The Lancet publishes major study of Boehringer Ingelheim's novel oral direct thrombin inhibitor dabigatran etexilate



    New drug effective in extended thromboprophylaxis following total hip
    replacement surgery

    TORONTO, Sept. 18 /CNW/ - Boehringer Ingelheim today announced the
publication of the RE-NOVATE study in the September 15 issue of The Lancet(i).
The results demonstrate that the oral direct thrombin inhibitor (DTI),
dabigatran etexilate, administered once daily for a median of 33 days, was as
effective as injectable enoxaparin in reducing the risk of venous
thromboembolism (VTE) after total hip replacement surgery, with a similar low
bleeding profile.
    Bengt Eriksson, MD, PhD, Principal Investigator, Department of
Orthopaedic Surgery, University Hospital Sahlgrenska/Ostra, Goteborg, Sweden
said, "Given the trend for shorter hospital stays following joint replacement
surgery and longer duration of thromboprophylaxis, it is becoming increasingly
important to have anticoagulant treatments available which are safe and easy
to use in an out-patient setting. Based on the positive results demonstrated
in the RE-NOVATE trial, once daily oral dabigatran etexilate may be an
attractive alternative to other thromboprophylaxis regimens currently used to
prevent VTE in patients undergoing hip replacement surgery."
    The RE-NOVATE trial demonstrated the efficacy of thromboprophylaxis with
the novel oral anticoagulant dabigatran etexilate for the extended period
(28 to 35 days) which current guidelines now recommend following hip
replacement surgery(ii). Reported trends for increasing duration of
prophylaxis and shorter hospital stays (average Canadian stay for hip
replacement is 9 days, down from 14 days 10 years ago)(iii) highlight the
shifting burden of thromboprophylaxis from in- to out-of-hospital, and focus
on the need for anticoagulant prophylaxis with a low rate of bleeding, that is
well tolerated and easy to use as an outpatient. The ability to extend
thromboprophylaxis in order to further reduce the risk of VTE beyond the
hospital stay is limited with currently available anticoagulants
(injection-only or requirement for coagulation monitoring), so a significant
unmet medical need exists for a fixed dose oral anticoagulant with no
requirements for monitoring.
    Both dabigatran etexilate doses (220mg and 150mg) were non-inferior to
40mg enoxaparin for the primary efficacy outcome (a composite of total venous
thromboembolic events, defined as deep-vein thrombosis - venographic or
symptomatic - and/or symptomatic pulmonary embolism, and all-cause mortality
during treatment) which occurred in 6.0% and 8.6% of the dabigatran etexilate
220 mg and 150mg groups versus 6.7% of the enoxaparin group. Importantly, a
pre-specified secondary outcome of major venous thromboembolism and venous
thromboembolism-related mortality (sometimes referred to as a more clinically
relevant endpoint) was also similar between groups, occurring in 3.1% and 4.3%
of the dabigatran etexilate 220 mg and 150 mg groups versus 3.9% of the
enoxaparin group.
    Dr. Andreas Barner, Vice-Chairman, Board of Managing Directors and Head
of Corporate Board Division Pharma Research, Development and Medicine,
Boehringer Ingelheim said, "Guidelines recommending extended prophylaxis have
proven to offer superior protection to patients from potentially
life-threatening blood clots. We are pleased that our new oral direct thrombin
inhibitor could offer the potential for physicians to ensure all patients
receive effective thromboprophylaxis for the recommended treatment period."
    Anticoagulation-related bleeding is the primary safety concern during hip
replacement surgery, since major bleeding into the replaced joint can have a
detrimental impact on clinical outcome(iv). Few major bleeding events were
reported, occurring at 2.0% and 1.3% for dabigatran etexilate 220 mg and 150mg
groups versus 1.6% in the enoxaparin group. Notably, about half of all major
bleeding events started before treatment. There were no major bleeding events
reported after hospital discharge in the dabigatran etexilate groups.
    Data from frequent liver function monitoring showed that the frequency of
increases in liver enzyme concentrations with dabigatran etexilate is low
during the entire extended treatment period, with alanine aminotransferase
(ALT) elevation greater than three times the upper limit of normal occurring
in slightly more patients in the enoxaparin group (3-0%, 3-0% and 5-3% of the
220 mg, 150 mg dabigatran etexilate and enoxaparin groups, respectively).
Similarly, the incidence of acute coronary events was low, with no significant
differences between all groups.
    Dabigatran etexilate is a novel oral direct thrombin inhibitor which
specifically and reversibly inhibits thrombin, the central and essential
enzyme in the coagulation cascade responsible for thrombus (clot)
formation(v),(vi). It provides a predictable and consistent anticoagulant
effect with no requirements for the coagulation monitoring that can limit the
utility of existing oral treatments such as warfarin.
    Dabigatran is an investigational compound. It has been submitted to
Health Canada for approval in a first intended indication; primary VTE
prevention following major orthopaedic surgery (such as total knee, total hip
replacement).

    About Boehringer Ingelheim

    The Boehringer Ingelheim group is one of the world's 20 leading
pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates
globally with 144 affiliates in 47 countries and more than 38,000 employees.
Since it was founded in 1885, the privately-owned company has been committed
to researching, developing, manufacturing and marketing novel products of high
therapeutic value for human and veterinary medicine.
    Boehringer Ingelheim Canada Ltd. is a member of the Boehringer Ingelheim
group of companies with international headquarters in Ingelheim, Germany.
Boehringer Ingelheim is the largest 100 per cent family-owned pharmaceutical
company and ranks among the top 20 pharmaceutical companies in the world.
Boehringer Ingelheim Canada Ltd. is proud to be a research-driven company for
both human and animal prescription medicines that contributes a significant
percentage of revenues to support research and development in Canada.

