New Analysis Shows Idarucizumab* Enables Rapid Initiation of Emergency Surgery in Dabigatran-Treated Patients

RIDGEFIELD, Conn., Sept. 1, 2015 /PRNewswire/ -- Results from an interim analysis of the Phase III RE-VERSE AD™ study demonstrate that 5g of idarucizumab enabled emergency surgery to be initiated rapidly in urgent situations involving patients treated with dabigatran (Pradaxa® dabigatran etexilate mesylate). The specific and immediate reversal of the anticoagulant effect of dabigatran enabled patients to be urgently brought to necessary procedures, with a median time of 1.7 hours between administration of idarucizumab and start of procedure. In the 24 hours after surgery, no bleeding complications were reported. The results were presented today at the ESC Congress 2015 in London, United Kingdom.

"Normal blood clotting is important during surgery. Dabigatran already has a short half-life of around 12 hours, allowing for normal surgery to be performed in a reasonable time after stopping the drug in many patients," said Prof. Jerrold Levy, RE-VERSE AD investigator and Professor of Anesthesiology and Co-Director of the Cardiothoracic Intensive Care Unit, Duke University Medical Center, North Carolina. "But in case of an emergency situation, we need to go to the operating room sooner. The data now presented show that immediately reversing dabigatran with idarucizumab would allow for rapid normalization of clotting and faster initiation of surgery in case it is needed."

The interim analysis from RE-VERSE AD included data from patients requiring emergency surgery or an invasive procedure (e.g., surgery for an aortic aneurysm or an open fracture after a fall), which could not be delayed for more than 8 hours. Of the 39 patients who presented with elevated anticoagulation levels at baseline (as measured with Ecarin Clotting Time), results showed:

Administration of idarucizumab allowed surgery to be initiated rapidly – the median time between the administration of idarucizumab and surgery was only 1.7 hours
Normal blood clotting during surgery was reported in 92 percent of patients
There were no post-surgical bleeding complications reported in the 24 hours following surgery
"These results reinforce the effectiveness and safety of idarucizumab in rare situations when a dabigatran-treated patient requires an emergency procedure," said Professor Jorg Kreuzer, Vice President Medicine Therapeutic Area Cardiovascular, Boehringer Ingelheim. "Idarucizumab provides immediate and complete reversal of dabigatran in most patients, which allows urgent surgery to be initiated rapidly, which may be vital in managing these patients."

Due to the serious and complex nature of the emergency the patients in the study presented with, six patients died within two days of the emergency procedure, another three died during the 90-day follow-up period. Mortality within 96 hours of study enrollment appeared to be related to the original reason for emergency admission to the hospital, while all later events appeared to be related to co-morbidities. Two patients suffered a thromboembolic event (on days 7 and 26 post surgery), but both were not receiving antithrombotic therapy at that time.

The U.S. Food and Drug Administration (FDA) granted Priority Review to the Biologics License Application (BLA) for idarucizumab in April 2015 for patients treated with dabigatran who require rapid reversal of the anticoagulant effects during emergency surgery or urgent procedures or in life-threatening or uncontrolled bleeding.  Idarucizumab is currently being assessed by different regulatory authorities, including the FDA, European Medicines Agency and Health Canada. Further submissions are ongoing.

About Idarucizumab
Idarucizumab is a humanized antibody fragment, or Fab, being investigated as a specific reversal agent for the anticoagulant effect of dabigatran in patients needing emergency surgery or urgent procedures or for life-threatening or uncontrolled bleeding events. The safety and efficacy of idarucizumab has not been established.

Boehringer Ingelheim scientists discovered and are developing idarucizumab. The research program was initiated in 2009, before PRADAXA was launched in the U.S. in 2010. The company has a rich history in supporting the development and manufacturing of biopharmaceutical products, and idarucizumab is an example of this dedication and experience.

The company completed three phase I trials of idarucizumab in human volunteers, and included these data in the idarucizumab Biologics License Application (BLA) submitted to the FDA. Interim data from RE-VERSE AD™ was also included in the idarucizumab BLA.

Boehringer Ingelheim is continuing to evaluate idarucizumab in RE-VERSE AD, a phase III global study that includes patients taking PRADAXA who have uncontrolled or life-threatening bleeding or require emergency procedures. The study is the first of its kind in patients, and has been underway since May 2014 enrolling patients in more than 35 countries.

RE-VERSE AD is designed to evaluate the types of patients and real-world situations healthcare professionals may see in the emergency setting. The broad inclusion criteria ensure that even the most severely ill or injured patients (e.g. patients with sepsis or a severe intracranial hemorrhage), who require urgent reversal of dabigatran, may be enrolled in the study. Patients were categorized into two groups – (A) patients with uncontrolled or life-threatening bleeding complications, e.g. intracranial hemorrhage or severe trauma after a car accident (Group A, n= 51), or (B) patients requiring emergency surgery or an invasive procedure, e.g. surgery for an open fracture after a fall (Group B, n=39). The primary endpoint of the study is the degree of reversal of the anticoagulant effect of dabigatran achieved by 5 g idarucizumab within 4 hours measured by diluted thrombin time (dTT) and ecarin clotting time (ECT).

