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Direct-Acting Oral Anticoagulants and Warfarin-Associated Intracerebral Hemorrhage Protocol Reduces Timing of Door to Correction Interventions.

Warfarin and direct-acting oral anticoagulants (DOACs) are most commonly used in the treatment of atrial fibrillation for the prevention of ischemic stroke and venous thromboembolism. (1-5) Warfarin therapy is also the standard of care for patients with mechanical heart valves to prevent valve thrombosis. (6) Intracerebral hemorrhage (ICH) is a serious life-threatening complication of warfarin. Direct-acting oral anticoagulant therapy is associated with 12% to 20% morbidity and mortality in all total ICH patients. (1,7) Specifically, mortality rates due to DOAC and warfarin-associated ICH range from 42% to 67%; up to 60% of these patients experience severe long-term disability. (8-11) Rapid reversal of oral anticoagulant therapy is required to emergently stop the developing hematoma to preserve cerebral blood flow and prevent further neurological complications. (4,10)


Warfarin, a vitamin K antagonist, was Food and Drug Administration (FDA) approved in 1954 and is the most frequently prescribed oral anticoagulant. (7) Current guidelines for spontaneous ICH management recommend that patients with a life-threatening ICH on warfarin therapy should have their international normalized ratio (INR) corrected as rapidly as possible. (7) Correction of a vitamin K antagonist consists of intravenous phytonadione in combination with fresh frozen plasma (FFP) and/or a prothrombin complex concentrate (PCC). (7) Our facility uses factor IX, a 3-factor PCC, as the PCC of choice for oral anticoagulant reversal.

The rate of DOAC-associated ICH is 40% to 70% lower than warfarin-associated ICH. (10) Directacting oral anticoagulants have been FDA approved since 2010 (Supplemental Digital Content 1, available at The development of DOAC reversal agents are still under clinical study. (12) The use of a PCC and/or an FFP is the current treatment option for reversing DOACs. (7) The DOACs are not a vitamin K antagonist; therefore, phytonadione is not an effective reversal treatment. (7) In May 2018, the US Food and Drug Administration approved Andexanet alfa as the first reversal agent only for life-threatening bleeding in patients who received rivaroxaban and apixaban. (13) A randomized control study is scheduled to begin in 2019 to examine the effect of Andexanet alfa has on homeostasis. (13) Currently, Andexant alfa is not approved for improving homeostasis. (13)

A gap analysis was conducted to improve and standardize our process in treating this patient population (Supplemental Digital Content 2, available at Findings showed that the ICH order set was not used consistently. Factor IX was on our formulary but not used regularly. In addition, we noted a lag time from order to administration of the reversal agents, which prolonged the time to correction. This resulted in inconsistent treatment intervention orders, often at irregular times. This created unpredictable results, often creating a bottleneck in the process of obtaining follow-up laboratory tests. Physicians were educated on order set use, and a specific anticoagulation reversal order set was developed in 2015. The order set developed for this project included adding factor IX, and recommended treatment interventions based on the INR and follow-up laboratory tests were timed to ensure close monitoring of INR.

Order sets have demonstrated an improvement in use of evidence-based practice and clinical outcomes. (14) A 2014 study examined the impact of the development of a standardized order set on the clinical care and outcomes of patients admitted with pneumonia. (14) Results showed a 34% decrease in mortality with order set implementation compared with those individuals in whom order sets were not used. (14) However, no statistical significance was noted in 30-day readmission rate or cost of care. (14) A 2015 study demonstrated similar results in reduced mortality in the order use group as compared with the no order set group. This study also showed reduced 30-day readmission rate and reduced cost of care. (15) However, it was noted that the practice of order set use must be part of a larger strategic effort to reduce variability. (15)

