- RE-VERSE AD™ interim analysis suggests reintroduction of alternate antithrombotic therapy possible at any time after idarucizumab administration
- Findings from an in vitro study suggest idarucizumab does not impact the effect of other commercially available blood thinners
- In vitro study results also suggest that the reversal effect of idarucizumab on dabigatran is not affected by the presence of coagulation factor concentrates
Boehringer Ingelheim announced results from two new analyses evaluating idarucizumab, recently approved under the Accelerated Approval pathway and marketed in the U.S. as Praxbind®, a specific reversal agent for Pradaxa® (dabigatran etexilate mesylate), that were presented at the American Heart Association (AHA) Scientific Sessions 2015 in Orlando. The analysis examined reinitiation of antithrombotic therapy after administration of idarucizumab. The reinitiation of antithrombotic therapy in patients with nonvalvular atrial fibrillation (NVAF) is important in order to address the underlying risk of stroke.
An interim analysis of data from the ongoing phase III RE-VERSE AD™ trial showed reinitiation of alternative antithrombotic therapy was possible any time after idarucizumab use. Reinitiation of alternative antithrombotic therapy (e.g. heparin) after treatment with idarucizumab ranged from 0.2 days to 77.2 days in patients who presented with uncontrolled or life-threatening bleeding and 0 days to 40.8 days in patients requiring emergency surgery or an urgent procedure. Reinitiation of PRADAXA after treatment with idarucizumab ranged from 1.3 days to 90.6 days in patients with uncontrolled or life-threatening bleeding, and 1 day to 63.31 days in patients requiring emergency surgery or an urgent procedure.
"Reinitiation of antithrombotic therapy as soon as medically appropriate should be considered to reduce the underlying stroke risk for patients with nonvalvular atrial fibrillation (NVAF)," said Charles Pollack, MD, Associate Provost and Professor of Emergency Medicine, Thomas Jefferson University in Philadelphia, and lead investigator of RE-VERSE AD. "The findings from this interim analysis from the phase III RE-VERSE AD study may provide physicians added insight into the reinitiation of antithrombotic therapy after dabigatran reversal in the rare emergency situations where administration of idarucizumab is deemed necessary."
A second presentation on idarucizumab included findings from an in vitro study investigating the efficacy of idarucizumab in the presence of coagulation factor concentrates [e.g., blood-clotting proteins recombinant Factor VIIa, 3- or 4-factor prothrombin complex concentrates (PCC), and activated PCC]. The results suggest that the use of idarucizumab did not inhibit the anticoagulation effects of other commercially available blood thinners (direct factor Xa inhibitors, heparins, or other direct thrombin inhibitors). The study also showed that the reversal effect of idarucizumab on dabigatran was not affected by the presence of coagulation factor concentrates. This result is important as these agents are frequently used in the management of patients presenting with acute hemorrhages.
"The data presented at AHA reinforce the clinical evidence on the use of idarucizumab in treating PRADAXA patients in emergency or urgent settings where reversal of anticoagulation is needed," said Sabine Luik, MD, senior vice president, Medicine & Regulatory Affairs, Boehringer Ingelheim. "The data presented today support that, although idarucizumab will be rarely used in clinical practice, a specific reversal agent may provide an important therapeutic option for physicians and patients."
About RE-VERSE AD™
RE-VERSE AD is a phase III global study that includes patients taking PRADAXA who have uncontrolled bleeding or require emergency procedures. The interim analysis from RE-VERSE AD included data from 90 patients with either uncontrolled or life-threatening bleeding complications, e.g. intracranial hemorrhage or severe trauma after a car accident (n= 51), or patients requiring emergency surgery or an urgent procedure, e.g. surgery for an open fracture after a fall (n=39). The study met its primary endpoint, achieving 100 percent maximum reversal as the median value within four hours of administration across all patients. Reversal was evident immediately after administration of the first vial of idarucizumab and was complete in all but 1 patient. In this interim analysis there were 18 deaths. Mortality could be attributed to a complication of the underlying reason for admission or associated with comorbidities. Thrombotic events occurred in five patients, none of whom was receiving antithrombotic therapy at the time of the event.
About Praxbind® (idarucizumab)
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Thromboembolic Risk
Re-elevation of Coagulation Parameters
Hypersensitivity Reactions
Risk in Patients with Hereditary Fructose Intolerance
ADVERSE REACTIONS
USE IN SPECIFIC POPULATIONS
Pregnancy and Nursing Mothers
Please see full Prescribing Information.
INDICATIONS AND USAGE
PRAXBIND is indicated in patients treated with Pradaxa® when reversal of the anticoagulant effects of dabigatran is needed:
This indication is approved under accelerated approval based on a reduction in unbound dabigatran and normalization of coagulation parameters in healthy volunteers. Continued approval for this indication may be contingent upon the results of an ongoing cohort case series study.
About Pradaxa® (dabigatran etexilate mesylate)
Indications and Usage
Pradaxa®(dabigatran etexilate mesylate) capsules is indicated:
IMPORTANT SAFETY INFORMATION ABOUT PRADAXA
WARNING: (A) PREMATURE DISCONTINUATION OF PRADAXA INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA
(A) PREMATURE DISCONTINUATION OF PRADAXA INCREASES THE RISK OF THROMBOTIC EVENTS
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
(B) SPINAL/EPIDURAL HEMATOMA
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:
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.
CONTRAINDICATIONS
PRADAXA is contraindicated in patients with:
WARNINGS & PRECAUTIONS
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 and restart PRADAXA as soon as medically appropriate.
Risk of Bleeding
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
Treatment and Reduction in the Risk of Recurrence of DVT/PE
ADVERSE REACTIONS
The most serious adverse reactions reported with PRADAXA were related to bleeding.
NVAF
DVT/PE
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).
Please see full Prescribing Information, including boxed WARNING and Medication Guide.
About Boehringer Ingelheim
Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation.
Boehringer Ingelheim is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, the company operates globally with 146 affiliates and more than 47,000 employees. Since its founding in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel treatments for human and veterinary medicine.
Boehringer Ingelheim is committed to improving lives and providing valuable services and support to patients and families. Our employees create and engage in programs that strengthen our communities. To learn more about how we make more health for more people, visit our Corporate Social Responsibility Report.
In 2014, Boehringer Ingelheim achieved net sales of about $16.96 billion dollars (13.3 billion euros). R&D expenditure corresponds to 19.9 percent of its net sales.
For more information please visit www.us.boehringer-ingelheim.com, or follow us on Twitter @BoehringerUS.
Boehringer Ingelheim Pharmaceuticals, Inc. either owns or uses the trademarks Pradaxa®, Praxbind® and RE-VERSE AD™ under license.
SOURCE Boehringer Ingelheim Pharmaceuticals, Inc.
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