Original article 563
A novel coagulation parameter monitoring bleeding tendency of Chinese nonvalvular atrial fibrillation patients prescribing dabigatran etexilate Hong Wang, Yun Zhou, Guodong Rong, Lin Lu and Jie Zhang The objective of this study was to find a new parameter to monitor bleeding tendency after dabigatran etexilate (Pradaxa) medication in Chinese nonvalvular atrial fibrillation patients. Blood samples of 231 nonvalvular atrial fibrillation patients were collected and five routine coagulation examinations (prothrombin time/International normalized ratio, activated partial thromboplastin time, fibrinogen assay, thrombin time and D-dimer) were assayed. After dabigatran etexilate administration, prolonged activated partial thromboplastin time and thrombin time were observed, especially TT. Derived parameter DTT (TT after dabigatran etexilate medication – TT before dabigatran etexilate medication) of bleeding patients was higher than nonbleeding patients (97.7 vs. 85.6 s, P U 0.038). When using DTT to distinguish patients with and without bleeding events, the cutoff value was 97.25 s, where sensitivity was 82.4% and specificity was 50.0%. The area under the curve was 0.786. TT is better than
Introduction Dabigatran etexilate (Pradaxa: Boehringer Ingelheim Pharma GmbH 7 Co., Germany) is an oral direct thrombin inhibitor (DTI) already used in many European and American nonvalvular atrial fibrillation (NVAF) patients for the prevention of stroke and systemic embolism. However, dabigatran etexilate application is only 2 years in China and the laboratory coagulation data from Chinese NVAF patients are rare. Therefore, one aim of this study is to provide the alterations of routine coagulation tests after dabigatran etexilate medication. It is well known that there is little experience with dabigatran-induced bleeding [1]. There are several reports presenting cases of dabigatran-induced haemorrhagic complications, such as gynaecological and gastrointestinal bleeding events [2,3]. However to our knowledge, rare published studies have focused on finding a coagulation indicator, cutoff value of which can distinguish bleeding and nonbleeding patients. Therefore, that is another aim of the present study.
Patients and methods Patients
In this single-centre and observational cohort study, we identified 231 patients. All patients were newly diagnosed with NVAF and consecutively recruited from the cardiovascular department of the First Affiliated Hospital of Nanjing Medical University (China) from 0957-5235 Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved.
other routine coagulation parameters in monitoring the effect of dabigatran etexilate. DTT can distinguish bleeding patients from nonbleeding patients. Blood Coagul Fibrinolysis 27:563–567 Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved.
Blood Coagulation and Fibrinolysis 2016, 27:563–567 Keywords: anticoagulants, atrial fibrillation, coagulation, dabigatran etexilate, thrombin time Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China Correspondence to Hong Wang, Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, P.R. China Tel: +86 25 6813 6275; e-mail: [email protected] Received 24 January 2015 Revised 23 September 2015 Accepted 26 September 2015
August 2013 to October 2014. Exclusion criteria were mechanical or biologic prosthetic valves, severe valvulopathies, severe congestive heart failure, congenital heart diseases, severe cognitive impairment and chronic inflammatory diseases. Furthermore, individuals were excluded if they had neoplastic diseases, liver diseases, renal diseases, diabetes, autoimmune systemic diseases or if they had taken any anticoagulants before. All patients gave informed consent prior to specimen collection. Among 231 patients, whose median age was 62 years (range from 25 to 92 years), 64.9% (150/231) were men. Dabigatran etexilate was prescribed at 110 mg twice daily (b.i.d.) in 207 patients and 150 mg b.i.d. in the other 24 patients. All patients gave informed consent prior to specimen collection according to the study, which was reviewed and approved by the Committee on the Ethics of Treatment of Human Subjects of the First Affiliated Hospital of Nanjing Medical University. Blood collection and coagulation parameters detection
Blood samples were collected before and 3 weeks after the dabigatran etexilate administration from all the patients who had fasted for at least 12 h, directly mixed in a vacutainer with 1 part of 3.2% Na citrate (ratio 9 : 1) and immediately centrifuged for 15 min at 1500g. Prothrombin time (PT)/International Normalized Ratio (INR), activated partial thromboplastin time (APTT), fibrinogen assay (FIB), thrombin time (TT) and D-dimer (DD) were measured by using Sysmex CA-7000 DOI:10.1097/MBC.0000000000000467
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
564 Blood Coagulation and Fibrinolysis 2016, Vol 27 No 5
coagulation analyser (Sysmex, Japan) with SIEMENS reagents. Normal ranges of these parameters were as follows: PT, (8–11)s; APTT, (14.5–34.5)s; FIB, (2–4)g/l; TT, (15–21)s; DD, less than 0.55 mg/l. Bleeding events
Major and minor bleeding events were classified according to the International Society on Thrombosis and Haemostasis (ISTH) [4]. Routine urine formed element analysis, faecal occult blood (OB) test, imaging examinations, general physical examinations and so on were conducted to exclude bleeding events before dabigatran etexilate medication. In the 3 weeks medication, any episode of major or minor bleeding events was recorded.
