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Management of Spinal Emergencies in Patients on Direct Oral Anticoagulants
Original Article
Management of Spinal Emergencies in Patients on Direct Oral Anticoagulants Christopher Beynon1, Arturo Olivares1, Christoph Gumbinger2, Alexander Younsi1, Klaus Zweckberger1, Andreas W. Unterberg1
OBJECTIVE: Spine surgeons increasingly encounter acute spinal pathologies in patients treated with direct oral anticoagulants (DOACs), but only limited data on the management of these patients are currently available.
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METHODS: We retrospectively analyzed patients who presented to our department with acute spinal pathology during treatment with DOAC and who required urgent surgical therapy. Patient characteristics and treatment modalities were studied, with specific focus on the management of hemostasis and surgical therapy. Furthermore, we analyzed 19 cases of spinal emergencies during DOAC treatment reported in the literature.
tranexamic acid may improve the coagulation before surgery, especially in cases of unavailable specific antidotes.
-
RESULTS: A total of 12 patients were identified and included in the present analysis. Patients suffered from acute spinal cord compression caused by spinal tumor manifestation (n [ 5), empyema (n [ 4), degenerative spinal stenosis (n [ 1), hematoma (n [ 1), and vertebral body fracture/dislocation (n [ 2). All patients underwent emergency surgical treatment. Prohemostatic substances were administered perioperatively in 10 patients (83%) and included administration of prothrombin complex concentrates (83%), tranexamic acid (17%), and transfusion of platelets (8%). A total of 9 patients (75%) showed postoperative improvement of neurologic symptoms, and the in-hospital mortality in this patient cohort was 17%.
-
CONCLUSIONS: Emergency spine surgery is feasible and should be considered in patients on treatment with DOAC. The (low) risk of intraoperative bleeding complications has to be weighed against the risk of permanent disability if surgical decompression is delayed. Administration of prothrombin complex concentrates and
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Key words - Anticoagulants - Hemorrhage - Hemostasis - Spine Abbreviations and Acronyms DOAC: Direct oral anticoagulants PCC: Prothrombin complex concentrate
INTRODUCTION
D
irect oral anticoagulants (DOAC) increasingly are used for the treatment and prevention of thromboembolic events. Several “real-world” registries have confirmed findings of pivotal trials that DOAC are safe and have considerable advantages compared with vitamin K antagonists.1 However, the management of patients presenting with bleeding complications or requiring emergency surgery is still a matter of debate. A specific antidote (idarucizumab) for the direct thrombin inhibitor dabigatran became available in 2015,2 but no specific antidotes for oral factor Xa inhibitors (apixaban, betrixaban, edoxaban, rivaroxaban) are yet available in the European Union. The majority of surgical procedures on the spine are carried out in an elective manner, and hemostasis can be optimized before surgery. However, spine surgeons often are confronted with spinal emergencies such as traumatic injury or spinal hemorrhage requiring immediate decompression of the spinal cord to avoid permanent neurologic impairment. In patients treated with antithrombotic medication, impaired hemostasis may increase the risk for intraoperative bleeding complications with potentially lifethreatening consequences.3 Administration of prothrombin complex concentrates (PCC) effectively reverses anticoagulation in patients on treatment with vitamin K antagonists, and it has been demonstrated previously that its use facilitates emergency spinal surgery in respective patients.4 In contrast, data on emergency spinal surgery in patents on DOAC are limited to case reports, predominantly dealing with DOAC-associated spontaneous spinal hemorrhage. Here we report our experiences on the emergency management of patients with spinal emergencies while on treatment with DOAC. Clinical findings, results of
From the Departments of 1Neurosurgery and 2Neurology, Heidelberg University Hospital, Heidelberg, Germany To whom correspondence should be addressed: Christopher Beynon, M.D., Ph.D. [E-mail: [email protected]] Citation: World Neurosurg. (2019). https://doi.org/10.1016/j.wneu.2019.07.234 Journal homepage: www.journals.elsevier.com/world-neurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
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No.
Sex, Age (Years)
1
Female (68)
2
Pathology (Spinal Level) Spontaneous/ Traumatic
Prohemostatic Treatment
Emergency Surgery
Time to Surgery from Admission, Hours
Blood Loss, mL
Transfusion
Outcome
Comment
Symptoms improved
Posterior fusion day 14 after admission
Epidural empyema (C2eC5) Spontaneous
Edoxaban (30-0-0)
Neck pain Tetraparesis (2/5)
PCC 2500 IU
Laminectomy C3eC5, Empyema evacuation
2
200 mL
e
Male (55)
Malignant melanoma metastasis (T11) Spontaneous
Apixaban (5-0-5)
Back pain Gait disturbance Hypesthesia Bladder dysfunction
PCC 3500 IU
Laminectomy T10-T12 Tumor debulking
5
400 mL
e
Neurologic Comfort measures symptoms only due to improved after widespread surgery tumor disease Died (day 22 after admission)
3
Male (79)
Epidural empyema (C2eT1) Spondylodiscitis (C5/6 and C 6/7) Spontaneous
Apixaban (2.5-0-2.5)
Back pain Tetraparesis Sepsis
PCC 3000 IU Transfusion platelets Tranexamic acid 1g
Corpectomy C5eC6 Empyema evacuation
1.5
1300 mL
4 RBC concentrates
Died (day 5 At admission after admission) high cardiac due to heart enzymes, insufficiency heart catheter
4
Male (66)
Liposarcoma metastasis (T5eT7) Spontaneous
Rivaroxaban (20-0-0)
Back pain Gait disturbance Hypesthesia
e
Laminectomy T5eT7 Tumor debulking
23.5
100 mL
e
Complete recovery
/
5
Female (66)
Intradural meningioma (T8) Spontaneous
Rivaroxaban (20-0-0)
Paraparesis Gait disturbance Bladder dysfunction
PCC 1000 IU Tranexamic acid 1g
Laminectomy T8 Tumor resection
24
500 mL
e
Symptoms improved
/
6
Male (89)
Degenerative stenosis Myelopathy (C4 eC6) Traumatic
Rivaroxaban (20-0-0)
Paraplegia
e
Laminectomy C3eC7
6
200 mL
e
No improvement
/
7
Male (73)
Prostate cancer metastasis Vertebral fracture (T6) Spontaneous
Edoxaban (30-0-0)
Back pain Paraparesis Sensory loss
PCC 2500 IU
Laminectomy T5eT7 Tumor debulking
11
200 mL
e
Symptoms improved
Posterior fusion d5 after admission
8
Female (76)
Epidural hematoma (C2eC7) Spontaneous
Edoxaban (60-0-0)
Neck pain Gait ataxia Hemiparesis
PCC 3000 IU
Hemilaminectomy C4eC5
4 days
100 mL
e
Symptoms improved
/
9
Female (63)
Epidural empyema (T4eT9) Spontaneous
Rivaroxaban (20-0-0)
Back pain Spinal myoclonus Sepsis
PCC 3500 IU
Laminectomy T4eT9 Empyema evacuation
7
500 mL
e
Symptoms improved
/
ORIGINAL ARTICLE
Clinical Symptoms
SPINAL EMERGENCIES IN PATIENTS ON DOACS
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DOAC, mg
CHRISTOPHER BEYNON ET AL.
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Table 1. Characteristics of Patients with Acute Spinal Pathology During Treatment with DOAC
ORIGINAL ARTICLE
Posterior fusion day 12 after admission No improvement
SPINAL EMERGENCIES IN PATIENTS ON DOACS
laboratory/imaging studies, and treatment modalities (prohemostatic therapy, surgical treatment), as well as the further inhospital course of patients, are analyzed. Furthermore, we summarize the available data in the literature on this issue and discuss therapeutic options with specific focus on the reversal of anticoagulant effects. METHODS
Spondylodiscitis (C4eC7) Epidural Empyema (C4eC7) Spontaneous
Atlanto-occipital dislocation Traumatic
Male (58)
Female (64)
11
12
DOAC, direct oral anticoagulants; C, cervical spine; PCC, prothrombin complex concentrate; IU, international unit; RBC, red blood cells; T, thoracic spine.
