Characteristics of the Patients

Table 1. Table 1. Clinical Characteristics of the Patients.

From June 2014 through February 2015, a total of 90 patients (51 patients in group A and 39 in group B) were enrolled at 184 sites in 35 countries. More than 90% of the patients were receiving dabigatran for stroke prevention in the context of atrial fibrillation. The median age of the patients was 76.5 years, and the median creatinine clearance was 58 ml per minute (Table 1). The condition of 16 of the patients in group A was hemodynamically unstable, and these patients had ongoing blood loss at study entry. A total of 18 patients in group A had intracranial hemorrhage, 20 had gastrointestinal bleeding, 9 had bleeding from trauma, and 11 had other causes of bleeding. The indications for emergency surgery in the patients in group B are listed in Table S4 in the Supplementary Appendix. The median time since the last dose of dabigatran, as reported by the patients, was 15.4 hours.

Follow-up

All the patients received 5 g of idarucizumab and were followed until death or for at least 1 month, except for 1 patient who withdrew informed consent and 1 who declined further follow-up and received palliative care. Among 90 treated patients, excluding 3 with missing information, the median duration of hospitalization (based only on dates, not times) was 8 calendar days (range, 2 to 93).

Reversal of Anticoagulation

At study entry, 22 patients had dilute thrombin times that were subsequently determined by central laboratory analysis to be within normal limits; likewise 9 patients (all of whom had normal dilute thrombin times) were found to have normal ecarin clotting times. These patients were enrolled and given idarucizumab on the basis of the inclusion criteria for the study but were excluded from the efficacy analysis because their baseline clotting tests were within the normal range. Therefore, the percentage reversal with idarucizumab as assessed by means of the dilute-thrombin-time test could be determined in 68 of the 90 patients (40 patients in group A and 28 in group B), and the percentage reversal as assessed by means of the ecarin-clotting-time test could be determined in 81 of 90 (47 in group A and 34 in group B).

Figure 1. Figure 1. Time Course of the Dilute Thrombin Time and Ecarin Clotting Time before and after the Administration of Idarucizumab. The analyses included 51 patients who had serious bleeding (group A; Panels A and C) and 39 who required urgent surgery or intervention (group B; Panels B and D). Idarucizumab was administered in two infusions. Blood samples were obtained at baseline, after the first infusion, at 10 to 30 minutes after the administration of the second infusion, and at 1, 2, 4, 12, and 24 hours. Data are presented as box-and-whisker plots, in which the top and bottom of the rectangles indicate the 75th and 25th percentiles, respectively; the horizontal lines within the rectangles indicate the 50th percentile; the lines above and below the rectangles indicate the 90th and 10th percentiles, respectively; and the dots above and below the lines indicate the 95th and 5th percentiles, respectively. The dashed lines indicate the upper limit of the normal range for the tests.

The median maximum percentage reversal in the patients in group A and in those in group B was 100% (95% confidence interval, 100 to 100), as assessed by both the dilute thrombin time and ecarin clotting time, and reversal was evident on the sample taken after the first infusion (Figure 1). The dilute thrombin time was normalized in 98% of the patients in group A who could be evaluated and in 93% of those in group B who could be evaluated, and the ecarin clotting time was normalized in 89% and 88% of the patients who could be evaluated, respectively (Figure 1, and Tables S5 and S6 in the Supplementary Appendix). At 12 hours and 24 hours, the dilute thrombin time was below the upper limit of the normal range in 90% of the patients in group A who could be evaluated and in 81% of those in group B, and the ecarin clotting time was below the upper limit of the normal range in 72% and 54% of the patients who could be evaluated, respectively. Similar results were observed with respect to the activated partial-thromboplastin time and the thrombin time as measured at the central laboratory (Fig. S1 in the Supplementary Appendix) or at the local hospitals (data not shown).

Clearance of dabigatran is influenced by renal function. As compared with the 68 patients with elevated results on the clotting tests at baseline, the 22 patients with normal results had better renal function (median creatinine clearance, 48 ml per minute in patients with elevated results vs. 67 ml per minute in those with normal results) and a longer time since the last dose of dabigatran (median, 12.8 hours vs. 30.3 hours). In group A, the proportion of patients with intracranial bleeding was higher among the 11 patients who had normal results on the clotting tests at baseline than among the 40 who had elevated results at baseline (64% vs. 28%). One death and 2 thrombotic events occurred among the 22 patients with normal results on either of the clotting tests at baseline, and 17 deaths and 3 thrombotic events occurred among the 68 patients with elevated results.

