- Email: [email protected]
Anticoagulation strategies in the perioperative period for lung transplant
Journal Pre-proof Anticoagulation strategies in the perioperative period for lung transplant Yaron D. Barac, M.D; PhD, Jacob Klapper, M.D, Angela Pollack, M.D, Jessica Poisson, M.D, Ian Welsby, M.D, M.G. Hartwig, M.D, Brandi Bottiger, M.D PII:
S0003-4975(20)30046-1
DOI:
https://doi.org/10.1016/j.athoracsur.2019.11.056
Reference:
ATS 33397
To appear in:
The Annals of Thoracic Surgery
Received Date: 22 September 2019 Revised Date:
27 October 2019
Accepted Date: 25 November 2019
Please cite this article as: Barac YD, Klapper J, Pollack A, Poisson J, Welsby I, Hartwig MG, Bottiger B, Anticoagulation strategies in the perioperative period for lung transplant, The Annals of Thoracic Surgery (2020), doi: https://doi.org/10.1016/j.athoracsur.2019.11.056. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 by The Society of Thoracic Surgeons
Anticoagulation strategies in the perioperative period for lung transplant Running Head Line: Prothrombin Complex Concentrate in Lung Transplant Yaron D. Barac M.D; PhD1, Jacob Klapper M.D1, Angela Pollack M.D2, Jessica Poisson M.D3, Ian Welsby M.D2, M.G. Hartwig M.D1, Brandi Bottiger M.D2
1
The Division of Cardiovascular and Thoracic Surgery, 2 Division of Cardiothoracic
Anesthesiology, 3Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA.
Total word count: 744
Corresponding author: Yaron D. Barac M.D.; Ph.D. Duke University Medical Center, 10 Duke Medicine Cir, Durham, NC 27710 Email: [email protected]
Keywords: Lung transplant, PCC
1
Abstract Lung Transplant (LTx) patients may require systemic anticoagulation in the perioperative period for various indications at the time of the procedure. 4-factor prothrombin complex concentrate has been approved in the US to reverse warfarin’s effects for patients requiring urgent surgery. We describe a perioperative anticoagulation strategy with warfarin that is reversed prior to incision using 4 factor complex concentrate (4-FPCC) for off-pump LTx patients.
2
When LTx recipients require anticoagulation at listing, increased bleeding and transfusion are expected during surgery if the drug effects are not rapidly reversed. There is no current “best practice” on which anticoagulant to use for systemic anticoagulation for this population of patients requiring urgent transplantation. If warfarin is selected, transfusion of fresh frozen plasma is traditionally needed to reverse its effects in the operating room. However, because transfusion during LTx has been associated with worsened outcomes, warfarin has been historically a less desirable choice for these recipients (1). Four-factor prothrombin complex concentrates (4-F PCC, KCentra, CSL Behring®) provides direct reversal of warfarin’s effects by replacement of vitamin K dependent factors. This human-derived factor concentrate is reconstituted in 20 mL of sterile water, and avoids administration of unnecessary volume in LTx patients. In cardiac transplant populations, reversal of warfarin by replacing vitamin K dependent factors with 4F-PCC has shown greater efficacy than administering fresh frozen plasma (FFP), but this has not been demonstrated in LTx patients (2). Here we describe four LTx patients who were anti-coagulated with warfarin, and subsequently reversed with 4-F PCC at the time of lung transplant.
