Final Phase III Study Results Reinforces Safety and Efficacy of Praxbind® as Reversal Agent for Pradaxa® Patients in Emergency Situations

RIDGEFIELD, Conn., July 11, 2017 /PRNewswire/ -- Boehringer Ingelheim today announced final results from RE-VERSE AD™. The study shows that idarucizumab, marketed in the U.S. as Praxbind®, was able to immediately reverse the anticoagulant effect of Pradaxa® (dabigatran etexilate mesylate) in patients in emergency situations. The effects were consistent both in patients requiring an urgent surgery or intervention, and in patients presenting with uncontrollable or life-threatening bleeding. The reversal of the anticoagulant effect of Pradaxa allowed physicians to quickly initiate necessary emergency interventions. The findings were presented at the International Society on Thrombosis and Haemostasis (ISTH) 26th Biennial Congress in Berlin, Germany and simultaneously published in the New England Journal of Medicine.

The primary endpoint of RE-VERSE AD was reversal of the anticoagulant effect of Pradaxa within four hours as measured by diluted thrombin time (dTT) and ecarin clotting time (ECT), and was observed in 100 percent of patients (95 percent CI, 100-100). Reversal became evident immediately after administration of idarucizumab and was maintained for 24 hours in most patients. Reversal was independent of age, sex, kidney function or dabigatran concentration at baseline. A single 5 g dose of idarucizumab was sufficient in 98 percent of patients.

The clinical outcomes captured as secondary endpoints provide insights into the clinical relevance of anticoagulation reversal: in patients enrolled with acute bleeding (Group A), who could be assessed for time to cessation of bleeding, it took a median of 2.5 hours until the bleeding had stopped; in patients enrolled with a need for urgent surgery or intervention (Group B), the required procedures could be initiated after a median of 1.6 hours. In 93.4 percent of patients requiring procedures, hemostasis during the procedure was described as normal.

"Emergencies or accidents can happen to anyone. Patients with atrial fibrillation on an anticoagulant may feel anxious about how they might be managed in an emergency," said Charles Pollack, M.D., lead investigator of RE-VERSE AD, Professor of Emergency Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, USA. "RE-VERSE AD has shown that idarucizumab reverses the anticoagulant effect of dabigatran within minutes, so that treating physicians can fully focus on dealing with the emergency at hand."

There were no adverse safety signals related to idarucizumab observed in the study. Patients in this study were elderly, had numerous comorbidities and presented with serious index events such as intracranial hemorrhage, multiple trauma or sepsis. Mortality rates at 90 days were 18.8 percent (Group A) and 18.9 percent (Group B). At 90 days, thrombotic events had occurred in 6.3 percent of Group A patients and 7.4 percent of Group B patients, which is consistent with rates reported after major surgical procedures or hospitalization for uncontrolled bleeding.

"These final data from RE-VERSE AD are consistent with the results we have seen to-date, which demonstrate the important role idarucizumab can play for patients," said Sabine Luik, M.D., senior vice president, Medicine & Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. "The good news for patients and physicians is that idarucizumab is available right now in more than 2,900 hospital pharmacies nationwide, where it can be used to treat patients when urgently needed."

Idarucizumab is the first and only approved specific reversal agent for a novel oral anticoagulant currently available. It is approved as a specific reversal agent for Pradaxa by the U.S. Food and Drug Administration (FDA) under accelerated approval. Continued approval for this indication may be contingent upon the results of an ongoing cohort case series study. Boehringer Ingelheim continues to study idarucizumab in the RE-VECTO™ program, which evaluates usage patterns in a clinical practice setting. Expected completion of the RE-VECTO program is end of 2018.

About RE-VERSE AD™

RE-VERSE AD (NCT02104947) is a phase III global study of patients taking dabigatran who require urgent procedures or have uncontrolled bleeding. The final analysis from RE-VERSE AD included data from patients requiring urgent procedures/emergency surgery, e.g. surgery for an open fracture after a fall, or patients with either uncontrolled or life-threatening bleeding complications, e.g. intracranial hemorrhage or severe trauma after a car accident. The primary endpoint, the degree of reversal of the anticoagulant effect of dabigatran (Pradaxa) achieved by idarucizumab within four hours, was measured by dTT and ECT.

