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Efficacy and Safety of Idarucizumab for Rapid Reversal from Dabigatran in Patients Undergoing Orthotopic Heart Transplantation
S288
The Journal of Heart and Lung Transplantation, Vol 38, No 4S, April 2019
Methods: Between 2008 and 2013, we assessed 33 HTx patients who developed BNR via the following criteria: ACR≤1R, AMR 0, cardiac dysfunction (LVEF≤40%, CI<2.0). Patients were then divided into those that developed BNR prior to 1-year post-transplant (n=23) and after 1-year post-transplant (n=10). The following 5-year subsequent endpoints were evaluated: survival, freedom from cardiac allograft vasculopathy (CAV) as defined by stenosis ≥ 30% by angiography, and non-fatal major adverse cardiac events (NF-MACE: myocardial infarction, new congestive heart failure, percutaneous coronary intervention, implantable cardioverter defibrillator/pacemaker implant, stroke). Results: Late BNR was associated with significantly reduced subsequent 5-year survival and an increase in the development of angiographic CAV compared to those with early BNR. The timing of BNR did not make a difference in the development of NF-MACE. (see Table) Conclusion: Late BNR in HTx is associated with poor long-term outcome. The mechanism of this rejection is not clear but represents a heightened immune response that is being missed on EMB. More aggressive augmentation of immunosuppression and/or immunomodulation are indicated in patients presenting with late BNR.
Patient demographics Age − years Male gender − no (%) Time since HTx − years [median (IQR)] Body mass index − kg/m2 Systolic blood pressure − mmHg Heart rate − beats per minute Creatinine − micromol/l Estimated glomerular filtration rate − ml/min/1.73m2 Hemoglobin − g/l Ferritin − mg/l [median (IQR)] Transferrin saturation − % C-reactive protein − mg/l [median (IQR)] Total plasma protein − g/l Troponin T − ng/l [median (IQR)] Troponin T − ng/l [median (IQR)] NT-proBNP − ng/l [median (IQR)] Treated with platelet inhibitors − no (%) Treated with platelet inhibitors − no (%)
56 § 15 119 (70) 7 (4-13) 25.4 § 9.6 129 § 25 84 § 19 106 § 33 64 § 19 134 § 15 128 (73-211) 26 § 11 1.6 (0.7-4.1) 68 § 4 13 (8-25) 13 (8-25) 337 (191-779) 74 (45) 24 (14)
713
Endpoints
Early BNR (n=23)
Late BNR (n=10)
Subsequent 5-Year Survival Subsequent 5-Year Freedom from CAV Subsequent 5-Year Freedom from NF-MACE
87.0% 82.6% 47.8%
50.0% 40.0% 30.0%
P-Value 0.020 <0.001 0.369
712 Prevalence of Iron Deficiency in Heart Transplant Recipients K. Brautaset, C.M. Østby, G. Tjønnas, E. Gude, A.K. Andreassen, L. Gullestad and K. Broch. Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway. Purpose: Many heart transplant recipients have reduced exercise capacity and health-related quality of life, despite good over-all results regarding graft function. We believe iron deficiency (ID) to be one of several peripheral factors to have an impact on exercise capacity in heart transplant recipients, unrelated to hemodynamic dysfunction. In the general population, ID is defined as serum ferritin < 30 mg/l. However, with comorbidities, this cut off has a low sensitivity. Trials with heart failure patients and ID, defined as ferritin < 100 mg/l, or ferritin 100-300 mg/l, combined with transferrin saturation < 20 %, show improved outcomes after intravenous iron-treatment. Solid organ transplantation triggers chronic, low-grade inflammation, which in turn affects positive acute-phase proteins as ferritin. A strict ID definition will therefor miss many heart transplant recipients with low iron stores. The objective of this study is to assess the prevalence of iron deficiency in heart transplant recipients. Methods: We assessed parameters of iron metabolism in 169 stable heart transplant recipients at their annual follow up, at least one year after transplantation. ID was defined as s-ferritin < 100 mg/l, or s-ferritin 100-300 mg/l, combined with transferrin saturation < 20 %. Results: Study demographics are presented in the Table. 81 patients (48 %) had ID defined as serum ferritin < 100 mg/l or ferritin between 100 and 300 mg/l in combination with a transferrin saturation < 20 %. 67 patients (40 %) had a ferritin below 100 mg/l, and 47 patients (28 %) had a transferrin saturation < 20 %. 43 patients (25 %) had a C-reactive protein > 4.0 mg/l, and 29 patients (17 %) had an sedimentation rate (SR) > 20 mm. Ferritin was weakly associated with SR (r = 0.24; p = 0.002) as well as estimated GFR (r = -0.22; p = 0.004) and age (r = 0.17; p = 0.02). Conclusion: ID is prevalent in heart transplant recipients. Trials should be initiated to evaluate whether intravenous iron substitution can improve functional capacity and quality of life in heart transplant recipients with ID.
