Acta Anaesthesiol Scand 2014; ••: ••–•• Printed in Singapore. All rights reserved

© 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd ACTA ANAESTHESIOLOGICA SCANDINAVICA

doi: 10.1111/aas.12303

Case Report

Dabigatran anticoagulation and Stanford type A aortic dissection: lethal coincidence Case report with literature review P. Stein1*, M. Bosshart2*, B. Brand3, A. Schlicker1, D. R. Spahn1 and D. Bettex2

1 Institute of Anaesthesiology, Divisions of 2Cardiovascular Anaesthesia and Intensive Care and 3Haematology, University and University Hospital of Zurich, Zurich, Switzerland

Background: Novel oral anticoagulants are now encountered in patients needing emergency surgery. Knowledge and treatment options are limited. Methods and result: We present the case of a 76-year-old patient who suffered from an acute Stanford type A aortic dissection, needing emergency surgical aortic repair. He was anticoagulated with dabigatran due to past atrial fibrillation. Despite haemodiafiltration, surgical revision and massive transfusion of packed red blood cells, fresh frozen plasma, platelets, coagulation factors, and recombinant factor VIIa, the patient died

A

76-year-old male patient complaining about spontaneous stabbing thoracic pain while watching a hockey game was admitted to a Swiss regional hospital. Respiration and vigilance were normal, the blood pressure was 85/44 mmHg (right arm) and 118/41 mmHg (left arm). The patient was in regular sinus rhythm, with an atrio-ventricular block I (atrio-ventricular delay: 238 ms, heart rate 54 bpm) and without electrocardiographic signs of myocardial ischemia. The computed tomographic angiography demonstrated an extensive aortic dissection Stanford type A originating at the level of the aortic valve, ending at the iliacal bifurcation and involving the right carotid artery. The patient was then immediately transferred to our university hospital by the Swiss air ambulance service. The patient was on chronic medical treatment for hypertension. Two months earlier, an aneurysm of

*The first two authors contributed equally to this work The patient’s relatives gave a written permission for publication of the case report

from intractable bleeding with sustained therapeutic levels of dabigatran. Conclusion: After reviewing the literature, we summarize the limited treatment options and show possible approaches for patients treated with dabigatran needing emergency surgery. Accepted for publication 06 February 2014 © 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd

the ascending aorta (diameter of 50 mm) with moderate aortic valve regurgitation and eccentric hypertrophy of the left ventricle had been diagnosed in echocardiography. His medication on admission was nebivolol 1.25 mg, perindopril 10 mg, and anticoagulation with dabigatran (150 mg twice daily) for atrial fibrillation, successfully cardioverted 2 months prior to the actual event. Coagulation studies showed an aPTT of 65 s (normal 26–36 s) and an international normalized ratio of 1.7 (normal < 1.2) on admission. A thrombelastometry (ROTEM, TEM Innovations GmbH, Munich, Germany) showed a prolonged clotting time of 516 s (normal range 100–240 s) in the INTEM (contact activated clotting) channel. The induction with target controlled intravenous infusion of propofol, fentanyl, and rocuronium was unremarkable. Orotracheal intubation was performed. Bilateral radial arterial lines, a central venous catheter and an 8.5 french introducer in the right jugular vein were inserted without any problems. Perioperative antimicrobial prophylaxis with 1.5 g of cefuroxime was initiated.

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P. Stein et al.

Fig. 1. Echocardiography (midoesophageal aortic valve long axis). Ascending aorta (A), aortic wall haematoma (crosses), dissection membrane (D), pericardial effusion (E).

