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Monday 21st February, 2005
Ximelagatran (Exanta) was found to be as effective as other common therapies
for preventing stroke and recurrent blood clots.
CHICAGO - A medication that could simplify anticoagulation therapy,
ximelagatran, was found to be as effective as other common therapies for
preventing stroke and recurrent blood clots, according to studies in the
February 9 issue of JAMA. Ximelagatran is currently approved for use in
some European countries but it has not been approved in the United
States because of concerns about adverse effects.
In the first study, Jean-Noel Fiessinger, M.D., of H?ital Europ?n
Georges Pompidou, Paris, and colleagues conducted a study of patients
with deep vein thrombosis (blood clot in veins of the legs, pelvis or
arms) to determine the efficacy and safety of oral ximelagatran compared
to standard treatment with the anticoagulants enoxaparin and warfarin.
According to background information in the article, current therapy
for patients with acute venous thromboembolism consists of 5 to 7 days
of the anticoagulant heparin overlapped with and followed by long-term,
oral anticoagulation with a therapy such as warfarin. Heparin must be
given parenterally (by injection, usually through the veins) and
administration requires considerable health care resources. Warfarin is
given orally, but has an unpredictable dose response, interacts with
many drugs, and can be affected by changes in diet; thus, continued
coagulation monitoring and dose adjustment are necessary. Ximelagatran
is administered orally and is rapidly absorbed and quickly converted to
its active form.
The trial (Thrombin Inhibitor in Venous Thromboembolism [THRIVE]
Treatment Study) included 2,489 patients with deep vein thrombosis. The
study was conducted at 279 centers in 28 countries from September 2000
through December 2002. Patients were randomized to receive 6 months of
treatment with either oral ximelagatran, twice daily, or subcutaneous
enoxaparin, twice daily for 5 to 20 days followed by warfarin.
The researchers found that the primary efficacy end point of
recurrent venous thromboembolism occurred in 26 and 24 patients in the
ximelagatran and enoxaparin/warfarin groups, respectively, corresponding
to estimated cumulative risks of 2.1 percent and 2.0 percent. The
absolute difference between ximelagatran and enoxaparin/warfarin was 0.2
percent. This met the prespecified criterion for non-inferiority. The
cumulative risk of major bleeding at 6 months in the ximelagatran-treated
patients was 1.3 percent compared with 2.2 percent for those receiving
enoxaparin/warfarin. All-cause death was not significantly different
between the 2 groups.
A total of 9.6 percent of patients in the ximelagatran group had
alanine aminotransferase levels (a measurement in the blood used as an
indicator of possible liver damage or disease) increase to greater than
3 times the upper limit of normal, vs. 2.0 percent in the enoxaparin/warfarin
group. Analysis of locally reported adverse events showed a higher rate
of serious coronary events with ximelagatran (10/1,240 patients)
compared with enoxaparin/warfarin (1/1,249 patients).
"In conclusion, for the initial and prolonged treatment of deep vein
thrombosis, direct thrombin inhibition with oral ximelagatran, 36 mg.
twice daily, was as effective as enoxaparin/warfarin, without the need
for coagulation monitoring or dose adjustment. The mechanism and
clinical importance of the increased liver enzyme levels in ximelagatran-treated
patients requires further evaluation. Prospective assessment of coronary
events in future studies is warranted," the authors write.
Editor's Note: This study was funded by Astra-Zeneca. For financial
disclosure information, please see the JAMA article.
Ximelagatran Proves as Effective, Simpler, Than Warfarin for
Preventing Stroke in Patients with Atrial Fibrillation
In a second study in this week's JAMA, Jonathan L. Halperin, M.D., of
Mount Sinai Medical Center, New York, and colleagues compared the
efficacy of ximelagatran with warfarin for prevention of stroke in
patients with atrial fibrillation.
Non-valvular atrial fibrillation is implicated in nearly15 percent of
strokes, according to background information in the article. Research
has indicated that warfarin decreases stroke risk by 62 percent, though
in practice, the risk of bleeding limits treatment with warfarin,
particularly among the elderly. Underuse of warfarin in patients with
atrial fibrillation at high risk of bleeding calls for safer, more
dependable alternatives. Ximelagatran offers fixed oral dosing without
need for coagulation monitoring, rapid onset and offset of action,
stable pharmacokinetics with little potential for drug interactions, and
no known food interactions.