Does Cell-Free DNA Detect the Development of De Novo Donor Specific Antibodies J.A. Kobashigawa,1 J. Patel,1 E. Kransdorf,1 D. Chang,1 M. Kittleson,1 S. Dimbil,1 R. Levine,1 S. Sana,1 A. Wolfson,1 L. Czer,1 M. Hamilton,1 R. Woodward,2 and F. Esmailian.1 1Smidt Heart Institute at Cedars-Sinai, Los Angeles, CA; and the 2CareDx, Inc., Brisbane, CA. Purpose: Donor Derived Cell-Free DNA (dd-cfDNA) has been demonstrated to detect both cellular and antibody mediated rejection after heart transplantation (Htx). The development of donor-specific antibodies (DSA) suggests that the recipient’s immune system recognizes that the donor heart as foreign and develops antibodies against it. It is not clear whether the DSA is actually causing harm to the donor heart resulting in an increase in dd-cfDNA. Methods: Between 2015-2017 we identified 24 stable HTx patients with dd-cfDNA draws in the first year who developed de novo DSA. In our program, blood is routinely drawn for DSA at 1,3,6 and 12 months after HTx. This group of patients with dd-cfDNA level (drawn within 1-month of a positive DSA result), was compared to a group of patients with dd-cfDNA levels (drawn within 1-month of a negative DSA result). All dd-cfDNA draws were from patients with normal endomyocardial biopsies and normal echocardiographic LVEF. Results: The average dd-cfDNA for the DSA group was 1.2% which was significantly elevated compared to the dd-cfDNA of the control group with negative DSA which was 0.4%. The mean DSA level defined as mean fluorescent intensity (MFI) level was 6,984 § 4,460. (MFI range 5,000 to 17,500). Conclusion: dd-cfDNA appears to be correlated to the development of DSA. Furthermore, it suggests that DSA may be injuring the donor heart and may necessitate treatment of these patients.
Endpoints dd-Cell Free DNA Result, Mean § SD
DSA within 1 Month of Cf-DNA (n=24)
No DSA within 1 Month of Cf-DNA (n=95)
P-Value
1.2 § 1.6%
0.4 § 0.6%
0.0002
714 Efficacy and Safety of Idarucizumab for Rapid Reversal from Dabigatran in Patients Undergoing Orthotopic Heart Transplantation I. Kim,1 H. Kim,1 W. Chang,1 J. Kim,1 N. Park,1 J. Youn,2 S. Choi,1 S. Jun,1 Y. Cho,1 H. Yoon,1 C. Nam,1 S. Han,1 S. Hur,1 and H. Park.1 1Keimyung University Dongsan Medical Center, Daegu, Republic of Korea; and the 2Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Daegu, Republic of Korea.
