The Journal of Emergency Medicine, Vol. 46, No. 4, pp. 525–529, 2014 Copyright Ó 2014 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/$ - see front matter
http://dx.doi.org/10.1016/j.jemermed.2013.11.097
Pharmacology in Emergency Medicine MANAGEMENT OF DABIGATRAN-ASSOCIATED INTRACEREBRAL AND INTRAVENTRICULAR HEMORRHAGE: A CASE REPORT Andrew C. Faust, PHARMD, BCPS* and Evan J. Peterson, PHARMD, BCPS† *Department of Pharmacy, Texas Health Presbyterian Hospital of Dallas, 8200 Walnut Hill Lane, Dallas, Texas and †Department of Pharmacy, Seton Medical Center Austin, Austin, Texas Reprint Address: Andrew C. Faust, PHARMD, BCPS, Department of Pharmacy, Texas Health Presbyterian Hospital of Dallas, 8200 Walnut Hill Lane, Dallas, TX 75231
, Abstract—Background: Dabigatran is an oral, reversibly bound, direct thrombin inhibitor currently approved in the United States for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. In the phase III trial leading to approval of the agent, the incidence of life-threatening bleeding was 1.80%/year in the dabigatran 150 mg twice daily arm. Because there is no direct antidote or reversal agent for this drug, the need to manage life-threatening hemorrhages with procoagulant products will arise. Objective: To describe a case of dabigatranassociated intracerebral and intraventricular hemorrhage and subsequent management with activated prothrombin complex concentrate. Case Report: An 85-year-old man currently taking dabigatran 150 mg twice daily presented to the Emergency Department for incoordination, expressive aphasia, and weakness. A computed tomography image of his head demonstrated an intracranial hemorrhage. The last dose of dabigatran was approximately 14 h prior to arrival, and conventional coagulation assays (thrombin time and activated partial thromboplastin time) confirmed the presence of dabigatran in the patient’s serum. The patient received 27.5 units/kg of activated prothrombin complex concentrate (FEIBAÒ; Baxter Healthcare Corporation, Deerfield, IL) after an initial intravenous fluid bolus. His activated partial thromboplastin time was not completely normalized by the use of FEIBA; however, the patient’s neurological examination slightly improved and remained stable throughout his hospital course despite some intraventricular expansion of the hematoma. After discharge to physical rehabilitation, the patient developed an ischemic cerebrovascular accident
and was discharged home on hospice. Conclusion: Due to lack of an available antidote, activated prothrombin complex concentrate was utilized as a nonspecific procoagulant to stabilize an intracerebral hemorrhage in a patient on dabigatran. Ó 2014 Elsevier Inc. , Keywords—dabigatran; intracerebral hemorrhage; anticoagulation reversal; FEIBA; ischemic stroke
INTRODUCTION Dabigatran (PradaxaÒ, Boehringer-Ingelheim, Ridgefield, CT) was the first novel oral anticoagulant alternative to vitamin K antagonists for the treatment and prevention of thromboembolic disease to be approved by the United States (US) Food and Drug Administration. This approval was based on data that demonstrated the superiority of dabigatran 150 mg twice daily over international normalized ratio-adjusted warfarin in preventing stroke or systemic embolism (1). The overall prevalence of major bleeding was not statistically different between the dabigatran group and the warfarin group (3.11%/year vs. 3.36%/year; p = 0.31); however, life-threatening bleeding, including intracerebral hemorrhage, was reduced with the use of dabigatran, compared to warfarin (1.45%/year vs. 1.80%/year; p = 0.04) (1). The incidence of bleeding may be reduced with the use of dabigatran, but the number is not nil, thus, it will be necessary to manage lifethreatening bleeding events. Unlike warfarin, there is no
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specific antidote to reverse the coagulopathy associated with dabigatran (2). Although animal data and small studies in healthy volunteers provide some direction to clinicians attempting to manage patients on dabigatran who present with life-threatening bleeding, there are few published reports of actual hemorrhaging patients managed with a procoagulant agent (3–18). In this case report, we present our experience managing a patient with an intracerebral hemorrhage currently taking dabigatran. CASE REPORT An 85-year-old, 75-kg man was brought to the Emergency Department (ED) for progressive right-sided weakness, paresis, and aphasia. His past medical history was significant for atrial fibrillation, hypertension, coronary artery disease, and a transient ischemic attack 2 weeks prior to admission (CHADS2 = 4, HAS-BLED = 3) (19). After the transient ischemic attack, the patient was converted from rivaroxaban to dabigatran 150 mg twice daily. Other home medications included atorvastatin 10 mg daily, losartan-hydrochlorothiazide 50–12.5 mg daily, and omeprazole 20 mg daily. On the evening of presentation, the patient developed right-hand incoordination and weakness, which progressed to expressive aphasia. His last dose of dabigatran was approximately 14 h prior to arrival. On arrival to our ED, the patient underwent computed tomography (CT) scanning of his head. This revealed an acute left basal ganglia and thalamic hemorrhage approximately 2.5 cm in diameter with mild left-to-right midline shift. His neurological examination at this time was pertinent for severe expressive and conductive aphasia, mild right facial droop, limited arousability, and no movement or resistance in either right arm or leg. His initial Glasgow Coma Scale (GCS) score was 9 (eye 3, verbal 2, motor 4), blood pressure was 182/98 mm Hg, and pulse 69 beats/min. Coagulation assays revealed a fibrinogen of 310 mg/dL, an activated partial thromboplastin time (aPTT) of 45.7 s (upper limit of normal 35.4 s), and a thrombin time (TT) of 195.6 s (upper limit of normal 20 s). His hemoglobin and hematocrit were 15.3 mg/dL and 43.5%, respectively, and his serum creatinine was 0.9 mg/dL, with an estimated creatinine clearance of 60 mL/min. Due to his recent dabigatran exposure and coagulation assays consistent with dabigatran, the emergency physician initiated our dabigatran reversal protocol. A 1-L intravenous sodium chloride 0.9% bolus was rapidly administered. He then received 2064 units (27.5 units/kg total body weight) of activated prothrombin complex concentrate (APCC) (FEIBAÒ, Baxter Healthcare Corporation, Deerfield, IL) as nonspecific procoagulant to reverse the effects of dabigatran. The dose recommended
