Abstract
Background and Purpose:
The ideal dosing regimen of 4-factor prothrombin complex concentrate (4FPCC) after warfarin-induced intracranial hemorrhage (WICH) remains unclear. We sought to compare the safety and efficacy of the 4FPCC package insert dosing strategy (standard dose [SD]) with our institutional guideline for high-dose (HD) 4FPCC for patients with WICH.
Methods:
We compared the percentage of SD and HD patients who achieved an international normalized ratio (INR) ≤1.3 at a single institution between January 2014 and July 2017. Additionally, we assessed hematoma expansion, recurrence of INR > 1.3, and occurrence of thrombotic events within 7 days of 4FPCC administration.
Results:
Of 48 patients with WICH, 30 received SD and 18 received HD. The median baseline INR was 2.5 (2.0-3.8) for SD patients and 3.3 (2.5-5) for HD patients (P = .147). Successful achievement of an INR ≤ 1.3 after the initial 4FPCC dose was obtained in 70% of patients in the SD group and 94% of patients in the HD group (P = .124). A higher percentage of patients in the SD group had an INR > 1.3 at some point after admission (30% vs 6%; P = .053). There was a trend toward more hematoma expansion in the SD group, but this was not statistically significant (17% in the SD group vs 0% in HD group; P = .056). There were 2 thrombotic events: one deep vein thrombosis in each group (P = .243).
Conclusions:
High-dose 4FPCC appears to be more effective at lowering INR and preventing bleed expansion in patients with WICH, while maintaining a similar safety profile.
Keywords: intracranial hemorrhage, warfarin, 4FPCC, reversal, intracerebral hemorrhage
Introduction
Warfarin, an oral vitamin K antagonist, is one of the most widely used anticoagulants in the world. Anticoagulation with warfarin increases the risk of intracranial hemorrhage (ICH) by 3-fold.1,2 The Neurocritical Care Society recommends 4-factor prothrombin complex concentrate (4FPCC) for urgent reversal of warfarin-induced ICH (WICH).3 Benefits of 4FPCC in WICH include rapid INR reversal and possible reduction in hematoma expansion.4,5 Hematoma volume can impact mortality and functional outcome after ICH.6 There are multiple 4FPCCs on the market including Kcentra, Octaplex, Cofact, and Kaskadil, each of which has variable amounts of factors II, VII, IX, X, proteins C, S, and Z, and heparin. The ideal target INR to prevent hematoma expansion is unknown; however, the Neurocritical Care Society suggests a target INR of less than 1.4.3 A further reduction in INR to less than 1.3 versus an INR of 1.3 or greater within 4 hours of admission may be beneficial in reducing rates of hematoma expansion.7
Although it is established that 4FPCC is the first-line therapy for WICH, the optimal dosing of 4FPCC remains unclear. The Kcentra package insert recommends dosing according to the predose INR value and bodyweight as follows: 25 U/kg for INR 2 to 3.9 (max of 2500 units), 35 U/kg for INR 4 to 6 (max of 3500 units), and 50 U/kg for INR > 6 (max of 5000 units).8 However, this is the recommended dosing strategy for all major warfarin-related bleeds, not just WICH.4 The Neurocritical Care Society recommends that 4FPCC dosing for WICH should be weight based and vary according to admission INR and type of PCC used, but they do not specify the dosing regimen.3
Prior to 2015, our institutional protocol recommended standard dosing of Kcentra for all warfarin-related bleeds based on the package insert. In August 2015, due to concerns that standard dosing could delay INR reversal, hamper neurosurgical intervention, lead to worse functional outcome and increase mortality rate, our institutional neurosurgical quality improvement and antithrombotic therapy committees began recommending that patients with WICH be given high-dose (HD) 4FPCC (see Figure 1). We sought to compare the safety and efficacy of the 4FPCC package insert dosing strategy (standard dose [SD]) with our institutional guideline for HD 4FPCC for patients with WICH.
Figure 1.
Four-factor prothrombin complex concentrate (4FPCC) dosing regimen.
Methods
We conducted a single-center, retrospective review at New York University Langone Health-Manhattan, an 825-bed, tertiary care academic teaching hospital. Due to the retrospective nature of this observational project done for quality assurance purposes, informed consent was not required and this project was exempt from review by our institutional review board.
We reviewed the electronic health records for all patients who received Kcentra, the 4FPCC on hospital formulary, between January 2014 and July 2017. Patients, who were ≥18 years of age, who received Kcentra for spontaneous or traumatic intracranial bleeds while on warfarin were included. All intracranial hemorrhages not related to warfarin were excluded. Patients were classified based on the date of presentation (January 2014-August 2015 was SD regimen, and August 2015-July 2017 was HD regimen), but patients in the SD period who received a higher dose of 4FPCC were included in the HD period. Treating clinicians and provision of clinical care were unchanged in the 2 periods with the exception of the adjustment to the 4FPCC dosing regimen.
