A Retrospective Propensity Score-Matched Early Thromboembolic Event Analysis of Prothrombin Complex Concentrate vs Fresh Frozen Plasma for Warfarin Reversal Prior to Emergency Neurosurgical Procedures

A Retrospective Propensity Score-Matched Early Thromboembolic Event Analysis of Prothrombin... Abstract BACKGROUND Reversal of therapeutic anticoagulation prior to emergency neurosurgical procedures is required in the setting of intracranial hemorrhage. Multifactor prothrombin complex concentrate (PCC) promises rapid efficacy but may increase the probability of thrombotic complications compared to fresh frozen plasma (FFP). OBJECTIVE To compare the rate of thrombotic complications in patients treated with PCC or FFP to reverse therapeutic anticoagulation prior to emergency neurosurgical procedures in the setting of intracranial hemorrhage at a level I trauma center. METHODS Sixty-three consecutive patients on warfarin therapy presenting with intracranial hemorrhage who received anticoagulation reversal prior to emergency neurosurgical procedures were retrospectively identified between 2007 and 2016. They were divided into 2 cohorts based on reversal agent, either PCC (n = 28) or FFP (n = 35). The thrombotic complications rates within 72 h of reversal were compared using the χ2 test. A multivariate propensity score matching analysis was used to limit the threat to interval validity from selection bias arising from differences in demographics, laboratory values, history, and clinical status. RESULTS Thrombotic complications were uncommon in this neurosurgical population, occurring in 1.59% (1/63) of treated patients. There was no significant difference in the thrombotic complication rate between groups, 3.57% (1/28; PCC group) vs 0% (0/35; FFP group). Propensity score matching analysis validated this finding after controlling for any selection bias. CONCLUSION In this limited sample, thrombotic complication rates were similar between use of PCC and FFP for anticoagulation reversal in the management of intracranial hemorrhage prior to emergency neurosurgical procedures. Prothrombin complex concentrate, Fresh frozen plasma, Anticoagulation reversal, Warfarin, Thrombotic complication, Emergency neurosurgical procedure, Propensity score matching ABBREVIATIONS ABBREVIATIONS FFP fresh frozen plasma INR International Normalized Ratio PCC prothrombin complex concentrate PSM propensity score matching Warfarin is an oral vitamin K antagonist commonly used to reduce the risk of stroke or systemic embolism in patients with atrial fibrillation and for the treatment and prevention of venous thromboembolism.1 Patients taking warfarin are at increased risk of clinical and radiographic deterioration following spontaneous or traumatic intracranial hemorrhage.2 Accordingly, pharmacologic reversal of warfarin-induced anticoagulation is indicated in the management of intracranial hemorrhage. However, clinicians must consider what is the safest and most expedient method for pharmacological reversal in their daily practice.3,4 Traditional pharmacological reversal of anticoagulation begins with vitamin K administration and the infusion of thawed plasma or fresh frozen plasma (FFP).3 Vitamin K is a necessary cofactor for the production of the vitamin K-dependent clotting factors (II, VII, IX, X) and proteins C and S, while FFP contains all soluble coagulation factors and proteins. The therapeutic effect of FFP administration is monitored by a reduction in the International Normalized Ratio (INR).5,6 Unfortunately, several drawbacks of FFP administration temper enthusiasm for its universal use. For example, FFP is associated with transfusion-related acute lung injury, circulatory overload, and allergic and anaphylactic reactions.7,8 Furthermore, the therapeutic effect of FFP reversal is gradual and may delay urgent neurosurgical intervention. An alternative method of anticoagulation reversal is administration of prothrombin complex concentrate (PCC). PCC generally contains clotting factors II, VII, IX, and X, with or without the addition of proteins C and S, in combinations that vary by formulary. For instance, 4-factor PCC (Kcentra®, CSL Behring, King of Prussia, Pennsylvania) contains a clinically significant amount of factor VII, while 3-factor PCC does not.9,10 Recent randomized controlled trials have demonstrated either superiority or noninferiority of PCC over FFP in terms of INR reversal and hemostatic efficacy in patients with major bleeding, patients undergoing semi-elective heart surgery, or in patients undergoing other urgent surgery.11-13 Similarly, in neurosurgical populations, PCC is effective14-19 and superior to FFP for both achieving INR reversal and time to reversal.5,20-28 Remarkably, PCC has not been directly compared to FFP in the patients requiring emergency neurosurgical procedures where urgent reversal of anticoagulation is critical. Evidence supporting the role of PCC in patients with warfarin-associated intracranial hemorrhage was found in a recent study by Steiner et al.28 This randomized controlled trial measured achievement of INR normalization and hematoma volumes in anticoagulated patients diagnosed with intracranial hemorrhage on CT scan. The PCC-treated group was noted to achieve a higher rate of INR normalization than the FFP-treated group. Additionally, superior INR normalization seemed to be associated with smaller hematoma expansion. In the FFP group, 5 of the 8 deaths occurred due to hematoma expansion, all within 48 h. Within 72 h of reversal, there were 3 thromboembolic events, 1 in the FFP group (n = 23) and 2 in the PCC group (n = 27). While this study was pioneering, it leaves unanswered the question of thrombotic complication rates in anticoagulated patients presenting with intracranial hemorrhage requiring emergency neurosurgical procedures. We sought to address this knowledge gap, which has direct relevance to neurosurgeons. We employ a multivariate propensity score matching (PSM) analysis to permit robust, unbiased comparisons between the PCC and FFP cohorts.29,30 PSM limits the threat to interval validity from selection bias arising from differences in underlying characteristics. In addition, PSM is superior to more traditional methods such as multiple linear regression because it does not extrapolate using assumptions of linearity if there are significant differences in underlying characteristics between the control and treatment groups. PSM analysis has only been applied sparsely in studies investigating PCC31,32, despite the advantages that this statistical model affords. METHODS Study Design and Patient Selection We performed a retrospective cohort analysis of acute thrombotic complications in anticoagulated patients who required urgent reversal with PCC or FFP for the indication of emergency neurosurgical procedure in the setting of intracranial hemorrhage. We identified 2 cohorts of patients on warfarin therapy presenting with intracranial hemorrhage who underwent anticoagulation reversal and a subsequent neurosurgical procedure between 2007 and 2016 at a level I trauma center: (1) patients who were given PCC (n = 28) and (2) patients who were given FFP alone (n = 35). All patients also received vitamin K. Indications for emergency neurosurgical procedure were in accordance with published guidelines. Appropriate Institutional Review Board approval and a waiver of informed patient consent were obtained. The primary endpoint was the incidence of thrombotic complications within 72 h of anticoagulation reversal. Thrombotic complications were defined as deep vein thrombosis, pulmonary embolism, ischemic stroke, or myocardial infarction as documented by the clinical record, radiological, and laboratory studies. Seventy-two hours defines the window for early postoperative complications at our institution. It provides a reliable metric to measure thrombotic events related to urgent use of reversal agents while simultaneously minimizing contamination of these events with the occurrence of thrombotic events associated with prolonged recumbency. This interval also allows comparison to other studies that report data at this point.28 Secondary endpoints included INR reversal, mortality rate during hospitalization, and rate of pulmonary complications within 1 wk of treatment. Pulmonary complications were defined as pneumonia, pneumothorax, respiratory distress requiring mechanical ventilation, and pulmonary edema and effusion documented in the clinical record and validated by radiological studies. Statistical Methods We used a multivariate PSM analysis to correct for any bias between groups. The PSM model identified the control group (FFP) that was most similar to treatment group (PCC) across the following factors which may affect thrombotic complication rates: age, gender, INR pretreatment and post-treatment, trauma, altered mental status, and the existence of heart failure.29,30,33 For trauma, altered mental status, and heart failure, each patient was assigned 1 point per variable. A composite score ranging from 0 to 3 was assigned to each patient based on the sum of these 3 variables. To perform the PSM analysis, we applied the following multivariate logistic regression model on all patients in both groups (n = 63). The dependent variable ‘group’ (PCC or FFP) was predicted by the following independent variables: age, gender, INR pretreatment and post-treatment, and composite score (trauma, altered mental status, heart failure). The resulting model was then used to assign each patient with a probability that they would be assigned to the PCC group based on these factors. For each patient in the PCC group, we identified a patient in the FFP group that was most closely matched in these factors (ie, the probability assigned by the regression model). Similar statistical methods have been validated in retrospective cohort studies.34 Two-sample t-tests and χ2 tests were used to compare continuous and categorical distributions, respectively. A P-value of < .05 was considered to be significant. RESULTS Patient Demographics and Risk Factors Among the 28 patients in the PCC cohort, the most common neurosurgical indications were intraparenchymal hemorrhage (n = 15), subdural hemorrhage (n = 10), and subarachnoid hemorrhage (n = 3). The most common neurosurgical procedures for the PCC cohort were craniotomy (n = 12), decompressive craniectomy (n = 9), and external ventricular drain (n = 5). As for the 35 patients in the FFP cohort, the most common neurosurgical indications were subdural hemorrhage (n = 24) and intraparenchymal hemorrhage (n = 11). The most common neurosurgical procedures for the FFP cohort were craniotomy (n = 27) and decompressive craniectomy (n = 7; Figure 1 and Table 1). FIGURE 1. View largeDownload slide Representative axial head CT scans for PCC and FFP groups showing the most common neurosurgical indications—subdural hemorrhage and intraparenchymal hemorrhage. IPH, intraparenchymal hemorrhage; SDH, subdural hemorrhage. FIGURE 1. View largeDownload slide Representative axial head CT scans for PCC and FFP groups showing the most common neurosurgical indications—subdural hemorrhage and intraparenchymal hemorrhage. IPH, intraparenchymal hemorrhage; SDH, subdural hemorrhage. TABLE 1. Neurosurgical Indications and Procedures for Treatment Group (PCC) and Control Group (FFP only) PCC (n = 28) FFP (n = 35) Neurosurgical indications Neurosurgical procedure Neurosurgical indications Neurosurgical procedure Intraparenchymal hemorrhage (15) Craniotomy (12) Subdural hemorrhage (24) Craniotomy (27) Subdural hemorrhage (10) Decompressive craniectomy (9) Intraparenchymal hemorrhage (11) Decompressive craniectomy (7) Subarachnoid hemorrhage (3) External ventricular drain (5) External ventricular drain (1) Endovascular embolization (2) PCC (n = 28) FFP (n = 35) Neurosurgical indications Neurosurgical procedure Neurosurgical indications Neurosurgical procedure Intraparenchymal hemorrhage (15) Craniotomy (12) Subdural hemorrhage (24) Craniotomy (27) Subdural hemorrhage (10) Decompressive craniectomy (9) Intraparenchymal hemorrhage (11) Decompressive craniectomy (7) Subarachnoid hemorrhage (3) External ventricular drain (5) External ventricular drain (1) Endovascular embolization (2) View Large TABLE 1. Neurosurgical Indications and Procedures for Treatment Group (PCC) and Control Group (FFP only) PCC (n = 28) FFP (n = 35) Neurosurgical indications Neurosurgical procedure Neurosurgical indications Neurosurgical procedure Intraparenchymal hemorrhage (15) Craniotomy (12) Subdural hemorrhage (24) Craniotomy (27) Subdural hemorrhage (10) Decompressive craniectomy (9) Intraparenchymal hemorrhage (11) Decompressive craniectomy (7) Subarachnoid hemorrhage (3) External ventricular drain (5) External ventricular drain (1) Endovascular embolization (2) PCC (n = 28) FFP (n = 35) Neurosurgical indications Neurosurgical procedure Neurosurgical indications Neurosurgical procedure Intraparenchymal hemorrhage (15) Craniotomy (12) Subdural hemorrhage (24) Craniotomy (27) Subdural hemorrhage (10) Decompressive craniectomy (9) Intraparenchymal hemorrhage (11) Decompressive craniectomy (7) Subarachnoid hemorrhage (3) External ventricular drain (5) External ventricular drain (1) Endovascular embolization (2) View Large Before PSM (Table 2), the patients who received PCC (n = 28) had a mean age of 64.3 yr (range 27-88) and were 60.7% male (n = 17). The patients in the FFP group (n = 35) had a mean age of 70.4 (range 40-97) and were 62.8% male (n = 22). There was a nonsignificant trend toward younger age in the PCC group compared with the FFP (t-test, P = .10). With regard to established risk factors for thrombosis in neurosurgical patients, patients in the PCC group less commonly presented with trauma (21.4%, n = 6) compared with patients in the FFP group (62.8%, n = 22; χ2 test, P = .004). We observed no significant differences in frequency of heart failure in the PCC group (14.3%, n = 4) and in the FFP group (17.1%, n = 6; χ2 test, P > .5). Patients in the PCC group presented with altered mental status in 75% of cases (n = 21), whereas those in the FFP group presented with altered mental status in 60% of cases (n = 21; χ2 test, P = .21) TABLE 2. Patient Characteristics and Complications for Treatment Group (PCC) and Control Group (FFP Only) PCC (n = 28) FFP (n = 35) P-value 95% confidence interval Age 64.3 (±15.5) yr 70.4 (± 13.3) yr .10 (–13.4 to 1.20) Gender 60.7% male (n = 17) 62.8% male (n = 22) >.5 (–0.26 to 0.22) Trauma 21.4% (n = 6) 57.14% (n = 20) .004 (–0.58 to –0.13) Heart failure 14.3% (n = 4) 17.1% (n = 6) >.5 (–0.21 to 0.15) Altered mental status 75% (n = 21) 60.0% (n = 21) .21 (–0.08 to 0.38) INR pretreatment 3.36 ± 1.85 3.11 ± 1.90 >.5 (–0.70 to 1.21) INR post-treatment 1.36 ± .31 1.37 ± 0.22 >.5 (–0.14 to 0.12) Mortality during hospitalization 17.9% (n = 5) 17.1% (n = 6) >.5 (–0.18 to 0.20) Pulmonary complications 39.3% (n = 11) 11.4% (n = 4) .009 (0.07 to 0.49) Number of patients with thrombotic complications (within 72 h) 3.57% (n = 1) 0% (n = 0) .23 (–0.03 to 0.10) PCC (n = 28) FFP (n = 35) P-value 95% confidence interval Age 64.3 (±15.5) yr 70.4 (± 13.3) yr .10 (–13.4 to 1.20) Gender 60.7% male (n = 17) 62.8% male (n = 22) >.5 (–0.26 to 0.22) Trauma 21.4% (n = 6) 57.14% (n = 20) .004 (–0.58 to –0.13) Heart failure 14.3% (n = 4) 17.1% (n = 6) >.5 (–0.21 to 0.15) Altered mental status 75% (n = 21) 60.0% (n = 21) .21 (–0.08 to 0.38) INR pretreatment 3.36 ± 1.85 3.11 ± 1.90 >.5 (–0.70 to 1.21) INR post-treatment 1.36 ± .31 1.37 ± 0.22 >.5 (–0.14 to 0.12) Mortality during hospitalization 17.9% (n = 5) 17.1% (n = 6) >.5 (–0.18 to 0.20) Pulmonary complications 39.3% (n = 11) 11.4% (n = 4) .009 (0.07 to 0.49) Number of patients with thrombotic complications (within 72 h) 3.57% (n = 1) 0% (n = 0) .23 (–0.03 to 0.10) Errors shown are standard deviations. View Large TABLE 2. Patient Characteristics and Complications for Treatment Group (PCC) and Control Group (FFP Only) PCC (n = 28) FFP (n = 35) P-value 95% confidence interval Age 64.3 (±15.5) yr 70.4 (± 13.3) yr .10 (–13.4 to 1.20) Gender 60.7% male (n = 17) 62.8% male (n = 22) >.5 (–0.26 to 0.22) Trauma 21.4% (n = 6) 57.14% (n = 20) .004 (–0.58 to –0.13) Heart failure 14.3% (n = 4) 17.1% (n = 6) >.5 (–0.21 to 0.15) Altered mental status 75% (n = 21) 60.0% (n = 21) .21 (–0.08 to 0.38) INR pretreatment 3.36 ± 1.85 3.11 ± 1.90 >.5 (–0.70 to 1.21) INR post-treatment 1.36 ± .31 1.37 ± 0.22 >.5 (–0.14 to 0.12) Mortality during hospitalization 17.9% (n = 5) 17.1% (n = 6) >.5 (–0.18 to 0.20) Pulmonary complications 39.3% (n = 11) 11.4% (n = 4) .009 (0.07 to 0.49) Number of patients with thrombotic complications (within 72 h) 3.57% (n = 1) 0% (n = 0) .23 (–0.03 to 0.10) PCC (n = 28) FFP (n = 35) P-value 95% confidence interval Age 64.3 (±15.5) yr 70.4 (± 13.3) yr .10 (–13.4 to 1.20) Gender 60.7% male (n = 17) 62.8% male (n = 22) >.5 (–0.26 to 0.22) Trauma 21.4% (n = 6) 57.14% (n = 20) .004 (–0.58 to –0.13) Heart failure 14.3% (n = 4) 17.1% (n = 6) >.5 (–0.21 to 0.15) Altered mental status 75% (n = 21) 60.0% (n = 21) .21 (–0.08 to 0.38) INR pretreatment 3.36 ± 1.85 3.11 ± 1.90 >.5 (–0.70 to 1.21) INR post-treatment 1.36 ± .31 1.37 ± 0.22 >.5 (–0.14 to 0.12) Mortality during hospitalization 17.9% (n = 5) 17.1% (n = 6) >.5 (–0.18 to 0.20) Pulmonary complications 39.3% (n = 11) 11.4% (n = 4) .009 (0.07 to 0.49) Number of patients with thrombotic complications (within 72 h) 3.57% (n = 1) 0% (n = 0) .23 (–0.03 to 0.10) Errors shown are standard deviations. View Large The INR pretreatment and post-treatment was documented (Table 2). The groups were well matched on presenting INR (t-test, P > .5). The therapeutic effect of both PCC and FFP was validated by measuring post-treatment INR, which was significantly lower than presenting INR (t-test, P < .001). There were no differences in post-treatment INR between groups (t-test, P > .5), confirming that both groups achieved anticoagulation reversal. Complications The overall thrombotic complication rate within 72 h of anticoagulation reversal was 3.57% (n = 1/28) and 0% (n = 0/35) for the PCC and FFP groups, respectively (Table 2). There was no significant difference in the thrombotic complication rates (χ2 test, P = .23). The rate of pulmonary complications within 1 wk of treatment was higher for the PCC group (39.3%, n = 11) than that for the FFP group (11.4%; n = 4; χ2 test, P = .009; Table 2). There was no difference in mortality during hospitalization between groups (PCC 17.9%, n = 5; FFP 17.1%, n = 6; χ2 test, P > .5). Patient Demographics and Risk Factors— PSM We performed a PSM analysis to match the PCC and FFP cohorts (28 patients each) according to age, gender, INR pretreatment and post-treatment, and several factors that are known to predispose neurosurgical patients to thrombosis including trauma, altered mental status, and preexisting heart failure (Table 3). After performing this analysis, we found that both age and gender differences from the unmatched analysis were diminished (t-test and χ2 test, P > .2). As for the established risk factors for thrombosis in neurosurgical patients, we did not observe a significant difference in the rate of heart failure (χ2 test, P > .5) and altered mental status (χ2 test, P = .09). There was a significant difference in the rate of trauma between the 2 patient cohorts (χ2 test, P = .013). PSM enabled mitigation of underlying differences between the 2 cohorts, particularly differences in age and gender, which make statistical analysis prone to selection bias. TABLE 3. Patient Characteristics and Complications for Treatment Group (PCC) and Control Group (FFP Only) After PSM With Age, Gender, INR Pretreatment, INR Post-treatment, and Composite Score (Trauma, Heart Failure, and Altered Mental Status) PCC (n = 28) FFP (n = 28) P-value 95% confidence interval Age 64.3 (± 15.5) yr 67.7 (± 12.7) yr .23 (–8.99 to 2.28) Gender 60.7% male (n = 17) 60.7% male (n = 17) >.5 (−0.26 to 0.26) Trauma 21.4% (n = 6) 53.5% (n = 15) .013 (–0.56 to –0.08) Heart failure 14.3% (n = 4) 10.7% (n = 3) >.5 (–0.14 to 0.21) Altered mental status 75% (n = 21) 53.57% (n = 15) .09 (–0.03 to 0.46) INR pretreatment 3.36 ± 1.85 2.92 ± 1.64 .32 (–0.46 to 1.34) INR post-treatment 1.36 ± .31 1.33 ± 0.18 >.5 (–0.12 to 0.17) Mortality during hospitalization 17.9% (n = 5) 14.3% (n = 4) >.5 (–0.16 to 0.23) Pulmonary complications 39.3% (n = 11) 14.2% (n = 4) .035 (0.03 to 0.47) Number of patients with thrombotic complications (within 72 h) 3.57% (n = 1) 0% (n = 0) .31 (–0.03 to 0.10) PCC (n = 28) FFP (n = 28) P-value 95% confidence interval Age 64.3 (± 15.5) yr 67.7 (± 12.7) yr .23 (–8.99 to 2.28) Gender 60.7% male (n = 17) 60.7% male (n = 17) >.5 (−0.26 to 0.26) Trauma 21.4% (n = 6) 53.5% (n = 15) .013 (–0.56 to –0.08) Heart failure 14.3% (n = 4) 10.7% (n = 3) >.5 (–0.14 to 0.21) Altered mental status 75% (n = 21) 53.57% (n = 15) .09 (–0.03 to 0.46) INR pretreatment 3.36 ± 1.85 2.92 ± 1.64 .32 (–0.46 to 1.34) INR post-treatment 1.36 ± .31 1.33 ± 0.18 >.5 (–0.12 to 0.17) Mortality during hospitalization 17.9% (n = 5) 14.3% (n = 4) >.5 (–0.16 to 0.23) Pulmonary complications 39.3% (n = 11) 14.2% (n = 4) .035 (0.03 to 0.47) Number of patients with thrombotic complications (within 72 h) 3.57% (n = 1) 0% (n = 0) .31 (–0.03 to 0.10) Errors shown are standard deviations. View Large TABLE 3. Patient Characteristics and Complications for Treatment Group (PCC) and Control Group (FFP Only) After PSM With Age, Gender, INR Pretreatment, INR Post-treatment, and Composite Score (Trauma, Heart Failure, and Altered Mental Status) PCC (n = 28) FFP (n = 28) P-value 95% confidence interval Age 64.3 (± 15.5) yr 67.7 (± 12.7) yr .23 (–8.99 to 2.28) Gender 60.7% male (n = 17) 60.7% male (n = 17) >.5 (−0.26 to 0.26) Trauma 21.4% (n = 6) 53.5% (n = 15) .013 (–0.56 to –0.08) Heart failure 14.3% (n = 4) 10.7% (n = 3) >.5 (–0.14 to 0.21) Altered mental status 75% (n = 21) 53.57% (n = 15) .09 (–0.03 to 0.46) INR pretreatment 3.36 ± 1.85 2.92 ± 1.64 .32 (–0.46 to 1.34) INR post-treatment 1.36 ± .31 1.33 ± 0.18 >.5 (–0.12 to 0.17) Mortality during hospitalization 17.9% (n = 5) 14.3% (n = 4) >.5 (–0.16 to 0.23) Pulmonary complications 39.3% (n = 11) 14.2% (n = 4) .035 (0.03 to 0.47) Number of patients with thrombotic complications (within 72 h) 3.57% (n = 1) 0% (n = 0) .31 (–0.03 to 0.10) PCC (n = 28) FFP (n = 28) P-value 95% confidence interval Age 64.3 (± 15.5) yr 67.7 (± 12.7) yr .23 (–8.99 to 2.28) Gender 60.7% male (n = 17) 60.7% male (n = 17) >.5 (−0.26 to 0.26) Trauma 21.4% (n = 6) 53.5% (n = 15) .013 (–0.56 to –0.08) Heart failure 14.3% (n = 4) 10.7% (n = 3) >.5 (–0.14 to 0.21) Altered mental status 75% (n = 21) 53.57% (n = 15) .09 (–0.03 to 0.46) INR pretreatment 3.36 ± 1.85 2.92 ± 1.64 .32 (–0.46 to 1.34) INR post-treatment 1.36 ± .31 1.33 ± 0.18 >.5 (–0.12 to 0.17) Mortality during hospitalization 17.9% (n = 5) 14.3% (n = 4) >.5 (–0.16 to 0.23) Pulmonary complications 39.3% (n = 11) 14.2% (n = 4) .035 (0.03 to 0.47) Number of patients with thrombotic complications (within 72 h) 3.57% (n = 1) 0% (n = 0) .31 (–0.03 to 0.10) Errors shown are standard deviations. View Large We also calculated the INR pretreatment and post-treatment for both PCC and FFP groups (Table 3). Patients who received PCC presented with a similar INR compared with patients who received FFP (t-test, P = .32). Both groups had a significantly decreased INR after administration of PCC or FFP (t-test, P < .001), with no significant difference in INR post-treatment between the 2 groups (t-test, P > .5; Figure 2). FIGURE 2. View largeDownload slide INR pretreatment and INR post-treatment after PSM, where treatment is administration of PCC or FFP. Error bars indicate standard deviation. No significant difference between PCC and FFP groups for either INR pretreatment or INR post-treatment. Significant reduction in INR after administration of either PCC or FFP. *P < .001, 2 sample t-test. FIGURE 2. View largeDownload slide INR pretreatment and INR post-treatment after PSM, where treatment is administration of PCC or FFP. Error bars indicate standard deviation. No significant difference between PCC and FFP groups for either INR pretreatment or INR post-treatment. Significant reduction in INR after administration of either PCC or FFP. *P < .001, 2 sample t-test. Complications—PSM The overall thrombotic complication rate within 72 h of anticoagulation reversal was 3.57% (n = 1/28) for the PCC group and 0% (n = 0/28) for the FFP group (Figure 3 and Table 3). There was no significant difference in the thrombotic complication rates (χ2 test, P = .31). We can say with 95% confidence that the difference in the thrombotic complication rates between PCC and FFP is between –3.3% and 10.5%. FIGURE 3. View largeDownload slide Rate of thrombotic complications (within 72 h of anticoagulation reversal) and rate of pulmonary complications (within 1 wk of treatment) for PCC and FFP groups after propensity score matching. No significant difference in thrombotic complication rate (P = .31, χ2 test). Higher rate of pulmonary complications for PCC group compared with FFP group. *P = .035, χ2 test. FIGURE 3. View largeDownload slide Rate of thrombotic complications (within 72 h of anticoagulation reversal) and rate of pulmonary complications (within 1 wk of treatment) for PCC and FFP groups after