Following local IRB approval, the electronic medical records of all adult LTx patients between 2/2014-8/2018 were queried. Patients were anticoagulated with warfarin at listing with a goal INR of 2-4. During LTx, 4-F PCC was administered immediately upon arrival to the OR and prior to incision, per recommended dose, which is based on body weight and INR (3). All procedures described here were performed off pump without mechanical circulatory support (MCS). Since 4F-PCC has a clinically irrelevant effect on antithrombin III levels, we heparinized to maintain a goal activated clotting time (ACT) of 200-250 for vascular anastomoses once the pulmonary artery is clamped. After reperfusion, heparin was reversed with protamine
3
prior to closure. We report 72-hour transfusion requirements, and clinical outcomes with attention to thromboembolic events. Of the entire cohort of 451 patients over the time period, four patients received 25 U/kg 4-F PCC for warfarin reversal prior to incision for off pump LTx, described in Figure 1. Indications for anticoagulation were either treatment for pulmonary embolism (Patient 1), or atrial fibrillation prophylaxis (Patients 2-4). Of these four patients, 72-hr transfusion requirements ranged from 0 to 2 U RBCs, 0 to 2 doses of cryoprecipitate, and 0 to 1U platelets. This is comparable to transfusion requirements for other off-pump lung transplants performed over the same time period at our institution (Data not shown). Warfarin was restarted once there was no concern for bleeding, 48-72 hours post-transplant. During the index hospitalization but after 30 days, well after the drug effect of PCC, patient 2 had an upper extremity DVT; no other patients experienced thromboembolic events. All patients recovered well and were discharged home.
Comment We administered 4F-PCC for warfarin reversal just prior to off-pump bilateral LTx in four patients with similar perioperative clinical characteristics and early outcomes. All patients required some transfusion over the first 72 hours, with similar requirements to other off-pump lung transplant patients over the time period (Data not shown). Specifically, there were four patients in the cohort that were on warfarin with subtherapeutic INRs (1.3) prior to transplant, and therefore not reversed with PCC. Transfusion requirements in this subgroup were similar to those who had therapeutic INRs and reversed (Data not shown). 4-factor prothrombin complex concentrate (Kcentra, 4F-PCC) is a human coagulation factor concentrate containing non-activated factors II, VII, IX and X, and endogenous inhibitor proteins S and C, with a half-life ranging from 4-40 h, and is reconstituted in 20 mL of sterile water. Dosing is based on body weight and INR. In a single 500 U dose vial, excipients of this drug include heparin (8-40U), human anti4
thrombin III (4-30 U), human albumin (40-80 mg), sodium chloride (60-120 mg) and sodium citrate (40-80 mg). Previous studies have shown that the most common adverse reactions (2.8%) were headache, nausea, arthralgias, and hypotension. It also carries a risk of transmissible infectious agents, since it is derived from human plasma. The most serious reactions described were major thromboembolic events. In a prospective, randomized controlled trial for PCC reversal of warfarin in the setting of acute major bleeding, the rate of major thromboembolic events was 9.7% in the 4F PCC treated group, vs 5 % in the plasma treated group (4). Vitamin K antagonism and 4-F PCC has been effectively used for warfarin reversal in the setting of patients on warfarin requiring urgent non-cardiac surgery with equal efficacy to FFP (5), in the perioperative setting for LVAD and cardiac transplant patients (6). There is a distinct advantage in avoiding unnecessary volume associated with FFP administration, with a small infusion volume of 20 mL of PCC, as well as ease of acquisition and storage, rapid INR correction (< 30 minutes), lack of need for ABO compatibility, and effective purification by viral inactivation/nanofiltration to remove potential pathogenic viruses. Regarding cost, the United Kingdom National Health Service reports that PCCs for emergency vitamin K antagonist reversal are more cost-effective than FFP (7). This strategy is appealing in the setting of LTx, where pulmonary artery clamping, right ventricular dysfunction, endothelial and lymphatic disruption of the lungs, and primary graft dysfunction are anticipated. Unfractionated and low molecular weight heparins, warfarin, and more recently direct acting oral anticoagulants have all been described for anticoagulation in the setting of LTx. Historically, drug effects have been difficult to reverse without transfusion of blood products. 4-F PCC approval has made it possible for rapid warfarin reversal without transfusion of FFP, albeit with the limitations of significant cost, and associated risk of thromboembolism (4). In non-surgical populations, the risk of thromboembolism associated with 4F- PCC administration for warfarin reversal is similar to those receiving FFP, approximately 7% (5). Notably, this
5
medication has not been studied in patients who have known underlying risk for thromboembolism, or in LTx patients requiring MCS. Given the risk of thromboembolism, a thoughtful discussion regarding timing and dose of this drug with all team members should be had prior to administration, particularly in the setting of MCS. In sum, the use of 4-F PCC for reversal of systemic anticoagulation with warfarin in the perioperative setting is feasible for LTx patients. It remains unclear if the benefits of this anticoagulation and reversal strategy, which spares FFP transfusions, outweighs the risk of potential thromboembolic complications of PCC in this patient population. Future studies are needed to unveil how and if PCCs effect this risk in postsurgical LTx patients, especially for those who require MCS.