Through a retrospective medical record review, we obtained and recorded data on baseline demographics, comorbidities, indication for warfarin, 4FPCC dose, INR before and after 4FPCC administration, clinical status, radiographic findings, and development of thrombotic events (deep vein thrombosis, pulmonary embolism, myocardial infarction, ischemic stroke) up to 7 days after administration of 4FPCC. A board-certified neurologist who was blinded to treatment group recorded National Institutes of Health Stroke Scale (NIHSS), Glasgow Coma Scale (GCS), modified Rankin Score (mRS), and reviewed all imaging obtained during the admission.
The primary outcome was the percentage of patients who achieved an INR of 1.3 or less after the administration of 4FPCC. Secondary outcomes included hematoma expansion, 3-month mRS, and occurrence of thrombotic events within 7 days of 4FPCC administration, hospital discharge, or death, whichever came first.
We collected and managed data using Research Electronic Data Capture, a secure web application for managing and building surveys, hosted by NYULH. We used χ2 and Fisher exact tests to analyze categorical variables, and Mann-Whitney U test to assess nonparametric continuous variables. SPSS version 23 was used for all statistical analysis. A P value of <.05 was considered statistically significant.
Results
During the 43-month study period, 270 patients received 4FPCC at our institution. Of these, 48 patients had WICH, 30 in the SD group and 18 in the HD group. Nearly every bleed was attributed to anticoagulation itself (46%) or trauma (48%).
Demographic data are provided in Table 1. The majority of patients in both groups (80% of SD and 78% of HD) were on warfarin for atrial fibrillation. Median baseline INR was not significantly different between groups (2.5 [2.0-3.8] for SD patients and 3.3 [2.5-5] for HD patients; P = .147). Antiplatelet use, admission platelet count, and admission blood pressure were similar for both groups. The majority of patients in both groups had subdural hemorrhages (60% of SD, 72% of HD). There was no significant difference in subdural hematoma size between both groups. About 25% of patients in each group had intracerebral hemorrhages, but patients in the SD group had larger bleeds and worse ICH scores (24 cc [4-46] vs 10 cc [3-42]; P = .683 and 3 [2-4] vs 1 [0-1]; P = .034). Premorbid mRS and clinical status on presentation, as measured by GCS and NIHSS, was similar for both groups.
Table 1.
Demographics.a
| Characteristics | SD (n = 30) | HD (n = 18) | P Value |
|---|---|---|---|
| Age, years, median (IQR) | 83 (69-87) | 75 (66-85) | .241 |
| Weight, kg, median (IQR) | 68 (61-86) | 69 (62-78) | .84 |
| Gender, male | 18 (60) | 13 (73) | .536 |
| Comorbid conditions | |||
| Hypertension | 22 (73) | 9 (50) | .127 |
| Prior ischemic stroke | 7 (23) | 6 (33) | .450 |
| Diabetes | 7 (23) | 4 (22) | .929 |
| Chronic renal failure | 8 (27) | 6 (33) | .746 |
| Prior intracranial hemorrhage | 1 (3) | 1 (6) | .709 |
| Cirrhosis | 1 (3) | 2 (11) | .281 |
| Anticoagulation indicationb | |||
| Atrial fibrillation | 24 (80) | 14 (78) | .854 |
| Deep vein thrombosis | 5 (17) | 2 (11) | .598 |
| Pulmonary embolism | 2 (7) | 2 (11) | .590 |
| Mechanical valve | 4 (13) | 2 (11) | .822 |
| Other | 2 (7) | 2 (11) | .590 |
| Antiplatelet use | 17 (56) | 13 (72) | .363 |
| Pertinent data on presentation, median (IQR) | |||
| Initial INR | 2.5 (2.0-3.8) | 3.3 (2.5-5) | .147 |
| Serum creatinine, mg/dL | 1.1 (0.8-1.3) | 1.2 (0.9-1.5) | .630 |
| Platelets, 103/μL | 165 (138-262) | 190 (167-278) | .302 |
| Systolic blood pressure at presentation, mm Hg, median (IQR) | 140 (122-165) | 157 (137-167) | .156 |
| Clinical status | |||
| Premorbid mRS, median (IQR) | 3 (0-4) | 4 (0-4) | .604 |
| GCS at presentation, median (IQR) | 14 (9-15) | 14 (13-15) | .841 |
| Admission NIHSS, median (IQR) | 3 (1-9) | 1 (0-11) | .746 |
| Location of bleedb | |||
| Subdural hematoma | 18 (60) | 13 (72) | .536 |
| Width, mm, median (IQR) | 8 (5-17) | 14 (5-17) | .708 |
| Intracerebral hemorrhage | 8 (27) | 4 (22) | .731 |
| ICH score, median (IQR) | 3 (2-4) | 1 (0-1) | .034 |
| Hematoma volume, mL, median (IQR) | 24 (4-46) | 10 (3-42) | .683 |
| Subarachnoid hemorrhage | 6 (20) | 6 (33) | .302 |
| Fischer score, median (IQR) | 3 (3-3) | 3 (1-3) | .240 |
| Intraventricular involvement | 6 (20) | 4 (22) | .854 |
| Mechanism of hemorrhage | |||
| Traumatic brain injury | 13 (43) | 10 (56) | .552 |
| Spontaneous | 14 (47) | 8 (44) | .881 |
| Hypertension | 2 (7) | 1 (6) | .878 |
| Ischemic stroke with hemorrhagic conversion | 1 (3) | 0 (0) | .434 |
Abbreviations: GCS, Glasgow Coma Scale; HD, high dose; INR, international normalized ratio; ICH, intracranial hemorrhage; IQR, interquartile range; mRS, modified Rankin Score; NIHSS, National Institutes of Health Stroke Scale; SD, standard dose.
