RELY-ABLE®: Unprecedented long-term data support safety profile and sustained efficacy of Pradaxa®

Pivotal data from the RELY-ABLE® study have provided additional data to support the long-term safety profile and efficacy of Pradaxa® (dabigatran etexilate) for stroke prevention in patients with non-valvular atrial fibrillation (AF).*1 The new long-term results presented at the American Heart Association’s (AHA) Scientific Sessions, are highly consistent with the findings from the landmark RE-LY® trial**, based upon which the treatment was approved in countries all over the world. The rates of stroke and haemorrhage observed during the 2.3 years of blinded follow-up in RELY-ABLE® correspond to the initial RE-LY® results, supporting the benefit of both doses of Pradaxa® for tailored brain protection.1-3

The combined data from RE-LY® and RELY-ABLE® equates to over four years of experience and provides the most comprehensive evaluation of the benefits and safety of any novel oral anticoagulant for stroke prevention in AF to date.

“Most patients with atrial fibrillation need life-long anticoagulant treatment to be protected from ischaemic stroke. The unique long-term data we now have for dabigatran etexilate are reassuring for both patients and physicians,” said RELY-ABLE® lead investigator Professor Stuart Connolly, Director of the Division of Cardiology at McMaster University, Hamilton, Ontario. “RELY-ABLE® shows that the results seen in RE-LY® continue to be observed during long-term follow up. We see the similar rates of stroke or systemic embolism and the similar rates of major bleeding with similar rates of intracerebral bleeding and intracranial haemorrhage.”

The international multi-centre RELY-ABLE® study followed 5,851 patients on Pradaxa® for a further 28 months after completion of the RE-LY® trial. It examined the long-term benefits of the two treatment doses (110mg bid and 150mg bid) in an ongoing randomised and blinded comparison.

The results from RELY-ABLE® support sustained dose benefits in the long-term use of Pradaxa®:1

• Rates of ischemic stroke
  1.15%/year on 150mg bid and 1.24%/year on 110mg bid
• Incidence of hemorrhagic stroke
  0.13%/year on the 150mg bid and 0.14%/year on 110mg bid
• Incidence of major bleeding
  3.74%/year on 150 mg bid and 2.99%/year on 110 mg bid
• Rates of intracranial bleeding
  0.33 %/year on the DE 150mg bid and 0.25%/year on DE 110mg bid

The consistent incidences of ischaemic and haemorrhagic stroke as well as rates of intracranial bleeding observed indicate that Pradaxa® provides ongoing protection to the brain. Furthermore, both doses of Pradaxa® had similar net clinical benefit and mortality rates. The safety profile of Pradaxa® was consistent with the findings from the RE-LY® trial.

“The results from the RELY-ABLE® study are consistent with the excellent results we have seen in the RE-LY® trial and strongly support the long-term safety profile and efficacy of Pradaxa® for stroke prevention in atrial fibrillation,” stated Professor Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim. “Physicians can be confident in the sustained brain protection and treatment advantages offered by both doses of Pradaxa®, and can tailor their treatment according to patient needs, as these first long-term clinical data for a novel oral anticoagulant show.”

Pradaxa® 150mg bid is the only novel oral anticoagulant, study of which has shown a significant reduction in the incidence of ischaemic strokes in patients with non-valvular AF compared to warfarin, offering a relative risk reduction of 25%.2,3 Nine out of ten strokes caused by AF are ischemic strokes,4 which can result in irreversible neurological injury with profound long-term consequences such as paralysis or inability to move one’s limbs or formulate speech.5

Furthermore in RE-LY®, Pradaxa® 150mg bid provided a 35% reduction in the overall risk of stroke and systemic embolism versus warfarin (INR 2-3, median TTR 67%6). Pradaxa® 110mg bid, which is indicated for certain patients, was shown to be non-inferior compared to warfarin for the prevention of stroke and systemic embolism. Both doses of Pradaxa® were associated with significantly lower total, intracranial and life-threatening bleeding compared to warfarin. Pradaxa 150mg showed a similar risk of major bleeds versus warfarin and Pradaxa® 110mg bid additionally demonstrated significantly lower major bleeding.2,3