propensity score matching. No significant difference in thrombotic complication rate (P = .31, χ2 test). Higher rate of pulmonary complications for PCC group compared with FFP group. *P = .035, χ2 test. The rate of pulmonary complications within 1 wk of treatment was higher for the PCC group (39.3%; n = 11) than the FFP group (14.2%, n = 4; χ2 test, p = 0.035; Figure 3 and Table 3). In the PCC group, pulmonary edema/pleural effusion accounted for 3 pulmonary complications, pneumonia for 3, general respiratory distress requiring mechanical ventilation for 3, and pneumothorax for 2. As for the FFP group, pulmonary edema/pleural effusion and pneumonia accounted for 2 pulmonary complications each. The sole thrombotic complication within the PCC group was a saddle pulmonary embolism. In this case, the neurosurgical indication was subarachnoid hemorrhage and the emergency neurosurgical procedure performed was endovascular embolization (Figure 4 and Table 4). FIGURE 4. View largeDownload slide Serial axial chest CT scan with arrows pointing to saddle pulmonary embolism, the sole thrombotic complication observed in the PCC group. FIGURE 4. View largeDownload slide Serial axial chest CT scan with arrows pointing to saddle pulmonary embolism, the sole thrombotic complication observed in the PCC group. TABLE 4. Thrombotic Complications for Treatment Group (PCC) and Control Group (FFP only) Thrombotic complication PCC or FFP Age Gender Neurosurgical indication Neurosurgical procedure Saddle pulmonary embolism PCC 85 Female Subarachnoid hemorrhage Endovascular embolization Thrombotic complication PCC or FFP Age Gender Neurosurgical indication Neurosurgical procedure Saddle pulmonary embolism PCC 85 Female Subarachnoid hemorrhage Endovascular embolization View Large TABLE 4. Thrombotic Complications for Treatment Group (PCC) and Control Group (FFP only) Thrombotic complication PCC or FFP Age Gender Neurosurgical indication Neurosurgical procedure Saddle pulmonary embolism PCC 85 Female Subarachnoid hemorrhage Endovascular embolization Thrombotic complication PCC or FFP Age Gender Neurosurgical indication Neurosurgical procedure Saddle pulmonary embolism PCC 85 Female Subarachnoid hemorrhage Endovascular embolization View Large We examined mortality data for all admissions. There were no differences in mortality rates during hospitalization between the groups. Mortality rate for the PCC group (17.9%, n = 5) was similar compared with the FFP group (14.3%, n = 4; χ2 test, P > .5). DISCUSSION Thrombotic Complications Data on the rate of thrombotic complications due to PCC in operative neurosurgical patients are scarce but immediately relevant to current neurosurgical practice. In this retrospective cohort study of 65 patients from 2007 to 2016 at a level 1 trauma center, the incidence of thrombotic complications between groups receiving PCC or FFP for anticoagulation reversal in the setting of intracranial hemorrhage prior to an emergency neurosurgical procedure was similar. Below we consider these results in light of the literature regarding thrombotic complications in surgical populations and discuss the efficacy of reversal afforded by PCC. The rate of thrombotic complications associated with PCC found in this study is consistent with the few reports that have investigated patients on warfarin therapy undergoing emergency neurosurgical procedures (Table 5).14,35-38 The reported rate of thrombotic complications due to PCC in nonoperative neurosurgical patients ranges between 0% and 13%.14,15,17-19,22,26,28,32 In a recent randomized controlled trial of all anticoagulated patients presenting with intracranial hemorrhage, Steiner et al28 reported a rate of 7.4% (PCC, n = 2/27) and 4.3% (FFP, n = 1/23) within 72 h of INR correction. In a similar patient population, Woo et al26 observed no cases of thrombotic complications, while Frontera et al22 observed 12.5% (PCC, n = 2/16) and 16% (FFP, n = 4/25), respectively. In spontaneous coagulopathy due to traumatic brain injury, reported rates are 4% (PCC, n = 3/74)) and 3.4% (FFP, n = 5/148).32 Including both operative and nonoperative neurosurgical cases, thrombotic complications following anticoagulation reversal appear uncommon and similar between the reversal agents. TABLE 5. Use of PCC for Anticoagulation Reversal of Elevated INR Prior to Emergency Surgery in Previous Studies Author and year Study design n Surgical population Primary outcome Secondary outcome Thrombotic complication rate (n) Sridharan et al 201644 Retrospective cohort 52 Emergency surgical procedure (mixed) INR reversal Clinical safety 13% (7) Beynon et al 201535 Retrospective cohort 9 Aneurysmal subarachnoid hemorrhage INR reversal Time to surgical intervention 0% (0) Beynon et al 201536 Retrospective cohort 5 Emergency brain tumor pathology INR reversal Time to surgical intervention 0% (0) Quick et al 201550 Retrospective cohort 41 Emergency surgical procedure (mixed) INR reversal Clinical safety 2.4% (1) Goldstein et al 201513 Randomized controlled trial 90 Emergency surgical procedure (mixed) Effective hemostasis INR reversal 7% (6) Beynon et al 201437 Retrospective cohort 18 Emergency spinal pathology INR reversal Time to surgical intervention 5.6% (1) Cabral et al 201314 Retrospective cohort 9 Intracranial hemorrhage INR reversal Clinical safety 0% (0) Majeed et al 201247 Prospective cohort 44 Emergency surgical procedure (mixed) Clinical safety Effective hemostasis 2.3% (1) Demeyere et al 201011 Randomized controlled trial 20 Heart surgery w/ cardiopulmonary bypass INR reversal Time to INR reversal 0% (0) Pabinger et al 200848 Prospective cohort 26 Emergency surgical procedure (mixed) INR reversal Effective hemostasis 0% (0) Riess et al 200749 Prospective cohort 57 Emergency surgical procedure (mixed) INR reversal Clotting factor levels 0% (0) Vigue et al 200738 Prospective cohort 18 Intracranial hemorrhage INR reversal Clinical safety 0% (0) Lubetsky et al 200457 Prospective cohort 10 Emergency surgical procedure (mixed) INR reversal Clinical safety 0% (0) Author and year Study design n Surgical population Primary outcome Secondary outcome Thrombotic complication rate (n) Sridharan et al 201644 Retrospective cohort 52 Emergency surgical procedure (mixed) INR reversal Clinical safety 13% (7) Beynon et al 201535 Retrospective cohort 9 Aneurysmal subarachnoid hemorrhage INR reversal Time to surgical intervention 0% (0) Beynon et al 201536 Retrospective cohort 5 Emergency brain tumor pathology INR reversal Time to surgical intervention 0% (0) Quick et al 201550 Retrospective cohort 41 Emergency surgical procedure (mixed) INR reversal Clinical safety 2.4% (1) Goldstein et al 201513 Randomized controlled trial 90 Emergency surgical procedure (mixed) Effective hemostasis INR reversal 7% (6) Beynon et al 201437 Retrospective cohort 18 Emergency spinal pathology INR reversal Time to surgical intervention 5.6% (1) Cabral et al 201314 Retrospective cohort 9 Intracranial hemorrhage INR reversal Clinical safety 0% (0) Majeed et al 201247 Prospective cohort 44 Emergency surgical procedure (mixed) Clinical safety Effective hemostasis 2.3% (1) Demeyere et al 201011 Randomized controlled trial 20 Heart surgery w/ cardiopulmonary bypass INR reversal Time to INR reversal 0% (0) Pabinger et al 200848 Prospective cohort 26 Emergency surgical procedure (mixed) INR reversal Effective hemostasis 0% (0) Riess et al 200749 Prospective cohort 57 Emergency surgical procedure (mixed) INR reversal Clotting factor levels 0% (0) Vigue et al 200738 Prospective cohort 18 Intracranial hemorrhage INR reversal Clinical safety 0% (0) Lubetsky et al 200457 Prospective cohort 10 Emergency surgical procedure (mixed) INR reversal Clinical safety 0% (0) View Large TABLE 5. Use of PCC for Anticoagulation Reversal of Elevated INR Prior to Emergency Surgery in Previous Studies Author and year Study design n Surgical population Primary outcome Secondary outcome Thrombotic complication rate (n) Sridharan et al 201644 Retrospective cohort 52 Emergency surgical procedure (mixed) INR reversal Clinical safety 13% (7) Beynon et al 201535 Retrospective cohort 9 Aneurysmal subarachnoid hemorrhage INR reversal Time to surgical intervention 0% (0) Beynon et al 201536 Retrospective cohort 5 Emergency brain tumor pathology INR reversal Time to surgical intervention 0% (0) Quick et al 201550 Retrospective cohort 41 Emergency surgical procedure (mixed) INR reversal Clinical safety 2.4% (1) Goldstein et al 201513 Randomized controlled trial 90 Emergency surgical procedure (mixed) Effective hemostasis INR reversal 7% (6) Beynon et al 201437 Retrospective cohort 18 Emergency spinal pathology INR reversal Time to surgical intervention 5.6% (1) Cabral et al 201314 Retrospective cohort 9 Intracranial hemorrhage INR reversal Clinical safety 0% (0) Majeed et al 201247 Prospective cohort 44 Emergency surgical procedure (mixed) Clinical safety Effective hemostasis 2.3% (1) Demeyere et al 201011 Randomized controlled trial 20 Heart surgery w/ cardiopulmonary bypass INR reversal Time to INR reversal 0% (0) Pabinger et al 200848 Prospective cohort 26 Emergency surgical procedure (mixed) INR reversal Effective hemostasis 0% (0) Riess et al 200749 Prospective cohort 57 Emergency surgical procedure (mixed) INR reversal Clotting factor levels 0% (0) Vigue et al 200738 Prospective cohort 18 Intracranial hemorrhage INR reversal Clinical safety 0% (0) Lubetsky et al 200457 Prospective cohort 10 Emergency surgical procedure (mixed) INR reversal Clinical safety 0% (0) Author and year Study design n Surgical population Primary outcome Secondary outcome Thrombotic complication rate (n) Sridharan et al 201644 Retrospective cohort 52 Emergency surgical procedure (mixed) INR reversal Clinical safety 13% (7) Beynon et al 201535 Retrospective cohort 9 Aneurysmal subarachnoid hemorrhage INR reversal Time to surgical intervention 0% (0) Beynon et al 201536 Retrospective cohort 5 Emergency brain tumor pathology INR reversal Time to surgical intervention 0% (0) Quick et al 201550 Retrospective cohort 41 Emergency surgical procedure (mixed) INR reversal Clinical safety 2.4% (1) Goldstein et al 201513 Randomized controlled trial 90 Emergency surgical procedure (mixed) Effective hemostasis INR reversal 7% (6) Beynon et al 201437 Retrospective cohort 18 Emergency spinal pathology INR reversal Time to surgical intervention 5.6% (1) Cabral et al 201314 Retrospective cohort 9 Intracranial hemorrhage INR reversal Clinical safety 0% (0) Majeed et al 201247 Prospective cohort 44 Emergency surgical procedure (mixed) Clinical safety Effective hemostasis 2.3% (1) Demeyere et al 201011 Randomized controlled trial 20 Heart surgery w/ cardiopulmonary bypass INR reversal Time to INR reversal 0% (0) Pabinger et al 200848 Prospective cohort 26 Emergency surgical procedure (mixed) INR reversal Effective hemostasis 0% (0) Riess et al 200749 Prospective cohort 57 Emergency surgical procedure (mixed) INR reversal Clotting factor levels 0% (0) Vigue et al 200738 Prospective cohort 18 Intracranial hemorrhage INR reversal Clinical safety 0% (0) Lubetsky et al 200457 Prospective cohort 10 Emergency surgical procedure (mixed) INR reversal Clinical safety 0% (0) View Large PCC has been more extensively studied in the setting of general surgery where anticoagulation is often complicated by substantial blood loss. Rates tend be higher than in the isolated neurosurgical population. In studies that involve cases of major, life-threatening bleeding, use of PCC for anticoagulation reversal has been found to be associated with thrombotic complication rates up to 21%.39-46 For cases requiring any type of emergency surgery, PCC has a thrombotic complication rate of up to 13%.44,47-50 At least 3 randomized controlled trials have also been conducted that have compared the thrombotic complication rates of PCC vs FFP for anticoagulation reversal in general surgical patient populations. Cases requiring urgent cardiopulmonary bypass appear to have a lower rate of thrombotic complications than other emergency surgery, with an incidence of zero in the cohorts reported by Demeyere et al.11 Goldstein et al13 investigated patients undergoing urgent invasive surgery and found that thrombotic complication rates were similar amongst PCC (7%, n = 6/88) and FFP (8%, n = 7/88) (Table 5). Similarly, Sarode et al12 found that in patients with major bleeding, the safety profiles were no different between the 2 groups. A post hoc, pooled analysis of the Goldstein et al13 and Sarode et al12 studies found the thromboembolic complication rates to be 7.3% (n = 14/191) in the PCC group and 7.1% (n = 14/197) in the FFP group.51 Secondary Endpoints