As the Benefits and Safety of Pradaxa^® (dabigatran etexilate mesylate) are Once Again Confirmed, Boehringer Ingelheim Continues to Look for New Ways for Pradaxa^® to Help More Patients

Burlington, ON, May 15, 2014- Following a recent article published by Bloomberg News, Boehringer Says New Pradaxa^® Bleeding Cases Aren’t a Concern, the company issued the following statement with regards to the findings of a recent targeted review of data from the RE-LY^® trial, which has re-confirmed the study’s findings on stroke, major bleeds, life-threatening bleeds, and fatal bleeds.

Boehringer Ingelheim stands firmly behind Pradaxa^®'s benefits and safety profile. We continue to invest in research to learn how Pradaxa^® can help more patients.

Boehringer Ingelheim continues to invest in research to learn how Pradaxa^® can help more patients.

Pradaxa^® 150 mg is the only novel oral anticoagulant which in its pivotal study vs. warfarin (RE-LY^®1 ) showed a superior reduction of ischemic strokes (the most common stroke for patients with atrial fibrillation (AF). The most serious adverse reactions reported with Pradaxa^® were related to bleeding. Pradaxa^® 110 mg, which is indicated for certain patients, was as effective as warfarin at reducing risk of stroke with lower rates of bleeding.

The Benefits and Safety of Pradaxa^® Have Been Confirmed

More than 100 regulatory agencies around the world approved Pradaxa^® for reducing the risk of stroke and systemic embolism in patients with atrial fibrillation (AF), based on the RE-LY^® “mega-trial” – a clinical study involving more than 18,000 patients in over 40 countries.

Boehringer Ingelheim scientists, external researchers, and regulators have analyzed RE-LY^® and patients’ experience with Pradaxa^®. RE-LY^®’s conclusions remain unchanged. The FDA has publicly stated that Pradaxa^® 150 mg twice daily offers a positive benefit-risk profile and provides an important health benefit when used as directed to reduce the risk of stroke and systemic embolism in patients with atrial fibrillation.

On May 13, 2014 the U.S. Food and Drug Administration (FDA) once again reaffirmed the positive benefit-risk profile of Pradaxa^® when used as directed when it issued a Drug Safety Communication that included results from a Medicare study of more than 134,000 patients 65 years of age or older comparing Pradaxa^® to warfarin. This study’s findings, except with regard to Myocardial Infarction (MI) (MI risk was similar for the two drugs), are consistent with the clinical trial results that provided the basis for Pradaxa^®’s approval. As a result of these latest findings, the FDA still considers Pradaxa^® to have a favorable benefit to risk profile and have made no changes to the current label or recommendations for use.

In November 2013, at the American Heart Association Scientific Sessions, Boehringer Ingelheim announced the then recent results from a long-term, combined analysis of the pivotal RE-LY^® trial and its extension safety study RELY-ABLE^®. There were no new safety findings identified in a long-term extension trial over 2 additional years. Rates of total bleeding, life threatening bleeding and major bleeding were similar to those seen during the RE-LY^® trial. There was no adjudication of outcome events occurring in RELY-ABLE^®.

Boehringer Ingelheim Recently Confirmed RE-LY^®’s Conclusions Again

During the US litigation involving Pradaxa^®, Boehringer Ingelheim learned that there might be previously uncategorized major bleeding events in the RE-LY^® trial. There was one case of a patient who suffered a ruptured spleen due to a car accident, resulting in trauma, bleeding and ultimately death. The death was properly reported and included in the RE-LY^® findings, but was not counted as a major bleed. Boehringer Ingelheim conducted its own, targeted review of RE-LY^®. We sought to determine whether there might have been other situations and how any such cases were distributed across treatment groups, including warfarin, during the RE-LY^® trial.

The cases identified in the new review frequently reflected complicated medical circumstances where the patient had multiple health issues and experienced multiple clinical events. Most of the cases involved a patient who died, and, importantly, all of those deaths were already properly reported in the RE-LY^® study. What resulted from the targeted review is that additional events (namely bleeding and stroke) have now been captured.

What makes a study such as RE-LY^® sufficiently robust is that the study was properly designed to minimize bias and systematic error, and had a sufficient number of participants such that any instances of human error would not affect the study’s outcome.  That is exactly how RE-LY^® was conducted.

Indeed, one of the strengths of RE-LY^® being such a sizeable trial, with multiple treatment arms, is that since the participant numbers are so large, the overall study results regarding bleeding would have changed only if there were a large number of additional unidentified major bleeds in the groups of patients that took Pradaxa^® and not in the group that took warfarin.  