A transoesophageal echocardiography probe was inserted and showed a normal left ventricular systolic function without any regional wall motion abnormality, a mild pericardial effusion without haemodynamic significance, a severe aortic regurgitation, a 5-cm aneurysm of the ascending aorta with an aortic wall haematoma of 2 cm, and a dissection membrane originating from the level of the aortic valve (Fig. 1). After sternotomy, 300 IU/kg of heparin and 30 mg/kg of tranexamic acid were administered. Before heparin, no signs of abnormal bleeding tendency were noticed. Arterial cannulation was performed via the right subclavian artery. After inserting a two-stage venous cannula via the right atrial appendage into the inferior vena cava, cardiopulmonary bypass was started. After cooling the patient to 28°C, antegrade cerebral perfusion was initiated, and a hemiarch repair was performed. Under systemic perfusion, the aortic root was replaced with a 27 mm Medtronic Freestyle prosthesis (Minneapolis, MN, USA). After rewarming, the aortic cross clamp was removed, the heart started to beat in sinus rhythm, and the patient was successfully weaned from the cardiopulmonary bypass. Heparin was antagonized by 300 IU/kg of protamine (equivalent dose to heparin), confirmed by an anti-factor Xa activity of 0.0 IU/ml. The perfusion time was 221 min, aortic cross clamping lasted 157 min, reperfusion time was 24 min, and selective antegrade cerebral perfusion was 62 min. There was a positive balance of 4840 ml during cardiopulmonary bypass. Four litres of crystalloid solution, 1800 ml of cardioplegia

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(Brettschneider’s solution), mannitol, and sodium bicarbonate were infused during bypass, with an estimated blood loss of 1.2 l. Coagulation studies, performed at the end of cardiopulmonary bypass, shortly before protamine, showed severe coagulopathy with an international normalized ratio of 2.9, factor XIII activity of 29%, and a platelet count of 29,000/mcl. Thromboelastometry showed a maximum clot firmness in the FIBTEM of only 4 mm (normal range 9–25 mm) and a clotting time in the INTEM of more than 800 s (normal range 100–240 s). There was no evidence of systemic fibrinolysis in the EXTEM (tissue factor activated clotting) or APTEM (aprotinin addition). Although factor substitution was in progress, international normalized ratio increased to > 7.5, thrombin clotting time > 120 s, and aPTT > 160 s. Factor V activity was < 2%. In contrast to international normalized ratio, which is strongly influenced by circulating dabigatran, the factor V result is reliable (Table 1, Figs 2 and 3). During the following 6 h of surgical haemostasis, the patient received a massive transfusion of 33 units of packed red blood cells, 14 units of platelets, and 20 units of fresh frozen plasma, as well as multiple coagulation factors (Table 1). The temperature decreased from 37°C to 34.6°C from bypass time to transfer to intensive care unit (ICU). The patient developed a progressive metabolic acidosis with a maximum lactate of 8.1 mmol/l (bicarbonate 17.6 mmol/l, pH 7.4) during cardiopulmonary bypass, reaching 13.2 mmol/l (bicarbonate 19.6 mmol/l, pH 7.31) after surgery. To maintain a minimal mean arterial pressure of 55 mmHg vasopressors (vasopressin 0.04 IU/min and norepinephrine up to 1.4 mcg/kg/min) were administered. Central nervous system (pupils, near infrared spectroscopy and bispectral index values) and kidneys (diuresis) seemed to perform normally. Despite all these measures, coagulopathic bleeding continued. The coagulation values could be partially normalized, but aPTT, thrombin clotting time, international normalized ratio, and INTEM clotting time remained significantly elevated (Table 1 and Fig. 2). Five hours after cardiopulmonary bypass, antifactor IIa levels of dabigatran were still high above the therapeutic threshold (> 0.03 mcg/ml). Therefore, the sternum was left open, and the patient transferred to ICU. Intermittent haemodiafiltration was immediately initiated to remove dabigatran. An effective blood flow of 320–370 ml/min with a cumulative blood volume of 83 l in total was estab-

Case of dabigatran and aortic dissection Table 1 Lab values and coagulation products. Hours after induction Haemoglobin (g/l) Platelet count (10∧3/mcl) Fibrinogen (g/l) Factor V (%) Factor XIII (%) INR aPTT (s) TCT (s) Anti IIa dabigatran (mcg/ml) FIBTEM (mm) INTEM clotting time (s) Factor VIII/vWf (IU) – cum Desmopressin (mcg) – cum rFVIIa (mg) – cum PCC (IU) – cum Factor XIII (IU) – cum Fibrinogen (g) – cum PRB (units) – cum FFP (units) – cum Platelets (units) – cum