6
References: 1. L.P. Ong Z, Tristan H, Muse K, et. al. Blood transfusion after lung transplantation: impact on early function and survival. Interactive CardioVascular and Thoracic Surgery, Volume 19, Issue suppl_1, 1 October 2014, Pages S74. 2. Ghadimi K, Levy JH, Welsby IJ. Prothrombin Complex Concentrates for Bleeding in the Perioperative Setting. Anesth Analg. 2016 May;122(5):1277300. 3. CSL Behring: Prothrombin Complex Concentrate (Human) KcentraTM Package Insert: https://www.fda.gov/ucm/groups/fdagov-public/@fdagovbiogen/documents/document/ucm350239.pdf. Accessed 10.19.2018. 4. Goldstein JN, Refaai MA, Milling TJ Jr, et al. Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, openlabel, non-inferiority, randomized trial. Lancet. 2015 May 23;385(9982):207787. 5. Pabinger I, Brenner B, Kalina U, et al. Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial. Journal of Thrombosis and Haemostasis 2008; 6: 622-631. 6. Barac YD, Nevo A, Jawitz O, et. al. Prothrombin Complex Concentrate Use in Durable and Short-Term Left Ventricular Assist Device Implantation. ASAIO J. 2019 Jan 24. 7. Guest JF, Watson HG, Limaye S. Modeling the cost-effectiveness of prothrombin complex concentrate compared with fresh frozen plasma in emergency warfarin reversal in the United kingdom. Clin Ther 2010; 32 (14) 2478-2493
7
Figure Legends Figure 1: Flow diagram showing inclusion and exclusion criteria, with patients receiving off pump lung transplant (LTx) and 4 factor Prothrombin complex concentrates (PCC) for warfarin reversal seen at the bottom left (N=4).
8
S0003-4975(20)30046-1
DOI:
https://doi.org/10.1016/j.athoracsur.2019.11.056
Reference:
ATS 33397
To appear in:
The Annals of Thoracic Surgery
Received Date: 22 September 2019 Revised Date:
27 October 2019
Accepted Date: 25 November 2019
Please cite this article as: Barac YD, Klapper J, Pollack A, Poisson J, Welsby I, Hartwig MG, Bottiger B, Anticoagulation strategies in the perioperative period for lung transplant, The Annals of Thoracic Surgery (2020), doi: https://doi.org/10.1016/j.athoracsur.2019.11.056. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 by The Society of Thoracic Surgeons
Anticoagulation strategies in the perioperative period for lung transplant Running Head Line: Prothrombin Complex Concentrate in Lung Transplant Yaron D. Barac M.D; PhD1, Jacob Klapper M.D1, Angela Pollack M.D2, Jessica Poisson M.D3, Ian Welsby M.D2, M.G. Hartwig M.D1, Brandi Bottiger M.D2
1
The Division of Cardiovascular and Thoracic Surgery, 2 Division of Cardiothoracic
Anesthesiology, 3Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA.
Total word count: 744
Corresponding author: Yaron D. Barac M.D.; Ph.D. Duke University Medical Center, 10 Duke Medicine Cir, Durham, NC 27710 Email: [email protected]
Keywords: Lung transplant, PCC
1
Abstract Lung Transplant (LTx) patients may require systemic anticoagulation in the perioperative period for various indications at the time of the procedure. 4-factor prothrombin complex concentrate has been approved in the US to reverse warfarin’s effects for patients requiring urgent surgery. We describe a perioperative anticoagulation strategy with warfarin that is reversed prior to incision using 4 factor complex concentrate (4-FPCC) for off-pump LTx patients.
