585344
research-article2015
AOPXXX10.1177/1060028015585344Annals of PharmacotherapyKantorovich et al
Research Report
Low-Dose 3-Factor Prothrombin Complex Concentrate for Warfarin Reversal Prior to Heart Transplant
Annals of Pharmacotherapy 1–7 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028015585344 aop.sagepub.com
Alexander Kantorovich, PharmD1,2, Jodie M. Fink, PharmD3, Michael A. Militello, PharmD4, Matthew R. Wanek, PharmD4, Nicholas G. Smedira, MD4, Edward G. Soltesz, MD4, and Nader Moazami, MD4
Abstract Background: Anticoagulation with warfarin is common in patients presenting for heart transplant. Prior to surgery, anticoagulation reversal is necessary to avoid significant intraoperative and perioperative bleeding complications. Commonly, warfarin reversal is achieved with vitamin K and fresh frozen plasma (FFP); however, these therapies have significant limitations. An alternative to FFP for reversal exists with prothrombin complex concentrate (PCC). A warfarin reversal protocol prior to heart transplant was implemented using low-dose PCC at our institution. Objective: To assess blood product use, effectiveness, and safety post–low-dose PCC administration in patients needing warfarin reversal prior to heart transplant compared with historical controls. Methods: This was a single-center, retrospective cohort study. The PCC cohort included patients undergoing heart transplant presenting with an international normalized ratio ≥1.5 on warfarin therapy and who received at least 1 dose of PCC. Blood product use was measured from postoperative day 0 to 2. Results: The PCC and historical control cohorts included 16 and 50 patients, respectively. There was a significant reduction in the use of FFP (4 vs 8 units, P = 0.0239) in the PCC cohort compared with the historical control cohort. No differences were identified in the use of other blood products as well as other secondary efficacy or safety end points. Conclusions: Use of PCC, per the reversal protocol, prior to heart transplant reduced FFP use and showed a non– statistically significant trend toward reductions in the use of other blood products in the intraoperative and perioperative setting, with no difference identified in thrombotic or embolic complications compared with historical controls. Keywords anticoagulation, transplantation, surgery, warfarin, cardiology
Introduction Therapeutic anticoagulation is common in patients requiring heart transplant because these patients are on warfarin for indications such as atrial fibrillation, venous thromboembolism (VTE), and the presence of mechanical heart valves or ventricular assist devices (VADs). Prior to heart transplant, anticoagulant reversal is often necessary to avoid significant intraoperative and perioperative bleeding. Reversal is commonly achieved with vitamin K, which competes with warfarin for the vitamin K reductase enzyme, as well as fresh frozen plasma (FFP), which contains clotting factors, including those depleted by warfarin.1 Limitations, however, exist with both strategies, such as time to international normalized ratio (INR) normalization with vitamin K. In addition, limitations of FFP include time necessary for thawing the product, large volumes necessary for adequate reversal, and the possibility of transfusion-related lung injury. Transfusion of blood products in the transplant population also increases the risk of
allosensitization with the introduction of antibodies leading to possible organ rejection. Another option for reversal is prothrombin complex concentrate (PCC), which contains the vitamin K–dependent clotting factors depleted by warfarin (factors II, VII, IX, and X).2 Heart transplant guidelines include PCC among the modalities for warfarin reversal; however, supportive evidence is minimal.3 At our institution in the summer of 2013, representatives from the departments of cardiothoracic surgery, hematology, and pharmacy developed a warfarin reversal protocol for patients undergoing heart transplant with a presenting INR of 1
Chicago State University College of Pharmacy, Chicago, IL, USA Advocate Christ Medical Center, Oak Lawn, IL, USA 3 University Hospitals Ahuja Medical Center, Beachwood, OH, USA 4 Cleveland Clinic, Cleveland, OH, USA 2
Corresponding Author: Nader Moazami, Kaufman Center for Heart Failure, Cleveland Clinic, 9500 Euclid Ave, Desk J4-1, Cleveland, OH 44195, USA. Email: [email protected]
Downloaded from aop.sagepub.com at UNIV CALIFORNIA SAN DIEGO on June 12, 2015
2
Annals of Pharmacotherapy
Figure 1. Heart transplant warfarin reversal protocol.
