Breakthrough therapy dabigatran provides consistent benefit across all atrial fibrillation types and stroke risk groups

Ingelheim, Germany, April 4 2011 – New data from two RE-LY® sub-group analyses presented today at the 60^th Annual Scientific Session of the American College of Cardiology (ACC) demonstrated that dabigatran etexilate 150mg bid is consistently superior to warfarin in stroke prevention in atrial fibrillation (AF), irrespective of a patient’s risk of stroke or type of AF.^1,2

RE-LY®, the largest AF trial to date, was a PROBE (prospective, randomised, open-label with blinded endpoint evaluation) trial designed to compare two fixed doses of the oral direct thrombin inhibitor dabigatran (110mg and 150mg bid) each administered in a blinded manner, with open label warfarin. Pradaxa® 110mg bid was shown to be as effective as warfarin.^3,4

The sub-group analyses assessed the rate of stroke and systemic embolism with dabigatran etexilate compared to well-controlled warfarin in patients with different types of AF (paroxysmal, persistent, permanent) and according to a refined stroke risk score CHA₂DS₂VASc,⁵ which complements the traditionally used CHADS₂ score⁶ and has been recommended in current European guidelines.⁵

The results showed:

• The reduction of stroke rates seen with dabigatran etexilate 150mg bid compared to well-controlled warfarin across all CHA ₂DS ₂VASc stroke risk groups were consistent with the overall RE-LY® trial conclusions [as indicated by the p-value for interaction=0.60], which established the superiority of dabigatran etexilate 150mg bid versus well-controlled warfarin ²
• The CHA ₂DS ₂VASc data were consistent with results from a previous sub-group analysis using the CHADS ₂ score, which showed that dabigatran etexilate 150mg bid reduced the rate of stroke across all stroke risk groups, including the patients in the high risk group [n=5,882] ⁷
• Dabigatran etexilate 150mg and 110mg bid doses have a favourable benefit risk profile compared to warfarin, including in patients with lower CHA ₂DS ₂VASc scores ²
• Dabigatran etexilate 150mg bid offers improved efficacy versus well-controlled warfarin (median TTR = 67%) ⁸ for the prevention of stroke irrespective of the type of AF (paroxysmal, persistent, permanent), consistent with the overall RE-LY® trial conclusions [as indicated by the p-value for interaction=0.16] ¹

Dr Jonas Oldgren, Uppsala University Hospital, Sweden said, "Continuing on from previous RE-LY® sub-group analyses, these data provide further evidence supporting dabigatran etexilate as an attractive alternative for stroke prevention in non-valvular AF across a wide range of patients and with different types of AF (paroxysmal to permanent). The availability of two dose strengths of dabigatran etexilate provides the opportunity to facilitate careful attention of individual patient characteristics."

The new CHA₂DS₂VASc risk score was recently incorporated into the revised 2010 European Society of Cardiology (ESC) guidelines and allows physicians to conduct a more detailed stroke risk assessment using a comprehensive risk factor-based approach. The ESC guidelines recommend antithrombotic therapy in all AF patients with at least one clinically relevant non-major’ risk factor (CHA₂DS₂VASc score = 1), broadening the range of patients who should be treated with anticoagulants.⁵

Professor Gregory Lip, Professor of Cardiovascular Medicine at the University of Birmingham Centre for Cardiovascular Sciences, City Hospital Birmingham said, "Due to the limitations of warfarin, only about 50% of patients receive an appropriate treatment for stroke prevention in AF. Now novel oral anticoagulants are becoming available that are not limited by drug/ food interactions and the need for frequent monitoring. On that background, more sensitive stroke risk measures like the new CHA2DS2VASc score may improve access to and uptake of more effective treatments, which may ultimately reduce the number of strokes experienced by patients with AF. Any stroke risk factor in association with AF can cause a stroke, and if we are serious about preventing stroke, the most effective treatment is oral anticoagulation therapy."

Guidelines now recommend dabigatran etexilate
Recently updated guidelines from the AHA/ ACCF/ HRS in the U.S. recommend dabigatran etexilate as an alternative to warfarin for the prevention of stroke in patients with paroxysmal to permanent AF and risk factors for stroke or blood clotting who do not have a prosthetic heart valve, significant heart valve disease, severe renal failure or advanced liver disease.⁹ Dabigatran etexilate has also recently been included in the Canadian Cardiovascular Society new guidelines on stroke prevention in AF, which generally recommend its use over warfarin for overall stroke reduction, particularly the 150mg dose twice-daily.¹0

Preclinical data on an antibody to neutralize dabigatran
Furthermore, first preclinical results investigating the use of an antibody targeting dabigatran will be presented at the ACC.¹¹ These data will review the potential for the reversal of dabigatran anticoagulant activity in both in vitro and in vivo models. These initial steps to the development of a neutralizing agent for dabigatran etexilate may further support the use of this novel oral anticoagulant in clinical practice.

