New England Journal of Medicine and the Lancet Publish Results from Landmark Rivaroxaban Studies



    Data from three Phase III studies show rivaroxaban superior to standard
    of care in preventing venous blood clots after elective total hip and
    knee replacement surgeries

    
    -   Head-to-Head trials involving over 9,000 patients following total hip
        and knee replacement surgery
    -   Bleeding rates were low and comparable between treatment arms
    

    TORONTO, June 26 /CNW/ -  Data from Phase III clinical trials published
today in the New England Journal of Medicine (NEJM) and the Lancet demonstrate
that the investigational antithrombotic rivaroxaban (Xarelto(R)), taken as a
once daily tablet, is significantly more effective than enoxaparin, a current
standard of care, in preventing venous blood clots in elective total hip and
knee replacement surgery patients. Bleeding rates in all three studies were
low and comparable between the two treatment arms.
    Venous blood clots, also known as venous thromboembolism or VTE, are
potentially deadly complications of major orthopedic surgery. VTE is a serious
life-threatening condition that includes deep vein thrombosis - a blood clot
in a deep vein (usually in the leg) - and pulmonary embolism - a blood clot in
the lungs. Venous clots in the legs may break apart and travel through the
bloodstream, blocking blood flow to the lungs.
    "Today's publications on rivaroxaban have the potential to revolutionize
the way we prevent the formation of dangerous blood clots," said Dr. A.G.G.
Turpie, Professor of Medicine, McMaster University, Hamilton, Ontario and
Principal Investigator for the RECORD program. "The results demonstrate that
we now seem to have an effective and safe oral anticoagulant for convenient
prevention of VTE. This is of great importance since patients undergoing hip
and knee replacements are at high risk of developing such potentially life
threatening complications. The risk of VTE extends beyond hospitalisation and
the new antithrombotic rivaroxaban will greatly facilitate extended outpatient
treatment."

    NEJM Publication
    The first study published in NEJM, RECORD1 (REgulation of Coagulation in
major Orthopedic surgery reducing the Risk of DVT and PE), showed that
rivaroxaban, a direct Factor Xa inhibitor, provided patients undergoing total
hip replacement surgery with a 70 per cent RRR in total VTE from 3.7 per cent
in those administered enoxaparin to 1.1 per cent for those on rivaroxaban -
without increasing bleeding rates.
    The second study in NEJM, RECORD3, showed that rivaroxaban provided
patients undergoing total knee replacement surgery with a 49 per cent RRR in
total VTE from 18.9 per cent in those administered enoxaparin to 9.6 per cent
for those on rivaroxaban - without increasing bleeding rates.

    The Lancet Publication
    Results from RECORD2 published in the Lancet demonstrate that extended
duration treatment with rivaroxaban substantially reduced the number of venous
blood clots in patients undergoing elective total hip replacement surgery
compared with short duration enoxaparin followed by placebo. The five-week
rivaroxaban regimen, despite being a longer course of treatment, showed a
similar low rate of bleeding when compared to the two-week enoxaparin regimen.
This further demonstrates the strong safety profile of rivaroxaban when
compared to enoxaparin followed by placebo. RECORD2 is the largest phase III,
prospective, randomized, double-blind trial to date to evaluate short versus
extended thromboprophylaxis in high-risk surgical patients.
    "The RECORD2 study is the largest to date evaluating the need for and
benefits of,continuing measures beyond hospital stay to prevent blood clots
after major orthopaedic surgery," said Dr. Turpie. "The study showed that
continued use of the new orally active anticoagulant drug rivaroxaban for up
to five weeks after hip replacement surgery substantially reduced risk of
serious blood clots by almost 80 per cent relative to the shorter comparator
treatment regimen of two weeks of enoxaparin. These results provide convincing
evidence of the need for extended treatment."
    Current treatments such as vitamin K antagonists (e.g., warfarin) and
heparins have been the mainstays of anticoagulant treatment for many years;
however, in the outpatient setting and for long-term use, each class has
disadvantages, such as administration by needle or the need for laboratory
monitoring of effects. These disadvantages highlight the need for new
anticoagulants that are safe, effective and do not require regular injections
or routine blood monitoring.
    "The RECORD study results show that rivaroxaban has the potential to set
a new clinical standard in the treatment of blood clots and reduce the
Canadian burden of VTE," said Dr. Shurjeel Choudhri, senior vice president and
head of Medical and Scientific Affairs, Bayer Inc. " Rivaroxaban is
significantly superior to enoxaparin in the prevention of VTE, with similar
bleeding rates and, offers patients relief from the inconveniences associated
with today's therapies."
    New Data to be Presented on June 27th at the International Congress on
Thrombosis (ICT)
    Five oral presentations and eight posters will be presented on
rivaroxaban at the 20th ICT which is being held in Athens, Greece from  25-28
June 2008. Amongst the highlights will be the new and pre-specified
meta-analysis of the RECORD1, 2 and 3 studies:
    "A meta-analysis of three pivotal studies of rivaroxaban - a novel, oral,
direct Factor Xa inhibitor - for thromboprophylaxis after orthopedic surgery"
by Alexander Turpie, Michael Lassen, and Ajay Kakkar, et al., to be presented
at 08:30-10:00 on Friday 27 June.
    All of the accepted abstracts are to be published in a supplement of
Pathophysiology of Haemostasis and Thrombosis.

