- Interim analysis from RE-VERSE AD™, the first patient study investigating the effect of a specific reversal agent to a NOAC in a real-world setting
BURLINGTON, ON, June 22, 2015 /CNW/ - Results from an interim analysis of the Phase III RE-VERSE AD™ patient study demonstrate that 5 g of idarucizumab* immediately reversed the anticoagulant effect of dabigatran (Pradaxa®) in patients requiring urgent anticoagulant reversal. No safety concerns relating to idarucizumab* were identified. The results have been simultaneously published in the New England Journal of Medicine (NEJM) and presented today at the International Society of Thrombosis and Haemostasis 2015 Congress in Toronto, Canada.1,2
"The initial data from RE-VERSE AD™ demonstrates the effects of idarucizumab* in real-world situations, which is important for healthcare professionals," said Dr. John Eikelboom, Associate Professor, Department of Medicine, McMaster University. "Patients experienced the reversal of the anticoagulant effect of dabigatran through the use of idarucizumab*, within minutes of administration in the critical case situations studied. Through the use of idarucizumab*, RE-VERSE AD™ has demonstrated the immediate reversal of the anticoagulant effects of dabigatran, which may allow physicians to focus on other aspects of emergency patient management."
RE-VERSE AD™ is designed to evaluate the types of patients and real-world situations healthcare professionals may see in the emergency setting.1,3 The broad inclusion criteria of this ongoing study ensure that even the most severely ill or injured patients (e.g. patients with sepsis or a severe intracranial haemorrhage), who require urgent reversal of dabigatran, may be enrolled in the study.1,3 Patients were categorized into two groups – (A) patients with uncontrolled or life-threatening bleeding complications, e.g. intracranial haemorrhage or severe trauma after a car accident (Group A, n= 51), or (B) patients requiring emergency surgery or an invasive procedure, e.g. surgery for an open fracture after a fall (Group B, n=39).1,3 The primary endpoint of the study is the degree of reversal of the anticoagulant effect of dabigatran achieved by 5 g idarucizumab* within 4 hours, measured using different laboratory tests.3
"Results from RE-VERSE AD™ are very encouraging and demonstrate how idarucizumab*reverses the anticoagulant effect of dabigatran and can support patient management during emergency situations," said Dr. Martina Flammer, Vice President, Medical and Drug Regulatory Affairs, Boehringer Ingelheim (Canada) Ltd. "As the study continues, we look forward to learning more about the potential of idarucizumab* and how it advances the care of patients requiring urgent reversal of the anticoagulant effect of dabigatran."
The interim analysis from RE-VERSE AD™ included data from 90 patients in the emergency setting who were taking dabigatran and required reversal. Of the 81 patients that presented with elevated anticoagulation levels at baseline as measured with ecarin clotting time (ECT), results showed:1
- The study met its primary endpoint, achieving 100 per cent maximum reversal as median value across all patients
- Reversal was evident immediately after administration of the first vial of idarucizumab*, and was complete in all but 1 patient
- After 4 and 12 hours, laboratory tests showed normal coagulation levels in almost 90 per cent of patients
- Normal blood clotting (haemostasis) during surgery was reported in 92 per cent of the patients that required surgery or invasive procedures
- There was no signal of a pro-coagulant effect following administration of idarucizumab*
- Thrombotic events occurred in five patients, none of whom was receiving antithrombotic therapy at the time of the event
- There were 18 deaths overall. 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
NOTES TO THE EDITORS
Idarucizumab* is a humanized antibody fragment, or Fab, designed as a specific reversal agent to dabigatran .3 Idarucizumab* binds specifically to dabigatran molecules only, neutralizing their anticoagulant effect without interfering with the coagulation cascade.3 Boehringer Ingelheim began research on idarucizumab* in 2009, before the first marketing authorization of Pradaxa® for stroke prevention in atrial fibrillation in 2010.4
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.5 The FDA granted idarucizumab* both Breakthrough and Orphan Drug designation.4,6 Further submissions are ongoing and accelerated processes will be pursued with regulatory authorities where available.4
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.3,9 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.3,10 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.3
The broad inclusion criteria reflect the types of patients that would require urgent anticoagulant reversal in the real-world emergency setting.1,3 These include severely ill or injured patients, e.g. patients with severe intracranial hemorrhage or severe acute trauma.3 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.3
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.3 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.3
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.1,3
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.1,3 In Group A patients, clinical outcomes included the extent of bleeding, severity of bleeding and haemodynamic stability.1,3 In Group B patients, haemostasis was classified as normal or as mildly, moderately or severely abnormal.1,3 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).1,3
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.11 It was then approved for the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF), in whom anticoagulation is appropriate.11 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.11 To date, over 130,000 Canadians with AF have received Pradaxa® for stroke prevention.4
Pradaxa® has been on the market for more than five years and is approved in over 100 countries.4
The efficacy and safety profile of Pradaxa® in its licensed indications is well documented in an extensive clinical trial programme.12-19 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).20-22 Most recently 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.22
As the first novel 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.4 Pradaxa® has the longest clinical trial experience in DVT and PE patients of any novel oral anticoagulant (NOAC).12,23-28 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).11
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
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.