PCC is consistently superior to FFP with regard to achievement of INR normalization in neurosurgical patients.20-22,25,28 In these patients, PCC achieves normalization 2 to 4 times faster than FFP.5,24,26,27 PCC therefore enables faster time to operation.32 In cases not requiring emergency surgery, PCC appears to be associated with attenuated intracranial hematoma expansion.23 PCC also rapidly reverses anticoagulation in cases of major, life-threatening bleeding in general surgical populations.12,40,41,43,45,46,52-56 Other studies have demonstrated the efficacy of PCC in achieving rapid anticoagulation reversal in bleeding patients who are facing urgent surgery.11,13,44,47-49,57 Our data confirm that PCC effectively achieves INR reversal in the emergency neurosurgical patient population. In this study, patients who received PCC had a higher rate of pulmonary complications within 1 wk of treatment. Pneumonia, respiratory distress requiring mechanical ventilation, and pneumothorax accounted for this difference. Other pulmonary complications, such as pleural effusion and pulmonary edema, were similar between groups. The etiology of this finding is unclear. A putative benefit of avoiding FFP is the absence of volume overload and secondary pleural effusions or pulmonary edema.7,8 We did not observe an increased rate of these events in the FFP group, and somewhat surprisingly, noted an increase in other pulmonary complications in the PCC group. While we are unaware of other studies that have reported this finding, PCC has been associated with other conditions. In cardiac patients receiving PCC, a higher incidence of acute kidney injury has been noted.31 We find no evidence to suggest that PCC systematically affected end organ function, as mortality rates during hospitalization were similar between groups. PCC has also not been associated with prolonged hospitalization or intensive care unit stay.40,50,52 These factors will require further study in larger samples of anticoagulated patients requiring emergency neurosurgical procedures. Strengths The use of multivariate PSM analysis in this study adds robustness and novelty to the existing neurosurgical literature concerning reversal of anticoagulation. This analysis method controls for age, gender, and other risk factors that could influence the rate of thrombotic complications including trauma, altered mental status, and preexisting heart failure.29,30,33 The advantage of multivariate PSM analysis in this study is that it enabled matching of control and treatment patients based on age, gender, INR pretreatment and post-treatment, trauma, altered mental status, and preexisting heart failure. Thus, we can be confident that our statistical comparisons of the rate of thrombotic complications between cohorts are robust and unbiased. Limitations A number of factors must be weighed when evaluating the findings of the current investigation. This study examines an uncommon complication in a highly selective patient population—namely, anticoagulated patients requiring emergency neurosurgical procedures at a level I trauma center. To accrue as many patients as possible, we analyzed data over a 10-yr window. Given the low incidence of thrombotic complications observed, single institution studies are inherently underpowered to assess significant differences between relatively rare adverse events. Nevertheless, these results are immediately relevant to practicing clinicians who encounter anticoagulated patients requiring emergency cranial procedures. The importance of these findings and critical nature of patients involved justify larger studies in multicenter, prospective, randomized settings. To mitigate against any bias inherent in a retrospective study, we employed PSM analysis. However, a modest-sized cohort can never account for all confounding factors. For instance, even after applying PSM, there was a higher proportion of patients with exposure to trauma in the group receiving FFP. Other confounding variables could affect outcomes in this study. Intracranial hematoma volume, for example, has been measured as an independent variable in some studies as a marker of the therapeutic efficacy of anticoagulation reversal agents. Expanding hematomas may lead to worse prognosis by adversely affecting mental status and mortality and are thus a measure of disease severity.28 Since our study focuses on thrombotic complications following anticoagulation reversal, we did not measure hematoma volumes. Instead, we measured INR, mental status, and mortality during hospitalization as direct measures of disease severity. The absence of differences in any of these variables provides assurance that the treatment and control groups were well matched with regard to disease severity and overall survival. We also note that there was an unexpected higher rate of pulmonary complications in the PCC group. One might hypothesize the reverse, arguing that pulmonary complications would be more common in the FFP group, as FFP has been associated with higher risk of circulatory overload and transfusion-related acute lung injury.7,8 Finally, we assess early thrombotic complications within 72 h of anticoagulation reversal. This is an appropriate window to assess early thrombotic events that allows for direct comparison between groups and across other reports in the literature. This interval also optimizes the balance between capturing events related to urgent reversal and factors that lead to spontaneous thrombotic events that often occur in critically ill patients even without reversal. Prolonged recumbency, native thrombotic state, and the presence or absence of ongoing anticoagulation therapy are independent factors affecting thrombosis.28,58 Seventy-two hours represents an acceptable time point to assess early thrombotic events related to urgent use of reversal agents with minimal cross contamination of spontaneous thrombotic events. CONCLUSION In this limited sample, we found that thrombotic complications in neurosurgical patients presenting with intracranial hemorrhage who required rapid anticoagulation reversal and an emergency neurosurgical procedure were uncommon but not rare. Use of PCC for anticoagulation reversal prior to emergency neurosurgical procedures did not pose an increased risk of thrombotic complications when compared with FFP. Considering the importance of this topic and growing use of PCC in the neurosurgical emergency setting, future randomized controlled trials at multiple institutions with an intent-to-treat analysis are indicated. 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Joseph B , Pandit V , Khalil M et al. Use of prothrombin complex concentrate as an adjunct to fresh frozen plasma shortens time to craniotomy in traumatic brain injury patients . Neurosurgery . 2015 ; 76 ( 5 ): 601 - 607 ; discussion 607 . Google Scholar CrossRef Search ADS PubMed 33. Rolston JD , Han SJ , Bloch O , Parsa AT . What clinical factors predict the incidence of deep venous thrombosis and pulmonary embolism in neurosurgical patients? J Neurosurg . 2014 ; 121 ( 4 ): 908 - 918 . Google Scholar CrossRef Search ADS PubMed 34. Lubelski D , Healy AT , Silverstein MP et al. Reoperation rates after anterior cervical discectomy and fusion versus posterior cervical foraminotomy: a propensity-matched analysis . Spine J . 2015 ; 15 ( 6 ): 1277 - 1283 . Google Scholar CrossRef Search ADS PubMed 35. Beynon C , Nofal M , Rizos T et al. Anticoagulation reversal with prothrombin complex concentrate in aneurysmal subarachnoid hemorrhage . J Emerg Med . 2015 ; 49 ( 5 ): 778 - 784 . 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Thromb Res . 2011 ; 128 ( 6 ): 577 - 582 . Google Scholar CrossRef Search ADS PubMed 40. Hickey M , Gatien M , Taljaard M , Aujnarain A , Giulivi A , Perry JJ . Outcomes of urgent warfarin reversal with frozen plasma versus prothrombin complex concentrate in the emergency department . Circulation . 2013 ; 128 ( 4 ): 360 - 364 . Google Scholar CrossRef Search ADS PubMed 41. Imberti D , Magnacavallo A , Dentali F et al. Emergency reversal of anticoagulation with vitamin K antagonists with 3-factor prothrombin complex concentrates in patients with major bleeding . J Thromb Thrombolysis . 2013 ; 36 ( 1 ): 102 - 108 . Google Scholar CrossRef Search ADS PubMed 42. Lankiewicz MW , Hays J , Friedman KD , Tinkoff G , Blatt PM . Urgent reversal of warfarin with prothrombin complex concentrate . J Thromb Haemost . 2006 ; 4 ( 5 ): 967 - 970 . Google Scholar CrossRef Search ADS PubMed 43. Preston FE , Laidlaw ST , Sampson B , Kitchen S . Rapid reversal of oral anticoagulation with warfarin by a prothrombin complex concentrate (Beriplex): efficacy and safety in 42 patients . Br J Haematol . 2002 ; 116 ( 3 ): 619 - 624 . Google Scholar CrossRef Search ADS PubMed 44. Sridharan M , Wysokinski WE , Pruthi R et al. Periprocedural warfarin reversal with prothrombin complex concentrate . Thromb Res . 2016 ; 139 : 160 - 165 . Google Scholar CrossRef Search ADS PubMed 45. Tilton R , Michalets EL , Delk B , Sutherland SE , Ramming SA . Outcomes associated with prothrombin complex concentrate for International Normalized Ratio reversal in patients on oral anticoagulants with acute bleeding . Ann Pharmacother . 2014 ; 48 ( 9 ): 1106 - 1119 . Google Scholar CrossRef Search ADS PubMed 46. Tran H , Collecutt M , Whitehead S , Salem HH . Prothrombin complex concentrates used alone in urgent reversal of warfarin anticoagulation . Intern Med J . 2011 ; 41 ( 4 ): 337 - 343 . Google Scholar CrossRef Search ADS PubMed 47. 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Google Scholar PubMed 51. Milling TJ Jr , Refaai MA , Goldstein JN et al. Thromboembolic events after vitamin K antagonist reversal with 4-factor prothrombin complex concentrate: exploratory analyses of two randomized, plasma-controlled studies . Ann Emerg Med . 2016 ; 67 ( 1 ): 96-105 e105 . Google Scholar CrossRef Search ADS 52. 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 ( 7-8 ): 869 - 875 . Google Scholar CrossRef Search ADS PubMed 53. Desmettre T , Dubart AE , Capellier G et al. Emergency reversal of anticoagulation: the real use of prothrombin complex concentrates: a prospective multicenter two year French study from 2006 to 2008 . Thromb Res . 2012 ; 130 ( 3 ): e178 - 183 . Google Scholar CrossRef Search ADS PubMed 54. Evans G , Luddington R , Baglin T . Beriplex P/N reverses severe warfarin-induced overanticoagulation immediately and completely in patients presenting with major bleeding . Br J Haematol . 2001 ; 115 ( 4 ): 998 - 1001 . Google Scholar CrossRef Search ADS PubMed 55. Yasaka M , Oomura M , Ikeno K , Naritomi H , Minematsu K . Effect of prothrombin complex concentrate on INR and blood coagulation system in emergency patients treated with warfarin overdose . Ann Hematol . 2003 ; 82 ( 2 ): 121 - 123 . Google Scholar CrossRef Search ADS PubMed 56. Yasaka M , Sakata T , Minematsu K , Naritomi H . Correction of INR by prothrombin complex concentrate and vitamin K in patients with warfarin related hemorrhagic complication . Thromb Res . 2002 ; 108 ( 1 ): 25 - 30 . Google Scholar CrossRef Search ADS PubMed 57. Lubetsky A , Hoffman R , Zimlichman R et al. Efficacy and safety of a prothrombin complex concentrate (Octaplex) for rapid reversal of oral anticoagulation . Thromb Res . 2004 ; 113 ( 6 ): 371 - 378 . Google Scholar CrossRef Search ADS PubMed 58. Pollack CV Jr , Reilly PA , Eikelboom J et al. Idarucizumab for dabigatran reversal . N Engl J Med . 2015 ; 373 ( 6 ): 511 - 520 . Google Scholar CrossRef Search ADS PubMed COMMENT This report is a retrospective analysis of neurosurgical patients who received either prothrombin complex concentrates (PCC) or fresh frozen plasma (FFP) for anticoagulation reversal for emergency neurosurgical procedures. The focus of their analysis is the rate of thrombotic complications within 72 hours in both groups. Over the ten-year period analyzed, there were 63 patients that met the inclusion criteria, 28 patients in the PCC cohort and 35 patients in the FFP cohort. A multivariate propensity score-matching analysis was utilized to minimize the effect of selection bias related to differences in demographics, lab values, history and clinical status. Only 1 of the 63 patients (1.59%) had a thrombotic complication. There was no difference in the thrombotic complication rate between the PCC group (1/28; 3.57%) and the FFP group (0/35; 0%). As compared to the patients in the FFP group, the patients in the PCC group had a higher rate of pulmonary complications, which included pneumonia, pneumothorax, respiratory distress requiring mechanical ventilation, pulmonary edema and pleural effusion. The cohorts were generally well matched with the exception that there were a higher number of trauma patients in the FFP group, however, this did not meet statistical significance (53.5% in the FFP group versus 21.4% in the PCC group; P = .013). Literature has demonstrated that PCC is superior to FFP in terms of INR normalization in neurosurgical patients. This study also provides evidence that administration of PCC does not increase the risk of thrombotic complications within 72 hours. However, one surprising finding in this study was the higher rate of pulmonary complications with the patients who received PCC. This is particularly notable given the well-known association of FFP, volume overload and pulmonary complications such as pleural effusions and pulmonary edema. I think this article begins to set the stage for a larger, multi-center study to further evaluate the use of PCC in the neurosurgical population. It will certainly be important to determine if PCC truly has a deleterious effect on the pulmonary system and, if so, to what extent. John Reavey-Cantwell Richmond, Virginia Copyright © 2017 by the Congress of Neurological Surgeons This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurosurgery Oxford University Press

