Intracerebral Hemorrhage In Anticoagulated Patients: Emergency Department Treatment & Anticoagulant Reversal, Warfarin, Vitamin K Antagonist | EB Medicine
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Intracerebral Hemorrhage In Anticoagulated Patients: Evidence-Based Emergency Department Management (Stroke CME)

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Table of Contents
 
Table of Contents
  1. Abstract
  2. Case Presentations
  3. Introduction
  4. Epidemiology
  5. Critical Appraisal of the Literature
  6. Etiology And Pathophysiology
  7. Differential Diagnosis
  8. Prehospital Care
    1. Measures To Control Elevated Intracranial Pressure In The Prehospital Setting
    2. Basic Airway Management
  9. Emergency Department Evaluation
    1. History
  10. Diagnostic Studies
    1. Imaging
  11. Treatment
    1. Airway And Blood Pressure
    2. Anticoagulant Reversal
    3. Guidelines And Recommendations For Vitamin K Antagonist-Associated Major Bleeding
    4. Reversal Of Antiplatelet Medications In Intracerebral Hemorrhage
    5. Reversal Of Novel Oral Anticoagulants In Intracerebral Hemorrhage
    6. Recombinant Factor VIIa
    7. Tranexamic Acid
    8. Management Of Elevated Intracranial Pressure
    9. Seizure Prophylaxis And Management
    10. Surgery
    11. Do Not Resuscitate Orders
  12. Controversies And Cutting Edge
    1. Novel Prehospital Computed Tomography Scanners
    2. Optic Nerve Sheath Diameter In Intracerebral Hemorrhage
    3. Potential Antidotes For Novel Oral Anticoagulants
  13. Disposition And Transport
  14. Summary
  15. Risk Management Pitfalls For Intracerebral Hemorrhage In Anticoagulated Patients
  16. Case Conclusions
  17. Clinical Pathway For Emergency Management Of Intracerebral Hemorrhage In Anticoagulated Patients
  18. Tables and Figures
    1. Table 1. Common Etiologies And Risk Factors For Intracerebral Hemorrhage
    2. Table 2. Randomized Controlled Trials Of Novel Oral Anticoagulants In Atrial Fibrillation
    3. Table 3. Differential Diagnosis In Intracerebral Hemorrhage
    4. Table 4. Important History To Obtain In Patients With Intracerebral Hemorrhage
    5. Table 5. The Intracerebral Hemorrhage Score
    6. Table 6. Recommended Reversal Agents For Anticoagulation
    7. Figure 1. CT Scan Of A Right Frontal Cortical Intracerebral Hemorrhage
    8. Figure 2. CT Scan Of A Right THalamic Intracerebral Hemorrhage With Intraventricular Hemorrhage
    9. Figure 3. CT Scan Of A Left Basal Ganglia Intracerebral Hemorrhage
    10. Figure 4. CT Scan Of A Left Basal Ganglia Intracerebral Hemorrhage With Subsequent Enlargement 6 Hours Later
    11. Figure 5. CT Scan Of An Intraventricular Hemorrhage With Extraventricular Drain Catheters Placed Bilaterally
    12. Figure 6. Optic Nerve Sheath (Outlined In White)
  19. References

Abstract

Spontaneous intracerebral hemorrhage is a true neurological emergency, and its management is made more complicated when patients are anticoagulated, as reversal of anticoagulation must be initiated simultaneously with diagnosis, treatment, and disposition. Recent advances such as newer laboratory testing and rapid computed tomography for diagnosis, blood pressure reduction to reduce hematoma expansion, and new anticoagulant reversal agents may allow for improved outcomes. Management of intracranial pressure is particularly important in anticoagulated patients, as is identifying patients who may benefit from rapid neurosurgical intervention and/or emergent transport to facilities capable of managing this disease.

Case Presentations

Immediately upon walking into your evening shift, a nurse gets your attention and instructs you to see a patient that she is concerned is having a stroke. The patient is a 78-year-old man with a history of congestive heart failure and a mechanical heart valve who has had 2 hours of headache and dysarthria. His family reports that he had no deficits prior to this. You immediately order a head CT, which demonstrates a small right parietal lobe bleed. The INR returns at 4.0 and you notice in the chart that the patient had a recent echocardiogram with an ejection fraction of 15%. You wonder how well he will tolerate reversal and what should be done about his blood pressure, which is 175/105 mm Hg.

Your second patient is a 65-year-old woman with atrial fibrillation. Her cardiologist put her on dabigatran, and she has been compliant with her medications. Today, she developed a headache and left-sided weakness approximately 1 hour prior to arrival. She is also taken immediately for a head CT, which demonstrates a 15-cc right thalamic intracerebral hemorrhage and a small amount of bleeding into her lateral ventricles. You wonder what the best strategy is for reversal agents for dabigatran.

