The Effect of Cardiopulmonary Bypass on Dabigatran

CASE REPORT

The Effect of Cardiopulmonary Bypass on Dabigatran Levels Kelly Byrne, MBChB, FANZCA

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ABIGATRAN IS a novel anticoagulant that is licensed for use for the prevention of stroke in the presence of atrial fibrillation. Its use has expanded rapidly in New Zealand, primarily due to there being no requirement for routine monitoring of its effect, as there is for warfarin. There are case reports in the literature describing management of patients coming for urgent cardiac surgery, which revolve mainly around the use of dialysis and massive transfusion of clotting factors to manage the bleeding associated with surgery.1–3 The current recommendations are to stop dabigatran 5 days preoperatively in patients who are likely to have a high bleeding risk. There is no published evidence with regard to the effect of cardiopulmonary bypass on dabigatran levels, or the effect of hemofiltration while on cardiopulmonary bypass on dabigatran levels. CASE REPORT

A 67-year-old woman presented for a semi-elective aortic valve replacement, mitral valve replacement, and 2-vessel coronary artery bypass. Her presenting complaints were breathlessness and palpitations, when she presented to a peripheral hospital in congestive heart failure (CHF) and rapid atrial fibrillation. Her weight was 77 kg, and height was 172 cm, giving a body surface area of 1.92 cm.2 Echocardiography revealed underlying structural heart disease most likely related to rheumatic heart disease. Her previous medical history included a nephrectomy in 1995 for renal cell cancer and moderate chronic obstructive airways disease. The patient had been on no medications prior to admission to the hospital. The preoperative echocardiogram showed a mildly dilated left ventricle with an ejection fraction of 40% to 50%; the right ventricle was of normal size and function. The left atrium was severely dilated, and the right atrium was mildly dilated. There was severe aortic stenosis with a peak pressure gradient of 74 mmHg and calculated valve area of 0.6 cm.2 The mitral valve leaflets were thickened, and there was severe mitral regurgitation. Coronary angiography revealed 40% left mainstem stenosis, a 70% left anterior descending lesion, modest proximal disease in the left circumflex, and a proximally occluded right coronary artery that was filling retrogradely from the left-sided system. Pulmonary artery pressures were measured at 59/33 mm Hg, with a pulmonary vascular resistance of 3.2 Woods units. Once admitted to the hospital, there had been treatment of the atrial fibrillation with metoprolol and amiodarone and treatment of the CHF with frusemide and enalapril. However, the heart failure had been difficult to control, with ongoing intermittent breathlessness and persistent pleural effusions. The

atrial fibrillation had been rate controlled, and there were periods when the patient was in sinus rhythm. This treatment occurred in a peripheral hospital in the 4 weeks leading up to surgery. During this period, the patient was worked up for surgery and was transferred to a tertiary center for surgery on December 27, with a planned surgery date of December 29. Once transferred to the tertiary center, sildenafil had been started to reduce the pulmonary artery pressures, but the patient had become hypotensive, and, in lieu of sildenafil, there had been regular ilioprost nebulizers. Of note, in the week leading up to surgery there had been significant deterioration of renal function and increasing signs of liver congestion. During the time in the peripheral hospital, dabigatran had been started to anticoagulate the patient for stroke prevention due to the paroxysmal atrial fibrillation. Due to other procedures such as dental extraction, the dabigatran had only been administered intermittently. It initially was stopped on December 3, restarted for a single dose on December 8, and restarted between December 17 and December 23 at a dose of 150 mg bid. It then was stopped in anticipation of surgery on December 29. Table 1 shows the blood results leading up to surgery. On the morning of surgery, the patient was planned to have an intra-aortic balloon pump (IABP), and, prior to this, 2 units of FFP were administered to reduce the chance of bleeding during this procedure. This precipitated an exacerbation of the underlying CHF, and the patient was unable to lie flat for placement of the IABP. Noninvasive bipap ventilation was instituted and additional IV frusemide was administered. There was some improvement of symptoms. At this stage, there was discussion regarding whether the case should be delayed in an attempt to further control the CHF or whether to proceed. Due to the significance of the valve lesions and the difficulty controlling the CHF over the previous month, it was decided to proceed realizing that this was a very high-risk case. The EuroSCORE 2 for preoperative risk evaluation predicted the perioperative mortality at 35%.

