426 Original article
Adherence to guidelines for perioperative management of anticoagulation results in decreased bleeding complications: a single-centre experience Maria T. DeSancho, Svetoslava Bardarova and John Chapin Guidelines describing the perioperative management of antithrombotic therapy in patients requiring temporary interruption of vitamin K antagonists (VKAs) were first published in 2008. The objective of this study is to evaluate the perioperative management of anticoagulation of patients on chronic VKA and the incidence of bleeding and thrombotic complications pre and postpublication of the 2008 American College of Chest Physicians (ACCP) guidelines. A retrospective review of 40 patients on chronic VKA requiring temporary discontinuation of VKA due to an invasive or surgical procedure who were referred to a single haematology practice from January 2006 to June 2010. Demographics, indications of VKA, risk factors for thrombosis, type of procedure, bridging regimen and bleeding complications were recorded pre and post-2008 ACCP guidelines. Sixty-one procedures were performed in 40 patients; 60% were women. Indications for anticoagulation were secondary prevention of venous thrombosis (n U 27), arterial thrombosis (n U 8) or both arterial thrombosis and venous thrombosis (n U 4), and primary prevention of arterial thrombosis (n U 1). Twenty patients (50%) had thrombophilia. The most common surgical and invasive procedures were gastrointestinal (33%), gynaecological (15%) and orthopaedic (11%). Bridging regimen with therapeutic-dose subcutaneous low
Introduction In 2008, the American College of Chest Physicians (ACCP) published its first guidelines for the perioperative management of anticoagulation in patients on chronic vitamin K antagonist (VKA) therapy [1]. The guidelines recommended that patients on chronic VKA who require an invasive or surgical procedure discontinue VKA approximately 5 days before the procedure to assure proper haemostasis [2]. In some instances, however, patients may need to be bridged with a short-acting anticoagulant to minimize thromboembolic complications during the period of time that VKA is discontinued. Conversely, the bleeding risk may increase with the use of bridging anticoagulation. Therefore, it is critical to know which patients may benefit from the use of bridge therapy. The bleeding risk associated with the invasive or surgical procedure must be assessed and balanced against the risk of thromboembolic while patients are off VKA [3]. Prior to the release of the ACCP guidelines in 2008, there was no clear consensus regarding the management of these challenging patients. 0957-5235 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
molecular heparin (LMWH) was used in 27 (67.5%) patients, prophylactic-dose LMWH in 12 (30%) and a combination of LMWH therapeutic and prophylactic-dose doses in 11 (27.5%). Three bleeding complications occurred prepublication of the 2008 ACCP practice guidelines, although no bleeding complications occurred after the guidelines were published. Adherence to the 2008 ACCP guidelines for the perioperative management of anticoagulation reduced bleeding complications in patients on chronic VKA treatment. Blood Coagul Fibrinolysis 26:426–429 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
Blood Coagulation and Fibrinolysis 2015, 26:426–429 Keywords: anticoagulants, bleeding, complications, guidelines as a topic, perioperative care, thrombosis Department of Medicine, Division of Hematology-Medical Oncology, New York Presbyterian Hospital, Weill Cornell Medical College, New York, New York, USA Correspondence to Maria T. DeSancho, MD, MSc, Department of Medicine, Division of Hematology-Medical Oncology, New York Presbyterian Hospital, Weill Cornell Medical College, New York, 10021, NY, USA E-mail: [email protected] Received 4 May 2014 Revised 12 December 2014 Accepted 5 January 2015
The purpose of our study was to evaluate the perioperative management of anticoagulation of patients on chronic VKA and to determine the incidence of bleeding and/or thrombotic complications pre and postpublication of the 2008 ACCP guidelines.
Materials and methods We conducted a retrospective study of patients on chronic VKA who were referred to our haematology clinic at New York Presbyterian Hospital, New York, New York, USA, from January 2006 to June 2011 for perioperative management of anticoagulation. The Institutional Review Board at our institution approved the study. A total of 40 consecutive patients on chronic VKA scheduled for an invasive or surgical procedure were identified. Patients undergoing dermatological or oral procedures were excluded. Demographics, indications for VKA therapy and thrombosis risk factors such as documented thrombophilia, malignancy, inflammatory bowel disease (IBD) or autoimmune disorder were collected. The type DOI:10.1097/MBC.0000000000000275
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Perioperative anticoagulation management DeSancho et al. 427
of invasive or surgical procedure and the time period of the procedure: 2006–2008 (pre-2008 ACCP Guidelines) and 2009–2011 (post-2008 ACCP Guidelines) was recorded. Methods of bridge therapy, bleeding and thrombotic complications and other complications were also evaluated. The same haematologist (M.T.D.) delineated periprocedural management of anticoagulation during the entire duration of the study. Before the publication of the 2008 guidelines, VKA was discontinued 5 days prior to the invasive or surgical procedure. Bridging with therapeutic dose of low molecular weight heparin (LMWH) or fondaparinux was initiated 36 h after the last dose of VKA. The last dose of LMWH was administered 24 h prior to the procedure. The international normalized ratio (INR) was checked either 1 day before or on the day of the procedure. A low dose of oral vitamin K was prescribed if the INR was more than 1.5. Postprocedure, therapeutic dose of LMWH was started 24 h after the procedure providing that proper haemostasis was achieved, along with the usual dose of warfarin. The LMWH was discontinued when the INR was 2.0.