    Notes to editors:
    -----------------

    Unmet Needs in Venous Thromboembolism
    Venous blood clots kill more people each year than breast cancer, AIDS
and motor vehicle crashes combined.(1)
    During hip or knee replacement procedures, the large veins of the leg
that carry blood back to the heart are damaged which significantly increases
the VTE risk for patients undergoing such major orthopedic surgery. In fact,
venous blood clots occur in 40-60 per cent of patients who undergo major
orthopedic surgery and do not receive preventative care.
    There were 68,746 hospitalizations for hip and knee replacements in
Canada 2005-2006, representing a 10-year increase of 101 per cent from
34,281 procedures in 1995-1996 and a one-year increase of 17 per cent from
58,714 procedures in 2004-2005. (1)(2)
    But the threat stretches beyond orthopedic surgeries: Blood clots are one
of the leading causes of global disease and death in many patient populations,
including those with atrial fibrillation at risk for stroke, those at risk for
acute myocardial infarction (heart attack) and acutely ill hospitalized
patients, such as those with cancer.
    To learn more about VTE please visit www.thrombosisadviser.com

    About RECORD1
    RECORD1 compared the safety and efficacy of rivaroxaban with enoxaparin
in 4,541 patients undergoing total hip replacement surgery. Patients were
randomized to receive oral rivaroxaban 10 mg once-daily or subcutaneous
enoxaparin injection 40 mg once-daily for five weeks.
    Overall, RECORD1 showed superiority for rivaroxaban, demonstrating a
70 per cent RRR (p(less than)0.001) in total VTE (the primary efficacy
endpoint which encompasses the composite of deep vein thrombosis, non-fatal
pulmonary embolism and all-cause mortality) when compared with enoxaparin, and
an 88 per cent RRR (p(less than)0.001) in major VTE (the main secondary
efficacy endpoint which focuses on VTE-related events).
    The primary safety endpoint was major bleeding. The superior efficacy of
rivaroxaban was not associated with any significant differences in the
incidence of major bleeding between rivaroxaban and enoxaparin groups
(0.3 per cent and 0.1 per cent respectively, p=0.178). Rivaroxaban has not
been associated with compromised liver function.

    About RECORD2
    RECORD2 compared the safety and efficacy of an extended rivaroxaban
treatment to short duration treatment with enoxaparin in 2,509 patients
undergoing total hip replacement surgery. Patients were randomized to receive
oral rivaroxaban 10 mg once-daily for 35+/-4 days or subcutaneous enoxaparin
injection 40 mg once-daily for 11-15 days, followed by placebo.
    Overall, RECORD2 demonstrated a 79 per cent RRR in total VTE (the primary
efficacy endpoint which encompasses the composite of deep vein thrombosis,
non-fatal pulmonary embolism and all-cause mortality) for the extended
rivaroxaban treatment when compared with the short duration treatment with
enoxaparin (p(less than)0.0001), and an 88 per cent RRR (p(less than)0.0001)
in major VTE (the main secondary efficacy endpoint which focuses on proximal
DVT and VTE-related events).
    The primary safety endpoint was major bleeding. The superior efficacy of
rivaroxaban was not associated with any significant differences in the
incidence of major bleeding between rivaroxaban and enoxaparin groups ((less
than)0.1 per cent and (less than)0.1 per cent respectively). Rivaroxaban has
not been associated with compromised liver function.

    About RECORD3
    RECORD3 compared the safety and efficacy of rivaroxaban with enoxaparin
in 2,531 patients undergoing total knee replacement surgery. Patients were
randomized to receive either oral rivaroxaban 10 mg once-daily for 10-14 days
or subcutaneous enoxaparin injection 40 mg once-daily for 10-14 days.
    Overall, RECORD3 demonstrated a 49 per cent RRR (p(less than)0.001) in
total VTE (the primary efficacy endpoint which encompasses the composite of
deep vein thrombosis, non-fatal pulmonary embolism and all-cause mortality)
for rivaroxaban when compared with enoxaparin, and a 62 per cent RRR (p(less
than)0.016) in major VTE (the main secondary efficacy endpoint which focuses
on VTE-related events).
    The primary safety endpoint was major bleeding. The superior efficacy of
rivaroxaban was not associated with any significant differences in the
incidence of major bleeding between rivaroxaban and enoxaparin groups (0.6 per
 cent and 0.5 per cent respectively, p=0.774). Rivaroxaban has not been
associated with compromised liver function.