in our dabigatran reversal protocol is 25 units/kg rounded up to the nearest vial size(s), which resulted in the 2064-unit dose. The patient received no other hemostatic agents or blood products. Dialysis was not initiated, as the patient maintained adequate urine output (0.65–1 mL/kg/h). Over the next 12 h, the patient became more arousable, however, his neurological deficits remained unchanged. His blood pressure was managed with intermittent intravenous hydralazine and enalaprilat and ranged from systolic blood pressures 162–183 mm Hg over diastolic blood pressures 70–100 mm Hg. His aPTT decreased slightly to 39.4 s when measured 7.5 h after APCC administration. Hemoglobin and hematocrit did not change during hospitalization. A follow-up CT scan, obtained 10 h after the initial scan on hospital day 1, showed mild increase in the size of the left basal ganglia hematoma, with a small amount of blood dissecting into the lateral ventricles. Blood pressure control (goal systolic blood pressure < 150 mm Hg) was obtained over the following 24 h and a CT scan performed on the morning of hospital day 2 showed stabilization of the hematoma. The patient’s GCS remained between 9 and 11. He never required mechanical ventilation or neurosurgical intervention, but he did require percutaneous gastrostomy tube placement due to unresolved dysphagia. After 6 days, the patient was discharged to intensive inpatient physical rehabilitation. Seven days after admission to inpatient rehabilitation (total hospital day 13), the patient developed increased confusion and lethargy. A CT scan of the head was obtained, which revealed a new left middle cerebral artery stroke. Due to the new ischemic cerebrovascular insult, the patient’s family wished to pursue hospice, and the patient was discharged with hospice after a 15day hospitalization. DISCUSSION Major, life-threatening, or fatal hemorrhage is one of the most feared adverse effects of anticoagulation therapy. Until recently, the only oral anticoagulants available were vitamin K antagonists. The use of agents like warfarin is somewhat more cumbersome than the newer oral anticoagulants; however, the effect of warfarin can be rapidly neutralized by a direct antidote – vitamin K and infusion of vitamin-K-dependent clotting factors (20). This had led to evidence-based recommendations on the management of vitamin K antagonist-related hemorrhages (20–22). On the other hand, dabigatran has no direct antidote and the ability to rapidly eliminate the drug’s effect does not currently exist (2). Therefore, practitioners have sought to use available nonspecific procoagulant products in an attempt to manage dabigatran-related hemorrhages (3–18).
Dabigatran-associated Intracerebral and Intraventricular Hemorrhage
Measurement of dabigatran anticoagulation is not directly quantifiable with conventional anticoagulation assays (3,4). Ecarin clotting time has demonstrated close linear correlation with direct thrombin inhibitor serum concentrations in healthy volunteers with typical ratios of 2–4 observed after administration of dabigatran 150 mg twice daily (22). The utility of the ecarin clotting time is currently limited, as many institutions, including ours, do not perform the test (3). Similarly, the dilute thrombin time assay (HemoclotÒ, Hyphen BioMed, Paris, France) has shown excellent linear correlation with dabigatran serum concentrations; however, calibration and availability also limit the applicability of this tool (3). The two coagulation assays utilized in our institution’s dabigatran management scheme are aPTT and TT. Both assays are sensitive for dabigatran effects but have distinct limitations (3,4,22). The aPTT shows a modest correlation with dabigatran serum concentrations over the range of those observed in randomized clinical trials (31–443 ng/mL), with elevations of 1.5 to 2 times normal (3). At higher dabigatran concentrations, a plateau effect may be reached, as there is a nonlinear increase in aPTT that may underestimate dabigatran levels (3). The TT is a widely available assay that provides measurement of thrombin inhibitor effects and demonstrates a relatively linear relationship with dabigatran concentrations, albeit with a relatively steep slope (3). This slope limits the utility of TT for dabigatran measurement as it may exceed the maximum measurable time, again leading to possible underestimation of dabigatran concentration. Despite these limitations, both TT and aPTT provide a qualitative assessment of the presence or absence of dabigatran in a patient’s serum (3,4). This feature is especially desirable if the last dose of dabigatran is unknown. In our patient’s case, his last dose was 14 h prior to admission and both aPTT and TT were still elevated. Animal data have suggested recombinant activated factor VII (rFVIIa) and APCC may be beneficial as possible reversal products for dabigatran-induced bleeding. Using doses of up to 500 mg/kg of rFVIIa, van Ryn and colleagues demonstrated an 11.6-fold to 1.1-fold reduction in bleeding time and a reduction in aPTT in a bleeding rat tail model (23). The same investigators evaluated high-dose APCC (50–100 units/kg) and found the product to have shortened bleeding times; however, APCC had limited effect on aPTT (23). The effect of nonspecific procoagulants on dabigatraninduced bleeding has not been prospectively studied, but dabigatran-induced coagulopathy has been evaluated in two small studies. APCC, rFVIIa, and nonactivated prothrombin complex concentrate (PCC) have been evaluated. PCC is a broad category of procoagulant products that contain variable amounts of factors II, VII, IX, and X (24). Up until 2013, the only PCC products available
