no prior stroke or TIA)
Bileaflet AVR without major risk factors for stroke
Low (, 4%/y risk of ATE or , 2%/mo risk of VTE)
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Recent (, 6 mo) stroke or TIA
Deficiency of protein C, protein S or antithrombin Antiphospholipid antibodies Multiple thrombophilias VTE within past 3–12 mo
Note: TSOACs are not indicated in the setting of mechanical heart valves. From Douketis JD, Spyropoulos AC, Spencer FA, et al; American College of Chest Physicians. 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(4):e326S–e350S.12 ©2012, The American College of Chest Physicians. Reprinted with permission. Abbreviations: TIA indicates transient ischemic attack; AVR, aortic valve replacement; ATE, arterial thromboembolism;VTE, venous thromboembolism; and MHV, mechanical heart valve.
For procedures with low bleeding risk, interruption of oral factor Xa inhibitors 24 hours preoperatively is likely sufficient.6 For high-risk procedures, holding the drug for 48 hours is recommended.11 Clearance of oral factor Xa inhibitors is one-third to one-half renal, thus it is only in the setting of significant renal impairment that a longer duration of cessation becomes necessary. For a patient with a creatinine clearance of 15 to 30 mL/min, undergoing a low-risk procedure, drug interruption for at $ 36 hours is recommended,11 whereas for a high-risk procedure, the drug should be held 48 to 96 hours prior.6,7 These recommendations are summarized in Table 6.
Resumption Postoperatively
Similar to preoperative cessation, the timing of postoperative anticoagulant resumption needs to account for operative and patient-specific factors, such as type of procedure,
adequacy of hemostasis, and likelihood of need for further procedures/reoperation. Treating physicians must keep in mind that the TSOAC will reach its peak effect within 1 to 4 hours of administration and there are no specific reversal agents should bleeding ensue. Importantly, patient intestinal absorption must be intact for the enteral agents to be effective. For most procedures, including major interventions in which there is a high postoperative risk of hemorrhage with therapeutic anticoagulation, or bleeding would be catastrophic (such as neurosurgical interventions), resumption of the agent should be deferred until adequate hemostasis is assured, and at a minimum, after 48 to 72 hours.7,11 For patients undergoing low-risk procedures in whom complete hemostasis is achieved immediately and no further interventions are expected, expert opinion suggests that TSOACs can be resumed after a minimum of 6 to 8 hours.7,11 It is reasonable, though not supported by evidence, to give a lower
Table 6. Timing of Cessation of TSOAC Prior to Low- and High-Bleeding Risk Invasive Procedures5,7,8,12 Creatinine Clearance (mL/min) . 60 30–60 15–30 , 15
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
Estimated Half-life (hrs)
LOW RISK (hrs)
HIGH RISK (hrs)
Estimated Half-life (hrs)
LOW RISK (hrs)
HIGH RISK (hrs)
Estimated Half-life (hrs)
LOW RISK (hrs)
HIGH RISK (hrs)
Estimated Half-life (hrs)
LOW RISK (hrs)
HIGH RISK (hrs)
14 18 28 Unknown
$ 24 $ 48 $ 48 $ 96
$ 48 $ 96 $ 96 $ 120
8.5 9 9.5 Unknown
$ 24 $ 24 $ 36 $ 96
$ 48 $ 48 $ 48 $ 96
7.5 17.5
$ 24 $ 24 $ 36 $ 96
$ 48 $ 48 $ 48 $ 96
8.6 9.4 17
$ 24 $ 24 $ 36 Unknown
$ 48 $ 48 $ 48 Unknown
$ 17.5 $ 17.5
$ 17
Abbreviation: TSOAC, target-specific oral anticoagulants. © Hospital Practice, Volume 42, Issue 1, February 2014, ISSN – 2154-8331 41 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.
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initial postoperative dose (75 mg for dabigatran, 10 mg for rivaroxaban) and then resume full-dose anticoagulation with the next scheduled administration.7
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Bridging Therapy
The predictable ebb of the anticoagulant effect of TSOACs likely makes bridging therapy unnecessary in most planned, uncomplicated procedures in which the agent can be resumed promptly postoperatively.6,11 There are currently no guidelines to direct decisions in this area, though patients at high risk for thromboembolism in whom an extended postoperative course without TSOAC administration is anticipated may benefit from bridging therapy. In such patients, the decision to bridge needs to take into account the patient’s specific risk for thromboembolism (Tables 4 and 5), as well as risk for bleeding, including type of procedure (Table 2) and underlying bleeding diathesis (Table 3). Expert opinion suggests that for patients at high risk for thromboembolism it is reasonable to extrapolate from guidelines recommending consideration of bridging therapy for interruption of VKA therapy and provide a parenteral bridge for patients who interrupt TSOAC use . 3 days preoperatively or resume . 3 days postoperatively.8 In a patient with normal renal function, the half-life of unfractionated heparin (UFH) is approximately 2 hours, which is roughly the expected time until peak effect for the TSOACs. Therefore, for patients who do receive bridging therapy postoperatively, TSOACs can be resumed at the
time the UFH drip is turned off. For low molecular-weight heparins (LMWH), expert opinion recommends beginning the TSOAC when the next LMWH dose would have been due.11 This approach to risk assessment, timing of cessation and resumption, and the role for bridging therapy is depicted graphically in Figure 1.
Urgent Surgery
If possible, surgery should be delayed 12 to 24 hours after the last dose of a TSOAC.6,7,11 When surgery must be undertaken more rapidly, or when there is reason to suspect decreased clearance, it would be advantageous to measure the patient’s level of anticoagulation and to have some means of reversing the anticoagulant effect. Whereas clinicians are familiar with measurement of effect with VKAs, TSOACs present a challenge. The first consideration is to know as precisely as possible when the agent was last administered; the largely predictable pharmacokinetics of these drugs allow some estimation of the anticoagulant effect, absent renal or hepatic dysfunction. 11 Dabigatran, rivaroxaban, apixaban, and edoxaban all reach peak plasma level in 1 to 4 hours after ingestion in patients with normal clearance and no drug–drug interactions, with trough levels occurring 12 to 24 hours after ingestion (16–24 hours for rivaroxaban).11 The anticoagulant effect of dabigatran can be grossly estimated by the activated partial thromboplastin time (aPTT), diluted thrombin time (dTT), or ecarin clotting time (ECT).