Later in your shift, a gentleman who appears to be in his mid-50s is brought in after his family noticed that he was sleepier than usual after returning from the grocery store an hour ago. He has a past medical history of atrial fibrillation, and is anticoagulated on rivaroxaban. On your exam, he keeps falling asleep when you try to talk to him, but with painful stimulation, he wakes up and follows commands. He is taken immediately for an emergent head CT, which demonstrates a 3-cm right cerebellar intracerebral hemorrhage. As you step out of the room to speak to the neurosurgeon, the nurse runs out to tell you that the patient has now developed sonorous respirations. As you prepare to intubate the patient, you wonder whether he needs to be hyperventilated and what the best reversal strategy is for rivaroxaban.

Introduction

Intracerebral hemorrhage (ICH), defined as “bleeding into the parenchyma of the brain that may extend into the ventricles and, in rare cases, the subarachnoid space,”1 is a devastating disease that must be recognized immediately in the emergency department (ED). Unlike ischemic stroke, which has a large body of evidence supporting intravenous tissue plasminogen activator (tPA) and endovascular treatment, ICH has no targeted modalities for treatment.2-7 Anticoagulated patients with ICH require rapid reversal of coagulopathy to limit hemorrhage progression; however, the optimal approach is debated. Despite the fact that there are no targeted therapies in the treatment of ICH, current strategies to improve outcome rest largely on reducing the risk of hematoma expansion early in treatment, as each milliliter of expansion decreases the patient’s chances of living independently.8

Epidemiology

ICH accounts for 10% to 20% of all strokes, worldwide.9 Approximately 25% of these patients are on an oral anticoagulant.10-16 Outcome data on ICH are clouded with uncertainty, as the cause of death of many of these patients is withdrawal of care. Nonetheless, ICH has a much higher mortality than ischemic stroke.17 A prospective registry out of Denmark demonstrated that mortality from ICH is significantly higher than in ischemic stroke (hazard ratio [HR], 1.564; 95% confidence interval [CI], 1.4-1.7; P < .001).17 Mortality of ICH at 1 year ranges from 38% to 50%.10,18,19

As the population ages, it is expected that there will be a growing number of patients who are anticoagulated. Oral anticoagulants are most frequently used for stroke prevention in atrial fibrillation or in the treatment of thromboembolic disease, and numerous studies have documented their benefit.20,21 Warfarin prescriptions quadrupled between 1988 and 1999, and the incidence of anticoagulant-associated ICH quintupled.22 It is estimated that over the next 50 years, the prevalence of atrial fibrillation will be 2.5 times greater than it is currently.23 This is reflected in the epidemiology of patients who sustain ICH. Flaherty et al followed a cohort of patients in 1988, and again a decade later. Although the incidence of ICH did not change significantly between the 2 time periods, anticoagulant-associated ICH became more common.19

When patients are on anticoagulants, their risk of ICH and associated morbidity and mortality increases significantly.24 In a retrospective study of patients with ICH, mortality was 67% in anticoagulated patients versus 55% in those not anticoagulated.25 ICH volume was also statistically larger compared to the nonanticoagulated group.25 An international normalized ratio (INR) > 3.5 nearly doubles the risk of a fatal ICH in patients who are on warfarin when adjusted for age, sex, cardiovascular disease, diabetes, heart failure, hypertension, and type of ICH.26

Since reversal of coagulopathy is a time-sensitive process, emergency clinicians must appropriately diagnose, manage, and disposition patients with ICH. In 2015, a retrospective study in Germany described patients with ICH who were on oral anticoagulants, and it demonstrated a significant survival benefit in patients who had INR reversal to < 1.3 and systolic blood pressure (SBP) to < 160 mm Hg within 4 hours after presentation.27 The results of this study support the critical role played by the emergency clinician in recognition and man-agement of these acute patients.

Critical Appraisal Of The Literature

A literature search was performed in PubMed with the search terms ICH reversal, ICH warfarin, ICH anticoagulation, and novel oral anticoagulants ICH. A total of 1738 articles from 1947 to the present were identified, 240 abstracts were reviewed, and 16 papers were selected for full review and referenced. The date of the literature search was May 15, 2015, with additional resources reviewed up to November 2015. The Cochrane Database of Systematic Reviews was searched for systematic reviews using the key term intracerebral hemorrhage, and 15 reviews were identified.

