CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 2, March 2012
AFRICA
61
Editorial
New antithrombotic drugs: a revolution in stroke
management
ALAN BRYER
Embolism 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 gener-
ally indicated for secondary, and in many cases, primary preven-
tion.
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 asso-
ciated 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 signifi-
cantly 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 increas-
es as patients with atrial fibrillation get older because stroke risk
increases with age while the relative efficacy of oral anticoagula-
tion 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 hazard-
ous. Although the benefits of oral anticoagulation with warfarin
are supported by a high degree of evidence for stroke preven-
tion 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 anticoagula-
tion 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 incon-
venient 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 cardio-
embolic stroke may experience significant difficulties in attend-
ing 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 replace-
ment 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 situa-
tion in many clinics in the developing world.
Numerous drug and dietary interactions compound the prob-
lem 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 antibiot-
ics, 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.
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 over-
whelming advantages of the new agents are that they exhibit
stable pharmacokinetics, obviating the need for coagulation
