ESC Congress 2016 Late Breaking Science Registry: Latest Data on Pradaxa (dabigatran etexilate mesylate) Safety and Effectiveness Profile Show Low Rates of Bleeding and Stroke in NVAF Patients in Routine Clinical Care

RIDGEFIELD, Conn., August 29, 2016 – First outcome results from the GLORIA^™-AF Registry show that treatment with Pradaxa^® (dabigatran etexilate mesylate) was associated with low incidences of stroke, major bleeding and life-threatening bleeding. The results from approximately 3,000 patients with non-valvular atrial fibrillation (NVAF) were presented in a late-breaking session at the ESC Congress 2016 in Rome, Italy. These data from GLORIA-AF add to the extensive body of data supporting the safety and effectiveness profile of PRADAXA for stroke risk reduction and are consistent with data seen in recently published studies assessing anticoagulant use in everyday clinical practice.

The data presented are from Phase II of the GLORIA-AF registry, and describe outcomes in 2,932 patients newly diagnosed with NVAF who were followed for two years. The findings show:

• Low incidence of safety outcomes for PRADAXA-treated patients in real-world clinical practice: only 1.12% of PRADAXA-treated patients experienced a major bleed, and only 0.54% experienced a life-threatening bleed
• PRADAXA effectively reduced the risk of stroke for NVAF patients: less than 1% of PRADAXA-treated patients experienced a stroke (0.63%)
• The safety and effectiveness of PRADAXA was maintained over two years of follow up in routine clinical care

“Practice-based studies such as the GLORIA-AF Registry complement clinical trials by including larger, more diverse patient populations with the co-morbidities encountered in various medical settings,” said Jonathan L. Halperin, M.D., the Robert and Harriet Heilbrunn Professor of Medicine at the Icahn School of Medicine at Mount Sinai, study author and member of the GLORIA-AF steering committee. “These interim findings from GLORIA-AF are consistent with the results of the randomized RE-LY^® trial and previous population-based studies, including a U.S. Food and Drug Administration analysis of more than 134,000 Medicare recipients. Taken together, these data reinforce the favorable risk-benefit profile of dabigatran in routine care of patients with atrial fibrillation.”

GLORIA-AF is one of the largest ongoing registry programs examining antithrombotic use in routine clinical care around the world. Up to 56,000 NVAF patients will be enrolled, with results expected to support physician decision-making regarding the use of antithrombotics for stroke prevention. To date, more than 34,500 patients have been included in the GLORIA-AF Registry Program.

Boehringer Ingelheim conducts a number of other studies investigating the use of its products in routine clinical care in anticoagulation management: RE-COVERY DVT/PE^™, a global observational study on the management of blood clots in the legs (deep vein thrombosis, DVT) and in the lungs (pulmonary embolism, PE). Another recently launched study is RE-VECTO, a global program to capture data on Praxbind^® (idarucizumab) usage in clinical practice. PRAXBIND is a specific reversal agent approved for use in emergency situations when reversal of the anticoagulant effect of PRADAXA is required, and is available and stocked in over 5,500 hospitals worldwide, including more than 2,760 hospital pharmacies in the U.S.

About the GLORIA-AF Registry Program
GLORIA-AF is a global Registry Program run in different phases and designed to characterize the population of newly diagnosed patients with NVAF at risk for stroke, and to study patterns, predictors and outcomes of different treatment regimens for stroke prevention. Patient characteristics, clinical usage patterns and patient outcomes of anticoagulation therapy will be documented in up to 56,000 patients in 2,200 sites and more than 50 countries throughout the world.

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 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, the company operates globally with 145 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.

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In 2015, Boehringer Ingelheim achieved net sales of about $15.8 billion (14.8 billion euros). R&D expenditure corresponds to 20.3 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^®, GLORIA^™-AF, RE-LY^®, RE-COVERY DVT/PE^™ and Praxbind^® under license.  

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