Post CPB

1 h post CPB

0 130 177 2,3 53 45 1,7 65

5 88 70

6 73 29 0,5 2 36 7,4 > 160 > 120

7 516 0 0 0 0 0 0 0 0 0

4

29

0 0 0 0 0 0 2 0 0

6 950 0 0 0 2000 1250 8 4 0 2

End OP

Start IHD

10 89 135

12 76 74

25 97 1,9 > 160 > 120 0,29 34 522 2000 40 3 10,000 5000 36 25 15 12

IHD 1 h

IHD 2 h

Exitus

13 77

14 85

17 79

28 68 1,9 > 160 > 120 0,39

2 60 2,5 > 160

0,29

2 13 94 2 > 160 > 120 0,26

2000 40 5 13,000 6250 46 37 22 16

2000 40 5 15,000 6250 56 41 26 18

2000 40 5 17,000 7500 66 45 30 18

2000 40 7 17,000 7500 68 55 36 20

180

0,45

160

0,4

140

0,35

120

0,3

100

0,25

80

0,2

60 IHD

40 Operation

20

ICU

0

mcg/ml (anti IIa)

s (TCT/aPTT)

aPTT, partial thromboplastin time; CPB, cardiopulmonary bypass; cum, cumulative; FFP, fresh frozen plasma; IHD, intermittent haemodiafiltration; INR, international normalized ratio; OP, operation; PCC, prothrombin complex concentrate; PRB, packed red blood cells; rFVIIa, recombinant activated factor VII; TCT, thrombin clotting time; vWf, von Willebrand factor.

0,15

aPTT (s)

0,1

TCT (s)

0,05

anti IIa (mcg/ml)

0 0

1

2

3

4

5

6

7 8 9 10 11 12 13 14 15 16 17 Hours after induction

lished for 4 h. A polyflux filter was used for that purpose. During 4 h of high-flux haemodiafiltration, dabigatran action on factor IIa decreased by one third from 0.39 mcg/ml to 0.26 mcg/ml (Fig. 2). After 4 h in ICU, because of continuous bleeding, the patient developed a cardiac tamponade with acute haemodynamic instability and progressive right ventricular dysfunction. The blood loss (from chest drainages) was 2500 ml in 4 h. After surgical revision with the need of internal cardiac massage, haemodynamic stabilization was reached. Two hours later, after ongoing blood loss of 1250 ml, the haemodynamics of the patient worsened again

Fig. 2. Laboratory values. aPTT, partial thromboplastin time; ICU, intensive care unit; IHD, intermittent haemodiafiltration; TCT, thrombin clotting time.

acutely. Despite new surgical revision, transfusion of a further fair amount of coagulation factors (Table 1 and Fig. 3) and continuous infusion of 1.5 mg/h of tranexamic acid, the patient died from haemorrhagic shock secondary to intractable coagulopathy.

Discussion A dissection of the aorta occurs when an intimal tear exposes the tunica media of the aorta to pulsatile blood flow. Depending on the localization of the intimal tear, a false lumen is created leading to proxi-

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P. Stein et al. 60 55 50 45

Units

40 35

PRB (units)

30

FFP (units) PC (units)

25 20 15 10 5 0 1

2

3

4

5

6

7 8 9 10 11 12 13 14 15 16 17 Hours after induction

80

18000

70

16000 14000

60 50

12000

rFVIIa (mg)

40

Fibrinogen (g)

10000

PCC (IU)

8000

30

6000

20

4000

10

2000

0

0 0

1

2

3

4

5

6

7

8

9

10 11 12 13 14 15 16 17

Hours after induction

mal or distal progression of the aortic injury. A Stanford type A dissection involves the ascending aorta and is associated with a mortality rate of 1% per hour within the first 48 h when medically treated.1 About 20% of the patients die before reaching the hospital.2 This condition is therefore a cardiosurgical emergency with a hospital mortality of 10–25%.3 Dabigatran etexilate is a prodrug readily metabolized to active dabigatran, which reversibly inhibits free and fibrin-bound thrombin. After oral intake, peak plasma concentrations are reached within 2–4 h. Plasma half-life time is 12–14 h. Eighty per cent of the drug is excreted via the renal pathway. Mean apparent volume of distribution (single-dose regimen) is 1860 l (69–90 l in steady state) with a total clearance of 2013 ml/min and a plasma protein binding of approximately 35%. Dabigatran prolongs aPTT, thrombin clotting time, ecarin clotting time and increases international normalized ratio. Ecarin clotting time shows the most linear correlation with dabigatran levels, thrombin clotting time shows the highest sensitivity.4–6 In our hospital, dabigatran is measured with a commercial

