The mixed reviews her latest
poetry collection drew from critics have sent 79-year-old
Amelia M's blood pressure soaring. This isn't good considering
Amelia's at high risk for stroke. Although her doctor
had mentioned that a promising new drug called ximelagatran
could help reduce her risk of stroke and of hemorrhage
as well, it's unlikely that she'll get her hands on it
anytime soon. The drug — much like Amelia's poetry
— also received mixed reviews and looks no closer
to hitting the market as a result. A couple of studies
published February 9 in the Journal of the American
Medical Association give the drug two thumbs down.
The promise of ximelagatran is
in the simplicity of its administration. It also carries
significantly less risk of hemorrhage than warfarin.
However, the drug's approval process has been dogged
by concerns about liver toxicity and high cost.
DVT
TAKES A DIVE
The first JAMA study, headed by Dr Jean-Noel
Fiessinger of the Hopital Europeen Georges Pompidou
in Paris, looked at ximelagatran's effectiveness in
preventing deep vein thrombosis (DVT). It randomized
2,489 patients with DVT to receive six months of treatment
with either oral ximelagatran, twice daily, or subcutaneous
enoxaparin, twice daily for five to twenty days, followed
by warfarin. The primary goal was to prevent recurrent
venous thromboembolism.
Such an event occurred in 26% of
the ximelagatran subjects, and in 24% of the enoxaparin-warfarin
subjects. This, as the researchers say, "met the prespecified
criterion for non-inferiority."
Fewer ximelagatran patients suffered
from bleeding with a cumulative risk of 1.3% after six
months, compared to a bleeding risk of 2.2% in the warfarin
group. There was also no significant difference in all-cause
mortality. However, alanine aminotransferase levels,
a marker of liver damage, were markedly elevated in
9.6% of patients in the ximelagatran group, compared
to just 2% of the warfarin group. Also, 10 patients
on ximelagatran suffered serious coronary events compared
to one patient in the warfarin group.
The researchers concluded that
while ximelagatran is as effective as warfarin in preventing
recurrent venous thromboembolism, we need to look more
closely at coronary events in future studies.
The other JAMA study, led
by Dr Gregory W Albers of the Stanford Stroke Center
in Palo Alto, California, involved 3,922 patients with
non-valvular atrial fibrillation and additional stroke
risk factors.
The researchers found that patients
treated with ximelagatran ran a 1.6% risk of a stroke
each year, compared to a 1.2% risk in the warfarin-treated
patients. All-cause mortality, however, was almost identical
in the two groups. Ximelagatran did not reduce the rates
of major bleeds, but it did reduce the rates of minor
bleeds. Again, serum alanine aminotransferase levels
rose in a disproportionately high number of ximelagatran
patients, but they generally fell back to normal within
six months whether treatment continued or not.
The researchers concluded that
while ximelagatran's simplicity is a real bonus, its
failure to improve on warfarin's stroke prevention performance,
combined with its higher cost, may rule it out as first-line
therapy, except in patients at elevated risk of bleeding.
Both studies agree that more investigation is needed
to rule out hepatotoxicity as well. The authors of this
second study also add that "The cost per quality-adjusted
life year gained would be $116,000, which exceeds the
usual limits for a cost-effective therapy."
WORTH
THE RISK
But in an accompanying editorial, Dr Victor Gurewich
of Beth Israel Deaconess Hospital Medical Center in
Boston, argues that warfarin's shortcomings make ximelagatran
the better choice. "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...must be balanced against the serious risk
of discouraging, if not foreclosing indefinitely, any
improvement in oral anticoagulant therapy."
JAMA Feb 9, 2005;293:681-98
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