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in the US were three-factor (3fPCC), which contain negligible quantities of factor VII (24). Four-factor PCC (4fPCC) contain significant amounts of factor VII and, until recently, were unavailable in the US. APCC contains activated factor VII and X and is available in the US. Eerenberg and colleagues evaluated the effects of a 4fPCC (CofactÒ, Sanquin Blood Supply, Amsterdam, The Netherlands) on coagulation assays in 12 healthy volunteers administered dabigatran 150 mg twice daily for five doses (5). Administration of 50 units/kg of PCC had no effect on aPTT or TT. In an ex vivo study, 10 healthy white male volunteers were given a single dose of 150-mg dabigatran (6). All tested doses of APCC (20–160 units/kg) and four-factor 4fPCC (KanokadÒ, LFB, Les Ulis, France) (12.5–50 units/kg) were shown to increase thrombin generation potential, but higher doses of APCC and PCC overcorrected beyond baseline values. Higher-dose APCC (40–160 units/kg) showed reductions in the lag time closer to baseline; however, there was no increased benefit from giving higher doses (80–160 units/kg) compared to the lower (40 units/kg) dose. No dose of rFVIIa showed a significant increase in thrombin generation potential, and only the highest dose of rFVIIa (120 mg/kg) reduced the lag time to baseline (6). Reversal data in hemorrhaging patients anticoagulated with dabigatran are limited to case reports (Table 1). Procoagulants used to reverse include combinations of APCC, rFVIIa, 3fPCC, 4fPCC, and tranexamic acid (7–16,18). Several have also incorporated hemodialysis as an adjunct reversal strategy (7,9–12,14). Approximately half of the patients in reported cases died, although the cause of death may have been unrelated to the bleed in several cases (7,9,10,13,16). Three other cases involving the reversal of dabigatran-induced central nervous system bleeding have been reported. In the first case, a patient suffered an epidural hematoma and spinal cord injury requiring surgery after falling off a roof (8). Bleeding during surgery was treated with blood products and 2 mg rFVIIa. These measures did not adequately maintain hemostasis, so the surgery was limited to decompression and reoperation was required 1 week later. Another patient suffered a right subdural hematoma with midline shift after a ground-level fall (12). Hemodialysis was planned for dabigatran removal and 8 units/kg APCC was administered to reduce bleeding and prevent bleeding complications associated with catheter placement. Hemodialysis seemed to successfully lower the dabigatran level and reduce, but not normalize, coagulation parameters. A repeat CT scan was stable and the patient was discharged to rehab after 10 days. Another patient with a ground-level fall was found to have right intraparenchymal hemorrhage, subdural hematoma, and subarachnoid hemorrhage and left frontal lobe and parietal lobe subarachnoid hemorrhage (13). The
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Table 1. Case Reports in Hemorrhaging Patients Using Nonspecific Procoagulants Bleeding Site/Indication
Reversal Agent(s)
Result
40 units/kg 4fPCC, 66 mg/kg rFVIIa, tranexamic acid rFVIIa* 36 units/kg 4fPCC, 90 mg/kg rFVIIa, hemodialysis 2 mg rFVIIa
Bleeding persisted through surgery, 2.5-L blood loss
PCC*, rFVIIa*, hemodialysis 50 units/kg 3fPCC, hemodialysis
INR and aPTT decreased; died of sepsis Died, repeat scanning not done
Intrapericardial (15) Gastrointestinal bleed (16) Gastrointestinal bleed (17)
75 units/kg 3fPCC, hemodialysis 8 units/kg APCC, hemodialysis rFVIIa* 21.6 mg rFVIIa, 10 g tranexamic acid, hemodialysis 26 units/kg APCC 22 units/kg 3fPCC 50 units/kg PCC, plasmapheresis
Gastrointestinal bleed (18)
30 mg/kg rFVIIa, hemodialysis
Bleeding stopped Bleed stabilized on CT scan IPH expansion, died Blood loss decreased from > 1500 mL/h to 800 mL/h after procoagulants, stopped after dialysis Bleeding stopped Multi-organ failure, died H/H continued to drop after PCC then stabilized after plasmapheresis Bleeding stabilized several days after initiation of dialysis
Bowel resection (7) Hip hematoma, diffuse bleeding (7) Gastrointestinal bleed (7) Epidural hematoma requiring spinal surgery (8) Gastrointestinal bleed (9) Gastrointestinal and retroperitoneal bleed (10) Gastrointestinal bleed (11) SDH (12) IPH, SDH, SAH (13) Postcardiac surgery bleeding (14)
Died after surgery Died Bleeding stopped after 10 h dialysis
4fPCC = 4-factor prothrombin complex concentrate; rFVIIa = activated recombinant factor VII; PCC = prothrombin complex concentrate; INR = international normalized ratio; aPTT = activated partial thromboplastin time; 3fPCC = 3-factor prothrombin complex concentrate; APCC = activated prothrombin complex concentrate; IPH = intraparenchymal hemorrhage; SDH = subdural hematoma; SAH = subarachnoid hemorrhage; H/H = hemoglobin/hematocrit; CT = computed tomography. * Dose not reported.