Because this study focuses on developing a standardized process to improve healthcare, the Donabedian conceptual model was used as a framework for examining health services and evaluating quality of healthcare. According to the model, information about quality of care can be drawn from 3 categories: structure, process, and outcome. (16) A Comprehensive Stroke Center's oral anticoagulant reversal protocol provided the structure to standardize the door-to-correction process. The outcome of care will be explained in the conclusion section of this article. It was hypothesized that creating a standardized process should decrease the time from door to reversal of INR. This required 2 assumptions: first, that the protocol would result in rapid initiation of therapy and, second, that the protocol was effective (the right combination of therapies). The purpose of this study was to examine the first hypothesis that the use of a protocol is associated with lower door-to-treatment times for eligible patients. The research question was: Does an oral anticoagulant reversal protocol have an impact in decreasing door to first intervention times for patients with DOAC- and warfarin-associated intracranial hemorrhage?


This study received exempt approval status from the institutional review board, and study risks were minimal. The design was a retrospective study of predata and postdata abstracted from the electronic medical record after patient discharge. The protocol was instituted on February 1, 2015, and the educational rollout occurred from September 2014 thru January 2015. The educational rollout included the reeducation of the protocol during the emergency and critical care simulation laboratories. Data collection for the control group occurred from July 20, 2013, through May 22, 2014. Data collection from the intervention group occurred from April 15, 2015, through December 9, 2016.

The electronic medical record was used to abstract data on DOAC-associated ICH and warfarin-associated ICH with an INR greater than 1.4. Informed consent was not required because this study examined existing data after patient discharge.

In 2011, the American Heart Association/American Stroke Association published recommendations for measuring quality of stroke care in comprehensive stroke centers. One of the metrics focused on patients who presented with ICH. The recommendation was for centers to track the median time from arrival (door time) to initiation of treatment with a PCC agent to normalize an elevated INR greater than 1.4 in patients with ICH and on warfarin therapy. For the purposes of this study, we chose to focus on door to first intervention treatment times because, in most cases, patients with warfarin-associated ICH consistently received phytonadione as a first intervention treatment. Patients with DOAC-associated ICH mostly received factor IX as a first treatment. (17) Computed tomography (CT) result time to first intervention times were also studied. The causal or independent variable was the DOACand warfarin-associated ICH standardized protocol. The effect or dependent variables were door time to treatment times and CT result time to first intervention.


Study participants included adults admitted through the emergency department (ED) in a 320-bed community comprehensive stroke center presenting with warfarin-associated ICH with an INR greater than 1.4, or DOAC-associated ICH. There were 50 participants: 25 in the preintervention group and 25 in the postintervention group. Patients admitted before implementation of the new protocol served as the control group, and patients admitted after protocol implementation of the new protocol served as the intervention group.

Preliminary data were obtained from internal sources in the critical care services quality improvement data (median, 698 vs 893 minutes). Under the assumption of 2 groups (2-tailed t test) and an approximately normal distribution, the effect size was determined to be approximately 0.4. An effect size of 0.3 required 15 subjects per group, and a sample size of 0.6 required 21 subjects per group. Therefore, we aimed to recruit a minimum of 42 subjects with approximately 21 in each group.


In 2015, our facility did not have a standardized process for treating oral anticoagulant-associated ICH. This resulted in delays in ordering of time-sensitive treatments and obtaining follow-up laboratory tests and lag times from order to reversal agent administration. There was no standardized oral anticoagulant reversal guideline for nurses who cared for this patient population. This made the process for treating this patient population inefficient. The development of a rapid anticoagulant reversal protocol consisted of a standardized nursing approach to treat oral anticoagulant-associated ICH (Fig 1).

Factor IX was added to the ED anticoagulant reversal order set. This made ordering factor IX available as a reversal option. Physicians and nurses were educated as part of this initiative. A mandatory e-learning module was developed with 100% completion rate by critical care and ED nursing staff.

Staff received an in-service handout (Fig 1) on the standardized process for administering phytonadione, FFP, and factor IX. Nursing staff competencies associated with the rapid anticoagulation reversal process during an oral anticoagulant-associated ICH were evaluated in a simulation laboratory scenario. The combination of the ICH reversal protocol and staff education resulted in a standardized process for an effective rapid anticoagulant reversal in eligible patients with oral anticoagulant-associated ICH.