PCC 2500 IU Tetraparesis Hypesthesia Rivaroxaban (20-0-0)
Suboccipital decompression Laminectomy C0eC2
5
900 mL
2 RBC concentrates 2 plasma concentrates
Revision surgery and posterior fusion day 9 after admission Symptoms improved PCC 3000 IU Neck pain Tetraparesis Bladder dysfunction Rivaroxaban (20-0-0)
Corpectomy C5 þ C6
11
100 mL
e
/ PCC 2000 IU Intradural meningioma (T7) Spontaneous Female (80) 10
Apixaban (2.5-0-2.5)
Paraparesis Hypesthesia
Laminectomy T7 Tumor resection
2.5
600 mL
e
Symptoms improved
CHRISTOPHER BEYNON ET AL.
WORLD NEUROSURGERY -: e1-e9, - 2019
This study was approved by the institutional review board. Data from all patients presenting to our institution with spinal emergencies while on DOAC therapy were included in this analysis (n ¼ 12). Data were retrospectively obtained from the medical charts of patients. All patients admitted to our department are subjected to examination of blood samples, including a full blood count, glucose, electrolytes, urea, creatinine, activated partial thromboplastin time, and international normalized ratio. The decisions to administer prohemostatic substances and to perform emergency surgery were taken by the consultant neurosurgeon on duty. Prohemostatic measures included the administration of PCC (Beriplex P/N; CSL Behring GmbH, Marburg, Germany), administration of tranexamic acid (Cyklokapron; Pfizer, Berlin, Germany), and transfusion of platelet concentrates. Surgery was initiated when preparations for surgery were completed. During the patients' further course, diagnostic procedures regarding thromboembolic or hemorrhagic events were carried out only if corresponding clinical symptoms occurred. Mechanical thromboembolic prophylaxis was provided by elastic stockings and furthermore, we administered low molecular weight heparin (Clexane; Sanofi-Aventis, Frankfurt, Germany) subcutaneously as soon as 8 hours after surgery. For descriptive statistics, we used GraphPad Prism 8 (GraphPad Software, San Diego, California, USA). A comprehensive literature strategy search was performed by 2 authors (C.B. and A.O.) independently in May 2019. Separate searches were carried out in the PubMed and Embase databases with the following search terms: “‘Spine surgery’ or ‘spinal emergency’ or ‘spinal hematoma’” and “‘anticoagulant’ or ‘apixaban’ or ‘betrixaban’ or ‘dabigatran’ or ‘edoxaban’ or ‘rivaroxaban.’” RESULTS Patient Characteristics A total of 12 patients (male: 6; female: 6) were identified, and details are described in Table 1. The median age was 71 years. Patients suffered from acute spinal cord compression caused by spinal tumor manifestation (n ¼ 5), empyema (n ¼ 4), degenerative spinal stenosis (n ¼ 1), hematoma (n ¼ 1), and vertebral body fracture/dislocation (n ¼ 2) (Figure 1). The most common clinical symptoms were limb paralysis (75%), pain (66%), hypesthesia/sensory loss (42%), and gait ataxia (33%). Patients presented with an intake of apixaban (25%), edoxaban (25%), and rivaroxaban (50%). Treatment Modalities All patients underwent emergency surgical treatment within a median time period of 6.5 hours. The decision to perform
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Figure 1. Exemplary magnetic resonance images of spinal pathologies of patients: (A) patient #4, tumor; (B) patient #1, empyema; (C) patient #8, hematoma).
emergency surgery and administer prohemostatic substances was taken by the attending neurosurgeon on duty. In the majority of cases (92%), surgery was initiated within 24 hours after hospital admission (Figure 2). (Hemi)laminectomy was carried out in 83% of patients and corpectomy on the cervical spine was performed anteriorly in 2 patients. Prohemostatic substances were administered perioperatively in 10 patients (83%) and included the administration of PCC (83%) and tranexamic acid (17%). Platelet concentrates were transfused in 1 patient with concomitant antiplatelet therapy. The median blood loss during surgery was 300 mL (interquartile range 174e525 mL), and intraoperative transfusion of red blood cells and/or plasma was necessary in 2 patients. Further In-Hospital Course and Short-Term Outcome Postoperative improvement of clinical symptoms was observed in 9 patients (75%). Two patients died during in-hospital treatment. Clinical symptoms of patient no. 2 with known malignant melanoma initially had improved after laminectomy and tumor debulking. However, the patient opted for comfort measures only
after development of severe dyspnea and diagnosis of widespread tumor manifestation. Patient no. 3, who had pre-existing heart insufficiency, died on the fifth day after multiple organ dysfunction due to sepsis. No surgical-site rehemorrhage or other hemorrhagic complications occurred, and no patient developed clinical signs of thromboembolic events. The literature review revealed a total of 19 reported spinal emergencies in patients on DOAC treatment (Table 2).3,5-22 The median age was 70 years, and all patients suffered from intraspinal hemorrhage. In the majority of cases, patients suffered from spontaneous hemorrhage (84%), whereas trauma-associated intraspinal hemorrhage occurred in 3 patients (16%). A total of 14 patients (74%) underwent surgical intervention, and prohemostatic treatment was reported in 8 patients (42%). Remarkably, some kind of intervention (e.g., knee surgery, spinal injection) within 4 hours to 1 month before symptom onset was reported in approximately every fourth patient (26%). Neurologic improvement was observed in 79% of patients during the further course, and no in-hospital mortality occurred. Clinical findings and treatment modalities were analyzed together with our present results and are described in Table 3.
DISCUSSION
Figure 2. The majority of patients (90%) underwent surgical therapy within 24 hours of hospital admission. In patient #8, the diagnosis of spinal epidural hematoma was established with a significant delay and surgery was initiated 4 days after hospital admission.
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Spinal emergencies such as hematoma-associated spinal cord compression may lead to severe neurologic deficits, paraplegia, and permanent care dependency. It is well-established that urgent surgical decompression is a crucial factor in the treatment of respective patients. Patients with spontaneous spinal epidural hematoma have the best chance of recovery to “normal” if operative intervention is carried out within 12 hours of symptom onset23 and surgery within 24 hours following traumatic spine injury has been associated with less complication rates in the further course.24 All patients in our study were treated
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2019.07.234
Study
Sex, Age (Years)
Pathology (Spinal Level) Spontaneous/ Traumatic
DOAC, mg
Clinical Symptoms
Prohemostatic Treatment
Emergency Surgery
Time to Surgery, Hours
Outcome
Comment
Female (61)
Subdural hematoma (C2 eT8) Spontaneous
Rivaroxaban (10-0-0)
Back pain Paraplegia
/
/
/
Complete recovery
Tibial osteotomy before symptom onset Improvement within 4 hours after symptom onset
Truumees et al., 20126
Male (72)
Epidural hematoma (T7 eT12) Vertebral body fractures (T7, T11, T12) Traumatic
Dabigatran (150-0-150)
Paraparesis Sensory loss
Transfusion FFP/ Platelets rFVIIa 2 mg
Laminectomy
Immediately
Symptoms improved
Severe hemorrhage during laminectomy Second surgery (instrumentation) after 7 days
Caputo et al., 20137
Male (70)
Epidural hematoma (L3 eL4) Spontaneous
Dabigatran (150-0-150)
Numbness Paraplegia
3-factor PCC
Laminectomy L3eL5 Hematoma evacuation
<2 hours
Complete recovery
Epidural steroid injection L4eL5 48 hours before symptom onset
Radcliff et al., 20148
Female (53)
Epidural hematoma (L4 eL5) Spontaneous
Rivaroxaban (dose NR)
Leg pain Paraparesis Bladder dysfunction
/
Laminectomy L4eL5 Hematoma evacuation
Emergency
Symptoms improved Residual neurogenic bladder
Knee arthroplasty day 6 before symptom onset
Bamps et al., 20159
Male (70)
Epidural hematoma (C2 eC4) Spontaneous
Dabigatran (150-0-150)
Neck pain Tetraplegia Sensory loss
PCC 25 IU/kg bw
Laminectomy C2 eC4 Hematoma evacuation
NR
Complete recovery
/
Castillo et al., 201510
Male (69)
Subdural hematoma (T3 eL1) Spontaneous
Rivaroxaban (20-0-0)
Back pain Paraplegia Bowel/bladder dysfunction
/
CSF drainage
11 days
No improvement
/
Zaarour et al., 20153
Male (58)
Subdural hematoma (C7 eT2) Spontaneous
Rivaroxaban (20-0-20)
Back pain Paraplegia Sensory loss
Aminocaproic acid
Corporectomy Hematoma evacuation
4 days
Symptoms improved
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DOAC, direct oral anticoagulants; C, cervical spine; T, thoracic spine; FFP, fresh-frozen plasma; rFVIIa, activated recombinant factor VII; L, lumbar spine; PCC, prothrombin complex concentrate; N/R, not reported; IU, international unit; bw, body weight; CSF, cerebrospinal fluid; N/A, not available. Continues
SPINAL EMERGENCIES IN PATIENTS ON DOACS
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Jaeger et al., 20125
CHRISTOPHER BEYNON ET AL.