From the Department of Anesthesia, Waikato Hospital, Pennbroke Street, Hamilton, New Zealand. Address reprint requests to Kelly Byrne, MBChB, FANZCA, Department of Anaesthesia, Waikato hospital, Pembroke Street, Hamilton, New Zealand. E-mail: [email protected] © 2015 Elsevier Inc. All rights reserved. 1053-0770/2602-0033$36.00/0 http://dx.doi.org/10.1053/j.jvca.2015.09.004 Key words: dabigatran, cardiopulmonary bypass, cardiac surgery, coagulation, new oral anticoagulants

Journal of Cardiothoracic and Vascular Anesthesia, Vol ], No ] (Month), 2015: pp ]]]–]]]

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Table 1. Preoperative Blood Test Results Date

Time Sodium Potassium Creatinine Estimated GFR Bilirubin Alk Phos GGT ALT INR APTT TCT Fib Dabigatran level

mmol/L mmol/L mmol/L

12/11/2014

12/15/2014

12/28/2014

12/29/2014

Reference Range

0736 138 4.0 110 45

0812 137 4.1 77 69

0816 132 3.6 178 25 18 147 160 69 1.6 46 60 3.6

0745 131 3.6 156 29

135-145 mmol/L 3.5-5.2 mmol/L 45-90 μmol/L

U/L U/L U/L secs secs G/L Ng/mL

1.4 39 67 3.8 20

0-20 μmol/L 40-130 U/L 0-50 U/L 0-40 U/L 0.9-1.2 26.5-38.5 s o20 s 1.5-4.5 g/L

Abbreviations: Alk Phos, alkaline phsphatase; ALT, alanine transaminase; APTT, activated partial thromboplastin time; fib, fibrinogen; GFR, glomerular filtration rate; GGT, gamma-glutamyl transferase; INR, international normalized ratio; TCT, thrombin clotting time.

The blood tests indicated that despite 6 days of cessation of dabigatran, there was still some dabigatran effect present. Prior to surgery, a dabigatran level was done that was 20 ng/mL. Data from the PETRO trial indicated that the normal therapeutic peak level is 182 ng/mL, and the trough level is 90 mg/ mL, although there is a wide interpatient variation. Preoperative thromboelastogram (TEG) is in Figure 1. Consideration of whether to enroll this patient for the idarucizumab trial, a specific monoclonal antibody for reversal

Fig 1.

of dabigatran, was undertaken at this stage.4 Due to the long period of cessation of dabigatran and the low plasma level, the site investigator for this trial did not consider this patient to be eligible for the trial. Dabigatran levels were determined using the Hemoclot Direct Thrombin Inhibitor assay (Hyphen Biomed, Neuvillesur-Oise, France). This assay uses a dilution of the patient’s plasma with normal plasma then adds thrombin and measures the time to clot. By assaying dabigatran standards with known

Preoperative thromboelastogram.

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DABIGATRAN AND CARDIOPULMONARY BYPASS

Fig 2.

Postbypass thromboelastogram.

