The effect of anticoagulation therapy on perioperative bleeding risk in patients undergoing heart transplantation

    Authors

    Keywords

    heart transplantation, oral anticoagulation therapy, vitamin K antagonist, dabigatran, bleeding complications

    DOI

    https://doi.org/10.15836/ccar2022.191

    Full Text

    **Background:** Oral anticoagulation therapy for the prevention of thromboembolic complications of atrial fibrillation in patients awaiting heart transplantation (HTx) traditionally includes warfarin, and in the last few years it increasingly includes dabigatran. Anticoagulation must be reversed before the surgery. The possibility of rapid reversal of the anticoagulant effect of dabigatran with idarucizumab seems to represent an advantage (1). A comparison of bleeding complications between these two strategies has not been completely investigated. **Patients and Methods:** We did a retrospective analysis of bleeding complications during and immediately after HTx performed in University Hospital Center Zagreb in 15 patients divided into 3 groups: patients who were on warfarin prior to HTx, patients who were on dabigatran prior to HTx, and control patients without indication for anticoagulation therapy. Patients were mutually paired to eliminate the influence of other risk factors including age, gender, etiology of heart failure, renal function, as well as whether surgery was primary or after previous sternotomy. For the comparison of bleeding complications we measured the utilization of blood products (red blood cells, platelets, fibrinogen, fresh frozen plasma (FFP), prothrombin complex (PC) and the amount of thoracic drainage within the first 24 hours after the HTx. **Results:** There was no significant difference in the utilization of blood products as well as the amount of 24h thoracic drainage between these three groups **(****Table 1****)**. Only 2/5 patients in the warfarin group were within the therapeutic INR range (2 pts below and 1 pts above the range). 24h thoracic drainage, FFP and PC consumption correlated with pretransplant INR **(****Table 2****).** ### TABLE 1: Comparison of different demographic and clinical characteristics, and crucial pretransplant/posttransplant laboratory findings between patient groups stratified according to anticoagulant use. | **Therapy groups:** | **No anticoagulation** **(n=5)** | **Warfarin** **(n=5)** | **Dabigatran** **(n=5)** | **p-value** | | --- | --- | --- | --- | --- | | Male gender, N (%) | 4 (80) | 4 (80) | 4 (80) | 1.000 | | Age at the time of HTx [y] (IQR) | 53 (53-57) | 59 (46-60) | 62 (46-63) | 0.756 | | Ischemic CMP, N (%) | 1 (20) | 1 (20) | 1 (20) | 1.000 | | Resternotomy, N (%) | 1 (20) | 1 (20) | 1 (20) | 1.000 | | eGFR [mL/min/1,73m2] (IQR) | 71 (66-84) | 65 (53-71) | 65 (50-76) | 0.423 | | Erythrocyte concentrate [mL] (IQR) | 260 (0-1510) | 250 (250-1020) | 550 (470-730) | 0.755 | | FFP [mL] (IQR) | 1020 (910-1060) | 1310 (1240-1380) | 1060 (1030-1150) | 0.385 | | Platelet concentrate [doses] (IQR) | 8 (6-8) | 8 (8-8) | 5 (0-10) | 0.919 | | Fibrinogen [g] (IQR) | 2 (2-3) | 2 (2-2) | 2 (2-4) | 0.698 | | Prothrombin complex [IU] (IQR) | 0 (0-0) | 0 (0-2500) | 0 (0-0) | 0.117 | | Thymoglobulin (IQR) | 