CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 5, June 2012
AFRICA
299
EINSTEIN-PE study results, with South African expert comment
Rivaroxaban has been shown to be as
effective as initial and long-term treatment
with enoxaparin and warfarin for pulmonary
embolism (PE), with a potentially improved
risk profile benefit.
1
The results of the
Einstein-PE study were announced at the
recent American College of Cardiology
meeting in Chicago and simultaneously
published in the March issue of
New
England Journal of Medicine
2012.
Commenting on the study results, Dr
Harry Buller, Academic Medical Centre,
Amsterdam pointed out that in the
overall EINSTEIN-DVT and EINSTEIN-
PE programme of 10 000 patients, there
was a very convincing 50% lower rate
of major bleeding, particularly intra-
cranial haemorrhage and retroperitoneal
bleeds with rivaroxaban compared with
the difficult-to-manage warfarin standard
therapy. ‘One of the patient groups who
particularly benefited with regard to major
bleeding with rivaroxaban was those over 75
years of age’, Dr Buller noted.
The EINSTEIN-PE study was been
heralded as a landmark study in the
field of pulmonary embolism and marks
a turning point in its management. It is
the largest-ever study of PE, recruiting
4 833 patients from 36 countries, including
South Africa.
Designed as a non-inferiority study, oral
rivaroxaban was given as 15 mg bid for
three weeks, followed by 20 mg daily. This
was compared to the standard treatment
of subcutaneous injections for five to 10
days with a low-molecular weight heparin
(LMWH) and an oral vitamin K antagonist
(warfarin) for the prevention of recurrent
thromboembolism.
‘Rivaroxaban was given as monotherapy,
which was a very brave step and it is the first
study to really bite the bullet with regard
to its challenge of conventional LMWH
therapy’, Dr Buller said. Rivaroxaban, an
oral factor Xa inhibitor, has already been
shown in phase III trials to be as effective
as standard anticoagulant therapy for the
treatment of deep-vein thrombosis and
stroke prevention in atrial fibrillation and
is currently registered in South Africa for
the prevention of venous thromboembolism
in patients undergoing major orthopaedic
surgery of the lower limbs.
The EINSTEIN-PE study recruited a
broad spectrum of patients with PE with and
without deep-vein thrombosis. Exclusions
included patients treated with LMWH,
fondaparinux or unfractionated heparin for
more than 48 hours or if they had already
received more than a single dose of a vitamin
K antagonist before randomisation. Also
patients who had undergone thrombectomy
or other surgical procedures were excluded.
Patients with contra-indications to vitamin
K were also excluded, as were patients with
active bleeding or at high risk of bleeding,
contra-indicating anti-coagulant therapy.
Randomisation was stratified according
to country and the attending physician’s
intention-to-treat duration of three, six or
12 months. Importantly, standard therapy
was well controlled and time in therapeutic
range (TTR) of the target INR (2–3) was
62.7%. The TTR percentage did vary from
57.8% during the first month, to 72.7%
during month 11. In the rivaroxaban group,
adherence to therapy was above 80%.
In the study, rivaroxaban demonstrated
efficacy comparable to that of the current
standard therapy in reducing the primary
endpoint of recurrent symptomatic VTE,
a composite of symptomatic deep-vein
thrombosis and non-fatal or fatal pulmonary
embolism (2.1 vs 1.8%, respectively;
p
=
0.003 for non-inferiority). Rivaroxaban
also demonstrated similar safety results
compared to current standard of care for
the principal safety outcome measuring
a composite of major and non-major
clinically relevant bleeding events
(10.3 vs 11.4%, respectively;
p
=
0.23).
Importantly, rivaroxaban treatment resulted
in a significant reduction in major bleeding
events (1.1 vs 2.2%, respectively;
p
=
0.003)
compared to the current standard therapy.
Acute coronary events were low (0.6%)
and were equally distributed between the
two groups.
1.
The Einstein investigators.
N Engl J Med
2012:
366
: 1287–1297.
Prof Guy Richards (University of the
Witwatersrand) comments on the
importance of the EINSTEIN-PE study
for South African clinicians
This is an interesting study, the first
assessing utilisation of one of the new orally
available anticoagulants to treat pulmonary
embolism. The outcomes were similar with
regard to prevention of recurrence but there
were differences with regard to safety.
Whereas overall major or clinically
relevant non-major bleeding was the same,
overall major bleeding episodes did differ,
with 26 (1.1%) occurring in the rivaroxaban
group and 52 (2.2%) in the standard-therapy
group. This difference had a standard
deviation of 0.49 (95% confidence interval
of 0.31–0.79) and was significant (
p
=
0.003). Within this latter group was included
other non-fatal episodes in critical sites, and
a large proportion of the differences within
the group of major bleeds was made up of
intra-cerebral bleeds, which occurred in one
patient (
<
0.1%) with rivaroxaban, and 10
(0.4%) with standard therapy.
Will this study change therapy? The
important considerations are firstly efficacy,
and in this regard rivaroxaban is non-inferior
to standard therapy. Second is safety, and
certainly with regard to major bleeding
episodes, it is superior, although the
numbers are small. Third is the issue of cost.
If it is priced too high, the cost efficacy may
make this therapy non-justifiable and this
may prove to be an obstacle. Fourthly, some
patients do not like injecting themselves
and may prefer to take a tablet that has been
proven to be equally efficacious.
Bayer is to be congratulated, however,
on successfully completing an arduous
study without any pre-knowledge as to what
the outcome would be. This study adds
significantly to our knowledge of these
new drugs and offers different options for
the treatment of pulmonary embolus in the
future.
Julia Aalbers
HEALTHCARE