quantities of dabigatran, a standard curve can be created. The patient plasma is tested, and the result of the dilute thrombin time is reported as ng/mL. This test previously has been validated in the literature, with acceptable reproducibility and bias.5 The patient was induced and intubated in the routine manner. After placement of a pulmonary artery catheter, the initial cardiac index was measured at 1.4 L/min, and the initial pulmonary artery pressure was 61/37. Prior to institution of bypass, the patient was loaded with 12 µg/ kg of levosimendan followed by an infusion of 0.1 µg/kg/ min. The preoperative activated clotting time (ACT) was 149, and heparin, 30,000 IU, was administered, producing an ACT of 908, which enabled institution of cardiopulmonary bypass. There was cannulation of the aorta with a 22-French aortic cannula, and venous return was secured through a 36/46-French 2-stage venous cannula. Tranexamic acid was administered at a loading dose of 30 mg/kg and an infusion of 16 mg/kg during the duration of the surgery to prevent bleeding. The heart was arrested with custodial cardioplegia at a dose of 1,300 mL. The surgery proceeded as planned with a cross-clamp time of 95 minutes and a bypass time of 146 minutes. The aortic valve was replaced with a 23-mm bioprosthetic valve, and the mitral valve was replaced with a 27-mm bioprosthetic valve, and saphenous vein grafts were placed on the left anterior descending and obtuse marginal coronary arteries. In order to manage both the CHF and attempt to remove further dabigatran while on bypass, a Hemocor H1000

hemofilter was added to the bypass circuit, and 2,000 mL of fluid were removed during bypass. Three hundred fifty mL of urine were produced during bypass, and the fluid balance for the case was negative 782 mL. Separation from bypass was unremarkable. The heparin was reversed with 250 mg of protamine, and the repeat ACT was 144. The postbypass pulmonary artery pressures had fallen to 45/24. There was significant bleeding postbypass. Repeat dabigatran levels done at this stage showed an increase in the dabigatran level to 53 ng/mL, and the repeat TEG is shown in Figure 2. Treatment of the bleeding was initiated with 2 units of platelets, 5 units of fresh frozen plasma, and 3 units of cryoprecipitate. Following this, the patient also received 90 µg/kg of factor VIIa and 20 units of DDAVP. During this time period, 2 units of packed red blood cells were given, and 1,609 mL of cell-saver blood was reinfused. At this time, the bleeding was controlled to an extent that the chest was able to be closed. Cardiac index during the post-bypass period was 1.3 L/min. Upon transfer to the intensive care unit, the patient remained on levosimendan, milrinone, and noradrenaline. Repeat dabigatran levels at this stage showed a level of 23 ng/mL. During the next 6 hours, there was increasing hemodynamic instability, and the patient returned to the OR at 1:56 AM. Upon opening the chest, there was some clot present over the heart, but the hemodynamic response to opening the chest was not typical for tamponade. At this stage, an IABP was inserted. A further 2 units of fresh frozen plasma, 1 unit of platelets, and 1 unit of packed red blood cells were given. The chest was left open, and

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BYRNE

Table 2. Blood Test Results Following Surgery Date

Time Sodium mmol/L Potassium mmol/L Creatinine mmol/L Estimated GFR Billirubin Alk Phos U/L GGT U/L ALT U/L INR APTT secs TCT secs Fib g/L Dabigatran level ng/mL

12/29/2014

12/29/2014

12/29/2014

12/30/2014

12/31/2014

1/1/2015

1/2/2015

1730

2045 140 3.6 135 35 21 43 36 47 1.2 66 76 1.7 23

2355

0315

0350

0330

0500

1.9 44 88 2.4 53

Reference Range

135-145 mmol/L 3.5-5.2 mmol/L 45-90 μmol/L

1.5 118 84 1.8 23

1.4 75 72 1.9

1.7 45 48 3

1.4 44 34 4.8

1.3 39 22 6.5

0-20 μmol/L 40-130 U/L 0-50 U/L 0-40 U/L 0.9-1.2 26.5-38.5 s o20 s 1.5-4.5 g/L

Abbreviations: Alk Phos, alkaline phsphatase; ALT, alanine transaminase; APTT, activated partial thromboplastin time; fib, fibrinogen; GFR, glomerular filtration rate; GGT, gamma-glutamyl transferase; INR, international normalized ratio; TCT, thrombin clotting time.

the patient was transferred to the intensive care unit. Over the following 12 hours, the hemodynamics stabilized, and the lactate fell to normal levels. Thirty-six hours later, the patient’s chest was closed, and the patient was extubated 6 hours later. Table 2 shows blood results following surgery, and Table 3 shows selected blood gas results from around the time of return to the OR transfer to the floor ensued, but, 12 hours later, the patient deteriorated and required readmission to the ICU and reintubation for increasing respiratory distress and signs of sepsis. Serratia marcescens grew from a blood culture, and despite maximal therapy, the patient continued to deteriorate and died 8 days after the initial surgery. DISCUSSION