Results There were a total of 40 patients on chronic VKA who underwent 61 invasive and surgical procedures. Sixty percent were women and the mean age was 53 years (range 21–81 years). The most common indication for VKA therapy was secondary prevention of venous thrombosis followed by secondary prevention of arterial thrombosis (Table 1). Thrombophilia was identified in 20 (50%) of the patients. The most common type of thrombophilia was the presence of antiphospholipid antibodies (aPLs) defined as the presence of a lupus anticoagulant and/or anticardiolipin and/or anti-B2 glycoprotein-1 IgG or IgM in two different occasions at least 12 weeks apart. There were six patients with a history of unusual thrombosis and four with a history of recurrent venous thrombosis (Table 2). There were a total of 17 invasive and surgical procedures (28%) performed between January 2006 and December 2008 and 44 procedures (72%) performed between January 2009 and July 2011. The most common surgical and invasive procedures during the study period were gastrointestinal, followed by gynaecological and orthopaedic (Table 3). Demographics and indications for anticoagulation with vitamin K antagonists
Table 1
Number of patients Number of procedures Female (%) Mean age and range Whites (%) Secondary prevention of VT Secondary prevention of AT Secondary prevention of AT and VT Primary prevention of AT
40 61 60 54 (21–81) 85 N ¼ 27 N¼8 N¼4 N¼1
Table 2
Type of thrombophilia and risk factors for thrombosis N ¼ 20 (50%)
Thrombophilia
N¼2 N¼1 N¼3 N¼3 N¼2 N¼1 N¼9 N¼3 N¼3 N¼1 N¼1 N¼4 N¼3 N¼1 N¼6
Antithrombin deficiency FVL homozygote Compound heterozygote FVL and PGM FVL heterozygote PGM heterozygote Hyperhomocysteinemia aPLs Malignancy Inflammatory bowel disease Rheumatoid arthritis HIT Recurrent VT Mechanical mitral valve Atrial fibrillation History of unusuala VT
aPLs, antiphospholipid antibodies; FVL, Factor V Leiden; HIT, prior history of heparin-induced thrombocytopenia; PGM, prothrombin gene mutation; V, Leiden. a Unusual VT, visceral, cerebral and retinal veins.
The most frequent bridging regimen used was therapeutic dose of enoxaparin, followed by prophylactic dose enoxaparin and combination of therapeutic–prophylactic dose of enoxaparin (Table 4). Four of the patients had inferior vena cava (IVC) filters. One patient with hereditary antithrombin deficiency received antithrombin concentrate when the anticoagulation was discontinued to achieve an antithrombin activity of 100%. Two patients received DDAVP due to a history of von Willebrand’s disease and thrombocytopathy, respectively. The first patient stopped VKA 5 days before the transrectal ultrasound-guided prostate biopsy. The patient started prophylactic dose enoxaparin with warfarin 24 h after the procedure. Enoxaparin was discontinued when the INR reached 2.0; there were no bleeding complications. The second patient stopped VKA 5 days prior to laparoscopic removal of an ovarian cyst and was bridged with therapeutic dose enoxaparin. Postprocedure and when haemostasis was achieved, prophylactic dose enoxaparin was initiated along with warfarin. Enoxaparin was discontinued when the INR was 2.0. There were no bleeding complications. Three patients experienced bleeding complications. Two patients had a major bleeding and one had clinically significant bleeding [4]. All the bleeding complications occurred during the period of 2006–2008, prior to the Table 3
Type of invasive and surgical procedures
Invasive procedures Gastrointestinal IVC filter retrieval Thyroid biopsy Epidural injection Urological Gynaecological Vascular Orthopaedic Ocular Lung biopsy
N ¼ 32 11 4 4 3 3 2 2 1 1 1
Surgical procedures Gastrointestinal Gynaecological Orthopaedic Plastic Cardiothoracic Breast Sinus surgery Urological
AT, arterial thrombosis; VT, venous thrombosis.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
N ¼ 29 9 7 6 2 2 1 1 1
428 Blood Coagulation and Fibrinolysis 2015, Vol 26 No 4
Table 4
Methods of bridge-therapy
Therapeutic enoxaparin Therapeutic fondaparinux Prophylactic enoxaparin Prophylactic fondaparinux Combination therapeutic and prophylactic dose of enoxaparin UFH No bridge No discontinuation of VKA
27 2 12 2 11 1 4 2
UFH, unfractionated heparin.
publication of the 2008 ACCP guidelines. Details of the bleeding complications are summarized in Table 5. There were no thrombotic complications during the study period. There was one patient with antiphospholipid syndrome, who developed severe thrombocytopenia after major cardiac surgery and required treatment with intravenous immune globulin (IVIG) and another patient who developed atrial fibrillation postoperatively.
