Optimizing the Dose of Three-Factor Prothrombin Complex Concentrate in Traumatic Brain Injury Patients on Warfarin Therapy Thao K. Huynh, Jennifer L. Costello,* and Jill A. Rebuck Department of Pharmacy, Lancaster General Health, Lancaster, Pennsylvania
STUDY OBJECTIVE To determine the percentage of patients with correction of their first international normalized ratio (INR) less than 1.5 after administration of moderate-dose three-factor prothrombin complex concentrate (PCC), 35 IU/kg compared with low-dose PCC, 25 IU/kg. DESIGN Retrospective review. SETTING Community teaching hospital. PATIENTS A total of 42 adult patients diagnosed with warfarin-associated traumatic brain injury (TBI) presented with an INR of 1.5 or more and received at least one dose of PCC during a 19-month study period. The low-dose group received PCC 25 IU/kg from November 2011–July 2012 and the moderate-dose group received PCC 35 IU/kg from August 2012–May 2013. MEASUREMENTS AND MAIN RESULTS Of the 42 patients, 25 were in the low-dose group and 17 were in the moderate-dose group. Baseline characteristics were similar between both groups in regard to age, sex, weight, creatinine clearance, weekly warfarin dose, initial INR, initial Glasgow Coma Score, and injury severity score. Of the patients in the low-dose group, 12% achieved INR reversal with first measured INR after PCC administration compared with 69% in the moderate-dose group (p0.05). The median time from injury to administration of PCC was also similar between groups (1.9 hrs vs 2.7 hrs in the low- and medium-dose groups, p>0.05). Clinical outcomes demonstrated that 57% more patients in the moderate-dose group achieved INR reversal compared with the lowdose group; the moderate-dose group also achieved INR reversal 5 hours sooner than the low-dose group (Table 2). The median time to repeat INR after PCC administration was 89 minutes versus 43 minutes in the moderateand low-dose groups, respectively (p=0.005). A slight reduction in the use of fresh frozen plasma (FFP) was found in the moderate-dose group, with no difference in the total units of
FFP administered between groups (p=0.255). There was also a reduction in the need to administer a second dose of PCC in the moderate-dose group. Three patients (12%) in the lowdose group required a second dose of PCC, whereas no patients in the moderate dose group required further administration of PCC (p=0.260). A total of two possible adverse events occurred, one in each group. In the low-dose group, one patient developed a nonocclusive thrombus within the left cephalic vein at the level of the elbow 3 days after PCC administration. In the moderate-dose group, thrombi in the right basilic and subclavian veins were identified 7 days after PCC administration and noted to be likely related to indwelling catheters. Both of these patients had a history of atrial fibrillation. Three deaths in the low-dose group and four in the moderate-dose group were attributed to respiratory arrest and/or withdrawal of care due to poor overall prognosis. Discussion To the best of our knowledge, this is the first study to evaluate a moderate dose of PCC, 35 IU/kg. Previously published data demonstrated that administration of 50 IU/kg of PCC followed by 25 IU/kg if the INR remained above 1.4 produced an incomplete reversal of INR.13 In our study, however, all but one patient achieved INR reversal within 24 hrs. Furthermore, we observed a higher percentage of patients who achieved INR reversal with a lower median time to INR less than 1.5 using PCC 35 IU/kg compared with 25 IU/kg. In previous trauma literature, the time to INR less than 1.5 with the addition of PCC compared with no
Table 1. Patient Baseline Characteristics Characteristicsa Age, yrs Male, n (%) Actual weight, kg Creatinine clearance, mL/min Weekly warfarin dose, mg Initial international normalized ratio Initial Glasgow Coma cale Injury severity score
Low-dose, PCC 25 IU/kg (n=25) 83 (79, 90) 11 (44) 75 (56, 93) 32 (27, 47) 27 (15, 32)b 2.8 (2.3, 3.6) 15 (14, 15) 17 (9, 25)
PCC = prothrombin complex concentrate. a Values are presented as median (interquartile range) unless otherwise noted. b No weekly warfarin dose identified in drug reconciliation for four patients. c No weekly warfarin dose identified in drug reconciliation for three patients.