Figure 1. A summary algorithm for perioperative TSOAC management.
Abbreviation: TSOAC, target-specific oral anticoagulant.
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Perioperative Management of TSOACs
Prothrombin time (PT) and the INR are not informative.11 Activated partial thromboplastin time increases in a curvilinear fashion with dabigatran plasma concentration, but plateaus at concentrations . 200 ng/mL.10,14 It may be used as a qualitative measurement of effect in which a trough aPTT . 2 times the upper limit of normal may suggest significant bleeding risk.10,11,15 Diluted thrombin time has a linear relationship with dabigatran concentration that is preserved at high concentrations14 but is susceptible to variation with testing reagents.16 A dTT assay calibrated for dabigatran is commercially available in Europe and indicates significant bleeding risk with dTT . 65 s, which corresponds to a dabigatran concentration . 200 ng/mL.15,16 Ecarin clotting time is not widely available but may offer a more direct measure of dabigatran’s effect. A trough ECT . 3 times the upper limit of normal suggests a heightened bleeding risk.15 The oral factor Xa inhibitors prolong the PT linearly with drug concentration.11,17 The extent of prolongation varies with the particular agent used as well as the institution’s assay18; therefore, institution- and drug-specific calibration are required for quantitative measurement of anticoagulant effect, and knowing the time since last dose is critical as the effect on PT is transient and time-dependent.11,18 The antiFXa level can also be measured reliably with oral factor Xa inhibitors, but no data yet exist on the correlation between anti-FXa level and bleeding risk.11,19 Because of institutional variation and difficulty interpreting these values, interdisciplinary consultation including pharmacy and laboratory personnel is recommended. For dabigatran, a reasonable initial approach is to measure aPTT and dTT for a qualitative assessment of whether there is significant drug activity, or to measure ECT if available. For Xa inhibitors, an institutionally calibrated PT should be obtained if possible; otherwise, standard PT and anti-Xa levels should be measured for a gross description of drug effect. These tests are summarized in Table 7.
Options for reversal of the anticoagulant effect of dabigatran are limited and specific antidotes are not yet commercially available.20 There is no role for fresh frozen plasma, except for plasma volume expansion in patients requiring massive transfusion; vitamin K is similarly of no utility unless there is a concomitant, marked vitamin K deficiency.11 There is conflicting evidence that prothrombin complex concentrate (PCC; factors II, VII, IX, and X) may be beneficial in dabigatran reversal.17,21 Pragst et al21 found that in rabbits treated with dabigatran that underwent an experimental kidney incision, time to hemostasis was lower with the administration of PCC. Eerenberg et al17 showed, however, that in healthy human volunteers, PCC, at a dose of 50 U/kg did not reverse the impact of dabigatran on aPTT, dTT, and ECT.17 Activated PCC, which contains activated factor VII (FVIIa), is more pro-coagulant than standard PCC.22 An analysis of trials of recombinant FVIIa (rFVIIa) found an increased risk of myocardial infarction and stroke among patients receiving rFVIIa compared with controls.23 Hemodialysis may also be considered because dabigatran is minimally protein bound (35%),10 though there are only case reports and small series to recommend its use.24–27 If renal function is intact, pharmacologic diuresis may promote drug clearance. Finally, a synthetic reversal agent which directly binds dabigatran and the FXa inhibitors, PER977 (aripazine), has been shown to restore laboratory coagulant function in human blood and reduce bleeding volume in rats, and is now under clinical investigation in humans.28 For the factor Xa inhibitors, PCC and rFVIIa may provide some benefit, though the risk of arterial thromboembolism needs to be considered as well.23 Laboratory measurements of rivaroxaban effect have been shown to reverse in healthy volunteers with PCC, and to a larger extent, with rFVIIa,17,22 though reduced bleeding has not been demonstrated with PCC or rFVIIa.29 The factor Xa inhibitors are highly protein bound and not expected to be cleared by dialysis.
Table 7. Laboratory Assessment of Anticoagulant Effect of the TSOACs Agent
PT
aPTT
Anti-FXa
--
High bleeding risk if trough value $ 2 x ULN
--
Increases linearly; requires institutional calibration
--
Dabigatran
Factor Xa inhibitors
Increases with anticoagulant effect; threshold for bleeding risk not yet identified
dTT
ECT
High bleeding risk if calibrated trough . 65 sec (available in Europe)
High bleeding risk if trough $ 3x ULN
--
--
Abbreviations: Anti-FXa, anti-activated factor X; aPTT, activated partial thromboplastin time; dTT, diluted thrombin time; ECT, ecarin clotting time; PT, prothrombin time; ULN, upper limit of normal; TSOAC, target-specific oral anticoagulants. © Hospital Practice, Volume 42, Issue 1, February 2014, ISSN – 2154-8331 43 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.
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Based on these data, it is reasonable to consider administration of PCC (25 U/kg) or aPCC (50 U/kg) when reversal of dabigatran or an oral Xa inhibitor is necessary in the setting of emergent major surgery or life-threatening bleeding. Recombinant FVIIa (90 µg/kg) may also be considered for reversal of the Xa inhibitors. It is important to keep in mind that the use of pro-coagulants to reverse the anticoagulant effect of TSOACs has not been well studied in humans and raises significant safety concerns given the increased risk of myocardial infarction and stroke associated with these agents.23 Diuresis should be pursued for dabigatran clearance if otherwise clinically appropriate, and hemodialysis is a further consideration.
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Conclusion
The TSOACs offer rapid onset and a more predictable pharmacokinetic profile compared with VKAs. Management of these agents in the perioperative setting is made challenging by the difficulty of measuring their anticoagulant effect and the lack of effective reversal agents, which is particularly consequential when urgent intervention is needed. To date, perioperative strategies remain largely predicated on extrapolations from pharmacokinetics rather than randomized trials. Surgical planning must account for patient bleeding risk and thrombosis, type of procedure, and expected drug clearance. Based on these considerations, a perioperative plan encompassing timing of TSOAC cessation and resumption, as well as bridging therapy, if needed, can be developed. Ongoing investigation aims to address the challenges we describe and will provide needed guidance for the safe and effective use of these agents perioperatively.