A Retrospective Propensity Score-Matched Early Thromboembolic Event Analysis of Prothrombin Complex Concentrate vs Fresh Frozen Plasma for Warfarin Reversal Prior to Emergency Neurosurgical Procedures

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Congress of Neurological Surgeons
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Copyright © 2017 by the Congress of Neurological Surgeons
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0148-396X
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1524-4040
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10.1093/neuros/nyx327
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Abstract

Abstract BACKGROUND Reversal of therapeutic anticoagulation prior to emergency neurosurgical procedures is required in the setting of intracranial hemorrhage. Multifactor prothrombin complex concentrate (PCC) promises rapid efficacy but may increase the probability of thrombotic complications compared to fresh frozen plasma (FFP). OBJECTIVE To compare the rate of thrombotic complications in patients treated with PCC or FFP to reverse therapeutic anticoagulation prior to emergency neurosurgical procedures in the setting of intracranial hemorrhage at a level I trauma center. METHODS Sixty-three consecutive patients on warfarin therapy presenting with intracranial hemorrhage who received anticoagulation reversal prior to emergency neurosurgical procedures were retrospectively identified between 2007 and 2016. They were divided into 2 cohorts based on reversal agent, either PCC (n = 28) or FFP (n = 35). The thrombotic complications rates within 72 h of reversal were compared using the χ2 test. A multivariate propensity score matching analysis was used to limit the threat to interval validity from selection bias arising from differences in demographics, laboratory values, history, and clinical status. RESULTS Thrombotic complications were uncommon in this neurosurgical population, occurring in 1.59% (1/63) of treated patients. There was no significant difference in the thrombotic complication rate between groups, 3.57% (1/28; PCC group) vs 0% (0/35; FFP group). Propensity score matching analysis validated this finding after controlling for any selection bias. CONCLUSION In this limited sample, thrombotic complication rates were similar between use of PCC and FFP for anticoagulation reversal in the management of intracranial hemorrhage prior to emergency neurosurgical procedures. Prothrombin complex concentrate, Fresh frozen plasma, Anticoagulation reversal, Warfarin, Thrombotic complication, Emergency neurosurgical procedure, Propensity score matching ABBREVIATIONS ABBREVIATIONS FFP fresh frozen plasma INR International Normalized Ratio PCC prothrombin complex concentrate PSM propensity score matching Warfarin is an oral vitamin K antagonist commonly used to reduce the risk of stroke or systemic embolism in patients with atrial fibrillation and for the treatment and prevention of venous thromboembolism.1 Patients taking warfarin are at increased risk of clinical and radiographic deterioration following spontaneous or traumatic intracranial hemorrhage.2 Accordingly, pharmacologic reversal of warfarin-induced anticoagulation is indicated in the management of intracranial hemorrhage. However, clinicians must consider what is the safest and most expedient method for pharmacological reversal in their daily practice.3,4 Traditional pharmacological reversal of anticoagulation begins with vitamin K administration and the infusion of thawed plasma or fresh frozen plasma (FFP).3 Vitamin K is a necessary cofactor for the production of the vitamin K-dependent clotting factors (II, VII, IX, X) and proteins C and S, while FFP contains all soluble coagulation factors and proteins. The therapeutic effect of FFP administration is monitored by a reduction in the International Normalized Ratio (INR).5,6 Unfortunately, several drawbacks of FFP administration temper enthusiasm for its universal use. For example, FFP is associated with transfusion-related acute lung injury, circulatory overload, and allergic and anaphylactic reactions.7,8 Furthermore, the therapeutic effect of FFP reversal is gradual and may delay urgent neurosurgical intervention. An alternative method of anticoagulation reversal is administration of prothrombin complex concentrate (PCC). PCC generally contains clotting factors II, VII, IX, and X, with or without the addition of proteins C and S, in combinations that vary by formulary. For instance, 4-factor PCC (Kcentra®, CSL Behring, King of Prussia, Pennsylvania) contains a clinically significant amount of factor VII, while 3-factor PCC does not.9,10 Recent randomized controlled trials have demonstrated either superiority or noninferiority of PCC over FFP in terms of INR reversal and hemostatic efficacy in patients with major bleeding, patients undergoing semi-elective heart surgery, or in patients undergoing other urgent surgery.11-13 Similarly, in neurosurgical populations, PCC is effective14-19 and superior to FFP for both achieving INR reversal and time to reversal.5,20-28 Remarkably, PCC has not been directly compared to FFP in the patients requiring emergency neurosurgical procedures where urgent reversal of anticoagulation is critical. Evidence supporting the role of PCC in patients with warfarin-associated intracranial hemorrhage was found in a recent study by Steiner et al.28 This randomized controlled trial measured achievement of INR normalization and hematoma volumes in anticoagulated patients diagnosed with intracranial hemorrhage on CT scan. The PCC-treated group was noted to achieve a higher rate of INR normalization than the FFP-treated group. Additionally, superior INR normalization seemed to be associated with smaller hematoma expansion. In the FFP group, 5 of the 8 deaths occurred due to hematoma expansion, all within 48 h. Within 72 h of reversal, there were 3 thromboembolic events, 1 in the FFP group (n = 23) and 2 in the PCC group (n = 27). While this study was pioneering, it leaves unanswered the question of thrombotic complication rates in anticoagulated patients presenting with intracranial hemorrhage requiring emergency neurosurgical procedures. We sought to address this knowledge gap, which has direct relevance to neurosurgeons. We employ a multivariate propensity score matching (PSM) analysis to permit robust, unbiased comparisons between the PCC and FFP cohorts.29,30 PSM limits the threat to interval validity from selection bias arising from differences in underlying characteristics. In addition, PSM is superior to more traditional methods such as multiple linear regression because it does not extrapolate using assumptions of linearity if there are significant differences in underlying characteristics between the control and treatment groups. PSM analysis has only been applied sparsely in studies investigating PCC31,32, despite the advantages that this statistical model affords. METHODS Study Design and Patient Selection We performed a retrospective cohort analysis of acute thrombotic complications in anticoagulated patients who required urgent reversal with PCC or FFP for the indication of emergency neurosurgical procedure in the setting of intracranial hemorrhage. We identified 2 cohorts of patients on warfarin therapy presenting with intracranial hemorrhage who underwent anticoagulation reversal and a subsequent neurosurgical procedure between 2007 and 2016 at a level I trauma center: (1) patients who were given PCC (n = 28) and (2) patients who were given FFP alone (n = 35). All patients also received vitamin K. Indications for emergency neurosurgical procedure were in accordance with published guidelines. Appropriate Institutional Review Board approval and a waiver of informed patient consent were obtained. The primary endpoint was the incidence of thrombotic complications within 72 h of anticoagulation reversal. Thrombotic complications were defined as deep vein thrombosis, pulmonary embolism, ischemic stroke, or myocardial infarction as documented by the clinical record, radiological, and laboratory studies. Seventy-two hours defines the window for early postoperative complications at our institution. It provides a reliable metric to measure thrombotic events related to urgent use of reversal agents while simultaneously minimizing contamination of these events with the occurrence of thrombotic events associated with prolonged recumbency. This interval also allows comparison to other studies that report data at this point.28 Secondary endpoints included INR reversal, mortality rate during hospitalization, and rate of pulmonary complications within 1 wk of treatment. Pulmonary complications were defined as pneumonia, pneumothorax, respiratory distress requiring mechanical ventilation, and pulmonary edema and effusion documented in the clinical record and validated by radiological studies. Statistical Methods We used a multivariate PSM analysis to correct for any bias between groups. The PSM model identified the control group (FFP) that was most similar to treatment group (PCC) across the following factors which may affect thrombotic complication rates: age, gender, INR pretreatment and post-treatment, trauma, altered mental status, and the existence of heart failure.29,30,33 For trauma, altered mental status, and heart failure, each patient was assigned 1 point per variable. A composite score ranging from 0 to 3 was assigned to each patient based on the sum of these 3 variables. To perform the PSM analysis, we applied the following multivariate logistic regression model on all patients in both groups (n = 63). The dependent variable ‘group’ (PCC or FFP) was predicted by the following independent variables: age, gender, INR pretreatment and post-treatment, and composite score (trauma, altered mental status, heart failure). The resulting model was then used to assign each patient with a probability that they would be assigned to the PCC group based on these factors. For each patient in the PCC group, we identified a patient in the FFP group that was most closely matched in these factors (ie, the probability assigned by the regression model). Similar statistical methods have been validated in retrospective cohort studies.34 Two-sample t-tests and χ2 tests were used to compare continuous and categorical distributions, respectively. A P-value of < .05 was considered to be significant. RESULTS Patient Demographics and Risk Factors Among the 28 patients in the PCC cohort, the most common neurosurgical indications were intraparenchymal hemorrhage (n = 15), subdural hemorrhage (n = 10), and subarachnoid hemorrhage (n = 3). The most common neurosurgical procedures for the PCC cohort were craniotomy (n = 12), decompressive craniectomy (n = 9), and external ventricular drain (n = 5). As for the 35 patients in the FFP cohort, the most common neurosurgical indications were subdural hemorrhage (n = 24) and intraparenchymal hemorrhage (n = 11). The most common neurosurgical procedures for the FFP cohort were craniotomy (n = 27) and decompressive craniectomy (n = 7; Figure 1 and Table 1). FIGURE 1. View largeDownload slide Representative axial head CT scans for PCC and FFP groups showing the most common neurosurgical indications—subdural hemorrhage and intraparenchymal hemorrhage. IPH, intraparenchymal hemorrhage; SDH, subdural hemorrhage. FIGURE 1. View largeDownload slide Representative axial head CT scans for PCC and FFP groups showing the most common neurosurgical indications—subdural hemorrhage and intraparenchymal hemorrhage. IPH, intraparenchymal hemorrhage; SDH, subdural hemorrhage. TABLE 1. Neurosurgical Indications and Procedures for Treatment Group (PCC) and Control Group (FFP only) PCC (n = 28) FFP (n = 35) Neurosurgical indications Neurosurgical procedure Neurosurgical indications Neurosurgical procedure Intraparenchymal hemorrhage (15) Craniotomy (12) Subdural hemorrhage (24) Craniotomy (27) Subdural hemorrhage (10) Decompressive craniectomy (9) Intraparenchymal hemorrhage (11) Decompressive craniectomy (7) Subarachnoid hemorrhage (3) External ventricular drain (5) External ventricular drain (1) Endovascular embolization (2) PCC (n = 28) FFP (n = 35) Neurosurgical indications Neurosurgical procedure Neurosurgical indications Neurosurgical procedure Intraparenchymal hemorrhage (15) Craniotomy (12) Subdural hemorrhage (24) Craniotomy (27) Subdural hemorrhage (10) Decompressive craniectomy (9) Intraparenchymal hemorrhage (11) Decompressive craniectomy (7) Subarachnoid hemorrhage (3) External ventricular drain (5) External ventricular drain (1) Endovascular embolization (2) View Large TABLE 1. Neurosurgical Indications and Procedures for Treatment Group (PCC) and Control Group (FFP only) PCC (n = 28) FFP (n = 35) Neurosurgical indications Neurosurgical procedure Neurosurgical indications Neurosurgical procedure Intraparenchymal hemorrhage (15) Craniotomy (12) Subdural hemorrhage (24) Craniotomy (27) Subdural hemorrhage (10) Decompressive craniectomy (9) Intraparenchymal hemorrhage (11) Decompressive craniectomy (7) Subarachnoid hemorrhage (3) External ventricular drain (5) External ventricular drain (1) Endovascular embolization (2) PCC (n = 28) FFP (n = 35) Neurosurgical indications Neurosurgical procedure Neurosurgical indications Neurosurgical procedure Intraparenchymal hemorrhage (15) Craniotomy (12) Subdural hemorrhage (24) Craniotomy (27) Subdural hemorrhage (10) Decompressive craniectomy (9) Intraparenchymal hemorrhage (11) Decompressive craniectomy (7) Subarachnoid hemorrhage (3) External ventricular drain (5) External ventricular drain (1) Endovascular embolization (2) View Large Before PSM (Table 2), the patients who received PCC (n = 28) had a mean age of 64.3 yr (range 27-88) and were 60.7% male (n = 17). The patients in the FFP group (n = 35) had a mean age of 70.4 (range 40-97) and were 62.8% male (n = 22). There was a nonsignificant trend toward younger age in the PCC group compared with the FFP (t-test, P = .10). With regard to established risk factors for thrombosis in neurosurgical patients, patients in the PCC group less commonly presented with trauma (21.4%, n = 6) compared with patients in the FFP group (62.8%, n = 22; χ2 test, P = .004). We observed no significant differences in frequency of heart failure in the PCC group (14.3%, n = 4) and in the FFP group (17.1%, n = 6; χ2 test, P > .5). Patients in the PCC group presented with altered mental status in 75% of cases (n = 21), whereas those in the FFP group presented with altered mental status in 60% of cases (n = 21; χ2 test, P = .21) TABLE 2. Patient Characteristics and Complications for Treatment Group (PCC) and Control Group (FFP Only) PCC (n = 28) FFP (n = 35) P-value 95% confidence interval Age 64.3 (±15.5) yr 70.4 (± 13.3) yr .10 (–13.4 to 1.20) Gender 60.7% male (n = 17) 62.8% male (n = 22) >.5 (–0.26 to 0.22) Trauma 21.4% (n = 6) 57.14% (n = 20) .004 (–0.58 to –0.13) Heart failure 14.3% (n = 4) 17.1% (n = 6) >.5 (–0.21 to 0.15) Altered mental status 75% (n = 21) 60.0% (n = 21) .21 (–0.08 to 0.38) INR pretreatment 3.36 ± 1.85 3.11 ± 1.90 >.5 (–0.70 to 1.21) INR post-treatment 1.36 ± .31 1.37 ± 0.22 >.5 (–0.14 to 0.12) Mortality during hospitalization 17.9% (n = 5) 17.1% (n = 6) >.5 (–0.18 to 0.20) Pulmonary complications 39.3% (n = 11) 11.4% (n = 4) .009 (0.07 to 0.49) Number of patients with thrombotic complications (within 72 h) 3.57% (n = 1) 0% (n = 0) .23 (–0.03 to 0.10) PCC (n = 28) FFP (n = 35) P-value 95% confidence interval Age 64.3 (±15.5) yr 70.4 (± 13.3) yr .10 (–13.4 to 1.20) Gender 60.7% male (n = 17) 62.8% male (n = 22) >.5 (–0.26 to 0.22) Trauma 21.4% (n = 6) 57.14% (n = 20) .004 (–0.58 to –0.13) Heart failure 14.3% (n = 4) 17.1% (n = 6) >.5 (–0.21 to 0.15) Altered mental status 75% (n = 21) 60.0% (n = 21) .21 (–0.08 to 0.38) INR pretreatment 3.36 ± 1.85 3.11 ± 1.90 >.5 (–0.70 to 1.21) INR post-treatment 1.36 ± .31 1.37 ± 0.22 >.5 (–0.14 to 0.12) Mortality during hospitalization 17.9% (n = 5) 17.1% (n = 6) >.5 (–0.18 to 0.20) Pulmonary complications 39.3% (n = 11) 11.4% (n = 4) .009 (0.07 to 0.49) Number of patients with thrombotic complications (within 72 h) 3.57% (n = 1) 0% (n = 0) .23 (–0.03 to 0.10) Errors shown are standard deviations. View Large TABLE 2. Patient Characteristics and Complications for Treatment Group (PCC) and Control Group (FFP Only) PCC (n = 28) FFP (n = 35) P-value 95% confidence interval Age 64.3 (±15.5) yr 70.4 (± 13.3) yr .10 (–13.4 to 1.20) Gender 60.7% male (n = 17) 62.8% male (n = 22) >.5 (–0.26 to 0.22) Trauma 21.4% (n = 6) 57.14% (n = 20) .004 (–0.58 to –0.13) Heart failure 14.3% (n = 4) 17.1% (n = 6) >.5 (–0.21 to 0.15) Altered mental status 75% (n = 21) 60.0% (n = 21) .21 (–0.08 to 0.38) INR pretreatment 3.36 ± 1.85 3.11 ± 1.90 >.5 (–0.70 to 1.21) INR post-treatment 1.36 ± .31 1.37 ± 0.22 >.5 (–0.14 to 0.12) Mortality during hospitalization 17.9% (n = 5) 17.1% (n = 6) >.5 (–0.18 to 0.20) Pulmonary complications 39.3% (n = 11) 11.4% (n = 4) .009 (0.07 to 0.49) Number of patients with thrombotic complications (within 72 h) 3.57% (n = 1) 0% (n = 0) .23 (–0.03 to 0.10) PCC (n = 28) FFP (n = 35) P-value 95% confidence interval Age 64.3 (±15.5) yr 70.4 (± 13.3) yr .10 (–13.4 to 1.20) Gender 60.7% male (n = 17) 62.8% male (n = 22) >.5 (–0.26 to 0.22) Trauma 21.4% (n = 6) 57.14% (n = 20) .004 (–0.58 to –0.13) Heart failure 14.3% (n = 4) 17.1% (n = 6) >.5 (–0.21 to 0.15) Altered mental status 75% (n = 21) 60.0% (n = 21) .21 (–0.08 to 0.38) INR pretreatment 3.36 ± 1.85 3.11 ± 1.90 >.5 (–0.70 to 1.21) INR post-treatment 1.36 ± .31 1.37 ± 0.22 >.5 (–0.14 to 0.12) Mortality during hospitalization 17.9% (n = 5) 17.1% (n = 6) >.5 (–0.18 to 0.20) Pulmonary complications 39.3% (n = 11) 11.4% (n = 4) .009 (0.07 to 0.49) Number of patients with thrombotic complications (within 72 h) 3.57% (n = 1) 0% (n = 0) .23 (–0.03 to 0.10) Errors shown are standard deviations. View Large The INR pretreatment and post-treatment was documented (Table 2). The groups were well matched on presenting INR (t-test, P > .5). The therapeutic effect of both PCC and FFP was validated by measuring post-treatment INR, which was significantly lower than presenting INR (t-test, P < .001). There were no differences in post-treatment INR between groups (t-test, P > .5), confirming that both groups achieved anticoagulation reversal. Complications The overall thrombotic complication rate within 72 h of anticoagulation reversal was 3.57% (n = 1/28) and 0% (n = 0/35) for the PCC and FFP groups, respectively (Table 2). There was no significant difference in the thrombotic complication rates (χ2 test, P = .23). The rate of pulmonary complications within 1 wk of treatment was higher for the PCC group (39.3%, n = 11) than that for the FFP group (11.4%; n = 4; χ2 test, P = .009; Table 2). There was no difference in mortality during hospitalization between groups (PCC 17.9%, n = 5; FFP 17.1%, n = 6; χ2 test, P > .5). Patient Demographics and Risk Factors— PSM We performed a PSM analysis to match the PCC and FFP cohorts (28 patients each) according to age, gender, INR pretreatment and post-treatment, and several factors that are known to predispose neurosurgical patients to thrombosis including trauma, altered mental status, and preexisting heart failure (Table 3). After performing this analysis, we found that both age and gender differences from the unmatched analysis were diminished (t-test and χ2 test, P > .2). As for the established risk factors for thrombosis in neurosurgical patients, we did not observe a significant difference in the rate of heart failure (χ2 test, P > .5) and altered mental status (χ2 test, P = .09). There was a significant difference in the rate of trauma between the 2 patient cohorts (χ2 test, P = .013). PSM enabled mitigation of underlying differences between the 2 cohorts, particularly differences in age and gender, which make statistical analysis prone to selection bias. TABLE 3. Patient Characteristics and Complications for Treatment Group (PCC) and Control Group (FFP Only) After PSM With Age, Gender, INR Pretreatment, INR Post-treatment, and Composite Score (Trauma, Heart Failure, and Altered Mental Status) PCC (n = 28) FFP (n = 28) P-value 95% confidence interval Age 64.3 (± 15.5) yr 67.7 (± 12.7) yr .23 (–8.99 to 2.28) Gender 60.7% male (n = 17) 60.7% male (n = 17) >.5 (−0.26 to 0.26) Trauma 21.4% (n = 6) 53.5% (n = 15) .013 (–0.56 to –0.08) Heart failure 14.3% (n = 4) 10.7% (n = 3) >.5 (–0.14 to 0.21) Altered mental status 75% (n = 21) 53.57% (n = 15) .09 (–0.03 to 0.46) INR pretreatment 3.36 ± 1.85 2.92 ± 1.64 .32 (–0.46 to 1.34) INR post-treatment 1.36 ± .31 1.33 ± 0.18 >.5 (–0.12 to 0.17) Mortality during hospitalization 17.9% (n = 5) 14.3% (n = 4) >.5 (–0.16 to 0.23) Pulmonary complications 39.3% (n = 11) 14.2% (n = 4) .035 (0.03 to 0.47) Number of patients with thrombotic complications (within 72 h) 3.57% (n = 1) 0% (n = 0) .31 (–0.03 to 0.10) PCC (n = 28) FFP (n = 28) P-value 95% confidence interval Age 64.3 (± 15.5) yr 67.7 (± 12.7) yr .23 (–8.99 to 2.28) Gender 60.7% male (n = 17) 60.7% male (n = 17) >.5 (−0.26 to 0.26) Trauma 21.4% (n = 6) 53.5% (n = 15) .013 (–0.56 to –0.08) Heart failure 14.3% (n = 4) 10.7% (n = 3) >.5 (–0.14 to 0.21) Altered mental status 75% (n = 21) 53.57% (n = 15) .09 (–0.03 to 0.46) INR pretreatment 3.36 ± 1.85 2.92 ± 1.64 .32 (–0.46 to 1.34) INR post-treatment 1.36 ± .31 1.33 ± 0.18 >.5 (–0.12 to 0.17) Mortality during hospitalization 17.9% (n = 5) 14.3% (n = 4) >.5 (–0.16 to 0.23) Pulmonary complications 39.3% (n = 11) 14.2% (n = 4) .035 (0.03 to 0.47) Number of patients with thrombotic complications (within 72 h) 3.57% (n = 1) 0% (n = 0) .31 (–0.03 to 0.10) Errors shown are standard deviations. View Large TABLE 3. Patient Characteristics and Complications for Treatment Group (PCC) and Control Group (FFP Only) After PSM With Age, Gender, INR Pretreatment, INR Post-treatment, and Composite Score (Trauma, Heart Failure, and Altered Mental Status) PCC (n = 28) FFP (n = 28) P-value 95% confidence interval Age 64.3 (± 15.5) yr 67.7 (± 12.7) yr .23 (–8.99 to 2.28) Gender 60.7% male (n = 17) 60.7% male (n = 17) >.5 (−0.26 to 0.26) Trauma 21.4% (n = 6) 53.5% (n = 15) .013 (–0.56 to –0.08) Heart failure 14.3% (n = 4) 10.7% (n = 3) >.5 (–0.14 to 0.21) Altered mental status 75% (n = 21) 53.57% (n = 15) .09 (–0.03 to 0.46) INR pretreatment 3.36 ± 1.85 2.92 ± 1.64 .32 (–0.46 to 1.34) INR post-treatment 1.36 ± .31 1.33 ± 0.18 >.5 (–0.12 to 0.17) Mortality during hospitalization 17.9% (n = 5) 14.3% (n = 4) >.5 (–0.16 to 0.23) Pulmonary complications 39.3% (n = 11) 14.2% (n = 4) .035 (0.03 to 0.47) Number of patients with thrombotic complications (within 72 h) 3.57% (n = 1) 0% (n = 0) .31 (–0.03 to 0.10) PCC (n = 28) FFP (n = 28) P-value 95% confidence interval Age 64.3 (± 15.5) yr 67.7 (± 12.7) yr .23 (–8.99 to 2.28) Gender 60.7% male (n = 17) 60.7% male (n = 17) >.5 (−0.26 to 0.26) Trauma 21.4% (n = 6) 53.5% (n = 15) .013 (–0.56 to –0.08) Heart failure 14.3% (n = 4) 10.7% (n = 3) >.5 (–0.14 to 0.21) Altered mental status 75% (n = 21) 53.57% (n = 15) .09 (–0.03 to 0.46) INR pretreatment 3.36 ± 1.85 2.92 ± 1.64 .32 (–0.46 to 1.34) INR post-treatment 1.36 ± .31 1.33 ± 0.18 >.5 (–0.12 to 0.17) Mortality during hospitalization 17.9% (n = 5) 14.3% (n = 4) >.5 (–0.16 to 0.23) Pulmonary complications 39.3% (n = 11) 14.2% (n = 4) .035 (0.03 to 0.47) Number of patients with thrombotic complications (within 72 h) 3.57% (n = 1) 0% (n = 0) .31 (–0.03 to 0.10) Errors shown are standard deviations. View Large We also calculated the INR pretreatment and post-treatment for both PCC and FFP groups (Table 3). Patients who received PCC presented with a similar INR compared with patients who received FFP (t-test, P = .32). Both groups had a significantly decreased INR after administration of PCC or FFP (t-test, P < .001), with no significant difference in INR post-treatment between the 2 groups (t-test, P > .5; Figure 2). FIGURE 2. View largeDownload slide INR pretreatment and INR post-treatment after PSM, where treatment is administration of PCC or FFP. Error bars indicate standard deviation. No significant difference between PCC and FFP groups for either INR pretreatment or INR post-treatment. Significant reduction in INR after administration of either PCC or FFP. *P < .001, 2 sample t-test. FIGURE 2. View largeDownload slide INR pretreatment and INR post-treatment after PSM, where treatment is administration of PCC or FFP. Error bars indicate standard deviation. No significant difference between PCC and FFP groups for either INR pretreatment or INR post-treatment. Significant reduction in INR after administration of either PCC or FFP. *P < .001, 2 sample t-test. Complications—PSM The overall thrombotic complication rate within 72 h of anticoagulation reversal was 3.57% (n = 1/28) for the PCC group and 0% (n = 0/28) for the FFP group (Figure 3 and Table 3). There was no significant difference in the thrombotic complication rates (χ2 test, P = .31). We can say with 95% confidence that the difference in the thrombotic complication rates between PCC and FFP is between –3.3% and 10.5%. FIGURE 3. View largeDownload slide Rate of thrombotic complications (within 72 h of anticoagulation reversal) and rate of pulmonary complications (within 1 wk of treatment) for PCC and FFP groups after propensity score matching. No significant difference in thrombotic complication rate (P = .31, χ2 test). Higher rate of pulmonary complications for PCC group compared with FFP group. *P = .035, χ2 test. FIGURE 3. View largeDownload slide Rate of thrombotic complications (within 72 h of anticoagulation reversal) and rate of pulmonary complications (within 1 wk of treatment) for PCC and FFP groups after propensity score matching. No significant difference in thrombotic complication rate (P = .31, χ2 test). Higher rate of pulmonary complications for PCC group compared with FFP group. *P = .035, χ2 test. The rate of pulmonary complications within 1 wk of treatment was higher for the PCC group (39.3%; n = 11) than the FFP group (14.2%, n = 4; χ2 test, p = 0.035; Figure 3 and Table 3). In the PCC group, pulmonary edema/pleural effusion accounted for 3 pulmonary complications, pneumonia for 3, general respiratory distress requiring mechanical ventilation for 3, and pneumothorax for 2. As for the FFP group, pulmonary edema/pleural effusion and pneumonia accounted for 2 pulmonary complications each. The sole thrombotic complication within the PCC group was a saddle pulmonary embolism. In this case, the neurosurgical indication was subarachnoid hemorrhage and the emergency neurosurgical procedure performed was endovascular embolization (Figure 4 and Table 4). FIGURE 4. View largeDownload slide Serial axial chest CT scan with arrows pointing to saddle pulmonary embolism, the sole thrombotic complication observed in the PCC group. FIGURE 4. View largeDownload slide Serial axial chest CT scan with arrows pointing to saddle pulmonary embolism, the sole thrombotic complication observed in the PCC group. TABLE 4. Thrombotic Complications for Treatment Group (PCC) and Control Group (FFP only) Thrombotic complication PCC or FFP Age Gender Neurosurgical indication Neurosurgical procedure Saddle pulmonary embolism PCC 85 Female Subarachnoid hemorrhage Endovascular embolization Thrombotic complication PCC or FFP Age Gender Neurosurgical indication Neurosurgical procedure Saddle pulmonary embolism PCC 85 Female Subarachnoid hemorrhage Endovascular embolization View Large TABLE 4. Thrombotic Complications for Treatment Group (PCC) and Control Group (FFP only) Thrombotic complication PCC or FFP Age Gender Neurosurgical indication Neurosurgical procedure Saddle pulmonary embolism PCC 85 Female Subarachnoid hemorrhage Endovascular embolization Thrombotic complication PCC or FFP Age Gender Neurosurgical indication Neurosurgical procedure Saddle pulmonary embolism PCC 85 Female Subarachnoid hemorrhage Endovascular embolization View Large We examined mortality data for all admissions. There were no differences in mortality rates during hospitalization between the groups. Mortality rate for the PCC group (17.9%, n = 5) was similar compared with the FFP group (14.3%, n = 4; χ2 test, P > .5). DISCUSSION Thrombotic Complications Data on the rate of thrombotic complications due to PCC in operative neurosurgical patients are scarce but immediately relevant to current neurosurgical practice. In this retrospective cohort study of 65 patients from 2007 to 2016 at a level 1 trauma center, the incidence of thrombotic complications between groups receiving PCC or FFP for anticoagulation reversal in the setting of intracranial hemorrhage prior to an emergency neurosurgical procedure was similar. Below we consider these results in light of the literature regarding thrombotic complications in surgical populations and discuss the efficacy of reversal afforded by PCC. The rate of thrombotic complications associated with PCC found in this study is consistent with the few reports that have investigated patients on warfarin therapy undergoing emergency neurosurgical procedures (Table 5).14,35-38 The reported rate of thrombotic complications due to PCC in nonoperative neurosurgical patients ranges between 0% and 13%.14,15,17-19,22,26,28,32 In a recent randomized controlled trial of all anticoagulated patients presenting with intracranial hemorrhage, Steiner et al28 reported a rate of 7.4% (PCC, n = 2/27) and 4.3% (FFP, n = 1/23) within 72 h of INR correction. In a similar patient population, Woo et al26 observed no cases of thrombotic complications, while Frontera et al22 observed 12.5% (PCC, n = 2/16) and 16% (FFP, n = 4/25), respectively. In spontaneous coagulopathy due to traumatic brain injury, reported rates are 4% (PCC, n = 3/74)) and 3.4% (FFP, n = 5/148).32 Including both operative and nonoperative neurosurgical cases, thrombotic complications following anticoagulation reversal appear uncommon and similar between the reversal agents. TABLE 5. Use of PCC for Anticoagulation Reversal of Elevated INR Prior to Emergency Surgery in Previous Studies Author and year Study design n Surgical population Primary outcome Secondary outcome Thrombotic complication rate (n) Sridharan et al 201644 Retrospective cohort 52 Emergency surgical procedure (mixed) INR reversal Clinical safety 13% (7) Beynon et al 201535 Retrospective cohort 9 Aneurysmal subarachnoid hemorrhage INR reversal Time to surgical intervention 0% (0) Beynon et al 201536 Retrospective cohort 5 Emergency brain tumor pathology INR reversal Time to surgical intervention 0% (0) Quick et al 201550 Retrospective cohort 41 Emergency surgical procedure (mixed) INR reversal Clinical safety 2.4% (1) Goldstein et al 201513 Randomized controlled trial 90 Emergency surgical procedure (mixed) Effective hemostasis INR reversal 7% (6) Beynon et al 201437 Retrospective cohort 18 Emergency spinal pathology INR reversal Time to surgical intervention 5.6% (1) Cabral et al 201314 Retrospective cohort 9 Intracranial hemorrhage INR reversal Clinical safety 0% (0) Majeed et al 201247 Prospective cohort 44 Emergency surgical procedure (mixed) Clinical safety Effective hemostasis 2.3% (1) Demeyere et al 201011 Randomized controlled trial 20 Heart surgery w/ cardiopulmonary bypass INR reversal Time to INR reversal 0% (0) Pabinger et al 200848 Prospective cohort 26 Emergency surgical procedure (mixed) INR reversal Effective hemostasis 0% (0) Riess et al 200749 Prospective cohort 57 Emergency surgical procedure (mixed) INR reversal Clotting factor levels 0% (0) Vigue et al 200738 Prospective cohort 18 Intracranial hemorrhage INR reversal Clinical safety 0% (0) Lubetsky et al 200457 Prospective cohort 10 Emergency surgical procedure (mixed) INR reversal Clinical safety 0% (0) Author and year Study design n Surgical population Primary outcome Secondary outcome Thrombotic complication rate (n) Sridharan et al 201644 Retrospective cohort 52 Emergency surgical procedure (mixed) INR reversal Clinical safety 13% (7) Beynon et al 201535 Retrospective cohort 9 Aneurysmal subarachnoid hemorrhage INR reversal Time to surgical intervention 0% (0) Beynon et al 201536 Retrospective cohort 5 Emergency brain tumor pathology INR reversal Time to surgical intervention 0% (0) Quick et al 201550 Retrospective cohort 41 Emergency surgical procedure (mixed) INR reversal Clinical safety 2.4% (1) Goldstein et al 201513 Randomized controlled trial 90 Emergency surgical procedure (mixed) Effective hemostasis INR reversal 7% (6) Beynon et al 201437 Retrospective cohort 18 Emergency spinal pathology INR reversal Time to surgical intervention 5.6% (1) Cabral et al 201314 Retrospective cohort 9 Intracranial hemorrhage INR reversal Clinical safety 0% (0) Majeed et al 201247 Prospective cohort 44 Emergency surgical procedure (mixed) Clinical safety Effective hemostasis 2.3% (1) Demeyere et al 201011 Randomized controlled trial 20 Heart surgery w/ cardiopulmonary bypass INR reversal Time to INR reversal 0% (0) Pabinger et al 200848 Prospective cohort 26 Emergency surgical procedure (mixed) INR reversal Effective hemostasis 0% (0) Riess et al 200749 Prospective cohort 57 Emergency surgical procedure (mixed) INR reversal Clotting factor levels 0% (0) Vigue et al 200738 Prospective cohort 18 Intracranial hemorrhage INR reversal Clinical safety 0% (0) Lubetsky et al 200457 Prospective cohort 10 Emergency surgical procedure (mixed) INR reversal Clinical safety 0% (0) View Large TABLE 5. Use of PCC for Anticoagulation Reversal of Elevated INR Prior to Emergency Surgery in Previous Studies Author and year Study design n Surgical population Primary outcome Secondary outcome Thrombotic complication rate (n) Sridharan et al 201644 Retrospective cohort 52 Emergency surgical procedure (mixed) INR reversal Clinical safety 13% (7) Beynon et al 201535 Retrospective cohort 9 Aneurysmal subarachnoid hemorrhage INR reversal Time to surgical intervention 0% (0) Beynon et al 201536 Retrospective cohort 5 Emergency brain tumor pathology INR reversal Time to surgical intervention 0% (0) Quick et al 201550 Retrospective cohort 41 Emergency surgical procedure (mixed) INR reversal Clinical safety 2.4% (1) Goldstein et al 201513 Randomized controlled trial 90 Emergency surgical procedure (mixed) Effective hemostasis INR reversal 7% (6) Beynon et al 201437 Retrospective cohort 18 Emergency spinal pathology INR reversal Time to surgical intervention 5.6% (1) Cabral et al 201314 Retrospective cohort 9 Intracranial hemorrhage INR reversal Clinical safety 0% (0) Majeed et al 201247 Prospective cohort 44 Emergency surgical procedure (mixed) Clinical safety Effective hemostasis 2.3% (1) Demeyere et al 201011 Randomized controlled trial 20 Heart surgery w/ cardiopulmonary bypass INR reversal Time to INR reversal 0% (0) Pabinger et al 200848 Prospective cohort 26 Emergency surgical procedure (mixed) INR reversal Effective hemostasis 0% (0) Riess et al 200749 Prospective cohort 57 Emergency surgical procedure (mixed) INR reversal Clotting factor levels 0% (0) Vigue et al 200738 Prospective cohort 18 Intracranial hemorrhage INR reversal Clinical safety 0% (0) Lubetsky et al 200457 Prospective cohort 10 Emergency surgical procedure (mixed) INR reversal Clinical safety 0% (0) Author and year Study design n Surgical population Primary outcome Secondary outcome Thrombotic complication rate (n) Sridharan et al 201644 Retrospective cohort 52 Emergency surgical procedure (mixed) INR reversal Clinical safety 13% (7) Beynon et al 201535 Retrospective cohort 9 Aneurysmal subarachnoid hemorrhage INR reversal Time to surgical intervention 0% (0) Beynon et al 201536 Retrospective cohort 5 Emergency brain tumor pathology INR reversal Time to surgical intervention 0% (0) Quick et al 201550 Retrospective cohort 41 Emergency surgical procedure (mixed) INR reversal Clinical safety 2.4% (1) Goldstein et al 201513 Randomized controlled trial 90 Emergency surgical procedure (mixed) Effective hemostasis INR reversal 7% (6) Beynon et al 201437 Retrospective cohort 18 Emergency spinal pathology INR reversal Time to surgical intervention 5.6% (1) Cabral et al 201314 Retrospective cohort 9 Intracranial hemorrhage INR reversal Clinical safety 0% (0) Majeed et al 201247 Prospective cohort 44 Emergency surgical procedure (mixed) Clinical safety Effective hemostasis 2.3% (1) Demeyere et al 201011 Randomized controlled trial 20 Heart surgery w/ cardiopulmonary bypass INR reversal Time to INR reversal 0% (0) Pabinger et al 200848 Prospective cohort 26 Emergency surgical procedure (mixed) INR reversal Effective hemostasis 0% (0) Riess et al 200749 Prospective cohort 57 Emergency surgical procedure (mixed) INR reversal Clotting factor levels 0% (0) Vigue et al 200738 Prospective cohort 18 Intracranial hemorrhage INR