    Note to editors

    About RE-NOVATE

    RE-NOVATE was a multinational, randomised, double-blind, non-inferiority,
phase III trial involving 3,494 patients undergoing total hip replacement
surgery in the European Union, South Africa, and Australia. Patients were
randomised to receive either oral dabigatran etexilate 150 mg or 220 mg once
daily (half dose given on day of surgery, 1-4 hours post-operatively) or
enoxaparin 40 mg once daily by subcutaneous injection started 12 hours before
surgery. The median treatment duration was 33 days for all treatment groups,
with 87% of patients receiving treatment for 28 to 35 days, and patients were
followed-up for 3 months after surgery. Presence of VTE was determined by
centrally adjudicated objective clinical testing for symptomatic events, and
centrally adjudicated bilateral venograms on the last day of treatment for
asymptomatic events. The methodological approach employed for the RE-NOVATE
study is one that has been used in all studies conducted in this therapeutic
area over the last 20 years. It is a well defined approach that has been
accepted by clinicians, consensus guidelines and regulatory authorities for
testing the efficacy of a new prophylactic anticoagulant.

    About dabigatran etexilate

    Dabigatran etexilate is a reversible oral direct thrombin inhibitor, a
novel oral anticoagulant in advanced development. It specifically and
reversibly inhibits thrombin, the central and essential enzyme in the
coagulation cascade responsible for thrombus (blood clot) formation(v,vi).
    Dabigatran etexilate can be given in a fixed oral dose, has a rapid onset
and offset of action, provides a predictable and consistent anticoagulation
effect without the need for coagulation monitoring, exhibits no drug-food
interactions and has a low potential for drug-drug interactions(vii,viii,ix).
Following oral administration the pro-drug dabigatran etexilate is rapidly
converted to its active form, dabigatran(vii).
    Dabigatran etexilate, developed by Boehringer Ingelheim, is currently
being evaluated in a number of thromboembolic disease indications in an
extensive, global clinical trial programme entitled RE-VOLUTION(TM).

    Further studies investigating dabigatran etexilate

    The RE-VOLUTION(TM) trial program is designed to investigate the novel
oral direct thrombin inhibitor dabigatran etexilate as a potential treatment,
prevention and prophylaxis for several thromboembolic disease conditions. It
is expected to involve more than 27,000 patients from Asia, Australia, Europe,
the Americas, and South Africa. Patients will be divided into different
treatment arms involving dabigatran etexilate compared with warfarin or
enoxaparin.
    RE-MODEL(TM) investigated thromboembolism prevention after knee
replacement surgery in more than 2,000 patients throughout the European Union,
South Africa and Australia. It started in November 2004. RE-MOBILIZE(TM)
investigated dabigatran etexilate for the same indication in a similar patient
population in North America (greater than 2,600 patients).
    RE-LY(TM), a phase III study also under the RE-VOLUTION(TM) trial
program, is investigating dabigatran etexilate as a potential treatment for
stroke prevention in atrial fibrillation. Total enrolment for this study is
targeted at greater than 15,000 patients from almost 1,000 study centres
worldwide.
    RE-COVER(TM) and RE-MEDY(TM) are investigating dabigatran etexilate for
acute treatment and secondary prevention of venous thromboembolism.

    References
    --------------------------
    (i) Eriksson BI, Dahl OE, Rosencher N et al. Dabigatran etexilate
    compared with enoxaparin for the extended prevention of venous
    thromboembolism following total hip replacement.
    The Lancet 2007;370:949-956
    (ii) Geerts WH, Pineo GF, Heit JA et al. Prevention of Venous
    Thromboembolism: The Seventh ACCP Conference on Antithrombotic and
    Thrombolytic Therapy. Chest 2004;126:338-400
    (iii) Canadian Institute for Health Information (CIHI). 2006 Canadian
    Joint Replacement Registry (CJRR) Report: Total Hip and Total Knee
    Replacements in Canada
    (iv) Lotke PA, Lonner JH. Deep venous thrombosis prophylaxis: better
    living through chemistry--in opposition. J Arthroplasty 2005;20:15-7
    (v) Di Nisio M, Middeldorp S, Buller H. Direct thrombin inhibitors.
    N Engl J Med 2005;353:1028-1040
    (vi) Eikelboom J, White H, Yusuf S. The evolving role of direct thrombin
    inhibitors in acute coronary syndromes. J Am Coll Cardiol 2003;41:70S-78S
    (vii) Stangier J, Rathgen K, Staehle H et al. The pharmacokinetics,
    pharmacodynamics and tolerability of dabigatran etexilate, a new oral
    direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol
    2007;64:292-303
    (viii) Sorbera LA, Bozza J, Castaner J. Dabigatran/dabigatran etexilate:
    prevention of DVT, prevention of ischemic stroke, thrombin inhibitor.
    Drugs Future 2005;30:877-885
    (ix) Eriksson BI, Dahl OE, Rosencher N et al. Dabigatran etexilate versus
    enoxaparin for the prevention of venous thromboembolism after total knee
    replacement: the RE-MODEL randomized trial. J Thromb Haemost 2007 Aug 24
    (Epub ahead of print)





For further information:

For further information: Rebecca Beitchman, Environics Communications,
(416) 969-2744, rbeitchman@environicspr.com

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