* 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.
- Pollack C.V. et al. Idarucizumab for dabigatran reversal. NEJM. 2015; June 22.
- Pollack C.V. Initial results of the RE-VERSE AD trial: idarucizumab reverses the anticoagulant effects of dabigatran in patients in an emergency setting of major bleeding, urgent surgery, or interventions. Oral presentation on Monday 22 June 2015 at the International Society of Thrombosis and Haemostasis 2015 Congress, Toronto, Canada.
- 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
- Boehringer Ingelheim Data on File.
- 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 June 2015.
- 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.
- Glund S, et al. A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb Haemost. 2015; 113: 943-951.
- Glund S. et al. Idarucizumab, a Specific Antidote for Dabigatran: Immediate, Complete and Sustained Reversal of Dabigatran Induced Anticoagulation in Elderly and Renally Impaired Subjects. Oral Presentation at The 56th American Society of Hematology Annual Meeting & Exposition, San Francisco, USA, 8 December 2014. Blood 2014; 124: Abstract 344.
- 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.
- Pollack C. et al. A Phase III Clinical Trial to Evaluate the Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD™). Poster presentation at the International Stroke Conference, Nashville, USA, 11-13 February 2015.
- Pradaxa® Product Monograph. June 5, 2015.
- Schulman S, et al. Extended Use of Dabigatran, Warfarin or Placebo in Venous Thromboembolism. N Engl J Med. 2013;368:709–18.
- Schulman S, et al. Dabigatran versus warfarin in the Treatment of Acute Venous Thromboembolism. N Engl J Med. 2009;361:2342–52.
- Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–51.
- 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.
- 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.
- 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.
- 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.
- Schulman S. et al. A Randomized Trial of Dabigatran Versus Warfarin in the Treatment of Acute Venous Thromboembolism (RE-COVER II). Oral presentation from Session 332: Antithrombotic Therapy 1. Presented on 12 December at the American Society of Hematology (ASH) Annual Meeting 2011.
- 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.
- 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.
- 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).
- Agnelli G, et al. Apixaban for Extended Treatment of Venous Thromboembolism. N Engl J Med 2013;368:699–708.
- The EINSTEIN Investigators. Oral Rivaroxaban for Symptomatic Venous Thromboembolism. N Engl J Med 2010;363:2499–2510.
- The EINSTEIN–PE Investigators. Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism. N Engl J Med 2012;366:1287-97.
- Prins MH. et al. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thrombosis Journal 2013, 11:21.
- Agnelli G. et al. Oral Apixaban for the Treatment of Acute Venous Thromboembolism. N Engl J Med 2013;369:799-808.
- The Hokusai-VTE Investigators. Edoxaban versus Warfarin for the Treatment of Symptomatic Venous Thromboembolism. N Engl J Med 2013;369: 1406-15.
SOURCE Boehringer Ingelheim (Canada) Ltd.
For further information: please visit www.boehringer-ingelheim.ca