CARDIOVASCULAR JOURNAL OF AFRICA • Vol 22, No 5, September/October 2011
AFRICA
287
European Society of Cardiology congress 2011
Progress with new anticoagulants for atrial fibrillation
Rivaroxaban closer to FDA
approval for stroke prevention in
atrial fibrillation
The FDA’s Cardiovascular and Renal
Drugs advisory committee has now voted
nine to two (with one abstention) in
favour of recommending rivaroxaban, an
oral factor Xa inhibitor, for prevention of
stroke in atrial fibrillation.
1
Apixaban in atrial fibrillation
This follows hot on the heels of the
release of the ARISTOTLE study with
apixaban
2,3
at the recent ESC congress in
Paris. Results of the study were presented
in a hot-line session by Prof Christopher
Granger, Duke Clinical Research Insitute,
North Carolina, USA. ‘With a 21% reduc-
tion in total stroke and 31% reduction in
bleeding, the ARISTOTLE trial has really
hit the sweet spot in terms of dose’, said
Granger.
In an accompanying editorial in the
New England Journal of Medicine
, Jessica
Mega from Harvard Medical School,
Boston, USA, wrote: ‘Apixaban is the
first of the newer anticoagulants to show
a significant reduction in the risk of death
from any cause, compared with warfarin.’
While warfarin and other vitamin K
antagonists are effective in preventing
stroke in patients with atrial fibrillation
(reducing the risk by two-thirds), use
has been limited by a narrow therapeutic
range, drug and food interactions and risk
of bleeding.
‘There’s an enormous unmet need in
the treatment of patients at risk of stroke
associated with atrial fibrillation. Only
about half of those who should be treated
are treated’, said Granger.
Currently, three alternatives to warfa-
rin are now on the horizon for South
African clinicians: dabigatran (a direct
thrombin inhibitor), approved for atri-
al fibrillation stroke prevention in the
USA, Europe and Japan; rivaroxaban (an
oral factor Xa inhibitor); and apixaban
(a direct oral factor Xa inhibitor). The
AVERROES study, reported on at last
year’s ESC congress, showed that patients
with atrial fibrillation who were unable to
take warfarin and treated with apixaban
had a significantly lower risk of stroke
and systemic embolic events than those
treated with aspirin.
‘The fact that both AVERROES and
ARISTOTLE give similar messages
provides us with real confidence in the
efficacy of apixaban’, said Granger. ‘It’s
particularly striking that the ARISTOTLE
study, which was designed to show non-
inferiority to warfarin, actually showed
superiority.’
In the Apixaban for Reduction in
Stroke and Other Thromboemoblic Events
in Atrial Fibrillation (ARISTOTLE) trial,
18 201 patients with atrial fibrillation
and at least one additional risk factor for
stroke were randomised to apixaban (
n
=
9 120) at a dose of 5 mg twice daily, or to
warfarin (
n
=
9 081) with a target interna-
tional normalised ratio (INR) of 2.0–3.0,
for prevention of stroke or systemic
embolism. Patients were recruited from 1
034 clinical sites in 39 countries.
Results at a median duration of follow
up of 1.8 years showed primary outcome
(ischaemic or haemorrhagic stroke or
systemic embolism) in 1.27% of patients
in the apixaban group and 1.60% in
the warfarin group (HR 0.79; 95% CI
0.66–0.95;
p
<
0.001 for non-inferiority).
The rate of death from any cause was
3.52% in the apixaban group and 3.94%
in the warfarin group (HR 0.89; 95% CI
0.80–0.99;
p
=
0.047).
The rate of haemorrhagic stroke was
0.24% per year in the apixaban group
compared with 0.47% per year in the
warfarin group (HR 0.51; 95% CI 0.35–
0.75;
p
<
0.001), and the rate of ischaemic
or uncertain types of stroke was 0.97%
per year in the apixaban and 1.05% per
year in the warfarin group (HR 0.92; 95%
CI 0.74–1.13;
p
=
0.42).
Major bleeding (defined according to
ISTH criteria) occurred in 327 patients
in the apixaban group and 462 patients
in the warfarin group (HR 0.6; 95% CI
0.60–0.80;
p
<
0.001). For every 1 000
patients treated, the authors have calcu-
lated that apixaban prevented six strokes,
15 episodes of major bleeding and eight
deaths.
Commenting in the
New England
Journal of Medicine
2
on the lower risk
of haemorrhagic stroke observed with
all three new anticoagulants, the authors
suggest there may be a specific risk
associated with warfarin, possibly related
to its inhibition of multiple coagulation
factors or interaction with tissue factor
VIIa complexes in the brain.
In her accompanying editorial in the
New England Journal of Medicine
,
3
Mega
wrote that switching to newer agents may
not be necessary for individual patients in
whom the INR has been well controlled
with warfarin. ‘Generic warfarin is
expected to be markedly less expensive
than the newer agents, even after the costs
associated with regular INR monitoring
are considered’, she said.
4
1.
Heartwire
, 8 September 2011.
2.
Granger CB,
et al
. Apixaban versus warfarin
in patients with atrial fibrillaion.
N Engl
J Med
2011; 365 (11): 981–992. Epub 27
Aug 2011.
3.
Mega JL. A new era for anticoagulation in
atrial fibrillation.
N Engl J Med
. E-pub 28
Aug 2011. 10.1056/NEJMel109748.
4.
ESC congress press statement 2011.
