PRADAXA® first drug in 50 years to gain approval for stroke prevention in atrial fibrillation

Boehringer IngelheimThe European Commission (EC) approved Boehringer Ingelheim's breakthrough oral anticoagulant, Pradaxa® (1) (dabigatran etexilate (2) ) for the prevention of stroke in patients with atrial fibrillation (AF) at risk of stroke. This EU label extension means that, for the first time in over 50 years, millions of AF patients across Europe will have access to a new treatment for the prevention of AF-related strokes which is effective and convenient (3,4,) and has demonstrated a good safety profile.

The EC has approved the use of dabigatran etexilate in the EU for the prevention of stroke and systemic embolism in adult patients with non-valvular AF with one or more risk factors. While overall the 150mg bid dose is recommended for the majority of patients, the 110mg bid dose is specifically available for elderly patients aged 80 years or above, for patients at increased risk of bleeding and for patients who are co-administered with dabigatran etexilate and the calcium channel blocker verapamil.

In 2008 dabigatran etexilate was granted EU approval for the primary prevention of venous thromboembolic events (blood clots) in adults who have undergone elective total hip or elective total knee replacement surgery. Speaking of the new EU label extension for the prevention of stroke in patients with AF, Professor Gregory Lip, Consultant Cardiologist & Professor of Cardiovascular Medicine, University of Birmingham Centre for Cardiovascular Sciences, Birmingham, United Kingdom commented, "The approval of dabigatran etexilate in Europe represents a major advance in the treatment of this condition. For the past 50 years physicians worldwide have been waiting for an alternative to vitamin K antagonist therapies, such as long time standard of care, warfarin." He continued, "Whilst effective, warfarin has many limitations such as the need for regular monitoring and various food-drug and drug-drug interactions, resulting in only half of eligible patients receiving warfarin and fewer than half of these patients being controlled within the desired therapeutic range."

Trudie Lobban, CEO of the Atrial Fibrillation Association added, "Atrial fibrillation raises the risk of stroke by five times, resulting in up to three million people worldwide suffering strokes related to this condition each year. Atrial fibrillation-related strokes are particularly severe and disabling, with one half of this population dying within one year after a stroke."

The approval of dabigatran etexilate for stroke prevention in AF patients is based on the groundbreaking results from RE-LY®, one of the largest studies ever conducted in AF including over 18,000 patients. RE-LY® was a PROBE (prospective, randomized, open-label with blinded endpoint evaluation) trial, comparing two fixed doses of the oral direct thrombin inhibitor dabigatran etexilate (110mg and 150mg bid) each administered in a blinded manner, with open label warfarin. (3-5)

Dabigatran etexilate 150mg bid is the only novel oral anticoagulant approved for stroke prevention in AF in Europe that has been proven superior to well-controlled warfarin (median TTR 67%) (5). Dabigatran etexilate 150mg bid reduced the risk of stroke and systemic embolism by 35% while also significantly lowering the risk of life-threatening and intracranial bleeding, compared to well-controlled warfarin. (3,4) Dabigatran etexilate 110mg bid has been shown non-inferior to warfarin in reducing the risk of stroke and systemic embolism with a significantly lower rate of major bleeding.

Dr. Stuart Connolly, co-principal investigator of RE-LY®, Director, Division of Cardiology at McMaster University and member of The Population Health Research Institute, Hamilton, Ontario added, "The landmark RE-LY® study results also showed us that dabigatran etexilate is consistently effective at preventing strokes across a wide range of patients with AF, irrespective of age, gender, stroke risk, type of atrial fibrillation, prior stroke, and comorbidities such as hypertension and diabetes."

In addition to the approval in Europe, dabigatran etexilate has already been approved for the prevention of stroke in atrial fibrillation in the US, Canada, Japan, Australia and several other countries across four continents. (1,6-9) In 2008 dabigatran etexilate was granted EU approval for the primary prevention of venous thromboembolic events (blood clots) in adults who have undergone elective total hip or elective total knee replacement surgery.