Clinical experience of Pradaxa® in all licensed indications is well established and continues to grow, equating to over one million patient-years in all licensed indications in over 70 countries worldwide7 and exceeding that of all other novel oral anticoagulants.8

Stroke Prevention in Atrial Fibrillation

AF is the most common sustained heart rhythm condition9, with one in four adults over the age of 4010 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.10,11 Up to three million people worldwide suffer strokes related to AF each year.12-15 Strokes due to AF tend to be severe, with an increased likelihood of death (20%), and disability (60%).16

Ischaemic strokes are the most common type of AF-related stroke, accounting for 92% of strokes experienced by AF patients and frequently leading to severe debilitation.17-21 Appropriate anticoagulation therapy can help to prevent many types of AF-related strokes and improve overall patient outcomes.22

Worldwide, AF is an extremely costly public health problem, with treatment costs equating to $6.65 billion in the US and over €6.2 billion across Europe each year.23,24 Given AF-related strokes tend to be more severe, this results in higher direct medical patient costs annually.25 The total societal burden of AF-related stroke reaches €13.5 billion per year in the European Union alone.11

About RELY-ABLE1

RELY-ABLE® (Long Term Multi-center Extension of Dabigatran Treatment in Patients with Atrial Fibrillation) was designed to provide additional information on the long-term effects of the two doses of dabigatran etexilate in patients who had completed RE-LY®. Enrolled patients continued to receive the same double-blind dose with 2,937 patients on dabigatran 150 mg bid and 2,914 patients on dabigatran 110 mg bid. Patients randomized to warfarin in RE-LY® were not eligible for RELY-ABLE®.1 From the beginning of RE-LY® to the end of RELY-ABLE®, the median duration of follow-up for patients was 4.3 years, with the longest duration reported at 5.5 years, and the median follow-up duration being 2.3 years.1

Patients continuing in RELY-ABLE® differed in several respects from those who did not. Continuing patients were less likely to have permanent AF , less likely to have heart failure and less likely to have had a major clinical event during the RE-LY® trial.

The primary outcomes were the occurrence of major ischaemic and haemorrhagic outcomes, as well as death and net clinical benefit (composite of all major ischaemic, haemorrhagic and fatal outcomes).

• Both doses of dabigatran etexilate showed low rates of ischaemic and haemorrhagic strokes
• Major bleeding rates were lower with the 110 mg bid dose versus the 150mg dose
• Net clinical benefits and low mortality rates were consistent between doses

Overall the results from RELY-ABLE® were highly consistent with the event rates experienced during the RE-LY® trial, providing support for the sustained efficacy and safety of dabigatran etexilate during long-term treatment

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 open label warfarin (INR 2.0-3.0, median TTR 67%6) 2,3. Patients were followed-up in the study for a median of 2 years with a minimum of 1 year follow-up.2

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 warfarin, dabigatran etexilate showed in the trial:2,3

• Significant reduction in the risk of stroke and systemic embolism – including ischaemic 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)26 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.

