In October 2015, the U.S. Food and Drug Administration granted accelerated approval to idarucizumab for patients who were taking dabigatran and required a reversal of the drug’s blood-thinning effects during a medical emergency, such as a hemorrhagic stroke. Prior to this approval, the standard for anticoagulation reversal was prothrombin complex concentrates (PCC). Two abstracts presented at the ASH annual meeting compared emergency reversal of anticoagulation with idarucizumab and PCCs – looking specifically at how their mechanisms of procoagulation differ and whether they are safe to use with additional coagulation factors.
Idarucizumab works with dabigatran by binding to the drug compound to neutralize its effect, and patients taking dabigatran, though it is generally safer than warfarin, can experience serious bleeding events. “A proportion of trauma patients presenting with coagulopathy also receive anticoagulant therapy, which can exacerbate coagulopathy and increase bleeding,” Oliver Grottke, MD, PhD, and colleagues from the RWTH University Hospital in Aachen, Germany, explained. “Emergency reversal of anticoagulation therapy may require therapy with specific reversal agents, as with idarucizumab for dabigatran or non-specific reversal agents, such as PCC.”
In each study, Dr. Grottke and investigators examined the procoagulant properties of these hemostatic therapies in pigs who had been treated with dabigatran.
In the first study, they investigated reversal of anticoagulation in 18 pigs. Dabigatran was given orally for three days and intravenously on day four. Animals were then randomized to receive idarucizumab (60 mg/kg), PCC (50 IU/kg), or saline (control) 15 minutes after a bleeding event.
Prior to injury, the authors reported that mean dabigatran levels were 543±186 ng/ml. After treatment, blood loss was greatest in the control group: 4,056±537 mL after saline treatment versus 1,822±222 mL after PCC (p<0.0001 vs. control) versus 1,086±134 mL after idarucizumab (p<0.0001 vs. all).
All controls developed severe clotting disorders and blood loss, with a mean survival time of 93 minutes (range = 62-146 minutes).
Post-injury and after PCC infusion, measures of coagulation on clotting assays (including thrombin-antithrombin complex, D-dimers, and fibrinopeptide A) were increased compared with patients receiving idarucizumab or control and remained elevated for more than 300 minutes. Similarly, thrombin generation (measured by endogenous thrombin potential [ETP]) increased immediately after PCC administration and persisted at 120 minutes (baseline ETP=267±84 nM/min; 120-minute ETP=848±114 nM/min).
After administration of idarucizumab, however, ETP was restored to baseline values. This “supernormal activation of coagulation” with four-factor PCC, the authors noted, suggests that these therapies activate coagulation through different mechanisms. “In contrast [with four-factor PCC], idarucizumab binds dabigatran and forms an irreversible complex, inactivating dabigatran in plasma, thereby restoring hemostatic function. This difference may influence the choice of therapy when idarucizumab is clinically available.”
Next, the investigators tested the safety and efficacy of idarucizumab or PCC given as first- or second-line therapy, and compared these approaches with a multimodal approach using tranexamic acid plus fibrinogen concentrate. “In cases of continuous bleeding and/or elevated dabigatran levels, further hemostatic therapy with coagulation factors such as tranexamic acid and fibrinogen concentrate may be required,” Dr. Grottke noted.
Twenty-eight pigs were included in this study. Animals were randomized to receive either 60 mg/kg idarucizumab or 50 U/kg PCC after the first injury. One hour later, the animals received the opposite treatment after the second injury.
In a second stage, tranexamic acid (20 mg/kg) plus fibrinogen concentrate (100 mg/kg) were added to hemostatic therapy after the first injury, and, again, the subjects then received the opposite hemostatic therapy (idarucizumab or PCC) after the second liver injury.
Investigators monitored blood loss and hemodynamic and coagulation parameters over five hours or until death.
“Under conditions of ongoing blood loss after injury and dabigatran anticoagulation, both idarucizumab and PCC prevented blood loss, although therapy with idarucizumab was more effective,” the authors reported.
As first-line treatment, idarucizumab resulted in a significant reduction in blood loss compared with PCC: 1,040±202 mL versus 1,389±194 mL at 60 minutes post-injury. The difference between these two groups remained significant following the second injury, despite increasing blood loss (idarucizumab + PCC=1,556±205 mL vs. PCC + idarucizumab = 1,981±361 mL; p<0.0001).
Similarly, when tranexamic acid and fibrinogen concentrate were added to the hemostatic therapies, blood loss was significantly lower than in subjects who received PCC alone:
- Initial tranexamic acid + fibrinogen concentrate + PCC: 1,696±186 mL (p=0.023 when compared with PCC monotherapy)
- Initial tranexamic acid + fibrinogen concentrate + idarucizumab: 1,416±139 mL (p<0.0001 when compared with PCC monotherapy)
Adding tranexamic acid and fibrinogen concentrate to idarucizumab therapy, however, resulted in no significant difference in blood loss.
The difference in blood loss between idarucizumab and PCC can be explained by the different mechanisms through which the therapies inhibit dabigatran’s anticoagulant effect. Furthermore, these data suggest that a multi-modal hemostasis approach with tranexamic acid and fibrinogen concentrate plus idarucizumab and PCC appears safe under these conditions.
Grottke O, Honickel M, Rossaint R, Braunschweig T. Prothrombin Complex Concentrate or Idarucizumab in a Multimodal Hemostatic Approach with Tranexamic Acid and Fibrinogen for the Acute Reversal of Dabigatran. Abstract #2275. Presented at the 2015 ASH Annual Meeting, December 6, 2015; Orlando, Florida.
Honickel M, van Ryn J, Grottke O. Mechanistic Differences of Prothrombin Complex Concentrate and Idarucizumab in a Trauma Model Under Dabigatran Anticoagulation. Abstract #1128. Presented at the 2015 ASH Annual Meeting, December 5, 2015; Orlando, Florida.