patient’s symptoms worsened and CT showed expansion of the intraparenchymal and left subarachnoid hemorrhages, so an unspecified dose of rFVIIa was given. However, the patient continued to decline, and repeat CT showed further expansion of the hemorrhages, so the patient was transitioned to comfort care and died. Another case reported the successful use of APCC for dabigatran reversal (15). A patient undergoing atrial fibrillation ablation developed hypotension and hemopericardium with 4.5 L blood withdrawn over an hour. After administration of fluids and blood products, he received 26 units/kg APCC. This resulted in visible cessation of bleeding at the conclusion of the 15-min infusion. Although bleeding subsided, the patient’s TT, aPTT, and dabigatran concentrations remained elevated and seemed minimally affected by APCC administration. After identifying that dabigatran was still in our patient’s serum, as evidenced by elevated coagulation assays, our management strategy focused around ensuring adequate renal elimination of the drug and provision of procoagulant products. Normal saline was administered in rapid fashion to promote renal elimination. Hemodialysis has been shown to remove approximately 60% of dabigatran, which is enhanced with the use of charcoal hemoperfusion (4). However, due to the logistics of initiating hemodialysis (e.g., catheter placement, dialysis machine availability, hemodynamic instability), we opted for a more pragmatic approach in our reversal scheme and therefore utilize dialysis as a second-line option. In
our patient’s case, his creatinine clearance and urine output were adequate. We then administered 2064 units of APCC, based on the aforementioned study, which utilized 26 units/kg APCC and the available package sizes (15). Our protocol utilizes a 25-units/kg dose, but due to available vial strengths, the dose was rounded up to 27.5 units/kg. APCC did not seem to reverse his coagulation assays; however, his neurological examination and respiratory status were unchanged and he avoided neurosurgical intervention. This may support the finding that bleeding reversal may not correlate with coagulation assay effects. Though his CT scan revealed increase in hemorrhage over the first 10 h, this may not necessarily be tied to a failure of APCC to adequately control the dabigatran-related coagulopathy. Hematoma expansion normally occurs in up to 72% of patients over the first 24 h, with 38% of patients experiencing significant (> 33%) increase in volume over that time period (25). Additionally, the patient’s blood pressure remained elevated over this time period. Current guidelines for the management of intracerebral hemorrhage focus on acute management of blood pressure based on blood pressure at presentation and the possibility of elevated intracranial pressure (21). Our patient may have benefited from a reduction in blood pressure to < 160/90 mm Hg, or possibly to a systolic blood pressure < 140 mm Hg. Thirteen days after administration of APCC, the patient developed a new ischemic stroke. This may have been due to an absence of anticoagulation or due to the
Dabigatran-associated Intracerebral and Intraventricular Hemorrhage
APCC itself. Nonactivated PCC generally show a low incidence of thrombosis, # 1.5% with 3fPCC and 3.9% with 4fPCC (26,27). The addition of activated clotting factors increases the incidence of thrombotic events, with some estimates as high as 7% (28). Recombinant activated factor VII has demonstrated significantly higher rates of thrombosis, the majority of which seem to be arterial events (29). In an evaluation of rFVIIa use in clinical trials, Levi and colleagues found a significantly higher rate of arterial thrombotic events in patients over 75 years of age who received rFVIIa compared to placebo (10.8% vs. 4.1%, p = 0.02) (29). These data illustrate the delicate balance of utilizing an activated coagulation product for managing the acute hemorrhage at a dose low enough to minimize the increased risk of thrombosis. CONCLUSION In this case report, we describe the use of a nonspecific procoagulant product (APCC) to assist in managing a life-threatening intracerebral hemorrhage. Our patient avoided neurosurgical intervention and remained neurologically stable despite an initial interval increase in his hemorrhage. Approximately 2 weeks into his hospitalization, the patient developed a new ischemic stroke and subsequently was discharged to hospice. Our report demonstrates the difficulty of managing such patients when there is a lack of reliable anticoagulation monitoring or a direct antidote. Additional data and experience are needed to best determine the most appropriate management strategy for patients on dabigatran presenting with an acute, life-threatening hemorrhage. REFERENCES 1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139–51. 2. Boehringer Ingelheim Pharmaceuticals, Inc. Pradaxa (dabigatran etexilate) package insert. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; December 2012. 3. Van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant effect. Thromb Haemost 2010;103:1116–27. 4. Miyares MA, Davis K. Newer oral anticoagulants: a review of laboratory monitoring options and reversal agents in the hemorrhagic patient. Am J Health Syst Pharm 2012;69:e28–39. 5. Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and Dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011;124:1573–9. 6. Marlu R, Hodaj E, Paris A, et al. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomized crossover ex vivo study in healthy volunteers. Thromb Haemost 2012;108:217–24. 7. Lillo-Le Louet A, Wolf M, Soufir L, et al. Life-threatening bleeding in four patients with an unusual excessive response to dabigatran: implications for emergency surgery and resuscitation. Thromb Haemost 2012;108:583–5.