References

1. Connolly SJ, et al. Randomized Comparison of the Effects of Two Doses of Dabigatran Etexilate on Clinical Outcomes Over 4.3 Years: Results of the RELY-ABLE Double-blind Randomized Trial. CS.04. Clinical Science: Special Reports: Valvular Heart Disease, PAD, Atrial Fibrillation: International Perspectives.  Presented on 7 November 2012 at the American Heart Association Scientific Sessions 2012.
2. Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-51.
3. Connolly SJ, et al. Newly identified events in the RE-LY trial. N Engl J Med. 2010;363:1875-6.
4. Hannon, N., et al. “Stroke Associated with Atrial Fibrillation – Incidence  and Early Outcomes in the North Dublin Population Stroke Study.” Cerebrovascular Diseases. 2010;29:43-49.
5. NHLBI website. “What is Stroke?” Available at: http://www.nhlbi.nih.gov/health/health-topics/topics/stroke. Accessed on: October 10, 2012.
6. Pradaxa European Summary of Product Characteristics, 2012
7. Boehringer Ingelheim data on file.
8. Eikelboom JW. et al. Does dabigatran improve stroke-prevention in atrial fibrillation? Reply to a rebuttal. J Thromb Haemost. 2010;8:1438–9.
9. Stewart S, et al. Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK. Heart. 2004;90:286-92.
10. Lloyd-Jones DM, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation. 2004;110:1042-6.
11. Fuster V, et al. ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation – executive summary. Circulation. 2006;114:700-52.
12. Global Atlas on Cardiovascular Disease Prevention and Control, World Health Organization in collaboration with the World Heart Federation and the World Stroke Organization 2011. Viewed May 2012 at http://www.world-heart-federation.org/fileadmin/user_upload/documents/Publications/Global_CVD_Atlas.pdf.
13. Atlas of Heart Disease and Stroke, World Health Organization, September 2004. Viewed Dec 2010 at http://www.who.int/cardiovascular_diseases/en/cvd_atlas_15_burden_stroke.pdf.
14. Wolf PA, et al. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22:983-8.
15. Marini C, et al. Contribution of atrial fibrillation to incidence and outcome of ischaemic stroke: results from a population-based study. Stroke. 2005;36:1115-9.
16. Gladstone DJ, et al. Potentially Preventable Strokes in High-Risk Patients With Atrial Fibrillation Who Are Not Adequately Anticoagulated. Stroke. 2009;40:235-240.
17. Paolucci S, et al. Functional outcome of ischemic and hemorrhagic stroke patients after inpatient rehabilitation. Stroke. 2003;34:2861−5.
18. Petrea RE, et al. Gender differences in stroke incidence and poststroke disability in the Framingham Heart Study. Stroke. 2009;40:1032-7
19. Meschia JF, et al. Genetic susceptibility to ischemic stroke. Nat Rev Neurol. 2011;7:369−78.
20. Andersen KK, et al. Hemorrhagic and ischemic strokes compared: stroke severity, mortality, and risk factors. Stroke. 2009;40:2068−72.
21. Roger VL, et al. AHA Statistical Update. Heart Disease and Stroke Statistics—2011 Update. A Report From the American Heart Association. Circulation 2011; 123:e18−e209.
22. Hart RG, et al. Meta-analysis: Antithrombotic Therapy to Prevent Stroke in Patients Who Have Nonvalvular Atrial Fibrillation Ann Intern Med. 2007;146:857-67.
23. Coyne KS, et al. Assessing the direct costs of treating nonvalvular atrial fibrillation in the United States. Value Health 2006; 9:348-56.
24. Ringborg A, et al. Costs of atrial fibrillation in five European countries: results from the Euro Heart Survey on atrial fibrillation. Europace 2008; 10:403-11.
25. Brüggenjürgen B, et al. The impact of atrial fibrillation on the cost of stroke: the Berlin acute stroke study. Value Health 2007;10:137-43
26. Di Nisio M, et al. Direct thrombin inhibitors. N Engl J Med 2005; 353:1028-40.

*Randomized Comparison of the Effects of Two Doses of Dabigatran Etexilate on Clinical Outcomes Over 4.3 Years: Results of the RELY-ABLE Double-blind Randomized Trial. Lead author: Stuart J Connolly. CS.04. Clinical Science: Special Reports: Valvular Heart Disease, PAD, Atrial Fibrillation: International Perspectives

**RE-LY® was a PROBE trial (prospective, randomized, open-label with blinded endpoint evaluation), comparing two fixed doses of the oral direct thrombin inhibitor dabigatran etexilate (110 mg bid and 150 mg bid) each administered in a blinded manner, with open label warfarin.