4

IU (PCC)

g (Fibrinogen) / mg (rFVIIa)

0

Fig. 3. Cumulatively administered blood and coagulation products. FFP, fresh frozen plasma; PC, platelet concentrate; PCC, prothrombin complex concentrate; PRB, packed red blood cells; rFVIIa, recombinant activated factor VII.

(Hyphen, Hemoclot, Neuville sur Oise, France) quantitative test with high accuracy also for other direct thrombin inhibitors. Patients with non-valvular atrial fibrillation and risk of stroke, treated with 150 mg dabigatran twice daily had lower rates of stroke and systemic embolism with similar rates of major haemorrhage in comparison to patients on warfarin (RE-LY trial).7 A fixed dose of dabigatran was as effective as warfarin for the treatment of acute venous embolism – with comparable occurrence of major and minor bleeding (RE-COVER trial).8 The RE-ALIGN trial, comparing warfarin to dabigatran in patients with mechanical heart valves, was terminated prematurely because of increased rates of thromboembolic and major (pericardial) bleeding complications in the dabigatran group.9 In Switzerland, dabigatran is approved for the prevention of stroke and embolism in patients with non-valvular atrial fibrillation. In addition, at least one of the following patient’s characteristics is necessary: previous stroke, transient ischemic attack, systemic embolism, left ventricular ejection fraction

Case of dabigatran and aortic dissection

< 40%, congestive heart failure (≥ NYHA II), or age > 75 years. Patients aged 65–74 years are eligible with one of the following comorbidities: diabetes mellitus, coronary artery disease, or hypertension. Since the RE-LY and RE-COVER studies, numerous cases with poor or fatal outcome have been published regarding major haemorrhage in patients treated with dabigatran needing emergency surgery.10,11 Reports about continuous bleeding after cardiac surgery,12 extensive intraparenchymal brain haemorrhage after a ground level fall,13,14 traumatic spinal epidural haematoma, and ongoing intraoperative bleeding,15 spontaneous intramural haematoma of the ascending aorta,16 bleeding after traumatic splenic laceration,17 iatrogenic pericardial tamponade,18 and emergency laparotomy because of bowel perforation,19 pulmonary haemorrhages due to tuberculous lung abscess,20 and subarachnoid haemorrhages21 have been published. For planned, urgent (not defined), or major (> 1 h) surgery, there was no significant difference in bleeding events in patients with pretreatment of warfarin compared to dabigatran after ‘regular’ (1–2 days with creatinine clearance > 50 ml/min, 3–5 days creatinine clearance 30–50 ml/min) discontinuation of dabigatran (data from the RE-LY trial).22 In the case of major haemorrhage in patients treated with dabigatran, there is no compelling evidence for any emergency bleeding treatment regimen. Until now, no specific antidote to dabigatran is available. Pharmacological treatment options arise from anecdotal case reports, ex vivo or animal studies, are off-label and of questionable efficacy. Efficacy of removing dabigatran from the human plasma by dialysis has been shown.12,23 Newer reports confirm that dabigatran plasma concentration can be reduced by dialysis but show rebound of dabigatran levels after discontinuation of dialysis.14,20 Dabigatran removal was possible with intermittent haemodialysis and continuous venovenous haemodiafiltration in emergency bleeding, but rebound of dabigatran concentrations up to 87% in 2 h was observed.14,21 Duration of dialysis had the greatest effect on reduction of dabigatran plasma levels.24 Activated charcoal can be given orally within 2 h after ingestion of dabigatran to interrupt the intestinal absorption of the drug.25 Reviewing the literature, there are conflicting statements concerning the application and transfusion of coagulation factors to overcome dabigatranmediated anticoagulation. In a rodent intracerebral haemorrhage model after dabigatran treatment, application of 100 IU/kg of prothrombin complex