24 (22-24) | 26 (24-29) | 28 (24-30) | 0.363 | | Thoracic drainage within the first 24h [mL] (IQR) | 400 (300-700) | 450 (400-550) | 600 (450-650) | 0.643 | | Hemoglobin before HTx [g/L] (IQR) | 139 (137-146) | 125 (121-160) | 142 (138-149) | 0.756 | | Platelets before HTx [10E9/L] (IQR) | 205 (200-260) | 282 (270-292) | 188 (174-202) | 0.102 | | PT-INR before HTx (IQR) | 0.96 (0.92-1.15) | 2.40 (1.18-2.41) | 1.09 (1.06-1.13) | 0.230 | | APTT before HTx [s] (IQR) | 24.60 (23.25-26.40) | 36.9 (27.7-37.5) | 31.3 (28.9-47.3) | 0.079 | | Fibrinogen before HTx [g/L] (IQR) | 3.75 (3.35-4.15) | 4.20 (3.40-5.70) | 3.85 (3.70-4.95) | 0.693 | | Hemoglobin 1st day after HTx [g/L] (IQR) | 101 (93-111) | 107 (95-112) | 96 (95-100) | 0.485 | | Platelets 1st day after HTx [10E9/L] (IQR) | 113 (94-163) | 135 (129-171) | 98 (92-131) | 0.330 | | PT-INR 1st day after HTx (IQR) | 1.02 (0.99-1.09) | 1.22 (1.03-1.43) | 1.18 (1.10-1.23) | 0.259 | | APTT 1st day after HTx [s] (IQR) | 25.7 (24.6-27.4) | 27.7 (23.9-28.4) | 25.4 (24.6-25.9) | 0.635 | | Fibrinogen 1st day after HTx [g/L] (IQR) | 4.50 (3.80-6.70) | 3.50 (3.40-3.70) | 3.4 (3.0-3.4) | 0.068 | | Hemoglobin 7th day after HTx [g/L] (IQR) | 102 (96-111) | 100 (92-101) | 88 (88-92) | 0.150 | | Platelets 7th day after HTx [10E9/L] (IQR) | 117 (97-193) | 112 (104-154) | 93 (73-108) | 0.228 | | PT-INR 7th day after HTx (IQR) | 1.00 (0.98-1.02) | 1.01 (0.95-1.12) | 1.08 (1.06-1.11) | 0.203 | | APTT 7th day after HTx [s] (IQR) | 20.5 (19.1-21.0) | 22.8 (21.3-23.3) | 21.7 (21.1-22.2) | 0.172 | | Fibrinogen 7th day after HTx [g/L] (IQR) | 2.3 (2.2-3.3) | 3.4 (2.9-5.2) | 3.5 (2.3-3.5) | 0.438 | [†] HTx – Heart Transplant; CMP – cardiomyopathy; eGFR – estimated Glomerular filtration rate; FFP– Fresh Frozen Plazma; PT-INR – Prothrombin Time – International Normalized Ratio; APTT – Activated Partial Thromboplastin Time. ### TABLE 2: Potential predictors of periprocedural bleeding in the observed heart transplant patient population. | **Correlation Pair** | **Spearman ρ** | **Correlation Significance** | | --- | --- | --- | | Total Chest Output in 24h & *Pretransplant PT-INR* | 0.645 | 0.009* | | Packed Red Blood Cell Transfusion Volume & *Ischemic Etiology of Heart Failure* | 0.543 | 0.036* | | Fresh Frozen Plasma Transfusion Volume & *Pretransplant PT-INR* | 0.661 | 0.007* | | Platelet Transfusion Volume & *Ischemic Etiology of Heart Failure* | 0.583 | 0.022* | | Prothrombin Complex Concentrate Transfusion & *Pretransplant PT-INR* | 0.592 | 0.020* | [†] PT-INR – Prothrombin Time – International Normalized Ratio * P < 0.05 **Conclusion:** Although there was no difference in the consumption of blood products and 24h thoracic drainage between patients who were on warfarin or dabigatran anticoagulation before HTx, it should be noted that the majority of patients on warfarin were not within the therapeutic INR range, and it was precisely the elevated INR that significantly correlated with the consumption of blood products and 24h thoracic drainage. It is necessary to conduct a study on a larger number of patients in order to find out whether the pre-HTx use of warfarin is equally safe and effective as the use of dabigatran, in terms of the perioperative bleeding.

