CARDIOVASCULAR JOURNAL OF AFRICA • Vol 22, No 2, March/April 2011
AFRICA
105
Stroke prevention in atrial fibrillation
Prof Michael Ezekowitz, Thomas
Jefferson Medical School, Wynnewood,
Pennsylvania, USA
When it comes to the prevention of throm-
bo-embolism, the entire picture is chang-
ing, thanks to the advent of new agents
such as the direct thrombin inhibitors,
notably dabigatran. ‘They are going to
have a huge impact and in future we will
see less use of warfarin and antiplatelet
agents such as aspirin and clopidogrel’,
says Prof Michael Ezekowitz. He was in
South Africa recently at the invitation of
Boehringer Ingelheim.
Dabigatran is the first of these novel
agents to be approved and Prof Ezekowitz
was one of the principal investigators in
the RE-LY study, which evaluated its effi-
cacy and safety relative to warfarin.
It is a common consensus that anti-
coagulation in atrial fibrillation is the
most preventive measure in cardiovascu-
lar medicine. Various studies have shown
consistently that warfarin reduces stroke
by around 75% in these patients. ‘And
yet physicians’ prescribing habits are
often more influenced by anticoagula-
tion’s risks, such as intracerebral bleed-
ing, rather than its benefits’, continues
Prof Ezekowitz. ‘It is well known that if a
physician encounters an anticoagulation-
related adverse event, he/she is much less
likely to prescribe warfarin again in the
next six months.’
The RE-LY trial compared dabigatran
to warfarin and one of its key findings
was a dramatic reduction in intracerebral
bleeding with the novel agent. ‘The trial
was very successful and the challenge
we face now is to translate its results into
clinical practice. It’s therefore important
to understand the pharmacology of dabi-
gatran so that we can match each clinical
situation with the drug, thus ensuring the
best decision.’
The prodrug dabigatran etexilate is
converted completely to active dabi-
gatran, ensuring that patients are thera-
peutically anticoagulated within an hour.
It is noteworthy that the P450 system,
which accounts for much of warfarin’s
variability, is not involved here.
Dabigatran reaches peak plasma
concentration at two hours. ‘It’s a twice-
daily oral treatment that needs to be taken
in the morning with breakfast and in
the evening with dinner’, observes Prof
Ezekowitz. ‘We as physicians need to
make patients aware of their responsibil-
ity to be compliant.’
In a study population of over 18 000
patients, dabigatran was shown to be
highly predictable and no monitoring is
required. Drug–drug interactions are few
and only rifampin is contraindicated, as
it increases the clearance of dabigatran,
resulting in sub-therapeutic levels.
‘Because 80% of dabigatran is elimi-
nated by the kidneys, it is important
to know patients’ renal status before
prescribing.’ Prof Ezekowitz underscores
that this requires measurement of creati-
nine clearance, and not just serum creati-
nine. ‘Dabigatran should only be used
when the creatinine clearance is above 30
ml/min’, he says.
The RE-LY study
The trial evaluated two doses of dabi-
gatran (110 and 150 mg) against warfa-
rin, and its primary objective was to
show non-inferiority of the new agent. ‘A
major achievement was getting the dose
right to ensure the optimal antithrombotic
effect with minimal bleeding’, says Prof
Ezekowitz.
Fifty per cent of patients were warfarin
naïve as this allowed for a fairer compari-
son of the two treatments. Those on estab-
lished warfarin treatment were potentially
biased by their having been shown to be
able to tolerate warfarin over time.
The trial produced some surpris-
ing findings. ‘While the 110-mg dose
achieved the objective of being non-infe-
rior to warfarin, the 150-mg dose was
shown to be superior to warfarin by 35%.
This efficacy was an extremely consistent
finding. Both doses were also shown to
be safer than warfarin in respect of life-
threatening bleeds – 33% for the lower
dose and 20% for the higher dose of
dabigatran.’
Another unexpected outcome occurred
in respect of haemorrhagic stroke. ‘While
we’re not yet sure of the mechanism via
which this occurs, both doses of dabi-
gatran reduced the incidence of haem-
orrhagic stroke dramatically. This find-
ing was highly statistically significant
and consistent across all subgroups. This
has very important implications for our
prescribing practice, which is currently
driven by fear of haemorrhage. We need
a change of mindset, as with dabigatran
we can actually prevent a large number
of events.’
All-cause and vascular mortality were
significantly reduced with the 150-mg
dose, while the 110-mg dose achieved
non-inferiority. The US Food and Drug
Administration have therefore approved
the twice-daily 150-mg dose as the opti-
mal one. Prof Ezekowitz believes, howev-
er, that there are patients for whom the
110-mg formulation is the better choice,
notably those at high risk of stroke and
systemic embolism. These data have yet
to be published, however.
Prof Ezekowitz cautions nonetheless
that dabigatran is not a perfect drug.
Both doses were associated with a higher
occurrence of dyspepsia than warfarin,
as well as a greater likelihood of gastro-
intestinal bleeding. That said that these
adverse events appeared to be more likely
in elderly individuals with compromised
renal function. Major gastrointestinal
bleeding was more common in patients
over 75 years old, making the case that
the lower dose might also be preferable in
these patients.
In summary, Prof Ezekowitz empha-
sised that ‘the 150-mg dose is superior
or at least non-inferior across all efficacy
and safety outcomes, with the exception
of major gastrointestinal bleeding, and the
110-mg dose of dabigatran is non-inferior
to well-controlled warfarin in terms of
efficacy, and superior in terms of safety.’
He concluded that when looking at the
control of warfarin, if you analysed the
results for different times in the thera-
peutic range, dabigatran was superior to
poorly controlled warfarin across every
parameter.
P Wagenaar, Gauteng correspondent