concentrate (PCC) prevented haematoma expansion.26 In rabbits, 50 IU/kg of PCC fully antagonized extensive blood loss due to dabigatran.27 On the contrary, 50 IU/kg of PCC had no antagonistic effect on dabigatran action in healthy volunteers.28 Moreover, ex vivo thrombelastography in human blood showed no significant effect of PCC on dabigatran anticoagulation.29 Anecdotal reports narrate effectiveness to stop dabigatran induced bleeding in combination with haemodialysis,12 others report ongoing coagulatory bleeding even after recombinant activated factor VII (rFVIIa) administration.13,15 Addition of rFVIIa to blood of patients anticoagulated with dabigatran normalized thrombelastographic R-values ex vivo.29 In the rodent intracerebral haemorrhage model mentioned above, 8 mg/kg of rFVIIa had no positive effect.26 On the other side, off-label use of rFVIIa increased the risk of arterial thromboembolic events30 and thus cannot be regarded as the first-line treatment. Promising reports exist regarding the use of activated PCC, namely factor eight inhibitor bypassing activitiy (FEIBA): with therapeutic levels of dabigatran, addition of 80 U/kg of FEIBA normalized the clotting values (lag time) in human blood in vitro.31 In a case report of cardiac ablation, 26 U/kg FEIBA intravenously stopped the anticoagulatory bleeding into the pericardium.18 A very low dose (8 U/kg) of FEIBA and dialysis was finally effective in the treatment of a patient with traumatic subdural intracranial haematoma14 (summary see Table 2). Summing up the above knowledge, our patient did neither benefit from prothrombin complex concentrate even in a cumulative dose of 250 IU/kg nor from 7 mg of recombinant activated factor VII. Bleeding after type A aortic dissection repair is not uncommon. Coagulation factor dilution, hypoperfusion, and extracorporeal circulation play an important role in coagulopathy after this invasive surgery. But even after reaching haemostatic sufficient levels of fibrinogen, factor V, factor XIII and probably all other coagulation factors, in combination with normovolaemia and normothermia, global coagulation tests (aPTT, thrombin clotting time, international normalized ratio) remained abnormal, and bleeding persisted. Even after multiple exchange transfusions (total of 55 × 0,25 = 13,75 l of packed red blood cells, 36 × 0,25 = 9 l of fresh frozen plasma) and 4 h of haemodiafiltration, our patient still showed therapeutic levels of dabigatran (Table 1, Figs 2 and 3). The most probable explanation is the redistribution of dabigatran from peripheral tissues back into the

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P. Stein et al. Table 2 Literature overview. Factor eight inhibitor bypassing activity (FEIBA)

Prothrombin complex concentrate (PCC)

Recombinant activated factor VII (rFVIIa)

+ In vitro study (80 U/kg)31 Case report (26 U/kg)18 Case report (8 U/kg + dialysis)14 − No report + Rodent intracranial haematoma model (100 IU/kg)26 Rabbit bleeding model (50 IU/kg)27 − In vivo study (healthy volunteers) (50 IU/kg)28 Ex vivo model29 Our case report (250 IU/kg) + Case report (+dialysis)12 Ex vivo study29 − Rodent intracranial haematoma model (8 mg/kg)26 Case reports13,15 Our case report (7 mg)

Effect of coagulation factor application to overcome dabigatran induced bleeding. Legend: +positive effect, −no effect.