Discussion Our study demonstrated that adherence to the 2008 ACCP guidelines for the perioperative management of anticoagulation eliminated bleeding complications in patients on chronic VKA who required temporary interruption of anticoagulation and used bridging anticoagulation [1]. In addition, there were no thrombotic complications that occurred before or after the implementation of the guidelines. In our study, patients were taking VKA primarily for secondary VTE prevention in contrast to the REGIMEN study in which the majority of the patients were taking VKA for arterial thromboprophylaxis [5]. In a study of VTE patients on chronic VKA who required temporary discontinuation of VKA for planned procedures, Skeith et al. [6] showed that there were more bleeding than thrombotic complications. However, in contrast with these two prior studies, we did not have any thrombotic complications. This latter finding may be due to the small sample size of our study. McBane et al. [7] similarly evaluated the periprocedural anticoagulation management of 775 patients over 10-year period and reported a low incidence (1.8%) of thrombotic and bleeding complications. However, active cancer was an independent risk factor for both recurrent thrombosis and major bleeding [7]. Table 5
The optimal dose of LMWH used for bridging therapy remains controversial [8,9]. In our study, all three patients who had major and clinically significant bleeding complications received a therapeutic dose of anticoagulant 24 h after completion of the invasive procedure. This finding is in agreement with a previous study in which the risk of major bleeding was strongly associated with the use of postoperative therapeutic dose of heparin or LMWH [8]. Our findings are also consistent with another study, which found that the major predictors of bleeding during the periprocedural management of anticoagulation were the re-initiation of heparin therapy within 24 h after the procedure, presence of a mitral mechanical heart, active cancer and prior bleeding history [10]. On the basis of our findings and that of previous reports [8,10], we believe that it is prudent to delay initiation of anticoagulant therapy in those patients who have a procedure or surgery associated with a high risk of bleeding. Alternatively, clinicians may consider using prophylactic doses of UFH or LMWH after the procedure with gradual increments in dose to achieve a therapeutic level or administer a half-therapeutic dose regimen [11]. The 2008 ACCP guidelines recommends delaying the initiation of therapeutic dose LMWH/UFH for 48– 72 h after surgery when haemostasis is adequate; administering low-dose LMWH/UFH after surgery when haemostasis is achieved; or completely avoiding LMWH or UFH after surgery (Grade 1C recommendation) [1]. The 2012 ACCP antithrombotic guidelines also suggest that the resumption of LMWH should be delayed for at least 24 h and probably longer (48–72 h) in patients undergoing major surgery (Grade 2C recommendation). Resumption of anticoagulation depends on demonstration of adequate haemostasis at the surgical site [12]. Overall, the majority of the patients in our study did not experience any bleeding complications. In contrast to the majority of studies in which the most common regimen for bridge therapy was therapeutic dose LMWH or UFH, we used prophylactic dose or a combination of prophylactic and therapeutic dose of LMWH in 25 of 61 (41%) surgical or invasive procedures [5,13]. This bridging regimen was implemented after the publication of the 2008 ACCP guidelines. Classification of patients into high, moderate and low-risk category for thrombosis is useful in deciding whether
Bleeding complications
Type of bleeding
Patient risk category
Procedure bleeding risk category
Type and timing of bridge therapy
Patient 1: Major Patient 2: Clinically significant
High: Homozygote FVL High: APS
High: Breast implant repair High: Prostate biopsy
Patient 3: Major
Moderate: VTE 12 months prior
Moderate: Laparoscopic GI surgery
Therapeutic LMWH 24 h postprocedure Therapeutic Fondaparinux 24 h postprocedure Therapeutic LMWH 24 h postprocedure
APS, antiphospholipid syndrome; FVL, factor V Leiden; GI, gastrointestinal; LMWH, low molecular weight heparin.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Perioperative anticoagulation management DeSancho et al. 429
bridge therapy with LMWH or other short-acting anticoagulant is indicated [1]. Similarly, awareness of the bleeding risk associated with the invasive or surgical procedure is paramount in determining the dose and timing of re-initiating anticoagulation [13,14]. Thus, adherence to the 2008 and 2012 ACCP antithrombotic guidelines is critical for reducing bleeding complications in patients on chronic VKA treatment who require temporary discontinuation for a surgical or invasive procedure and have indications for using bridge therapy. In spite of the guidelines, significant controversy persists on whether to use bridge therapy or not in certain patients with a history of VTE with moderate thrombotic risk. Skeith et al. [6] support a conservative perioperative anticoagulation approach in patients on chronic anticoagulation defined as more than 3 months on VKA for VTE. The management