The American Heart Association/American Stroke Association (AHA/ASA) published a 2015 update to their 2007 and 2010 guidelines for the management of ICH.11,28,29 The European Stroke Organisation published guidelines for the management of spontaneous ICH in 2014.30 With regard to indications for anticoagulation, The American College of Chest Physicians published “Evidence-Based Clinical Practice Guidelines for Management of Anticoagulation Therapy: Antithrombotic Therapy and Prevention of Thrombosis” in 2012.31

Using standard evidence-level scales, the majority of clinical evidence of vitamin K antagonist (VKA)-associated ICH falls into the “strong evidence” categories; however, evidence associated with novel oral anticoagulant (NOAC)-associated ICH falls into the “weak evidence” categories. There are several reasons for this. First, ICH is a rare disease, and properly designed clinical trials are often too resource-intensive to perform. Second, NOACs have not been available for sufficient time to quantify the extent of their use within the population and their impact on the clinical evaluation and treatment of ICH. When available, recommendations in this article are evidence-based. Recommendations based on accepted practice or expert consensuses are explicitly noted as such.

The overall strength of evidence supporting correction of coagulopathy in the setting of ICH by replacing appropriate factors or platelets in the setting of severe coagulation factor deficiency or severe thrombocytopenia is strong, with Class I, Level of Evidence C in the 2015 AHA ICH management guidelines.28 These same guidelines give a Class I, Level of Evidence C to withholding VKAs in VKA-associated ICH, receiving therapy to replace vitamin K-dependent factors and correct the INR, and receiving intravenous vitamin K.28 However, in the setting of NOACs, the most rapid and effective ways to reverse coagulopathy are still under study, and no guidelines describe the best method of reversal.

Risk Management Pitfalls For Intracerebral Hemorrhage In Anticoagulated Patients

  1. “I thought that the ICU would take care of this patient’s blood pressure.”
    Blood pressure management should begin in the ED in patients with ICH. It is generally safe to take measures to reduce blood pressure in this setting.
  2. “I did not want to use PCC to manage reversal of ICH because it was too expensive.” Expense is relative to outcomes. In the appropriate patient population (VKA or factor Xa inhibitors), PCC is likely the most effective method to reverse coagulopathy in the setting of ICH. PCCs are ideal in patients who may not tolerate a larger volume of infusion, such as those with congestive heart failure.
  3. “My patient on dabigatran had an ICH, but I did not put in a dialysis catheter; that is too invasive.”
    Dabigatran is a small molecule, and thus is able to be dialyzed. Idarucizumab has recently been approved as an antidote for dabigatran, but if it is not available, dialysis is a consideration.
  4. “The patient with the cerebellar hemorrhage became more sleepy prior to transfer, but I assumed the accepting neurosurgeon would be waiting in the ED.”
    Never make assumptions and always provide up-to-date communication with the accepting physician whenever transferring a patient. Patients with cerebellar hemorrhage and declining mental status are candidates for emergent decompressive surgery.
  5. “My nurses were uncomfortable starting a nicardipine infusion for the patient’s ICH and had never heard of clevidipine, so we continued with labetalol, even though it didn’t seem to be working.”
    Frequently, patients with ICH require continuous infusion of antihypertensives to maintain adequate blood pressure control.
  6. “My patient with hydrocephalus waited in the ED a very long time for transportation and he deteriorated, but no one let me know.”
    Patients with ICH are at high risk for hydrocephalus, which can be corrected by external ventricular drain placement. They should be rapidly transported to an appropriate facility, and even flown if necessary, as they are at high risk of decompensating.
  7. “I thought it was a regular headache, so I did not order a head CT.”
    Key factors may be present in the presentation of ICH that will help clue emergency clinicians that a more ominous problem is present. Head CT should be considered in patients with headache, especially in patients who are anticoagulated.
  8. “I did not transfer the patient because….”
    Patients with ICH have better outcomes when cared for by a team of neuroscience specialists in an ICU. If these resources are unavailable, patients need to be transferred to another facility.
  9. “The patient did not mention taking warfarin and his INR was normal, so I did not ask about any other agents.”
    More and more patients will be taking NOACs, and emergency clinicians must screen for all anticoagulants once an ICH has been diagnosed. This is especially important when patients present with atrial fibrillation or have another reason that they may require anticoagulation.
  10. “I thought the elderly patient from the nursing home had severe dementia and the history we received in the report from EMS did not sound concerning for an ICH.”
    Age is an important risk factor for ICH, and a thorough workup should be performed in patients who are confused or have a change in mental status. It is important to note a baseline mental status in patients who present with an altered mental status.

Tables and Figures

Table 1. Common Etiologies And Risk Factors For Intracerebral Hemorrhage

References

Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.

To help the reader judge the strength of each reference, pertinent information about the study will be included in bold type following the reference, where available. In addition, the most informative references cited in this paper, as determined by the authors, will be noted by an asterisk (*) next to the number of the reference.

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Authors

Natalie Kreitzer, MD; Opeolu Adeoye, MD, MS, FACEP, FAHA

Publication Date

December 1, 2015

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January 1, 2019

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