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Trends in Parenteral Direct Thrombin Inhibitor Use in Pediatric Patients: Analysis of a Large Administrative Database.

Parenteral direct thrombin inhibitors (DTIs) have been used in the pediatric population in a variety of patient care scenarios. (1-6) Primarily, DTIs have been used in patients unable to receive unfractionated heparin because of heparin-induced thrombocytopenia (HIT). (2,5,7) These patients are often additionally receiving mechanical circulatory support or are undergoing cardiac surgical or interventional procedures and are receiving high doses of unfractionated heparin for extended periods of time.

Characterizing the use and monitoring practices of DTIs in pediatric patients at children's hospitals may be useful for hypothesis generation and analysis of trends over time. Currently, there are few data for DTI use at children's hospitals. Argatroban is the only parenteral DTI that is Food and Drug Administration-approved for use in children in the setting of HIT. Current published data are often in the form of case reports or case series and do not encompass multiple institutions or practice settings. A retrospective analysis of a large database can provide useful information regarding current practice with DTIs in pediatric patients that a single center may not be able to provide.


We plan to characterize the use of DTIs in pediatric patients at children's hospitals, including the monitoring practices for DTIs and bleeding complications associated with DTIs.


A retrospective, descriptive study was designed and institutional review board exemption was obtained. Data for this study were obtained from the Pediatric Health Information System, an administrative database that contains inpatient, emergency department, ambulatory surgery, and observation data from 43 not-for-profit, tertiary care pediatric hospitals in the United States. These hospitals are affiliated with the Child Health Corporation of America (Shawnee Mission, Kansas), a business alliance of children's hospitals. Data quality and reliability are assured through a joint effort between the Child Health Corporation of America and participating hospitals. The data warehouse function for the Pediatric Health Information System database is managed by Thomson Reuters (Ann Arbor, Michigan). For the purposes of external benchmarking, participating hospitals provide discharge/ encounter data including demographics, diagnoses, and procedures. Forty-two of these hospitals also submit resource utilization data (e.g. pharmaceuticals, imaging, and laboratory) into the Pediatric Health Information System. Data are de-identified at the time of data submission, and data are subjected to a number of reliability and validity checks before being included in the database. For this study, patient data from 41 hospitals met study criteria (2 hospitals did not have parenteral DTI use) and were included.

The Pediatric Health Information System database was queried for pediatric patients discharged from January 1, 2004 to December 31, 2011 if they received one of the following DUs during admission: argatroban, bivalirudin, desirudin, or lepirudin. Patients were excluded if they were 19 years of age or older or had missing data. If patients received a parenteral DTI during multiple admissions within the study period, only the first of these admissions was used.

Patient demographic data, hospital length of stay, mortality, disease state, and procedure information (from International Classification of Diseases, Ninth Revision [ICD-9] codes) were collected from the query from the index hospitalization. Additionally, type of DTI, length of DTI therapy, and laboratory monitoring during DTI therapy were collected from the query from the index hospitalization. Bleeding was assessed by manual evaluation of ICD-9 codes that were representative of bleeding complications.

Descriptive statistical methods were used to characterize the patient population (mean, standard deviation, median, range). Patients were divided into 2 time periods (2004-2007, 2008-2011) and differences in patient demographics, DTI utilization, and DTI monitoring were compared. The Student t test was used for continuous data and the Fisher exact test for categorical data, and a P value of <.05 was determined to be statistically significant a priori.


A total of 208 patients met study criteria (50.9% male; n = 106); children (2-12 years of age) were the most populous age group (34.6%; n = 72), and the largest number of patients were of white race/ethnicity (64.4%; n = 134). Congenital heart disease was present in 43.8% (n = 91), and 28.4% (n = 59) underwent a cardiovascular surgical procedure. Median hospital length of stay was 32 days (range, 1-285 days). A DTI was given in the cardiac catheterization laboratory 6.7% (n = 14) of the time.