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8. Truumees E, Gaudu T, Dieterichs C, et al. Epidural hematoma and intraoperative hemorrhage in a spine trauma patient on Pradaxa (dabigatran). Spine 2012;37:e863–5. 9. Maddry JK, Amir MK, Sessions D, et al. Fatal dabigatran toxicity secondary to acute renal failure. Am J Emerg Med 2013;31:462. e1–2. 10. Cano EL, Miyares MA. Clinical challenges in a patient with dabigatraninduced fatal hemorrhage. Am J Geriatr Pharmacother 2012;10:160–3. 11. Wychowski MK, Kouides PA. Dabigatran-induced gastrointestinal bleeding in an elderly patient with moderate renal impairment. Ann Pharmacother 2012;46:e10. 12. Chang DN, Dager WE, Chin AI. Removal of dabigatran by hemodialysis. Am J Kidney Dis 2013;61:487–9. 13. Garber ST, Sivakumar W, Schmidt RH. Neurosurgical complications of direct thrombin inhibitors – catastrophic hemorrhage after mild traumatic brain injury in a patient receiving dabigatran. J Neurosurg 2012;116:1093–6. 14. Warkentin TE, Margetts P, Connolly SJ, et al. Recombinant factor VIIa (rFVIIa) and hemodialysis to manage massive dabigatranassociated postcardiac surgery bleeding. Blood 2012;119:2172–4. 15. Dager WE, Gosselin RC, Roberts AJ. Reversing dabigatran in a lifethreatening bleed occurring during cardiac ablation with factor eight inhibitor bypassing activity. Crit Care Med 2013;41:1–5. 16. Dumkow LE, Voss JR, Peters M, et al. Reversal of dabigatraninduced bleeding with a prothrombin complex concentrate and fresh frozen plasma. Am J Health Syst Pharm 2012;69:1646–50. 17. Kamboj J, Kottalgi M, Cirra VR, Shah N, Kamboj R. Direct thrombin inhibitors: a case indicating benefit from ‘plasmapheresis’ in toxicity: a call for establishing ‘‘guidelines’’ in overdose and to find an ‘‘antidote!’’ Am J Ther 2012;19:e182–5. 18. Harinstein LM, Morgan JW, Russo N. Treatment of dabigatranassociated bleeding: case report and review of the literature. J Pharm Pract 2013;26:264–9. 19. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Study. Chest 2010;138:1093–100. 20. Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141:e44S–88. 21. Morgenstern LB, Hemphill JC III, Anderson C, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2010;41:2108–29. 22. Stagier J, Nejmiz G, Reilly P, et al. Pharmacokinetic and pharmacodynamics of the oral direct thrombin inhibitor dabigatran in a dose finding trial in atrial fibrillation (abstract). J Thromb Haemost 2005; 3(Suppl 1):OR271. 23. Van Ryn J, Ruehl D, Priepke H, et al. Reversibility of the anticoagulant effect of high doses of the direct thrombin inhibitor dabigatran by recombinant factor VIIa or activated prothrombin complex concentrate (abstract 0370). Haematologica 2008;93(Suppl 1):148. 24. Vigue B. Bench-to-bedside review: optimising emergency reversal of vitamin K antagonists in severe haemorrhage – from theory to practice. Crit Care 2009;13:209. 25. Davis SM, Broderick J, Hennerici M, et al. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology 2006;66:1178–81. 26. Sorensen B, Spahn DR, Innerhofer P, et al. Clinical review: prothrombin complex concentrates – evaluation of safety and thrombogenicity. Crit Care 2011;15:201. 27. Wojcik C, Chymik ML, Cure EG. Activated prothrombin complex concentrate factor VIII inhibitor bypassing activity (FEIBA) for the reversal of warfarin-induced coagulopathy. Int J Emerg Med 2009; 2:217–25. 28. Sarode R, Milling TJ, Refaai MA, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation 2013;128:1234–43. 29. Levi M, Levy JH, Andersen JF, et al. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med 2010; 363:1791–800.
http://dx.doi.org/10.1016/j.jemermed.2013.11.097
Pharmacology in Emergency Medicine MANAGEMENT OF DABIGATRAN-ASSOCIATED INTRACEREBRAL AND INTRAVENTRICULAR HEMORRHAGE: A CASE REPORT Andrew C. Faust, PHARMD, BCPS* and Evan J. Peterson, PHARMD, BCPS† *Department of Pharmacy, Texas Health Presbyterian Hospital of Dallas, 8200 Walnut Hill Lane, Dallas, Texas and †Department of Pharmacy, Seton Medical Center Austin, Austin, Texas Reprint Address: Andrew C. Faust, PHARMD, BCPS, Department of Pharmacy, Texas Health Presbyterian Hospital of Dallas, 8200 Walnut Hill Lane, Dallas, TX 75231
, Abstract—Background: Dabigatran is an oral, reversibly bound, direct thrombin inhibitor currently approved in the United States for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. In the phase III trial leading to approval of the agent, the incidence of life-threatening bleeding was 1.80%/year in the dabigatran 150 mg twice daily arm. Because there is no direct antidote or reversal agent for this drug, the need to manage life-threatening hemorrhages with procoagulant products will arise. Objective: To describe a case of dabigatranassociated intracerebral and intraventricular hemorrhage and subsequent management with activated prothrombin complex concentrate. Case Report: An 85-year-old man currently taking dabigatran 150 mg twice daily presented to the Emergency Department for incoordination, expressive aphasia, and weakness. A computed tomography image of his head demonstrated an intracranial hemorrhage. The last dose of dabigatran was approximately 14 h prior to arrival, and conventional coagulation assays (thrombin time and activated partial thromboplastin time) confirmed the presence of dabigatran in the patient’s serum. The patient received 27.5 units/kg of activated prothrombin complex concentrate (FEIBAÒ; Baxter Healthcare Corporation, Deerfield, IL) after an initial intravenous fluid bolus. His activated partial thromboplastin time was not completely normalized by the use of FEIBA; however, the patient’s neurological examination slightly improved and remained stable throughout his hospital course despite some intraventricular expansion of the hematoma. After discharge to physical rehabilitation, the patient developed an ischemic cerebrovascular accident
and was discharged home on hospice. Conclusion: Due to lack of an available antidote, activated prothrombin complex concentrate was utilized as a nonspecific procoagulant to stabilize an intracerebral hemorrhage in a patient on dabigatran. Ó 2014 Elsevier Inc. , Keywords—dabigatran; intracerebral hemorrhage; anticoagulation reversal; FEIBA; ischemic stroke