Abstracts Purpose: To evaluate the effectiveness and safety of idarucizumab before urgent heart transplantation (HTPL) in patients using dabigatran. Methods: Between March 2017 and January 2018, consecutive patients who underwent HTPL were evaluated at a single tertiary university hospital. Total 17 HTPL recipients were included in the present study. Patients were grouped into no-anticoagulation therapy (9 patients; Group 1), extracorporeal membrane oxygenator with heparin therapy (3 patients; Group 2), and dabigatran for stroke prevention in atrial fibrillation with idarucizumab reversal before HTPL surgery (5 patients; Group 3). Surgery time (pump time, and total surgery time), amount of packed red blood cell transfusion during surgery, and composite events (bleeding complications, stroke, venous thrombosis, death) during perioperative period were evaluated among three groups. Results: Mean age of recipients was (51.2 § 16.1 years, male 52.9%). Surgery time was longest in group 2 (Total surgery time: 328.3 § 55.8, 336.4 § 43.0, 288.8 § 38.7; pump time 159.0 § 21.7, 161.9 § 27.2, 127.0 § 17.9). Packed RBC transfusion volume was also higher in group 2 (133.3 § 230.9, 511.1 § 105.4, 40.0 § 89.4). When compared with group 2, pump time was significantly shorter (p=0.028) and amount of PC transfusion was significantly lower (p=0.002) in group 3 (figure 1). Amount of transfusion was highest in group 2. Composite events were developed in only group 2 (four patients: vaginal bleeding 1; embolic cerebral infarction 1; venous thrombosis 1; non-cardiac death 1).
S289 Conclusion: In terms of effectiveness and safety, using idarucizumab before HTPL was beneficial compared with heparin use during ECMO and comparable with non-anticoagulation, non-antiplatelet patients. Candidates for HTPL who are indicated for anticoagulation therapy may consider dabigatran with idarucizumab.
715 Use of dd-cfDNA in Real World Practice: Single Center Experience J. Smith,1 J. Fuentes,1 T. Khuu,1 W. Carpenter,1 D. Cruz,1 M. Cadeiras,2 M.C. Deng,1 and E.C. DePasquale.1 1UCLA, Los Angeles, CA; and the 2UC Davis, Sacramento, CA. Purpose: Gene expression profiling testing (GEP; AlloMap) and donorderived cell free DNA (dd-cfDNA; AlloSure) each provide non-invasive means to detect possible heart allograft rejection, including acute cellular rejection (ACR). This report describes the largest single center use of ddcfDNA to date. Methods: Post heart transplant (HT) management is standardized at our center such that endomyocardial biopsy is used for rejection surveillance in the early period with crossover to GEP testing at day 56. Elevated GEP (≥34) prompts biopsy. dd-cfDNA was utilized in conjunction with biopsy or in lieu of biopsy (barrier to biopsy). A cohort of 26 HT patients underwent dd-cfDNA testing, including 3 multiorgan (same donor) and 5 retransplant patients. The dd-cfDNA (%, AlloSure) and GEP (AlloMap, score 0-40) results were correlated patient survival. Results: Among 26 HT patients there was a total 70 dd-cfDNA tests (mean 2.7 per pt). dd-cfDNA usage was due to inability to biopsy (33%), anticoagulation (22%), elevated GEP (26%), with graft dysfunction, prior rejection, biopsy refusal, tricuspid regurgitation and critically ill status comprising 4% each. Mean day post HT for first dd-cfDNA test was 201 (IQR 90-517), with earliest at day 7 post HT. Mean dd-cfDNA was 0.3 § 0.5%. Mean GEP score was 32.8 § 5.3. There were no deaths in this cohort. One patient had confirmed AMR2 (dd-cfDNA 0.25%). Mean LVEF 54% § 5. Conclusion: In surveillance of heart allograft recipients for rejection, consideration of dd-cfDNA levels may improve patient management decisions particularly when endomyocardial biopsy may not be feasible.