Heparin-induced thrombocytopenia was documented in 15.6% (n = 32) of the population, and 30.3% (n = 63) of the population had documented acute kidney injury or chronic kidney disease. Only one patient, who was receiving lepirudin, had an enzyme-linked immunosorbent assay sent, and no patient had a serotonin assay for HIT. Argatroban was the most commonly used DTI (73.1%; n = 144), followed by bivalirudin (23.1%; n = 48) and lepirudin (7.7%; n = 16). Patient demographics for each of the DTIs are summarized in Table 1. Overall mortality was 19.7% (n = 41).

Few differences were noted when DTI use and patient demographics were compared between the 2 time periods. Bivalirudin was used more frequently in the most recent period (13.6% [n = 8] versus 26.9% [n = 40], P--.04), with less lepirudin use (20.3% [n = 12] versus 2.7% [n = 4], P < .001), and no change in argatroban use (69.5% [n = 41] versus 74.5% [n = 111], P = .46) between the 2 time periods. Five patients received both argatroban and bivalirudin and 3 patients received both argatroban and lepirudin during the admission. Mean length of therapy for argatroban was 8.3 days (median, 4 days; range, 1-102 days); for bivalirudin, 3.0 days (median, 1 day; range, 1-17 days); and for lepirudin, 8.8 days (median, 5.5 days; range, 1-31 days); and the median length of therapy did not vary significantly for each of the drugs between the 2 time periods (P > .05 for all). Mean day of service of DTI initiation was as follows: argatroban, 24.9; bivalirudin, 20.9; and lepirudin, 10.1. Fewer patients were mechanically ventilated in the later time period, and this was the only difference in patient demographics between the 2 time periods (Table 2).

Monitoring for DTIs consisted primarily of activated partial thromboplastin time (89.9%; n = 187) and prothrombin time (82.2%; n = 171). Activated partial thromboplastin time and prothrombin time were used most often in patients receiving argatroban and lepirudin in comparison with bivalirudin (P < .001) and thrombin time was used more often in patients receiving lepirudin (Table 3). Monitoring of any laboratory test for a DTI did not change from the early period to the late period, with the exception of activated clotting time, which increased in use over time (5.1% versus 17.5%; P = .02).

Codes for bleeding complications were present in 37.9% (n = 79) of patients. The most common codes for bleeding were associated with adverse events of anticoagulant medications, hemorrhages or hematomas complicating a procedure, and gastrointestinal bleeding (Table 4). Codes for bleeding complications were more often associated with lepirudin (62.5%; n = 10) and argatroban (41.5%; n = 63) as compared with bivalirudin use (18.8%; n = 9) (P = .002).


This is the first evaluation of DTI use in pediatric patients on a national scale. Currently, it appears that the use of DTIs in pediatric patients is infrequent and in critically ill patients with a high incidence of mortality. Most of the data concerning DTI use in pediatric patients is in case reports or case series in patients who are often critically ill, which reflects the high mortality seen in this report. (8-10) This may reflect the high proportion of use in patients with congenital heart disease and the incidence of cardiovascular surgery in the data set. Additionally, for reasons that are not clear, despite the Food and Drug Administration-approved indication for argatroban use in children, bivalirudin and lepirudin were still used.

The bleeding complications associated with the DTIs in this report are high, representing approximately one-third of patients reported. Again, the utilization of these agents appears to be in the critically ill population and those patients undergoing interventions associated with high mortality and high complication rates, such as cardiovascular surgery, cardiac catheterization procedures, and extra-corporeal membrane oxygenation. This analysis is also limited, as direct correlations between DTI use and bleeding complications cannot be made. Additionally, pathophysiology that may have been the result of occult bleeding may have not been coded as bleeding or may not have been captured in the review of bleeding codes. Interestingly, HIT was documented in only 15% of the population. This was surprising to us, and we thought this percentage of patients would have been higher, as this would be a primary indication for using a DTI instead of unfractionated heparin for anticoagulation. Heparin-induced thrombocytopenia can be difficult to diagnose, particularly in a critically ill patient or a patient requiring multiple blood transfusions, as this could cause frequent alterations in platelet count. However, this is much higher than the reported incidence of HIT in patients receiving unfractionated heparin. (11) Clinicians may have been clinically suspicious of HIT and initiated DTI therapy, but unable to make a definitive diagnosis of HIT.

