CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 1, January/February 2010
56
AFRICA
pointed out that the higher rates of
bleeding seen in these studies needed
to be viewed in the context of the trial
programme, including the actual surgi-
cal site in its evaluation.) The find-
ings on major VTE versus total VTE
mirrored each other, with both doses of
dabigatran showing non-inferiority
vis-
a-vis
enoxaparin.
8
There are two distinct phases to
consider in the treatment of VTE
9
–
managing acute events and prevent-
ing secondary events. The RE-COVER
study of acute symptomatic VTE,
the first of four treatment studies,
randomised 2 500 patients to standard
care with warfarin or to dabigatran. The
question this study addressed was: ‘Can
we replace the warfarin element with
dabigatran while maintaining the initial
parenteral phase with a low-molecular
weight heparin’, Prof Kakkar noted.
10
‘The results showed highly signifi-
cant non-inferiority of dabigatran in
the treatment of VTE after initial use of
low-molecular weight heparin. Major
bleeding was not significantly lower
with dabigatran and all bleeding was
significantly lower. This means that
beyond the benefits we’ve seen with
prophylaxis, dabigatran also has the
potential to replace warfarin in the
treatment of VTE. Warfarin’s narrow
therapeutic window has always been
problematic, in that if you fall outside
it, you disadvantage the patient.’
A long-acting agent like dabigatran
also offers the potential for a better
option for stroke prevention. This strong
rationale for using a thrombin inhibitor
for stroke prevention underpinned the
RE-LY study, which looked at patients
with atrial fibrillation plus one stroke
risk factor. Two doses of dabigatran
(150 and 110 mg) were evaluated rela-
tive to warfarin.
‘RE-LY delivered striking results’,
Prof Kakkar continued. ‘It was designed
as a non-inferiority trial and while the
lower dose of dabigatran did indeed
emerge as non-inferior to warfarin when
it came to preventing stroke, the higher
dose was found to be superior to warfa-
rin for stroke prevention. In addition,
although one would intuitively expect
a novel anticoagulant to cause more
bleeding than warfarin, it turned out
that there was no difference in bleeding
rates for warfarin and the higher dose
of dabigatran, while the lower dose was
associated with a lower incidence of
bleeding.’ He added the qualifier that
while there was less major bleeding
overall with dabigatran, the higher dose
was, however, associated with increased
gastrointestinal bleeding specifically.
Dabigatran also had a striking impact
on haemorrhagic stroke. Both doses
were associated with a lower incidence
of intracranial haemorrhage. ‘This is
a very positive finding for the oral
agent, suggesting we can overcome
the risk of intracranial haemorrhage
associated with warfarin’, noted Prof
Kakkar. Balancing this, however, was
a higher risk of myocardial infarction
with dabigatran, which he described
as ‘difficult to understand’. Dabigatran
also carried a higher risk for dyspepsia.
‘However, in terms of net clinical bene-
fit, the lower dose of dabigatran was
equal to warfarin and the higher dose
was superior. Warfarin used to be our
gold standard – but the thrombin inhibi-
tor appears to be an improvement.’
Turning to acute coronary syndrome,
Prof Kakkar observed, ‘we need to
do better in reducing recurrent events
(stroke, myocardial infarction, angina)
at day 30. Currently there are only
phase II data on dabigatran in this
context, but they validate that targeting
a thrombin inhibitor might work.’
Summing up, Prof Kakkar stated
that extensive clinical evaluation has
validated the benefits of thrombin inhi-
bition as well as its safety. ‘It may be
too early to call dabigatran “the ulti-
mate coagulant”, but there’s no ques-
tion that it will be very useful to us. In
addition, all the ongoing clinical trials
will provide us with study subjects
we didn’t have before, allowing us to
answer various questions that will ulti-
mately improve clinical outcomes for
our patients.’
Stop press
Xarelto 10
®
has now been registered in
South Africa. Xarelto 10 film-coated
tablets are indicated for the prevention
of VTE in patients undergoing major
orthopaedic surgery of the lower limbs.
For more information contact Sandhya
Misra at Bayer Schering Pharma on 011
921-5021.
Kakkar AK, Brenner B, Dahl OE,
1.
et al
.
Extended duration rivaroxalan versus short-
term enoxaparin for the prevention of venous
thrombo-embolism after total hip arthro-
plasty: double-blind, randomised controlled
trial.
Lancet
2008;
372
: 31–39.
Eriksson BI, Boris LC, Friedman RJ,
2.
et al
.
Rivaroxaban versus enoxaparin for thrombo-
prophylaxis after hip arthroplasty.
N Eng J
Med
2008;
358
: 2765–2775.
Lassen MR, Ageno W, Borris LC,
3.
et al
.
Rivaroxaban versus enoxaparin for thrombo-
prophylaxis after total knee arthroplasty.
N
Engl J Med
2008;
358
: 2776–2786.
Turpie AG, Bauer KA, Davidson B,
4.
et al
.
Once daily oral rivaroxaban compared with
subcutaneous enoxaparin every 12 hours for
thromboprophylaxis after total knee replace-
ment. RECORD 4.
ASH Annual Meeting
Abstracts
2008;
112
: 35.
Eriksson BI, Dahl OE, Rosencher N,
5.
et al
.
Dabigatran etexilate versus enoxaparin for
prevention of venous thromboembolism after
total hip replacement: a randomised, double-
blind non-inferiority trial.
Lancet
2007;
370
:
949–956.
Eriksson BI, Dahl OE, van Dijk CN,
6.
et al
. A
new oral anticoagulant dabigatran etexilate,
is effective and safe in preventing venous
thromboembolism after total knee replace-
ment surgery (the RE-MODEL trial).
Blood
2006;
108
: Abstract 573.
The REMOBILIZE Writing Committee
7.
2008. The oral thrombin inhibitor, dabigatran
etexilate versus the north American enoxa-
parin regimen for the prevention of venous
thromboembolism after knee arthroplasty
surgery. Doi:10.1016/j.arth.2008.01.132.
Caprini JA, Hwang E, Hantel S,
8.
et al
. The
oral direct thrombin inhibitor, dabigatran
etexilate is effective and safe for prevention
of major venous thromboembolism follow-
ing major orthopaedic surgery.
J Thromb
Haemost
2007;
5
. Abstract O-W-050.
Schulam S, Kearon C, Kakkar AK, Mismetti
9.
P, Schellong S, Eriksson H,
et al
. Dabigatran
versus warfarin in the treatment of acute
venous thromboembolism.
N Engl J Med
2009;
361
(24): 2342–2352.
Ezekowitz MD, Connolly S, Parekh A, Reilly
10.
PA, Varrone J,
et al
. Rationale and design of
RE-LY; randomised evaluation of long-term
anticoagulant therapy, warfarin, compared
with dabigatran.
Am Heart J
2009;
157
(5):
805–810.