    Literature

    1. Crespo-Leiro MG, López-Vilella R, López Granados A, Mirabet-Pérez S, Díez-López C, Barge-Caballero E, et al. Use of Idarucizumab to reverse the anticoagulant effect of dabigatran in cardiac transplant surgery. A multicentric experience in Spain. Clin Transplant. 2019 December;33(12):e13748. https://doi.org/10.1111/ctr.13748
    Cardiologia Croatica
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    The effect of anticoagulation therapy on perioperative bleeding risk in patients undergoing heart transplantation

    Extended Abstract
    Issue9-10
    Published
    Pages191-192
    PDF via DOIhttps://doi.org/10.15836/ccar2022.191
    heart transplantation
    oral anticoagulation therapy
    vitamin K antagonist
    dabigatran
    bleeding complications

    Authors

    Petra Mjehović*ORCIDUniversity of Zagreb School of Medicine, Zagreb, Croatia
    Mia Dubravčić DošenORCIDUniversity of Zagreb School of Medicine, Zagreb, Croatia
    Marijan PašalićORCIDUniversity of Zagreb School of Medicine, Zagreb, Croatia
    Maja ČikešORCIDUniversity of Zagreb School of Medicine, Zagreb, Croatia
    Dora FabijanovićORCIDUniversity of Zagreb School of Medicine, Zagreb, Croatia
    Nina JakušORCIDUniversity of Zagreb School of Medicine, Zagreb, Croatia
    Hrvoje JurinORCIDUniversity of Zagreb School of Medicine, Zagreb, Croatia
    Daniel LovrićORCIDUniversity of Zagreb School of Medicine, Zagreb, Croatia
    Ivo PlanincORCIDUniversity of Zagreb School of Medicine, Zagreb, Croatia
    Jure SamardžićORCIDUniversity of Zagreb School of Medicine, Zagreb, Croatia
    Branka Golubić ĆepulićORCIDUniversity of Zagreb School of Medicine, Zagreb, Croatia
    Ines BojanićORCIDUniversity of Zagreb School of Medicine, Zagreb, Croatia
    Sanja MazićORCIDUniversity of Zagreb School of Medicine, Zagreb, Croatia
    Željko ČolakORCIDUniversity of Zagreb School of Medicine, Zagreb, Croatia
    Hrvoje GašparovićORCIDUniversity of Zagreb School of Medicine, Zagreb, Croatia
    Davor MiličićORCIDUniversity of Zagreb School of Medicine, Zagreb, Croatia
    Boško SkorićORCIDUniversity of Zagreb School of Medicine, Zagreb, Croatia

    *Correspondence email: petra.mjehovic@gmail.com

    Full Text

    Background: Oral anticoagulation therapy for the prevention of thromboembolic complications of atrial fibrillation in patients awaiting heart transplantation (HTx) traditionally includes warfarin, and in the last few years it increasingly includes dabigatran. Anticoagulation must be reversed before the surgery. The possibility of rapid reversal of the anticoagulant effect of dabigatran with idarucizumab seems to represent an advantage (1). A comparison of bleeding complications between these two strategies has not been completely investigated.

    Patients and Methods: We did a retrospective analysis of bleeding complications during and immediately after HTx performed in University Hospital Center Zagreb in 15 patients divided into 3 groups: patients who were on warfarin prior to HTx, patients who were on dabigatran prior to HTx, and control patients without indication for anticoagulation therapy. Patients were mutually paired to eliminate the influence of other risk factors including age, gender, etiology of heart failure, renal function, as well as whether surgery was primary or after previous sternotomy. For the comparison of bleeding complications we measured the utilization of blood products (red blood cells, platelets, fibrinogen, fresh frozen plasma (FFP), prothrombin complex (PC) and the amount of thoracic drainage within the first 24 hours after the HTx.

    Results: There was no significant difference in the utilization of blood products as well as the amount of 24h thoracic drainage between these three groups (Table 1). Only 2/5 patients in the warfarin group were within the therapeutic INR range (2 pts below and 1 pts above the range). 24h thoracic drainage, FFP and PC consumption correlated with pretransplant INR (Table 2).

    TABLE 1: Comparison of different demographic and clinical characteristics, and crucial pretransplant/posttransplant laboratory findings between patient groups stratified according to anticoagulant use.

