The communication to be sent to healthcare professionals strengthens that patients taking Pradaxa® should have their renal function evaluated prior to treatment initiation. While on treatment, renal function should be assessed in clinical situations where a decline in renal function is suspected (e.g. hypovolemia, dehydration and with certain comedications). In patients older than 75 or with renal impairment renal function should be assessed at least yearly whilst on treatment. Given Pradaxa® is mainly excreted renally, the treatment should not be prescribed to patients with severe renal impairment (creatinine clearance less than 30 ml/min).

Further to the healthcare professional communication, Boehringer Ingelheim has agreed with the EMA to strengthen the Summary of Product Characteristics (SmPC) and the prescriber guides accordingly. It is of critical importance that healthcare professionals abide by the information regarding the appropriate and safe use of Pradaxa® as provided in the label, and report any adverse events suspected to be associated with the use of the treatment to Boehringer Ingelheim in their respective countries or to their national health authority.

The main reason for using an anticoagulant such as Pradaxa® is to prevent blood clots which can lead to stroke or VTE events. Caution is however warranted with the use of all anticoagulants since they increase the risk of bleeding. It is well established that this risk increases with age or when multiple risk factors for bleeding are combined in an individual patient such as renal impairment, prior history of bleeding or concomitant treatment with other antithrombotics (e.g. aspirin or clopidogrel).(2) While Pradaxa® does not require routine international normalized ratio (INR) monitoring like the long-time standard of care warfarin, clinical surveillance including the assessment of renal function needs to be undertaken by treating physicians before initiation and over the course of the therapy as appropriate.

The effectiveness and favourable safety profile of Pradaxa® has been proven within an extensive clinical trial programme(3-7), passing independent regulatory scrutiny and approval worldwide.

Compared to well-controlled warfarin (median time in therapeutic range (TTR) 67.3%), the following results were seen with Pradaxa® in the landmark RE-LY® trial:(3,4)

• Pradaxa® 150mg bid significantly reduced the risk of stroke and systemic embolism by 35%, providing clinically important stroke prevention in non-valvular AF
• Pradaxa® 150mg bid significantly reduced both ischaemic (RRR 25 %) and haemorrhagic stroke (RRR 74%)
• Pradaxa® 110mg bid showed similar rates of stroke and systemic embolism as well-controlled warfarin
• Both doses of Pradaxa® significantly reduced intracranial and life threatening bleeding compared to warfarin
• Pradaxa® 110mg bid also significantly reduced major bleeds.

The RE-LY® trial was a PROBE trial (prospective, randomized, open-label with blinded endpoint evaluation), 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)

Boehringer Ingelheim closely monitors the use of all its medicines including Pradaxa® and will continue to work with health authorities to ensure that usage of the product appropriately reflects the label. Boehringer Ingelheim is confident that the additional guidance supports the correct use of Pradaxa® in clinical practice, enabling healthcare professionals and patients to gain the most benefit from this novel treatment.

About AF and stroke
AF is the most common sustained heart rhythm condition,(8) with one in four adults over the age of 40 (9) developing the condition in their lifetime. People with AF are more likely to experience blood clots, which increases the risk of stroke by five-fold.(9,10) Up to three million people worldwide suffer strokes related to AF each year.(11-14) Strokes due to AF tend to be severe, with an increased likelihood of death (20%), and disability (60%).(15) Many AF-related strokes can be prevented with appropriate antithrombotic therapy.(16) 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 patient costs which are higher than non AF-related strokes annually (€11,799 vs €8,817 P < 0.001).(17)

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% (1)) open label warfarin.(3,4) 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 (median TTR 67.3%), the following results were seen with Pradaxa® in the landmark RE-LY® trial:(3,4)

• Pradaxa® 150mg bid significantly reduced the risk of stroke and systemic embolism by 35%, providing clinically important stroke prevention in non-valvular AF
• Pradaxa® 150mg bid significantly reduced both ischaemic (RRR 25%) and haemorrhagic stroke (RRR 74%)
• Pradaxa® 110mg bid showed similar rates of stroke and systemic embolism as well-controlled warfarin
• Both doses of Pradaxa® significantly reduced intracranial and life threatening bleeding compared to warfarin
• Pradaxa® 110mg bid also significantly reduced major bleeds.

About dabigatran etexilate
Dabigatran etexilate is at the forefront of a new generation of oral anticoagulants/direct thrombin inhibitors (DTIs) 18 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
• Prevention of thromboembolism after heart valve replacement.

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 endeavours.

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.

1. Pradaxa, European Summary of Product Characteristics, 2011.
2. Lip GY, et al. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation. Am Coll Cardiol 2011;57:173-180.
3. Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51.
4. Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L. Newly identified events in the RE-LY® trial. N Engl J Med 2010;363(19):1875-1876.
5. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran etexilate versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361:2342-52.
6. Eriksson BI, et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 2007;5:2178–85.
7. Eriksson BI, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 2007;370:949–56.
8. Stewart S, Murphy N, Walker A, et al. Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK. Heart 2004;90:286-92.
9. Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation 2004;110:1042-6.
10. Fuster V, Rydn LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation – executive summary. Circulation 2006;114:700-52.
11. Kannel WB, et al. Final Draft Status of the Epidemiology of Atrial Fibrillation. Med Clin North Am. 2008;92(1):17–40.
12. Atlas of Heart Disease and Stroke, World Health Organization, September 2004. Viewed Dec 2010 at www.who.int/cardiovascular_diseases/en/ cvd_atlas_15_burden_stroke.pdf .
13. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22(8):983-8.
14. Marini C, De Santis F, Sacco S, et al. Contribution of atrial fibrillation to incidence and outcome of ischaemic stroke: results from a population-based study. Stroke 2005;36:1115-9.
15. Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation: the Framingham study. Stroke 1996;27:1760-4.
16. Hart RG, Pearce LA, Aguilar MI, et al. Meta-Analysis: antithrombotic therapy to prevent stroke in patients who have non-valvular atrial fibrillation. Ann Intern Med 2007;146:857-67.
17. Bruggenjurgen B et al. The Impact of Atrial Fibrillation on the Cost of Stroke: The Berlin Acute Stroke Study. Value Health 2007;10:137–43.
18. Di Nisio M, et al. Direct Thrombin Inhibitors. N Engl J Med 2005;353:1028-40.

* Previous stroke, transient ischemic attack, or systemic embolism (SEE); Left ventricular ejection fraction < 40 %; Symptomatic heart failure, ≥ New York Heart Association (NYHA) Class 2; Age ≥ 75 years; Age ≥ 65 years associated with one of the following: diabetes mellitus, coronary artery disease, or hypertension.