Moderate-dose, PCC 35 IU/kg (n=17) 81 (72, 85) 9 (53) 82 (60, 87) 29 (22, 54) 18 (13, 31)c 2.4 (2.1, 3.3) 15 (14, 15) 17 (11, 26)
p value 0.124 0.754 0.691 0.672 0.336 0.411 0.872 0.546
PCC TRAUMATIC BRAIN INJURY Huynh et al
263
Table 2. Clinical Outcomes Low-dose, PCC 25 IU/kg (n=25) Primary end point First INR after PCC < 1.5, n (%) Secondary end points Stabilization of bleed on head CT, n (%) Time to INR < 1.5, hrsc Total length of stay, daysc Total intensive care unit stay, days Blood product administered, n (%) FFP administered, n (%) Adverse events, n (%)
Moderate-dose, PCC 35 IU/kg (n=17) 11 (69)a
3 (12) 16 (70)b 6.9 (5.4, 10.1) 3 (3, 4) 2 (1, 3) 11 (44) 11 (44) 1 (4)
11 (73)b 1.9 (1.3, 6.6) 3 (2, 5) 2 (1, 3) 6 (35) 5 (29) 1 (6)
p value < 0.001 1.000 0.037 0.805 0.820 0.750 0.520 1.000
PCC = prothrombin complex concentrate; INR = international normalized ratio; CT = computed tomography; FFP = fresh frozen plasma. a No repeat INR was performed for one patient. b No follow-up head CT performed for two patients. c Values are presented as median (interquartile range).
PCC was 16.6 hours versus 30.3 hours.9 The time to INR reversal in both of our study groups was less than what has been previously reported. However, the shorter time to INR reversal in our study may be due to the fact that baseline INR measured in the majority of our patients did not exceed 3.6, whereas a baseline INR of 5 or greater was associated with an inability of PCC to be adequate at reversing the INR to below 3 in 24 hours.11 Also, our study may be confounded by the longer interval of time between PCC administration and INR measurement in the moderate-dose group. Before our study initiation, four-factor PCC was not yet approved in the United States. However, since the recent Food and Drug Administration approval of four-factor PCC (Kcentra, CSL Behring, King of Prussia, PA), the role of three-factor PCC in comparison is not yet defined. In this study, we cannot assume the effects of the three-factor PCC are the same as the four-factor PCC. Given the novelty of the four-factor PCC, future efficacy, safety, and cost analyses may need to be performed. Several limitations of our study exist. We did not perform a randomized, controlled, prospective, multicenter investigation of the 25 versus 35 IU/kg doses. However, based on the retrospective nature of our study, times of laboratory collections were noted. As a result, the confounding variable of length of time between PCC administration and INR measurement was observed. Also, thromboelastogram was not available for use in the study. Another limitation to our study was that power was not achieved since we did not meet the sample size. We underestimated the difference in the groups to achieve power; there was a 57% difference between groups although we had planned on
30%. Given a small sample size and disproportionate number of patients between groups, data from a few patients may potentially have magnified the effect on our study outcomes. Conclusion In patients with TBI, moderately dosed PCC at 35 IU/kg was associated with a higher percentage of INR reversal and more rapid time to INR normalization compared with a lower dosage of 25 IU/kg. Future randomized, controlled studies are warranted to further investigate this novel dose and the impact on potential reductions in FFP use. Acknowledgment The authors thank Michael Horst for his extensive guidance with the statistics of this study.
