Interim sub-group analysis shows the reversal agent idarucizumab* enables rapid initiation of emergency surgery in dabigatran-treated patients

• Median time to surgery was under two hours in patient study of dabigatran patients treated with idarucizumab¹
• No post-surgical bleeding complications were reported within 24 hours following surgery in the Phase III RE-VERSE AD™ study¹

BURLINGTON, ON, Sept. 8, 2015 /CNW/ -  Results from an interim analysis of the Phase III RE-VERSE AD™ study demonstrate that 5g of idarucizumab* enabled emergency surgery to be initiated rapidly in urgent situations involving a sub-group of patients treated with dabigatran requiring emergency surgery within 8 hours.¹ The specific and immediate reversal of the anticoagulant effect of dabigatran enabled patients to be urgently brought to necessary procedures, with a median time of 1.7 hours between administration of idarucizumab* and start of procedure.¹ In the 24 hours after surgery, no bleeding complications were reported.¹ The results were presented September 1, 2015 at the European Society of Cardiology (ESC) Congress  in London, United Kingdom.

"Normal blood clotting is important during surgery. Dabigatran already has a short half-life of around 12 hours, allowing for normal surgery to be performed in a reasonable time after stopping the drug in many patients," said Prof. Jerrold Levy, RE-VERSE AD™ investigator and Professor of Anesthesiology and Co-Director of the Cardiothoracic Intensive Care Unit, Duke University Medical Centre, North Carolina, USA. "But in case of an emergency situation, we need to go to the operating room sooner. The data now presented show that immediately reversing dabigatran with idarucizumab* would allow for rapid normalization of clotting and faster initiation of surgery in case it is needed."

The interim sub-group analysis from RE-VERSE AD™ included data from patients requiring emergency surgery or an invasive procedure, e.g. surgery for an aortic aneurysm or an open fracture after a fall, which could not be delayed for more than 8 hours.^1,2 Of the 39 patients who presented with elevated anticoagulation levels at baseline, as measured with Ecarin Clotting Time (ETC), results showed:¹

• Administration of idarucizumab* allowed surgery to be initiated rapidly – the median time between the administration of idarucizumab* and surgery was only 1.7 hours
• Normal blood clotting during surgery was reported in 92% of patients
• There were no post-surgical bleeding complications reported in the 24 hours following surgery

"Idarucizumab* provides immediate and complete reversal of dabigatran in most patients, allowing urgent surgery to be initiated rapidly," said Dr. Martina Flammer, Vice President, Medical and Drug Regulatory Affairs, Boehringer Ingelheim (Canada) Ltd. "These latest results from the RE-VERSE AD™ study further support the efficacy and safety of idarucizumab* and how it can help with patient management during emergency situations requiring surgical intervention."

Due to the serious and complex nature of the emergency the patients in the study presented with, six patients died within two days of the emergency procedure, another three died during the follow-up period.¹ Mortality within 96 hours of study enrolment appeared to be related to the original reason for emergency admission to the hospital, while all later events appeared to be related to co-morbidities.² Two patients suffered a thromboembolic event (on days 7 and 26 post surgery), but both were not receiving antithrombotic therapy at that time.¹

Idarucizumab* is currently being assessed by different regulatory authorities including Health Canada, the U.S. Food and Drug Administration and the European Medicines Agency.³ Further submissions are ongoing.

*Idarucizumab is an investigational compound. Its safety and efficacy has not yet been fully established and it is currently not authorized for sale in Canada.

