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Ingelheim, Germany, May 15, 2014 - Most patients with non-valvular atrial fibrillation (NVAF) at risk of stroke need to take an anti-coagulant. NVAF patients face a five-fold increased risk of having a stroke.
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 NVAF patients). 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.
Time and again, the benefits and safety of Pradaxa® have been confirmed. A recent targeted review of data from the RE-LY trial has re-confirmed the study’s findings on stroke, major bleeds, life-threatening bleeds, and fatal bleeds.
Boehringer Ingelheim continues to invest in research to learn how Pradaxa® can help more patients.
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 NVAF 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 non-valvular atrial fibrillation (NVAF).
On May 13, 2014 the 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. The new study found that, among new users of blood-thinning drugs, Pradaxa® was associated with a lower risk of clot-related strokes, bleeding in the brain, and death. The study also found an increased risk of major gastrointestinal bleeding with Pradaxa® and a similar risk of MI compared to warfarin.
In April 2014, the U.S. FDA approved Pradaxa® for additional indications: the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients who have been treated with a parenteral anticoagulant for five to 10 days, and to reduce the risk of recurrent DVT and PE in patients who have been previously treated. Also in April 2014 the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion recommending approval of Pradaxa® in the same indication. In Europe, DVT and PE events are estimated to affect 750,000 people per year.
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.
Ineed, 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 nearly evenly 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 May 7, 2014, Boehringer Ingelheim announced further details of its new study to investigate Pradaxa® for the prevention of recurrent stroke in high-risk patients. The current knowledge around preventing a recurrent stroke in patients suffering a stroke of undetermined source is limited. This study addresses a significant unmet medical need in patients at high risk of recurrent stroke, aiming to support physician’s decisions. Further studies in new cardiovascular patient populations are being prepared.
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 50 countries.
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 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 non-valvular atrial fibrillation.
NOTES TO THE EDITORS
About Pradaxa® (dabigatran etexilate) Clinical experience of Pradaxa® (dabigatran etexilate) exceeds that of all other novel oral anticoagulants, equating to over 2.9 million patient-years in all licensed indications worldwide. Pradaxa® has already been in the market for more than 6 years and is approved in over 100 countries.2
Currently approved indications for Pradaxa® are:3
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (AF) and a risk factor for stroke
Primary prevention of venous thromboembolic events in patients undergoing elective total hip replacement surgery
Primary prevention of venous thromboembolic events in patients undergoing elective total knee replacement surgery
A number of countries including the USA, have already approved Pradaxa® for patients with a deep vein thrombosis or a pulmonary embolism in the following indication:4
Treatment of deep vein thrombosis and pulmonary embolism
Prevention of recurrent deep vein thrombosis and pulmonary embolism
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.3,5 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.6 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.5,7
Boehringer Ingelheim 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.
References 1RE-LY® was a global, phase III, PROBE (prospective, randomized, open-label with blinded endpoint evaluation) design trial comparing two fixed doses of the oral direct thrombin inhibitor Pradaxa® (110mg and 150mg bid) each administered in a blinded manner, with open label warfarin. 2Boehringer Ingelheim data on file. 3Pradaxa® European Summary of Product Characteristics 2014. 4PRADAXA Prescribing Information, 2014. Available at: http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf. Last accessed: May 2014. 5Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet. 2008;47(5):285–95. 6Di Nisio M, et al. Direct thrombin inhibitors. N Engl J Med. 2005;353:1028–40. 7Stangier J, et al. Pharmacokinetic Profile of the Oral Direct Thrombin Inhibitor Dabagitran Etexilate in Healthy Volunteers and Patients Undergoing Total Hip Replacement. J Clin Pharmacol. 2005;45:555–63.
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