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SA JOURNAL OF DIABETES & VASCULAR DISEASE
REVIEW
VOLUME 9 NUMBER 1 • MARCH 2012
5
The advent of the direct thrombin inhibitors and factor
Xa inhibitors represents a quantum leap forward in the long-
term prevention of recurrent stroke of cardiac origin. The two
overwhelming advantages of the new agents are that they exhibit
stable pharmacokinetics, obviating the need for coagulation
monitoring or dose titration, and that they lack clinically significant
food or drug interactions. Additional advantages are that they
offer fixed once- or twice-daily oral dosing and a rapid onset
of action. It seems likely that, in time, these agents will replace
warfarin as treatment of choice for the prevention of cardioembolic
stroke.
September 2009 heralded the publication of the first of three
important studies in which the front runners of these new agents,
dabigatran, and subsequently apixaban and rivaroxaban, were
each compared to warfarin in patients with atrial fibrillation, in
order to determine whether or not these new agents provided
more consistent and predictable anticoagulation than warfarin
for a primary endpoint of stroke or systemic embolism. Results
from these trials indicate that all three novel anticoagulants are
either non-inferior or superior to warfarin in reducing the risk of
stroke and systemic embolisation.
10-12
Furthermore, all three drugs
have either an equivalent or reduced risk of major bleeding and
intracranial haemorrhage compared with warfarin. However, there
is continued debate and discussion in the literature concerning the
variability in the trial designs of these studies, particularly pertaining
to issues such as the differences in the case mix affecting stroke
risk (e.g. differences in the CHADS
2
scores, prevalence of prior
stroke, patient age, whether or not patients were warfarin naïve,
and the interpretation of the TTR data).
Although the current trials show favourable safety profiles for
these newer agents, long-term data are still required, as most
patients with atrial fibrillation require lifelong oral anticoagulation.
Nevertheless, these agents appear to provide a number of
significant benefits over warfarin, and potential patients should
be informed of these in order to make informed choices. On the
other hand, there are a number of concerns which will need to be
addressed.
Widespread use of these newer agents is expected in the future
once they are approved by the relevant regulatory authorities.
Inevitably, the potential risk for overdose will increase in this
population, particularly among the elderly, and there is currently
no easy way of detecting this with routine coagulation tests. There
is also currently no solid evidence to guide the management of
bleeding complications that can occur with these newer agents.
The thrombin time and ecarin clotting time do illustrate a linear
response to serum dabigatran concentration, but are not readily
available. Consequently, many patients already taking and
tolerating warfarin, with good INR control, may reasonably prefer
not to switch to dabigatran or one of the factor Xa inhibitors until
there is more clarity on these issues.
A major limiting factor for the future widespread use of the
newer anticoagulants in the developing world will be their high
cost compared to warfarin. In evaluating the health economics of
introducing these newer therapies into the public health domain
of African countries, the cost of these drugs will need to be
compared not only with the cost of warfarin but also with the cost
and availability of INR-monitoring facilities. Furthermore, the cost
of non-compliance and inadequate TTR on warfarin treatment,
as well as associated complications of warfarin therapy will need
to be carefully considered. The analysis of cost-effectiveness
of the new drugs will need to include these ramifications for
stroke prevention so that their true risk–benefit can be properly
assessed.
Fortunately there are a number of competing drugs in this new
class, with other similar products in development (betrixaban,
edoxaban). This is likely to drive down the prices of these new
agents, allowing for more widespread use. These drugs also
have the potential to expand the number of patients eligible for
oral anticoagulant therapy, including those patients with atrial
fibrillation who are unable or unwilling to use warfarin.
Dabigatran has already received regulatory approval in the
United States for use in patients with atrial fibrillation and it
has rapidly entered clinical practice. It is likely that apixaban and
rivaroxaban will also get regulatory approval and the debate in
the literature concerning their comparative efficacy and safety will
continue.
Many physicians are reluctant to prescribe warfarin for elderly
patients in atrial fibrillation for various reasons (e.g. concerns for
risk of falls, history of previous bleeding) despite clear evidence
of increased benefit in these patients compared with younger
patients. These physicians would likely have fewer reservations
about prescribing one of the newer agents. The consistent
anticoagulant effect achieved with the new oral anticoagulants
may also translate into greater efficacy and safety due to
avoidance of the frequent sub- and supra-therapeutic drug
levels, which are common with warfarin and the other vitamin K
antagonists.
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