This trial, SPORTIF V (Stroke Prevention using an Oral Thrombin
Inhibitor in Atrial Fibrillation), was conducted in 2000-2001 at 409
North American sites, involving 3,922 patients with non-valvular atrial
fibrillation and additional stroke risk factors. Patients received
warfarin or ximelagatran.
The researchers found that the primary event rate (for strokes) with
ximelagatran was 1.6 percent per year and with warfarin was 1.2 percent
per year. When all-cause death was included in addition to stroke and
systemic embolic events, the rate difference was 0.10 percent per year.
There was no difference between treatment groups in rates of major
bleeding, but total bleeding (major and minor) was lower with
ximelagatran (37 percent vs. 47 percent per year). Serum alanine
aminotransferase levels rose to greater than 3 times the upper limit of
normal (an indication of liver toxicity) in 6.0 percent of patients
treated with ximelagatran, usually within 6 months and typically
declined whether or not treatment continued.
"The SPORTIF V trial is the largest yet reported trial involving
patients with atrial fibrillation for prevention of stroke and systemic
embolism. Low rates of thromboembolism and bleeding occurred when
ximelagatran was given in a fixed dose without anticoagulation
monitoring. Further investigation is needed to clarify the risk of
serious hepatic reactions and identify predictive features to select
appropriate patients for treatment with ximelagatran. In the balance are
a large number of potentially preventable fatal or disabling strokes
that accumulate as a consequence of the limitations and underutilization
of warfarin," the authors write.
Ximelagatran Not Likely to be Cost-Effective in Preventing Stroke
in Most Patients With Atrial Fibrillation
In a related article in this week's JAMA, Cara L. O'Brien, M.D., and
Brian F. Gage, M.D., M.Sc., of the Washington University School of
Medicine, St. Louis, compared the projected quality-adjusted survival
and costs of ximelagatran, warfarin, and aspirin in patients with
chronic atrial fibrillation.
With a more favorable pharmacokinetic profile, equal efficacy in
stroke prevention, and probable lower risk of bleeding, ximelagatran may
increase quality-adjusted survival compared with warfarin, according to
background information in the article. However, it is unclear whether
this improvement justifies the additional cost and offsets rare liver
The study included the analysis of a hypothetical group of
70-year-old patients with chronic atrial fibrillation, varying risk of
stroke, and no contraindications to anticoagulation.
"We found that switching therapy for a patient with atrial
fibrillation and low bleeding risk from warfarin to ximelagatran would
increase survival modestly (0.12 quality-adjusted life-year [QALY]) at a
substantial cost. In the base case, the cost per QALY gained would be
$116,000, which exceeds the usual limits for a cost-effective therapy,"
the authors write. "For ximelagatran to cost less than $50,000 per QALY
it would have to cost less than $1,100 per year or be prescribed to
patients who have an elevated risk of intracranial hemorrhage or a low
quality of life with warfarin therapy."
Editorial: Ximelagatran - Promises and Concerns
In an accompanying editorial, Victor Gurewich, M.D., of Beth Israel
Deaconess Hospital Medical Center, Boston, comments on the studies on
ximelagatran in this week's JAMA.
"With respect to the more troublesome possibility of long-term
adverse effects from [ximelagatran], it seems unlikely that yet another
clinical trial will resolve this question. Diligent postmarketing
surveillance is essential to monitor use and to determine the risks
associated with this agent, and this may be the best, if not the only,
way to deal with this question. It is possible that such data will
become available from Europe, but this is unlikely at present since for
now only short-term use has been approved. In the United States, the
Food and Drug Administration, perhaps feeling the effects of recently
having to withdraw drugs from the market, has denied approval of
ximelagatran because of concerns about hepatotoxicity. However, this
precaution concerning the risk of hepatotoxicity from ximelagatran must
be balanced against the serious risk of discouraging, if not foreclosing
indefinitely, any improvement in oral anticoagulant therapy, which
remains an important and growing therapeutic need."
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