Monitoring of DTIs was consistent across time periods and little variation was noted in the type of monitoring among DTIs. Activated partial thromboplastin time was the most commonly used laboratory monitoring test, followed by prothrombin time. However, patients receiving bivalirudin were monitored less frequently with both of these tests as compared with patients receiving argatroban or lepirudin. It is not entirely clear why patients receiving bivalirudin were monitored less frequently with these standard laboratory tests, unless patients received it in a specialized area (such as the cardiac catheterization laboratory) for a short duration and tests such as activated clotting time or no tests were used. A limitation to using a database for this type of analysis is the lack of documentation of indication for a monitoring test. Some laboratory tests may have been ordered as part of a panel of tests and not used for clinical decision making. Evaluation of indications for laboratory monitoring of DTIs should occur at individual institutional levels. A standardized approach to the monitoring of DTIs in pediatric patient is warranted.

The use of DTIs will likely increase over time as experience is gained with use and newer agents become available.

Strategies should be identified for appropriate monitoring and indications for use prior to the utilization of DTIs.


Direct thrombin inhibitors are infrequently used in pediatric patients and are currently used in patients with high mortality. Further investigations into their use in less critically ill patients are warranted to determine the benefit of DTI use in pediatric patients.


(1.) Scott LK, Grier LR, Conrad SA. Heparin-induced thrombocytopenia in a pediatric patient receiving extracorporeal support and treated with argatroban. Pediatr Crit Care Med. 2006; 7(3):255-257.

(2.) Rayapudi S, Torres A Jr, Deshpande GG, et al. Bivalirudin for anticoagulation in children. Pediatr Blood Cancer. 2008; 51(6):798-801.

(3.) Knoderer CA, Knoderer HM, Turrentine MW, Kumar M. Lepirudin anticoagulation for heparin-induced thrombocytopenia after cardiac surgery in a pediatric patient. Pharmacotherapy. 2006; 26(5):709-712.

(4.) Nguyen TN, Gal P, Ransom JL, Carlos R. Lepirudin use in a neonate with heparin-induced thrombocytopenia. Ann Pharmacother. 2003; 37(2):229-233.

(5.) Deitcher SR, Topoulos AP, Bartholomew JR, Kichuk-Chrisant MR. Lepirudin anticoagulation for heparin-induced thrombocytopenia. J Pediatr. 2002; 140(2):264-266.

(6.) Greinacher A, Volpel H, Janssens U, et al. Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia: a prospective study. Circulation. 1999; 99(1):73-80.

(7.) Dyke PC, Russo P, Mureebe L, Russo J, Tobias JD. Argatroban for anticoagulation during cardiopulmonary bypass in an infant. Paediatr Anaesth. 2005; 15(4):328-333.

(8.) Dager WE, Gosselin RC, Yoshikawa R, Owings JT. Lepirudin in heparin-induced thrombocytopenia and extracorporeal membranous oxygenation. Ann Pharmacother. 2004; 38(4):598-601.

(9.) Dragomer D, Chalfant A, Biniwale R, Reemtsen B, Federman M. Novel techniques in the use of bivalirudin for cardiopulmonary bypass anticoagulation in a child with heparin-induced thrombocytopenia. Perfusion. 2011; 26(6):516-518.

(10.) Hursting MJ, Dubb J, Verme-Gibboney CN. Argatroban anticoagulation in pediatric patients: a literature analysis. J Pediatr Hematol Oncol. 2006; 28(1):410.

(11.) Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood. 2005; 106(8):2710-2715.

