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Dabigatran Excess: Case Report and Review of the Literature

Introduction Novel oral anticoagulants are increasingly used for stroke prophylaxis in patients with non-valvular atrial fibrillation. While these agents offer a more predictable pharmacokinetic profile, the lack of readily available laboratory tests to monitor the level of anticoagulation and absence of an antidote or established therapies to reverse the anticoagulant effect make management of cases of over-anticoagulation challenging. Case Report In this case report an 87-year-old man with a history of atrial fibrillation presented with dabigatran excess in the setting of life-threatening, acute renal and hepatic failure. The authors review the use of dabigatran in elderly patients, the available data on management of patients with excess anticoagulation, and the potential options for reversal of the anticoagulation effect. Conclusion Further investigation into reliable means of monitoring and reversing the anticoagulant effect of dabigatran is crucial to the management of such patients.


INTRODUCTION
Dabigatran etexilate is an oral direct thrombin inhibitor approved for use as an alternative to the vitamin K antagonist, warfarin, for stroke A. Sarma and J. E. Rossi contributed equally to the writing of this paper.
prophylaxis in patients with non-valvular atrial fibrillation. Its predictable pharmacokinetic profile provides significant user appeal since routine monitoring of its anticoagulant effect and dose titration are not required. Furthermore, when compared with warfarin in the Randomized Evaluation of the Long-Term Anticoagulation Therapy (RE-LY) trial, dabigatran was superior to warfarin in preventing stroke and systemic embolization at 150 mg twice-daily (1.11% versus 1.69% per year, relative risk (RR) 0.66, 95% CI 0.53-0.82, P\0.001 for superiority) and non-inferior to warfarin at 110 mg twice-daily (1.53% versus 1.69% per year, RR 0.91, 95% CI 0.74-1.11, P\0.001 for noninferiority) [1]. With respect to bleeding, patients randomized to 110 mg twice-daily experienced a lower rate of major bleeding as compared to warfarin (2.71% versus 3.36% per year, P = 0.003), while those randomized to 150 mg twice-daily had a similar rate of major bleeding (3.11% versus 3.36%, P = 0.31). In a recent Mini-Sentinel analysis of adverse post-marketing events, dabigatran was not associated with a higher risk of bleeding as compared to warfarin in clinical use [2]. Despite a similar or superior safety profile, two major disadvantages of dabigatran include the lack of a reversal agent and no validated, clinically available measure to monitor anticoagulant activity, both of which are critical to the care of patients presenting with active bleeding. Here, the authors report a case of an 87-year-old man on dabigatran who presented with a coagulopathy in the setting of acute renal and hepatic failure. Given that 80% of dabigatran is renally cleared, the authors caution clinicians to carefully monitor renal function and adjust dosing accordingly, especially in elderly patients who are particularly susceptible to asymptomatic changes in renal function.

CASE REPORT
An 87-year-old man with a history of atrial fibrillation with CHA 2 DS 2 -VASc score of 5, heart failure with preserved ejection fraction, and hypertension presented to the emergency room with weakness, decreased oral intake, and mild cough. Consent for publication of this case report was obtained from the patient's wife. Five months earlier, the patient started dabigatran etexilate 150 mg orally twice-daily for  (Fig. 1), and oxygen saturation 96% on 2 L/min of supplemental oxygen. On examination, the patient was ill appearing but in no acute distress. The patient had 10 cm of jugular venous distension with monophasic waves and hepatojugular reflux. There were bibasilar crackles present on lung examination. Cardiac auscultation revealed a bradycardic, irregular rhythm, normal first heart sound with a physiologically split second heart sound, and a III/VI systolic murmur loudest at the upper sternal border. The abdomen was benign without organomegaly. There was 3? pitting edema of the extremities with normal pulses bilaterally.
Upon arrival to the emergency department 2 L of intravenous (IV) normal saline and 1 mg of IV glucagon were administered. A chest X-ray revealed a right lower lobe infiltrate (Fig. 2 On admission to the cardiac intensive care unit, the heart rate was irregular at 48 beats/min and the blood pressure was 90/50 mmHg. The patient rapidly developed worsening hypoxia and was placed on 70% oxygen at 35 L/min delivered by high flow nasal cannula. During a phlebotomy, the patient became acutely unresponsive with a loss of palpable pulses. The patient did not demonstrate any overt signs of active bleeding at any point during the hospitalization. On admission, the hematocrit was 43.5%, consistent with the patient's baseline value. In the setting of receiving a total of 4.5 L of IV normal saline during the first day of hospitalization, the hematocrit dropped to a nadir of 33.9%, but gradually improved without infusion of red blood cells to 38.3% on day of discharge. However, taking into account the history of a recent fall, need for central venous access, and presence of multi-organ failure in the elderly gentleman with possible need for dialysis, the decision was made to reverse the coagulopathy. A reversal strategy was pursued that attempted to counteract both dabigatran toxicity and the potential for decreased hepatic synthesis of clotting factors given concern for hepatic injury in the setting of an acute transaminitis. The patient's history of heart failure and acute renal failure limited the amount of high volume blood products that could be administered and more concentrated forms of coagulation factor replacement were  (Table 1). The hepatic transaminases and renal function also peaked on the first day with an alanine aminotransferase (ALT) of 4,590 U/L, aspartate aminotransferase (AST) of 4,965 U/L, and Cr of 3.07 mg/dL (eGFR B20 mL/min/1.73 m 2 ). Thereafter, the patient's Cr, transaminases, and coagulation parameters trended downward over the course of 10 days (Fig. 3).
The patient was stabilized and treated for pneumonia in the intensive care unit for 7 days.
The patient was extubated on day 5, had no signs of bleeding, and was discharged home on hospital day 19. On hospital day 5, the patient's international normalized ratio (INR) was 1.8 (see Fig. 3 for trend) with a PTT of 46.9 s, at which time an unfractionated heparin infusion was started for stroke prevention secondary to atrial fibrillation given a CHA 2 DS 2 -VASc score of 5 (indicating a high yearly risk of stroke), and concern that the patient was unable to reliably take oral medications in the setting of acute illness and deconditioning. However, the patient regained ability to take oral medications more quickly than anticipated and was, therefore, started on warfarin on hospital day 7. On the day of discharge, the Cr was 0.70 mg/dL (eGFR C60 mL/min/1.73 m 2 ) with a PTT of 41.3 s and INR of 1.8 on warfarin. The ALT and AST were last measured on hospital day 10 at 271 and 32 U/L, respectively.