aAll values shown as n (%) unless specified.
bSome patients had more than one indication or bleed location.
Dosing of 4FPCC and utilization of other reversal agents are shown in Table 2. The median total dose and weight-based dose of 4FPCC were significantly lower in the SD group (1750 [1500-2125] units vs 2000 [1500-2750] units; P = .019 and 25 U/kg [25-25] vs 25 U/kg [25-37.5]; P = .0001). Although 13% of SD patients and 6% of HD patients received an additional dose of 4FPCC, this was not significantly different. Other medical and surgical management was not significantly different for both groups.
Table 2.
Intracranial Hemorrhage Management.a
| Characteristics | SD (n = 30) | HD (n = 18) | P Value |
|---|---|---|---|
| 4FPCC administration | 30 (100) | 18 (100) | 1 |
| Dose, U/kg, median (IQR) | 25 (25-25) | 25 (25-37.5) | .0001 |
| Dose, units, median (IQR) | 1750 (1500-2125) | 2000 (1500-2750) | .019 |
| Received more than one dose of 4FPCC | 4 (13) | 1 (6) | .393 |
| Vitamin K administration | 30 (100) | 17 (94) | .192 |
| Dose, mg, median (IQR) | 10 (10-10) | 10 (10-10) | .96 |
| Duration, days, median (IQR) | 1 (1-2) | 1 (1-3) | .388 |
| FFP administration | 6 (20) | 4 (22) | .854 |
| Platelet administration | 14 (47) | 4 (22) | .127 |
| Cryoprecipitate administration | 1 (3) | 0 (0) | .434 |
| Surgical evacuation of the hematoma | 5 (17) | 6 (33) | .184 |
Abbreviations: HD, high dose; INR, international normalized ratio; IQR, interquartile range; SD, standard dose; FFP, Fresh Frozen Plasma; 4FPCC, 4-factor prothrombin complex concentrate.
aAll values shown as n (%) unless specified.
Primary and secondary outcomes are outlined in Table 3. Successful achievement of INR ≤ 1.3 after the initial 4FPCC dose was obtained in 70% of patients in the SD group and 94% of patients in the HD group and (P = .124). A higher percentage of patients in the SD group had an INR > 1.3 at some point after admission (30% vs 6%; P = .053). There was a trend toward less hematoma expansion in the HD group, but this was not statistically significant (0% in HD group vs 17% in the SD group; P = .056). There were 2 thrombotic events: one deep vein thrombosis in each group (P = .243). There was no significant difference between discharge or postdischarge neurological status for patients in the HD or SD group. The NYU Langone Medical Center waived review of this quality improvement project.
Table 3.