Dabigatran and Idarucizumab Concentrations

Figure 2. Figure 2. Time Courses of Plasma Concentrations of Unbound Dabigatran and Idarucizumab before and after the Administration of Idarucizumab. The analyses included 51 patients who had serious bleeding (group A; Panels A and C) and 39 who required urgent surgery or intervention (group B; Panels B and D). Data are presented as box-and-whisker plots, in which the top and bottom of the rectangles indicate the 75th and 25th percentiles, respectively; the horizontal lines within the rectangles indicate the 50th percentile; the lines above and below the rectangles indicate the 90th and 10th percentiles, respectively; and the dots above and below the lines indicate the 95th and 5th percentiles, respectively.

At baseline, the median plasma concentration of total dabigatran was 132 ng per milliliter (range, 5 to 886) in group A and 114 ng per milliliter (range, 7 to 3600) in group B. Except for the plasma concentrations of total dabigatran of more than 1000 ng per milliliter in two patients in group B, the dabigatran concentrations were similar to those measured in the RE-LY trial.9 The median plasma concentration of unbound dabigatran at baseline was 84 ng per milliliter (range, 3 to 641) in group A and 76 ng per milliliter (range, 4 to 2880) in group B (Figure 2A and 2B, and Fig. S2 in the Supplementary Appendix). In samples obtained after the first vial of idarucizumab was administered, the concentration of unbound dabigatran was less than 20 ng per milliliter — a level that produces little or no anticoagulant effect — in all but one patient.

Blood samples were available from 86 patients at 4 hours, 83 patients at 12 hours, and 78 patients at 24 hours; the reasons for missing samples included death or technical difficulties (Table S7 in the Supplementary Appendix). At 4 hours after treatment, 83 of the 86 patients had a concentration of unbound dabigatran near the lower limit of quantification, 1 had a concentration of 31 ng per milliliter, and 2 had high concentrations of 848 ng per milliliter and 1510 ng per milliliter (Figure 2A and 2B, and Table S8 in the Supplementary Appendix). The concentration of unbound dabigatran was less than 20 ng per milliliter in 77 of the 83 patients (93%) at 12 hours and in 62 of the 78 (79%) at 24 hours. By 4 hours after administration, the geometric mean plasma concentration of idarucizumab had decreased by 80% from the peak level (Figure 2C and 2D, and Table S9 in the Supplementary Appendix).

Clinical Outcomes

Among the 51 patients in group A, 3 had no bleeding assessment at baseline. The time to the cessation of bleeding could not be ascertained in 13 patients, of whom 5 had intracranial hemorrhage, 4 had gastrointestinal bleeding, 2 had intramuscular bleeding, 1 had pericardial bleeding, and 1 had retroperitoneal bleeding. In the remaining patients, the median investigator-reported time to the cessation of bleeding was 11.4 hours.

Idarucizumab obviated the need for emergency dialysis in 1 patient in group B who had ingested a massive overdose of dabigatran; the condition of 2 other patients in group B remained too unstable for surgery despite the reversal of anticoagulation. The remaining 36 patients in group B underwent urgent procedures, and normal intraoperative hemostasis was reported in 33 (92%). Mildly or moderately abnormal hemostasis during the procedure was reported in 2 patients and 1 patient, respectively.

Table 2. Table 2. Serious Adverse Events Leading to Death.

There were 18 deaths overall, with 9 in each study group (Table 2); 10 deaths were due to vascular causes, including 5 fatal bleeding events. Death within 96 hours after treatment appeared to be related to the index event (2 patients had septic shock, 3 had intracranial hemorrhage, and 1 each had multiorgan failure, hemodynamic collapse, respiratory failure, and cardiac arrest), whereas all the later deaths appeared to be associated with coexisting conditions. Data regarding blood-product use and the reinitiation of antithrombotic therapy are provided in Tables S10 and S11, respectively, in the Supplementary Appendix.

Thrombotic Events and Serious Adverse Events

Thrombotic events, classified as early (≤72 hours after idarucizumab administration) or late (>72 hours after administration), occurred in five patients: deep-vein thrombosis and pulmonary embolism occurred in one patient 2 days after treatment; deep-vein thrombosis, pulmonary embolism, and left atrial thrombus occurred in one patient 9 days after treatment; deep-vein thrombosis alone occurred in one patient 7 days after treatment; non–ST-segment elevation myocardial infarction occurred in one patient 13 days after treatment; and ischemic stroke occurred in one patient 26 days after treatment. None of these patients were receiving antithrombotic therapy when the events occurred.

A total of 21 patients (13 patients in group A and 8 in group B) had serious adverse events during study participation. In addition to the 18 deaths and the thrombotic events that occurred in 5 patients, these events included gastrointestinal hemorrhage (in 2 patients) and postoperative wound infection, delirium, right ventricular failure, and pulmonary edema (in 1 patient each). Some patients had more than one event.