Conflict of Interest Statment
Brian Bergmark, MD, discloses no conflicts of interest. Robert P. Giugliano, MD, SM, is a consultant, member of the advisory committee/board, has received research funding, and been awarded honoraria for presenting continuing medical education (CME) lectures from Daiichi Sankyo; he is a consultant and CME lecturer for Sanofi; he is a consultant, member of the advisory committee/board, recipient of research/grant funding, and a CME lecturer for Merck. Dr Giugliano is a consultant and a member of the advisory committee/board of Janssen; he has received honoraria for presenting CME lectures for Bristol-Myers Squibb.
References 1. Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–1151.
2. Connolly SJ, Eikelboom J, Joyner C, et al; AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364(9):806–817. 3. Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–891. 4. U.S. Food and Drug Administration. FDA approves Pradaxa to prevent stroke in people with atrial fibrillation [press release]. 2010. http://www. fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm230241. htm. Accessed November 13, 2013. 5. Giugliano RP, Ruff CT, Braunwald E, et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093–2104. 6. Healey JS, Eikelboom J, Douketis J, et al; RE-LY Investigators. Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the randomized evaluation of longterm anticoagulation therapy (RE-LY) randomized trial. Circulation. 2012;126(3):343–348. 7. Schulman S, Crowther MA. How I treat with anticoagulants in 2012: new and old anticoagulants, and when and how to switch. Blood. 2012;119(13):3016–3023. 8. Spyropoulos AC, Douketis JD. How I treat anticoagulated patients undergoing an elective procedure or surgery. Blood. 2012;120(15): 2954–2962. 9. Omran H, Bauersachs R, Ruebenacker 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(1):65–73. 10. Stangier J, Rathgen K, Stähle H, Gansser D, Roth W. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol. 2007;64(3):292–303. 11. Heidbuchel H, Verhamme P, Alings M, et al; European Heart Rhythm Association. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2013;15(15):625–651. 12. Douketis JD, Spyropoulos AC, Spencer FA, et al; American College of Chest Physicians. 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(4):e326S-e350S. 13. Schulman S, Kearon C, Kakkar AK, et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342–2352. 14. Baglin T, Keeling D, Kitchen S; British Committee for Standards in Haematology. Effects on routine coagulation screens and assessment of anticoagulant intensity in patients taking oral dabigatran or rivaroxaban: guidance from the British Committee for Standards in Haematology. Br J Haematol. 2012;159(4):427–429. 15. Huisman MV, Lip GY, Diener H, Brueckmann M, van Ryn J, Clemens A. Dabigatran etexilate for stroke prevention in patients with atrial fibrillation: resolving uncertainties in routine practice. Thromb Haemost. 2012;107(5):838–847. 16. Stangier J, Feuring M. Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis. 2012;23(2):138–343. 17. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124(14):1573–1579. 18. Mueck W, Lensing AW, Agnelli G, Décousus H, Prandoni P, Misselwitz F. Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation Treated for Stroke Prevention. Clin Pharmacokinet. 2011;50(10):675–686.
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Perioperative Management of TSOACs 19. Asmis L, Alberio L, Angelillo-Scherrer A, et al. Rivaroxaban: Quantification by anti-FXa assay and influence on coagulation tests: a study in 9 Swiss laboratories. Thromb Res. 2012;129(4):492–498. 20. Sarma A, Rossi JE, Connors JM, Giugliano RP. Dabigatran excess: case report and review of the literature. Cardiol Ther. 2013;1(2):111–124. 21. Pragst I, Zeitler S, Doerr B, et al. Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model. J Thromb Haemost. 2012;10(9):1841–1848. 22. Marlu R, Hodaj E, Paris A, Albaladejo P, Crackowski JL, Pernod G. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost. 2012;108(2):217–224. 23. Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med. 2010;363(19):1791–1800. 24. Khadzhynov D, Wagner F, Formella S, et al. Effective elimination of dabigatran by haemodialysis. A phase I single-centre study in patients with end-stage renal disease. Thromb Haemost. 2013;109(4):596–605. 25. Wanek MR, Horn ET, Elapavaluru S, Baroody SC, Sokos G. Safe use of hemodialysis for dabigatran removal before cardiac surgery. Ann Pharmacother. 2012;46(9):e21. 26. Warkentin TE, Margetts P, Connolly SJ, Lamy A, Ricci C, Eikelboom JW. Recombinant factor VIIa (rFVIIa) and hemodialysis to manage massive dabigatran-associated postcardiac surgery bleeding. Blood. 2012;119(9):2172–2174. 27. Chang DN, Dager WE, Chin AI. Removal of dabigatran by hemodialysis. Am J Kidney Dis. 2013;61(3):487–489.
28. Bakhru S, Laulicht B, Jiang X, et al. A synthetic small molecule antidote for anticoagulants [published online ahead of print September 1, 2013]. Eur Heart J. 2013;34(Suppl 1). doi:10.1093/eurheartj/eht308.1078. 29. Godier A, Miclot A, Le Bonniec B, et al. Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology. 2012;116(1):94–102. 30. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138(5):1093–1100. 31. Lip GY, Frison L, Halperin JL, Lane DA. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS-BLED (Hypertension, Abnormal Renal/ Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) Score. J Am Coll Cardiol. 2011;57(2):173–180. 32. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: The Euro Heart Survey on Atrial Fibrillation. Chest. 2010;137(2):263–272. 33. European Heart Rhythm Association; European Association for CardioThoracic Surgery; Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010;31(19):2369–2429. 34. The Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment symptomatic venous thromboembolism. N Engl J Med. 2013; 369(15):1406-1415.