References 1. Rosand J, Eckman MH, Knudsen KA, Singer DE, Greenberg SM. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med 2004;164:880–4. 2. Kuwashiro T, Yasaka M, Itabashi R, et al. Effect of prothrombin complex concentrate on hematoma enlargement and clinical outcome in patients with anticoagulant-associated intracerebral hemorrhage. Cerebrovasc Dis 2011;31:170–6. 3. Gaetani P, Revay M, Sciacca S, et al. Traumatic brain injury in the elderly: considerations in a series of 103 patients older than 70. J Neurosurg Sci 2012;56:231–7. 4. Patanwala AE, Acquisto NM, Erstad BL. Prothrombin complex concentrate for critical bleeding. Ann Pharmacother 2011;45:990–9. 5. Dager WE. Using prothrombin complex concentrates to rapidly reverse oral anticoagulant effects. Ann Pharmacother 2011;45:1016–20. 6. Barillari G, Pasca S, Barillari A, De Angelis V. Emergency reversal of anticoagulation: from theory to real use of prothrombin complex concentrates. A retrospective Italian experience. Blood Transfus 2012;10:87–94. 7. Sarode R, Matevosyan K, Bhagat R, Rutherford C, Madden C, Beshay JE. Rapid warfarin reversal: a 3-factor prothrombin
264
PHARMACOTHERAPY Volume 34, Number 3, 2014
complex concentrate and recombinant factor VIIa cocktail for intracerebral hemorrhage. J Neurosurg 2012;116:491–7. 8. Toth P, Van Veen JJ, Robinson K, et al. Real world usage of PCC to “rapidly” correct warfarin induced coagulopathy. Blood Transfus 2012;10:1–7. Available from DOI: 10.2450/ 2012.0113-12 [Epub ahead of print]. 9. Chapman SA, Irwin ED, Beal AL, Kulinski NM, Hutson KE, Thorson MA. Prothrombin complex concentrate versus standard therapies for INR reversal in trauma patients receiving warfarin. Ann Pharmacother 2011;45:869–75. 10. Chong CT, Lew TW, Kuperan P, Tan JJ, Tan HL, Kwek TK. Rapid reversal of coagulopathy in warfarin-related intracranial haemorrhages with prothrombin complex concentrates. Anaesth Intensive Care 2010;38:474–80.
11. Holland L, Warkentin TE, Refaai M, Crowther MA, Johnston MA, Sarode R. Suboptimal effect of a three-factor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic international normalized ratio due to warfarin overdose. Transfusion 2009;49:1171–7. 12. Majeed A, Eelde A, Agren A, Schulman S, Holmstr€ om M. Thromboembolic safety and efficacy of prothrombin complex concentrates in the emergency reversal of warfarin coagulopathy. Thromb Res 2012;129:146–51. 13. Switzer JA, Rocker J, Mohorn P, et al. Clinical experience with three-factor prothrombin complex concentrate to reverse warfarin anticoagulation in intracranial hemorrhage. Stroke 2012;43:2500–2.
STUDY OBJECTIVE To determine the percentage of patients with correction of their first international normalized ratio (INR) less than 1.5 after administration of moderate-dose three-factor prothrombin complex concentrate (PCC), 35 IU/kg compared with low-dose PCC, 25 IU/kg. DESIGN Retrospective review. SETTING Community teaching hospital. PATIENTS A total of 42 adult patients diagnosed with warfarin-associated traumatic brain injury (TBI) presented with an INR of 1.5 or more and received at least one dose of PCC during a 19-month study period. The low-dose group received PCC 25 IU/kg from November 2011–July 2012 and the moderate-dose group received PCC 35 IU/kg from August 2012–May 2013. MEASUREMENTS AND MAIN RESULTS Of the 42 patients, 25 were in the low-dose group and 17 were in the moderate-dose group. Baseline characteristics were similar between both groups in regard to age, sex, weight, creatinine clearance, weekly warfarin dose, initial INR, initial Glasgow Coma Score, and injury severity score. Of the patients in the low-dose group, 12% achieved INR reversal with first measured INR after PCC administration compared with 69% in the moderate-dose group (p0.05). The median time from injury to administration of PCC was also similar between groups (1.9 hrs vs 2.7 hrs in the low- and medium-dose groups, p>0.05). Clinical outcomes demonstrated that 57% more patients in the moderate-dose group achieved INR reversal compared with the lowdose group; the moderate-dose group also achieved INR reversal 5 hours sooner than the low-dose group (Table 2). The median time to repeat INR after PCC administration was 89 minutes versus 43 minutes in the moderateand low-dose groups, respectively (p=0.005). A slight reduction in the use of fresh frozen plasma (FFP) was found in the moderate-dose group, with no difference in the total units of