NOTES TO THE EDITORS

About idarucizumab*
Idarucizumab* is a humanized antibody fragment, or Fab, designed as a specific reversal agent to dabigatran.⁴ Idarucizumab* binds specifically to dabigatran molecules only, neutralizing their anticoagulant effect without interfering with the coagulation cascade.⁴ Boehringer Ingelheim began research on idarucizumab* in 2009, before the first marketing authorization of Pradaxa^® for stroke prevention in atrial fibrillation in 2010.⁵

In February and March 2015, idarucizumab* was submitted under an accelerated approval pathway to the U.S. Food and Drug Administration, European Medicines Agency and Health Canada for use in patients who require urgent reversal of dabigatran.³ The FDA granted idarucizumab* both Breakthrough and Orphan Drug designation.^5,6 Further submissions are ongoing and accelerated processes will be pursued with regulatory authorities where available.⁵

About RE-VERSE AD™ (NCT02104947)
RE-VERSE AD™ is an ongoing, global Phase III patient study initiated by Boehringer Ingelheim in 2014 to investigate idarucizumab* in the emergency setting.^4,7 Up to 300 patients taking dabigatran, aged 18 years or over are expected to be enrolled from more than 400 centres in 38 countries worldwide.^4,8 Group A includes patients with overt, uncontrollable or life-threatening bleeding deemed to require reversal, whereas Group B includes patients who needed surgery or an invasive procedure within 8 hours for which normal blood clotting (haemostasis) were required.⁴

The broad inclusion criteria reflect the types of patients that would require urgent anticoagulant reversal in the real-world emergency setting.^2,4 These include severely ill or injured patients, e.g. patients with severe intracranial hemorrhage or severe acute trauma.⁴ Furthermore, the study investigators are also allowed to administer any other type of therapies for patient management (including other blood products), as demanded by the clinical situation.⁴

Patients received 5 g of intravenous idarucizumab* administered as two 50 ml bolus infusions, each containing 2.5 g, no more than 15 minutes apart.⁴ Blood was collected and assessed for anticoagulant effect at baseline, after administration of the first vial of idarucizumab*, and then between 10 and 30 minutes and 1, 2, 4, 12 and 24 hours after administration of the second vial.⁴

The primary endpoint was the maximum degree of reversal of the anticoagulant effect of dabigatran, determined using different laboratory tests (including the coagulations tests diluted thrombin time (dTT) and ecarin clotting time (ECT)) at any point from the end of the first idarucizumab* infusion, up to 4 hours after administration of the second infusion.^2,4

Secondary endpoints include the proportion of patients achieving complete normalization of the dTT or ECT in 4 hours, the reduction in unbound dabigatran concentration, and clinical outcomes as assessed by the treating clinician.^2,4 In Group A patients, clinical outcomes included the extent of bleeding, severity of bleeding and haemodynamic stability.^2,4 In Group B patients, haemostasis was classified as normal or as mildly, moderately or severely abnormal.^2,4 Adverse events were monitored from the time of idarucizumab* infusion to 90 days post-infusion including suspected thrombotic events or deaths (classified as vascular or non-vascular in origin).^2,4

About dabigatran etexilate
Pradaxa^® (dabigatran etexilate) was first approved for the prevention of venous thromboembolic events (VTE) in patients who have undergone elective total hip replacement or total knee replacement surgery.⁹ It was then approved for the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF), in whom anticoagulation is appropriate.⁹ Pradaxa^® was most recently  approved for the treatment of venous thromboembolism events (deep vein thrombosis [DVT], pulmonary embolism [PE]) and prevention of recurrent DVT and PE.⁹ To date, over 130,000 Canadians with AF have received Pradaxa^® for stroke prevention.⁵

Pradaxa^® has been on the market for more than five years and is approved in over 100 countries.⁵ 

The efficacy and safety profile of Pradaxa^® in its licensed indications is well documented in an extensive clinical trial programme.^10-17 In addition, the favourable benefit-risk profile of Pradaxa^® is supported by safety assessments from regulatory authorities including the European Medicines Agency and the U.S. Food and Drug Administration (FDA).^18-20 In May 2014, in one of the largest real-world analyses of its kind, the FDA once again re-affirmed the favourable benefit/risk profile of Pradaxa^® when it issued results from this study, including more than 134,000 patients.²⁰

As the first direct oral anticoagulant to market, clinical experience with Pradaxa^® continues to grow and equates to over four million patient-years in all licensed indications to date.⁵ DVT and PE patients can start taking Pradaxa^® in a simple fixed dose regimen after initial treatment with an injectable anticoagulant such as low-molecular-weight heparin (LMWH).⁹

For dosing, side effects, warnings and precautions, please refer to the Pradaxa^® Product Monograph:  http://www.boehringer-ingelheim.ca/content/dam/internet/opu/ca_EN/documents/humanhealth/product_monograph/PradaxaPMEN.pdf

Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, Boehringer Ingelheim operates globally with 146 affiliates and a total of more than 47,700 employees. The focus of the family-owned company, founded in 1885, is researching, developing, manufacturing and marketing new medications of high therapeutic value for human and veterinary medicine.