WORLD NEUROSURGERY -: e1-e9, - 2019
Table 2. Reported Spinal Emergencies in Patients Treated with DOAC
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Study
Sex, Age (Years)
Pathology (Spinal Level) Spontaneous/ Traumatic
DOAC, mg
Clinical Symptoms
Prohemostatic Treatment
Emergency Surgery
Time to Surgery, Hours
Outcome
Comment
Subdural hematoma (T6 eT8) Spontaneous
Rivaroxaban (20-0-0)
Back pain Paraplegia Hypesthesia
PCC
Laminectomy T6 eT8 Hematoma evacuation
1 day
No improvement
/
Kircelli and Cöven, 210612
Male (70)
Subdural hematoma (C3 eC6) Spontaneous
Rivaroxaban (dose NR)
Cervical pain Tetraparesis
NR
Hematoma evacuation
NR
Neurologic sequelae
Spinal surgery (Laminectomy C3 eC6) 1 month prior to symptom onset
Ozel et al., 201613
Female (69)
Epidural hematoma (C2 eC4) Spontaneous
Rivaroxaban (10-0-0)
Cervical pain Tetraparesis
/
Conservative
/
Complete recovery
Hip arthroplasty 5 days before symptom onset
Sarwal et al., 201614
Male (81)
Epidural hematoma (T1 eT12) Spontaneous
Rivaroxaban (20-0-0)
Back pain Paraplegia Sensory loss
/
Conservative
/
Slight improvement
/
Colell et al., 210715
Female (75)
Subdural hematoma (T1 eT7) Spontaneous
Apixaban (2.5-0-2.5)
Paraparesis hypesthesia
NR
Laminectomy T1eT3 Hematoma evacuation
36 hours
Symptoms improved
Second surgery on day 7 after admission
De Vlieger et al., 201716
Female (80)
Subdural hematoma (T11 eL1) Spontaneous
Rivaroxaban (15-0-0)
Leg pain Paraplegia Hypesthesia
PCC 50 IU/kg bw Tranexamic acid 2g
Laminectomy T11eL1 Hematoma evacuation
5 hours
Pain improved No neurologic recovery
Ismail et al., 201717
Male (72)
Epidural hematoma (T11 eL2) Spontaneous
Rivaroxaban (20-0-0)
Back pain Paraparesis Bladder dysfunction
Transfusion FFP
Laminectomy T11eL2 Hematoma evacuation
4 hours
Complete recovery
/
Wolfe et al., 201718
Male (67)
Subdural hematoma/ subarachnoid hemorrhage (C6eC7) Traumatic
Dabigatran (dose NR)
Neck and back pain Unilateral weakness Unilateral hypesthesia
e
Conservative
N/A
Symptoms improved
/
ORIGINAL ARTICLE
Male (72)
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Dargazanli et al., 201611
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Table 2. Continued
ORIGINAL ARTICLE
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DOAC, direct oral anticoagulants; C, cervical spine; T, thoracic spine; FFP, fresh-frozen plasma; rFVIIa, activated recombinant factor VII; L, lumbar spine; PCC, prothrombin complex concentrate; N/R, not reported; IU, international unit; bw, body weight; CSF, cerebrospinal fluid; N/A, not available.
/ Symptoms improved Bladder dysfunction / Conservative NR Back pain Paraparesis Gait ataxia Bladder dysfunction Subdural hematoma (T1 eT5) Spontaneous Mchaourab et al., 201922
Male (68)
Apixaban (dose NR)
/ Complete recovery NR Laminectomy C3eC7 Hematoma evacuation Idarucizumab 5 g Neck pain Hemiparesis Epidural hematoma (C4 eT5) Spontaneous Mathais et al., 201821
Male (78)
Dabigatran (150-0-150)
/ NR NR Laminectomy Hematoma evacuation NR Neck pain Tetraplegia Respiratory insufficiency Epidural hematoma (C0 eC7) Spontaneous Male (74) Goldfine et al., 201820
Bang et al., 201819
Subdural hematoma (T9 eL2) Traumatic
Rivaroxaban (dose NR)
SPINAL EMERGENCIES IN PATIENTS ON DOACS
Female (age NR)
Rivaroxaban (dose NR)
Paraplegia
NR
Laminectomy
NR
No improvement
/
CHRISTOPHER BEYNON ET AL.
Table 3. Characteristics and Treatment Modalities of Spinal Emergencies in Patients on DOAC Treatment (Present Study and Case Reports) n (%) Patient Characteristics
n (%) Prohemostatic Treatment
Male
19 (61%)
PCC
Female
12 (39%)
Transfusion FFP
2 (6%)
Mean age, years
70 8
Transfusion platelets
2 (6%)
Trauma
5 (16%)
Antifibrinolytics
4 (13%)
rFVIIa
1 (3%)
Apixaban
5 (16%)
Idarucizumab
1 (3%)
Dabigatran
5 (16%) Management
DOAC
14 (45%)
Edoxaban
3 (10%)
Conservative
5 (16%)
Rivaroxaban
18 (58%)
Surgery
26 (84%)
Two-step surgery
6 (19%)
Clinical symptoms Paresis
28 (90%) Surgical procedure
Pain
23 (74%)
Hypesthesia
14 (45%)
Laminectomy
21 (68%)
Corpectomy
3 (10%)
Bowel/bladder dysfunction 6 (19%)
Hematoma evacuation
11 (35%)
Other
Empyema evacuation
3 (10%)
Tumor resection/ debulking
5 (16%)
CSF drainage
1 (3%)
7 (23%)
Pathology Epidural hematoma
10 (32%)
Subdural hematoma
10 (32%) Outcome
Subarachnoid hemorrhage
1 (3%)
Worse
0 (0%)
Empyema
4 (13%)
Unchanged
3 (10%)
Fracture/dislocation
3 10 (%)
Improved
27 (87%)
Tumor/metastasis
5 (16%)
Bleeding complication
0 (0%)
Degenerative spinal stenosis
1 (3%)
Thromboembolic event
0 (0%)
In-hospital mortality
2 (6%)
Localization Cervical
14 (45%)
Thoracic
19 (61%)
Lumbar
6 (19%)
DOAC, direct oral anticoagulants; PCC, prothrombin complex concentrate; FFP, fresh-frozen plasma; rFVIIa, activated recombinant factor VII; CSF, cerebrospinal fluid.
