CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 3, May/June 2010
AFRICA
173
Boehringer launches first direct thrombin inhibitor:
dabigatran (Pradaxa
®
)
Dabigatran, an oral reversible direct
thrombin inhibitor, already available in
Europe and the United Kingdom, has
been licensed for anti-coagulant use in
orthopaedic hip and knee surgery in South
Africa. At the launch of this novel anti-
coagulant, Prof Simon Frostick, professor
of orthopaedics at Liverpool University
pointed out that experience from clini-
cal trials and in-practice experience has
shown dabigatran to be a safe and effec-
tive agent in deep-vein thrombosis (DVT)
prophylaxis.
Last year at the European Society of
Cardiology (ESC) congress, dabigatran
etexilate was introduced to cardiologists
around the world in the RELY trial.
1
This
trial in 18 113 patients with atrial fibril-
lation showed that dabigatran at doses of
110 or 150 mg twice daily was as effec-
tive as warfarin in reducing stroke and
systemic embolism. Major bleeding rates
were lower than warfarin using the lower
dose, and similar on the higher dose.
The rate of haemorrhagic stroke was less
with dabigatran than in patients receiving
warfarin.
Public concern regarding ‘clot
deaths’ in hospital have led to calls in
the United Kingdom and South Africa
for effective prophylaxis to be used in
all at-risk patients. ‘Risk stratification
protocols developed by the South African
Society for Thrombosis and Haemostasis
(SASTH) are now being used in all
Mediclinic and Netcare private hospi-
tals, and also in the state sector’, Prof
Mervyn Mer, Department of Medicine
at the Witwatersrand University noted.
‘In my view, a death from a venous
thrombo-embolic (VTE) event follow-
ing surgery or a hospital stay, where
no appropriate thrombo-prophylaxis has
been given, is entirely unacceptable’, Prof
Mer declared.
Traditionally, new anticoagulant
modalities are evaluated in the orthopae-
dic arena, as total knee or hip surgery
carries a high risk of VTE and its fatal
consequence, pulmonary embolism if
anti-coagulation measures are not applied
effectively and for a considerable time
post surgery. ‘Risk of bleeding is always
at the top of the list of orthopaedic
concerns when evaluating new and exist-
ing anti-coagulants’, Prof Frostick noted.
The prevalence of VTE is difficult
to pinpoint as it is often asymptomatic,
undiagnosed and unrecognised at death
and post mortems are infrequently done.
Using an epidemiological model, one
study
1
estimated the number of VTE
deaths in major countries in Europe to
be in the order of 370 000. Almost three-
quarters of these deaths were hospital
acquired; very few actually occurred in
the orthopaedic arena, as in this disci-
pline, the focused use of anti-coagulants
has reduced the number of VTE deaths.
In the United States, a study
2
on the
characteristics of patients operated on
between 1990 and 2004 for hip or knee
orthroplasty showed an in-hospital mortal-
ity rate of 0.35%. Pulmonary embolism
was the most frequent adverse event.
Middle-aged women undergoing
knee or hip replacement are particularly
vulnerable and a United Kingdom study
has found that one in 45 women admit-
ted between 1996 and 2001 for surgery
was re-admitted to hospital with venous
thrombo-embolism during the 12 weeks
after surgery.
3
While in the 1990s it was possible to
argue that prophylaxis with anti-coag-
ulants (LMWH, unfractionated heparin
or warfarin) did not reduce symptomatic
thrombo-embolic events,
4
the advent of
new agents has led to a body of evidence
that VTEs are preventable and many
guidelines are now available for the use
of agents in both medical and surgical
patients.
5
Racial variations exist: a recent review
has noted African-American patients have
a significantly higher rate of incident
VTE leading to pulmonary embolism.
6
There are no prevalence data on DVT in
African patients, but it is clear that VTE is
not solely a caucasian phenomenon.
‘Aspirin is ineffective in VTE prophy-
laxis and with new designer-molecule
anti-coagulants such as dabigatran, which
target specific events in the coagulation
cascade, we do not need to use the older
sledge hammer-like anticoagulants’, Prof
Frostick pointed out. ‘When selecting an
anti-coagulant, bleeding rates are a major
factor; but tolerability, efficacy, simplicity
and flexibility are valuable features of the
newer anti-coagulants’, he stressed.
‘Dabigatran is effective in prevent-
ing VTE events, with similar bleeding
rates to enoxaparin in both hip and knee
surgery.
7,8
Its time-to-peak levels is six
hours following surgery, due to surgery-
induced delay, which allows for clot-
ting around the wound site to be more
effective. Normally a half dose is given
initially, either 75/110 mg on the evening
of surgery’, Prof Frostick pointed out.
The trials with dabigatran were
designed as non-inferiority trials with
preset margins. In the RE-MODEL trial,
dabigatran 150/220 mg was compared
to subcutaneous enoxaparin 40 mg once
daily for six to 10 days, starting on the
evening before surgery. Patients were
followed up for three months. Both doses
of dabigatran were non-inferior to enoxa-
parin on the basis of the pre-specified
non-inferiority criteria. The incidence of
major bleeding did not differ significantly
between the three groups (dabigatran 150,
200 mg and enoxaparin 40 mg). There
were no significant differences in the inci-
dence of liver enzyme elevation or acute
coronary events.
‘It should be noted that in high-risk
patients undergoing total knee replace-
ment, a reasonable approach would be
to continue prophylaxis for 35 days; a
similar period to that recommended for
hip replacement by the American College
of Chest Physicians (ACCP) guidelines
and the UK NICE guidelines 2010’, Prof
Frostick added.
‘When comparing rivaroxaban and
dabigatran, independent analyses suggest
a superior action of rivaroxaban to enoxa-
parin at the cost of an increased bleeding
risk. The rivaroxaban data on major bleed-
ing events is not truly representative of
the actual bleeding rates as this category
of major bleeds did not include site bleed-
ing data unless it required re-operation’,
Dr Frostick pointed out. ‘In the trials of
dabigatran, site bleeding was included
in the definition of major bleeds. With
dabigatran in both knee and hip surgery,
most of the major bleeds occurred at the
surgical site; for example, in RENOVATE,
91% of the major bleeds were at the surgi-
cal site while some 46% (150-mg dose)
and 56% (220-mg dose) of major bleeds
occurred before drug administration.’
continued on p.174