Social responsibility is an important element of the corporate culture at Boehringer Ingelheim. This includes worldwide involvement in social projects, such as the initiative "Making more Health" and caring for the employees. Respect, equal opportunities and reconciling career and family form the foundation of the mutual cooperation. In everything it does, the company focuses on environmental protection and sustainability.

In 2014, Boehringer Ingelheim achieved net sales of about 13.3 billion euros. R&D expenditure corresponds to 19.9 per cent of its net sales.

The Canadian headquarters of Boehringer Ingelheim was established in 1972 in Montreal, Quebec and is now located in Burlington, Ontario. Boehringer Ingelheim employs more than 550 people across Canada.

References

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2.	Pollack C. V. et al. Idarucizumab for dabigatran reversal. NEJM. 2015 Aug 6; 373(6):511-20.
3.	Boehringer Ingelheim Press Release – 03 March 2015. Boehringer Ingelheim submits applications for approval of idarucizumab, specific reversal agent to dabigatran etexilate (Pradaxa^®), to EMA, FDA and Health Canada. http://www.boehringer-ingelheim.com/news/news_releases/press_releases/2015/03_march_2015_dabigatranetexilate.html. Last accessed August 2015.
4.	Pollack C. V. et al. Design and rationale for RE-VERSE AD: A phase 3 study of idarucizumab, a specific reversal agent for dabigatran. Thromb Haemost. 2015 May 28;114(1). http://dx.doi.org/10.1160/TH15-03-0192
5.	Boehringer Ingelheim Data on File.
6.	Boehringer Ingelheim Press Release – 30 June 2014. U.S. FDA grants Breakthrough Therapy Designation to Pradaxa^® (dabigatran etexilate) specific investigational antidote. http://www.boehringer-ingelheim.com/news/news_releases/press_releases/2014/30_june_2014_dabigatranetexilate.html. Last accessed June 2015.
7.	Boehringer Ingelheim Press Release – 22 May 2015. Antidote for rapid reversal of Pradaxa^® (dabigatran etexilate) progresses into next stage of clinical investigation with study in patients. http://www.boehringer-ingelheim.com/news/news_releases/press_releases/2014/22_may_2014_dabigatranetexilate.html  Last accessed June 2015.
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9.	Pradaxa^® Product Monograph. June 5, 2015.
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11.	Schulman S, et al. Dabigatran versus warfarin in the Treatment of Acute Venous Thromboembolism. N Engl J Med. 2009;361:2342–52.
12.	Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–51.
13.	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.
14.	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.
15.	Eriksson BI. et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, doubleblind, non-inferiority trial. Thromb Haemost. 2011;105(4):721-9.
16.	Ginsberg JS. et al. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthoplasty. 2009;24(1):1–9.
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18.	FDA Drug Safety Communication: Update on the risk for serious bleeding events with the anticoagulant Pradaxa (dabigatran) – 2 November 2012 http://www.fda.gov/Drugs/drugsafety/ucm326580.htm Last accessed July 22, 2014.
19.	European Medicines Agency Press release - 25 May 2012: EMA/337406/2012. European Medicines Agency updates patient and prescriber information for Pradaxa. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2012/05/news_detail_001518.jsp. Last accessed 22 July 2014.
20.	FDA Drug Safety Communication: FDA study of Medicare patients finds risks lower for stroke and death but higher for gastrointestinal bleeding with Pradaxa (dabigatran) compared to warfarin – 13 May 2014. http://www.fda.gov/Drugs/DrugSafety/ucm396470.htm (Accessed June 25, 2014).

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