surgically and, in the majority of cases, procedures were carried out on the day of patient admission. The literature search revealed conservative treatment in 4 patients with spontaneous spinal hemorrhage during DOAC treatment. In 1 patient, the prognosis was deemed futile and in his further course, he remained wheel-chair bound without sensorimotor function.14
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One patient had only mild symptoms,18 and 2 patients experienced spontaneous recovery within 4 hours after hospital admission.5,13 Although spontaneous recovery may rarely occur in patients with anticoagulant-associated intraspinal hematoma, the majority of these patients should undergo surgical decompression as soon as possible to avoid permanent neurologic impairment. Conservative management should be reserved for cases in which neurologic deficits are absent, continuous clinical recovery is observed early, or in cases in whom surgical therapy is associated with an unacceptable high risk of perioperative morbidity and mortality. However, it has to be emphasized that urgent surgery during DOAC treatment should be reserved for cases with acute neurologic impairment due to compression of spinal cord or nerve roots. Elective surgery in DOAC-treated patients should be carried out only after complete restoration of hemostasis following cessation of drug intake. Whether a delay of surgical decompression is justified to allow restoration of hemostasis in an emergency patient has to be decided on several factors, such as dynamics of the acute pathology and present comorbidities. Intraoperative hemostasis was regarded as “unremarkable” in all patients, and no hemorrhagic complications such as onsite rehemorrhage was observed during the further postoperative course. These findings are consistent with reports of other authors, and only a single case of severe intraoperative hemorrhage was reported by Truumees et al.6 in a patient with dabigatran intake and traumatic vertebral fractures. Croci et al.25 recently reported their findings on 82 DOAC-treated patients who underwent spine surgery at their institution. No bleeding complications occurred in 7 patients who had withdrawn DOAC medication less than 24 hours before surgery. However, compared with patients with DOAC withdrawal >24 hours before surgery, red blood cells were transfused significantly more often. Several guidelines on the management of bleeding complications and performing emergency surgery in patients treated with DOAC are available.1 Administration of idarucizumab is recommended for specific dabigatran reversal, and this approach was reported in a patient with complete recovery after cervical laminectomy and evacuation of a spontaneous epidural hematoma.21 Prohemostatic options in patients with factor Xa inhibitors include administration of PCC, desmopressin, and antifibrinolytics. The specific antidote andexanet alfa was recently approved by the Food and Drug Administration for reversal of apixaban and rivaroxaban in cases of life-threatening bleeding.26 This antidote may present a more effective method of anticoagulation reversal in patients in need of emergency surgery, but approval of andexanet alfa is still pending in the European Union. We administered PCC in the majority of patients (83%), and it was also the most commonly used agent in cases reported by other authors. However, the efficacy of PCC administration is not clear, as the rationale for its use is based on pathophysiologic considerations and data on its clinical use
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for DOAC reversal are limited. The use of PCC is associated with an increased risk of thromboembolism due to its prothrombotic activity. Importantly, we did not observe any thromboembolic events in our patients, and we did not identify respective findings in reported cases of patients with acute spinal pathology while on DOAC therapy, even after administration of prohemostatic substances. Nevertheless, further studies with large numbers of patients are needed to characterize the potential and limitations of prohemostatic treatment in patients undergoing emergency surgery during DOAC therapy. As outlined, the time frame from symptom onset to neurosurgical decompression is crucial to achieve a favorable neurologic outcome. Performing surgical procedures 2-staged is an option to limit the invasiveness of initial surgery, thereby minimizing the risk of surgical bleeding. This approach was chosen in 4 patients who underwent posterior fusion after initial decompression surgery. Three of these 4 patients had suffered from spinal empyema or tumor manifestation and in our view, these patients are particularly suitable for this approach. Two-staged surgery also was reported in a case of intraoperative severe hemorrhage during dabigatran therapy.6 A patient with persistent subdural hematoma after initial laminectomy and hematoma evacuation also underwent second surgery.15 There are several limitations of our study, as it represents a retrospective analysis with limited patient numbers. The risk of neurologic impairment and disability cannot be definitely predicted, and the further course of patients if surgery would have been delayed or even not performed is unknown. Measures to detect thromboembolic events were only initiated if suspicious clinical symptoms occurred and therefore, thromboembolism may have been underdiagnosed in the present study. Despite these limitations, the present study represents the largest series on patients treated for acute spinal pathology during treatment with DOAC.
CONCLUSIONS Our initial experiences demonstrate that emergency surgery is feasible in patients treated for acute spinal pathology during DOAC treatment. Early surgery may prevent permanent neurologic impairment caused by persistent compression of neural structures. The literature review of published cases supports our clinical observations as neurologic improvement following DOACassociated intraspinal hemorrhage was observed in more than 75% of patients. Specific antidotes are available for the direct thrombin inhibitor dabigatran and are currently introduced for factor Xa inhibitors. Prohemostatic agents such as PCC and tranexamic acid may promote coagulation in patients undergoing emergency surgery but further studies are necessary to evaluate their effectiveness in clinical practice.
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2019.07.234
ORIGINAL ARTICLE CHRISTOPHER BEYNON ET AL.
SPINAL EMERGENCIES IN PATIENTS ON DOACS
REFERENCES 1. Steffel J, Verhamme P, Potpara TS, et al. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J. 2018;39:1330-1393. 2. Pollack CV, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373:511-520. 3. Zaarour M, Hassan S, Thumallapally N, Dai Q. Rivaroxaban-induced nontraumatic spinal subdural hematoma: an uncommon yet lifethreatening complication. Case Rep Hematol. 2015; 2015:275380. 4. Beynon C, Potzy A, Unterberg AW, Sakowitz OW. Prothrombin complex concentrate facilitates emergency spinal surgery in anticoagulated patients. Acta Neurochir (Wien). 2014;156:741-747. 5. Jaeger M, Jeanneret B, Schaeren S. Spontaneous spinal epidural haematoma during Factor Xa inhibitor treatment (Rivaroxaban). Eur Spine J. 2012; 21(suppl 4):S433-435. 6. Truumees E, Gaudu T, Dieterichs C, Geck M, Stokes J. Epidural hematoma and intraoperative hemorrhage in a spine trauma patient on Pradaxa (dabigatran). Spine (Phila Pa 1976). 2012;37: E863-E865. 7. Caputo AM, Gottfried ON, Nimjee SM, Brown CR, Michael KW, Richardson WJ. Spinal epidural hematoma following epidural steroid injection in a patient treated with dabigatran: a case report. JBJS Case Connect. 2013;3(2 suppl 9):e64. 8. Radcliff KE, Ong A, Parvizi J, Post Z, Orozco F. Rivaroxaban-induced epidural hematoma and cauda equina syndrome after total knee arthroplasty: a case report. Orthop Surg. 2014;6:69-71. 9. Bamps S, Decramer T, Vandenbussche N, et al. Dabigatran-associated spontaneous acute cervical epidural hematoma. World Neurosurg. 2015;83: 257-258. 10. Castillo JM, Afanador HF, Manjarrez E, Morales XA. Non-traumatic spontaneous spinal
subdural hematoma in a patient with non-valvular atrial fibrillation during treatment with rivaroxaban. Am J Case Rep. 2015;16:377-381.
20. Goldfine C, Glazer C, Ratzan RM. Spontaneous spinal epidural hematoma from rivaroxaban. Clin Pract Cases Emerg Med. 2018;2:151-154.
11. Dargazanli C, Lonjon N, Gras-Combe G. Nontraumatic spinal subdural hematoma complicating direct factor Xa inhibitor treatment (rivaroxaban): a challenging management. Eur Spine J. 2016; 25(suppl 1):100-103.
21. Mathais Q, Esnault P, Cruc M, Bernard C, Prunet B, Gaillard PE. Spontaneous cervical spinal epidural hematoma associated with dabigatran. World Neurosurg. 2018;112:264-266.