Disclaimer
Recently, dabigatran etexilate has been approved for clinical use in stroke risk reduction in non-valvular AF in the USA, the prevention of stroke, and systemic embolism in adults with AF in Canada and the prevention of ischemic stroke and systemic embolism in patients with non-valvular AF in Japan, South Korea, Indonesia, New Zealand, Columbia and Namibia.

The CHA₂DS₂VASc risk score⁵

• More detailed assessment for risk of stroke in patients with atrial fibrillation compared with the traditionally used CHADS ₂ score
• Especially recommended for patients with AF formerly considered at low-to-intermediate risk by the CHADS ₂ score
• Derived from CHADS ₂ and assigns points to additional risk factors, such as female gender, age 65–75, and vascular disease
• Outperforms the CHADS ₂ in identifying 'truly low risk' AF patients who do not need antithrombotic therapy, whilst those with ≥1 stroke risk factor can be considered for oral anticoagulation therapy.

About types of AF12

• Paroxysmal or intermittent AF is a type of fibrillation where abnormal electrical signals and rapid heart rate begin suddenly and then stop on their own. Symptoms can be mild or severe and last for seconds, minutes, hours, or days
• Persistent AF is a condition in which the abnormal heart rhythm continues until it's stopped with treatment
• Permanent AF happens when a normal heart rhythm can't be restored with treatment. Both paroxysmal and persistent AF may become more frequent and, over time, result in permanent AF.

About AF and stroke
AF is the most common heart rhythm condition,¹³ affecting nearly one in four people over the age of 40¹⁴ and 1% of the total population, rising to 10% in people over the age of 80.¹³ People with AF are more likely to experience blood clots, which increases the risk of stroke by five-fold.^15,16 Up to three million people worldwide suffer strokes related to AF each year,^17-19 which are typically severe and disabling, with one half of this population dying within one year.20 Strokes due to AF tend to be severe, with an increased likelihood of death (20%), and disability (60%).²⁰ Many AF-related strokes can be prevented with appropriate antithrombotic therapy.²¹

About RE-LY®
RE-LY® (Randomized Evaluation of Long term anticoagulant therapY) was a global, phase III, randomised trial of 18,113 patients enrolled in over 900 centres in 44 countries. The PROBE (prospective, randomized, open-label with blinded endpoint evaluation) trial was designed to compare two fixed doses of the oral direct thrombin inhibitor dabigatran (110mg and 150mg bid) each administered in a blinded manner, with open label warfarin (target INR of 2.0-3.0). 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
• Significantly lower major bleeding events with dabigatran etexilate 110mg bid
• Comparable rates of stroke/systemic embolism 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.
• RE-LY® was a PROBE (prospective, randomized, open-label with blinded endpoint evaluation) trial designed to compare two fixed doses of the oral direct thrombin inhibitor dabigatran (110mg and 150mg bid) each administered in a blinded manner, with open label warfarin.

About dabigatran etexilate
Dabigatran etexilate is at the forefront of a new generation of oral anticoagulants/direct thrombin inhibitors (DTIs)²² 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.

Dabigatran etexilate has been approved for stroke risk reduction in patients with AF in the USA, Canada, Japan, South Korea, Indonesia, New Zealand, Columbia and Namibia (Please refer to the information for the respective country).^23-25
In addition, dabigatran etexilate has already been approved in 75 countries under the trademark Pradaxa® (in Canada: Pradax®) for the primary prevention of venous thromboembolic events (blood clots) in adults who have undergone elective total hip or elective total knee replacement surgery.

About the dabigatran etexilate clinical trial programme
Boehringer Ingelheim’s clinical trial program 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 surgeries
• Treatment of acute VTE
• Secondary prevention of VTE
• Stroke prevention in AF.

Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 142 affiliates in 50 countries and more than 41,500 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.

In 2009, Boehringer Ingelheim posted net sales of 12.7 billion euro while spending 21% of net sales in its largest business segment Prescription Medicines on research and development.

Please be advised
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