INTRODUCTION Dabigatran (PradaxaÒ, Boehringer-Ingelheim, Ridgefield, CT) was the first novel oral anticoagulant alternative to vitamin K antagonists for the treatment and prevention of thromboembolic disease to be approved by the United States (US) Food and Drug Administration. This approval was based on data that demonstrated the superiority of dabigatran 150 mg twice daily over international normalized ratio-adjusted warfarin in preventing stroke or systemic embolism (1). The overall prevalence of major bleeding was not statistically different between the dabigatran group and the warfarin group (3.11%/year vs. 3.36%/year; p = 0.31); however, life-threatening bleeding, including intracerebral hemorrhage, was reduced with the use of dabigatran, compared to warfarin (1.45%/year vs. 1.80%/year; p = 0.04) (1). The incidence of bleeding may be reduced with the use of dabigatran, but the number is not nil, thus, it will be necessary to manage lifethreatening bleeding events. Unlike warfarin, there is no
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specific antidote to reverse the coagulopathy associated with dabigatran (2). Although animal data and small studies in healthy volunteers provide some direction to clinicians attempting to manage patients on dabigatran who present with life-threatening bleeding, there are few published reports of actual hemorrhaging patients managed with a procoagulant agent (3–18). In this case report, we present our experience managing a patient with an intracerebral hemorrhage currently taking dabigatran. CASE REPORT An 85-year-old, 75-kg man was brought to the Emergency Department (ED) for progressive right-sided weakness, paresis, and aphasia. His past medical history was significant for atrial fibrillation, hypertension, coronary artery disease, and a transient ischemic attack 2 weeks prior to admission (CHADS2 = 4, HAS-BLED = 3) (19). After the transient ischemic attack, the patient was converted from rivaroxaban to dabigatran 150 mg twice daily. Other home medications included atorvastatin 10 mg daily, losartan-hydrochlorothiazide 50–12.5 mg daily, and omeprazole 20 mg daily. On the evening of presentation, the patient developed right-hand incoordination and weakness, which progressed to expressive aphasia. His last dose of dabigatran was approximately 14 h prior to arrival. On arrival to our ED, the patient underwent computed tomography (CT) scanning of his head. This revealed an acute left basal ganglia and thalamic hemorrhage approximately 2.5 cm in diameter with mild left-to-right midline shift. His neurological examination at this time was pertinent for severe expressive and conductive aphasia, mild right facial droop, limited arousability, and no movement or resistance in either right arm or leg. His initial Glasgow Coma Scale (GCS) score was 9 (eye 3, verbal 2, motor 4), blood pressure was 182/98 mm Hg, and pulse 69 beats/min. Coagulation assays revealed a fibrinogen of 310 mg/dL, an activated partial thromboplastin time (aPTT) of 45.7 s (upper limit of normal 35.4 s), and a thrombin time (TT) of 195.6 s (upper limit of normal 20 s). His hemoglobin and hematocrit were 15.3 mg/dL and 43.5%, respectively, and his serum creatinine was 0.9 mg/dL, with an estimated creatinine clearance of 60 mL/min. Due to his recent dabigatran exposure and coagulation assays consistent with dabigatran, the emergency physician initiated our dabigatran reversal protocol. A 1-L intravenous sodium chloride 0.9% bolus was rapidly administered. He then received 2064 units (27.5 units/kg total body weight) of activated prothrombin complex concentrate (APCC) (FEIBAÒ, Baxter Healthcare Corporation, Deerfield, IL) as nonspecific procoagulant to reverse the effects of dabigatran. The dose recommended
in our dabigatran reversal protocol is 25 units/kg rounded up to the nearest vial size(s), which resulted in the 2064-unit dose. The patient received no other hemostatic agents or blood products. Dialysis was not initiated, as the patient maintained adequate urine output (0.65–1 mL/kg/h). Over the next 12 h, the patient became more arousable, however, his neurological deficits remained unchanged. His blood pressure was managed with intermittent intravenous hydralazine and enalaprilat and ranged from systolic blood pressures 162–183 mm Hg over diastolic blood pressures 70–100 mm Hg. His aPTT decreased slightly to 39.4 s when measured 7.5 h after APCC administration. Hemoglobin and hematocrit did not change during hospitalization. A follow-up CT scan, obtained 10 h after the initial scan on hospital day 1, showed mild increase in the size of the left basal ganglia hematoma, with a small amount of blood dissecting into the lateral ventricles. Blood pressure control (goal systolic blood pressure < 150 mm Hg) was obtained over the following 24 h and a CT scan performed on the morning of hospital day 2 showed stabilization of the hematoma. The patient’s GCS remained between 9 and 11. He never required mechanical ventilation or neurosurgical intervention, but he did require percutaneous gastrostomy tube placement due to unresolved dysphagia. After 6 days, the patient was discharged to intensive inpatient physical rehabilitation. Seven days after admission to inpatient rehabilitation (total hospital day 13), the patient developed increased confusion and lethargy. A CT scan of the head was obtained, which revealed a new left middle cerebral artery stroke. Due to the new ischemic cerebrovascular insult, the patient’s family wished to pursue hospice, and the patient was discharged with hospice after a 15day hospitalization. DISCUSSION Major, life-threatening, or fatal hemorrhage is one of the most feared adverse effects of anticoagulation therapy. Until recently, the only oral anticoagulants available were vitamin K antagonists. The use of agents like warfarin is somewhat more cumbersome than the newer oral anticoagulants; however, the effect of warfarin can be rapidly neutralized by a direct antidote – vitamin K and infusion of vitamin-K-dependent clotting factors (20). This had led to evidence-based recommendations on the management of vitamin K antagonist-related hemorrhages (20–22). On the other hand, dabigatran has no direct antidote and the ability to rapidly eliminate the drug’s effect does not currently exist (2). Therefore, practitioners have sought to use available nonspecific procoagulant products in an attempt to manage dabigatran-related hemorrhages (3–18).