12. Kircelli A, Cöven I. Spontan spinal epidural hematoma in a patient receiving rivaroxaban after atrial fibrillation. Am J Cardiol. 2018;121:e13-e14. 13. Ozel O, Demircay E, Kircelli A, Cansever T. Atypical presentation of an epidural hematoma in a patient receiving rivaroxaban after total hip arthroplasty. Orthopedics. 2016;39:e558-e560. 14. Sarwal G, Dandurand C, Lee AYY, Vu VH. Could anticoagulation with rivaroxaban have precipitated a spinal epidural hematoma: from independent mobility to paraplegia. UBC Med J. 2016;8:134-137. 15. Colell A, Arboix A, Caiazzo F, Grivé E. Iatrogenic spinal subdural hematoma due to apixaban: a case report and review of the literature. Case Rep Hematol. 2018;2018:4507638. 16. De Vlieger J, Dietvorst S, Demaerel R, Verhamme P, Nuttin B, Vanassche T. Neurosurgery in a patient at peak levels of rivaroxaban: taking into account all factors. Res Pract Thromb Haemost. 2017;1:296-300. 17. Ismail R, Zaghrini E, Hitti E. Spontaneous spinal epidural hematoma in a patient on rivaroxaban: case report and literature review. J Emerg Med. 2017;53:536-539. 18. Wolfe AR, Faroqui RM, Visvikis GA, Mantello MT, Perel AB, Tewari SO. Spinal subarachnoid and subdural hematoma presenting as a BrownSéquard-like myelopathy following minor trauma in a patient on dabigatran etexilate. Radiol Case Rep. 2017;12:257-260.
22. Mchaourab A, Evans GYR, Austin R. Spontaneous spinal subdural haematoma in a patient on apixaban. BMJ Case Rep. 2019;12:e227311. 23. Mukerji N, Todd N. Spinal epidural haematoma; factors influencing outcome. Br J Neurosurg. 2013; 27:712-717. 24. Bourassa-Moreau E, Mac-Thiong J-M, Feldman DE, Thompson C, Parent S. Nonneurological outcomes following complete traumatic spinal cord injury: the impact of surgical timing. J Neurotrauma. 2013;30:1596-1601. 25. Croci DM, Dalolio M, Guzman R, et al. Direct oral anticoagulants in patients undergoing spine surgery [e-pub ahead of print]. World Neurosurg https://doi. org/10.1016/j.wneu.2019.01.236, accessed August 24, 2019. 26. Culbreth SE, Rimsans J, Sylvester K, Pallin DJ, Connors JM. Andexanet alfa-The first 150 days. Am J Hematol. 2019;94:E21-E24.
Conflict of interest statement: Christopher Beynon has received personal fees outside the submitted work from Bayer Healthcare, Boehringer Ingelheim, and CSL Behring. For the remaining authors, no competing financial interests exist. Received 12 May 2019; accepted 31 July 2019 Citation: World Neurosurg. (2019). https://doi.org/10.1016/j.wneu.2019.07.234 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com
19. Bang WS, Kim KT, Park MK, Sung JK, Lee H, Cho DC. Acute spinal subdural hematoma in a patient taking rivaroxaban. J Korean Med Sci. 2018; 33:e40.
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Management of Spinal Emergencies in Patients on Direct Oral Anticoagulants Christopher Beynon1, Arturo Olivares1, Christoph Gumbinger2, Alexander Younsi1, Klaus Zweckberger1, Andreas W. Unterberg1
OBJECTIVE: Spine surgeons increasingly encounter acute spinal pathologies in patients treated with direct oral anticoagulants (DOACs), but only limited data on the management of these patients are currently available.
-
METHODS: We retrospectively analyzed patients who presented to our department with acute spinal pathology during treatment with DOAC and who required urgent surgical therapy. Patient characteristics and treatment modalities were studied, with specific focus on the management of hemostasis and surgical therapy. Furthermore, we analyzed 19 cases of spinal emergencies during DOAC treatment reported in the literature.
tranexamic acid may improve the coagulation before surgery, especially in cases of unavailable specific antidotes.
-
RESULTS: A total of 12 patients were identified and included in the present analysis. Patients suffered from acute spinal cord compression caused by spinal tumor manifestation (n [ 5), empyema (n [ 4), degenerative spinal stenosis (n [ 1), hematoma (n [ 1), and vertebral body fracture/dislocation (n [ 2). All patients underwent emergency surgical treatment. Prohemostatic substances were administered perioperatively in 10 patients (83%) and included administration of prothrombin complex concentrates (83%), tranexamic acid (17%), and transfusion of platelets (8%). A total of 9 patients (75%) showed postoperative improvement of neurologic symptoms, and the in-hospital mortality in this patient cohort was 17%.
-
CONCLUSIONS: Emergency spine surgery is feasible and should be considered in patients on treatment with DOAC. The (low) risk of intraoperative bleeding complications has to be weighed against the risk of permanent disability if surgical decompression is delayed. Administration of prothrombin complex concentrates and
-
Key words - Anticoagulants - Hemorrhage - Hemostasis - Spine Abbreviations and Acronyms DOAC: Direct oral anticoagulants PCC: Prothrombin complex concentrate
INTRODUCTION
D
irect oral anticoagulants (DOAC) increasingly are used for the treatment and prevention of thromboembolic events. Several “real-world” registries have confirmed findings of pivotal trials that DOAC are safe and have considerable advantages compared with vitamin K antagonists.1 However, the management of patients presenting with bleeding complications or requiring emergency surgery is still a matter of debate. A specific antidote (idarucizumab) for the direct thrombin inhibitor dabigatran became available in 2015,2 but no specific antidotes for oral factor Xa inhibitors (apixaban, betrixaban, edoxaban, rivaroxaban) are yet available in the European Union. The majority of surgical procedures on the spine are carried out in an elective manner, and hemostasis can be optimized before surgery. However, spine surgeons often are confronted with spinal emergencies such as traumatic injury or spinal hemorrhage requiring immediate decompression of the spinal cord to avoid permanent neurologic impairment. In patients treated with antithrombotic medication, impaired hemostasis may increase the risk for intraoperative bleeding complications with potentially lifethreatening consequences.3 Administration of prothrombin complex concentrates (PCC) effectively reverses anticoagulation in patients on treatment with vitamin K antagonists, and it has been demonstrated previously that its use facilitates emergency spinal surgery in respective patients.4 In contrast, data on emergency spinal surgery in patents on DOAC are limited to case reports, predominantly dealing with DOAC-associated spontaneous spinal hemorrhage. Here we report our experiences on the emergency management of patients with spinal emergencies while on treatment with DOAC. Clinical findings, results of
From the Departments of 1Neurosurgery and 2Neurology, Heidelberg University Hospital, Heidelberg, Germany To whom correspondence should be addressed: Christopher Beynon, M.D., Ph.D. [E-mail: [email protected]] Citation: World Neurosurg. (2019). https://doi.org/10.1016/j.wneu.2019.07.234 Journal homepage: www.journals.elsevier.com/world-neurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY -: e1-e9, - 2019
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No.