FFP administered between groups (p=0.255). There was also a reduction in the need to administer a second dose of PCC in the moderate-dose group. Three patients (12%) in the lowdose group required a second dose of PCC, whereas no patients in the moderate dose group required further administration of PCC (p=0.260). A total of two possible adverse events occurred, one in each group. In the low-dose group, one patient developed a nonocclusive thrombus within the left cephalic vein at the level of the elbow 3 days after PCC administration. In the moderate-dose group, thrombi in the right basilic and subclavian veins were identified 7 days after PCC administration and noted to be likely related to indwelling catheters. Both of these patients had a history of atrial fibrillation. Three deaths in the low-dose group and four in the moderate-dose group were attributed to respiratory arrest and/or withdrawal of care due to poor overall prognosis. Discussion To the best of our knowledge, this is the first study to evaluate a moderate dose of PCC, 35 IU/kg. Previously published data demonstrated that administration of 50 IU/kg of PCC followed by 25 IU/kg if the INR remained above 1.4 produced an incomplete reversal of INR.13 In our study, however, all but one patient achieved INR reversal within 24 hrs. Furthermore, we observed a higher percentage of patients who achieved INR reversal with a lower median time to INR less than 1.5 using PCC 35 IU/kg compared with 25 IU/kg. In previous trauma literature, the time to INR less than 1.5 with the addition of PCC compared with no
Table 1. Patient Baseline Characteristics Characteristicsa Age, yrs Male, n (%) Actual weight, kg Creatinine clearance, mL/min Weekly warfarin dose, mg Initial international normalized ratio Initial Glasgow Coma cale Injury severity score
Low-dose, PCC 25 IU/kg (n=25) 83 (79, 90) 11 (44) 75 (56, 93) 32 (27, 47) 27 (15, 32)b 2.8 (2.3, 3.6) 15 (14, 15) 17 (9, 25)
PCC = prothrombin complex concentrate. a Values are presented as median (interquartile range) unless otherwise noted. b No weekly warfarin dose identified in drug reconciliation for four patients. c No weekly warfarin dose identified in drug reconciliation for three patients.
Moderate-dose, PCC 35 IU/kg (n=17) 81 (72, 85) 9 (53) 82 (60, 87) 29 (22, 54) 18 (13, 31)c 2.4 (2.1, 3.3) 15 (14, 15) 17 (11, 26)
p value 0.124 0.754 0.691 0.672 0.336 0.411 0.872 0.546
PCC TRAUMATIC BRAIN INJURY Huynh et al
263
Table 2. Clinical Outcomes Low-dose, PCC 25 IU/kg (n=25) Primary end point First INR after PCC < 1.5, n (%) Secondary end points Stabilization of bleed on head CT, n (%) Time to INR < 1.5, hrsc Total length of stay, daysc Total intensive care unit stay, days Blood product administered, n (%) FFP administered, n (%) Adverse events, n (%)
Moderate-dose, PCC 35 IU/kg (n=17) 11 (69)a
3 (12) 16 (70)b 6.9 (5.4, 10.1) 3 (3, 4) 2 (1, 3) 11 (44) 11 (44) 1 (4)
11 (73)b 1.9 (1.3, 6.6) 3 (2, 5) 2 (1, 3) 6 (35) 5 (29) 1 (6)
p value < 0.001 1.000 0.037 0.805 0.820 0.750 0.520 1.000
PCC = prothrombin complex concentrate; INR = international normalized ratio; CT = computed tomography; FFP = fresh frozen plasma. a No repeat INR was performed for one patient. b No follow-up head CT performed for two patients. c Values are presented as median (interquartile range).