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ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20
Perioperative Management of Target-Specific Oral Anticoagulants Brian Bergmark MD & Robert P. Giugliano MD, SM To cite this article: Brian Bergmark MD & Robert P. Giugliano MD, SM (2014) Perioperative Management of Target-Specific Oral Anticoagulants, Hospital Practice, 42:1, 38-45 To link to this article: http://dx.doi.org/10.3810/hp.2014.02.1090
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Date: 05 November 2015, At: 15:45
C l i n i c a l F o c u s : H o s p i ta l A d m i s s i o n s , L at e s t P r o t o c o l s , P r e o p e r a t i v e M e d i c i n e , a n d T r a n s i t i o n s o f C a r e
Perioperative Management of Target-Specific Oral Anticoagulants
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DOI: 10.3810/hp.2014.02.1090
Brian Bergmark, MD 1 Robert P. Giugliano, MD, SM 2 1 Department of Medicine, Brigham and Women’s Hospital, Boston, MA; 2Department of Medicine, Cardiovascular Division, Brigham and Women’s Hospital; Harvard Medical School; Thrombolysis in Myocardial Infarction (TIMI) Study Group, Boston, MA
Abstract: Target-specific oral anticoagulants (TSOACs), which offer rapid onset and more predictable pharmacokinetics/dynamics compared with vitamin K antagonists, are rapidly growing in number and approved indications. At least 1 in 10 Americans receiving outpatient anticoagulant therapy requires interruption of anticoagulation for an invasive procedure annually, and management of these new agents in the perioperative setting is made challenging by difficulty measuring anticoagulant effect and the lack of effective reversal. Surgical planning must account for individual patient risks for bleeding and thrombosis, the type of procedure, and expected drug clearance. Based upon these considerations, a perioperative plan encompassing timing of TSOAC cessation and resumption, as well as bridging therapy, if needed, can be developed. Perioperative strategies remain largely predicated on extrapolations from pharmacokinetics and expert opinion, though a growing body of literature is providing greater guidance in this important area. Keywords: anticoagulation; surgery; perioperative management; bleeding; novel oral anticoagulant
Introduction
Correspondence: Robert P. Giugliano, MD, SM, Department of Medicine, Brigham and Women’s Hospital, TIMI Study Office, 350 Longwood Avenue, 1st Floor, Boston, MA 02115. Tel: 617-278-0145 Fax: 617-734-7329 E-mail: [email protected]
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Use of vitamin K antagonists (VKAs) has been the mainstay of oral anticoagulation for decades. Though effective, warfarin and related drugs are limited by numerous drug and food interactions, significant inter-individual and intra-individual variations in drug effect, slow time of onset, narrow therapeutic window, and required, continuous monitoring. These challenges prompted the search for alternative agents with rapid onset, predictable pharmacokinetics and pharmacodynamics, and a wide therapeutic window, obviating the need for monitoring of effect.1–3 The first of these target-specific oral anticoagulants (TSOACs) to reach the US market was dabigatran, a direct thrombin inhibitor, which was approved by the US Food and Drug Administration (FDA) for treatment of patients with nonvalvular atrial fibrillation (AF) in 2010.4 Rivaroxaban and apixaban, both oral factor Xa inhibitors, have subsequently been approved and the number of indications for each drug is expanding (Table 1). Edoxaban, a third factor Xa inhibitor, was recently found to be noninferior to warfarin for stroke prevention in patients with nonvalvular AF. Edoxaban therapy was associated with lower rates of patient bleeding and cardiovascular death.5 As use of the TSOACs has accelerated, clinicians have become familiar with their limitations, which are principally related to an inability to accurately measure drug effect and lack of effective reversal of anticoagulation. These issues manifest as uncertainty regarding whether a patient is taking the medication as prescribed and difficulty
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Perioperative Management of TSOACs
Table 1. Approved Indications for TSOACs Agent
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Dabigatran FDA EMA Rivaroxaban FDA EMA Apixaban FDA EMA Edoxaban
Table 2. Procedural Bleeding Risks8
AF
Prevent VTE
Treat VTE
ACS
2010 2011
-2008
RE-MEDY7 RE-SONATE7
--
2011 2011
2011 2008
2012 2011
-2013
2012 2012 ENGAGE AF-TIMI 485
-2011 2011 (Japan)
AMPLIFY18
--
HOKUSAI-VTE34 --
Abbreviations: ACS, acute coronary syndromes; AF, atrial fibrillation; AMPLIFY, Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy; EMA, European Medicine Agency; ENGAGE AF – TIMI 48, Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation—Thrombolysis in Myocardial Infarction 48; FDA, (US) Food and Drug Administration; HOKUSAI-VTE, Edoxaban Versus Warfarin for the Treatment of Symptomatic Venous Thomboembolism; PE, pulmonary embolism; RE-MEDY/ RE-SONATE, Extended Use of Dabigatran, Warfarin, or Placebo in Venous Thromboembolism (vs warfarin, RE-MEDY; vs placebo, RE-SONATE);VTE, venous thromboembolism.
managing unplanned and planned bleeding (ie, surgery and invasive procedures). Perioperative TSOAC management is a particularly common challenge. In the United States, approximately 10% of patients receiving anticoagulation therapy require drug interruption for an invasive procedure annually.6 Important issues in perioperative management of anticoagulation include balancing the risk of bleeding and risk of thrombosis, timing of TSOAC cessation preoperatively, reinitiation postoperatively, transitioning among anticoagulants when bridging therapy is used, and managing unplanned procedures. A nascent body of evidence has begun to provide guidance in this setting, though recommendations remain largely predicated on extrapolations from pharmacokinetic/dynamic data and expert opinion.7
Assessment of Risk
The first consideration in perioperative management is assessment of patient risk for bleeding and for thrombosis. The risk assessment includes the type of operation planned, the indication for anticoagulation, and patient-specific factors predisposing to either bleeding or thrombosis. The type of procedure can be classified as high-risk for bleeding, defined as a 2% to 4% 2-day risk of major bleed; or low-risk, with a 0 to 2% chance of patient bleeding in the first 2 days.8 Table 2 provides examples of high- and low-risk procedures. Patient-level risk of bleeding can be quantified in the outpatient setting using the HAS-BLED score (Table 3), which may be reasonable to consider perioperatively
High-Risk (2-day risk of major bleed 2%–4%) Heart valve replacement Coronary artery bypass surgery Abdominal aortic aneurysm repair Neurosurgical/urological/head and neck/abdominal/breast cancer surgery Bilateral knee arthroplasty Laminectomy Transurethral prostate resection Kidney biopsy Polypectomy, variceal treatment, biliary sphincterotomy, pneumatic dilatation PEG placement Endoscopically guided fine-needle aspiration Multiple tooth extractions (. 3) Vascular and general surgery Most major operations lasting . 45 minutes Spinal/epidural anesthesia (based on expert opinion) Low-Risk (2-day risk of major bleed 0%–2%) Abdominal hysterectomy Gastrointestinal endoscopy ± biopsy, enteroscopy, biliary/pancreatic stent without sphincterotomy, endosonography without fine-needle aspiration Pacemaker and cardiac defibrillator insertion and electrophysiologic testing Simple dental extractions Carpal tunnel repair Knee/hip arthroplasty and shoulder/foot/hand surgery and arthroscopy Dilatation and curettage Skin cancer excision Abdominal hernia repair Hemorrhoid surgery Axillary node dissection Hydrocele repair Cataract and non-cataract eye surgery Noncoronary angiography Bronchoscopy ± biopsy Central venous catheter removal Cutaneous and bladder/prostate/thyroid/breast/lymph node biopsies Abbreviation: PEG, percutaneous endoscopic gastrostomy. From Spyropoulos AC, Douketis JD. How I treat anticoagulated patients undergoing an elective procedure or surgery. Blood. 2012;120(15):2954–2962.8 © 2012, The American Society of Hematology. Used with permission.