    Male gender, N (%)
    No anticoagulation (n=5)
    4 (80)
    Warfarin (n=5)
    4 (80)
    Dabigatran (n=5)
    4 (80)
    p-value
    1.000
    Age at the time of HTx [y] (IQR)
    No anticoagulation (n=5)
    53 (53-57)
    Warfarin (n=5)
    59 (46-60)
    Dabigatran (n=5)
    62 (46-63)
    p-value
    0.756
    Ischemic CMP, N (%)
    No anticoagulation (n=5)
    1 (20)
    Warfarin (n=5)
    1 (20)
    Dabigatran (n=5)
    1 (20)
    p-value
    1.000
    Resternotomy, N (%)
    No anticoagulation (n=5)
    1 (20)
    Warfarin (n=5)
    1 (20)
    Dabigatran (n=5)
    1 (20)
    p-value
    1.000
    eGFR [mL/min/1,73m2] (IQR)
    No anticoagulation (n=5)
    71 (66-84)
    Warfarin (n=5)
    65 (53-71)
    Dabigatran (n=5)
    65 (50-76)
    p-value
    0.423
    Erythrocyte concentrate [mL] (IQR)
    No anticoagulation (n=5)
    260 (0-1510)
    Warfarin (n=5)
    250 (250-1020)
    Dabigatran (n=5)
    550 (470-730)
    p-value
    0.755
    FFP [mL] (IQR)
    No anticoagulation (n=5)
    1020 (910-1060)
    Warfarin (n=5)
    1310 (1240-1380)
    Dabigatran (n=5)
    1060 (1030-1150)
    p-value
    0.385
    Platelet concentrate [doses] (IQR)
    No anticoagulation (n=5)
    8 (6-8)
    Warfarin (n=5)
    8 (8-8)
    Dabigatran (n=5)
    5 (0-10)
    p-value
    0.919
    Fibrinogen [g] (IQR)
    No anticoagulation (n=5)
    2 (2-3)
    Warfarin (n=5)
    2 (2-2)
    Dabigatran (n=5)
    2 (2-4)
    p-value
    0.698
    Prothrombin complex [IU] (IQR)
    No anticoagulation (n=5)
    0 (0-0)
    Warfarin (n=5)
    0 (0-2500)
    Dabigatran (n=5)
    0 (0-0)
    p-value
    0.117
    Thymoglobulin (IQR)
    No anticoagulation (n=5)
    24 (22-24)
    Warfarin (n=5)
    26 (24-29)
    Dabigatran (n=5)
    28 (24-30)
    p-value
    0.363
    Thoracic drainage within the first 24h [mL] (IQR)
    No anticoagulation (n=5)
    400 (300-700)
    Warfarin (n=5)
    450 (400-550)
    Dabigatran (n=5)
    600 (450-650)
    p-value
    0.643
    Hemoglobin before HTx [g/L] (IQR)
    No anticoagulation (n=5)
    139 (137-146)
    Warfarin (n=5)
    125 (121-160)
    Dabigatran (n=5)
    142 (138-149)
    p-value
    0.756
    Platelets before HTx [10E9/L] (IQR)
    No anticoagulation (n=5)
    205 (200-260)
    Warfarin (n=5)
    282 (270-292)
    Dabigatran (n=5)
    188 (174-202)
    p-value
    0.102
    PT-INR before HTx (IQR)
    No anticoagulation (n=5)
    0.96 (0.92-1.15)
    Warfarin (n=5)
    2.40 (1.18-2.41)
    Dabigatran (n=5)
    1.09 (1.06-1.13)
    p-value
    0.230
    APTT before HTx [s] (IQR)
    No anticoagulation (n=5)
    24.60 (23.25-26.40)
    Warfarin (n=5)
    36.9 (27.7-37.5)
    Dabigatran (n=5)
    31.3 (28.9-47.3)
    p-value
    0.079
    Fibrinogen before HTx [g/L] (IQR)
    No anticoagulation (n=5)
    3.75 (3.35-4.15)
    Warfarin (n=5)
    4.20 (3.40-5.70)
    Dabigatran (n=5)
    3.85 (3.70-4.95)
    p-value
    0.693
    Hemoglobin 1st day after HTx [g/L] (IQR)
    No anticoagulation (n=5)
    101 (93-111)
    Warfarin (n=5)
    107 (95-112)
    Dabigatran (n=5)
    96 (95-100)
    p-value
    0.485
    Platelets 1st day after HTx [10E9/L] (IQR)
    No anticoagulation (n=5)
    113 (94-163)
    Warfarin (n=5)
    135 (129-171)
    Dabigatran (n=5)
    98 (92-131)
    p-value
    0.330
    PT-INR 1st day after HTx (IQR)
    No anticoagulation (n=5)
    1.02 (0.99-1.09)
    Warfarin (n=5)
    1.22 (1.03-1.43)
    Dabigatran (n=5)
    1.18 (1.10-1.23)
    p-value
    0.259
    APTT 1st day after HTx [s] (IQR)
    No anticoagulation (n=5)
    25.7 (24.6-27.4)
    Warfarin (n=5)
    27.7 (23.9-28.4)
    Dabigatran (n=5)
    25.4 (24.6-25.9)
    p-value
    0.635
    Fibrinogen 1st day after HTx [g/L] (IQR)
    No anticoagulation (n=5)
    4.50 (3.80-6.70)
    Warfarin (n=5)
    3.50 (3.40-3.70)
    Dabigatran (n=5)
    3.4 (3.0-3.4)
    p-value
    0.068
    Hemoglobin 7th day after HTx [g/L] (IQR)
    No anticoagulation (n=5)
    102 (96-111)
    Warfarin (n=5)
    100 (92-101)
    Dabigatran (n=5)
    88 (88-92)
    p-value
    0.150
    Platelets 7th day after HTx [10E9/L] (IQR)
    No anticoagulation (n=5)
    117 (97-193)
    Warfarin (n=5)
    112 (104-154)
    Dabigatran (n=5)
    93 (73-108)
    p-value
    0.228
    PT-INR 7th day after HTx (IQR)
    No anticoagulation (n=5)
    1.00 (0.98-1.02)
    Warfarin (n=5)
    1.01 (0.95-1.12)
    Dabigatran (n=5)
    1.08 (1.06-1.11)
    p-value
    0.203
    APTT 7th day after HTx [s] (IQR)
    No anticoagulation (n=5)
    20.5 (19.1-21.0)
    Warfarin (n=5)
    22.8 (21.3-23.3)
    Dabigatran (n=5)
    21.7 (21.1-22.2)
    p-value
    0.172
    Fibrinogen 7th day after HTx [g/L] (IQR)
    No anticoagulation (n=5)
    2.3 (2.2-3.3)
    Warfarin (n=5)
    3.4 (2.9-5.2)
    Dabigatran (n=5)
    3.5 (2.3-3.5)
    p-value
    0.438