Table 1
Population characteristics of all the patients
Total number Median age (range) Age 75 years Male Hypertension Creatinine clearance rate CHADS2 score
HAS-BLED score
Patients follow-up
Patients with bleeding events were followed for a period time (from 3 days to 2 weeks after dabigatran etexilate medication). The clinical managements (aiming at the bleeding events) and changes of bleeding events and coagulation parameters were observed. Statistical analysis
Categorical variables were reported as counts (percentage) and continuous variables as means standard deviation (SD). The Chi-square test and the Student’s t-test were used for group comparisons. Receiver operating characteristic (ROC) curve analysis, including calculation of area under the ROC curve (AUC), was used to evaluate the diagnostic performance of coagulation parameters to separate patients with bleeding events from those without bleeding events. Statistical analyses were performed using SPSS software (version 18.0: IBM, Armonk, New York, USA). Statistical significance was set at P value less than 0.05.
Results Patient characteristics
Two hundred and thirty-one NVAF patients were included in this study. Population characteristics of the patients are listed in Table 1. In the two dosage groups, 110 and 150 mg, the majority were men. Median age of 110 mg group was older than that of 150 mg group. There were 79.2 and 70.8% patients with hypertension in the two groups, respectively. CHADS2 and HAS-BLED score of most patients belonged to 2. Routine coagulation parameters before and after medication
No matter 110 group and 150 mg group, PT/INR, FIB and D-dimer did not significantly change after receiving dabigatran etexilate when compared with the results before medication (P > 0.05). On the contrary, APTT and TT were obviously increased (P < 0.01). The mean prolongation for APTT and TT were 9.56 and 84.49 s in 110 mg group, and 9.98 and 103.05 s in 150 mg group. The mean elevation folds for APTT and TT were 1.36 and
>50 ml/min 30–50 ml/min 0 1 2 3 4 5 6 0 1 2 3 4 5
Medication at 110 mg
Medication at 150 mg
207 63 (25–92) 24 150 164 142 65 7 19 54 75 33 16 3 36 49 106 12 4 0
24 56 (50–74) 0 12 17 19 5 1 5 4 13 0 1 0 1 6 11 4 2 0
5.69 in 110 mg group, and 1.38 and 5.75 in 150 mg group, respectively. In addition, only TT had a significant difference between the two doses group (104.4 vs. 116.1 s, P ¼ 0.016). Bleeding events
Only minor bleeding events, which respectively occurred in 17 (8.21%) and five (20.83%) patients in 110 and 150 mg group, were observed during 3 weeks dabigatran etexilate medication. These bleeding events are listed in Table 2. In the two dose groups, the incidences of total minor bleeding events were 9.18% (19/207) in 110 mg group and 20.83% (5/24) in 150 mg group, respectively. Because bleeding events in 150 mg group were fewer, we chose 110 mg group to calculate the significance of coagulation parameters after dabigatran etexilate administration between bleeding and nonbleeding patients. We also calculated four derived parameters: DAPTT (APTT after dabigatran etexilate medication – APTT before dabigatran etexilate medication), DTT (TT after dabigatran etexilate medication – TT before dabigatran etexilate medication), APTT ratio (APTT after dabigatran etexilate medication/APTT before dabigatran etexilate medication) and TT ratio (TT after dabigatran Table 2
Minor bleeding events in two dose groups 110 mg (n ¼ 207)
150 mg (n ¼ 24)
Minor bleeding events
n
%
n
%
Skin and mucosal Faecal OB test positive (without a fall in haemoglobin level of 2 g/dl) Nakea haematuria Increased urine RBC counta (without nakea haematuria) Total
5
2.42
1
4.17
10
4.83
3
1 3
0.48 1.45
0 1
0 4.17
19
9.18
5
20.83
OB, occult blood; RBC, red blood cell.