as well.9 Omran et al9 found that a HAS-BLED score of $ 3 was highly predictive of perioperative hemorrhage among patients on long-term anticoagulation therapy who underwent a scheduled invasive procedure.9 Patient-specific risk for thrombosis varies with a number of factors, including the indication for anticoagulation, high CHADS2 or CHA2DS2-VASc score (Table 4) in AF, recent (# 3 months) venous thromboembolism (VTE), and active malignancy (summarized in Table 5). Once assessment of bleeding risk and thrombosis risk has been made, an anticoagulation strategy can be devised to address the timing of TSOAC cessation and resumption relative to surgery and whether or not bridging anticoagulation should be administered.
© Hospital Practice, Volume 42, Issue 1, February 2014, ISSN – 2154-8331 39 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.
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Table 3. The HAS-BLED Score30,31
H A S B L E D
Risk Factor
Points
Score
Bleeds/100 Patient-Years for Patients with AF
Annual Bleeding Risk for Patients with AF, %
Hypertension (. 160 mm Hg SBP) Abnormal renal and/or liver function Stroke Bleeding history or diathesis
+1 +1 or +2 +1 +1 +1 +1 +1 or +2 0–9
1 2 3 4 5
1.02 1.88 3.74 8.70 12.50
3.4 4.1 5.8 8.9 9.1
$6
$ 12.50
$ 9.1
Labile INR (TTR , 60%) Elderly (aged . 65 years) Drugs/Alcohol (1 point each) Total
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Abbreviations: AF, atrial fibrillation; INR, international normalized ratio; SBP, systolic blood pressure; TTR, time in therapeutic range.
Timing of Preoperative Cessation
Timing of preoperative anticoagulant cessation needs to take into account operative bleeding risk, desired level of anticoagulation at the time of surgery, and expected clearance of the agent. For dabigatran, which has a half-life of 14 to 17 hours and is 80% renally cleared, the length of effect after cessation varies inversely with creatinine clearance.10 For a patient with normal renal function, drug interruption 48 hours prior to procedure is expected to allow return of physiologic hemostasis.7,10 Expert opinion suggests that for interventions with low bleeding risk (for instance, procedures in which an international normalized ratio [INR] of 1.5 in a warfarin-treated patient would be safe), holding dabigatran for only 24 hours preoperatively is reasonable.7 Minor dental procedures, such as extraction of 1 to 3 teeth, are considered low risk by expert opinion.11,12 In the setting of renal dysfunction, a longer interval should be allowed between dabigatran interruption and surgery, as shown in Table 6.
An analysis of the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, which demonstrated a lower ischemic stroke rate with use of dabigatran 150 mg twice daily compared with warfarin in patients with nonvalvular AF,13 examined the outcomes of patients who underwent planned or urgent invasive procedures during the trial period.6 A total of 4591 patients were included in the analysis. Major perioperative bleeding occurred in 3% to 5% of patients with no significant difference among the dabigatran-110 mg-, dabigatran-150 mg-, and warfarintreated groups.6 Dabigatran use was interrupted on average 49 hours preoperatively, whereas warfarin was held an average of 114 hours pre-procedure.6 Among patients undergoing urgent surgery, rates of major bleeding were higher in the cohort as a whole (17%–21%), but similar among the 3 trial groups.6 The RE-LY analysis suggests that dabigatran provides comparable perioperative patient safety to warfarin and supports the relevance of a 48-hour pre-procedural duration of drug interruption.
Table 4. The CHADS2 and CHA2DS2-VASc Scores32,33 Risk Factor
CHADS2 Points
CHA2DS2-VASc Points
CHA2DS2-VASc Score
Annual Stroke Risk, %
C H A
Congestive heart failure Hypertension ($ 140/90 mm Hg) Age
+1 +1 +1 ($ 75 years)
1 2 3
1.3 2.2 3.2
D S V S
Diabetes Mellitus Stroke/TIA/Thromboembolism Vascular disease Sex
+1 +2 -
4 5 6
4.0 6.7 9.8
$7
$ 9.5
Total
0–6
+1 +1 +1 ($ 65 years) or +2 ($ 75 years) +1 +2 +1 +0 (Men) or +1 (Women) 0–9
Abbreviation: TIA, transient ischemic attack.