The stroke coordinator provided the primary investigator with a randomized list of potential study participants with DOAC- and warfarin-associated ICH diagnosis. Study participants were selected based on the following inclusion criteria: adults, warfarin-associated ICH with an INR greater than 1.4, or DOAC-associated ICH diagnosis. Exclusion criteria consisted of participants younger than 18 years, warfarin-associated ICH with an INR less than 1.4, prisoners, pregnant women, and participants who did not wish to have any medical treatment. Study participants eligible before the implementation of the protocol were placed in the preintervention group. Study participants selected after the standardization of a rapid anticoagulant protocol were placed in the postintervention group. Data from selected study participants were entered in an identifiable data form and a case report form. Forms were secured in an encrypted server.


This was a retrospective quality assessment research study. There were no procedures specific to patients. All study participants received initial treatment by the ED physician. Study participants with warfarin-associated ICH were receiving warfarin before study participation. Warfarin-associated ICH study participants with an INR greater than 1.4 were treated with one of the following treatment options: (1) intravenous phytonadione and FFP, (2) intravenous phytonadione and factor IX, or (3) intravenous phytonadione, FFP, and factor IX.

Study participants with DOAC-associated ICH were receiving rivaroxaban or apixaban preceding the commencement of the study. Direct-acting oral anticoagulant-associated ICH study participants were treated with one of the following treatment options: (1) FFP, (2) factor IX, or (3) FFP and factor IX. Factor IX was the first intervention treatment in 86% of DOAC-associated ICH study participants. There was 1 study participant with DOAC-associated ICH who received FFP as the first intervention treatment. Treatment options were chosen according to the physician preference. First intervention treatments were measured in minutes and compared between the 2 groups. Data were entered into a spreadsheet, with demographic and physiologic variables. Study variables were reviewed for completeness by the medical center's research committee as part of the hospital's institutional review board process.

Data Analysis

Statistical data were analyzed using SPSS Statistics 24 for Windows, version 24.18 Normal measures of central tendency were examined for each of the measured variables. The primary research question was answered using an independent samples t test to compare the mean time in door to treatment for the 2 study groups (before and after protocol change).


The sample consisted of 50 hospitalized patients ranging in age from 56 to 94 years. The sample was 56% female and 44% male. The mean (SD) age was 79.02 (10.05) years. Length of stay ranged from 1 to 43 days, with a mean (SD) of 5.94 (7.31). The protocol change had a significant effect on the following findings (Table 1). Door to first treatment time for phytonadione in minutes decreased from 232.73 (SD, 199.37) to posttest findings of 111.35 (SD, 64.59). Door to first treatment time for factor IX decreased from 183.86 (SD, 230.20) to 116.58 (SD, 69.11). Door-to-treatment findings for phytonadione administration were significantly decreased from 184, [t.sub.40] = 2.60, P < .05, as were door to factor IX administration, [t.sub.24] = 1.17, P < .05. These findings support the hypothesis that use of the new protocol was associated with lower door-to-treatment times for eligible patients. The initiation of the oral anticoagulant reversal protocol improved the quality of healthcare in that it was associated with a decrease in CT result time to first intervention from 78.88 (SD, 59.62) in the preimplementation period to 54.20 (SD, 35.25) in the postimplementation period. Although there is a mean difference of 24.68 between the 2 groups, there was a nonsignificant effect for CT result time to first intervention time, [t.sub.48] = 1.78, P = .081.


