Use of prothrombin complex concentrates for urgent reversal of dabigatran in the Emergency Department

New oral anticoagulants (NOACs) are being implemented for use in daily clinical practice, anticoagulants that should theoretically replace the well-known vitamin K antagonists in the near future. Based on their inhibitory properties, NOACs can be classified into two main groups: direct thrombin inhibitors with dabigatran as the only available compound1 and factor Xa inhibitors, namely rivaroxaban and apixaban.2 Dabigatran has a low oral bioavailability, a low protein binding (35%) and its half-life reaches 14–17 hours in patients with normal renal function, but is longer in patients with impaired renal function and advanced age.3,4 A number of advantages of dabigatran over vitamin K antagonists have been reported, such as the lack of need for periodic blood testing or for any dose adjustment.5,6 Specific blood tests, such as the diluted thrombin time (Haemoclot®), are being developed but are not yet universally available at any given moment. However, the main limitation in the use of dabigatran is that there is currently no available antidote for this drug. A small number of options have been proposed in the event of an overdose: activated charcoal whenever possible, dialysis and/or the use of prohemostatic agents such as prothrombin complex concentrates (PCC), activated prothrombin complex concentrates (FEIBA), and recombinant activated factor VII (rFVIIa).1,7

We describe our experience in the emergency department (ED) with the urgent reversal of dabigatran anticoagulation using PCC. We collected data from all patients administered dabigatran who were treated at the ED between July 2011 and June 2012. From among these cases, any patient who developed a hemorrhagic complication was included. Relevant data from the electronic clinical history and prescriptions were collected. Additionally, we followed up patients for six months and we reviewed thrombotic complications. A descriptive data analysis was performed and we compared the blood parameters at the start of the treatment with dabigatran, at the moment of the hemorrhagic episode, and before and after the administration of PCC. The study was approved by the hospital Ethics Committee.

From a total of 68 patients under treatment with dabigatran, 5 patients developed bleeding complications in the intestinal tract (80% rectal bleedings and 20% melenas) and were therefore included in the study. The demographic data related to the start of treatment with dabigatran and the types of hemorrhagic complications are summarized in Table 1. The reason for dabigratan treatment in these 5 patients was atrial fibrillation. Patients had a median age of 82 years (range 76–88 years), were predominantly male (80%), had a median body weight of 57 kg (range 51–67 kg), and had a median creatinine-clearance of 53.7 mL/min (range 35.5–113 mL/min). None of the patients had any history of prior GI bleeding, one of the patients developed hepatopathy and all patients were being treated with antiplatelets. We calculated the HAS-BLED Score for all patients (Table),8 showing all of them to have a high estimated bleeding risk, with an estimated rate of major bleeding within the first year of between 5–20%. Probably these patients, especially those with 5 points or those with kidney function impaired, should not be treated with oral anticoagulants. Furthermore, 3 patients were being treated with proton-pump inhibitors. All of these patients were receiving a dosage of 110 mg dabigatran twice a day (for a total daily dose of 220 mg). The median time from the start of treatment to the hemorrhagic episode was 27 days (range 6–122 days). Figure 1 shows activated partial thromboplastin (aPTT) ratios. We found no significant differences in the coagulation tests performed before and after the bleeding episode, although a tendency was noted in the INR values (1.8±1.2 vs. 1.2±0.2) and in the aPTT ratio (2.4±1.5 vs. 1.5±0.6). All patients received treatment with a prothrombin complex concentrate (Octaplex®, Octapharma, Vienna, Austria). Table 1 lists the dosage/weight, the administration of vitamin K, the need for transfusion, the time from ED admission to the cessation of bleeding, and the final patient allocation. Four patients required hospital admission, and one patient (20%) died of septic shock of abdominal origin and coagulopathy secondary to massive/severe hemorrhage (rectal bleeding) 24 hours after admission. No patient had a thrombotic event during the next six months of follow up.

Table 1.Demographic and clinical characteristics, bleeding complications.

We present our initial experience in the reversal of dabigatran using PCC. Studies performed in animal models have produced conflicting results. Pragst et al.9 demonstrated the potential efficacy of PCC (Beriplex®) in the reversal of the dabigatran effect in a rabbit model. However, studies developed in murine models suggest that PCC treatment prevents excess bleeding much more effectively in warfarin-induced coagulopathy than in dabigatran-induced coagulopathy.10 In healthy volunteers, the effects of PCC on the dabigatran biological activity could not be confirmed, which differs from the findings of studies using rFVIIa or FEIBA.11 Of note, a study on 12 healthy volunteers showed that PCC did not reverse the biological effects of 150 mg dabigatran b.i.d.11 When compared to placebo, there was no difference in the decrease of the prolongation of aPTT. The normalization of the aPTT was observed 24 hours after the cessation of dabigatran administration.12 In our cohort study, only one patient showed a prolonged aPTT ratio that demonstrated a tendency to normalization from 3.2 to 1.4 after administration of PCC. This demonstrates a trend that has not yet been described regarding the effect of PCC in the prolongation of aPTT in patients treated with dabigatran. This correlated with an adequate clinical control of the hemorrhagic complication with only one death in our cohort study and an acceptable control in 4 of the 5 patients. Recently Lillo-Le Louet et al.13 reported the death of 4 patients after the reversal of dabigatran-induced bleeding. In 2 patients, PCC (Kaskadil® and Kanokad®) was used, and one patient was treated with recombinant FVIIa. With regard to these findings, we observe that there are some differences in the characteristics of our patient group. In addition to the fact that the composition of the PCC administered to our patients (Octaplex®) differs from the PCC used by Lillo-Le Louet et al. (Kaskadil®), our patients reported no renal impairment and were not administered high doses of dabigatran. We have shown that PCC could be useful and safe in dabigatran-treated patients with intestinal bleeding complications. However, further clinical trials are warranted to confirm this preliminary report.

Figure 1.Coagulation tests before and after the bleeding episode. Activated partial thromboplastin (aPTT) ratio at the emergency department during the bleeding episode (before PCC administration) and after the treatment of the hemorrhage (post-PCC administration).