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Perioperative Management of TSOACs
Table 5. Risk Stratification for Perioperative Thromboembolism12 Risk category
MHV
Atrial Fibrillation
VTE
High (. 10%/y risk of ATE or . 10%/mo risk of VTE)
Any mechanical mitral valve
CHADS2 score of 5 or 6
Recent (, 3 mo) VTE
Caged-ball or tilting disc valve in mitral/aortic position
Recent (, 3 mo) stroke or TIA
Severe thrombophilia
Intermediate (4%–10%/y risk of ATE or 4%–10%/mo risk of VTE)
Rheumatic valvular heart disease
Bileaflet AVR with major risk factors for stroke
CHADS2 score of 3 or 4
Recurrent VTE Nonsevere thrombophilia Active cancer VTE . 12 mo ago
CHADS2 score of 0–2 (and no prior stroke or TIA)
Bileaflet AVR without major risk factors for stroke
Low (, 4%/y risk of ATE or , 2%/mo risk of VTE)
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Recent (, 6 mo) stroke or TIA
Deficiency of protein C, protein S or antithrombin Antiphospholipid antibodies Multiple thrombophilias VTE within past 3–12 mo
Note: TSOACs are not indicated in the setting of mechanical heart valves. From Douketis JD, Spyropoulos AC, Spencer FA, et al; American College of Chest Physicians. 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(4):e326S–e350S.12 ©2012, The American College of Chest Physicians. Reprinted with permission. Abbreviations: TIA indicates transient ischemic attack; AVR, aortic valve replacement; ATE, arterial thromboembolism;VTE, venous thromboembolism; and MHV, mechanical heart valve.
For procedures with low bleeding risk, interruption of oral factor Xa inhibitors 24 hours preoperatively is likely sufficient.6 For high-risk procedures, holding the drug for 48 hours is recommended.11 Clearance of oral factor Xa inhibitors is one-third to one-half renal, thus it is only in the setting of significant renal impairment that a longer duration of cessation becomes necessary. For a patient with a creatinine clearance of 15 to 30 mL/min, undergoing a low-risk procedure, drug interruption for at $ 36 hours is recommended,11 whereas for a high-risk procedure, the drug should be held 48 to 96 hours prior.6,7 These recommendations are summarized in Table 6.
Resumption Postoperatively
Similar to preoperative cessation, the timing of postoperative anticoagulant resumption needs to account for operative and patient-specific factors, such as type of procedure,
adequacy of hemostasis, and likelihood of need for further procedures/reoperation. Treating physicians must keep in mind that the TSOAC will reach its peak effect within 1 to 4 hours of administration and there are no specific reversal agents should bleeding ensue. Importantly, patient intestinal absorption must be intact for the enteral agents to be effective. For most procedures, including major interventions in which there is a high postoperative risk of hemorrhage with therapeutic anticoagulation, or bleeding would be catastrophic (such as neurosurgical interventions), resumption of the agent should be deferred until adequate hemostasis is assured, and at a minimum, after 48 to 72 hours.7,11 For patients undergoing low-risk procedures in whom complete hemostasis is achieved immediately and no further interventions are expected, expert opinion suggests that TSOACs can be resumed after a minimum of 6 to 8 hours.7,11 It is reasonable, though not supported by evidence, to give a lower
Table 6. Timing of Cessation of TSOAC Prior to Low- and High-Bleeding Risk Invasive Procedures5,7,8,12 Creatinine Clearance (mL/min) . 60 30–60 15–30 , 15
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
Estimated Half-life (hrs)
LOW RISK (hrs)
HIGH RISK (hrs)
Estimated Half-life (hrs)
LOW RISK (hrs)
HIGH RISK (hrs)
Estimated Half-life (hrs)
LOW RISK (hrs)
HIGH RISK (hrs)
Estimated Half-life (hrs)
LOW RISK (hrs)
HIGH RISK (hrs)
14 18 28 Unknown
$ 24 $ 48 $ 48 $ 96
$ 48 $ 96 $ 96 $ 120
8.5 9 9.5 Unknown
$ 24 $ 24 $ 36 $ 96
$ 48 $ 48 $ 48 $ 96
7.5 17.5
$ 24 $ 24 $ 36 $ 96
$ 48 $ 48 $ 48 $ 96
8.6 9.4 17
$ 24 $ 24 $ 36 Unknown
$ 48 $ 48 $ 48 Unknown
$ 17.5 $ 17.5
$ 17
Abbreviation: TSOAC, target-specific oral anticoagulants. © Hospital Practice, Volume 42, Issue 1, February 2014, ISSN – 2154-8331 41 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.
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initial postoperative dose (75 mg for dabigatran, 10 mg for rivaroxaban) and then resume full-dose anticoagulation with the next scheduled administration.7
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Bridging Therapy
The predictable ebb of the anticoagulant effect of TSOACs likely makes bridging therapy unnecessary in most planned, uncomplicated procedures in which the agent can be resumed promptly postoperatively.6,11 There are currently no guidelines to direct decisions in this area, though patients at high risk for thromboembolism in whom an extended postoperative course without TSOAC administration is anticipated may benefit from bridging therapy. In such patients, the decision to bridge needs to take into account the patient’s specific risk for thromboembolism (Tables 4 and 5), as well as risk for bleeding, including type of procedure (Table 2) and underlying bleeding diathesis (Table 3). Expert opinion suggests that for patients at high risk for thromboembolism it is reasonable to extrapolate from guidelines recommending consideration of bridging therapy for interruption of VKA therapy and provide a parenteral bridge for patients who interrupt TSOAC use . 3 days preoperatively or resume . 3 days postoperatively.8 In a patient with normal renal function, the half-life of unfractionated heparin (UFH) is approximately 2 hours, which is roughly the expected time until peak effect for the TSOACs. Therefore, for patients who do receive bridging therapy postoperatively, TSOACs can be resumed at the
time the UFH drip is turned off. For low molecular-weight heparins (LMWH), expert opinion recommends beginning the TSOAC when the next LMWH dose would have been due.11 This approach to risk assessment, timing of cessation and resumption, and the role for bridging therapy is depicted graphically in Figure 1.
Urgent Surgery
If possible, surgery should be delayed 12 to 24 hours after the last dose of a TSOAC.6,7,11 When surgery must be undertaken more rapidly, or when there is reason to suspect decreased clearance, it would be advantageous to measure the patient’s level of anticoagulation and to have some means of reversing the anticoagulant effect. Whereas clinicians are familiar with measurement of effect with VKAs, TSOACs present a challenge. The first consideration is to know as precisely as possible when the agent was last administered; the largely predictable pharmacokinetics of these drugs allow some estimation of the anticoagulant effect, absent renal or hepatic dysfunction. 11 Dabigatran, rivaroxaban, apixaban, and edoxaban all reach peak plasma level in 1 to 4 hours after ingestion in patients with normal clearance and no drug–drug interactions, with trough levels occurring 12 to 24 hours after ingestion (16–24 hours for rivaroxaban).11 The anticoagulant effect of dabigatran can be grossly estimated by the activated partial thromboplastin time (aPTT), diluted thrombin time (dTT), or ecarin clotting time (ECT).
