CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 1, January/February 2010
AFRICA
55
The ultimate anticoagulants?
Two new anticoagulants that can be
administered orally are poised to
change the face of anticoagulation as
we know it. Rivaroxaban and dabigat-
ran (neither available in South Africa
as yet) have both shown positive results
in clinical trials. At the congress of the
South African Society of Thrombosis
and Haemostasis, held in Johannesburg
on 22 November 2009, Profs Sylvia
Haas and Ajay Kakkar presented the
evidence for rivaroxaban and dabigat-
ran, respectively.
While very positive about the
promise of rivaroxaban, Prof Haas of
Technical University,Munich, Germany,
cautioned nonetheless that ‘what is ulti-
mate today may not be ultimate tomor-
row’, given a constantly changing envi-
ronment. ‘Rivaroxaban is a factor Xa
inhibitor, and this factor is an attractive
target for anticoagulation, as it prevents
thrombin generation without blocking
various other effects. Targeting it is
therefore a very efficient mechanism
of inhibition of thrombin generation.
When factor Xa is activated, there is an
immediate downward shift in thrombin
concentration. Inhibiting it is therefore
a sensible strategy for preventing a
thrombin burst.’
Rivaroxaban is a once-daily, selec-
tive, oral, direct factor Xa inhibitor with
potential value in a broad variety of
clinical indications. Phase three studies
for the primary prevention of venous
thrombo-embolism (VTE) are already
complete. Prof Haas reviewed the find-
ings of the RECORD programme,
which evaluated rivaroxaban relative to
parenteral enoxaparin, a low-molecular
weight heparin, in over 12 000 patients.
The programme comprised four stud-
ies in total, allowing for meta-analy-
sis. Two studies (RECORD 1 and 2)
1,2
compared the use of the drugs follow-
ing hip-replacement surgery and two
(RECORD 3 and 4)
3,4
compared them
in knee-replacement surgery.
‘RECORD 1, designed as a non-
inferiority trial, showed the clear-cut
superiority of rivaroxaban. RECORD
2, designed as a superiority trial,
confirmed the safety and efficacy of
rivaroxaban given as long-term prophy-
laxis to prevent VTE after total hip
replacement. There were no other types
of major bleeding associated with its
use. The findings also showed that
extended prophylaxis was superior to
that of short duration. Where this medi-
cation is not yet included in anticoagu-
lation guidelines after major orthopae-
dic surgery, we need to motivate for
the necessary amendments’, Prof Haas
commented.
RECORD 3 and 4 showed simi-
lar patterns in respect of total knee
replacement. Once again, there was
clear-cut superiority of rivaroxaban
with regard to preventing symptomatic
VTE and reducing all-cause mortality.
It was non-inferior to enoxaparin when
it came to clinically relevant non-major
bleeding and cardiovascular events. ‘In
summary, the RECORD programme
showed that rivaroxaban significantly
reduced VTE events without increasing
bleeding rates.’
Various other phase III trials, such
as MAGELLAN and EINSTEIN, are
evaluating rivaroxaban in other settings,
including deep-vein thrombosis and
pulmonary embolism, and are still
ongoing. ‘If the results are good, they
will establish rivaroxaban as a new
concept of VTE therapy – a single anti-
coagulant that replaces two different
anticoagulants used for initial and acute
therapy as well as for long-term antico-
agulation’, observed Prof Haas.
The ROCKET study is comparing a
fixed dose of rivaroxaban in atrial fibril-
lation and evaluating stroke prevention
compared with standard warfarin treat-
ment. Results are expected in 2010.
ATLAS TIMI 5, evaluating rivaroxa-
ban’s role in acute coronary syndrome,
is expected to deliver results in either
2010 or 2011.
Prof Haas summarised the clinical
utility of rivaroxaban as follows:
it is formulated as a small tablet to be
●●
taken once daily
the first pill is given six to eight
●●
hours postoperatively
there is no need for injections or
●●
routine anticoagulation monitoring
there are no problems associated
●●
with switching from one compound
to another
it can be combined with aspirin and
●●
NSAIDs (non-steroidal anti-inflam-
atories)
it has potent, rapid anticoagulant
●●
effects (within two to four hours)
it has high oral bioavailability (
●●
>
80%)
it has low potential for food–drug
●●
and drug–drug interactions
It can be given in a fixed dose,
●●
regardless of age, gender or extreme
body weight.
‘And there is no toll to pay in respect
of liver toxicity, renal effects and other
side effects generally’, she concluded.
Prof Ajay Kakkar, of the Thrombosis
Research Institute, Barts, and the
London School of Medicine and
Dentistry, made the case for dabigat-
ran being the ‘ideal anticoagulant’ as
he reviewed the data on its efficacy in
preventing and treating VTE.
In his view, the ideal anticoagulant
should be a once-daily treatment that
can be given in a fixed dose, in or out
of hospital. It needs to be predictable
with a wide therapeutic window. It
should require no monitoring and have
minimal interactions with food or other
drugs.
‘Thrombin is the ultimate part of
the coagulation cascade. It therefore
makes sense to target it. Like rivaroxa-
ban, dabigatran is an orally adminis-
tered medication. Unlike rivaroxaban,
it targets thrombin (activated Factor II)
and is a pro-drug that binds quickly to
the thrombin burst with high affinity
and specificity. It is predictable and is
given in a fixed dose with no need for
monitoring.’
The RE-NOVATE trial
5
evaluated
dabigatran (220 or 150 mg) versus
enoxaparin (40 mg) in total hip
replacement, while RE-MODEL
6
and
RE-MOBILIZE
7
looked at the drug
in total knee replacement. When the
VTE data were viewed in their totality,
there was a non-inferiority of dabigat-
ran to enoxaparin in RE-NOVATE
versus RE-MODEL but against the
higher dose of enoxaparin 60 mg in
RE-MOBILIZE, dabigatran failed to
achieve non-inferiority. (Prof Kakkar