Efficacy and Safety End Points.a
| Characteristics | SD (n = 30) | HD (n = 18) | P Value |
|---|---|---|---|
| INR 1.3 or less after 4FPCC | 21 (70) | 17 (94) | .124 |
| Follow-up INR value, median (IQR) | 1.2 (1.1-1.6) | 1.1 (1.0-1.2) | .001 |
| Time to follow-up INR (min), median (IQR) | 360 (199-527) | 295 (145-460) | .433 |
| Any follow-up INR > 1.3 | 9 (30) | 1 (6) | .053 |
| Complications | |||
| Deep vein thrombosis | 1 (3) | 1 (6) | .787 |
| Pulmonary embolism | 0 (0) | 0 (0) | – |
| Myocardial infarction | 0 (0) | 0 (0) | – |
| Ischemic stroke | 0 (0) | 0 (0) | – |
| Hematoma expansion after 4FPCC | 5 (17) | 0 (0) | .056 |
| Hospital mortality | 5 (17) | 2 (11) | .598 |
| Hospital length of stay, days | 4 (2-11) | 3 (2-7) | .365 |
| Discharge neurological assessment | |||
| Discharge GCS, median (IQR) | 15 (14-15) | 15 (14-15) | .359 |
| Discharge MRS, median (IQR) | 4 (4-5) | 4 (3-4) | .219 |
| Discharge NIHSS, median (IQR) | 1 (0-2) | 0 (0-1) | .555 |
| Data on postdischarge neurologic status available | 19 (60) | 13 (41) | .753 |
| Median MRS at 3 months, median (IQR) | 4 (3-4) | 4 (3-4) | .223 |
| Median month of postdischarge mRS, median (IQR) | 3 (2-3) | 3 (2-3) | .940 |
| MRS of 4-6 at 3 months | 10 (53) | 7 (54) | .946 |
Abbreviations: GCS, Glasgow Coma Scale; HD, high dose; INR, international normalized ratio; IQR, interquartile range; mRS, modified Rankin Score; NIHSS, National Institutes of Health Stroke Scale; SD, standard dose; 4FPCC, 4-factor prothrombin complex concentrate.
aAll values shown as n (%) unless specified.
Discussion
Warfarin ICH is associated with a high morbidity and mortality; mRS after WICH frequently range from 4 to 6.5,9 As a result, practitioners utilize 4FPCC in an effort to reduce hematoma expansion in order to prevent neurologic deterioration in patients with WICH. However, the use of 4FPCC is not without risks; Milling et al and Goldstein et al both found that 7% of patients treated with 4FPCC had thromboembolic events.10,11 To balance the risks and benefits of 4FPCC, guidelines recommend that dosing be weight based and vary according to admission INR.3 Institutional dosing strategies, however, vary, and while some hospitals adhere to the 4FPCC package insert recommendations, others utilize alternative dosing strategies.8,12-15
Due to the lack of consensus on the optimal 4FPCC dosing strategy and concerns that WICH is the most serious of all warfarin-related bleeds, we developed our own protocol for emergent reversal of WICH. We then performed this quality assessment to compare the efficacy and safety of the 4FPCC package insert dosing strategy (SD) with our institutional guideline for HD 4FPCC for patients with WICH. We found that HD 4FPCC was nonsignificantly more effective at lowering INR, keeping INR low and preventing hematoma expansion. However, it did not impact neurologic status at discharge or 3 months after discharge, though it is worth noting that the median premorbid mRS was 4, which markedly limited the potential to demonstrate a favorable effect of HD 4FPCC on neurologic outcome. We also found that administration of HD 4FPCC did not increase the rate of thromboembolic events.
Although there are a number of published reports of a variety of 4FPCC dosing strategies for patients with warfarin-related bleeds, ours is the first to look at an aggressive HD strategy to treat WICH stratified based on both INR and an assessment of whether or not a patient has a life-threatening condition.12-16 Notably, the median 4FPCC dose in our HD group was only 25 U/kg (2000 units), far less than the maximum dose of 50 U/kg (maximum of 5000 units). Similar to our findings, Abdoellakhan et al found that 96% of patients treated with a median of 1750 units of 4FPCC achieved INR ≤ 1.5, whereas only 68% of patients treated with a median of 1000 units of 4FPCC obtained this goal (P = .01).12 Despite the fact that the higher dose of 4FPCC lowered INR more effectively, it did not demonstrate improved neurologic outcomes in patients who received HD 4FPCC. Additionally, Rivosecchi et al found that administering 25 U/kg 4FPCC to all patients with WICH and an INR of 1.4 to 3.9 resulted in reduction of INR to ≤1.3 in 79% of patients with a baseline INR 1.4 to 1.9 (n = 29), but only 51% of patients with a baseline INR 2 to 3.9 (n = 92).13
Our study has several limitations that must be taken into consideration. First, this was a single-center study with a small number of patients who included both spontaneous and traumatic WICH. Our institution uses Kcentra, but our results cannot necessarily be extrapolated to other forms of 4FPCC. Because this study was retrospective, our postdischarge assessment could not be completed on all patients (34% of our total population was lost to follow-up). Lastly, this study did not have a standardized time frame to recheck INR after 4FPCC, making the absolute time to INR reversal variable, and practitioners were not obligated to follow the standard dosing regimen between 2014 and 2015, resulting in crossover of some patients from 2014 to 2015 into the 2015 to 2017 cohort.
Conclusion
Although HD 4FPCC did not demonstrate a statistically significant decrease in INR or reduction in hematoma expansion, the trend in INR and hematoma expansion favoured the HD over SD regimen while maintaining a similar safety profile. Despite these findings, larger studies are warranted to evaluate the impact of HD 4FPCC on hematoma expansion, functional outcomes, and mortality.
Footnotes
Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The authors received no financial support for the research, authorship, and/or publication of this article.
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