Figure 1. A summary algorithm for perioperative TSOAC management.
Abbreviation: TSOAC, target-specific oral anticoagulant.
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Perioperative Management of TSOACs
Prothrombin time (PT) and the INR are not informative.11 Activated partial thromboplastin time increases in a curvilinear fashion with dabigatran plasma concentration, but plateaus at concentrations . 200 ng/mL.10,14 It may be used as a qualitative measurement of effect in which a trough aPTT . 2 times the upper limit of normal may suggest significant bleeding risk.10,11,15 Diluted thrombin time has a linear relationship with dabigatran concentration that is preserved at high concentrations14 but is susceptible to variation with testing reagents.16 A dTT assay calibrated for dabigatran is commercially available in Europe and indicates significant bleeding risk with dTT . 65 s, which corresponds to a dabigatran concentration . 200 ng/mL.15,16 Ecarin clotting time is not widely available but may offer a more direct measure of dabigatran’s effect. A trough ECT . 3 times the upper limit of normal suggests a heightened bleeding risk.15 The oral factor Xa inhibitors prolong the PT linearly with drug concentration.11,17 The extent of prolongation varies with the particular agent used as well as the institution’s assay18; therefore, institution- and drug-specific calibration are required for quantitative measurement of anticoagulant effect, and knowing the time since last dose is critical as the effect on PT is transient and time-dependent.11,18 The antiFXa level can also be measured reliably with oral factor Xa inhibitors, but no data yet exist on the correlation between anti-FXa level and bleeding risk.11,19 Because of institutional variation and difficulty interpreting these values, interdisciplinary consultation including pharmacy and laboratory personnel is recommended. For dabigatran, a reasonable initial approach is to measure aPTT and dTT for a qualitative assessment of whether there is significant drug activity, or to measure ECT if available. For Xa inhibitors, an institutionally calibrated PT should be obtained if possible; otherwise, standard PT and anti-Xa levels should be measured for a gross description of drug effect. These tests are summarized in Table 7.
Options for reversal of the anticoagulant effect of dabigatran are limited and specific antidotes are not yet commercially available.20 There is no role for fresh frozen plasma, except for plasma volume expansion in patients requiring massive transfusion; vitamin K is similarly of no utility unless there is a concomitant, marked vitamin K deficiency.11 There is conflicting evidence that prothrombin complex concentrate (PCC; factors II, VII, IX, and X) may be beneficial in dabigatran reversal.17,21 Pragst et al21 found that in rabbits treated with dabigatran that underwent an experimental kidney incision, time to hemostasis was lower with the administration of PCC. Eerenberg et al17 showed, however, that in healthy human volunteers, PCC, at a dose of 50 U/kg did not reverse the impact of dabigatran on aPTT, dTT, and ECT.17 Activated PCC, which contains activated factor VII (FVIIa), is more pro-coagulant than standard PCC.22 An analysis of trials of recombinant FVIIa (rFVIIa) found an increased risk of myocardial infarction and stroke among patients receiving rFVIIa compared with controls.23 Hemodialysis may also be considered because dabigatran is minimally protein bound (35%),10 though there are only case reports and small series to recommend its use.24–27 If renal function is intact, pharmacologic diuresis may promote drug clearance. Finally, a synthetic reversal agent which directly binds dabigatran and the FXa inhibitors, PER977 (aripazine), has been shown to restore laboratory coagulant function in human blood and reduce bleeding volume in rats, and is now under clinical investigation in humans.28 For the factor Xa inhibitors, PCC and rFVIIa may provide some benefit, though the risk of arterial thromboembolism needs to be considered as well.23 Laboratory measurements of rivaroxaban effect have been shown to reverse in healthy volunteers with PCC, and to a larger extent, with rFVIIa,17,22 though reduced bleeding has not been demonstrated with PCC or rFVIIa.29 The factor Xa inhibitors are highly protein bound and not expected to be cleared by dialysis.
Table 7. Laboratory Assessment of Anticoagulant Effect of the TSOACs Agent
PT
aPTT
Anti-FXa
--
High bleeding risk if trough value $ 2 x ULN
--
Increases linearly; requires institutional calibration
--
Dabigatran
Factor Xa inhibitors
Increases with anticoagulant effect; threshold for bleeding risk not yet identified
dTT
ECT
High bleeding risk if calibrated trough . 65 sec (available in Europe)
High bleeding risk if trough $ 3x ULN
--
--
Abbreviations: Anti-FXa, anti-activated factor X; aPTT, activated partial thromboplastin time; dTT, diluted thrombin time; ECT, ecarin clotting time; PT, prothrombin time; ULN, upper limit of normal; TSOAC, target-specific oral anticoagulants. © Hospital Practice, Volume 42, Issue 1, February 2014, ISSN – 2154-8331 43 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.
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Brian Bergmark and Robert P. Giugliano
Based on these data, it is reasonable to consider administration of PCC (25 U/kg) or aPCC (50 U/kg) when reversal of dabigatran or an oral Xa inhibitor is necessary in the setting of emergent major surgery or life-threatening bleeding. Recombinant FVIIa (90 µg/kg) may also be considered for reversal of the Xa inhibitors. It is important to keep in mind that the use of pro-coagulants to reverse the anticoagulant effect of TSOACs has not been well studied in humans and raises significant safety concerns given the increased risk of myocardial infarction and stroke associated with these agents.23 Diuresis should be pursued for dabigatran clearance if otherwise clinically appropriate, and hemodialysis is a further consideration.