Brady S. Moffett, PharmD, MPH; Jun Teruya, MD, DSc

Accepted for publication October 28, 2013. From the Department of Pharmacy, Texas Children's Hospital, and the Department of Pediatrics, Section of Pediatric Cardiology, Baylor College of Medicine, Houston (Dr Moffett); and the Department of Pathology & Immunology, Pediatrics, and Medicine, Texas Children's Hospital and Baylor College of Medicine, Houston (Dr Teruya).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Brady S. Moffett, PharmD, MPH, Department of Pharmacy, Texas Children's Hospital, 6621 Fannin St, Suite WB 1120, Houston, TX 77030 (e-mail:
Table 1. Demographics of Direct Thrombin Inhibitor Use in Pediatric

Category                               Argatroban   Bivalirudin
                                       (n = 144)     (n = 48)
Age category, No. (%)
  Neonates (1-30 d)                    18 (12.5)     8 (16.7)
  Infants (31 d-1 y) (a)               39 (27.1)     6 (12.5)
  Children (2-12 y) (a)                45 (31.3)      24 (50)
  Adolescents and young                42 (29.2)     10 (20.8)
  adults (13-21 y)
Male, No. (%)                          74 (51.4)     27 (56.3)
Race/ethnicity, No. (%)
  African American                     22 (15.3)     6 (12.5)
  Asian                                 3 (2.1)       1 (2.1)
  White                                89 (61.8)     34 (70.8)
  Hispanic                             23 (15.9)     14 (29.2)
Mechanical ventilation, No. (%) (a)    107 (74.3)    21 (43.8)
Intensive care unit                    133 (92.4)    38 (79.2)
  admission, No. (%) (a)
Extracorporeal membrane                 12 (8.3)     6 (12.5)
  oxygenation, No. (%)
Congenital heart disease, No. (%)      63 (43.8)     21 (43.8)
Cardiovascular surgery, No. (%)        44 (30.6)     11 (22.9)
Mortality, No. (%)                     32 (22.2)     5 (10.4)

Category                               Lepirudin     Total
                                       (n = 16)    (N = 208)
Age category, No. (%)
  Neonates (1-30 d)                     1 (6.3)    27 (12.9)
  Infants (31 d-1 y) (a)               7 (43.8)     52 (25)
  Children (2-12 y) (a)                3 (18.8)    72 (34.6)
  Adolescents and young                5 (31.3)    57 (27.4)
  adults (13-21 y)
Male, No. (%)                          5 (31.3)    106 (50.9)
Race/ethnicity, No. (%)
  African American                     3 (18.8)    31 (14.9)
  Asian                                  0 (0)      4 (1.9)
  White                                11 (68.8)   134 (64.4)
  Hispanic                               0 (0)     37 (17.8)
Mechanical ventilation, No. (%) (a)    11 (68.8)   139 (66.8)
Intensive care unit                    11 (68.8)   182 (87.5)
  admission, No. (%) (a)
Extracorporeal membrane                3 (18.8)    21 (10.1)
  oxygenation, No. (%)
Congenital heart disease, No. (%)      7 (43.8)    91 (43.8)
Cardiovascular surgery, No. (%)         4 (25)     59 (28.4)
Mortality, No. (%)                      4 (25)     41 (19.7)

(a) One or more categories P < .05.

Table 2. Patient Demographics by Time Periods

Category                             2004-2007    2008-2011
                                      (n = 59)    (n = 149)
Age category, No. (%)
  Neonates (1-30 d)                   9 (15.3)    18 (12.1)
  Infants (31 d-1 y)                 17 (28.8)    35 (23.5)
  Children (2-12 y)                  17 (28.8)    55 (36.9)
  Adolescents and                    16 (27.1)    41 (27.5)
  young adults (13-21 y)
Male, No. (%)                        29 (49.2)    77 (51.7)
Race/ethnicity, No.
  African American                   10 (16.9)    21 (14.1)
  Asian                               1 (1.7)      3 (2.0)
  White                              43 (72.9)    91 (61.1)
  Hispanic                            9 (15.3)    28 (18.8)
Length of stay, median (IQR), d      36 (17-82)   28 (13-65)
Mechanical ventilation, No. (%)      46 (77.9)    93 (62.4)
Intensive care unit                  53 (89.8)    129 (86.6)
  admission, No. (%)
Extracorporeal membrane               5 (8.5)     19 (12.8)
  oxygenation, No. (%)
Congenital heart disease, No. (%)    26 (44.1)    65 (43.6)
Cardiovascular surgery, No. (%)      21 (35.6)    38 (25.5)
Mortality, No. (%)                   13 (22.0)    28 (18.8)