Boehringer Ingelheim conducted the targeted review and then provided documentation to the Population Health Research Institute (PHRI), a research institution in Hamilton, Ontario that served as the central coordinating center for RE-LY^®. PHRI then had two external experts review the documents. The external experts independently evaluated and categorized case events and determined whether the cases presented events that RE-LY^® had not yet counted as bleeds or strokes.

The external experts reported back to Boehringer Ingelheim and, while there are additional events that RE-LY^® needs to account for, RE-LY^®’s conclusions remain unchanged. The additional events were distributed across treatment groups, including warfarin, and confirmed the study’s findings on major bleeds, life-threatening bleeds, fatal bleeds, or stroke.

Boehringer Ingelheim Continues to Invest in Researching Pradaxa ^®

•On August 15, 2013, Boehringer Ingelheim announced a multi-year agreement with Brigham and Women’s Hospital, an internationally recognized teaching affiliate of Harvard Medical School to conduct a long-term study program to assess comparative effectiveness and safety, as well as prescribing patterns, of oral anticoagulants, including Pradaxa^® for the reduction of stroke risk in U.S. patients with atrial fibrillation.
•On September 3, 2013, Boehringer Ingelheim announced plans for two future studies of Pradaxa^® in new cardiovascular patient populations, as well as further plans to gather real-world evidence in AF patients. These plans are the cornerstone of an initiative to expand the scientific knowledge of stroke prevention and interventional cardiology with Pradaxa^®.
•In November 2013 Boehringer Ingelheim presented results from a Phase I trial for an antidote for Pradaxa^®. The results showed that a compound the company developed specifically for Pradaxa^® immediately, completely and sustainably reversed the anticoagulation effect of Pradaxa^® in healthy male volunteers. Boehringer Ingelheim has initiated the next phase of studies in patients.
•On March 11, 2014, Boehringer Ingelheim announced the enrollment of the 10,000th patient in to its AF registry program GLORIA^™-AF, the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with atrial fibrillation, one of the largest AF registry programs currently running worldwide. The GLORIA-AF Registry Program is expected to be one of the largest worldwide registries and is actively recruiting patients with the aim of including up to 56,000 patients across 2,200 sites in 35 countries.

About Pradaxa^® (dabigatran etexilate)
Pradaxa^®, a direct thrombin inhibitor (DTI), was the first widely approved drug in a new generation of direct oral anticoagulants, available to target a high unmet medical need in the prevention and treatment of acute and chronic thromboembolic diseases. Potent antithrombotic effects are achieved with direct thrombin inhibitors by specifically blocking the activity of thrombin, the central enzyme in the process responsible for clot (thrombus) formation. In contrast to vitamin-K antagonists, which variably act via different coagulation factors, Pradaxa^® provides effective, predictable and reproducible anticoagulation with a low potential for drug-drug interactions and no drug-food interactions, without the need for routine coagulation monitoring or dose adjustment.

Clinical experience of Pradaxa^® (dabigatran etexilate) exceeds that of all other novel oral anticoagulants, equating to over 2 million patient-years of experience worldwide. Pradaxa^® has already been in the market for more than 6 years and is approved in over 100 countries.

Currently approved indications in Canada for Pradaxa^® are:
•Prevention of stroke and systemic embolism in patients with atrial fibrillation (AF) in whom anticoagulation is appropriate
•Prevention of venous thromboembolic events (VTE) in patients who have undergone elective total hip replacement or total knee replacement surgery

About Boehringer Ingelheim (Canada) Ltd.
The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, Boehringer Ingelheim operates globally with 142 affiliates and a total of more than 47,400 employees. The focus of the family-owned company, founded in 1885, is researching, developing, manufacturing and marketing new medications of high therapeutic value for human and veterinary medicine.

Taking social responsibility is an important element of the corporate culture at Boehringer Ingelheim. This includes worldwide involvement in social projects, such as the initiative “Making more Health” and caring for the employees. Respect, equal opportunities and reconciling career and family form the foundation of the mutual cooperation. In everything it does, the company focuses on environmental protection and sustainability.

In 2013, Boehringer Ingelheim achieved net sales of about 14.1 billion euros. R&D expenditure corresponds to 19.5% of its net sales.

The Canadian headquarters of Boehringer Ingelheim was established in 1972 in Montreal, Quebec and is now located in Burlington, Ontario. Boehringer Ingelheim employs more than 550 people across Canada.

For more information please visit www.boehringer-ingelheim.ca