Dabigatran-associated Intracerebral and Intraventricular Hemorrhage
Measurement of dabigatran anticoagulation is not directly quantifiable with conventional anticoagulation assays (3,4). Ecarin clotting time has demonstrated close linear correlation with direct thrombin inhibitor serum concentrations in healthy volunteers with typical ratios of 2–4 observed after administration of dabigatran 150 mg twice daily (22). The utility of the ecarin clotting time is currently limited, as many institutions, including ours, do not perform the test (3). Similarly, the dilute thrombin time assay (HemoclotÒ, Hyphen BioMed, Paris, France) has shown excellent linear correlation with dabigatran serum concentrations; however, calibration and availability also limit the applicability of this tool (3). The two coagulation assays utilized in our institution’s dabigatran management scheme are aPTT and TT. Both assays are sensitive for dabigatran effects but have distinct limitations (3,4,22). The aPTT shows a modest correlation with dabigatran serum concentrations over the range of those observed in randomized clinical trials (31–443 ng/mL), with elevations of 1.5 to 2 times normal (3). At higher dabigatran concentrations, a plateau effect may be reached, as there is a nonlinear increase in aPTT that may underestimate dabigatran levels (3). The TT is a widely available assay that provides measurement of thrombin inhibitor effects and demonstrates a relatively linear relationship with dabigatran concentrations, albeit with a relatively steep slope (3). This slope limits the utility of TT for dabigatran measurement as it may exceed the maximum measurable time, again leading to possible underestimation of dabigatran concentration. Despite these limitations, both TT and aPTT provide a qualitative assessment of the presence or absence of dabigatran in a patient’s serum (3,4). This feature is especially desirable if the last dose of dabigatran is unknown. In our patient’s case, his last dose was 14 h prior to admission and both aPTT and TT were still elevated. Animal data have suggested recombinant activated factor VII (rFVIIa) and APCC may be beneficial as possible reversal products for dabigatran-induced bleeding. Using doses of up to 500 mg/kg of rFVIIa, van Ryn and colleagues demonstrated an 11.6-fold to 1.1-fold reduction in bleeding time and a reduction in aPTT in a bleeding rat tail model (23). The same investigators evaluated high-dose APCC (50–100 units/kg) and found the product to have shortened bleeding times; however, APCC had limited effect on aPTT (23). The effect of nonspecific procoagulants on dabigatraninduced bleeding has not been prospectively studied, but dabigatran-induced coagulopathy has been evaluated in two small studies. APCC, rFVIIa, and nonactivated prothrombin complex concentrate (PCC) have been evaluated. PCC is a broad category of procoagulant products that contain variable amounts of factors II, VII, IX, and X (24). Up until 2013, the only PCC products available
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in the US were three-factor (3fPCC), which contain negligible quantities of factor VII (24). Four-factor PCC (4fPCC) contain significant amounts of factor VII and, until recently, were unavailable in the US. APCC contains activated factor VII and X and is available in the US. Eerenberg and colleagues evaluated the effects of a 4fPCC (CofactÒ, Sanquin Blood Supply, Amsterdam, The Netherlands) on coagulation assays in 12 healthy volunteers administered dabigatran 150 mg twice daily for five doses (5). Administration of 50 units/kg of PCC had no effect on aPTT or TT. In an ex vivo study, 10 healthy white male volunteers were given a single dose of 150-mg dabigatran (6). All tested doses of APCC (20–160 units/kg) and four-factor 4fPCC (KanokadÒ, LFB, Les Ulis, France) (12.5–50 units/kg) were shown to increase thrombin generation potential, but higher doses of APCC and PCC overcorrected beyond baseline values. Higher-dose APCC (40–160 units/kg) showed reductions in the lag time closer to baseline; however, there was no increased benefit from giving higher doses (80–160 units/kg) compared to the lower (40 units/kg) dose. No dose of rFVIIa showed a significant increase in thrombin generation potential, and only the highest dose of rFVIIa (120 mg/kg) reduced the lag time to baseline (6). Reversal data in hemorrhaging patients anticoagulated with dabigatran are limited to case reports (Table 1). Procoagulants used to reverse include combinations of APCC, rFVIIa, 3fPCC, 4fPCC, and tranexamic acid (7–16,18). Several have also incorporated hemodialysis as an adjunct reversal strategy (7,9–12,14). Approximately half of the patients in reported cases died, although the cause of death may have been unrelated to the bleed in several cases (7,9,10,13,16). Three other cases involving the reversal of dabigatran-induced central nervous system bleeding have been reported. In the first case, a patient suffered an epidural hematoma and spinal cord injury requiring surgery after falling off a roof (8). Bleeding during surgery was treated with blood products and 2 mg rFVIIa. These measures did not adequately maintain hemostasis, so the surgery was limited to decompression and reoperation was required 1 week later. Another patient suffered a right subdural hematoma with midline shift after a ground-level fall (12). Hemodialysis was planned for dabigatran removal and 8 units/kg APCC was administered to reduce bleeding and prevent bleeding complications associated with catheter placement. Hemodialysis seemed to successfully lower the dabigatran level and reduce, but not normalize, coagulation parameters. A repeat CT scan was stable and the patient was discharged to rehab after 10 days. Another patient with a ground-level fall was found to have right intraparenchymal hemorrhage, subdural hematoma, and subarachnoid hemorrhage and left frontal lobe and parietal lobe subarachnoid hemorrhage (13). The
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Table 1. Case Reports in Hemorrhaging Patients Using Nonspecific Procoagulants Bleeding Site/Indication
Reversal Agent(s)
Result
40 units/kg 4fPCC, 66 mg/kg rFVIIa, tranexamic acid rFVIIa* 36 units/kg 4fPCC, 90 mg/kg rFVIIa, hemodialysis 2 mg rFVIIa
Bleeding persisted through surgery, 2.5-L blood loss
PCC*, rFVIIa*, hemodialysis 50 units/kg 3fPCC, hemodialysis
INR and aPTT decreased; died of sepsis Died, repeat scanning not done
Intrapericardial (15) Gastrointestinal bleed (16) Gastrointestinal bleed (17)
75 units/kg 3fPCC, hemodialysis 8 units/kg APCC, hemodialysis rFVIIa* 21.6 mg rFVIIa, 10 g tranexamic acid, hemodialysis 26 units/kg APCC 22 units/kg 3fPCC 50 units/kg PCC, plasmapheresis
Gastrointestinal bleed (18)
30 mg/kg rFVIIa, hemodialysis
Bleeding stopped Bleed stabilized on CT scan IPH expansion, died Blood loss decreased from > 1500 mL/h to 800 mL/h after procoagulants, stopped after dialysis Bleeding stopped Multi-organ failure, died H/H continued to drop after PCC then stabilized after plasmapheresis Bleeding stabilized several days after initiation of dialysis
Bowel resection (7) Hip hematoma, diffuse bleeding (7) Gastrointestinal bleed (7) Epidural hematoma requiring spinal surgery (8) Gastrointestinal bleed (9) Gastrointestinal and retroperitoneal bleed (10) Gastrointestinal bleed (11) SDH (12) IPH, SDH, SAH (13) Postcardiac surgery bleeding (14)
Died after surgery Died Bleeding stopped after 10 h dialysis
4fPCC = 4-factor prothrombin complex concentrate; rFVIIa = activated recombinant factor VII; PCC = prothrombin complex concentrate; INR = international normalized ratio; aPTT = activated partial thromboplastin time; 3fPCC = 3-factor prothrombin complex concentrate; APCC = activated prothrombin complex concentrate; IPH = intraparenchymal hemorrhage; SDH = subdural hematoma; SAH = subarachnoid hemorrhage; H/H = hemoglobin/hematocrit; CT = computed tomography. * Dose not reported.