2
When LTx recipients require anticoagulation at listing, increased bleeding and transfusion are expected during surgery if the drug effects are not rapidly reversed. There is no current “best practice” on which anticoagulant to use for systemic anticoagulation for this population of patients requiring urgent transplantation. If warfarin is selected, transfusion of fresh frozen plasma is traditionally needed to reverse its effects in the operating room. However, because transfusion during LTx has been associated with worsened outcomes, warfarin has been historically a less desirable choice for these recipients (1). Four-factor prothrombin complex concentrates (4-F PCC, KCentra, CSL Behring®) provides direct reversal of warfarin’s effects by replacement of vitamin K dependent factors. This human-derived factor concentrate is reconstituted in 20 mL of sterile water, and avoids administration of unnecessary volume in LTx patients. In cardiac transplant populations, reversal of warfarin by replacing vitamin K dependent factors with 4F-PCC has shown greater efficacy than administering fresh frozen plasma (FFP), but this has not been demonstrated in LTx patients (2). Here we describe four LTx patients who were anti-coagulated with warfarin, and subsequently reversed with 4-F PCC at the time of lung transplant.
Following local IRB approval, the electronic medical records of all adult LTx patients between 2/2014-8/2018 were queried. Patients were anticoagulated with warfarin at listing with a goal INR of 2-4. During LTx, 4-F PCC was administered immediately upon arrival to the OR and prior to incision, per recommended dose, which is based on body weight and INR (3). All procedures described here were performed off pump without mechanical circulatory support (MCS). Since 4F-PCC has a clinically irrelevant effect on antithrombin III levels, we heparinized to maintain a goal activated clotting time (ACT) of 200-250 for vascular anastomoses once the pulmonary artery is clamped. After reperfusion, heparin was reversed with protamine
3
prior to closure. We report 72-hour transfusion requirements, and clinical outcomes with attention to thromboembolic events. Of the entire cohort of 451 patients over the time period, four patients received 25 U/kg 4-F PCC for warfarin reversal prior to incision for off pump LTx, described in Figure 1. Indications for anticoagulation were either treatment for pulmonary embolism (Patient 1), or atrial fibrillation prophylaxis (Patients 2-4). Of these four patients, 72-hr transfusion requirements ranged from 0 to 2 U RBCs, 0 to 2 doses of cryoprecipitate, and 0 to 1U platelets. This is comparable to transfusion requirements for other off-pump lung transplants performed over the same time period at our institution (Data not shown). Warfarin was restarted once there was no concern for bleeding, 48-72 hours post-transplant. During the index hospitalization but after 30 days, well after the drug effect of PCC, patient 2 had an upper extremity DVT; no other patients experienced thromboembolic events. All patients recovered well and were discharged home.
Comment We administered 4F-PCC for warfarin reversal just prior to off-pump bilateral LTx in four patients with similar perioperative clinical characteristics and early outcomes. All patients required some transfusion over the first 72 hours, with similar requirements to other off-pump lung transplant patients over the time period (Data not shown). Specifically, there were four patients in the cohort that were on warfarin with subtherapeutic INRs (1.3) prior to transplant, and therefore not reversed with PCC. Transfusion requirements in this subgroup were similar to those who had therapeutic INRs and reversed (Data not shown). 4-factor prothrombin complex concentrate (Kcentra, 4F-PCC) is a human coagulation factor concentrate containing non-activated factors II, VII, IX and X, and endogenous inhibitor proteins S and C, with a half-life ranging from 4-40 h, and is reconstituted in 20 mL of sterile water. Dosing is based on body weight and INR. In a single 500 U dose vial, excipients of this drug include heparin (8-40U), human anti4
