Pradaxa® – Development of antidote may expand range of methods to reverse anticoagulant effect during emergency situations

New findings presented at the 2012 American Heart Association Scientific Sessions in Los Angeles provide early indications that a highly specific and selective antidote currently in development can, when approved, deliver safe and effective rapid reversal of the anticoagulation effect of Pradaxa® (dabigatran). If needed, the potential antidote may be used during critical care situations or where existing reversal strategies may not be sufficient.1 Following the successful completion of the early research phase, the progression into phase 1 clinical trial development was initiated for the investigational antidote (a fully humanized monoclonal antibody fragment – Fab).

The investigational antidote should be regarded as an additional option for patient management in critical care situations and may support the established reversal strategies already available in emergency medicine. In research, the Fab holds promise as one of the first specific antidotes developed for any of the novel oral anticoagulants (NOACs) used for stroke prevention in atrial fibrillation (AF).1

A risk of bleeding is a known possible treatment complication of all anticoagulant therapies used for stroke prevention in AF.2 Even in the absence of a specific antidote, both doses of dabigatran etexilate demonstrated significantly lower life-threatening and intracranial bleeding than warfarin during the landmark clinical trial RE-LY® clinical trial programme . Additionally, significantly lower major and fatal bleeding events were experienced with dabigatran etexilate 110mg bid.3,4

Further to existing reversal strategies, Boehringer Ingelheim is developing a specific antidote to dabigatran. Driven by the company’s commitment to scientific innovation, the antidote is expected to provide physicians with an additional option for management of bleeding during critical care situations where rapid reversal is required.

The results from the preclinical studies show the Fab to offer:1

• Very tight binding affinity to dabigatran molecules – high specificity with no effect on other molecules including warfarin
• Rapid, dose-dependent decrease in experimentally-induced blood loss, sustained for up to 6 hours after intravenous injection
• Safe reversal of the anticoagulation effect of dabigatran (demonstrated in ex vivo clotting tests)

The management of severe bleeds in clinical practice remains the same for all anticoagulant treatments,5,6 with dabigatran having the additional option of removal from the blood system via hemodialysis.7

No specific fast acting antidote is currently available to reverse the anticoagulant effect of any of the NOACs or warfarin.6 In the case of warfarin, vitamin K is frequently misunderstood as an antidote while it is actually a supplement, which simply replaces the vitamin K needed for the synthesis of the coagulation factors blocked by warfarin. Reversal of the anticoagulant effect of warfarin is a rather slow and complex procedure which may take up to 36 hours.8

Boehringer Ingelheim remains dedicated to advancing science and ensuring that physicians have all the tools they may require to effectively manage critical care situations, improving the overall benefit of treatments and optimising patient management. As such, the development of the Fab progressed to phase I clinical trials.

“These new findings are encouraging and demonstrate the potential of an antibody for rapid reversal of the anticoagulant effect of Pradaxa®, restoring a patient’s coagulation. Although emergency situations are relatively rare in clinical practice, Boehringer Ingelheim is committed to ensuring the best brain protection for people living with atrial fibrillation, which includes ensuring that physicians have every option they may require in the critical care situation”, stated Dr. Joanne van Ryn, Department of CardioMetabolic Disease Research, Boehringer Ingelheim.

It is widely accepted that the benefits of anticoagulant treatment for stroke prevention in AF far outweigh the risk of bleeding.9,10 The benefits of Pradaxa® have been recognised worldwide, leading to widespread regulatory approvals and recent reconfirmation of the positive benefit/risk profile by the European Medicines Agency.11,12 Clinical trial and real-life experience of dabigatran now equates to over one million patient-years in all licensed indications and exceeds that of all other novel oral anticoagulants used for stroke prevention in AF.11,13

Stroke Prevention in Atrial Fibrillation

AF is the most common sustained heart rhythm condition14, with one in four adults over the age of 40 developing the condition in their lifetime15. 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.17-20 Strokes due to AF tend to be severe, with an increased likelihood of death (20%), and disability (60%).21