716 Heart Transplantation Outcomes in Liver Cirrhosis: Influence of Ascites on Post-Transplantation Survival H. Kim, J. Kim, S. Lee, H. Joo, K. Yoo and Y. Youn. Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
The Journal of Heart and Lung Transplantation, Vol 38, No 4S, April 2019
Methods: Between 2008 and 2013, we assessed 33 HTx patients who developed BNR via the following criteria: ACR≤1R, AMR 0, cardiac dysfunction (LVEF≤40%, CI<2.0). Patients were then divided into those that developed BNR prior to 1-year post-transplant (n=23) and after 1-year post-transplant (n=10). The following 5-year subsequent endpoints were evaluated: survival, freedom from cardiac allograft vasculopathy (CAV) as defined by stenosis ≥ 30% by angiography, and non-fatal major adverse cardiac events (NF-MACE: myocardial infarction, new congestive heart failure, percutaneous coronary intervention, implantable cardioverter defibrillator/pacemaker implant, stroke). Results: Late BNR was associated with significantly reduced subsequent 5-year survival and an increase in the development of angiographic CAV compared to those with early BNR. The timing of BNR did not make a difference in the development of NF-MACE. (see Table) Conclusion: Late BNR in HTx is associated with poor long-term outcome. The mechanism of this rejection is not clear but represents a heightened immune response that is being missed on EMB. More aggressive augmentation of immunosuppression and/or immunomodulation are indicated in patients presenting with late BNR.
Patient demographics Age − years Male gender − no (%) Time since HTx − years [median (IQR)] Body mass index − kg/m2 Systolic blood pressure − mmHg Heart rate − beats per minute Creatinine − micromol/l Estimated glomerular filtration rate − ml/min/1.73m2 Hemoglobin − g/l Ferritin − mg/l [median (IQR)] Transferrin saturation − % C-reactive protein − mg/l [median (IQR)] Total plasma protein − g/l Troponin T − ng/l [median (IQR)] Troponin T − ng/l [median (IQR)] NT-proBNP − ng/l [median (IQR)] Treated with platelet inhibitors − no (%) Treated with platelet inhibitors − no (%)
56 § 15 119 (70) 7 (4-13) 25.4 § 9.6 129 § 25 84 § 19 106 § 33 64 § 19 134 § 15 128 (73-211) 26 § 11 1.6 (0.7-4.1) 68 § 4 13 (8-25) 13 (8-25) 337 (191-779) 74 (45) 24 (14)
713
Endpoints
Early BNR (n=23)
Late BNR (n=10)
Subsequent 5-Year Survival Subsequent 5-Year Freedom from CAV Subsequent 5-Year Freedom from NF-MACE
87.0% 82.6% 47.8%
50.0% 40.0% 30.0%
P-Value 0.020 <0.001 0.369
712 Prevalence of Iron Deficiency in Heart Transplant Recipients K. Brautaset, C.M. Østby, G. Tjønnas, E. Gude, A.K. Andreassen, L. Gullestad and K. Broch. Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway. Purpose: Many heart transplant recipients have reduced exercise capacity and health-related quality of life, despite good over-all results regarding graft function. We believe iron deficiency (ID) to be one of several peripheral factors to have an impact on exercise capacity in heart transplant recipients, unrelated to hemodynamic dysfunction. In the general population, ID is defined as serum ferritin < 30 mg/l. However, with comorbidities, this cut off has a low sensitivity. Trials with heart failure patients and ID, defined as ferritin < 100 mg/l, or ferritin 100-300 mg/l, combined with transferrin saturation < 20 %, show improved outcomes after intravenous iron-treatment. Solid organ transplantation triggers chronic, low-grade inflammation, which in turn affects positive acute-phase proteins as ferritin. A strict ID definition will therefor miss many heart transplant recipients with low iron stores. The objective of this study is to assess the prevalence of iron deficiency in heart transplant recipients. Methods: We assessed parameters of iron metabolism in 169 stable heart transplant recipients at their annual follow up, at least one year after transplantation. ID was defined as s-ferritin < 100 mg/l, or s-ferritin 100-300 mg/l, combined with transferrin saturation < 20 %. Results: Study demographics are presented in the Table. 81 patients (48 %) had ID defined as serum ferritin < 100 mg/l or ferritin between 100 and 300 mg/l in combination with a transferrin saturation < 20 %. 67 patients (40 %) had a ferritin below 100 mg/l, and 47 patients (28 %) had a transferrin saturation < 20 %. 43 patients (25 %) had a C-reactive protein > 4.0 mg/l, and 29 patients (17 %) had an sedimentation rate (SR) > 20 mm. Ferritin was weakly associated with SR (r = 0.24; p = 0.002) as well as estimated GFR (r = -0.22; p = 0.004) and age (r = 0.17; p = 0.02). Conclusion: ID is prevalent in heart transplant recipients. Trials should be initiated to evaluate whether intravenous iron substitution can improve functional capacity and quality of life in heart transplant recipients with ID.
Does Cell-Free DNA Detect the Development of De Novo Donor Specific Antibodies J.A. Kobashigawa,1 J. Patel,1 E. Kransdorf,1 D. Chang,1 M. Kittleson,1 S. Dimbil,1 R. Levine,1 S. Sana,1 A. Wolfson,1 L. Czer,1 M. Hamilton,1 R. Woodward,2 and F. Esmailian.1 1Smidt Heart Institute at Cedars-Sinai, Los Angeles, CA; and the 2CareDx, Inc., Brisbane, CA. Purpose: Donor Derived Cell-Free DNA (dd-cfDNA) has been demonstrated to detect both cellular and antibody mediated rejection after heart transplantation (Htx). The development of donor-specific antibodies (DSA) suggests that the recipient’s immune system recognizes that the donor heart as foreign and develops antibodies against it. It is not clear whether the DSA is actually causing harm to the donor heart resulting in an increase in dd-cfDNA. Methods: Between 2015-2017 we identified 24 stable HTx patients with dd-cfDNA draws in the first year who developed de novo DSA. In our program, blood is routinely drawn for DSA at 1,3,6 and 12 months after HTx. This group of patients with dd-cfDNA level (drawn within 1-month of a positive DSA result), was compared to a group of patients with dd-cfDNA levels (drawn within 1-month of a negative DSA result). All dd-cfDNA draws were from patients with normal endomyocardial biopsies and normal echocardiographic LVEF. Results: The average dd-cfDNA for the DSA group was 1.2% which was significantly elevated compared to the dd-cfDNA of the control group with negative DSA which was 0.4%. The mean DSA level defined as mean fluorescent intensity (MFI) level was 6,984 § 4,460. (MFI range 5,000 to 17,500). Conclusion: dd-cfDNA appears to be correlated to the development of DSA. Furthermore, it suggests that DSA may be injuring the donor heart and may necessitate treatment of these patients.
Endpoints dd-Cell Free DNA Result, Mean § SD
DSA within 1 Month of Cf-DNA (n=24)
No DSA within 1 Month of Cf-DNA (n=95)
P-Value
1.2 § 1.6%
0.4 § 0.6%
0.0002
714 Efficacy and Safety of Idarucizumab for Rapid Reversal from Dabigatran in Patients Undergoing Orthotopic Heart Transplantation I. Kim,1 H. Kim,1 W. Chang,1 J. Kim,1 N. Park,1 J. Youn,2 S. Choi,1 S. Jun,1 Y. Cho,1 H. Yoon,1 C. Nam,1 S. Han,1 S. Hur,1 and H. Park.1 1Keimyung University Dongsan Medical Center, Daegu, Republic of Korea; and the 2Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Daegu, Republic of Korea.