a
Normal range:
A novel coagulation parameter monitoring bleeding tendency of Chinese nonvalvular atrial fibrillation patients prescribing dabigatran etexilate Hong Wang, Yun Zhou, Guodong Rong, Lin Lu and Jie Zhang The objective of this study was to find a new parameter to monitor bleeding tendency after dabigatran etexilate (Pradaxa) medication in Chinese nonvalvular atrial fibrillation patients. Blood samples of 231 nonvalvular atrial fibrillation patients were collected and five routine coagulation examinations (prothrombin time/International normalized ratio, activated partial thromboplastin time, fibrinogen assay, thrombin time and D-dimer) were assayed. After dabigatran etexilate administration, prolonged activated partial thromboplastin time and thrombin time were observed, especially TT. Derived parameter DTT (TT after dabigatran etexilate medication – TT before dabigatran etexilate medication) of bleeding patients was higher than nonbleeding patients (97.7 vs. 85.6 s, P U 0.038). When using DTT to distinguish patients with and without bleeding events, the cutoff value was 97.25 s, where sensitivity was 82.4% and specificity was 50.0%. The area under the curve was 0.786. TT is better than
Introduction Dabigatran etexilate (Pradaxa: Boehringer Ingelheim Pharma GmbH 7 Co., Germany) is an oral direct thrombin inhibitor (DTI) already used in many European and American nonvalvular atrial fibrillation (NVAF) patients for the prevention of stroke and systemic embolism. However, dabigatran etexilate application is only 2 years in China and the laboratory coagulation data from Chinese NVAF patients are rare. Therefore, one aim of this study is to provide the alterations of routine coagulation tests after dabigatran etexilate medication. It is well known that there is little experience with dabigatran-induced bleeding [1]. There are several reports presenting cases of dabigatran-induced haemorrhagic complications, such as gynaecological and gastrointestinal bleeding events [2,3]. However to our knowledge, rare published studies have focused on finding a coagulation indicator, cutoff value of which can distinguish bleeding and nonbleeding patients. Therefore, that is another aim of the present study.
Patients and methods Patients
In this single-centre and observational cohort study, we identified 231 patients. All patients were newly diagnosed with NVAF and consecutively recruited from the cardiovascular department of the First Affiliated Hospital of Nanjing Medical University (China) from 0957-5235 Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved.
other routine coagulation parameters in monitoring the effect of dabigatran etexilate. DTT can distinguish bleeding patients from nonbleeding patients. Blood Coagul Fibrinolysis 27:563–567 Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved.
Blood Coagulation and Fibrinolysis 2016, 27:563–567 Keywords: anticoagulants, atrial fibrillation, coagulation, dabigatran etexilate, thrombin time Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China Correspondence to Hong Wang, Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, P.R. China Tel: +86 25 6813 6275; e-mail: [email protected] Received 24 January 2015 Revised 23 September 2015 Accepted 26 September 2015
August 2013 to October 2014. Exclusion criteria were mechanical or biologic prosthetic valves, severe valvulopathies, severe congestive heart failure, congenital heart diseases, severe cognitive impairment and chronic inflammatory diseases. Furthermore, individuals were excluded if they had neoplastic diseases, liver diseases, renal diseases, diabetes, autoimmune systemic diseases or if they had taken any anticoagulants before. All patients gave informed consent prior to specimen collection. Among 231 patients, whose median age was 62 years (range from 25 to 92 years), 64.9% (150/231) were men. Dabigatran etexilate was prescribed at 110 mg twice daily (b.i.d.) in 207 patients and 150 mg b.i.d. in the other 24 patients. All patients gave informed consent prior to specimen collection according to the study, which was reviewed and approved by the Committee on the Ethics of Treatment of Human Subjects of the First Affiliated Hospital of Nanjing Medical University. Blood collection and coagulation parameters detection
Blood samples were collected before and 3 weeks after the dabigatran etexilate administration from all the patients who had fasted for at least 12 h, directly mixed in a vacutainer with 1 part of 3.2% Na citrate (ratio 9 : 1) and immediately centrifuged for 15 min at 1500g. Prothrombin time (PT)/International Normalized Ratio (INR), activated partial thromboplastin time (APTT), fibrinogen assay (FIB), thrombin time (TT) and D-dimer (DD) were measured by using Sysmex CA-7000 DOI:10.1097/MBC.0000000000000467
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
564 Blood Coagulation and Fibrinolysis 2016, Vol 27 No 5
coagulation analyser (Sysmex, Japan) with SIEMENS reagents. Normal ranges of these parameters were as follows: PT, (8–11)s; APTT, (14.5–34.5)s; FIB, (2–4)g/l; TT, (15–21)s; DD, less than 0.55 mg/l. Bleeding events
Major and minor bleeding events were classified according to the International Society on Thrombosis and Haemostasis (ISTH) [4]. Routine urine formed element analysis, faecal occult blood (OB) test, imaging examinations, general physical examinations and so on were conducted to exclude bleeding events before dabigatran etexilate medication. In the 3 weeks medication, any episode of major or minor bleeding events was recorded.