reversal Clinical safety 0% (0) Lubetsky et al 200457 Prospective cohort 10 Emergency surgical procedure (mixed) INR reversal Clinical safety 0% (0) View Large PCC has been more extensively studied in the setting of general surgery where anticoagulation is often complicated by substantial blood loss. Rates tend be higher than in the isolated neurosurgical population. In studies that involve cases of major, life-threatening bleeding, use of PCC for anticoagulation reversal has been found to be associated with thrombotic complication rates up to 21%.39-46 For cases requiring any type of emergency surgery, PCC has a thrombotic complication rate of up to 13%.44,47-50 At least 3 randomized controlled trials have also been conducted that have compared the thrombotic complication rates of PCC vs FFP for anticoagulation reversal in general surgical patient populations. Cases requiring urgent cardiopulmonary bypass appear to have a lower rate of thrombotic complications than other emergency surgery, with an incidence of zero in the cohorts reported by Demeyere et al.11 Goldstein et al13 investigated patients undergoing urgent invasive surgery and found that thrombotic complication rates were similar amongst PCC (7%, n = 6/88) and FFP (8%, n = 7/88) (Table 5). Similarly, Sarode et al12 found that in patients with major bleeding, the safety profiles were no different between the 2 groups. A post hoc, pooled analysis of the Goldstein et al13 and Sarode et al12 studies found the thromboembolic complication rates to be 7.3% (n = 14/191) in the PCC group and 7.1% (n = 14/197) in the FFP group.51 Secondary Endpoints PCC is consistently superior to FFP with regard to achievement of INR normalization in neurosurgical patients.20-22,25,28 In these patients, PCC achieves normalization 2 to 4 times faster than FFP.5,24,26,27 PCC therefore enables faster time to operation.32 In cases not requiring emergency surgery, PCC appears to be associated with attenuated intracranial hematoma expansion.23 PCC also rapidly reverses anticoagulation in cases of major, life-threatening bleeding in general surgical populations.12,40,41,43,45,46,52-56 Other studies have demonstrated the efficacy of PCC in achieving rapid anticoagulation reversal in bleeding patients who are facing urgent surgery.11,13,44,47-49,57 Our data confirm that PCC effectively achieves INR reversal in the emergency neurosurgical patient population. In this study, patients who received PCC had a higher rate of pulmonary complications within 1 wk of treatment. Pneumonia, respiratory distress requiring mechanical ventilation, and pneumothorax accounted for this difference. Other pulmonary complications, such as pleural effusion and pulmonary edema, were similar between groups. The etiology of this finding is unclear. A putative benefit of avoiding FFP is the absence of volume overload and secondary pleural effusions or pulmonary edema.7,8 We did not observe an increased rate of these events in the FFP group, and somewhat surprisingly, noted an increase in other pulmonary complications in the PCC group. While we are unaware of other studies that have reported this finding, PCC has been associated with other conditions. In cardiac patients receiving PCC, a higher incidence of acute kidney injury has been noted.31 We find no evidence to suggest that PCC systematically affected end organ function, as mortality rates during hospitalization were similar between groups. PCC has also not been associated with prolonged hospitalization or intensive care unit stay.40,50,52 These factors will require further study in larger samples of anticoagulated patients requiring emergency neurosurgical procedures. Strengths The use of multivariate PSM analysis in this study adds robustness and novelty to the existing neurosurgical literature concerning reversal of anticoagulation. This analysis method controls for age, gender, and other risk factors that could influence the rate of thrombotic complications including trauma, altered mental status, and preexisting heart failure.29,30,33 The advantage of multivariate PSM analysis in this study is that it enabled matching of control and treatment patients based on age, gender, INR pretreatment and post-treatment, trauma, altered mental status, and preexisting heart failure. Thus, we can be confident that our statistical comparisons of the rate of thrombotic complications between cohorts are robust and unbiased. Limitations A number of factors must be weighed when evaluating the findings of the current investigation. This study examines an uncommon complication in a highly selective patient population—namely, anticoagulated patients requiring emergency neurosurgical procedures at a level I trauma center. To accrue as many patients as possible, we analyzed data over a 10-yr window. Given the low incidence of thrombotic complications observed, single institution studies are inherently underpowered to assess significant differences between relatively rare adverse events. Nevertheless, these results are immediately relevant to practicing clinicians who encounter anticoagulated patients requiring emergency cranial procedures. The importance of these findings and critical nature of patients involved justify larger studies in multicenter, prospective, randomized settings. To mitigate against any bias inherent in a retrospective study, we employed PSM analysis. However, a modest-sized cohort can never account for all confounding factors. For instance, even after applying PSM, there was a higher proportion of patients with exposure to trauma in the group receiving FFP. Other confounding variables could affect outcomes in this study. Intracranial hematoma volume, for example, has been measured as an independent variable in some studies as a marker of the therapeutic efficacy of anticoagulation reversal agents. Expanding hematomas may lead to worse prognosis by adversely affecting mental status and mortality and are thus a measure of disease severity.28 Since our study focuses on thrombotic complications following anticoagulation reversal, we did not measure hematoma volumes. Instead, we measured INR, mental status, and mortality during hospitalization as direct measures of disease severity. The absence of differences in any of these variables provides assurance that the treatment and control groups were well matched with regard to disease severity and overall survival. We also note that there was an unexpected higher rate of pulmonary complications in the PCC group. One might hypothesize the reverse, arguing that pulmonary complications would be more common in the FFP group, as FFP has been associated with higher risk of circulatory overload and transfusion-related acute lung injury.7,8 Finally, we assess early thrombotic complications within 72 h of anticoagulation reversal. This is an appropriate window to assess early thrombotic events that allows for direct comparison between groups and across other reports in the literature. This interval also optimizes the balance between capturing events related to urgent reversal and factors that lead to spontaneous thrombotic events that often occur in critically ill patients even without reversal. Prolonged recumbency, native thrombotic state, and the presence or absence of ongoing anticoagulation therapy are independent factors affecting thrombosis.28,58 Seventy-two hours represents an acceptable time point to assess early thrombotic events related to urgent use of reversal agents with minimal cross contamination of spontaneous thrombotic events. CONCLUSION In this limited sample, we found that thrombotic complications in neurosurgical patients presenting with intracranial hemorrhage who required rapid anticoagulation reversal and an emergency neurosurgical procedure were uncommon but not rare. Use of PCC for anticoagulation reversal prior to emergency neurosurgical procedures did not pose an increased risk of thrombotic complications when compared with FFP. Considering the importance of this topic and growing use of PCC in the neurosurgical emergency setting, future randomized controlled trials at multiple institutions with an intent-to-treat analysis are indicated. 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Google Scholar PubMed 51. Milling TJ Jr , Refaai MA , Goldstein JN et al. Thromboembolic events after vitamin K antagonist reversal with 4-factor prothrombin complex concentrate: exploratory analyses of two randomized, plasma-controlled studies . Ann Emerg Med . 2016 ; 67 ( 1 ): 96-105 e105 . Google Scholar CrossRef Search ADS 52. 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 ( 7-8 ): 869 - 875 . Google Scholar CrossRef Search ADS PubMed 53. Desmettre T , Dubart AE , Capellier G et al. Emergency reversal of anticoagulation: the real use of prothrombin complex concentrates: a prospective multicenter two year French study from 2006 to 2008 . Thromb Res . 2012 ; 130 ( 3 ): e178 - 183 . Google Scholar CrossRef Search ADS PubMed 54. Evans G , Luddington R , Baglin T . Beriplex P/N reverses severe warfarin-induced overanticoagulation immediately and completely in patients presenting with major bleeding . Br J Haematol . 2001 ; 115 ( 4 ): 998 - 1001 . Google Scholar CrossRef Search ADS PubMed 55. Yasaka M , Oomura M , Ikeno K , Naritomi H , Minematsu K . Effect of prothrombin complex concentrate on INR and blood coagulation system in emergency patients treated with warfarin overdose . Ann Hematol . 2003 ; 82 ( 2 ): 121 - 123 . Google Scholar CrossRef Search ADS PubMed 56. Yasaka M , Sakata T , Minematsu K , Naritomi H . Correction of INR by prothrombin complex concentrate and vitamin K in patients with warfarin related hemorrhagic complication . Thromb Res . 2002 ; 108 ( 1 ): 25 - 30 . Google Scholar CrossRef Search ADS PubMed 57. Lubetsky A , Hoffman R , Zimlichman R et al. Efficacy and safety of a prothrombin complex concentrate (Octaplex) for rapid reversal of oral anticoagulation . Thromb Res . 2004 ; 113 ( 6 ): 371 - 378 . Google Scholar CrossRef Search ADS PubMed 58. Pollack CV Jr , Reilly PA , Eikelboom J et al. Idarucizumab for dabigatran reversal . N Engl J Med . 2015 ; 373 ( 6 ): 511 - 520 . Google Scholar CrossRef Search ADS PubMed COMMENT This report is a retrospective analysis of neurosurgical patients who received either prothrombin complex concentrates (PCC) or fresh frozen plasma (FFP) for anticoagulation reversal for emergency neurosurgical procedures. The focus of their analysis is the rate of thrombotic complications within 72 hours in both groups. Over the ten-year period analyzed, there were 63 patients that met the inclusion criteria, 28 patients in the PCC cohort and 35 patients in the FFP cohort. A multivariate propensity score-matching analysis was utilized to minimize the effect of selection bias related to differences in demographics, lab values, history and clinical status. Only 1 of the 63 patients (1.59%) had a thrombotic complication. There was no difference in the thrombotic complication rate between the PCC group (1/28; 3.57%) and the FFP group (0/35; 0%). As compared to the patients in the FFP group, the patients in the PCC group had a higher rate of pulmonary complications, which included pneumonia, pneumothorax, respiratory distress requiring mechanical ventilation, pulmonary edema and pleural effusion. The cohorts were generally well matched with the exception that there were a higher number of trauma patients in the FFP group, however, this did not meet statistical significance (53.5% in the FFP group versus 21.4% in the PCC group; P = .013). Literature has demonstrated that PCC is superior to FFP in terms of INR normalization in neurosurgical patients. This study also provides evidence that administration of PCC does not increase the risk of thrombotic complications within 72 hours. However, one surprising finding in this study was the higher rate of pulmonary complications with the patients who received PCC. This is particularly notable given the well-known association of FFP, volume overload and pulmonary complications such as pleural effusions and pulmonary edema. I think this article begins to set the stage for a larger, multi-center study to further evaluate the use of PCC in the neurosurgical population. It will certainly be important to determine if PCC truly has a deleterious effect on the pulmonary system and, if so, to what extent. John Reavey-Cantwell Richmond, Virginia Copyright © 2017 by the Congress of Neurological Surgeons This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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NeurosurgeryOxford University Press

Published: Jun 29, 2017

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