New Real-World Analysis Finds Lower Risk of Major Bleeding and Similar Risk of Stroke with Standard Dose of Pradaxa^® Compared to Rivaroxaban in NVAF Patients Newly Initiating Treatment

Ridgefield, Conn., January 25, 2018 – Boehringer Ingelheim today announced results from a retrospective, observational real-world study assessing the safety and effectiveness of novel oral anticoagulants (NOACs) among patients with non-valvular atrial fibrillation (NVAF) treated through the U.S. Department of Defense Military Health System. The study examined major bleeding and stroke rates in NVAF patients who had initiated treatment with Pradaxa^® compared to those treated with rivaroxaban or apixaban. The results were presented at the International Stroke Conference 2018 in Los Angeles, California.

“With an increasing number of the 2.7 million Americans living with atrial fibrillation being treated with NOACs, real-world analyses like this that compare their effectiveness and safety are important,” said Todd C. Villines, M.D., Assistant Professor of Medicine at Georgetown School of Medicine, and lead investigator of the study. “As a researcher and treating physician I hope that this large-scale, U.S. practice-based comparison will provide additional insight on available NOAC therapies, including Pradaxa.”

The approved labelling for Pradaxa does not include data comparing the product to other NOAC therapies, and there are no clinical trials providing a head-to-head comparison of NOAC therapies. Pradaxa is indicated to reduce the risk of stroke and systemic embolism in patients with NVAF.

The study analyzed data from NVAF patients newly initiating treatment with Pradaxa, rivaroxaban or apixaban. The study examined two cohorts: one that resulted in 12,763 propensity score matched Pradaxa (150 mg bid) and rivaroxaban (20 mg daily) patients, and another that resulted in 4,802 propensity score matched Pradaxa (150 mg bid) and apixaban (5 mg bid) patients. The primary outcomes for the study were risk of major bleeding and stroke.

Pradaxa patients demonstrated lower rates of major bleeding compared to rivaroxaban patients [2.08 percent (266/12,763) vs 2.53 percent (323/12,763); hazard ratio (HR) 0.82; 95 percent confidence interval (CI) 0.70-0.97; p=0.0182] and similar rates of stroke [0.60 percent (77/12,763) vs 0.78 percent (100/12,763); HR 0.77, CI 0.57-1.04; p=0.0844]. In the exploratory analysis, Pradaxa and apixaban patients showed similar rates of major bleeding [1.60 percent (77/4,802) vs 1.21 percent (58/4,802); HR 1.37, CI 0.97-1.94; p=0.0702] and stroke [0.44 percent (21/4,802) vs 0.35 percent (17/4,802); HR 1.26, CI 0.66-2.39; p=0.4892].

Limitations of the study include the potential for residual confounding as an observational, on-treatment study. The study also used data from electronic health records, which may not have been optimal to identify baseline risk and outcomes. Finally, there were limited Pradaxa users available for matching with apixaban.

“There are countless factors to consider when choosing a medicine to treat a chronic condition. Assessing Pradaxa in the real-world setting, especially against other NOACs, is part of our responsibility to patients and physicians making those complex treatment decisions,” said Sabine Luik, M.D., senior vice president, Medicine & Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. “We believe that research and information are the most powerful tools physicians have to help them provide their patients with ideal care."

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.

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Boehringer Ingelheim Pharmaceuticals, Inc. either owns or uses the trademarks Pradaxa^®under license.

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