vascular space. This is consistent with other findings of a rebound of plasma levels after discontinuation of haemodialysis.21 As long as redistribution from peripheral tissue occurs, we suggest that – if at all – continuous instead of or in addition to intermittent haemodialysis may achieve low plasma dabigatran levels. An antibody to dabigatran was characterized and successfully tested in a rodent model. Because of structural similarities to thrombin, the antibody binds to dabigatran and quickly reverses its anticoagulatory effects without any thrombin-like (prothrombotic) activity. Such a clinically applicable and licensed product is urgently needed.32 From the existing pharmacological treatment options, along with correction of lacking clotting factors, only FEIBA shows a somewhat promising potential of treating dabigatran-induced coagulopathy. Unfortunately, as in many other hospitals, FEIBA is not readily available in our institution. It should be noted that FEIBA is not designed nor tested for reversing dabigatran-induced coagulopathy, and the current evidence is solely based on case reports. To our knowledge, we are the first group to describe dabigatran effects on rotational thrombelastometry (ROTEM). This needs further investigation, as INTEM clotting time prolongation, bleeding, and therapeutic anticoagulatory levels of dabigatran corresponded.

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In the context of the limited treatment options to overcome bleeding on dabigatran anticoagulation, preoperative haemodialysis and delaying the intervention even for a classic emergency like a type A aortic dissection should be considered until antifactor IIa levels of dabigatran are below the therapeutic levels, and thrombin clotting time is normalized. Continuous haemodialysis may be necessary to maintain low anti-factor IIa levels.33

Acknowledgements Conflict of interest: D. R. S. academic department is receiving grant support from the Swiss National Science Foundation, Berne, Switzerland (grant numbers: 33CM30_124117 and 406440-131268), the Swiss Society of Anesthesiology and Reanimation (SGAR), Berne, Switzerland (no grant numbers are attributed), the Swiss Foundation for Anesthesia Research, Zurich, Switzerland (no grant numbers are attributed), Bundesprogramm Chancengleichheit, Berne, Switzerland (no grant numbers are attributed), CSL Behring, Berne, Switzerland (no grant numbers are attributed), Vifor SA, Villars-sur-Glâne, Switzerland (no grant numbers are attributed). D. R. S. was the chairman of the ABC Faculty and a member of the ABC Trauma Faculty which both are managed by Thomson Physicians World GmbH, Mannheim, Germany and sponsored by an unrestricted educational grant from Novo Nordisk A/S, Bagsvärd, Denmark. In the past 5 years, D. R. S. has received honoraria or travel support for consulting or lecturing from the following companies: Abbott AG, Baar, Switzerland, AstraZeneca AG, Zug, Switzerland, Bayer (Schweiz) AG, Zürich, Switzerland, Baxter S.p.A., Roma, Italy, B. Braun Melsungen AG, Melsungen, Germany, Boehringer Ingelheim (Schweiz) GmbH, Basel, Switzerland, Bristol-Myers-Squibb, Rueil-Malmaison Cedex, France, CSL Behring GmbH, Hattersheim am Main, Germany and Bern, Switzerland, Curacyte AG, Munich, Germany, Ethicon Biosurgery, Sommerville, New Jersey, USA, Fresenius SE, Bad Homburg v.d.H., Germany, Galenica AG, Bern, Switzerland (including Vifor SA, Villars-sur-Glâne, Switzerland), GlaxoSmithKline GmbH & Co. KG, Hamburg, Germany, Janssen-Cilag AG, Baar, Switzerland, Novo Nordisk A/S, Bagsvärd, Denmark, Octapharma AG, Lachen, Switzerland, Organon AG, Pfäffikon/SZ, Switzerland, Oxygen Biotherapeutics, Costa Mesa, CA, Pentapharm GmbH (now tem Innovations GmbH), Munich, Germany, Roche Pharma (Schweiz) AG, Reinach, Switzerland, and Schering-Plough International, Inc., Kenilworth, New Jersey, USA. Funding: None for the case report. Author’s contribution: P. S.: Treated the patient, reviewed the literature, and wrote the manuscript; M. B.: Treated the patient and wrote the manuscript; B. B.: Treated the patient, directed coagulation management, and wrote the manuscript; A. S.: Treated the patient and wrote the manuscript; D. R. S.: Wrote the manuscript; D. B.: Treated the patient and wrote the manuscript.

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Address: Philipp Stein Institute of Anaesthesiology University Hospital and University of Zurich Raemistrasse 100 CH-8091 Zurich Switzerland e-mail: [email protected]