PCC was 16.6 hours versus 30.3 hours.9 The time to INR reversal in both of our study groups was less than what has been previously reported. However, the shorter time to INR reversal in our study may be due to the fact that baseline INR measured in the majority of our patients did not exceed 3.6, whereas a baseline INR of 5 or greater was associated with an inability of PCC to be adequate at reversing the INR to below 3 in 24 hours.11 Also, our study may be confounded by the longer interval of time between PCC administration and INR measurement in the moderate-dose group. Before our study initiation, four-factor PCC was not yet approved in the United States. However, since the recent Food and Drug Administration approval of four-factor PCC (Kcentra, CSL Behring, King of Prussia, PA), the role of three-factor PCC in comparison is not yet defined. In this study, we cannot assume the effects of the three-factor PCC are the same as the four-factor PCC. Given the novelty of the four-factor PCC, future efficacy, safety, and cost analyses may need to be performed. Several limitations of our study exist. We did not perform a randomized, controlled, prospective, multicenter investigation of the 25 versus 35 IU/kg doses. However, based on the retrospective nature of our study, times of laboratory collections were noted. As a result, the confounding variable of length of time between PCC administration and INR measurement was observed. Also, thromboelastogram was not available for use in the study. Another limitation to our study was that power was not achieved since we did not meet the sample size. We underestimated the difference in the groups to achieve power; there was a 57% difference between groups although we had planned on
30%. Given a small sample size and disproportionate number of patients between groups, data from a few patients may potentially have magnified the effect on our study outcomes. Conclusion In patients with TBI, moderately dosed PCC at 35 IU/kg was associated with a higher percentage of INR reversal and more rapid time to INR normalization compared with a lower dosage of 25 IU/kg. Future randomized, controlled studies are warranted to further investigate this novel dose and the impact on potential reductions in FFP use. Acknowledgment The authors thank Michael Horst for his extensive guidance with the statistics of this study.
References 1. Rosand J, Eckman MH, Knudsen KA, Singer DE, Greenberg SM. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med 2004;164:880–4. 2. Kuwashiro T, Yasaka M, Itabashi R, et al. Effect of prothrombin complex concentrate on hematoma enlargement and clinical outcome in patients with anticoagulant-associated intracerebral hemorrhage. Cerebrovasc Dis 2011;31:170–6. 3. Gaetani P, Revay M, Sciacca S, et al. Traumatic brain injury in the elderly: considerations in a series of 103 patients older than 70. J Neurosurg Sci 2012;56:231–7. 4. Patanwala AE, Acquisto NM, Erstad BL. Prothrombin complex concentrate for critical bleeding. Ann Pharmacother 2011;45:990–9. 5. Dager WE. Using prothrombin complex concentrates to rapidly reverse oral anticoagulant effects. Ann Pharmacother 2011;45:1016–20. 6. Barillari G, Pasca S, Barillari A, De Angelis V. Emergency reversal of anticoagulation: from theory to real use of prothrombin complex concentrates. A retrospective Italian experience. Blood Transfus 2012;10:87–94. 7. Sarode R, Matevosyan K, Bhagat R, Rutherford C, Madden C, Beshay JE. Rapid warfarin reversal: a 3-factor prothrombin
264
PHARMACOTHERAPY Volume 34, Number 3, 2014
complex concentrate and recombinant factor VIIa cocktail for intracerebral hemorrhage. J Neurosurg 2012;116:491–7. 8. Toth P, Van Veen JJ, Robinson K, et al. Real world usage of PCC to “rapidly” correct warfarin induced coagulopathy. Blood Transfus 2012;10:1–7. Available from DOI: 10.2450/ 2012.0113-12 [Epub ahead of print]. 9. Chapman SA, Irwin ED, Beal AL, Kulinski NM, Hutson KE, Thorson MA. Prothrombin complex concentrate versus standard therapies for INR reversal in trauma patients receiving warfarin. Ann Pharmacother 2011;45:869–75. 10. Chong CT, Lew TW, Kuperan P, Tan JJ, Tan HL, Kwek TK. Rapid reversal of coagulopathy in warfarin-related intracranial haemorrhages with prothrombin complex concentrates. Anaesth Intensive Care 2010;38:474–80.
11. Holland L, Warkentin TE, Refaai M, Crowther MA, Johnston MA, Sarode R. Suboptimal effect of a three-factor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic international normalized ratio due to warfarin overdose. Transfusion 2009;49:1171–7. 12. Majeed A, Eelde A, Agren A, Schulman S, Holmstr€ om M. Thromboembolic safety and efficacy of prothrombin complex concentrates in the emergency reversal of warfarin coagulopathy. Thromb Res 2012;129:146–51. 13. Switzer JA, Rocker J, Mohorn P, et al. Clinical experience with three-factor prothrombin complex concentrate to reverse warfarin anticoagulation in intracranial hemorrhage. Stroke 2012;43:2500–2.
