CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 3, April 2012
168
AFRICA
Drug Trends in Cardiology
New anticoagulants offer consistent stroke-reduction benefit in
atrial fibrillation
Poor warfarin therapy set to benefit from renewed interest in effective anticoagulation in atrial
fibrillation
‘All the new anticoagulants, dabigatran,
rivaroxaban and apixaban are non-inferi-
or to warfarin in the prevention of stroke
and embolic events in atrial fibrillation
(AF), offering an approximate relative
reduction in risk (RRR) of 10% per
year when compared to current warfarin
therapy’, Dr Louis van Zijl, physician
and clinical trial investigator, based in
Worcester, Western Cape noted in his
presentation at the SA Hypertension
congress. ‘While we envisage that warfa-
rin therapy will still be the control arm
for randomised clinical trials for years to
come, we need to face up to our failure
to use this agent properly during the past
50 years’, he noted.
Warfarin’s development originated in
the early 1900s in the veterinary arena
where ‘spoilt clover delivering a sweet
smell’ led to anticoagulation and death
in cattle. Coumarin was identified as the
active agent in 1939 and named warfarin
in recognition of the Wisconsin Alumini
Research Foundation’s (plus -arin from
Coumarin) role in funding the research.
In 1948, an attempted suicide due to
ingestion of warfarin (as used in rat
poison) was reversed by giving vitamin
K, leading to warfarin’s celebrated use in
1954 when Dwight Eisenhouer suffered a
myocardial infarction (MI).
Its widespread application in AF
had, however, to wait many years before
numerous trials
1
showed that warfarin
versus placebo resulted in a 64% RRR
for stroke, leading to its ‘gold-standard
usage’ in this condition. The need for a
more accurate risk calculator is evident
on reviewing this early article,
1
which
noted that ‘the numbers of AF patients
that would need to be treated for one year
to prevent one ischaemic stroke are about
200, 70 and 20 for those at low, moderate
and high risk, respectively’.
The most recent ESC guidelines for
the management of atrial fibrillation
2
advise the initial use of the older risk
calculator, the CHADS
2
score, in AF
patients. ‘If patients are then adjudged to
be at intermediate risk, the newer scoring
system, the CHA
2
DS
2
VASC score, which
involves more risk factors, should be used.
‘A further innovation in the new guidelines
is the assessment of bleeding risk using
the HASBLED score. ‘However, clinical
dilemmas remain as the factors of
ageing, high blood pressure and previous
cerebrovascular disease occupy both sides
of the benefit and risk scale’, Dr van Zijl
noted. ‘This means that we must use
extreme caution in these patients not to
cause them any harm.’
In the real world, clinical registries
have added to our insights on treating
these patients. In a large Danish registry
of more than 130 000 patients with
non-valvular AF,
3
there was a neutral or
positive clinical benefit using vitamin
K antagonists alone in patients with a
CHADS
2
score greater than 0 and in those
with a CHA
2
DS
2
VASC score greater than 1.
‘There was no sufficient beneficial
effect of giving aspirin alone, or vitamin
K antagonists together with aspirin, so
aspirin does not have a role to play in
preventing strokes in AF’, Dr van Zijl
pointed out. ‘It is clear from the guidelines
and the real-world clinical data that
medium- and high-risk patients should be
treated aggressively with anticoagulants.
I believe we all have to become assertive
anticoagulators’, Dr van Zijl stressed.
The vitamin K antagonists have a
narrow therapeutic window and this
complicates the clinician’s ability to
reach an optimal INR of 2.5 and also to
avoid the increased risk of intracranial
haemorrhage when an INR higher than
3 is prevalent. ‘The time in therapeutic
range (TTR) is the measure of our clinical
success, as a failure to stay within the
TTR does not come without risk’, he said.
‘The promise of the new anti-
coagulants, rivaroxiban and apixaban
as factor Xa inhibitors, and dabigatran,
a direct factor IIa inhibitor, are their
simple dosing regimen, fewer food and
drug interactions, less labour- and cost
intensive with regard to on-going INR
monitoring, and an increased quality of
life for patients due to their increased
efficacy’, Dr van Zijl said.
For the clinician, challenges remain
in the selection of which agent to use,
as the clinical trials differ with regard
to many aspects such as study design,
with blinding being double or single
blinded, type of patients at risk included
in the study, demographics, and definition
of major bleeding. Also interpretation
is complicated by data presented in a
variety of ways, from intention to treat, to
modification of treatment analyses. ‘I was
privileged to be involved in most of the
studies, in ROCKET, ARISTOTLE and
ENGAGE, which is still underway, but
unfortunately not in the RE-LY studies’,
Dr van Zijl noted.
Dr van Zijl discussed these various
aspects, which constitute the current
clinical challenges, also using data
provided by Dr Michael Gibson, one of
the senior investigators of anticoagulant
trials. ‘It is becoming clearer that we will
use the differing pharmacokinetics of
the three agents, rivaroxaban, apixaban
and dabigatran to make our choice of
oral anticoagulant agent in AF. For
example, dabigatran is 80% eliminated
via the kidneys and in patients with
renal insufficiency, we would consider
this fact’, he said
With regard to usage of these agents
in resource-constrained settings, Dr van
Zijl noted that there are some predictors
that can identify patients who will be poor
warfarin responders (such as those whose
warfarin control is not in place by 30 days),
which can be used as predictors of an
at-risk situation under warfarin. ‘In these
patents, we will certainly have to strongly
consider these new anticoagulants’, he
concluded.
J Aalbers
1. Hart RG,
et al. Neurology
1998;
51
(3): 674–681.
2. Camm AJ,
et al
.
Eur Heart J
2010;
31
(19):
2369–2429.
3. Olesen JB,
et al
.
Thrombosis Haemost
2011;
106
(4) 739–749.