About Pradaxa® (dabigatran etexilate mesylate) Capsules

Indications and Usage
Pradaxa® (dabigatran etexilate mesylate) capsules is indicated:

to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation;
for the treatment of deep venous thrombosis and pulmonary embolism in patients who have been treated with a parenteral anticoagulant for 5-10 days;
to reduce the risk of recurrence of deep venous thrombosis and pulmonary embolism in patients who have been previously treated


Premature discontinuation of any oral anticoagulant, including PRADAXA, increases the risk of thrombotic events. If anticoagulation with PRADAXA is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant 
Epidural or spinal hematomas may occur in patients treated with PRADAXA who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:
-- use of indwelling epidural catheters
-- concomitant use of other drugs that affect hemostasis, such as non-steroidal anti‑inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants
-- a history of traumatic or repeated epidural or spinal punctures
-- a history of spinal deformity or spinal surgery
-- optimal timing between the administration of PRADAXA and neuraxial procedures is not known
Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.  Consider the benefits and risks before neuraxial intervention in patients who are or will be anticoagulated.
PRADAXA is contraindicated in patients with:

active pathological bleeding;
known serious hypersensitivity reaction (e.g., anaphylactic reaction or anaphylactic shock) to PRADAXA;
mechanical prosthetic heart valve
Increased Risk of Thrombotic Events after Premature Discontinuation
Premature discontinuation of any oral anticoagulant, including PRADAXA, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events.  If PRADAXA is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.

Risk of Bleeding

PRADAXA increases the risk of bleeding and can cause significant and, sometimes, fatal bleeding. Promptly evaluate any signs or symptoms of blood loss (e.g., a drop in hemoglobin and/or hematocrit or hypotension). Discontinue PRADAXA in patients with active pathological bleeding.
Risk factors for bleeding include concomitant use of medications that increase the risk of bleeding (e.g., anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs). PRADAXA's anticoagulant activity and half-life are increased in patients with renal impairment.
Reversal of Anticoagulant Effect: A specific reversal agent for dabigatran is not available. Hemodialysis can remove dabigatran; however clinical experience for hemodialysis as a treatment for bleeding is limited.  Activated prothrombin complex concentrates, recombinant Factor VIIa, or concentrates of factors II, IX or X may be considered but their use has not been evaluated.  Protamine sulfate and vitamin K are not expected to affect dabigatran anticoagulant activity.  Consider administration of platelet concentrates where thrombocytopenia is present or long-acting antiplatelet drugs have been used.
Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves
The use of PRADAXA is contraindicated in patients with mechanical prosthetic valves due to a higher risk for thromboembolic events, especially in the post-operative period, and an excess of major bleeding for PRADAXA vs. warfarin. Use of PRADAXA for the prophylaxis of thromboembolic events in patients with AFib in the setting of other forms of valvular heart disease, including bioprosthetic heart valve, has not been studied and is not recommended.

Effect of P-gp Inducers & Inhibitors on Dabigatran Exposure
Concomitant use of PRADAXA with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided.  P-gp inhibition and impaired renal function are major independent factors in increased exposure to dabigatran.  Concomitant use of P-gp inhibitors in patients with renal impairment is expected to increase exposure of dabigatran compared to either factor alone.

Reduction of Risk of Stroke/Systemic Embolism in NVAF

For patients with moderate renal impairment (CrCl 30-50 mL/min), consider reducing the dose of PRADAXA to 75 mg twice daily when dronedarone or systemic ketoconazole is coadministered with PRADAXA.
For patients with severe renal impairment (CrCl 15-30 mL/min), avoid concomitant use of PRADAXA and P-gp inhibitors.
Treatment and Reduction in the Risk of Recurrence of DVT/PE

For patients with CrCl <50 mL/min, avoid use of PRADAXA and concomitant P-gp inhibitors
The most serious adverse reactions reported with PRADAXA were related to bleeding.

Most frequent adverse reactions leading to discontinuation of PRADAXA were bleeding & gastrointestinal (GI) events
PRADAXA 150 mg resulted in higher rates of major and any GI bleeds compared to warfarin.
In patients ≥75 years of age, the risk of major bleeding may be greater with PRADAXA vs warfarin.
Patients on PRADAXA 150 mg had an increased incidence of GI adverse reactions. These were commonly dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, and GI ulcer).

Rates of any GI bleeds were higher in patients receiving PRADAXA 150 mg vs warfarin and placebo
In the active-controlled studies, there was a higher rate of clinical myocardial infarction (MI) in PRADAXA patients [20 (0.66/100) patient-years)] vs warfarin [5 (0.17/100 patient-years)].  In the placebo-controlled study, there was similar rate of non-fatal and fatal clinical MI in PRADAXA patients [1 (0.32/100 patient-years)] vs placebo [1 (0.34/100 patient-years)].
GI adverse reactions were similar in patients receiving PRADAXA 150 mg vs warfarin.  They were commonly dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms (including gastritis, GERD, esophagitis, erosive gastritis and gastric hemorrhage).
Drug hypersensitivity reactions were reported in ≤ 0.1% of patients receiving PRADAXA.

Other Measures Evaluated
In NVAF patients, a higher rate of clinical MI was reported in patients who received PRADAXA (0.7/100 patient-years for 150 mg dose) than in those who received warfarin (0.6).

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Boehringer Ingelheim Pharmaceuticals, Inc. either owns or uses the trademarks Pradaxa®, PRADAXA with associated design®, and RE-VERSE AD™ under license.

*Idarucizumab is the recommended International Nonproprietary Name (INN). Idarucizumab is an investigational drug, which has not been approved for clinical use, and further safety and efficacy testing will be required.

SOURCE Boehringer Ingelheim Pharmaceuticals, Inc.