The study, which began in May 2014, is the largest study to investigate a reversal agent for a novel oral anticoagulant (NOAC) in real-world emergency settings. It enrolled a total of 503 patients at 173 sites in 39 countries, which were included in one of two groups:

• Group A: 301 patients (60 percent) presenting with uncontrolled or life-threatening bleeding (e.g. gastrointestinal [GI] and intracranial [ICH] bleeds)
• Group B: 202 patients (40 percent) requiring an invasive procedure or an emergency surgery or intervention (e.g. because of a hip fracture)

About Praxbind® (idarucizumab)

INDICATIONS AND USAGE
PRAXBIND is indicated in patients treated with Pradaxa® when reversal of the anticoagulant effects of dabigatran is needed:

• For emergency surgery/urgent procedures
• In life‐threatening or uncontrolled bleeding

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.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS
Thromboembolic Risk

• Dabigatran-treated patients have underlying diseases predisposing them to thromboembolic events.  Reversing dabigatran therapy exposes patients to the thrombotic risk of their underlying disease.  To reduce this risk, resumption of anticoagulant therapy should be considered as soon as medically appropriate.

Re-elevation of Coagulation Parameters

• Elevated coagulation parameters (e.g., activated partial thromboplastin time or ecarin clotting time) have been observed in a limited number of PRAXBIND-treated patients.  If reappearance of clinically relevant bleeding together with elevated coagulation parameters is observed or if patients requiring a second emergency surgery/urgent procedure have elevated coagulation parameters, an additional full dose may be considered.

Hypersensitivity Reactions

• There is insufficient clinical experience evaluating risk of hypersensitivity to idarucizumab, but a possible relationship could not be excluded.  Risk of hypersensitivity (e.g., anaphylactoid reaction) to idarucizumab or excipients needs to be weighed cautiously against the potential benefit.  If serious allergic reaction occurs, immediately discontinue PRAXBIND and institute appropriate treatment.

Risk in Patients with Hereditary Fructose Intolerance

• PRAXBIND contains 4 g sorbitol as an excipient.  When prescribing PRAXBIND in patients with hereditary fructose intolerance consider the total daily amount of sorbitol/fructose consumption from all sources as serious adverse reactions (e.g. hypoglycemia, hypophosphatemia, metabolic acidosis, increase in uric acid, acute liver failure and death) may occur. 

ADVERSE REACTIONS

• The most frequently reported adverse reaction in ≥5% of idarucizumab-treated healthy volunteers was headache (12/224).   The most frequently reported adverse reactions in ≥5% of patients were hypokalemia (9/123), delirium (9/123), constipation (8/123), pyrexia (7/123) and pneumonia (7/123). 
• As with all proteins there is a potential for immunogenicity with idarucizumab.  In treated patients, treatment-emergent antibodies with low titers were observed (9/224).

USE IN SPECIFIC POPULATIONS

Pregnancy and Nursing Mothers

• PRAXBIND should be given to a pregnant or nursing woman only if clearly needed.

Please see full Prescribing Information.

About Pradaxa® (dabigatran etexilate mesylate)

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

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:

• 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.

CONTRAINDICATIONS
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

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

• 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 (idarucizumab) for dabigatran is available when reversal of the anticoagulant effect of dabigatran is needed:
• For emergency surgery/urgent procedures
• In life-threatening or uncontrolled bleeding

Hemodialysis can remove dabigatran; however clinical experience for hemodialysis as a treatment for bleeding is limited. Prothrombin complex concentrates or recombinant Factor VIIa 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), reduce 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.

ADVERSE REACTIONS
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)

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 top 20 pharmaceutical companies. Headquartered in Ingelheim, Germany, the company operates globally with approximately 50,000 employees. Since its founding in 1885, the company has remained family-owned and today creates value through innovation for three business areas including human pharmaceuticals, animal health and biopharmaceutical contract manufacturing.

Boehringer Ingelheim is committed to improving lives and providing valuable services and support to patients and their families.  Our employees create and engage in programs that strengthen our communities. Please visit our website to learn more about how we make more health for more people through our Corporate Social Responsibility initiatives.

In 2016, Boehringer Ingelheim achieved net sales of about $17.6 billion (15.9 billion euros). R&D expenditure corresponds to 19.6 percent of its net sales.

For more information please visit www.boehringer-ingelheim.us, or follow us on Twitter @BoehringerUS.  

Boehringer Ingelheim Pharmaceuticals, Inc. either owns or uses the trademarks Pradaxa®, Praxbind®, RE-VERSE AD™ and RE-VECTO™ under license.

SOURCE Boehringer Ingelheim Pharmaceuticals

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