Sex, Age (Years)
1
Female (68)
2
Pathology (Spinal Level) Spontaneous/ Traumatic
Prohemostatic Treatment
Emergency Surgery
Time to Surgery from Admission, Hours
Blood Loss, mL
Transfusion
Outcome
Comment
Symptoms improved
Posterior fusion day 14 after admission
Epidural empyema (C2eC5) Spontaneous
Edoxaban (30-0-0)
Neck pain Tetraparesis (2/5)
PCC 2500 IU
Laminectomy C3eC5, Empyema evacuation
2
200 mL
e
Male (55)
Malignant melanoma metastasis (T11) Spontaneous
Apixaban (5-0-5)
Back pain Gait disturbance Hypesthesia Bladder dysfunction
PCC 3500 IU
Laminectomy T10-T12 Tumor debulking
5
400 mL
e
Neurologic Comfort measures symptoms only due to improved after widespread surgery tumor disease Died (day 22 after admission)
3
Male (79)
Epidural empyema (C2eT1) Spondylodiscitis (C5/6 and C 6/7) Spontaneous
Apixaban (2.5-0-2.5)
Back pain Tetraparesis Sepsis
PCC 3000 IU Transfusion platelets Tranexamic acid 1g
Corpectomy C5eC6 Empyema evacuation
1.5
1300 mL
4 RBC concentrates
Died (day 5 At admission after admission) high cardiac due to heart enzymes, insufficiency heart catheter
4
Male (66)
Liposarcoma metastasis (T5eT7) Spontaneous
Rivaroxaban (20-0-0)
Back pain Gait disturbance Hypesthesia
e
Laminectomy T5eT7 Tumor debulking
23.5
100 mL
e
Complete recovery
/
5
Female (66)
Intradural meningioma (T8) Spontaneous
Rivaroxaban (20-0-0)
Paraparesis Gait disturbance Bladder dysfunction
PCC 1000 IU Tranexamic acid 1g
Laminectomy T8 Tumor resection
24
500 mL
e
Symptoms improved
/
6
Male (89)
Degenerative stenosis Myelopathy (C4 eC6) Traumatic
Rivaroxaban (20-0-0)
Paraplegia
e
Laminectomy C3eC7
6
200 mL
e
No improvement
/
7
Male (73)
Prostate cancer metastasis Vertebral fracture (T6) Spontaneous
Edoxaban (30-0-0)
Back pain Paraparesis Sensory loss
PCC 2500 IU
Laminectomy T5eT7 Tumor debulking
11
200 mL
e
Symptoms improved
Posterior fusion d5 after admission
8
Female (76)
Epidural hematoma (C2eC7) Spontaneous
Edoxaban (60-0-0)
Neck pain Gait ataxia Hemiparesis
PCC 3000 IU
Hemilaminectomy C4eC5
4 days
100 mL
e
Symptoms improved
/
9
Female (63)
Epidural empyema (T4eT9) Spontaneous
Rivaroxaban (20-0-0)
Back pain Spinal myoclonus Sepsis
PCC 3500 IU
Laminectomy T4eT9 Empyema evacuation
7
500 mL
e
Symptoms improved
/
ORIGINAL ARTICLE
Clinical Symptoms
SPINAL EMERGENCIES IN PATIENTS ON DOACS
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DOAC, mg
CHRISTOPHER BEYNON ET AL.
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Table 1. Characteristics of Patients with Acute Spinal Pathology During Treatment with DOAC
ORIGINAL ARTICLE
Posterior fusion day 12 after admission No improvement
SPINAL EMERGENCIES IN PATIENTS ON DOACS
laboratory/imaging studies, and treatment modalities (prohemostatic therapy, surgical treatment), as well as the further inhospital course of patients, are analyzed. Furthermore, we summarize the available data in the literature on this issue and discuss therapeutic options with specific focus on the reversal of anticoagulant effects. METHODS
Spondylodiscitis (C4eC7) Epidural Empyema (C4eC7) Spontaneous
Atlanto-occipital dislocation Traumatic
Male (58)
Female (64)
11
12
DOAC, direct oral anticoagulants; C, cervical spine; PCC, prothrombin complex concentrate; IU, international unit; RBC, red blood cells; T, thoracic spine.
PCC 2500 IU Tetraparesis Hypesthesia Rivaroxaban (20-0-0)
Suboccipital decompression Laminectomy C0eC2
5
900 mL
2 RBC concentrates 2 plasma concentrates
Revision surgery and posterior fusion day 9 after admission Symptoms improved PCC 3000 IU Neck pain Tetraparesis Bladder dysfunction Rivaroxaban (20-0-0)
Corpectomy C5 þ C6
11
100 mL
e
/ PCC 2000 IU Intradural meningioma (T7) Spontaneous Female (80) 10
Apixaban (2.5-0-2.5)
Paraparesis Hypesthesia
Laminectomy T7 Tumor resection
2.5
600 mL
e
Symptoms improved
CHRISTOPHER BEYNON ET AL.
WORLD NEUROSURGERY -: e1-e9, - 2019
This study was approved by the institutional review board. Data from all patients presenting to our institution with spinal emergencies while on DOAC therapy were included in this analysis (n ¼ 12). Data were retrospectively obtained from the medical charts of patients. All patients admitted to our department are subjected to examination of blood samples, including a full blood count, glucose, electrolytes, urea, creatinine, activated partial thromboplastin time, and international normalized ratio. The decisions to administer prohemostatic substances and to perform emergency surgery were taken by the consultant neurosurgeon on duty. Prohemostatic measures included the administration of PCC (Beriplex P/N; CSL Behring GmbH, Marburg, Germany), administration of tranexamic acid (Cyklokapron; Pfizer, Berlin, Germany), and transfusion of platelet concentrates. Surgery was initiated when preparations for surgery were completed. During the patients' further course, diagnostic procedures regarding thromboembolic or hemorrhagic events were carried out only if corresponding clinical symptoms occurred. Mechanical thromboembolic prophylaxis was provided by elastic stockings and furthermore, we administered low molecular weight heparin (Clexane; Sanofi-Aventis, Frankfurt, Germany) subcutaneously as soon as 8 hours after surgery. For descriptive statistics, we used GraphPad Prism 8 (GraphPad Software, San Diego, California, USA). A comprehensive literature strategy search was performed by 2 authors (C.B. and A.O.) independently in May 2019. Separate searches were carried out in the PubMed and Embase databases with the following search terms: “‘Spine surgery’ or ‘spinal emergency’ or ‘spinal hematoma’” and “‘anticoagulant’ or ‘apixaban’ or ‘betrixaban’ or ‘dabigatran’ or ‘edoxaban’ or ‘rivaroxaban.’” RESULTS Patient Characteristics A total of 12 patients (male: 6; female: 6) were identified, and details are described in Table 1. The median age was 71 years. Patients suffered from acute spinal cord compression caused by spinal tumor manifestation (n ¼ 5), empyema (n ¼ 4), degenerative spinal stenosis (n ¼ 1), hematoma (n ¼ 1), and vertebral body fracture/dislocation (n ¼ 2) (Figure 1). The most common clinical symptoms were limb paralysis (75%), pain (66%), hypesthesia/sensory loss (42%), and gait ataxia (33%). Patients presented with an intake of apixaban (25%), edoxaban (25%), and rivaroxaban (50%). Treatment Modalities All patients underwent emergency surgical treatment within a median time period of 6.5 hours. The decision to perform
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ORIGINAL ARTICLE CHRISTOPHER BEYNON ET AL.
SPINAL EMERGENCIES IN PATIENTS ON DOACS
Figure 1. Exemplary magnetic resonance images of spinal pathologies of patients: (A) patient #4, tumor; (B) patient #1, empyema; (C) patient #8, hematoma).
emergency surgery and administer prohemostatic substances was taken by the attending neurosurgeon on duty. In the majority of cases (92%), surgery was initiated within 24 hours after hospital admission (Figure 2). (Hemi)laminectomy was carried out in 83% of patients and corpectomy on the cervical spine was performed anteriorly in 2 patients. Prohemostatic substances were administered perioperatively in 10 patients (83%) and included the administration of PCC (83%) and tranexamic acid (17%). Platelet concentrates were transfused in 1 patient with concomitant antiplatelet therapy. The median blood loss during surgery was 300 mL (interquartile range 174e525 mL), and intraoperative transfusion of red blood cells and/or plasma was necessary in 2 patients. Further In-Hospital Course and Short-Term Outcome Postoperative improvement of clinical symptoms was observed in 9 patients (75%). Two patients died during in-hospital treatment. Clinical symptoms of patient no. 2 with known malignant melanoma initially had improved after laminectomy and tumor debulking. However, the patient opted for comfort measures only
after development of severe dyspnea and diagnosis of widespread tumor manifestation. Patient no. 3, who had pre-existing heart insufficiency, died on the fifth day after multiple organ dysfunction due to sepsis. No surgical-site rehemorrhage or other hemorrhagic complications occurred, and no patient developed clinical signs of thromboembolic events. The literature review revealed a total of 19 reported spinal emergencies in patients on DOAC treatment (Table 2).3,5-22 The median age was 70 years, and all patients suffered from intraspinal hemorrhage. In the majority of cases, patients suffered from spontaneous hemorrhage (84%), whereas trauma-associated intraspinal hemorrhage occurred in 3 patients (16%). A total of 14 patients (74%) underwent surgical intervention, and prohemostatic treatment was reported in 8 patients (42%). Remarkably, some kind of intervention (e.g., knee surgery, spinal injection) within 4 hours to 1 month before symptom onset was reported in approximately every fourth patient (26%). Neurologic improvement was observed in 79% of patients during the further course, and no in-hospital mortality occurred. Clinical findings and treatment modalities were analyzed together with our present results and are described in Table 3.