Table 1
Population characteristics of all the patients
Total number Median age (range) Age 75 years Male Hypertension Creatinine clearance rate CHADS2 score
HAS-BLED score
Patients follow-up
Patients with bleeding events were followed for a period time (from 3 days to 2 weeks after dabigatran etexilate medication). The clinical managements (aiming at the bleeding events) and changes of bleeding events and coagulation parameters were observed. Statistical analysis
Categorical variables were reported as counts (percentage) and continuous variables as means standard deviation (SD). The Chi-square test and the Student’s t-test were used for group comparisons. Receiver operating characteristic (ROC) curve analysis, including calculation of area under the ROC curve (AUC), was used to evaluate the diagnostic performance of coagulation parameters to separate patients with bleeding events from those without bleeding events. Statistical analyses were performed using SPSS software (version 18.0: IBM, Armonk, New York, USA). Statistical significance was set at P value less than 0.05.
Results Patient characteristics
Two hundred and thirty-one NVAF patients were included in this study. Population characteristics of the patients are listed in Table 1. In the two dosage groups, 110 and 150 mg, the majority were men. Median age of 110 mg group was older than that of 150 mg group. There were 79.2 and 70.8% patients with hypertension in the two groups, respectively. CHADS2 and HAS-BLED score of most patients belonged to 2. Routine coagulation parameters before and after medication
No matter 110 group and 150 mg group, PT/INR, FIB and D-dimer did not significantly change after receiving dabigatran etexilate when compared with the results before medication (P > 0.05). On the contrary, APTT and TT were obviously increased (P < 0.01). The mean prolongation for APTT and TT were 9.56 and 84.49 s in 110 mg group, and 9.98 and 103.05 s in 150 mg group. The mean elevation folds for APTT and TT were 1.36 and
>50 ml/min 30–50 ml/min 0 1 2 3 4 5 6 0 1 2 3 4 5
Medication at 110 mg
Medication at 150 mg
207 63 (25–92) 24 150 164 142 65 7 19 54 75 33 16 3 36 49 106 12 4 0
24 56 (50–74) 0 12 17 19 5 1 5 4 13 0 1 0 1 6 11 4 2 0
5.69 in 110 mg group, and 1.38 and 5.75 in 150 mg group, respectively. In addition, only TT had a significant difference between the two doses group (104.4 vs. 116.1 s, P ¼ 0.016). Bleeding events
Only minor bleeding events, which respectively occurred in 17 (8.21%) and five (20.83%) patients in 110 and 150 mg group, were observed during 3 weeks dabigatran etexilate medication. These bleeding events are listed in Table 2. In the two dose groups, the incidences of total minor bleeding events were 9.18% (19/207) in 110 mg group and 20.83% (5/24) in 150 mg group, respectively. Because bleeding events in 150 mg group were fewer, we chose 110 mg group to calculate the significance of coagulation parameters after dabigatran etexilate administration between bleeding and nonbleeding patients. We also calculated four derived parameters: DAPTT (APTT after dabigatran etexilate medication – APTT before dabigatran etexilate medication), DTT (TT after dabigatran etexilate medication – TT before dabigatran etexilate medication), APTT ratio (APTT after dabigatran etexilate medication/APTT before dabigatran etexilate medication) and TT ratio (TT after dabigatran Table 2
Minor bleeding events in two dose groups 110 mg (n ¼ 207)
150 mg (n ¼ 24)
Minor bleeding events
n
%
n
%
Skin and mucosal Faecal OB test positive (without a fall in haemoglobin level of 2 g/dl) Nakea haematuria Increased urine RBC counta (without nakea haematuria) Total
5
2.42
1
4.17
10
4.83
3
1 3
0.48 1.45
0 1
0 4.17
19
9.18
5
20.83
OB, occult blood; RBC, red blood cell.
a
Normal range:
