378 Original article
Retrospective evaluation of the clinical use of prothrombin complex concentrate for the reversal of anticoagulation with vitamin K antagonists Jennifer L. Cruz, Mary C. Moss, Sheh-Li Chen, Kayla M. Hansen and Lindsey B. Amerine Anticoagulation reversal is a time-sensitive intervention for the prevention of life-threatening hemorrhagic events occurring with bleeding or surgery. Recommendations for the most effective and well tolerated reversal agent in these settings remain controversial. Several clinical guidelines for the management of intracerebral hemorrhage support use of prothrombin complex concentrates (PCCs) for the rapid reversal of warfarin-associated coagulopathy despite limited clinical data. The purpose of this investigation was to evaluate the efficacy and safety of PCC for the rapid reversal of anticoagulation by vitamin K antagonists for lifethreatening bleeding or emergent surgery and to assess adherence to a hospital-based protocol. A retrospective chart review was conducted of adult patients receiving PCC for the reversal of anticoagulation. Patients were assessed according to indication for anticoagulation reversal. The primary outcome measure was adequacy of international normalized ratio reversal. Other outcomes included cessation of bleeding, thrombotic complications, and adherence to an institutional-based guideline for the use of PCC. ICU and hospital length of stay and 30-day mortality was assessed. There were 70 patients included in this study. Mean international normalized ratio was reduced from 3.1 to
Background Anticoagulation reversal is a time-sensitive intervention for the prevention of life-threatening hemorrhagic events occurring with bleeding or surgery. Rapid reversal of warfarin anticoagulation is frequently required in emergency and acute care settings. Recommendations for the most effective and well tolerated reversal agent in these settings remain controversial. Conventional methods include infusions of thawed fresh frozen plasma (FFP) and the administration of vitamin K (phytonadione) [1,2]. However, both of these interventions have limitations. Vitamin K has a slow onset of action and FFP requires blood typing, thawing, and delivery which may delay its administration [1]. In addition, the use of FFP carries the potential for volume overload, infection, or transfusion-related acute lung injury. While both are effective and validated, the limitations of these agents prompt clinicians to explore alternative options. In particular, prothrombin complex concentrate (PCC) is an alternative agent with increasing use in the reversal of anticoagulation, despite limited clinical data. 0957-5235 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
1.6 following administration of at least one dose of PCC. Cessation of bleeding occurred in 65.7% of patients. Clinical assessment was unclear in 18.6%. Thrombotic complications were observed in 7.1% of patients. The 30-day mortality rate was found to be 14.3%. These data demonstrate that PCC is a well tolerated and effective method for anticoagulation reversal associated with a relatively high 30-day survival rate. Blood Coagul Fibrinolysis 26:378–382 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
Blood Coagulation and Fibrinolysis 2015, 26:378–382 Keywords: hemorrhage, prothrombin complex concentrate, warfarin international normalized ratio Department of Pharmacy, University of North Carolina Hospitals, Chapel Hill, North Carolina, USA Correspondence to Jennifer L. Cruz, PharmD, BCPS, University of North Carolina Hospitals, 101 Manning Drive CB #7600, Chapel Hill, NC 27514, USA Tel: +1 919 843 9558; e-mail: [email protected] Received 17 March 2014 Revised 18 September 2014 Accepted 26 November 2014
In contrast to the concerns surrounding FFP and vitamin K, PCC does not require blood typing cross-matching, is virally inactivated, does not pose a risk of fluid overload, and its preparation and administration may be done more quickly than FFP [3]. Prior to the recent approval of KCentra, which is the first US Food and Drug Administration (FDA)-approved four-factor preparation for the reversal of acquired coagulopathy due to vitamin K antagonists (VKAs), PCCs were available in the United States as only three-factor products containing therapeutic levels of nonactivated vitamin K-dependent factors (factor II, factor IX, and factor X) [4]. Profilnine SD (factor IX complex) is a low-purity three-factor PCC approved for the prevention and control of bleeding in patients with factor IX deficiency, hemophilia B [5]. On the basis of limited clinical data demonstrating a rapid increase in clotting factors and correction of the international normalized ratio (INR), evidence-based guidelines recommend four-factor PCC along with vitamin K for the reversal of warfarin in the setting of elevated INR and major bleeding [6]. There are reports of three-factor DOI:10.1097/MBC.0000000000000259
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Prothrombin complex concentrate Cruz et al. 379
products used as well; however, they are not US FDAapproved for this indication [1,5,7]. A major concern with PCC administration is the increased risk of thromboembolism. This adverse effect may range in severity from minor thrombophlebitis to fulminant disseminated intravascular coagulation (DIC). The risk of thromboembolism must be weighed against the benefits of PCC administration for the rapid and effective reversal of VKAs [6,8]. In order to minimize these risks, agents which promote platelet activity, such as desmopressin, or reversal of anticoagulation, such as protamine and other human or factor products, should be avoided [9]. In addition, there is a dose-dependent effect related to thrombosis incidence; risk is increased with additional or increased dosages [10]. The ninth edition of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis provides recommendations for the reversal of major bleeding due to VKAs. These include rapid reversal with PCC rather than with FFP. In addition to PCC, 5–10 mg of intravenous (i.v.) vitamin K by slow i.v. injection should be administered concomitantly (grade 2C recommendation) [6]. Published clinical data for the successful use of PCC for reversal of bleeding describe a variety of protocols dosing for PCC ranging from 20 to 50 units/kg intravenously with the addition of either vitamin K 5– 10 mg alone or vitamin K and 2 units of FFP [1,7]. Our university-based tertiary medical center currently has a PCC guideline for urgent warfarin reversal. The use of three-factor PCC is recommended for any INR greater than or equal to 1.5 that is associated with a major bleed or in a patient requiring surgery within 12 h. Dosing is based upon the degree of INR elevation. A dose of 30 units per kilogram of body weight is recommended for an INR less than or equal to 6. When the INR is greater than 6, PCC is recommended to be dosed between 30 and 50 units per kilogram. Concomitant administration of vitamin K (5– 10 mg by mouth or intravenously) is also recommended. The guideline suggests oral administration of vitamin K due to the concern for anaphylaxis with the i.v. route [11,12]. The purpose of this investigation was to evaluate the use, effectiveness, and safety of PCC for the rapid reversal of anticoagulation by warfarin for life-threatening bleeding or emergent surgery, with the primary endpoint being the mean reduction in INR. In addition, adherence to the hospital-based guideline was assessed through secondary endpoints including clinical outcomes such as cessation of bleeding, occurrence of thromboembolic events, and 30-day mortality.
Methods A retrospective cohort analysis was performed. Adult patients, at least 18 years of age, treated at an academic
medical center, who received the institution’s preferred PCC product, Profilnine SD (factor IX complex), from July 2008 through June 2012 for the reversal of anticoagulation were reviewed for indication, administration, and monitoring as described below. Patients were identified based on medication charges from the pharmacy system (PharmNet: Pharmacy Medication Manager Version 2007.08.1.14; Cerner Corporation, Kansas City, Missouri, USA). Patients were classified according to specific reversal indication and concomitant reversal agents administered. Patients receiving PCC for VKA reversal were analyzed separately; these patients were further stratified according to presence or absence of FFP administration. Effectiveness of PCC for the reversal of anticoagulation in patients with major bleeding or need for emergent surgery was measured according to mean INR reduction. Secondary outcomes included ICU length of stay, hospital length of stay, incidence of thromboembolic events, 30-day mortality, appropriateness of indication, accurate dosing per protocol, and proper monitoring and follow-up. Electronic medical records (WebCIS Version 3.9.1; UNC Healthcare, Chapel Hill, North Carolina, USA) were utilized to obtain the aforementioned data including a review of daily progress notes. This study was approved by the hospital’s Institutional Review Board and conducted in accordance with all stipulations. Descriptive statistics were performed for all analyses. Mean values (with ranges), raw values, and percentages were reported as appropriate.
Results Ninety-six patients were identified as having received a dose of PCC during the time period analyzed. Two patients were excluded for treatment of a factor deficiency. Twenty-one cases were excluded because the patients were not receiving any anticoagulation. Three patients received PCC for non-VKA anticoagulation reversal (two dabigatran, one heparin) and thus were not included in the analysis. Baseline characteristics for the remaining 70 patients are shown in Table 1. The Table 1
Baseline characteristics‘
Characteristic Age (mean) Sex Female Ethnicity Caucasian African American Asian Other Unknown Weight (mean) Anticoagulation Warfarin Warfarin þ enoxaparin Warfarin þ aspirin þ clopidogrel
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
% (n) 71.3 years 52.9% (37) 64.3% (45) 22.9% (16) 1.4% (1) 2.9% (2) 8.6% (6) 83.4 kg 95.7% (67) 1.4% (1) 2.9% (2)
380 Blood Coagulation and Fibrinolysis 2015, Vol 26 No 4
Indications for prothrombin complex concentrate administration
Table 2
Table 3
Clinical outcomes
Bleeding
n (%)
Length of stay
Mean days
(65.7%) (15.7%) (18.6%) (%) (92.9%) (7.1%)
ICU Hospital
5 12
N ¼ 70M Intracranial bleeding Gastrointestinal bleeding Other bleeding Peri-procedural Craniotomy EVD placement Other
42 3 12 20 8 2 10
EVD, external ventricular device.
M
May include multiple indications per patient.
mean age was 71 years old (range 24–94). The average patient weight was 83.4 kg, with a range of 47.3–130 kg. The majority of patients were receiving warfarin alone. An enoxaparin bridge was used in one patient, and two were taking ‘triple therapy’ consisting of warfarin, clopidogrel, and aspirin. Indications for PCC are shown in Table 2. The most common indication for PCC was intracranial bleeding (60%). Periprocedural PCC was given to 28.6% of patients (10 of whom also had intracranial bleeding). Gastrointestinal bleeding was present in 4.3%, and the remaining 17.1% had other forms of bleeding. The mean baseline INR was 3.1 (1.5–12.0), and was reported for all patients (Fig. 1). After PCC administration, mean INR was reduced to 1.6 (1.1–3.2), which equates to a mean reduction of 1.5. Three patients in this group did not have post-PCC INR values available. Average time to follow-up INR was 4.9 h (0.5–36). After one dose of PCC, the INR remained equal to or greater than 1.5 in 38 patients. Concomitant FFP was given in over half of these instances (65.7%). Roughly, 21% of all patients (15) were given a second dose of PCC. Of these, 15 patients receiving additional doses of PCC, five were noted to have continuation of bleeding (two of which had inadequate INR reversal), seven achieved cessation of bleeding, and the outcome was unclear in the remaining 3 cases. Recombinant factor VIIa was administered to one patient after receiving four doses of PCC in addition to FFP and vitamin K.
Cessation Continuation Unclear Adverse events No events Thrombotic events
46 11 13 n 65 5
30 day survival Survivors
n (%) 60 (85.7%)
Continuation of bleeding was observed in 12 patients (17.1%). Reasons for continuation of bleeding included expansion of cerebral bleed, as evidenced by computed tomography (CT) scan, re-hemorrhage, or lack of improvement on follow-up head CT. Of these patients, the mean number of PCC doses given was 2 (1–4). A majority of patients [46 (65.7%)], however, achieved cessation of bleeding. For patients receiving less than or equal to 30 units/kg of factor IX complex, the mean change in INR was 1.0 (0.1 to 3.1), compared to 2.2 (0.2 to 10.5) in patients receiving 31–50 units/kg. The mean PCC dose for patients achieving a post-PCC INR equal to or below 1.6 was 30.9 units/kg (10.4 –51.5 units/kg). The mean dose of PCC for patients achieving a post-treatment INR greater than 1.6 was 33.5 units/kg (25.5– 52.1 units/kg). Fifty per cent (12) of these patients received two or more doses of PCC, resulting in a mean total dose of 70.2 units/kg in this subset. Of the 43 patients achieving a post-treatment INR equal to or below 1.6, six (14.0%) experienced continued bleeding. Of the 24 patients with an INR remaining above 1.6, six (25.0%) had continued bleeding. The 30-day mortality rate was 22.9% (16). Of those patients, nine were transitioned to comfort care. In the remaining seven patients, cerebral herniation/hemorrhage was the suspected cause of death in three cases, one patient suffered a fatal myocardial infarction, and causes were not obtained for three patients. For the entire cohort of patients analyzed, the average ICU length of stay was 5 days (
Retrospective evaluation of the clinical use of prothrombin complex concentrate for the reversal of anticoagulation with vitamin K antagonists Jennifer L. Cruz, Mary C. Moss, Sheh-Li Chen, Kayla M. Hansen and Lindsey B. Amerine Anticoagulation reversal is a time-sensitive intervention for the prevention of life-threatening hemorrhagic events occurring with bleeding or surgery. Recommendations for the most effective and well tolerated reversal agent in these settings remain controversial. Several clinical guidelines for the management of intracerebral hemorrhage support use of prothrombin complex concentrates (PCCs) for the rapid reversal of warfarin-associated coagulopathy despite limited clinical data. The purpose of this investigation was to evaluate the efficacy and safety of PCC for the rapid reversal of anticoagulation by vitamin K antagonists for lifethreatening bleeding or emergent surgery and to assess adherence to a hospital-based protocol. A retrospective chart review was conducted of adult patients receiving PCC for the reversal of anticoagulation. Patients were assessed according to indication for anticoagulation reversal. The primary outcome measure was adequacy of international normalized ratio reversal. Other outcomes included cessation of bleeding, thrombotic complications, and adherence to an institutional-based guideline for the use of PCC. ICU and hospital length of stay and 30-day mortality was assessed. There were 70 patients included in this study. Mean international normalized ratio was reduced from 3.1 to
Background Anticoagulation reversal is a time-sensitive intervention for the prevention of life-threatening hemorrhagic events occurring with bleeding or surgery. Rapid reversal of warfarin anticoagulation is frequently required in emergency and acute care settings. Recommendations for the most effective and well tolerated reversal agent in these settings remain controversial. Conventional methods include infusions of thawed fresh frozen plasma (FFP) and the administration of vitamin K (phytonadione) [1,2]. However, both of these interventions have limitations. Vitamin K has a slow onset of action and FFP requires blood typing, thawing, and delivery which may delay its administration [1]. In addition, the use of FFP carries the potential for volume overload, infection, or transfusion-related acute lung injury. While both are effective and validated, the limitations of these agents prompt clinicians to explore alternative options. In particular, prothrombin complex concentrate (PCC) is an alternative agent with increasing use in the reversal of anticoagulation, despite limited clinical data. 0957-5235 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
1.6 following administration of at least one dose of PCC. Cessation of bleeding occurred in 65.7% of patients. Clinical assessment was unclear in 18.6%. Thrombotic complications were observed in 7.1% of patients. The 30-day mortality rate was found to be 14.3%. These data demonstrate that PCC is a well tolerated and effective method for anticoagulation reversal associated with a relatively high 30-day survival rate. Blood Coagul Fibrinolysis 26:378–382 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
Blood Coagulation and Fibrinolysis 2015, 26:378–382 Keywords: hemorrhage, prothrombin complex concentrate, warfarin international normalized ratio Department of Pharmacy, University of North Carolina Hospitals, Chapel Hill, North Carolina, USA Correspondence to Jennifer L. Cruz, PharmD, BCPS, University of North Carolina Hospitals, 101 Manning Drive CB #7600, Chapel Hill, NC 27514, USA Tel: +1 919 843 9558; e-mail: [email protected] Received 17 March 2014 Revised 18 September 2014 Accepted 26 November 2014
In contrast to the concerns surrounding FFP and vitamin K, PCC does not require blood typing cross-matching, is virally inactivated, does not pose a risk of fluid overload, and its preparation and administration may be done more quickly than FFP [3]. Prior to the recent approval of KCentra, which is the first US Food and Drug Administration (FDA)-approved four-factor preparation for the reversal of acquired coagulopathy due to vitamin K antagonists (VKAs), PCCs were available in the United States as only three-factor products containing therapeutic levels of nonactivated vitamin K-dependent factors (factor II, factor IX, and factor X) [4]. Profilnine SD (factor IX complex) is a low-purity three-factor PCC approved for the prevention and control of bleeding in patients with factor IX deficiency, hemophilia B [5]. On the basis of limited clinical data demonstrating a rapid increase in clotting factors and correction of the international normalized ratio (INR), evidence-based guidelines recommend four-factor PCC along with vitamin K for the reversal of warfarin in the setting of elevated INR and major bleeding [6]. There are reports of three-factor DOI:10.1097/MBC.0000000000000259
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Prothrombin complex concentrate Cruz et al. 379
products used as well; however, they are not US FDAapproved for this indication [1,5,7]. A major concern with PCC administration is the increased risk of thromboembolism. This adverse effect may range in severity from minor thrombophlebitis to fulminant disseminated intravascular coagulation (DIC). The risk of thromboembolism must be weighed against the benefits of PCC administration for the rapid and effective reversal of VKAs [6,8]. In order to minimize these risks, agents which promote platelet activity, such as desmopressin, or reversal of anticoagulation, such as protamine and other human or factor products, should be avoided [9]. In addition, there is a dose-dependent effect related to thrombosis incidence; risk is increased with additional or increased dosages [10]. The ninth edition of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis provides recommendations for the reversal of major bleeding due to VKAs. These include rapid reversal with PCC rather than with FFP. In addition to PCC, 5–10 mg of intravenous (i.v.) vitamin K by slow i.v. injection should be administered concomitantly (grade 2C recommendation) [6]. Published clinical data for the successful use of PCC for reversal of bleeding describe a variety of protocols dosing for PCC ranging from 20 to 50 units/kg intravenously with the addition of either vitamin K 5– 10 mg alone or vitamin K and 2 units of FFP [1,7]. Our university-based tertiary medical center currently has a PCC guideline for urgent warfarin reversal. The use of three-factor PCC is recommended for any INR greater than or equal to 1.5 that is associated with a major bleed or in a patient requiring surgery within 12 h. Dosing is based upon the degree of INR elevation. A dose of 30 units per kilogram of body weight is recommended for an INR less than or equal to 6. When the INR is greater than 6, PCC is recommended to be dosed between 30 and 50 units per kilogram. Concomitant administration of vitamin K (5– 10 mg by mouth or intravenously) is also recommended. The guideline suggests oral administration of vitamin K due to the concern for anaphylaxis with the i.v. route [11,12]. The purpose of this investigation was to evaluate the use, effectiveness, and safety of PCC for the rapid reversal of anticoagulation by warfarin for life-threatening bleeding or emergent surgery, with the primary endpoint being the mean reduction in INR. In addition, adherence to the hospital-based guideline was assessed through secondary endpoints including clinical outcomes such as cessation of bleeding, occurrence of thromboembolic events, and 30-day mortality.
Methods A retrospective cohort analysis was performed. Adult patients, at least 18 years of age, treated at an academic
medical center, who received the institution’s preferred PCC product, Profilnine SD (factor IX complex), from July 2008 through June 2012 for the reversal of anticoagulation were reviewed for indication, administration, and monitoring as described below. Patients were identified based on medication charges from the pharmacy system (PharmNet: Pharmacy Medication Manager Version 2007.08.1.14; Cerner Corporation, Kansas City, Missouri, USA). Patients were classified according to specific reversal indication and concomitant reversal agents administered. Patients receiving PCC for VKA reversal were analyzed separately; these patients were further stratified according to presence or absence of FFP administration. Effectiveness of PCC for the reversal of anticoagulation in patients with major bleeding or need for emergent surgery was measured according to mean INR reduction. Secondary outcomes included ICU length of stay, hospital length of stay, incidence of thromboembolic events, 30-day mortality, appropriateness of indication, accurate dosing per protocol, and proper monitoring and follow-up. Electronic medical records (WebCIS Version 3.9.1; UNC Healthcare, Chapel Hill, North Carolina, USA) were utilized to obtain the aforementioned data including a review of daily progress notes. This study was approved by the hospital’s Institutional Review Board and conducted in accordance with all stipulations. Descriptive statistics were performed for all analyses. Mean values (with ranges), raw values, and percentages were reported as appropriate.
Results Ninety-six patients were identified as having received a dose of PCC during the time period analyzed. Two patients were excluded for treatment of a factor deficiency. Twenty-one cases were excluded because the patients were not receiving any anticoagulation. Three patients received PCC for non-VKA anticoagulation reversal (two dabigatran, one heparin) and thus were not included in the analysis. Baseline characteristics for the remaining 70 patients are shown in Table 1. The Table 1
Baseline characteristics‘
Characteristic Age (mean) Sex Female Ethnicity Caucasian African American Asian Other Unknown Weight (mean) Anticoagulation Warfarin Warfarin þ enoxaparin Warfarin þ aspirin þ clopidogrel
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
% (n) 71.3 years 52.9% (37) 64.3% (45) 22.9% (16) 1.4% (1) 2.9% (2) 8.6% (6) 83.4 kg 95.7% (67) 1.4% (1) 2.9% (2)
380 Blood Coagulation and Fibrinolysis 2015, Vol 26 No 4
Indications for prothrombin complex concentrate administration
Table 2
Table 3
Clinical outcomes
Bleeding
n (%)
Length of stay
Mean days
(65.7%) (15.7%) (18.6%) (%) (92.9%) (7.1%)
ICU Hospital
5 12
N ¼ 70M Intracranial bleeding Gastrointestinal bleeding Other bleeding Peri-procedural Craniotomy EVD placement Other
42 3 12 20 8 2 10
EVD, external ventricular device.
M
May include multiple indications per patient.
mean age was 71 years old (range 24–94). The average patient weight was 83.4 kg, with a range of 47.3–130 kg. The majority of patients were receiving warfarin alone. An enoxaparin bridge was used in one patient, and two were taking ‘triple therapy’ consisting of warfarin, clopidogrel, and aspirin. Indications for PCC are shown in Table 2. The most common indication for PCC was intracranial bleeding (60%). Periprocedural PCC was given to 28.6% of patients (10 of whom also had intracranial bleeding). Gastrointestinal bleeding was present in 4.3%, and the remaining 17.1% had other forms of bleeding. The mean baseline INR was 3.1 (1.5–12.0), and was reported for all patients (Fig. 1). After PCC administration, mean INR was reduced to 1.6 (1.1–3.2), which equates to a mean reduction of 1.5. Three patients in this group did not have post-PCC INR values available. Average time to follow-up INR was 4.9 h (0.5–36). After one dose of PCC, the INR remained equal to or greater than 1.5 in 38 patients. Concomitant FFP was given in over half of these instances (65.7%). Roughly, 21% of all patients (15) were given a second dose of PCC. Of these, 15 patients receiving additional doses of PCC, five were noted to have continuation of bleeding (two of which had inadequate INR reversal), seven achieved cessation of bleeding, and the outcome was unclear in the remaining 3 cases. Recombinant factor VIIa was administered to one patient after receiving four doses of PCC in addition to FFP and vitamin K.
Cessation Continuation Unclear Adverse events No events Thrombotic events
46 11 13 n 65 5
30 day survival Survivors
n (%) 60 (85.7%)
Continuation of bleeding was observed in 12 patients (17.1%). Reasons for continuation of bleeding included expansion of cerebral bleed, as evidenced by computed tomography (CT) scan, re-hemorrhage, or lack of improvement on follow-up head CT. Of these patients, the mean number of PCC doses given was 2 (1–4). A majority of patients [46 (65.7%)], however, achieved cessation of bleeding. For patients receiving less than or equal to 30 units/kg of factor IX complex, the mean change in INR was 1.0 (0.1 to 3.1), compared to 2.2 (0.2 to 10.5) in patients receiving 31–50 units/kg. The mean PCC dose for patients achieving a post-PCC INR equal to or below 1.6 was 30.9 units/kg (10.4 –51.5 units/kg). The mean dose of PCC for patients achieving a post-treatment INR greater than 1.6 was 33.5 units/kg (25.5– 52.1 units/kg). Fifty per cent (12) of these patients received two or more doses of PCC, resulting in a mean total dose of 70.2 units/kg in this subset. Of the 43 patients achieving a post-treatment INR equal to or below 1.6, six (14.0%) experienced continued bleeding. Of the 24 patients with an INR remaining above 1.6, six (25.0%) had continued bleeding. The 30-day mortality rate was 22.9% (16). Of those patients, nine were transitioned to comfort care. In the remaining seven patients, cerebral herniation/hemorrhage was the suspected cause of death in three cases, one patient suffered a fatal myocardial infarction, and causes were not obtained for three patients. For the entire cohort of patients analyzed, the average ICU length of stay was 5 days (
