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REVIEW
SA JOURNAL OF DIABETES & VASCULAR DISEASE
4
VOLUME 9 NUMBER 1 • MARCH 2012
Correspondence to: Prof Alan Bryer
Division of Neurology and Stroke Unit, Groote Schuur Hospital and
University of Cape Town
e-mail: Alan.Bryer@uct.ac.za
S Afr J Diabetes Vasc Dis
2012;
9
: 4–5
New antithrombotic drugs: a revolution
in stroke management
ALAN BRYER
E
mbolism of cardiac origin accounts for 20%
of ischaemic strokes. Atrial fibrillation is by
far the most common cause of cardioembolic
stroke, and anticoagulation is the treatment generally
indicated for secondary, and in many cases, primary
prevention.
1
The decision to prescribe warfarin is
usually based on an accurate assessment of the likely
absolute annual risk of stroke without warfarin, and
whether or not such benefits of warfarin treatment
are likely to outweigh the risk of bleeding associated
with its use.
For more than 20 years, the use of warfarin has
been the cornerstone of antithrombotic therapy
for patients with TIA or ischaemic stroke due to cardioembolism,
particularly those associated with atrial fibrillation. Warfarin remains
the commonest anticoagulant used worldwide (although other
similar vitamin K antagonists are prescribed in many countries).
Adjusted-dose warfarin anticoagulation with an international
normalised ratio (INR) range between 2.0 and 3.0 is significantly
more effective than antiplatelet therapy for preventing recurrent
stroke in patients with atrial fibrillation and results in a risk reduction
of between 60 and 68% compared to placebo.
2,3
By contrast, the
most commonly used alternative to warfarin is aspirin, which
provides substantially less-consistent benefit and reduces the risk
of recurrent stroke and other major vascular events in patients
with atrial fibrillation by only 17 to 21%.
4,5
Similarly, combination antiplatelet therapy with aspirin and
clopidogrel is not as effective as warfarin and is associated with
a significant increase in major bleeding.
6
Furthermore, although
current data indicate that combination treatment with aspirin and
clopidogrel does result in a greater reduction in major vascular
events when compared with aspirin alone, this is offset by an
increase in major haemorrhages. The absolute benefit of oral
anticoagulation with warfarin versus antiplatelet therapy increases
as patients with atrial fibrillation get older because stroke risk
increases with age while the relative efficacy of oral anticoagulation
therapy to prevent ischaemic stroke does not change.
7
Despite the efficacy and affordability of warfarin, many
patients with cardioembolic stroke or TIA are not treated with this
agent because it is perceived to be inconvenient or hazardous.
Although the benefits of oral anticoagulation with warfarin are
supported by a high degree of evidence for stroke prevention due
to cardioembolic stroke, there are many disadvantages associated
with its use. The long-term efficacy and safety of warfarin depends
on maintaining a narrow range of anticoagulation
intensity (INR 2.0–3.0) and this may be compromised
by the patient’s dietary intake, exposure to other
drugs, and co-existing illnesses. Consequently, many
drug-compliant patients are not well controlled and
require regular monitoring of the INR.
The need for sustained patient monitoring is not
only inconvenient for the patient but also requires
adequate healthcare infrastructure, which is often
lacking in developing countries. For instance, patients
who have residual disability after a cardioembolic
stroke may experience significant difficulties in
attending clinics where their INR can be monitored
and their warfarin dose adjusted accordingly. This problem is often
compounded in rural areas where the distances patients have to
travel to clinics may be considerable and infrastructure at such
clinics for INR monitoring may be lacking.
As patients on warfarin need to be within the target INR range
in order to achieve benefit, there is also an increased risk for
serious bleeding complications when the target INR is exceeded. In
a
post-hoc
analysis of the RE-LY trial, a wide variation in the time
in therapeutic range (TTR) across participating countries persisted
despite efforts to improve the generally poor quality of INR control
seen in many trials. This ranged from a high 77% in Sweden to as
low as between 41 and 58% in 16 other countries, mostly Asia,
Eastern Europe, South America and South Africa.
8
An audit of anticoagulation was undertaken in a cohort of
patients attending a prothrombin clinic at a tertiary South African
hospital in order to determine the TTR on dose-adjusted warfarin.
Patients were included in the audit if the indication for warfarin
was atrial fibrillation or a mechanical valve replacement and
they had been on warfarin for at least one month. Of the 190
patients included in the analyses, the mean TTR was 55.5%, with a
complication rate of 8.4% (5.8% bleeding, 2.6% thrombotic). The
TTRs for the majority of the patients in this study were lower than
acceptable, at the lower end of published norms and associated
with a high complication rate. Neither clinic attendance nor time
on warfarin correlated with the TTR. The results of this audit
indicate that the level of anticoagulation was inadequate in the
majority of patients treated with warfarin at this large clinic.
9
It is
likely that these results reflect the situation in many clinics in the
developing world.
Numerous drug and dietary interactions compound the problem
of warfarin’s narrow therapeutic range and the difficulties in
achieving adequate TTR. Warfarin can interact with a multitude
of commonly prescribed drugs (such as statins, various antibiotics,
non-steroidal anti-inflammatory agents and some of the most
popular over-the-counter analgesics such as paracetamol and
aspirin). Given the problems associated with its use, clinicians are
frequently compelled to prescribe less efficacious antiplatlet agents
for prevention of cardioembolic stroke.
Alan Bryer