involves withholding warfarin 5 days preoperatively with no LMWH given. Postoperatively, warfarin is initiated on the same day of surgery, and prophylactic dose LMWH is given postoperatively only if patients are admitted to the hospital. These authors reported a postoperative recurrent VTE rate of 0.32%, and a major bleeding rate of 1.26% at 30 days [6]. However, this study did not take into account the presence of high-risk thrombophilia. Our study has several limitations, including the relatively small number of patients, the retrospective before-andafter study design and its conduct at a single centre. Nevertheless, our study showcases a variety of surgical and invasive procedures that are frequently performed in clinical practice and thus is generalizable to institutions that see similar patients such as ours. In summary, the perioperative management of patients on chronic VKA remains challenging for clinicians and should be individualized for every patient. Our study shows that adherence to the 2008 ACCP antithrombotic guidelines eliminated bleeding complications in patients on chronic VKA therapy receiving bridge therapy while undergoing an invasive or surgical procedure. Multicentre prospective studies are needed to confirm our findings and to further optimize the management of these patients.
Acknowledgements We kindly acknowledge Dr Stephen M. Pastores for providing a critical review of this manuscript.
Conflicts of interest
The authors have no conflict of interest or financial disclosures to state. M.T.DeS. designed, followed the participants in the study, evaluated the data and wrote the manuscript. S.B. followed the participants in the study and contributed to data collection and entry. J.C. contributed to data analysis, writing and critical revision of the manuscript. All authors approved the final version of the manuscript.
References 1
2
3 4
5
6
7
8
9
10
11
12
13
14
Douketis J, Berger P, Dunn A, Jeffer A, Spyropoulos A, Becker R, Ansell J. The perioperative management of antithrombotic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008; 133:299–399. White RH, McKittrick T, Hutchinson R, Twitchell J. Temporary discontinuation of warfarin therapy: changes in the international normalized ratio. Ann Intern Med 1995; 122:40–42. Kearon C, Hirsh J. Management of anticoagulation before and after elective surgery. N Engl J Med 1997; 336:1506–1511. Spyropoulos AC, Turpie AG, Dunn AS, Spandorfer J, Douketis J, Jacobson A, Frost FJ, REGIMEN Investigators. Clinical outcomes with unfractionated heparin or low-molecular-weight heparin as bridging therapy in patients on long-term oral anticoagulants: the REGIMEN registry. J Thromb Haemost 2006; 4:1246–1252. Skeith L, Taylor J, Lazo-Langner A, Kovacs J. Conservative perioperative anticoagulation management in patients with chronic venous thromboembolic disease: a cohort study. J Thromb Haemost 2012; 10:2298–2304. Douketis JD, Spyropoulos AC, Spencer FA, Mayr M, Jaffer AK, Eckman MH, 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 EvidenceBased Clinical Practice Guidelines. Chest 2012; 141:326–350. Dunn AS, Spyropoulos AC, Turpie AG. Bridging therapy in patients on long-term oral anticoagulants who require surgery: the Prospective Peri-operative Enoxaparin Cohort Trial (PROSPECT). J Thromb Haemost 2007; 5:2211–2218. 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; 10:261–267. McBane R, Wysokinski WE, Daniels PR, Litin SC, Slusser J, Hodge DO, et al. Periprocedural anticoagulation management of patients with venous thromboembolism. Arterioscler Thromb Vasc Biol 2010; 30:442–448. Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in nonsurgical patients. J Thromb Haemost 2005; 3:692–694. Jaffer AK, Brotman DJ, Bash LD, Mahmood SK, Lott B, White RH. Variations in perioperative warfarin management: outcomes and practice patterns at nine hospitals. Am J Med 2010; 123:141–149. Klamroth R, Gottstein S, Essers E, Lansgraf H. Bridging with enoxaparin using a half-therapeutic dose regimen: safety and efficacy. Vasa 2010; 39:243–248. Spyropoulos AC, Douketis JD. How I treat anticoagulated patients undergoing an elective procedure or surgery. Blood 2012; 120:2954– 2962. Douketis JD. Perioperative management of patients who are receiving warfarin therapy: an evidence-based practical approach. Blood 2011; 117:5044–5049.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Adherence to guidelines for perioperative management of anticoagulation results in decreased bleeding complications: a single-centre experience Maria T. DeSancho, Svetoslava Bardarova and John Chapin Guidelines describing the perioperative management of antithrombotic therapy in patients requiring temporary interruption of vitamin K antagonists (VKAs) were first published in 2008. The objective of this study is to evaluate the perioperative management of anticoagulation of patients on chronic VKA and the incidence of bleeding and thrombotic complications pre and postpublication of the 2008 American College of Chest Physicians (ACCP) guidelines. A retrospective review of 40 patients on chronic VKA requiring temporary discontinuation of VKA due to an invasive or surgical procedure who were referred to a single haematology practice from January 2006 to June 2010. Demographics, indications of VKA, risk factors for thrombosis, type of procedure, bridging regimen and bleeding complications were recorded pre and post-2008 ACCP guidelines. Sixty-one procedures were performed in 40 patients; 60% were women. Indications for anticoagulation were secondary prevention of venous thrombosis (n U 27), arterial thrombosis (n U 8) or both arterial thrombosis and venous thrombosis (n U 4), and primary prevention of arterial thrombosis (n U 1). Twenty patients (50%) had thrombophilia. The most common surgical and invasive procedures were gastrointestinal (33%), gynaecological (15%) and orthopaedic (11%). Bridging regimen with therapeutic-dose subcutaneous low