thrombin III (4-30 U), human albumin (40-80 mg), sodium chloride (60-120 mg) and sodium citrate (40-80 mg). Previous studies have shown that the most common adverse reactions (2.8%) were headache, nausea, arthralgias, and hypotension. It also carries a risk of transmissible infectious agents, since it is derived from human plasma. The most serious reactions described were major thromboembolic events. In a prospective, randomized controlled trial for PCC reversal of warfarin in the setting of acute major bleeding, the rate of major thromboembolic events was 9.7% in the 4F PCC treated group, vs 5 % in the plasma treated group (4). Vitamin K antagonism and 4-F PCC has been effectively used for warfarin reversal in the setting of patients on warfarin requiring urgent non-cardiac surgery with equal efficacy to FFP (5), in the perioperative setting for LVAD and cardiac transplant patients (6). There is a distinct advantage in avoiding unnecessary volume associated with FFP administration, with a small infusion volume of 20 mL of PCC, as well as ease of acquisition and storage, rapid INR correction (< 30 minutes), lack of need for ABO compatibility, and effective purification by viral inactivation/nanofiltration to remove potential pathogenic viruses. Regarding cost, the United Kingdom National Health Service reports that PCCs for emergency vitamin K antagonist reversal are more cost-effective than FFP (7). This strategy is appealing in the setting of LTx, where pulmonary artery clamping, right ventricular dysfunction, endothelial and lymphatic disruption of the lungs, and primary graft dysfunction are anticipated. Unfractionated and low molecular weight heparins, warfarin, and more recently direct acting oral anticoagulants have all been described for anticoagulation in the setting of LTx. Historically, drug effects have been difficult to reverse without transfusion of blood products. 4-F PCC approval has made it possible for rapid warfarin reversal without transfusion of FFP, albeit with the limitations of significant cost, and associated risk of thromboembolism (4). In non-surgical populations, the risk of thromboembolism associated with 4F- PCC administration for warfarin reversal is similar to those receiving FFP, approximately 7% (5). Notably, this
5
medication has not been studied in patients who have known underlying risk for thromboembolism, or in LTx patients requiring MCS. Given the risk of thromboembolism, a thoughtful discussion regarding timing and dose of this drug with all team members should be had prior to administration, particularly in the setting of MCS. In sum, the use of 4-F PCC for reversal of systemic anticoagulation with warfarin in the perioperative setting is feasible for LTx patients. It remains unclear if the benefits of this anticoagulation and reversal strategy, which spares FFP transfusions, outweighs the risk of potential thromboembolic complications of PCC in this patient population. Future studies are needed to unveil how and if PCCs effect this risk in postsurgical LTx patients, especially for those who require MCS.
6
References: 1. L.P. Ong Z, Tristan H, Muse K, et. al. Blood transfusion after lung transplantation: impact on early function and survival. Interactive CardioVascular and Thoracic Surgery, Volume 19, Issue suppl_1, 1 October 2014, Pages S74. 2. Ghadimi K, Levy JH, Welsby IJ. Prothrombin Complex Concentrates for Bleeding in the Perioperative Setting. Anesth Analg. 2016 May;122(5):1277300. 3. CSL Behring: Prothrombin Complex Concentrate (Human) KcentraTM Package Insert: https://www.fda.gov/ucm/groups/fdagov-public/@fdagovbiogen/documents/document/ucm350239.pdf. Accessed 10.19.2018. 4. Goldstein JN, Refaai MA, Milling TJ Jr, et al. Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, openlabel, non-inferiority, randomized trial. Lancet. 2015 May 23;385(9982):207787. 5. Pabinger I, Brenner B, Kalina U, et al. Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial. Journal of Thrombosis and Haemostasis 2008; 6: 622-631. 6. Barac YD, Nevo A, Jawitz O, et. al. Prothrombin Complex Concentrate Use in Durable and Short-Term Left Ventricular Assist Device Implantation. ASAIO J. 2019 Jan 24. 7. Guest JF, Watson HG, Limaye S. Modeling the cost-effectiveness of prothrombin complex concentrate compared with fresh frozen plasma in emergency warfarin reversal in the United kingdom. Clin Ther 2010; 32 (14) 2478-2493
7
Figure Legends Figure 1: Flow diagram showing inclusion and exclusion criteria, with patients receiving off pump lung transplant (LTx) and 4 factor Prothrombin complex concentrates (PCC) for warfarin reversal seen at the bottom left (N=4).
8