CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 6, November/December 2010
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AFRICA
is however common, but seems to be self-limiting and results in
less than 1% of patients discontinuing the drug. New reversible
P2y(12) receptor inhibitors such as elinogrel and cangrelor are
currently in clinical development trials.
‘Clearly, the “one size fits all” and “one mechanism fits
all” usage of anti-platelet agents reflects limitations of current
evidence and of our lack of understanding. This will change in
the near future’, Dr Klug concluded.
Anti-coagulation in atrial fibrillation
Prof Lord Kakkar, London, UK
‘Anti-coagulation to prevent thrombo-embolic stroke is vital,
as about one-sixth of all strokes are due to pre-existing atrial
fibrillation’, Prof Kakkar stressed at the outset of his presenta-
tion. While his talk concentrated on the role of anti-coagulation
to prevent thrombo-embolic stroke, Prof Kakkar noted that
co-morbid conditions that heighten the potential risk of stroke
in atrial fibrillation patients, such as hypertension, heart failure,
arterial disease and diabetes, also require treatment with the
increasingly effective therapies that are now available.
Warfarin became the standard of care from the early studies of
vitamin K antagonists, which compared warfarin use to placebo
and showed a 70% reduction in the frequency and morbidity
of strokes. ‘Warfarin is also better than aspirin in preventing
thrombo-embolic stroke; while full-dose warfarin, reaching INR
targets of between 2 and 4, is better than low-dose warfarin’, Prof
Kakkar noted. ‘Despite warfarin’s known benefits, if we look at
the atrial fibrillation (AF) studies in some 11 000 patients in the
USA from either clinical trials or registries, only 50 to 60% of
patients are treated with this agent. So large numbers of patients
who could derive benefit are not receiving medication to reduce
their stroke risk.’
With regard to novel anti-coagulant drugs, a number are
under development, and target different factors in the coagula-
tion cascade, such as activated factor X or activated factor II
(thrombin). As there are limited data from prospective phase III
randomised clinical trials of these new agents, Kakkar concen-
trated on available results of rivaroxaban and the evidence for
dabigatran, an orally active direct inhibitor of thrombin.
The ROCKET study of rivaroxaban in atrial fibrillation has
been presented at the American Heart Association meeting. It
is a large study of 14 000 patients randomised to receive either
warfarin to a target INR of 2.5 mg or rivaroxaban 20 mg once
daily or 15 mg/day for patients with moderate renal impairment.
It showed non-inferiority of rivaroxaban to warfarin in AF.
Apixaban, a second orally active Xa inhibitor is being stud-
ied in the ARISTOTLE study in AF, with dosages of 5 mg
bid apixaban versus warfarin. The results of the AVERROES
study on patients with atrial fibrillation who are unsuitable for
a vitamin K antagonist was announced at the European Society
of Cardiology in September 2010. Apixaban was shown to be
significantly better than aspirin in reducing the frequency of
stroke or systemic embolic events in this study. ‘This is certainly
interesting data as there was no significant increase in major
bleeding complications with apixaban versus aspirin’, Prof
Kakkar pointed out. Recently an ACS trial with apixiban added
to aspirin has been stopped early because of increased bleeding
in the combination arm compared to aspirin alone.
Results of the RE-LY study of two doses of dabigatran (110
or 150 mg bid) compared to warfarin dosages aimed at an INR
of 2.5 in at-risk atrial fibrillation patients have been published.
‘These results are quite striking, with the lower dose of dabi-
gatran being equal to warfarin (1.53 event rate vs 1.69) in reduc-
ing the rate of stroke and systemic embolic events. The 150-mg
dabigatran dose BD not only achieved non-inferiority, but was
superior to warfarin in reducing events. Both doses of dabigatran
were associated with a lower incidence of haemorrhagic stroke
than seen with warfarin. This is certainly the most striking of the
positive results for dabigatran, as this is a most feared bleeding
event’, Dr Kakkar stressed.
Importantly, dabigatran performed well throughout the two-
and-a-half years of follow up across all INR ranges of warfarin
treatment and regardless of whether patients were exposed previ-
ously to vitamin K antagonists or were vitamin K naïve.
Rivaroxaban – the latest Einstein results
Prof Harry Buller, Amsterdam, Netherlands
The results of several Einstein studies provide the clinician
with some valuable insights into the utility of rivaroxaban as
a treatment option for long-term anticoagulation. Prof Buller
reviewed these findings and their implications at the Southern
African Society of Thrombosis and Haemostasis conference on
31 October 2010.
In the initial treatment of venous thrombo-embolism (VTE),
there are a number of treatment options, of which low-molecular-
weight heparin is the most frequently used. However, vitamin K
antagonists have been the only choice for extended treatment,
i.e. three to six months or longer. The question of how long
to continue treatment is now being reconsidered and there is a
strong move in the USA and Canada towards continuing treat-
ment indefinitely. ‘Our understanding of anticoagulation at the
molecular level also means that the number of anticoagulants
available to us has increased dramatically in recent years – and
there are many more still in development’, said Prof Buller. He
cautioned against viewing the new drugs by class, underscoring
that each needed to be viewed individually.
Three Einstein studies recently evaluated rivaroxaban rela-
tive to enoxaparin followed by a vitamin K antagonist, with a
view to showing non-inferiority. The Einstein DVT (deep-vein
thrombosis) and PE (pulmonary embolism) studies were 30-day
observational studies that evaluated rivaroxaban (15 mg twice
daily or 20 mg once daily). The Einstein Extension study looked
at patients with combined DVT and PE.
The Einstein DVT study’s main efficacy measure was the
prevention of recurrences, while safety was assessed in terms of
major and clinically relevant non-major bleeding. The findings
in respect of first symptomatic recurrence of VTE were 2.1% for
rivaroxaban and 3% for enoxaparin plus warfarin. For recurrent
DVT, they were 0.8% for rivaroxaban and 1.6% for enoxapa-
rin plus warfarin. ‘There was therefore strong evidence that
rivaroxaban – a single drug given in a fixed dose – is at least as
good as the comparator’, continued Prof Buller. ‘When primary
efficacy outcomes were evaluated by subgroup, there was also a
tendency in favour of rivaroxaban, with variables such as gender,
‘Evidence-based medicine provides the structure; in the
care of the individual patient clinical insight and judgement
are always paramount’
– Dr Eric Klug