Introduction In 2008, the American College of Chest Physicians (ACCP) published its first guidelines for the perioperative management of anticoagulation in patients on chronic vitamin K antagonist (VKA) therapy [1]. The guidelines recommended that patients on chronic VKA who require an invasive or surgical procedure discontinue VKA approximately 5 days before the procedure to assure proper haemostasis [2]. In some instances, however, patients may need to be bridged with a short-acting anticoagulant to minimize thromboembolic complications during the period of time that VKA is discontinued. Conversely, the bleeding risk may increase with the use of bridging anticoagulation. Therefore, it is critical to know which patients may benefit from the use of bridge therapy. The bleeding risk associated with the invasive or surgical procedure must be assessed and balanced against the risk of thromboembolic while patients are off VKA [3]. Prior to the release of the ACCP guidelines in 2008, there was no clear consensus regarding the management of these challenging patients. 0957-5235 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
molecular heparin (LMWH) was used in 27 (67.5%) patients, prophylactic-dose LMWH in 12 (30%) and a combination of LMWH therapeutic and prophylactic-dose doses in 11 (27.5%). Three bleeding complications occurred prepublication of the 2008 ACCP practice guidelines, although no bleeding complications occurred after the guidelines were published. Adherence to the 2008 ACCP guidelines for the perioperative management of anticoagulation reduced bleeding complications in patients on chronic VKA treatment. Blood Coagul Fibrinolysis 26:426–429 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
Blood Coagulation and Fibrinolysis 2015, 26:426–429 Keywords: anticoagulants, bleeding, complications, guidelines as a topic, perioperative care, thrombosis Department of Medicine, Division of Hematology-Medical Oncology, New York Presbyterian Hospital, Weill Cornell Medical College, New York, New York, USA Correspondence to Maria T. DeSancho, MD, MSc, Department of Medicine, Division of Hematology-Medical Oncology, New York Presbyterian Hospital, Weill Cornell Medical College, New York, 10021, NY, USA E-mail: [email protected] Received 4 May 2014 Revised 12 December 2014 Accepted 5 January 2015
The purpose of our study was to evaluate the perioperative management of anticoagulation of patients on chronic VKA and to determine the incidence of bleeding and/or thrombotic complications pre and postpublication of the 2008 ACCP guidelines.
Materials and methods We conducted a retrospective study of patients on chronic VKA who were referred to our haematology clinic at New York Presbyterian Hospital, New York, New York, USA, from January 2006 to June 2011 for perioperative management of anticoagulation. The Institutional Review Board at our institution approved the study. A total of 40 consecutive patients on chronic VKA scheduled for an invasive or surgical procedure were identified. Patients undergoing dermatological or oral procedures were excluded. Demographics, indications for VKA therapy and thrombosis risk factors such as documented thrombophilia, malignancy, inflammatory bowel disease (IBD) or autoimmune disorder were collected. The type DOI:10.1097/MBC.0000000000000275
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Perioperative anticoagulation management DeSancho et al. 427
of invasive or surgical procedure and the time period of the procedure: 2006–2008 (pre-2008 ACCP Guidelines) and 2009–2011 (post-2008 ACCP Guidelines) was recorded. Methods of bridge therapy, bleeding and thrombotic complications and other complications were also evaluated. The same haematologist (M.T.D.) delineated periprocedural management of anticoagulation during the entire duration of the study. Before the publication of the 2008 guidelines, VKA was discontinued 5 days prior to the invasive or surgical procedure. Bridging with therapeutic dose of low molecular weight heparin (LMWH) or fondaparinux was initiated 36 h after the last dose of VKA. The last dose of LMWH was administered 24 h prior to the procedure. The international normalized ratio (INR) was checked either 1 day before or on the day of the procedure. A low dose of oral vitamin K was prescribed if the INR was more than 1.5. Postprocedure, therapeutic dose of LMWH was started 24 h after the procedure providing that proper haemostasis was achieved, along with the usual dose of warfarin. The LMWH was discontinued when the INR was 2.0.