Dabigatran is a novel anticoagulant that currently has no reversal agent, although a monoclonal antibody to reverse dabigatran currently is under development. In patients with renal impairment for whom dabigatran is prescribed, the recommendation is to cease dabigatran 5 days prior to surgery if bleeding is expected to be problematic.6 It is unclear how the dabigatran level correlates to the potential risk for bleeding. The thrombin clotting time (TCT) is the most sensitive measure of the presence of dabigatran. A normal TCT indicates very low levels of dabigatran, and the TCT does seem to correlate with the plasma levels, at least in some patients.7 However, it does not always seem to correlate that well with bleeding, as a previous case report in a cardiac transplant patient indicated a

TCT level in the 60s was not associated with excessive bleeding.2 The TCT also may be increased in the presence of heparin, other direct thrombin inhibitors, fibrin/fibrinogen degradation products, and in the presence of high levels of serum proteins (eg, myeloma).8 The effect of a given plasma level of dabigatran is not clear in the literature. A previous case report, in which plasma levels were measured post-surgery, found that, clinically, bleeding stopped when the plasma level fell to 27 ng/mL, although this was associated with massive transfusion and repeated doses of activated factor VII.7 Data from the PETRO trial, which looked at the likelihood of thromboembolic events while on dabigatran, indicated that the mean therapeutic peak level is 182 ng/mL, and the mean trough level is 90 ng/mL while taking a dose of 150 mg bid.9 Plasma level data from the RELY trial, which studied 2 doses of dabigatran in a total of 9,183 patients, found a mean trough level of 60 ng/mL in the group taking a dose of 110 mg bid and a mean trough level of 91 ng/mL in the group taking 150 mg bid. However, there was a large interpatient variation with the 10th to 90th centile range being 28.2-155 ng/mL in the 110-mg bid group and between 39.8 ng/mL and 215 ng/mL in the 150 mg group.10 It is likely the initial starting level in this patient of 20 ng/mL was a level at which anticoagulation of the patient was negligible. However, the level of 53 ng/mL, when coming off bypass, is at a level near what would be considered a trough level in patients taking the drug regularly and therefore is highly likely to exert a significant effect on the coagulation system at this level.

Table 3. Selected Blood Gas Results From Post-Bypass, Chest Re-Opening and Stabilization of the Patient Date

Time pH PCO2 (kPa) PO2 (kPa) Base excess Lactate (g/L) Glucose (mm) Hb (g/L) O2

12/29/2014

12/29/2014

12/29/2014

12/29/2014

12/30/2014

12/30/2014

12/30/2014

12/30/2014

1727 7.35 5.3 38 3.5 2.6 6.9 66 99

1753 7.31 6 33 3.7 2.9 6.3 84 100

1901 7.36 5.5 41 2.2 4.1 6.2 70 100

2219 7.28 6 18.4 5.5 5.6 5.1 80 99

0155 7.15 5.4 55.1 13.6 11.4 9 82 99

0318 7.24 4.6 28.8 11.7 9.3 8.1 73 99

0829 7.39 4.4 15.3 4.4 4.4 13.3 111 99

1749 7.42 4.5 13.1 2.7 2.1 7.3 111 98

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DABIGATRAN AND CARDIOPULMONARY BYPASS