Monitoring of Anticoagulant Assays
There is no established laboratory method for monitoring dabigatran's activity. While its While monitoring of the PT/INR is standard for warfarin therapy, it is relatively insensitive to dabigatran's effect at therapeutic levels [3][4][5].
In contrast, the aPTT increases in a curvilinear fashion with increasing dabigatran concentration, but the concentration-response curve plateaus at dabigatran concentrations above 200 ng/mL [3][4][5][6][7], which is close to the peak therapeutic level achieved by most patients [8]. Thus, the aPTT is a sensitive test for detecting dabigatran activity, but its value may not accurately reflect dabigatran concentrations above therapeutic levels.
Similarly, in vitro studies show a linear relationship between the ACT and dabigatran concentrations up to 250 ng/mL, with a flattening of the concentration-response curve above 500 ng/mL [3]. However, the ACT has not been systematically tested in patients and, therefore, its clinical utility remains uncertain.
The TT directly assesses thrombin activity and exhibits a linear relationship with increasing dabigatran concentration up to 600 ng/mL, at which point the value generally exceeds the maximum measurement time of most coagulometers [3,6]. Thus, the standard TT may be most useful in determining the presence or absence of circulating dabigatran, but may be too sensitive for overdose evaluations [3-5, 7, 9]. The HemoClot Ò thrombin inhibitor assay (Hyphen BioMed, Neuville-sur-Oise, France) is not yet commercially available in the US, but holds promise as a useful assay for determining drug concentration [3,4,7,9]. The diluted TT assay exhibits a linear relationship with dabigatran concentrations, even at high levels. Thus, dabigatran standards can be supplied to run a calibration curve and thereby determine plasma dabigatran concentration. The ECT is another promising assay of thrombin generation that exhibits a linear relationship with plasma concentrations of dabigatran [3,5]. However, ECT is currently only available in the research setting [9] and was not available at the authors' institution.  [20]. When the type of bleeding was further analyzed, an increased risk of extracranial bleeding with age emerged, but the risk of intracranial bleeding remained lower for dabigatran as compared with warfarin regardless of age [20].
Interestingly, patients with CrCl \50 mL/min experienced a more than twofold increased risk of major bleeding with both dabigatran and warfarin as compared to patients with CrCl C80 mL/min even though warfarin, unlike dabigatran, is not renally excreted [20]. Given a lack of association between treatment and CrCl with major bleeding, factors other than a  [20].
Because dabigatran is not metabolized by the cytochrome (CYP) P450 system, drugs affecting CYP enzymes should not affect dabigatran [5,21]. Dabigatran is, however, a substrate of the efflux transporter P-gp [17]. Inducers of P-gp (e.g., rifampin) decrease peak dabigatran concentrations, while P-gp inhibitors (e.g., ketoconazole and dronedarone) increase peak concentrations. This latter interaction is of particular importance in patients with renal impairment in whom dose adjustments of dabigatran or avoidance of the P-gp inhibitor should be considered depending on the specific co-administered drug and degree of renal impairment [5,17,21]. Of note, no dose adjustment of dabigatran is recommended in combination with moderate P-gp inhibitors (e.g., verapamil, amiodarone, quinidine, and clarithromycin) [17].

Methods for Reversal of Dabigatran's Anticoagulant Effect
Reports of major bleeding in patients receiving dabigatran have garnered attention in large part due to the fact that, unlike warfarin, there is currently no antidote for its anticoagulant effect. Given its relatively short half-life (12-17 h) compared to vitamin K antagonists, drug cessation and supportive care is often sufficient in patients with normal renal function who will excrete the drug within hours [3,10,12,14,22]. By 12 h, dabigatran plasma concentrations fall below 100 ng/mL and aPTT falls to 1.5 times baseline values in patients with normal renal function taking 150 mg of dabigatran twice-daily [3]. Even with impaired CrCl, promoting diuresis when possible is encouraged as a means of eliminating the drug [7]. As shown in Fig. 3, the present patient's coagulation parameters improved in conjunction with improving renal function. When overdose is suspected, dabigatran can be absorbed by activated charcoal given within 1-2 h of ingestion, although this has only been tested in vitro [3,6,23]. However, case reports of dabigatran overdose cite new renal failure rather than either intentional or accidental ingestion as the usual culprit, limiting the utility of this potential method [12,13,15,16].
Many therapies used to reverse other anticoagulants are ineffective with dabigatran. Vitamin K and protamine sulfate, well-known antidotes of warfarin and heparin, respectively, are not beneficial for over-anticoagulation with dabigatran [3,22]. Use of cryoprecipitate has been cited in two case reports without clinical benefit [16,24]. While the 2011 focused update on the management of patients with atrial fibrillation (update on dabigatran) from the

American College of Cardiology, American
Heart Association, and Heart Rhythm Society suggest the use of FFP, many cases report utilization of FFP without a significant change in the aPTT or INR [3,6,22,23,25].

Recombinant activated factor VII (rFVIIa)
was developed for treatment of bleeding in hemophiliac patients with inhibitors to factors VIII and IX. Exogenous factor VIIa can directly activate thrombin on the surface of platelets in the absence of tissue factor and has, therefore, gained interest as a potential means of reversing dabigatran's effect [3,6,23]. However, rFVIIa did not reverse the antithrombotic effects of melagatran (the active form of the oral direct thrombin inhibitor, ximelagatran, which is not available for clinical use) in a single-blind, randomized study of 47 healthy male volunteers [26].
In an ex vivo study of eight patients with atrial fibrillation taking dabigatran 150 mg twice-daily, Davis et al. [27] investigated the Rapid Thromboelastographic-derived activated clotting time (RapidTEG-ACT) as a method of measuring both the anticoagulant activity of dabigatran and the potential for reversibility with human inactivated thrombin (HTI), rFVIIa, and a four-factor PCC. In concert with aPTT, PT, TT, and ACT, measurement of reaction time from test initiation to initial fibrin formation using thromboelastography (called the TEG R-value) is a potentially useful laboratory value for assessing dabigatran's anticoagulant activity. The addition of HTI (currently only available topically and, therefore, unsuited for in vivo testing for this indication) and rFVIIa to patients' peripheral blood significantly reduced the TEG R-value while the PCC analog did not. This study suggests a potential utility for rFVIIa that requires further investigation in vivo and clinically.
In a case report of a 79-year-old participant in the RE-LY trial who unintentionally underwent cardiac surgery with therapeutic levels of circulating dabigatran, the authors reported initially trying three doses of 2.4 mg/dose of rFVIIa without success in controlling the patient's post-operative bleeding [24]. The authors subsequently administered two doses of 7.2 mg/dose and, although they did not report coagulation parameters, they cited a reduction in the patient's bleeding as a favorable sign that high-dose rFVIIa may reduce dabigatran-associated bleeding.
However, the patient also underwent hemodialysis (HD), which may have contributed to the reduction in bleeding.
Furthermore, given the potential of rFVIIa to precipitate myocardial infarction and stroke, care should be taken in using rFVIIa for bleeding events in non-hemophiliacs. The FDA has issued a black box warning due to an increased potential for thrombotic events when rVIIa is used outside of the product's approved indications [28]. Several cases reports, including the present, have commented on the utilization of PCC, of which there are two types available [12,23] [29]. In the present case, the patient's coagulopathy did rapidly correct, but the independent contribution of Profilnine could not be determined as it was administered concomitantly with vitamin K and FFP (Fig. 3).
An activated PCC (aPCC) available in the US  While evidence in support of HD is limited to case reports, the consistently cited benefit of this modality makes it a promising treatment option in cases of dabigatran-associated bleeding. Given the bleeding risk associated with placing a dialysis catheter in a patient with severe coagulopathy, other methods to reverse the anticoagulant effect of dabigatran will be necessary complements to a treatment strategy incorporating HD. In addition, although typically utilized for patients experiencing bleeding in the setting of acute renal failure, it is possible that HD confers a benefit over supportive therapy and promotion of diuresis in patients presenting with bleeding in the context of normal renal function.

Elevations in Liver Enzymes with Oral Direct Thrombin Inhibitors
The first developed oral direct thrombin inhibitor, ximelagatran, was associated with ALT elevations in 6.4% of patients (as compared to 1.2% taking placebo) [39].