Results There were a total of 40 patients on chronic VKA who underwent 61 invasive and surgical procedures. Sixty percent were women and the mean age was 53 years (range 21–81 years). The most common indication for VKA therapy was secondary prevention of venous thrombosis followed by secondary prevention of arterial thrombosis (Table 1). Thrombophilia was identified in 20 (50%) of the patients. The most common type of thrombophilia was the presence of antiphospholipid antibodies (aPLs) defined as the presence of a lupus anticoagulant and/or anticardiolipin and/or anti-B2 glycoprotein-1 IgG or IgM in two different occasions at least 12 weeks apart. There were six patients with a history of unusual thrombosis and four with a history of recurrent venous thrombosis (Table 2). There were a total of 17 invasive and surgical procedures (28%) performed between January 2006 and December 2008 and 44 procedures (72%) performed between January 2009 and July 2011. The most common surgical and invasive procedures during the study period were gastrointestinal, followed by gynaecological and orthopaedic (Table 3). Demographics and indications for anticoagulation with vitamin K antagonists
Table 1
Number of patients Number of procedures Female (%) Mean age and range Whites (%) Secondary prevention of VT Secondary prevention of AT Secondary prevention of AT and VT Primary prevention of AT
40 61 60 54 (21–81) 85 N ¼ 27 N¼8 N¼4 N¼1
Table 2
Type of thrombophilia and risk factors for thrombosis N ¼ 20 (50%)
Thrombophilia
N¼2 N¼1 N¼3 N¼3 N¼2 N¼1 N¼9 N¼3 N¼3 N¼1 N¼1 N¼4 N¼3 N¼1 N¼6
Antithrombin deficiency FVL homozygote Compound heterozygote FVL and PGM FVL heterozygote PGM heterozygote Hyperhomocysteinemia aPLs Malignancy Inflammatory bowel disease Rheumatoid arthritis HIT Recurrent VT Mechanical mitral valve Atrial fibrillation History of unusuala VT
aPLs, antiphospholipid antibodies; FVL, Factor V Leiden; HIT, prior history of heparin-induced thrombocytopenia; PGM, prothrombin gene mutation; V, Leiden. a Unusual VT, visceral, cerebral and retinal veins.
The most frequent bridging regimen used was therapeutic dose of enoxaparin, followed by prophylactic dose enoxaparin and combination of therapeutic–prophylactic dose of enoxaparin (Table 4). Four of the patients had inferior vena cava (IVC) filters. One patient with hereditary antithrombin deficiency received antithrombin concentrate when the anticoagulation was discontinued to achieve an antithrombin activity of 100%. Two patients received DDAVP due to a history of von Willebrand’s disease and thrombocytopathy, respectively. The first patient stopped VKA 5 days before the transrectal ultrasound-guided prostate biopsy. The patient started prophylactic dose enoxaparin with warfarin 24 h after the procedure. Enoxaparin was discontinued when the INR reached 2.0; there were no bleeding complications. The second patient stopped VKA 5 days prior to laparoscopic removal of an ovarian cyst and was bridged with therapeutic dose enoxaparin. Postprocedure and when haemostasis was achieved, prophylactic dose enoxaparin was initiated along with warfarin. Enoxaparin was discontinued when the INR was 2.0. There were no bleeding complications. Three patients experienced bleeding complications. Two patients had a major bleeding and one had clinically significant bleeding [4]. All the bleeding complications occurred during the period of 2006–2008, prior to the Table 3
Type of invasive and surgical procedures
Invasive procedures Gastrointestinal IVC filter retrieval Thyroid biopsy Epidural injection Urological Gynaecological Vascular Orthopaedic Ocular Lung biopsy
N ¼ 32 11 4 4 3 3 2 2 1 1 1
Surgical procedures Gastrointestinal Gynaecological Orthopaedic Plastic Cardiothoracic Breast Sinus surgery Urological
AT, arterial thrombosis; VT, venous thrombosis.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
N ¼ 29 9 7 6 2 2 1 1 1
428 Blood Coagulation and Fibrinolysis 2015, Vol 26 No 4
Table 4
Methods of bridge-therapy
Therapeutic enoxaparin Therapeutic fondaparinux Prophylactic enoxaparin Prophylactic fondaparinux Combination therapeutic and prophylactic dose of enoxaparin UFH No bridge No discontinuation of VKA
27 2 12 2 11 1 4 2
UFH, unfractionated heparin.
publication of the 2008 ACCP guidelines. Details of the bleeding complications are summarized in Table 5. There were no thrombotic complications during the study period. There was one patient with antiphospholipid syndrome, who developed severe thrombocytopenia after major cardiac surgery and required treatment with intravenous immune globulin (IVIG) and another patient who developed atrial fibrillation postoperatively.