The rapid reversal and implementation of a standardized anticoagulant reversal protocol are significant to nursing in the prevention of hematoma expansion. (17) Warfarin-associated ICH is estimated to occur at 0.62% to 3.7% per year, and the risk of DOAC-associated ICH is 0.5% per year. (4,19) Hematoma expansion is prevalent shortly after onset, and 55% deteriorate in the first 24 to 48 hours. (17) Prevention of hematoma expansion in ICH patients is imperative for decreasing mortality rates. (4,10,17)

Inconsistent treatment protocol, timing of laboratory results, and administration of reversal agents were impacting the timing of anticoagulant reversal and possibly our clinical outcomes. As a designated Joint Commission Comprehensive Stroke Center, these metrics and outcomes were closely monitored and reported to the members of the Medical Center Neuro Excellence Committee. The Neuro Excellence Committee members include interdisciplinary members from critical care, emergency department, and the medical/surgical neurological floor. This heightened awareness and communication with staff and neurologists may also have had a positive impact on the timing of coagulant reversal.

Limitations of the Study

Scope was our primary limitation; findings were from a single center community hospital. A larger multisite study may be needed to determine whether a standardized anticoagulant reversal protocol in patients with DOAC- and warfarin-associated ICH improves patient ICH outcomes in a variety of hospital settings. (16) Additional research is needed to improve treatment strategies for the rapid correction of DOAC- and warfarin-associated ICH. Finally, this midsized community hospital has a very high percentage of certified staff who have the increased knowledge of the significance and clinical impact of providing reversal agents timely. A hospital with fewer certified staff may not produce the same study outcomes. The education and simulations training may have increased the emergency department nurses and physicians' awareness and importance of rapid identification of and treatment for the acute stroke patient and potential for ICH if on anticoagulation therapy. The emergency room nurses are able to initiate the Code Stroke alert in our facility to expedite the physician examination. This may have contributed to decreased door-to-imaging times, which led to improved intervention times. The revised order sets decreased the lag time in door to first intervention and follow-up; the use of the order sets, however, was not tracked, and it cannot be determined whether the revisions made a significant impact on the findings.


The paradox in stroke prevention is that warfarin and DOACs used in the treatment of atrial fibrillation for ischemic stroke prevention also place a person at risk for ICH. (7,11) The implementation of a standardized anticoagulant reversal protocol at a comprehensive stroke center statistically reduced door to first intervention times for eligible patients. Anticoagulant therapy is also a risk factor for hematoma enlargement and poor outcomes especially within the first 24 to 48 hours. Current guidelines recommend correcting oral anticoagulant therapy as rapidly as possible. (7)

This study showed that the use of a standardized anticoagulant reversal protocol can reduce door-to-treatment times for eligible patients. This study design could be easily replicated in other hospital settings. In many emergency departments in the United States, stroke patients need to wait for a complete workup, including the noncontrast CT result as well as the laboratory INR results, to have the correct treatment option. A standardized approach in treating oral anticoagulant-associated ICH may improve the waiting time from door to treatment times and ultimately improve patient outcomes.

Questions or comments about this article may be directed to Rosemary C. Olivier, MSN RN CCRN SCRN, at rosemaryolivier@ She is a Critical Care Nurse Leader, St Jude Medical Center, Fullerton, CA.

Diane Cleeson, MSN ANP-BC, is Neurology Nurse Practitioner, St Jude Medical Center, Fullerton, CA.

Claudia Skinner, DNP RN CIC CCRN-K NE-BC FAPIC, is Director, Center of Excellence, St Jude Medical Center, Fullerton, CA.

Marysol Cacciata, MSN RN CCRN-K, is Research Coordinator, St Jude Medical Center, Fullerton, CA.

Mary Wickman, PhD RN, is Professor and Director, Nursing, Vanguard University, Costa Mesa, CA.

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (

DOI: 10.1097/JNN.0000000000000430


We would like to thank the Neuroscience Nursing Research Center, UT Southwestern, Dallas, TX, for the support and guidance they provided in this research project.