Abbreviations: INR, international normalized ratio; IV, intravenous; PCC, prothrombin complex concentrate.
1.5 or greater with low-dose PCC. The protocol was created in an effort to reduce blood product use and was based on a thorough review of relevant clinical trials using PCC for INR reversal as well as internal expert opinion. Our intent was to produce a protocol that limited PCC doses to minimize exposure and avoid thrombotic events in a potentially high-risk population. The protocol, shown in Figure 1, utilizes both a weight-based and INR-specific dosing scheme and allows a maximum of 3 doses to be administered to patients. This study evaluated the effectiveness and safety of this protocol for warfarin reversal prior to heart transplant using PCC and compared the results related to blood product use, the need for reoperation for bleeding, and adverse events post-implementation with a historical control group prior to implementation. To our knowledge, this is the first study evaluating a warfarin reversal protocol utilizing low-dose PCC with dosing based on weight (units/kg) and baseline INR.
Methods This was a single-center, non-interventional, retrospective cohort study approved by the institutional review board,
which waived the requirement for individual informed consent. All data were gathered from the electronic medical record and collected and managed using REDCap (Research Electronic Data Capture) electronic data capture tools hosted at Cleveland Clinic.4 Patients were included in the PCC cohort if they underwent heart transplant after June 2013 when the warfarin reversal protocol was implemented, presented for transplant with an INR of ≥1.5, and received at least 1 dose of PCC. To be included in the historical control cohort, patients had to have undergone heart transplant, been on warfarin prior to surgery, and presented with an INR of ≥1.5 and should not have received PCC. Historical control patients were identified from the institution’s heart transplant master list starting immediately prior to the initiation of the warfarin reversal protocol (June 2013) and going backward in time until a 2.5:1 ratio of historical control patients to PCC patients was reached. The 2.5:1 ratio of patients was decided on by the study authors a priori to improve the chances of finding a difference within the study arms without a power analysis. The standard of care for warfarin reversal in the historical control group included vitamin K and FFP
Downloaded from aop.sagepub.com at UNIV CALIFORNIA SAN DIEGO on June 12, 2015
3
Kantorovich et al without the use of other reversal agents. Blood product administration in both study groups was at the sole discretion of the transplant surgeon. There was no standardization for blood product administration; thus, no limitations or set number of units of a product were mandated to be administered. Finally, there were no major differences in surgical coagulation monitoring between cohorts. The co-primary objectives of the study were to assess the use of each specific blood product associated with the use of PCC in addition to vitamin K for warfarin reversal prior to heart transplant as compared with a historical control group. Blood product use was defined as the use of packed red blood cells (pRBCs), FFP, cryoprecipitate, or platelets and was measured in units of each product. Blood product use data came from the blood bank to ensure accuracy. Secondary outcomes included the incidence of in-hospital mortality, the need for reoperation for bleeding, all types of thromboembolic events (confirmed by imaging), duration of chest tube use, time to extubation, intensive care unit (ICU) length of stay, and hospital length of stay. Data on blood product use were collected from postoperative day (POD) 0 to POD 2 to ensure accurate collection of pretransplant, intraoperative, and post-transplant blood products for both cohorts; data on thromboembolic events and reoperation for bleeding were collected from POD 0 to POD 14. POD 0 was defined as beginning at midnight on the day of surgery. The secondary end points of duration of chest tube use, time to extubation, ICU length of stay, and hospital length of stay were assessed starting from POD 0. PCCs are available in multiple formulations, including activated PCC, 3-factor PCC, and 4-factor PCC, which was recently approved by the Food and Drug Administration (FDA). The main differences between these products are the content of factor VII in each formulation and whether or not factor VII is in an activated or inactivated state (factor VII vs factor VIIa).4 The product utilized in our study was factor IX complex, also known as Profilnine SD (Grifols Biologicals Inc, Los Angeles, CA), a 3-factor PCC consisting of no more than 150, 35, and 100 units of factors II, VII, and X, respectively, for every 100 units of factor IX.5,6 Normalcy was determined using the Shapiro-Wilk test. Continuous variables were evaluated using t tests or MannWhitney U tests, and categorical variables were evaluated using χ2 or Fisher’s exact tests as appropriate. Descriptive statistics were utilized to present patient baseline characteristics. A significance value (α) of 0.05 was used for all statistical calculations and was set a priori.
