FDA panel unanimously recommends approval for dabigatran

The FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 9-0 in favor of approval of dabigatran (Pradaxa, Boehringer-Ingelheim) for the prevention of stroke in patients with AF. The panel was split on whether both doses (150 mg bid and 110 mg bid) used in the RE-LY trial should gain approval, though in an informal straw poll a majority appeared to favor approval for both doses. (The FDA reviewers had recommended approval for only the higher dosage.) Most panel members also supported language on the label summarizing the superiority of the 150 mg dose over warfarin in RE-LY.

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Here is the Boehringer-Ingelheim press release:

FDA Committee Unanimously Recommends Approval of Dabigatran Etexilate for Stroke Prevention in Atrial Fibrillation

For non-US and non-UK Healthcare Media only

Ingelheim, Germany, September 20, 2010 – The U.S. Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee today voted 9 to 0 in favour of recommending dabigatran etexilate for stroke prevention in patients with atrial fibrillation (AF).

For decades, vitamin K anatgonists such as warfarin have been the most efficacious therapeutic option for stroke prevention in AF. Current recommendations for patients with non-valuvlar atrial fibrillation treated with warfarin recommend maintaining an international normalized ratio (INR) in the range of 2.0-3.0 through frequent blood monitoring and dose adjustments, which can be challenging for physicians and patients. In RE-LY®, dabigatran etexilate demonstrated efficacy without the need for ongoing INR monitoring or dose adjustments. Furthermore, there were no food restrictions on those taking dabigatran in RE-LY®. A total of 6.3 million people in the US, Japan, Germany, Italy, France, UK and Spain were living with AF in 2007 and this is expected to increase to 7.5 million by 2017 primarily due to the ageing population. 1

“We are pleased with the committee’s recommendation, which marks an important step in advancing care for patients with atrial fibrillation,” said Professor Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim. “We believe dabigatran etexilate will offer patients and doctors the first new treatment option for stroke prevention in atrial fibrillation in more than 50 years. We look forward to working with the FDA as it finalizes its review of dabigatran.”

Notes to editors

About RE-LY®
RE-LY® (Randomized Evaluation of Long term anticoagulant therapy) was a global, phase III, randomized trial of 18,113 patients enrolled in over 900 centres in 44 countries, investigating whether dabigatran etexilate (2 blinded doses) is as effective as well controlled warfarin with target INR of 2.0-3.0 for stroke prevention. Patients were followed-up in the study for a median of 2 years with a minimum of 1 year follow-up.

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, dabigatran etexilate showed in the trial: 2

  • Significant reduction in the risk of stroke and systemic embolism – including haemorrhagic strokes with dabigatran etexilate 150 mg bid
  • Significantly lower major bleeding events with dabigatran etexilate 110 mg bid
  • Significantly lower life threatening and intracranial bleeding with both doses
  • Significant reduction in vascular mortality with dabigatran etexilate 150 mg bid.

About AF and stroke
AF is the most common heart rhythm condition, affecting around 1% of the total population, rising to 10% in people over the age of 80. 3 A total of 6.3 million people in the US, Japan, Germany, Italy, France, UK and Spain were living with AF in 2007 and this is expected to increase to 7.5 million by 2017 primarily due to the ageing population. 1 People with AF are at increased risk of blood clots, which raises stroke risk by five times. 4,5 Up to three million people worldwide suffer strokes related to AF each year. 6-8Strokes due to AF tend to be severe, with an increased likelihood of death (20%), and disability (60%), with resultant societal costs and burden to the healthcare system. 9 AF alone is associated with a cost of up to €13.5 billion across the European Union. 10 Warfarin is the current standard of care for reducing stroke in patients with AF. It is highly effective when patients blood clotting value is maintained within the narrow therapeutic INR range of 2.0-3.0 as in a clinical trial setting. 11 However in clinical practice, due to the well-known limitations with warfarin only 51% of diagnosed patients with AF at risk of stroke receive warfarin 12 and fewer than half of these are controlled within the narrow therapeutic range. 13

About dabigatran etexilate
Dabigatran etexilate is at the forefront of a new generation of oral anticoagulants/direct thrombin inhibitors (DTIs) 14 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.

Dabigatran etexilate has already been approved in 75 countries under the trademark Pradaxa® for the primary prevention of venous thromboembolic events (blood clots) in adults who have undergone elective total hip or elective total knee replacement surgery.

Disclaimer
Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial prevention. This information is provided for medical education purposes only.

Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 142 affiliates in 50 countries and more than 41,500 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.

In 2009, Boehringer Ingelheim posted net sales of 12.7 billion euro while spending 21% of net sales in its largest business segment Prescription Medicines on research and development.

Please be advised
This release is from Boehringer Ingelheim Corporate Headquarters in Germany. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses. Please take account of this when referring to the information provided in this document. This press release is not intended for distribution within the U.S.A.

References
1Benyoucef S, Hughes M, Mehta N. Atrial Fibrillation. Decision Resources, December 2008.
2Connolly SJ, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2009; 361:1139-51.
3Stewart 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.
4Fuster 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.
5Kannel WB, Abbott RD, Savage DD, et al. Coronary heart disease and atrial fibrillation: The Framingham Study. Am Heart J 1983; 106:389-96.
6Atlas of Heart Disease and Stroke, World Health Organization, September 2004. Viewed July 2009 at http://www.who.int/cardiovascular_diseases/en/cvd_atlas_15_burden_stroke.pdf.
7Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991: 22(8);983-8.
8Marini C, De Santis F, Sacco S, et al. Contribution of atrial fibrillation to incidence and outcome of ischemic stroke: results from a population-based study. Stroke 2005; 36:1115-9.
9Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation: the Framingham study. Stroke 1996; 27:1760-4.
10Fuster 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.
11Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999; 131:492-501.
12Hylek EM, DAntonio J, Evans-Molina C, et al. Translating the results of randomized trials into clinical practice. The challenge of warfarin candidacy among hospitalized elderly patients with atrial fibrillation. Stroke 2006; 37:1075-80.
13Samsa GP, Matchar DB, Goldstein LB, et al. Quality of anticoagulation management among patients with atrial fibrillation: results of a review of medical records from 2 communities. Arch Intern Med 2000; 160:967-73.
14Di Nisio M, et al. Direct Thrombin Inhibitors. N Engl J Med 2005; 353:1028-40.The European Atrial Fibrillation Trial Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet 1993; 342:1255-1262.

Comments

  1. Labelling will be critical. but I agree with the FDA reviewers and do NOT believe that a superiority claim should be allowed for the following reasons:

    1) superiority not demonstrated in the US population

    2) non-blinded open label PROBE design can (and probably did) result in some degree of bias

    3) lack of replication of results in any other RCT

    4) remember results of ximelagatran experience where open label designed study yielded a non-inferior result vs warfarin, but the blinded trial did not find non-inferiority

  2. Awesome news

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