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Caption: FIGURE 1 The Oral Anticoagulant Associated Intracerebral Hemorrhage (ICH) Protocol.
TABLE 1. Results of t Test CT to First
Intervention and Door to Treatment Times

                             Door to Treatment

                         Pre                    Post

                Mean      SD     n     Mean      SD      n

CT to first    78.88    59.62    25   54.20     35.25    25

Door to CT     70.67    70.27    24   35.71     35.70    24

Door to CT     84.13    75.05    24   50.27     42.63    22

Door to INR    79.56    59.81    25   57.48     43.05    25

Door to        232.73   199.38   22   111.35    64.59    20
vitamin K

Door to FFP    376.14   149.74   22   378.15    167.1    20

Door to        183.86   230.20   7    116.58    69.11    19
factor IX

Door to        589.38   251.37   16   559.15    298.3    20
INR < 1.4

               95% CI for Mean
                 Difference         t       df

CT to first     -3.17, 52.53       1.78     48

Door to CT       2.57, 67.34     2.17 (a)   46

Door to CT      -2.87, 70.58       1.86     44

Door to INR    -159.65, 220.10     0.32     34

Door to         26.98, 215.77    2.60 (a)   40
vitamin K

Door to FFP     100.80, 96.78     -0.04     40

Door to        -51.11, -185.66   1.17 (a)   24
factor IX

Door to         -7.55, 51.71       1.50     48
INR < 1.4

Abbreviations: CI, confidence interval; CT, computed
tomography; INR, international normalized ratio.

(a) P < .05.

FIGURE 1 The Oral Anticoagulant--Associated
Intracerebral Hemorrhage (ICH) Protocol.

Why do we care?
  * It is a life-threatening emergency
  * Hemotoma expansion is common after the first few hours
    of onset and 55% deteriorate in the first 24-48 hours
Top Priorities:
  * To keep SBP < 140 & rapid reversal agent administration
  * To give all products together or when available STAT
  * Initiate all reversal agents ordered in the ED prior
    to tranfer to CCU.
Resource: Rapid Response Nurse x 6006
  * To assists with BP control and
    administration of reversal agents

Oral Anticoagulant Associated ICH Reversal Agents

Generic          Phytonadione          FFP

Brand Name       Vitamin K             FFP

Dose             10 mg/50 cc IVPB      2 to 4 units

Dose             Give as an IV         Order type & screen STAT and
Instructions     piggyback slowly      Blood Bank & transfuse order
                 over 30 minutes       STAT
                                       -Can pick up 4 units FFP
                 Never give IVP        at one time from BBK
                                       -Can run 2 units FFP at
                                       one time/IV line rapidly
                                       per MD direction. This
                                       should take 15-30 minutes
                                       Assess need for diuretic.
                                       Caution with history of CHF

Side Effects     Anaphylactic          Volume overload
                 reaction, shock,      Allergic reaction/TRALI
                 respiratory arrest,   (transfusion-related acute
                 cardiac arrest        lung injury),
                                       pulmonary edema

INR Recheck      1 hour after          30 min post transfusion
(For warfarin    administration        completion
ICH only)

Oral Anticoagulant Associated ICH Reversal Agents

Generic          Factor IX

Brand Name       Profilnine PPCC

Dose             Usual dose-35
                 units/kg or
                 per MD direction

Dose             Give slowly IV
Instructions     over 2-5

Side Effects     Mild: hives
                 rash, urticarial,
                 stuffy nose, fever

INR Recheck
(For warfarin
ICH only)

ICH = Intracerebral Hemorrhage; CCU = Critical Unit;
ED = Emergency Department; FFP = Fresh Frozen Plasma;
IV = Intravenous; IVP = Intravenous Push;
IVPB = Intravenous Piggyback;
TRALI = Transfusion-Related Acute Lung Injury;
BBK = Blood Bank; PCC = Prothrombin Complex Concentrate;
CHF = Congestive Heart Failure; INR = International
Normalized Ratio
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Article Details
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Author:Olivier, Rosemary C.; Gleeson, Diane; Skinner, Claudia; Cacciata, Marysol; Wickman, Mary
Publication:Journal of Neuroscience Nursing
Article Type:Report
Date:Apr 1, 2019
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