Results The study enrolled both adult and pediatric patients; however, the majority of patients included were adults. In all, 16 patients taking warfarin who underwent heart transplant after the introduction of the warfarin reversal protocol were
included in the PCC cohort. Two of the patients were adolescents aged 12 and 16, respectively. Of the 16 patients in the PCC cohort, 11 had LVADs as a bridge to transplant. Patients in the PCC cohort underwent surgery between July 2013 and December 2013. The historical control cohort included 50 patients, including 1 5-year-old pediatric patient, all of whom underwent heart transplant between June 2010 and April 2013. Baseline characteristics among groups are outlined in Table 1. Similar to the PCC cohort, most patients in the historical control cohort were on warfarin prior to transplant because of the presence of a VAD. Other indications for anticoagulation in both cohorts included VTE and atrial fibrillation, which was the most common indication. The historical control group had a higher rate of VADs present compared with the PCC group (74% vs 69%). In addition, 1 patient in the historical control group was administered recombinant factor VIIa in the operating room to correct a coagulopathy; unfortunately, the patient died during surgery because of bleeding complications and was included in the analysis because the administration of the other factor product did not have an influence on the patient’s outcome. The PCC cohort utilized a mean of 2.1 (standard deviation [SD] = 0.86) doses and 1605 (SD = 649) International Units (IU) per patient prior to surgery at a weight-based mean dose of 19.6 (SD = 5.6) IU/kg. Per our protocol, the goal INR was
research-article2015
AOPXXX10.1177/1060028015585344Annals of PharmacotherapyKantorovich et al
Research Report
Low-Dose 3-Factor Prothrombin Complex Concentrate for Warfarin Reversal Prior to Heart Transplant
Annals of Pharmacotherapy 1–7 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028015585344 aop.sagepub.com
Alexander Kantorovich, PharmD1,2, Jodie M. Fink, PharmD3, Michael A. Militello, PharmD4, Matthew R. Wanek, PharmD4, Nicholas G. Smedira, MD4, Edward G. Soltesz, MD4, and Nader Moazami, MD4
Abstract Background: Anticoagulation with warfarin is common in patients presenting for heart transplant. Prior to surgery, anticoagulation reversal is necessary to avoid significant intraoperative and perioperative bleeding complications. Commonly, warfarin reversal is achieved with vitamin K and fresh frozen plasma (FFP); however, these therapies have significant limitations. An alternative to FFP for reversal exists with prothrombin complex concentrate (PCC). A warfarin reversal protocol prior to heart transplant was implemented using low-dose PCC at our institution. Objective: To assess blood product use, effectiveness, and safety post–low-dose PCC administration in patients needing warfarin reversal prior to heart transplant compared with historical controls. Methods: This was a single-center, retrospective cohort study. The PCC cohort included patients undergoing heart transplant presenting with an international normalized ratio ≥1.5 on warfarin therapy and who received at least 1 dose of PCC. Blood product use was measured from postoperative day 0 to 2. Results: The PCC and historical control cohorts included 16 and 50 patients, respectively. There was a significant reduction in the use of FFP (4 vs 8 units, P = 0.0239) in the PCC cohort compared with the historical control cohort. No differences were identified in the use of other blood products as well as other secondary efficacy or safety end points. Conclusions: Use of PCC, per the reversal protocol, prior to heart transplant reduced FFP use and showed a non– statistically significant trend toward reductions in the use of other blood products in the intraoperative and perioperative setting, with no difference identified in thrombotic or embolic complications compared with historical controls. Keywords anticoagulation, transplantation, surgery, warfarin, cardiology