DISCUSSION
Figure 2. The majority of patients (90%) underwent surgical therapy within 24 hours of hospital admission. In patient #8, the diagnosis of spinal epidural hematoma was established with a significant delay and surgery was initiated 4 days after hospital admission.
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Spinal emergencies such as hematoma-associated spinal cord compression may lead to severe neurologic deficits, paraplegia, and permanent care dependency. It is well-established that urgent surgical decompression is a crucial factor in the treatment of respective patients. Patients with spontaneous spinal epidural hematoma have the best chance of recovery to “normal” if operative intervention is carried out within 12 hours of symptom onset23 and surgery within 24 hours following traumatic spine injury has been associated with less complication rates in the further course.24 All patients in our study were treated
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2019.07.234
Study
Sex, Age (Years)
Pathology (Spinal Level) Spontaneous/ Traumatic
DOAC, mg
Clinical Symptoms
Prohemostatic Treatment
Emergency Surgery
Time to Surgery, Hours
Outcome
Comment
Female (61)
Subdural hematoma (C2 eT8) Spontaneous
Rivaroxaban (10-0-0)
Back pain Paraplegia
/
/
/
Complete recovery
Tibial osteotomy before symptom onset Improvement within 4 hours after symptom onset
Truumees et al., 20126
Male (72)
Epidural hematoma (T7 eT12) Vertebral body fractures (T7, T11, T12) Traumatic
Dabigatran (150-0-150)
Paraparesis Sensory loss
Transfusion FFP/ Platelets rFVIIa 2 mg
Laminectomy
Immediately
Symptoms improved
Severe hemorrhage during laminectomy Second surgery (instrumentation) after 7 days
Caputo et al., 20137
Male (70)
Epidural hematoma (L3 eL4) Spontaneous
Dabigatran (150-0-150)
Numbness Paraplegia
3-factor PCC
Laminectomy L3eL5 Hematoma evacuation
<2 hours
Complete recovery
Epidural steroid injection L4eL5 48 hours before symptom onset
Radcliff et al., 20148
Female (53)
Epidural hematoma (L4 eL5) Spontaneous
Rivaroxaban (dose NR)
Leg pain Paraparesis Bladder dysfunction
/
Laminectomy L4eL5 Hematoma evacuation
Emergency
Symptoms improved Residual neurogenic bladder
Knee arthroplasty day 6 before symptom onset
Bamps et al., 20159
Male (70)
Epidural hematoma (C2 eC4) Spontaneous
Dabigatran (150-0-150)
Neck pain Tetraplegia Sensory loss
PCC 25 IU/kg bw
Laminectomy C2 eC4 Hematoma evacuation
NR
Complete recovery
/
Castillo et al., 201510
Male (69)
Subdural hematoma (T3 eL1) Spontaneous
Rivaroxaban (20-0-0)
Back pain Paraplegia Bowel/bladder dysfunction
/
CSF drainage
11 days
No improvement
/
Zaarour et al., 20153
Male (58)
Subdural hematoma (C7 eT2) Spontaneous
Rivaroxaban (20-0-20)
Back pain Paraplegia Sensory loss
Aminocaproic acid
Corporectomy Hematoma evacuation
4 days
Symptoms improved
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ORIGINAL ARTICLE
DOAC, direct oral anticoagulants; C, cervical spine; T, thoracic spine; FFP, fresh-frozen plasma; rFVIIa, activated recombinant factor VII; L, lumbar spine; PCC, prothrombin complex concentrate; N/R, not reported; IU, international unit; bw, body weight; CSF, cerebrospinal fluid; N/A, not available. Continues
SPINAL EMERGENCIES IN PATIENTS ON DOACS
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Jaeger et al., 20125
CHRISTOPHER BEYNON ET AL.
WORLD NEUROSURGERY -: e1-e9, - 2019
Table 2. Reported Spinal Emergencies in Patients Treated with DOAC
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Study
Sex, Age (Years)
Pathology (Spinal Level) Spontaneous/ Traumatic
DOAC, mg
Clinical Symptoms
Prohemostatic Treatment
Emergency Surgery
Time to Surgery, Hours
Outcome
Comment
Subdural hematoma (T6 eT8) Spontaneous
Rivaroxaban (20-0-0)
Back pain Paraplegia Hypesthesia
PCC
Laminectomy T6 eT8 Hematoma evacuation
1 day
No improvement
/
Kircelli and Cöven, 210612
Male (70)
Subdural hematoma (C3 eC6) Spontaneous
Rivaroxaban (dose NR)
Cervical pain Tetraparesis
NR
Hematoma evacuation
NR
Neurologic sequelae
Spinal surgery (Laminectomy C3 eC6) 1 month prior to symptom onset
Ozel et al., 201613
Female (69)
Epidural hematoma (C2 eC4) Spontaneous
Rivaroxaban (10-0-0)
Cervical pain Tetraparesis
/
Conservative
/
Complete recovery
Hip arthroplasty 5 days before symptom onset
Sarwal et al., 201614
Male (81)
Epidural hematoma (T1 eT12) Spontaneous
Rivaroxaban (20-0-0)
Back pain Paraplegia Sensory loss
/
Conservative
/
Slight improvement
/
Colell et al., 210715
Female (75)
Subdural hematoma (T1 eT7) Spontaneous
Apixaban (2.5-0-2.5)
Paraparesis hypesthesia
NR
Laminectomy T1eT3 Hematoma evacuation
36 hours
Symptoms improved
Second surgery on day 7 after admission
De Vlieger et al., 201716
Female (80)
Subdural hematoma (T11 eL1) Spontaneous
Rivaroxaban (15-0-0)
Leg pain Paraplegia Hypesthesia
PCC 50 IU/kg bw Tranexamic acid 2g
Laminectomy T11eL1 Hematoma evacuation
5 hours
Pain improved No neurologic recovery
Ismail et al., 201717
Male (72)
Epidural hematoma (T11 eL2) Spontaneous
Rivaroxaban (20-0-0)
Back pain Paraparesis Bladder dysfunction
Transfusion FFP
Laminectomy T11eL2 Hematoma evacuation
4 hours
Complete recovery
/
Wolfe et al., 201718
Male (67)
Subdural hematoma/ subarachnoid hemorrhage (C6eC7) Traumatic
Dabigatran (dose NR)
Neck and back pain Unilateral weakness Unilateral hypesthesia
e
Conservative
N/A
Symptoms improved
/
ORIGINAL ARTICLE
Male (72)
SPINAL EMERGENCIES IN PATIENTS ON DOACS
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Table 2. Continued
ORIGINAL ARTICLE
WORLD NEUROSURGERY -: e1-e9, - 2019
DOAC, direct oral anticoagulants; C, cervical spine; T, thoracic spine; FFP, fresh-frozen plasma; rFVIIa, activated recombinant factor VII; L, lumbar spine; PCC, prothrombin complex concentrate; N/R, not reported; IU, international unit; bw, body weight; CSF, cerebrospinal fluid; N/A, not available.
/ Symptoms improved Bladder dysfunction / Conservative NR Back pain Paraparesis Gait ataxia Bladder dysfunction Subdural hematoma (T1 eT5) Spontaneous Mchaourab et al., 201922
Male (68)
Apixaban (dose NR)
/ Complete recovery NR Laminectomy C3eC7 Hematoma evacuation Idarucizumab 5 g Neck pain Hemiparesis Epidural hematoma (C4 eT5) Spontaneous Mathais et al., 201821
Male (78)
Dabigatran (150-0-150)
/ NR NR Laminectomy Hematoma evacuation NR Neck pain Tetraplegia Respiratory insufficiency Epidural hematoma (C0 eC7) Spontaneous Male (74) Goldfine et al., 201820
Bang et al., 201819
Subdural hematoma (T9 eL2) Traumatic
Rivaroxaban (dose NR)
SPINAL EMERGENCIES IN PATIENTS ON DOACS
Female (age NR)
Rivaroxaban (dose NR)
Paraplegia
NR
Laminectomy
NR
No improvement
/
CHRISTOPHER BEYNON ET AL.
