CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 2, March 2012
62
AFRICA
monitoring or dose titration, and that they lack clinically signifi-
cant 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 concern-
ing the variability in the trial designs of these studies, particu-
larly 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 anticoagula-
tion. 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 manage-
ment 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 inhibi-
tors 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 fibril-
lation 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 anti-
coagulant 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.
ALAN BRYER,
Division of Neurology and Stroke Unit, Groote Schuur
Hospital and University of Cape Town, South Africa
References
1.
Font MA, Krupinski J, Arboix A. Anti thrombotic medication for cardi-
oembolic stroke prevention.
Stroke Res Treatment
2011: 607852. Epub
2011 June 22.
2.
Hart RG, Benadente O, McBride R, Pearce LA. Antithrombotic therapy
to prevent stroke in patients with atrial fibrillation: a meta-analysis.
A
Int Med
1999;
131
(7): 492–501.
3.
Saxena R, Koudstaal PJ. Anticoagulants for preventing stroke in
patients with non-rheumatic atrial fibrillation and a history or stroke
or transient ischaemic attack.
Cochrane Database Syst Rev
2003; 3:
CD000185.
4.
European atrial fibrillation study group. Secondary prevention in non-
rheumatic atrial fibrillation after transient ischaemic attack or minor
stroke.
Lancet
1993;
342
:1255–1262.
5.
The atrial fibrillation investigators. The efficacy of aspirin in patients
with atrial fibrillation. Analysis of pooled data from 3 randomized
trials.
Arch Internal Med
1997;
157
(11): 1237–1240.
6.
ACTIVE writing group. Clopidogrel plus aspirin versus oral antico-
agulation for atrial fibrillation in the atrial fibrillation Clopidogrel
trial with irbesartan for prevention of vascular events (ACTIVE W): a
randomised controlled trial.
Lancet
2006;
367
: 1903–1912.
7.
Hankey GJ, Eikelboom JW. Antithrombotic drugs for patients with
ischaemic stroke and transient ischaemic attack to prevent recurrent
major vascular events.
Lancet neurol
2010;
9
: 273–284.
8.
Wallentin L, Yusuf S, Ezekowitz MD,
et al
. Efficacy and safety of
dabigatran compared with warfarin at different levels of international
normalised ratio control for stroke prevention in atrial fibrillation: an
analysis of the RE-LY trial.
Lancet
2010;
376
: 975–983.
9.
Stanley A, Ntsekhe M, Commerford PJ. An audit of an anti-coagula-
tion clinic at a tertiary hospital. Poster presentation, Department of
Medicine Research Day Groote Schuur Hospital, University of Cape
Town, South Africa. Oct 2008.
10. Connolly SJ, Ezekowitz MD, Yusuf S,
et al.
Dabigatran versus warfarin
in patients with atrial fibrillation.
N Engl J Med
2009;
361
: 1139–1151.
11. Granger CB, Alexander JH, McMurray JJV,
et al
. Apixaban versus
warfarin in patients with atrial fibrillation.
N Engl J Med
2011;
365
:
981–992.
12. Patel MR, Mahaffey KW, Garg J,
et al.
Rivaroxaban versus warfarin
in non-valvular atrial fibrillation.
N Engl J Med
2011;
365
: 883–891.