Introduction Therapeutic anticoagulation is common in patients requiring heart transplant because these patients are on warfarin for indications such as atrial fibrillation, venous thromboembolism (VTE), and the presence of mechanical heart valves or ventricular assist devices (VADs). Prior to heart transplant, anticoagulant reversal is often necessary to avoid significant intraoperative and perioperative bleeding. Reversal is commonly achieved with vitamin K, which competes with warfarin for the vitamin K reductase enzyme, as well as fresh frozen plasma (FFP), which contains clotting factors, including those depleted by warfarin.1 Limitations, however, exist with both strategies, such as time to international normalized ratio (INR) normalization with vitamin K. In addition, limitations of FFP include time necessary for thawing the product, large volumes necessary for adequate reversal, and the possibility of transfusion-related lung injury. Transfusion of blood products in the transplant population also increases the risk of
allosensitization with the introduction of antibodies leading to possible organ rejection. Another option for reversal is prothrombin complex concentrate (PCC), which contains the vitamin K–dependent clotting factors depleted by warfarin (factors II, VII, IX, and X).2 Heart transplant guidelines include PCC among the modalities for warfarin reversal; however, supportive evidence is minimal.3 At our institution in the summer of 2013, representatives from the departments of cardiothoracic surgery, hematology, and pharmacy developed a warfarin reversal protocol for patients undergoing heart transplant with a presenting INR of 1
Chicago State University College of Pharmacy, Chicago, IL, USA Advocate Christ Medical Center, Oak Lawn, IL, USA 3 University Hospitals Ahuja Medical Center, Beachwood, OH, USA 4 Cleveland Clinic, Cleveland, OH, USA 2
Corresponding Author: Nader Moazami, Kaufman Center for Heart Failure, Cleveland Clinic, 9500 Euclid Ave, Desk J4-1, Cleveland, OH 44195, USA. Email: [email protected]
Downloaded from aop.sagepub.com at UNIV CALIFORNIA SAN DIEGO on June 12, 2015
2
Annals of Pharmacotherapy
Figure 1. Heart transplant warfarin reversal protocol.
Abbreviations: INR, international normalized ratio; IV, intravenous; PCC, prothrombin complex concentrate.
1.5 or greater with low-dose PCC. The protocol was created in an effort to reduce blood product use and was based on a thorough review of relevant clinical trials using PCC for INR reversal as well as internal expert opinion. Our intent was to produce a protocol that limited PCC doses to minimize exposure and avoid thrombotic events in a potentially high-risk population. The protocol, shown in Figure 1, utilizes both a weight-based and INR-specific dosing scheme and allows a maximum of 3 doses to be administered to patients. This study evaluated the effectiveness and safety of this protocol for warfarin reversal prior to heart transplant using PCC and compared the results related to blood product use, the need for reoperation for bleeding, and adverse events post-implementation with a historical control group prior to implementation. To our knowledge, this is the first study evaluating a warfarin reversal protocol utilizing low-dose PCC with dosing based on weight (units/kg) and baseline INR.