Discussion Our study demonstrated that adherence to the 2008 ACCP guidelines for the perioperative management of anticoagulation eliminated bleeding complications in patients on chronic VKA who required temporary interruption of anticoagulation and used bridging anticoagulation [1]. In addition, there were no thrombotic complications that occurred before or after the implementation of the guidelines. In our study, patients were taking VKA primarily for secondary VTE prevention in contrast to the REGIMEN study in which the majority of the patients were taking VKA for arterial thromboprophylaxis [5]. In a study of VTE patients on chronic VKA who required temporary discontinuation of VKA for planned procedures, Skeith et al. [6] showed that there were more bleeding than thrombotic complications. However, in contrast with these two prior studies, we did not have any thrombotic complications. This latter finding may be due to the small sample size of our study. McBane et al. [7] similarly evaluated the periprocedural anticoagulation management of 775 patients over 10-year period and reported a low incidence (1.8%) of thrombotic and bleeding complications. However, active cancer was an independent risk factor for both recurrent thrombosis and major bleeding [7]. Table 5
The optimal dose of LMWH used for bridging therapy remains controversial [8,9]. In our study, all three patients who had major and clinically significant bleeding complications received a therapeutic dose of anticoagulant 24 h after completion of the invasive procedure. This finding is in agreement with a previous study in which the risk of major bleeding was strongly associated with the use of postoperative therapeutic dose of heparin or LMWH [8]. Our findings are also consistent with another study, which found that the major predictors of bleeding during the periprocedural management of anticoagulation were the re-initiation of heparin therapy within 24 h after the procedure, presence of a mitral mechanical heart, active cancer and prior bleeding history [10]. On the basis of our findings and that of previous reports [8,10], we believe that it is prudent to delay initiation of anticoagulant therapy in those patients who have a procedure or surgery associated with a high risk of bleeding. Alternatively, clinicians may consider using prophylactic doses of UFH or LMWH after the procedure with gradual increments in dose to achieve a therapeutic level or administer a half-therapeutic dose regimen [11]. The 2008 ACCP guidelines recommends delaying the initiation of therapeutic dose LMWH/UFH for 48– 72 h after surgery when haemostasis is adequate; administering low-dose LMWH/UFH after surgery when haemostasis is achieved; or completely avoiding LMWH or UFH after surgery (Grade 1C recommendation) [1]. The 2012 ACCP antithrombotic guidelines also suggest that the resumption of LMWH should be delayed for at least 24 h and probably longer (48–72 h) in patients undergoing major surgery (Grade 2C recommendation). Resumption of anticoagulation depends on demonstration of adequate haemostasis at the surgical site [12]. Overall, the majority of the patients in our study did not experience any bleeding complications. In contrast to the majority of studies in which the most common regimen for bridge therapy was therapeutic dose LMWH or UFH, we used prophylactic dose or a combination of prophylactic and therapeutic dose of LMWH in 25 of 61 (41%) surgical or invasive procedures [5,13]. This bridging regimen was implemented after the publication of the 2008 ACCP guidelines. Classification of patients into high, moderate and low-risk category for thrombosis is useful in deciding whether
Bleeding complications
Type of bleeding
Patient risk category
Procedure bleeding risk category
Type and timing of bridge therapy
Patient 1: Major Patient 2: Clinically significant
High: Homozygote FVL High: APS
High: Breast implant repair High: Prostate biopsy
Patient 3: Major
Moderate: VTE 12 months prior
Moderate: Laparoscopic GI surgery
Therapeutic LMWH 24 h postprocedure Therapeutic Fondaparinux 24 h postprocedure Therapeutic LMWH 24 h postprocedure
APS, antiphospholipid syndrome; FVL, factor V Leiden; GI, gastrointestinal; LMWH, low molecular weight heparin.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Perioperative anticoagulation management DeSancho et al. 429