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.22-26 Appropriate anticoagulation therapy can help to prevent many types of AF-related strokes and improve overall patient outcomes.27

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.28,29 Given AF-related strokes tend to be more severe, this results in higher direct medical patient costs annually.30 The total societal burden of AF-related stroke reaches €13.5 billion per year in the European Union alone.16

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%5).3,4 Patients were followed-up in the study for a median of 2 years with a minimum of 1 year follow-up.3

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: 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)31 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. Van Ryn. J. et al. In vitro Chacterization, Pharmacokinetics and Reversal of supratherapeutic doses of dabigatran-induced bleeding in rats by a specific antibody fragment antidote to dabigatran. Oral Presentation 9928. Presented on 5 November 2012 at the American Heart Association Scientific Sessions 2012.
2. Levine MN, Raskob G, Landefeld S, Kearon C. Hemorrhagic complications of anticoagulant treatment. Chest. 2001;119(1,Suppl.):108S–121S.
3. Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009; 361:1139-51.
4. Connolly SJ, et al. Newly identified events in the RE-LY trial. N Engl J Med. 2010;363:1875-6.
5. Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6,Suppl.):160S–198S.
6. Kaatz S, Kouides PA, Garcia DA, et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors.Am J Hematol. 2012;87(Suppl.1):S141–5.
7. Pradaxa European Summary of Product Characteristics, 2012.
8. Hanley JP. Warfarin reversal. J Clin Pathol. 2004;57:1132–9.
9. Lip GY, Andreotti F, Fauchier L, et al. Bleeding risk assessment and management in atrial fibrillation patients: a position document from the European Heart Rhythm Association, endorsed by the European Society of Cardiology Working Group on Thrombosis. Europace. 2011;13:723–46.
10. Singer DE, Chang Y, Fang MC, et al. The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Ann Intern Med. 2009;151:297-305.
11. Boehringer Ingelheim data on file
12. European Medicines Agency. Press Release, dated May 25th 2012. Available at http://www.emea.europa.eu/ema/index.jsp?curl=pages/medicines/human/public_health_alerts/2012/05/human_pha_detail_000061.jsp&mid=WC0b01ac058001d126
13. Eikelboom JW, et al. Does dabigatran improve stroke-prevention in atrial fibrillation? Reply to a rebuttal. J Thromb Haemost. 2010;8:1438–9.
14. Stewart S, et al. Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK. Heart. 2004;90:286-92.
15. Lloyd-Jones DM, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation. 2004;110:1042-6.
16. Fuster V, et al. ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation – executive summary. Circulation. 2006;114:700-52.
17. 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.
18. 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.
19. Wolf PA, et al. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22:983-8.
20. 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.
21. Gladstone DJ, et al. Potentially Preventable Strokes in High-Risk Patients With Atrial Fibrillation Who Are Not Adequately Anticoagulated. Stroke. 2009;40:235-240.
22. Paolucci S, et al. Functional outcome of ischemic and hemorrhagic stroke patients after inpatient rehabilitation. Stroke. 2003;34:2861−5.
23. Petrea RE, et al. Gender differences in stroke incidence and poststroke disability in the Framingham Heart Study. Stroke. 2009;40:1032-7.
24. Meschia JF, et al. Genetic susceptibility to ischemic stroke. Nat Rev Neurol. 2011;7:369−78.
25. Andersen KK, et al. Hemorrhagic and ischemic strokes compared: stroke severity, mortality, and risk factors. Stroke. 2009; 40:2068−72.
26. 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.
27. 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.
28. Coyne KS, et al. Assessing the direct costs of treating nonvalvular atrial fibrillation in the United States. Value Health 2006; 9:348-56.
29. 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.
30. 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.
31. Di Nisio M, et al. Direct thrombin inhibitors. N Engl J Med 2005; 353:1028-40.