Methods This was a single-center, non-interventional, retrospective cohort study approved by the institutional review board,
which waived the requirement for individual informed consent. All data were gathered from the electronic medical record and collected and managed using REDCap (Research Electronic Data Capture) electronic data capture tools hosted at Cleveland Clinic.4 Patients were included in the PCC cohort if they underwent heart transplant after June 2013 when the warfarin reversal protocol was implemented, presented for transplant with an INR of ≥1.5, and received at least 1 dose of PCC. To be included in the historical control cohort, patients had to have undergone heart transplant, been on warfarin prior to surgery, and presented with an INR of ≥1.5 and should not have received PCC. Historical control patients were identified from the institution’s heart transplant master list starting immediately prior to the initiation of the warfarin reversal protocol (June 2013) and going backward in time until a 2.5:1 ratio of historical control patients to PCC patients was reached. The 2.5:1 ratio of patients was decided on by the study authors a priori to improve the chances of finding a difference within the study arms without a power analysis. The standard of care for warfarin reversal in the historical control group included vitamin K and FFP
Downloaded from aop.sagepub.com at UNIV CALIFORNIA SAN DIEGO on June 12, 2015
3
Kantorovich et al without the use of other reversal agents. Blood product administration in both study groups was at the sole discretion of the transplant surgeon. There was no standardization for blood product administration; thus, no limitations or set number of units of a product were mandated to be administered. Finally, there were no major differences in surgical coagulation monitoring between cohorts. The co-primary objectives of the study were to assess the use of each specific blood product associated with the use of PCC in addition to vitamin K for warfarin reversal prior to heart transplant as compared with a historical control group. Blood product use was defined as the use of packed red blood cells (pRBCs), FFP, cryoprecipitate, or platelets and was measured in units of each product. Blood product use data came from the blood bank to ensure accuracy. Secondary outcomes included the incidence of in-hospital mortality, the need for reoperation for bleeding, all types of thromboembolic events (confirmed by imaging), duration of chest tube use, time to extubation, intensive care unit (ICU) length of stay, and hospital length of stay. Data on blood product use were collected from postoperative day (POD) 0 to POD 2 to ensure accurate collection of pretransplant, intraoperative, and post-transplant blood products for both cohorts; data on thromboembolic events and reoperation for bleeding were collected from POD 0 to POD 14. POD 0 was defined as beginning at midnight on the day of surgery. The secondary end points of duration of chest tube use, time to extubation, ICU length of stay, and hospital length of stay were assessed starting from POD 0. PCCs are available in multiple formulations, including activated PCC, 3-factor PCC, and 4-factor PCC, which was recently approved by the Food and Drug Administration (FDA). The main differences between these products are the content of factor VII in each formulation and whether or not factor VII is in an activated or inactivated state (factor VII vs factor VIIa).4 The product utilized in our study was factor IX complex, also known as Profilnine SD (Grifols Biologicals Inc, Los Angeles, CA), a 3-factor PCC consisting of no more than 150, 35, and 100 units of factors II, VII, and X, respectively, for every 100 units of factor IX.5,6 Normalcy was determined using the Shapiro-Wilk test. Continuous variables were evaluated using t tests or MannWhitney U tests, and categorical variables were evaluated using χ2 or Fisher’s exact tests as appropriate. Descriptive statistics were utilized to present patient baseline characteristics. A significance value (α) of 0.05 was used for all statistical calculations and was set a priori.
Results The study enrolled both adult and pediatric patients; however, the majority of patients included were adults. In all, 16 patients taking warfarin who underwent heart transplant after the introduction of the warfarin reversal protocol were
included in the PCC cohort. Two of the patients were adolescents aged 12 and 16, respectively. Of the 16 patients in the PCC cohort, 11 had LVADs as a bridge to transplant. Patients in the PCC cohort underwent surgery between July 2013 and December 2013. The historical control cohort included 50 patients, including 1 5-year-old pediatric patient, all of whom underwent heart transplant between June 2010 and April 2013. Baseline characteristics among groups are outlined in Table 1. Similar to the PCC cohort, most patients in the historical control cohort were on warfarin prior to transplant because of the presence of a VAD. Other indications for anticoagulation in both cohorts included VTE and atrial fibrillation, which was the most common indication. The historical control group had a higher rate of VADs present compared with the PCC group (74% vs 69%). In addition, 1 patient in the historical control group was administered recombinant factor VIIa in the operating room to correct a coagulopathy; unfortunately, the patient died during surgery because of bleeding complications and was included in the analysis because the administration of the other factor product did not have an influence on the patient’s outcome. The PCC cohort utilized a mean of 2.1 (standard deviation [SD] = 0.86) doses and 1605 (SD = 649) International Units (IU) per patient prior to surgery at a weight-based mean dose of 19.6 (SD = 5.6) IU/kg. Per our protocol, the goal INR was