"The approval of dabigatran etexilate in Europe marks an important milestone in the history of Boehringer Ingelheim and also in the continuing fight for improved prevention of stroke, a disease which continues to have a large unmet need," said Professor Andreas Barner, Chairman of the Board of Managing Directors, Boehringer Ingelheim. "It is a result of nearly 20 years of innovative research and development by our scientists. We will now ensure that this new breakthrough treatment is made available to physicians and atrial fibrillation patients throughout Europe as soon as possible."

About AF and stroke
AF is the most common sustained heart rhythm condition, 10 affecting around 1% of the total population, with one in four adults over the age of 4011 developing the condition in their lifetime, rising to 10% in people over the age of 80. (10) People with AF are more likely to experience blood clots, which increases the risk of stroke by five-fold. (11,12) Up to three million people worldwide suffer strokes related to AF each year. (13-16) Strokes due to AF tend to be severe, with an increased likelihood of death (20%), and disability (60%). (17) Many AF-related strokes can be prevented with appropriate antithrombotic therapy. (18) AF-related strokes currently represent a significant cost to healthcare systems across Europe. Given AF-related strokes tend to be more severe this results in direct medical costs which are higher than non AF-related strokes (€11,799 vs €8,817 P < 0.001). (19)

About RE-LY®
RE-LY® (Randomized Evaluation of Long term anticoagulant therapY) was a global, phase III, PROBE (prospective, randomized, open-label with blinded endpoint evaluation) trial of 18,113 patients enrolled in over 900 centres in 44 countries designed to compare two fixed doses of the oral direct thrombin inhibitor dabigatran (110mg and 150mg bid) each administered in a blinded manner, with well controlled (INR 2.0-3.0, median TTR 67%) open label warfarin. (3-5) Patients were followed-up in the study for a median of 2 years with a minimum of 1 year follow-up. (3,4)

The primary endpoint of the trial was incidence of stroke (including haemorrhagic) or systemic embolism. Secondary outcome measures included all-cause death, incidence of stroke (including haemorrhagic), systemic embolism, pulmonary embolism, acute myocardial infarction, and vascular death (including death from bleeding).

Compared to well controlled warfarin, dabigatran etexilate showed in the trial: (3,4)

  • Significant reduction in the risk of stroke and systemic embolism – including haemorrhagic strokes with dabigatran etexilate 150mg bid
  • Similar rates of stroke/systemic embolism with dabigatran etexilate 110mg bid
  • Significantly lower major bleeding events with dabigatran etexilate 110mg bid
  • Significantly lower life threatening and intracranial bleeding with both doses
  • Significant reduction in vascular mortality with dabigatran etexilate 150mg bid.

About dabigatran etexilate
Dabigatran etexilate is at the forefront of a new generation of oral anticoagulants/direct thrombin inhibitors (DTIs) (2) targeting 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 (both free and clot-bound), the central enzyme in the process responsible for clot (thrombus) formation. In contrast to vitamin-K antagonists, which variably act via different coagulation factors, dabigatran etexilate provides effective, predictable and consistent anticoagulation with a low potential for drug-drug interactions and no drug-food interactions, without the need for routine coagulation monitoring or dose adjustment.

About the dabigatran etexilate clinical trial programme
Boehringer Ingelheim's clinical trial programme to evaluate the efficacy and safety of dabigatran etexilate encompasses studies in:

  • Primary prevention of venous thromboembolism (VTE) in patients undergoing elective total hip and knee replacement surgery
  • Treatment of acute VTE
  • Secondary prevention of VTE
  • Stroke prevention in AF.

About Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 145 affiliates and more than 42,000 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.

As a central element of its culture, Boehringer Ingelheim pledges to act socially responsible. Involvement in social projects, caring for employees and their families, and providing equal opportunities for all employees form the foundation of the global operations. Mutual cooperation and respect, as well as environmental protection and sustainability are intrinsic factors in all of Boehringer Ingelheim's endeavors.

In 2010, Boehringer Ingelheim posted net sales of about 12.6 billion euro while spending almost 24% of net sales in its largest business segment Prescription Medicines on research and development.

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