CARDIOVASCULAR JOURNAL OF AFRICA • Vol 22, No 1, January/February 2011
50
AFRICA
Drug Trends in Cardiology
South African experts comment on FDA approval of dabigatran in
atrial fibrillation
The US Food and Drug Administration
(FDA) Cardiovascular and Renal Drugs
Advisory Committee voted 9 to 0 in favour
of recommending dabigatran etexilate, an
oral direct thrombin inhibitor for stroke
prevention in patients with non-valvular
atrial fibrillation (AF).
The FDA approved the standard dose of
150mg bid (as also submitted byBoehringer
Ingelheim in the European Union) without
dose adjustments for tested p-GP inhibitors
or for moderately renal-impaired patients.
No approval was given for the 110-mg
strength; the justification seems to be that
FDA felt the evidence was better for the
150-mg dose. However, the approval of
the 75-mg strength for patients with severe
renal impairment (15–30 ml/min) was driv-
en by the FDA, based on criteria modelling.
Boehringer Ingelheim (BI) SA
commented that the omission of the
110-mg dose came as a surprise and BI
strongly supports the market need for both
doses to be made available so physicians
will be able to tailor therapy.
Interestingly, the Canadian health
authority has approved dabigatran for the
prevention of stroke and systemic embo-
lism in patients with atrial fibrillation
in whom anticoagulation is appropriate,
marking the second approval of this new
oral anticoagulant following the recent
marketing authorisation by the FDA.
The Health Canada approval makes
dabigatran etexilate available to AF
patients in Canada in whom anticoagula-
tion is appropriate, with the flexibility of
two dosing regimens. A 150-mg bid dose
is approved for the prevention of stroke and
systemic embolism in patients with AF, and
a 110-mg bid dose is specifically recom-
mended for patients aged 80 years or older
and is also available for patients at higher
risk of bleeding.
Comment from Dr Eric Klug, Sunninghill
Hospital, Johannesburg
This is an exciting announcement; for
the first time, an alternative to warfarin/
coumadin in the anti-thrombotic manage-
ment of atrial fibrillation. It was a surprise
that approval did not include the 110-mg
dose. The FDA clearly felt that the 150-mg
dose found to be superior to warfarin
should be used but added approval for the
necessary lower safe dose (75 mg) for renal
dysfunction.
Comment from Prof Alan Bryer, Head:
Division of Neurology and Stroke Unit,
Groote Schuur Hospital and University
of Cape Town; Chairman: South African
Stroke Society
The advent of the direct thrombin antago-
nists such as dabigatran represents a major
breakthrough in the prevention of stroke
in patients with atrial fibrillation. In most
parts of the world, the standard treatment
for prevention of stroke in patients with
atrial fibrillation is warfarin. However,
treatment with warfarin is associated with
a number of disadvantages, including an
unpredictable response with a narrow ther-
apeutic window that requires routine anti-
coagulation monitoring and often, frequent
dose adjustments.
Warfarin also has a slow onset of action
and takes about a week to reach an optimal
INR, and similarly has a slow offset of
action. A significant percentage of patients
do not achieve optimal anti-coagulation
within the ideal therapeutic window and
many patients discontinue therapy. There
are also numerous drug interactions with
warfarin therapy.
Dabigatran, which has been approved
by the FDA for secondary prevention of
stroke in patients with atrial fibrillation,
has a rapid onset of action and patients
are fully anti-coagulated within 36 hours.
Similarly, it has a rapid offset of action with
normal coagulation after 48 hours follow-
ing discontinuation. It has predictable anti-
coagulant effects independent of factors
such as age, body weight or race and has a
low interaction rate with other drugs. There
is no requirement to monitor coagulation,
which is a major advantage for patients
who have to take this drug.
The results of the much-awaited RE-LY
trial have recently been published. In a
population of patients with atrial fibril-
lation and a risk of stroke, the mean
observation time in this study was two
years (18 113 patients randomly assigned
to fixed doses of dabigatran or adjusted-
dose warfarin). For the primary endpoint
of stroke (ischaemic and haemorrhagic
stroke) and systemic embolism, the higher
dose of dabigatran (150 mg twice daily)
demonstrated superior efficacy and a simi-
lar rate of major bleeds compared to warfa-
rin. The lower dose of dabigatran (110 mg
twice daily) was shown to cause less bleed-
ing and was as effective as warfarin.
Prof Hans-Christoph Diener, a member
of the steering committee of this trial,
presented data from the trial at the World
Stroke Congress in Seoul on 14 October
2010. A sub-study of those patients who
had had a prior transient ischaemic attack
(TIA) or stroke before being randomised
in the RE-LY trial were analysed and this
sample represented 20% of the overall
population of the study.
The results in this sub-group were iden-
tical to those of the overall trial. A compli-
cation that is most feared in patients receiv-
ing anti-coagulation is cerebral bleeds and
parenchymal haemorrhage and this was
reduced in the two groups of patients taking
either dose of dabigatran, compared with
those on warfarin who had had a prior TIA
or stroke before randomisation (consid-
ered secondary prevention). Although the
group of patients with prior TIA or stroke
represented only 20% of the total sample of
18 113 patients, both doses of dabigatran
were shown to be non-inferior to warfarin
but with less major haemorrhage.
These interesting results will no doubt
be explored in further studies, but the intro-
duction of the direct thrombin antagonists
are undoubtedly the beginning of a new era
in stroke prevention in patients with atrial
fibrillation. However, in South Africa and
other developing countries, where more
than 80% of the country’s population is
dependent on the public sector for health-
care, the cost of dabigatran and other
similar drugs in development is likely to
determine whether or not these drugs will
replace warfarin in the prevention of stroke
in patients with atrial fibrillation.
E Klug, A Bryer, J Aalbers