    About the RECORD program

    RECORD (REgulation of Coagulation in major Orthopedic surgery reducing
the Risk of DVT and PE), is a global program of clinical trials involving
12,729 patients, comparing rivaroxaban with enoxaparin in patients following
either total knee or hip replacement surgery. The RECORD 1, 2 and 3 studies
compared oral rivaroxaban 10mg once daily with daily subcutaneous injections
of 40 mg enoxaparin.

    
     -  In RECORD1, rivaroxaban demonstrated a 70 per cent RRR in total VTE
        in patients undergoing total hip replacement (THR) surgery compared
        with enoxaparin, with a similar safety profile. The duration of
        thromboprophylaxis in both treatments was five weeks.
     -  In RECORD2, extended-duration rivaroxaban (35+/-4 days) demonstrated
        a 79 per cent RRR in total VTE and a similar rate of major bleeding
        in patients undergoing THR surgery compared to patients dosed with
        short-duration therapy with enoxaparin (11-15 days) followed by
        placebo. The results of RECORD2 were published online in the Lancet
        on 25 June.
     -  In RECORD3, rivaroxaban demonstrated 49 per cent RRR in total VTE in
        patients undergoing total knee replacement (TKR) surgery compared to
        enoxaparin, with a similar safety profile. Both treatments were
        continued for 10-14 days after surgery.
     -  In RECORD4, 10mg once-daily rivaroxaban was compared to the North
        American-approved regimen for enoxaparin of 30mg injected twice-
        daily. Rivaroxaban demonstrated a 31 per cent RRR in total VTE in
        patients undergoing TKR surgery compared to enoxaparin, with a
        similar safety profile. Both treatments were continued for
        10-14 days. Results from this study were presented in May at the 9th
        Annual Meeting of the European Federation of National Associations of
        Orthopaedics & Traumatology (EFORT) in Nice, France.
    

    About Rivaroxaban

    The extensive clinical trial program for rivaroxaban makes it the most
studied oral, direct Factor Xa inhibitor in the world today. Based on the
clinical evidence in more than 20,000 patients, rivaroxaban has not been
associated with compromised liver function. A more definitive statement will
be made once the data from long-term exposure to rivaroxaban in the VTE
treatment and stroke prevention in atrial fibrillation (SPAF) programs is
available. Almost 50,000 patients are expected to be evaluated in the total
clinical development program.
    Rivaroxaban is currently not licensed for sale in Canada. Bayer Inc. has
submitted a regulatory filing to Health Canada for approval to market
rivaroxaban. Upon approval, rivaroxaban will be marketed solely by Bayer Inc.
in Canada. The trade name of rivaroxaban is expected to be Xarelto(R), pending
health authority approval.

    About Bayer Inc.

    Bayer Inc. (Bayer) is a Canadian subsidiary of Bayer AG, an international
research-based group with core businesses in health care, crop science, and
innovative materials.
    Headquartered in Toronto, Ontario, Bayer Inc. operates the Bayer Group's
HealthCare and MaterialScience businesses in Canada. Bayer Crop Science Inc.,
headquartered in Calgary, Alberta operates as a separate legal entity in
Canada. Together, the companies play a vital role in improving the quality of
life for Canadians - producing products that fight diseases, protecting crops
and animals, and developing high-performance materials for applications in
numerous areas of daily life. Canadian Bayer facilities include the Toronto
headquarters and offices in Ottawa and Calgary.
    Bayer Inc. has approximately 1,000 employees across Canada and had sales
of over $986 million CDN in 2007. Globally, the Bayer Group had sales of over
32 billion Euro in 2007.Bayer Inc. invested approximately $45 million CDN in
research and development in 2007. Worldwide, the Bayer Group spends the
equivalent of over 2.5 billion Euro in 2007 in R&D.

    Forward-looking statements

    This release may contain forward-looking statements based on current
assumptions and forecasts made by Bayer Group or subgroup management. Various
known and unknown risks, uncertainties and other factors could lead to
material differences between the actual future results, financial situation,
development or performance of the company and the estimates given here. These
factors include those discussed in Bayer's public reports which are available
on the Bayer website at www.bayer.com. The company assumes no liability
whatsoever to update these forward-looking statements or to conform them to
future events or developments.

    
    References
    --------------------------------------
    1   Canadian Patient Safety Institute Getting started kit: Venous
        thromboembolism prevention how-to guide., March 2008

    2   Canadian Institute for Health Information. Canadian Joint Replacement
        Registry (CJRR) 2007Annual Report on Hip and Knee Replacements in
        Canada. Accessed at: http://secure.cihi.ca/cihiweb/dispPage.jsp?
        cw_page=PG_835_E&cw_topic=835&cw_rel(equal
        sign)AR_30_E
    





For further information:

For further information: Fiona Robinson, Senior Consultant, Hill and
Knowlton Canada, (416) 413-4737, Fiona.robinson@hillandknowlton.ca; Emily
Hanft, Business Communications Specialist, Bayer Inc., (416) 240-5434,
emily.hanft.b@bayer.com


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