CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 4, July/August 2014
194
AFRICA
Drug Trends in Cardiology
Clearing hurdles in anticoagulation therapy
Prof Sylvia Haas, emeritus professor of
Medicine, Technical University Munich,
Germany
The hurdles that need to be cleared
when initiating therapy with the novel
anticoagulants (NOACs) are the following,
says Prof Sylvia Haas:
•
‘The different dosing regimens, depend-
ing on whether these agents are being
used for venous thromboembolism
(VTE) treatment or stroke prevention.
•
The practical usage of them.
•
The management of bleeding associated
with their use.’
She was speaking at a meeting held in
Johannesburg in late July as a guest of Bayer
Healthcare.
What makes the NOACs different from
earlier anticoagulant therapies? They are
administered orally (unlike the heparins),
have a wide therapeutic window (unlike
warfarin), fast onset/offset of action, carry
a low risk of food/drug interactions and
have a predictable mode of action. In
addition, they require no monitoring and
are administered in a fixed dose. ‘That we
no longer need to bridge patients is a major
advantage’, she said.
The NOACs’ many indications and
different dosing regimens can be both
an advantage and a source of confusion.
Prof Haas feels that the former aspect
far outweighs the latter. ‘We just need
to know what is right for each patient,
taking into account the pharmacology of
the agent and the pathophysiology of the
underlying disease.’
She cautioned that it’s also important
to bear in mind the differences between
arterial clots (associated with acute coro-
nary syndromes) and venous clots [associ-
ated with VTE (deep-vein thrombosis and
pulmonary embolism) and atrial fibrilla-
tion]. The former are characterised by high
shear rates, the latter by low shear rates.
Conventional VTE therapy entails over-
lapping parenteral anticoagulation [with
low-molecular weight heparin (LMWH) or
fondaparinux] with warfarin in the initial
phase of treatment, before warfarin alone
is used for long-term maintenance after an
INR value of at least 2.0 has been reached.
The development of NOACs for VTE
treatment raises the question of whether a
NOAC should replace both of the conven-
tional agents or just warfarin.
Prof Haas mentioned that history has
shown pitfalls with the former option and
therefore some manufacturers developed
their compounds only to replace warfarin,
i.e. the treatment with two anticoagulants
(dual-drug approach) remains in place.
However, rivaroxaban has been success-
fully developed to replace both the initial
therapeutic doses of parenteral anticoagu-
lation and warfarin for secondary preven-
tion and long-term anticoagulation.
The phase II dose-finding ODIXa-DVT
study,
1
which evaluated rivaroxaban versus
enoxaparin and warfarin for the treatment
of proximal deep-vein thrombosis, found
rivaroxaban to be comparable to standard
anticoagulation therapy in respect of efficacy
(thrombus regression) and safety (the
incidence of major bleeding up to two days
after last administration of the study drug).
A second phase II study
2
also showed
different doses of rivaroxaban to be at
least as good as standard care, paving the
way for the phase III EINSTEIN-DVT
and EINSTEIN-PE studies, which used the
so-called single-drug approach consisting
of intensified anticoagulation with 15 mg
rivaroxaban twice a day for three weeks,
followed by 20 mg once daily for long-term
anticoagulation.
In these phase III studies the efficacy
curves ran in parallel for rivaroxaban
versus enoxaparin and warfarin, showing
non-inferiority. However, major bleeding
was significantly lower in those receiving
rivaroxaban versus those receiving
standard care.
While the NOACs undoubtedly add value,
itisimportanttobeawareof othermedications
a patient may be taking. Rivaroxaban, for
example, is not recommended with HIV
protease inhibitors (e.g. ritonavir) a third-line
treatment in HIV-positive patients or azole
antimycotics. All NOACs should also be used
with caution in patients taking other drugs
that affect haemostasis, such as NSAIDs,
aspirin or platelet-aggregation inhibitors.
Standard atrial fibrillation doses should not
be used in patients receiving dual antiplatelet
therapy, for example, after coronary stenting.
Converting patients from warfarin to a
NOAC needs careful consideration: ‘Stop
the warfarin, continue measuring the INR
and introduce the new agent when the INR
value is approaching the lower end of the
recommended range of 2.0’, said Prof Haas.
Switching from LMWH to a NOAC (and
vice versa) is easy, i.e. introduce the NOAC or
LMWH, respectively, when the next dose of
the last anticoagulant would have been given.
The EINSTEIN studies showed that
rivaroxaban’s safety and efficacy parameters
are maintained, even in ‘fragile’ patients
[older than 75 years, with reduced creatinine
clearance (
<
50 ml/min) and/or body weight
≤ 50 kg). It also holds true in cancer patients.
In patients about to undergo surgery,
in general the NOAC should be stopped
at least 48 hours prior to the procedure
in patients at high risk of bleeding and
at least 24 hours prior in patients with
lower bleeding risk, however, more time
might be needed with dabigatran should a
patient’s renal clearance be poor. It should
be reintroduced once haemostasis has been
achieved, at least eight hours after surgery.
3
The procedure for reversing severe
bleeding is currently the same as for
warfarin. ‘The race for specific antidotes
is, however, gaining momentum’, observed
Prof Haas. ‘Three types of antidote are
currently in development but they remain a
work in progress.’
Concluding, she underscored that
the NOACs are effective and safe, and
more convenient to use than vitamin K
antagonists. All carry a bleeding risk,
however, so responsible use is critical. This
entails a careful assessment of benefits
versus risks, as well as knowledge of the
chosen drug’s pharmacology, switching
procedures and bleeding management.
P Wagenaar
1. Agnelli G,
et al
.
Circulation
2007;
116
:
180–187.
2. Buller HR,
et al
.
Blood
2008;
112
: 2242–2247.
3. Heidbuchel H,
et al
.
Eur Heart J
2013;
34
:
2094–2106.
