CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 6, July 2012
350
AFRICA
Faculty of Consulting Physicians of South Africa (FCPSA)
Saving brain with dabigatran
Dr Ken Butcher is associate professor
of Neurology at the University of
Alberta, Canada. His major clinical and
research interests include acute stroke
care. He holds a Canada research chair
in Cerebrovascular Disease, and the
Heart and Stroke Foundation of Alberta
professorship in Stroke Medicine.
At the FCPSA 2012 congress, Dr Butcher
stressed from the outset the urgency
of rapid diagnosis in stroke/transient
ischaemic attack (TIA). The presentation
of ischaemic and haemorrhagic stroke
has complete overlap, with Dr Butcher
noting that ‘one is blind until imaging is
performed’.
Patients with focal neurological
deficits (speech issues and weakness)
undoubtedly require a scan, but so too
do those whose symptoms resolve
en
route
. This is supported by the finding
that 50% of TIA patients have evidence
of ischaemic infarction on MRI. Early
recurrent stroke is also common after a
TIA or minor stroke.
Lacunar infarcts (LACI) are classically
hypothesised to occur as a result of
lipohyalinosis, whereas the cortical
infarcts (PACI) are thought to occur
as a result of artery–artery and cardio-
embolism. Nonetheless, the mechanism
cannot be reliably determined based on
infarct pattern, making it necessary to
investigate for all possible aetiologies,
including cardio-embolism, which is most
often secondary to atrial fibrillation (AF).
‘AF is a major stroke risk factor,
equating to a five-fold increase in risk’, Dr
Butcher said. In terms of cardio-embolic
stroke, thrombi tend to be fairly large,
although they often break up. Emboli will
more often go to the left hemisphere, but
can end up in any arterial territory within
the brain. Cardio-embolic strokes tend
to be larger, and associated with greater
disability and higher mortality rates.
‘In my practice, virtually all patients
with AF require anticoagulation, as they
have suffered a TIA/stroke, putting them
at high risk for recurrence. Even patients
with lower risk-stratification scores
(CHADS) are at significant risk for stroke
and most should be anticoagulated. The
stroke risk in paroxysmal AF patients is
also just as significant.’
‘Dabigatran binds both free and
clot-bound thrombin, making it a very
powerful anticoagulant. Cardiologists note
that patients on dabigatran undergoing
percutaneous coronary intervention (PCI)
with stenting, experience fewer clots than
patients on other therapies’, he said. Bare-
metal stents are recommended for these
patients, in order to avoid exposure to
triple antithrombotic therapy for more
than one month.
Presenting the RE-LY study,
1
Dr
Butcher noted the well-balanced cohort
in each of the three arms: warfarin, and
dabigatran 110 and 150 mg bid. The
150-mg dose was clearly superior, and
so has become the default dose or dose
of choice.
‘The relative risk reduction (RRR)
in stroke and systemic emboli was 34%
while the absolute risk reduction was
0.59%. Although seemingly small, it
translates to a number needed to treat
(NNT) of 169 patients per year to avert a
cerebrovascular event. This translates into
significant numbers over the lifetime of
a patient, and even greater cost benefits
from a population health perspective’, Dr
Butcher stressed.
The amazing aspect is that these
benefits do not come with an increase
in major bleeds. ‘More importantly, most
of the improved safety related to fewer
intracranial haemorrhages. I interpret this
to mean that there is something about
warfarin that is bad for the brain. This
is likely related to knocking out all of
the vitamin K-dependent clotting factors
with warfarin therapy, which does not
occur with the novel oral anticoagulants.
The improved safety profile of dabigatran
occurred across all sites of intracranial
bleeds whether subdural, intracerebral or
subarachnoid’, Dr Butcher pointed out.
The real side effect of warfarin is
dyspepsia. ‘I use a proton pump
inhibitor with these drugs to provide
cytoprotection, particularly in the elderly.
In most patients, the dyspepsia is not
severe’, he added.
Referring to the two major arguments
related to not choosing to use these
new agents, Dr Butcher noted the most
frequently cited issues were cost and
reversibility. With regard to cost, the
Canadian experience is that the drug is
available at a cost equivalent to that of
clopidogrel.
‘When I discuss this aspect with
patients, they are often amenable to bear
the costs of these agents, which are more
beneficial for them in terms of lifestyle.
In Canada, we have had availability for
18 months without funding from the
medical aids or State and have been able
to get re-imbursement only two months
ago. Despite this, dabigatran is frequently
chosen by AF patients after discussion.’
The societal cost of stroke is self-evident
across the world.
Dr Butcher then presented a number of
cases of warfarin-associated intracranial
haemorrhages,
2
noting that they expand
and are not easy to reverse, even using
prothrombin complex concentrates
(PCCs). ‘So, if warfarin was readily
reversible, without mortality or morbidity,
the sceptics would have a better argument
about the current lack of a dabigatran
antidote’, he said.
‘We do have a plan for patients
with smaller haematomas on the new
anticoagulants. That is to use a five-factor
PCC which is a combination of various
coagulation factors, such as factor II, VIIa
and X, with activated charcoal.’
3
With regard to aspects such as
myocardial infarction (MI) with these
new agents, Dr Butcher noted that he
prescribes dabigatran to prevent ischaemic
stroke and not MI. ‘It is a spurious
argument not to use dabigatran due to
the risk of ischaemic heart disease, as
most cardiologists have not accepted the
‘Thrombin time is directly related to dabi-
gatran concentration, which is incredibly
useful when considering thrombolysis in a
patient taking dabigatran’
– Ken Butcher
‘Using the 110-mg dabigatran dose
is viable as you have not lost efficacy
compared to warfarin. Although the
150-mg dose is preferred in younger
patients with normal renal function, I
would still use it in situations where this is
the only dosage available’
– Ken Butcher
‘It is in the company’s interest to ensure
the drug is as affordable as possible so
that it can be used widely’
– Kevin Ho,
medical director