Category                              P Value

Age category, No. (%)
  Neonates (1-30 d)                     .54
  Infants (31 d-1 y)                    .42
  Children (2-12 y)                     .27
  Adolescents and                       .95
  young adults (13-21 y)
Male, No. (%)                           .74
Race/ethnicity, No.
  African American                      .60
  Asian                                 .88
  White                                 .11
  Hispanic                              .55
Length of stay, median (IQR), d         .29
Mechanical ventilation, No. (%)         .03
Intensive care unit                     .52
  admission, No. (%)
Extracorporeal membrane                 .38
  oxygenation, No. (%)
Congenital heart disease, No. (%)       .95
Cardiovascular surgery, No. (%)         .15
Mortality, No. (%)                      .59

Abbreviation: IQR, interquartile range.

Table 3. Monitoring Tests Used for Direct Thrombin Inhibitors

Category                              Argatroban   Bivalirudin
                                      (n = 144)     (n = 48)

Prothrombin time, No. (%) (a)         127 (88.2)    29 (60.4)
Activated partial                     137 (95.1)    34 (70.8)
  thromboplastin time, No. (%) (a)
Activated clotting time, No. (%)      19 (13.2)     9 (18.8)
Thrombin time, No. (%) (a)            19 (13.2)      3 (6.3)

Category                              Lepirudin
                                      (n = 16)

Prothrombin time, No. (%) (a)         15 (93.8)
Activated partial                     16 (100)
  thromboplastin time, No. (%) (a)
Activated clotting time, No. (%)       1 (6.3)
Thrombin time, No. (%) (a)            5 (31.3)

(a) One or more categories P < .05.

Table 4. Bleeding Complications in Patients Receiving Direct Thrombin

Bleeding                                        Patients
Complications                              (N = 208), No. (%)

Anticoagulants causing adverse effects         24 (11.5)
in therapeutic use
Hemorrhage complicating a procedure            23 (11.1)
Hemoptysis                                     12 (5.8)
Hemorrhage of gastrointestinal tract,          10 (4.8)
Hematoma complicating a procedure              10 (4.8)
Hematuria                                       9 (4.3)
Intracerebral hemorrhage                        7 (3.3)
Other disorders of menstruation and             7 (3.3)
  other abnormal bleeding from
  female genital tract
Epistaxis                                       6 (2.9)
Subdural hemorrhage                             6 (2.9)
Hematuria, unspecified                          5 (2.4)
Blood in stool                                  4 (1.9)
Iatrogenic cerebrovascular infarction           4 (1.9)
  or hemorrhage
Intraventricular hemorrhage                     3 (1.4)
Gastrointestinal hemorrhage of fetus or         2 (0.9)
Hematemesis                                     2 (0.9)
Hemoglobinuria due to hemolysis                 2 (0.9)
  from external causes
Hemoperitoneum (nontraumatic)                   2 (0.9)
Hemorrhagic disorder due to intrinsic
circulating anticoagulants                      2 (0.9)
Pulmonary hemorrhage of fetus or                2 (0.9)
Conjunctival hemorrhage                         1 (0.4)
Cutaneous hemorrhage of newborn                 1 (0.4)
Esophageal varices with bleeding                1 (0.4)
Hemorrhage of rectum and anus                   1 (0.4)
Nontraumatic hematoma of soft tissue            1 (0.4)
Subarachnoid hemorrhage                         1 (0.4)
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Author:Moffett, Brady S.; Teruya, Jun
Publication:Archives of Pathology & Laboratory Medicine
Date:Sep 1, 2014
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