    HTx – Heart Transplant; CMP – cardiomyopathy; eGFR – estimated Glomerular filtration rate; FFP– Fresh Frozen Plazma; PT-INR – Prothrombin Time – International Normalized Ratio; APTT – Activated Partial Thromboplastin Time.

    TABLE 2: Potential predictors of periprocedural bleeding in the observed heart transplant patient population.

    Total Chest Output in 24h & Pretransplant PT-INR
    Spearman ρ
    0.645
    Correlation Significance
    0.009*
    Packed Red Blood Cell Transfusion Volume & Ischemic Etiology of Heart Failure
    Spearman ρ
    0.543
    Correlation Significance
    0.036*
    Fresh Frozen Plasma Transfusion Volume & Pretransplant PT-INR
    Spearman ρ
    0.661
    Correlation Significance
    0.007*
    Platelet Transfusion Volume & Ischemic Etiology of Heart Failure
    Spearman ρ
    0.583
    Correlation Significance
    0.022*
    Prothrombin Complex Concentrate Transfusion & Pretransplant PT-INR
    Spearman ρ
    0.592
    Correlation Significance
    0.020*

    PT-INR – Prothrombin Time – International Normalized Ratio * P < 0.05

    Conclusion: Although there was no difference in the consumption of blood products and 24h thoracic drainage between patients who were on warfarin or dabigatran anticoagulation before HTx, it should be noted that the majority of patients on warfarin were not within the therapeutic INR range, and it was precisely the elevated INR that significantly correlated with the consumption of blood products and 24h thoracic drainage. It is necessary to conduct a study on a larger number of patients in order to find out whether the pre-HTx use of warfarin is equally safe and effective as the use of dabigatran, in terms of the perioperative bleeding.

    Literature

    1. 1.
      Crespo-Leiro MG, López-Vilella R, López Granados A, Mirabet-Pérez S, Díez-López C, Barge-Caballero E, et al. Use of Idarucizumab to reverse the anticoagulant effect of dabigatran in cardiac transplant surgery. A multicentric experience in Spain. Clin Transplant. 2019 December;33(12):e13748.DOI