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Conclusion
The TSOACs offer rapid onset and a more predictable pharmacokinetic profile compared with VKAs. Management of these agents in the perioperative setting is made challenging by the difficulty of measuring their anticoagulant effect and the lack of effective reversal agents, which is particularly consequential when urgent intervention is needed. To date, perioperative strategies remain largely predicated on extrapolations from pharmacokinetics rather than randomized trials. Surgical planning must account for patient bleeding risk and thrombosis, type of procedure, and expected drug clearance. Based on these considerations, a perioperative plan encompassing timing of TSOAC cessation and resumption, as well as bridging therapy, if needed, can be developed. Ongoing investigation aims to address the challenges we describe and will provide needed guidance for the safe and effective use of these agents perioperatively.
Conflict of Interest Statment
Brian Bergmark, MD, discloses no conflicts of interest. Robert P. Giugliano, MD, SM, is a consultant, member of the advisory committee/board, has received research funding, and been awarded honoraria for presenting continuing medical education (CME) lectures from Daiichi Sankyo; he is a consultant and CME lecturer for Sanofi; he is a consultant, member of the advisory committee/board, recipient of research/grant funding, and a CME lecturer for Merck. Dr Giugliano is a consultant and a member of the advisory committee/board of Janssen; he has received honoraria for presenting CME lectures for Bristol-Myers Squibb.
References 1. Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–1151.
2. Connolly SJ, Eikelboom J, Joyner C, et al; AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364(9):806–817. 3. Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–891. 4. U.S. Food and Drug Administration. FDA approves Pradaxa to prevent stroke in people with atrial fibrillation [press release]. 2010. http://www. fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm230241. htm. Accessed November 13, 2013. 5. Giugliano RP, Ruff CT, Braunwald E, et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093–2104. 6. Healey JS, Eikelboom J, Douketis J, et al; RE-LY Investigators. Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the randomized evaluation of longterm anticoagulation therapy (RE-LY) randomized trial. Circulation. 2012;126(3):343–348. 7. Schulman S, Crowther MA. How I treat with anticoagulants in 2012: new and old anticoagulants, and when and how to switch. Blood. 2012;119(13):3016–3023. 8. Spyropoulos AC, Douketis JD. How I treat anticoagulated patients undergoing an elective procedure or surgery. Blood. 2012;120(15): 2954–2962. 9. Omran H, Bauersachs R, Ruebenacker 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(1):65–73. 10. Stangier J, Rathgen K, Stähle H, Gansser D, Roth W. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol. 2007;64(3):292–303. 11. Heidbuchel H, Verhamme P, Alings M, et al; European Heart Rhythm Association. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2013;15(15):625–651. 12. Douketis JD, Spyropoulos AC, Spencer FA, et al; American College of Chest Physicians. 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(4):e326S-e350S. 13. Schulman S, Kearon C, Kakkar AK, et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342–2352. 14. Baglin T, Keeling D, Kitchen S; British Committee for Standards in Haematology. Effects on routine coagulation screens and assessment of anticoagulant intensity in patients taking oral dabigatran or rivaroxaban: guidance from the British Committee for Standards in Haematology. Br J Haematol. 2012;159(4):427–429. 15. Huisman MV, Lip GY, Diener H, Brueckmann M, van Ryn J, Clemens A. Dabigatran etexilate for stroke prevention in patients with atrial fibrillation: resolving uncertainties in routine practice. Thromb Haemost. 2012;107(5):838–847. 16. Stangier J, Feuring M. Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis. 2012;23(2):138–343. 17. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124(14):1573–1579. 18. Mueck W, Lensing AW, Agnelli G, Décousus H, Prandoni P, Misselwitz F. Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation Treated for Stroke Prevention. Clin Pharmacokinet. 2011;50(10):675–686.
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05_Bergmark.indd 44
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Perioperative Management of TSOACs 19. Asmis L, Alberio L, Angelillo-Scherrer A, et al. Rivaroxaban: Quantification by anti-FXa assay and influence on coagulation tests: a study in 9 Swiss laboratories. Thromb Res. 2012;129(4):492–498. 20. Sarma A, Rossi JE, Connors JM, Giugliano RP. Dabigatran excess: case report and review of the literature. Cardiol Ther. 2013;1(2):111–124. 21. Pragst I, Zeitler S, Doerr B, et al. Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model. J Thromb Haemost. 2012;10(9):1841–1848. 22. Marlu R, Hodaj E, Paris A, Albaladejo P, Crackowski JL, Pernod G. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost. 2012;108(2):217–224. 23. Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med. 2010;363(19):1791–1800. 24. Khadzhynov D, Wagner F, Formella S, et al. Effective elimination of dabigatran by haemodialysis. A phase I single-centre study in patients with end-stage renal disease. Thromb Haemost. 2013;109(4):596–605. 25. Wanek MR, Horn ET, Elapavaluru S, Baroody SC, Sokos G. Safe use of hemodialysis for dabigatran removal before cardiac surgery. Ann Pharmacother. 2012;46(9):e21. 26. Warkentin TE, Margetts P, Connolly SJ, Lamy A, Ricci C, Eikelboom JW. Recombinant factor VIIa (rFVIIa) and hemodialysis to manage massive dabigatran-associated postcardiac surgery bleeding. Blood. 2012;119(9):2172–2174. 27. Chang DN, Dager WE, Chin AI. Removal of dabigatran by hemodialysis. Am J Kidney Dis. 2013;61(3):487–489.
28. Bakhru S, Laulicht B, Jiang X, et al. A synthetic small molecule antidote for anticoagulants [published online ahead of print September 1, 2013]. Eur Heart J. 2013;34(Suppl 1). doi:10.1093/eurheartj/eht308.1078. 29. Godier A, Miclot A, Le Bonniec B, et al. Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology. 2012;116(1):94–102. 30. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138(5):1093–1100. 31. Lip GY, Frison L, Halperin JL, Lane DA. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS-BLED (Hypertension, Abnormal Renal/ Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) Score. J Am Coll Cardiol. 2011;57(2):173–180. 32. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: The Euro Heart Survey on Atrial Fibrillation. Chest. 2010;137(2):263–272. 33. European Heart Rhythm Association; European Association for CardioThoracic Surgery; Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010;31(19):2369–2429. 34. The Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment symptomatic venous thromboembolism. N Engl J Med. 2013; 369(15):1406-1415.
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![[Perioperative management of new oral anticoagulants].](/assets/img/hold.png)