patient’s symptoms worsened and CT showed expansion of the intraparenchymal and left subarachnoid hemorrhages, so an unspecified dose of rFVIIa was given. However, the patient continued to decline, and repeat CT showed further expansion of the hemorrhages, so the patient was transitioned to comfort care and died. Another case reported the successful use of APCC for dabigatran reversal (15). A patient undergoing atrial fibrillation ablation developed hypotension and hemopericardium with 4.5 L blood withdrawn over an hour. After administration of fluids and blood products, he received 26 units/kg APCC. This resulted in visible cessation of bleeding at the conclusion of the 15-min infusion. Although bleeding subsided, the patient’s TT, aPTT, and dabigatran concentrations remained elevated and seemed minimally affected by APCC administration. After identifying that dabigatran was still in our patient’s serum, as evidenced by elevated coagulation assays, our management strategy focused around ensuring adequate renal elimination of the drug and provision of procoagulant products. Normal saline was administered in rapid fashion to promote renal elimination. Hemodialysis has been shown to remove approximately 60% of dabigatran, which is enhanced with the use of charcoal hemoperfusion (4). However, due to the logistics of initiating hemodialysis (e.g., catheter placement, dialysis machine availability, hemodynamic instability), we opted for a more pragmatic approach in our reversal scheme and therefore utilize dialysis as a second-line option. In
our patient’s case, his creatinine clearance and urine output were adequate. We then administered 2064 units of APCC, based on the aforementioned study, which utilized 26 units/kg APCC and the available package sizes (15). Our protocol utilizes a 25-units/kg dose, but due to available vial strengths, the dose was rounded up to 27.5 units/kg. APCC did not seem to reverse his coagulation assays; however, his neurological examination and respiratory status were unchanged and he avoided neurosurgical intervention. This may support the finding that bleeding reversal may not correlate with coagulation assay effects. Though his CT scan revealed increase in hemorrhage over the first 10 h, this may not necessarily be tied to a failure of APCC to adequately control the dabigatran-related coagulopathy. Hematoma expansion normally occurs in up to 72% of patients over the first 24 h, with 38% of patients experiencing significant (> 33%) increase in volume over that time period (25). Additionally, the patient’s blood pressure remained elevated over this time period. Current guidelines for the management of intracerebral hemorrhage focus on acute management of blood pressure based on blood pressure at presentation and the possibility of elevated intracranial pressure (21). Our patient may have benefited from a reduction in blood pressure to < 160/90 mm Hg, or possibly to a systolic blood pressure < 140 mm Hg. Thirteen days after administration of APCC, the patient developed a new ischemic stroke. This may have been due to an absence of anticoagulation or due to the
Dabigatran-associated Intracerebral and Intraventricular Hemorrhage
APCC itself. Nonactivated PCC generally show a low incidence of thrombosis, # 1.5% with 3fPCC and 3.9% with 4fPCC (26,27). The addition of activated clotting factors increases the incidence of thrombotic events, with some estimates as high as 7% (28). Recombinant activated factor VII has demonstrated significantly higher rates of thrombosis, the majority of which seem to be arterial events (29). In an evaluation of rFVIIa use in clinical trials, Levi and colleagues found a significantly higher rate of arterial thrombotic events in patients over 75 years of age who received rFVIIa compared to placebo (10.8% vs. 4.1%, p = 0.02) (29). These data illustrate the delicate balance of utilizing an activated coagulation product for managing the acute hemorrhage at a dose low enough to minimize the increased risk of thrombosis. CONCLUSION In this case report, we describe the use of a nonspecific procoagulant product (APCC) to assist in managing a life-threatening intracerebral hemorrhage. Our patient avoided neurosurgical intervention and remained neurologically stable despite an initial interval increase in his hemorrhage. Approximately 2 weeks into his hospitalization, the patient developed a new ischemic stroke and subsequently was discharged to hospice. Our report demonstrates the difficulty of managing such patients when there is a lack of reliable anticoagulation monitoring or a direct antidote. Additional data and experience are needed to best determine the most appropriate management strategy for patients on dabigatran presenting with an acute, life-threatening hemorrhage. REFERENCES 1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139–51. 2. Boehringer Ingelheim Pharmaceuticals, Inc. Pradaxa (dabigatran etexilate) package insert. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; December 2012. 3. Van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant effect. Thromb Haemost 2010;103:1116–27. 4. Miyares MA, Davis K. Newer oral anticoagulants: a review of laboratory monitoring options and reversal agents in the hemorrhagic patient. Am J Health Syst Pharm 2012;69:e28–39. 5. Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and Dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011;124:1573–9. 6. Marlu R, Hodaj E, Paris A, et al. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomized crossover ex vivo study in healthy volunteers. Thromb Haemost 2012;108:217–24. 7. Lillo-Le Louet A, Wolf M, Soufir L, et al. Life-threatening bleeding in four patients with an unusual excessive response to dabigatran: implications for emergency surgery and resuscitation. Thromb Haemost 2012;108:583–5.
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