Table 3. Characteristics and Treatment Modalities of Spinal Emergencies in Patients on DOAC Treatment (Present Study and Case Reports) n (%) Patient Characteristics
n (%) Prohemostatic Treatment
Male
19 (61%)
PCC
Female
12 (39%)
Transfusion FFP
2 (6%)
Mean age, years
70 8
Transfusion platelets
2 (6%)
Trauma
5 (16%)
Antifibrinolytics
4 (13%)
rFVIIa
1 (3%)
Apixaban
5 (16%)
Idarucizumab
1 (3%)
Dabigatran
5 (16%) Management
DOAC
14 (45%)
Edoxaban
3 (10%)
Conservative
5 (16%)
Rivaroxaban
18 (58%)
Surgery
26 (84%)
Two-step surgery
6 (19%)
Clinical symptoms Paresis
28 (90%) Surgical procedure
Pain
23 (74%)
Hypesthesia
14 (45%)
Laminectomy
21 (68%)
Corpectomy
3 (10%)
Bowel/bladder dysfunction 6 (19%)
Hematoma evacuation
11 (35%)
Other
Empyema evacuation
3 (10%)
Tumor resection/ debulking
5 (16%)
CSF drainage
1 (3%)
7 (23%)
Pathology Epidural hematoma
10 (32%)
Subdural hematoma
10 (32%) Outcome
Subarachnoid hemorrhage
1 (3%)
Worse
0 (0%)
Empyema
4 (13%)
Unchanged
3 (10%)
Fracture/dislocation
3 10 (%)
Improved
27 (87%)
Tumor/metastasis
5 (16%)
Bleeding complication
0 (0%)
Degenerative spinal stenosis
1 (3%)
Thromboembolic event
0 (0%)
In-hospital mortality
2 (6%)
Localization Cervical
14 (45%)
Thoracic
19 (61%)
Lumbar
6 (19%)
DOAC, direct oral anticoagulants; PCC, prothrombin complex concentrate; FFP, fresh-frozen plasma; rFVIIa, activated recombinant factor VII; CSF, cerebrospinal fluid.
surgically and, in the majority of cases, procedures were carried out on the day of patient admission. The literature search revealed conservative treatment in 4 patients with spontaneous spinal hemorrhage during DOAC treatment. In 1 patient, the prognosis was deemed futile and in his further course, he remained wheel-chair bound without sensorimotor function.14
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ORIGINAL ARTICLE CHRISTOPHER BEYNON ET AL.
SPINAL EMERGENCIES IN PATIENTS ON DOACS
One patient had only mild symptoms,18 and 2 patients experienced spontaneous recovery within 4 hours after hospital admission.5,13 Although spontaneous recovery may rarely occur in patients with anticoagulant-associated intraspinal hematoma, the majority of these patients should undergo surgical decompression as soon as possible to avoid permanent neurologic impairment. Conservative management should be reserved for cases in which neurologic deficits are absent, continuous clinical recovery is observed early, or in cases in whom surgical therapy is associated with an unacceptable high risk of perioperative morbidity and mortality. However, it has to be emphasized that urgent surgery during DOAC treatment should be reserved for cases with acute neurologic impairment due to compression of spinal cord or nerve roots. Elective surgery in DOAC-treated patients should be carried out only after complete restoration of hemostasis following cessation of drug intake. Whether a delay of surgical decompression is justified to allow restoration of hemostasis in an emergency patient has to be decided on several factors, such as dynamics of the acute pathology and present comorbidities. Intraoperative hemostasis was regarded as “unremarkable” in all patients, and no hemorrhagic complications such as onsite rehemorrhage was observed during the further postoperative course. These findings are consistent with reports of other authors, and only a single case of severe intraoperative hemorrhage was reported by Truumees et al.6 in a patient with dabigatran intake and traumatic vertebral fractures. Croci et al.25 recently reported their findings on 82 DOAC-treated patients who underwent spine surgery at their institution. No bleeding complications occurred in 7 patients who had withdrawn DOAC medication less than 24 hours before surgery. However, compared with patients with DOAC withdrawal >24 hours before surgery, red blood cells were transfused significantly more often. Several guidelines on the management of bleeding complications and performing emergency surgery in patients treated with DOAC are available.1 Administration of idarucizumab is recommended for specific dabigatran reversal, and this approach was reported in a patient with complete recovery after cervical laminectomy and evacuation of a spontaneous epidural hematoma.21 Prohemostatic options in patients with factor Xa inhibitors include administration of PCC, desmopressin, and antifibrinolytics. The specific antidote andexanet alfa was recently approved by the Food and Drug Administration for reversal of apixaban and rivaroxaban in cases of life-threatening bleeding.26 This antidote may present a more effective method of anticoagulation reversal in patients in need of emergency surgery, but approval of andexanet alfa is still pending in the European Union. We administered PCC in the majority of patients (83%), and it was also the most commonly used agent in cases reported by other authors. However, the efficacy of PCC administration is not clear, as the rationale for its use is based on pathophysiologic considerations and data on its clinical use
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for DOAC reversal are limited. The use of PCC is associated with an increased risk of thromboembolism due to its prothrombotic activity. Importantly, we did not observe any thromboembolic events in our patients, and we did not identify respective findings in reported cases of patients with acute spinal pathology while on DOAC therapy, even after administration of prohemostatic substances. Nevertheless, further studies with large numbers of patients are needed to characterize the potential and limitations of prohemostatic treatment in patients undergoing emergency surgery during DOAC therapy. As outlined, the time frame from symptom onset to neurosurgical decompression is crucial to achieve a favorable neurologic outcome. Performing surgical procedures 2-staged is an option to limit the invasiveness of initial surgery, thereby minimizing the risk of surgical bleeding. This approach was chosen in 4 patients who underwent posterior fusion after initial decompression surgery. Three of these 4 patients had suffered from spinal empyema or tumor manifestation and in our view, these patients are particularly suitable for this approach. Two-staged surgery also was reported in a case of intraoperative severe hemorrhage during dabigatran therapy.6 A patient with persistent subdural hematoma after initial laminectomy and hematoma evacuation also underwent second surgery.15 There are several limitations of our study, as it represents a retrospective analysis with limited patient numbers. The risk of neurologic impairment and disability cannot be definitely predicted, and the further course of patients if surgery would have been delayed or even not performed is unknown. Measures to detect thromboembolic events were only initiated if suspicious clinical symptoms occurred and therefore, thromboembolism may have been underdiagnosed in the present study. Despite these limitations, the present study represents the largest series on patients treated for acute spinal pathology during treatment with DOAC.
CONCLUSIONS Our initial experiences demonstrate that emergency surgery is feasible in patients treated for acute spinal pathology during DOAC treatment. Early surgery may prevent permanent neurologic impairment caused by persistent compression of neural structures. The literature review of published cases supports our clinical observations as neurologic improvement following DOACassociated intraspinal hemorrhage was observed in more than 75% of patients. Specific antidotes are available for the direct thrombin inhibitor dabigatran and are currently introduced for factor Xa inhibitors. Prohemostatic agents such as PCC and tranexamic acid may promote coagulation in patients undergoing emergency surgery but further studies are necessary to evaluate their effectiveness in clinical practice.
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2019.07.234
ORIGINAL ARTICLE CHRISTOPHER BEYNON ET AL.
SPINAL EMERGENCIES IN PATIENTS ON DOACS
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Conflict of interest statement: Christopher Beynon has received personal fees outside the submitted work from Bayer Healthcare, Boehringer Ingelheim, and CSL Behring. For the remaining authors, no competing financial interests exist. Received 12 May 2019; accepted 31 July 2019 Citation: World Neurosurg. (2019). https://doi.org/10.1016/j.wneu.2019.07.234 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com
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