There is little research into whether the effect of dabigatran can be detected by the TEG. In this patient, the initial TEG suggested that the coagulation system was intact, in fact somewhat hypercoagulable. The 2 conclusions that can be drawn from this were that either the level of the dabigatran was not sufficient to effect coagulation or that the effect of dabigatran was not detected by the TEG. As dabigatran is renally excreted, it is able to be cleared by hemodialysis, and there are several case reports of dabigatran overdose being treated in this way.1,3,11 However, there are little data about whether hemofiltration has any effect on dabigatran levels. Dabigatran is a small molecule that is not highly plasma protein bound (only 35% of dabigatran is bound to plasma proteins), so it might be expected that some dabigatran should be cleared in this way. It has a volume of distribution that exceeds total body water, indicating moderate deposition of dabigatran in the tissues. In a low-output state, going on cardiopulmonary bypass may improve renal blood flow, which would be expected to increase the dabigatran clearance. Therefore, the increase in dabigatran levels postbypass is perplexing. In a previous case series, there was an up to 87% rebound following the cessation of intermittent hemodialysis, which was thought to reflect redistribution of dabigatran from the peripheral to the central compartment.11

To the authors’ knowledge, there are no previous published case reports of the effect of cardiopulmonary bypass on dabigatran levels, and redistribution from the peripheral compartment is the mostly likely explanation for the increase in dabigatran levels. Amiodarone is an inhibitor of the efflux transporter P-GY that potentially can increase the maximum plasma concentration and the area under the curve of dabigatran.12 Amiodarone has a long half-life, and its concomitant administration in this patient may have contributed to the increase in dabigatran levels following cardiopulmonary bypass. Despite stopping the dabigatran for more than the recommended period and the intermittent dosing that had occurred before then, an increase in dabigatran levels occurred following cardiopulmonary bypass. This increase in dabigatran levels caused what was initially a subtherapeutic dose of dabigatran to become one that exerts a significant effect on the coagulation system. On the basis of this case report, the period for which dabigatran needs to be stopped for prior to cardiac surgery may vary markedly between individuals. Patients in whom the TCT remains elevated, dabigatran plasma levels should be measured, or surgery should be delayed until the TCT has normalized. In patients in whom there are detectable dabigatran levels in the plasma, surgery should be delayed, as this level may increase postbypass.

REFERENCES 1. Stein P, Bosshart M, Brand B, et al: Dabigatran anticoagulation and Stanford type A aortic dissection: Lethal coincidence: Case report with literature review. Acta Anaesthesiol Scand 58:630-637, 2014 2. Wanek MR, Horn ET, Elapavaluru S, et al: Safe use of hemodialysis for dabigatran removal before cardiac surgery. Ann Pharmacother 46:e21, 2012 3. Ashikhmina E, Tomasello N, Connors JM, et al: Type A aortic dissection in a patient on dabigatran: Hemostasis post circulatory arrest. Ann Thorac Surg 98:2215-2216, 2014 4. Pollack CV Jr, Reilly PA, Eikelboom J, et al: Idarucizumab for dabigatran reversal. N Engl J Med 373:511-520, 2015 5. Stangier J, Feuring M: Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis 23:138-143, 2012 6. Mathers S, Ballantyne S, Stokes J: Queensland health guideline for managing patients on dabigatran. Available at: https://www.health.qld. gov.au/qhcss/mapsu/documents/dabigatran_info.pdf. Accessed 5/7/2015. 7. Warkentin TE, Margetts P, Connolly SJ, et al: Recombinant factor VIIa (rFVIIa) and hemodialysis to manage massive dabigatranassociated postcardiac surgery bleeding. Blood 119:2172-2174, 2012

8. van RJ, Stangier J, Haertter S, et al: Dabigatran etexilate–a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 103: 1116-1127, 2010 9. Ezekowitz MD, Reilly PA, Nehmiz G, et al: Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study). Am J Cardiol 100: 1419-1426, 2007 10. Reilly PA, Lehr T, Haertter S, et al: The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: The RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol 63:321-328, 2014 11. Singh T, Maw TT, Henry BL, et al: Extracorporeal therapy for dabigatran removal in the treatment of acute bleeding: A single center experience. Clin J Am Soc Nephrol 8:1533-1539, 2013 12. European Medicines agency. Summary of product characteristics —Dabigatran. Last update 18/02/2015. Available at: http://www.ema. europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/ human/000829/WC500041059.pdf. Accessed 25/8/2015.

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