bridge therapy with LMWH or other short-acting anticoagulant is indicated [1]. Similarly, awareness of the bleeding risk associated with the invasive or surgical procedure is paramount in determining the dose and timing of re-initiating anticoagulation [13,14]. Thus, adherence to the 2008 and 2012 ACCP antithrombotic guidelines is critical for reducing bleeding complications in patients on chronic VKA treatment who require temporary discontinuation for a surgical or invasive procedure and have indications for using bridge therapy. In spite of the guidelines, significant controversy persists on whether to use bridge therapy or not in certain patients with a history of VTE with moderate thrombotic risk. Skeith et al. [6] support a conservative perioperative anticoagulation approach in patients on chronic anticoagulation defined as more than 3 months on VKA for VTE. The management involves withholding warfarin 5 days preoperatively with no LMWH given. Postoperatively, warfarin is initiated on the same day of surgery, and prophylactic dose LMWH is given postoperatively only if patients are admitted to the hospital. These authors reported a postoperative recurrent VTE rate of 0.32%, and a major bleeding rate of 1.26% at 30 days [6]. However, this study did not take into account the presence of high-risk thrombophilia. Our study has several limitations, including the relatively small number of patients, the retrospective before-andafter study design and its conduct at a single centre. Nevertheless, our study showcases a variety of surgical and invasive procedures that are frequently performed in clinical practice and thus is generalizable to institutions that see similar patients such as ours. In summary, the perioperative management of patients on chronic VKA remains challenging for clinicians and should be individualized for every patient. Our study shows that adherence to the 2008 ACCP antithrombotic guidelines eliminated bleeding complications in patients on chronic VKA therapy receiving bridge therapy while undergoing an invasive or surgical procedure. Multicentre prospective studies are needed to confirm our findings and to further optimize the management of these patients.
Acknowledgements We kindly acknowledge Dr Stephen M. Pastores for providing a critical review of this manuscript.
Conflicts of interest
The authors have no conflict of interest or financial disclosures to state. M.T.DeS. designed, followed the participants in the study, evaluated the data and wrote the manuscript. S.B. followed the participants in the study and contributed to data collection and entry. J.C. contributed to data analysis, writing and critical revision of the manuscript. All authors approved the final version of the manuscript.
References 1
2
3 4
5
6
7
8
9
10
11
12
13
14
Douketis J, Berger P, Dunn A, Jeffer A, Spyropoulos A, Becker R, Ansell J. The perioperative management of antithrombotic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008; 133:299–399. White RH, McKittrick T, Hutchinson R, Twitchell J. Temporary discontinuation of warfarin therapy: changes in the international normalized ratio. Ann Intern Med 1995; 122:40–42. Kearon C, Hirsh J. Management of anticoagulation before and after elective surgery. N Engl J Med 1997; 336:1506–1511. Spyropoulos AC, Turpie AG, Dunn AS, Spandorfer J, Douketis J, Jacobson A, Frost FJ, REGIMEN Investigators. Clinical outcomes with unfractionated heparin or low-molecular-weight heparin as bridging therapy in patients on long-term oral anticoagulants: the REGIMEN registry. J Thromb Haemost 2006; 4:1246–1252. Skeith L, Taylor J, Lazo-Langner A, Kovacs J. Conservative perioperative anticoagulation management in patients with chronic venous thromboembolic disease: a cohort study. J Thromb Haemost 2012; 10:2298–2304. Douketis JD, Spyropoulos AC, Spencer FA, Mayr M, Jaffer AK, Eckman MH, 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 EvidenceBased Clinical Practice Guidelines. Chest 2012; 141:326–350. Dunn AS, Spyropoulos AC, Turpie AG. Bridging therapy in patients on long-term oral anticoagulants who require surgery: the Prospective Peri-operative Enoxaparin Cohort Trial (PROSPECT). J Thromb Haemost 2007; 5:2211–2218. 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; 10:261–267. McBane R, Wysokinski WE, Daniels PR, Litin SC, Slusser J, Hodge DO, et al. Periprocedural anticoagulation management of patients with venous thromboembolism. Arterioscler Thromb Vasc Biol 2010; 30:442–448. Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in nonsurgical patients. J Thromb Haemost 2005; 3:692–694. Jaffer AK, Brotman DJ, Bash LD, Mahmood SK, Lott B, White RH. Variations in perioperative warfarin management: outcomes and practice patterns at nine hospitals. Am J Med 2010; 123:141–149. Klamroth R, Gottstein S, Essers E, Lansgraf H. Bridging with enoxaparin using a half-therapeutic dose regimen: safety and efficacy. Vasa 2010; 39:243–248. Spyropoulos AC, Douketis JD. How I treat anticoagulated patients undergoing an elective procedure or surgery. Blood 2012; 120:2954– 2962. Douketis JD. Perioperative management of patients who are receiving warfarin therapy: an evidence-based practical approach. Blood 2011; 117:5044–5049.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
![[Perioperative management and therapy of bleeding complications].](/assets/img/hold.png)
