The addition of a novel factor Xa inhibitor to antiplatelet therapy
resulted in a dose-dependent increase in bleeding, but there was also
a trend toward a reduction in clinically relevant ischemic events, a
new study has shown. Investigators say the drug, known as apixaban,
is promising as an adjunct to aspirin or dual antiplatelet therapy in
patients with a recent acute coronary syndrome.

"Patients after acute coronary syndrome continue to have recurrent
events," lead investigator Dr John Alexander (Duke Clinical Research
Institute, Durham, NC) told heartwire. "Everybody is happy with how
effective aspirin and clopidogrel are, but if you look at event
curves, they're all going up.

"We know that with warfarin and, to some extent, direct thrombin
inhibitors like ximelagatran, more potent anticoagulation can reduce
those events, but, as with all effective anticoagulants, they
increase bleeding."

The phase 2 apixaban study, known as APPRAISE-1, was presented this
week at the European Society of Cardiology Congress 2008.

Bleeding and Efficacy Trading Off

Apixaban is direct, selective inhibitor of factor Xa, one of the
proteins involved in the clotting process. The study included 1715
patients with a recent acute coronary syndrome (<7 days) and was
designed to test different doses of apixaban on top of standard
antiplatelet therapies. An interim analysis of data showed an excess
of major and minor bleeding at the highest doses--10 mg twice daily
and 20 mg once daily--of apixaban, and these doses were discontinued.

Overall, 317 patients were randomized to apixaban 2.5 mg twice daily,
318 patients to apixaban 10 mg daily, and 611 patients to placebo.
The rate of major bleeding, defined by the International Society of
Thrombosis and Hemostasis (ISTH), plus clinically relevant nonmajor
bleeding, was highest in those treated with the 10-mg dose of
apixaban. In addition to the bleeding risks, investigators observed a
trend in the reduction of ischemic events, with the 10-mg dose of
apixaban having the lowest incidence of cardiovascular death, MI, or
stroke.

"Phase 2 studies often don't have these nice dose-response signals,"
said Alexander. "We got lucky here in seeing a signal on safety and
efficacy, and that is very useful for studying doses in phase 3
studies."

Alexander said the study used the ISTH definition of major bleeding
plus clinically relevant nonmajor bleeding because it is encompasses
nearly any bleeding that requires medical intervention, a sensitive
marker that allowed investigators to distinguish the differing risks
among the different doses. There were lower bleeding rates with
different definitions, but there still appeared to be a net clinical
benefit depending on the definition used.

Investigators left the use of clopidogrel prior to randomization up
to the discretion of the attending clinicians, with about 75% of
patients being treated with aspirin and clopidogrel. ISTH major and
clinical relevant nonmajor bleeding was increased more among patients
taking clopidogrel compared with patients not taking clopidogrel.
Alexander noted that most of these clopidogrel patients underwent PCI
and were younger and more likely to be male and enrolled in a North
American or Western European center.

There are ongoing phase 3 studies investigating the role of factor Xa
inhibitors in patients with atrial fibrillation, although one study
has already missed its primary end point. Bristol-Myers Squibb and
Pfizer, the companies that license and market apixaban together,
released the results of the ADVANCE-1 trial last week, a study that
tested whether apixaban was statistically noninferior to enoxaparin
for the prevention of asymptomatic deep vein thrombosis, pulmonary
embolism, and death by any cause in patients undergoing knee-
replacement surgery. The drug failed to meet statistical criteria for
noninferiority when compared with enoxaparin.