Abstracts Purpose: To evaluate the effectiveness and safety of idarucizumab before urgent heart transplantation (HTPL) in patients using dabigatran. Methods: Between March 2017 and January 2018, consecutive patients who underwent HTPL were evaluated at a single tertiary university hospital. Total 17 HTPL recipients were included in the present study. Patients were grouped into no-anticoagulation therapy (9 patients; Group 1), extracorporeal membrane oxygenator with heparin therapy (3 patients; Group 2), and dabigatran for stroke prevention in atrial fibrillation with idarucizumab reversal before HTPL surgery (5 patients; Group 3). Surgery time (pump time, and total surgery time), amount of packed red blood cell transfusion during surgery, and composite events (bleeding complications, stroke, venous thrombosis, death) during perioperative period were evaluated among three groups. Results: Mean age of recipients was (51.2 § 16.1 years, male 52.9%). Surgery time was longest in group 2 (Total surgery time: 328.3 § 55.8, 336.4 § 43.0, 288.8 § 38.7; pump time 159.0 § 21.7, 161.9 § 27.2, 127.0 § 17.9). Packed RBC transfusion volume was also higher in group 2 (133.3 § 230.9, 511.1 § 105.4, 40.0 § 89.4). When compared with group 2, pump time was significantly shorter (p=0.028) and amount of PC transfusion was significantly lower (p=0.002) in group 3 (figure 1). Amount of transfusion was highest in group 2. Composite events were developed in only group 2 (four patients: vaginal bleeding 1; embolic cerebral infarction 1; venous thrombosis 1; non-cardiac death 1).
S289 Conclusion: In terms of effectiveness and safety, using idarucizumab before HTPL was beneficial compared with heparin use during ECMO and comparable with non-anticoagulation, non-antiplatelet patients. Candidates for HTPL who are indicated for anticoagulation therapy may consider dabigatran with idarucizumab.
715 Use of dd-cfDNA in Real World Practice: Single Center Experience J. Smith,1 J. Fuentes,1 T. Khuu,1 W. Carpenter,1 D. Cruz,1 M. Cadeiras,2 M.C. Deng,1 and E.C. DePasquale.1 1UCLA, Los Angeles, CA; and the 2UC Davis, Sacramento, CA. Purpose: Gene expression profiling testing (GEP; AlloMap) and donorderived cell free DNA (dd-cfDNA; AlloSure) each provide non-invasive means to detect possible heart allograft rejection, including acute cellular rejection (ACR). This report describes the largest single center use of ddcfDNA to date. Methods: Post heart transplant (HT) management is standardized at our center such that endomyocardial biopsy is used for rejection surveillance in the early period with crossover to GEP testing at day 56. Elevated GEP (≥34) prompts biopsy. dd-cfDNA was utilized in conjunction with biopsy or in lieu of biopsy (barrier to biopsy). A cohort of 26 HT patients underwent dd-cfDNA testing, including 3 multiorgan (same donor) and 5 retransplant patients. The dd-cfDNA (%, AlloSure) and GEP (AlloMap, score 0-40) results were correlated patient survival. Results: Among 26 HT patients there was a total 70 dd-cfDNA tests (mean 2.7 per pt). dd-cfDNA usage was due to inability to biopsy (33%), anticoagulation (22%), elevated GEP (26%), with graft dysfunction, prior rejection, biopsy refusal, tricuspid regurgitation and critically ill status comprising 4% each. Mean day post HT for first dd-cfDNA test was 201 (IQR 90-517), with earliest at day 7 post HT. Mean dd-cfDNA was 0.3 § 0.5%. Mean GEP score was 32.8 § 5.3. There were no deaths in this cohort. One patient had confirmed AMR2 (dd-cfDNA 0.25%). Mean LVEF 54% § 5. Conclusion: In surveillance of heart allograft recipients for rejection, consideration of dd-cfDNA levels may improve patient management decisions particularly when endomyocardial biopsy may not be feasible.
716 Heart Transplantation Outcomes in Liver Cirrhosis: Influence of Ascites on Post-Transplantation Survival H. Kim, J. Kim, S. Lee, H. Joo, K. Yoo and Y. Youn. Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.