CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 9, October 2012
AFRICA
525
Rivaroxaban in acute coronary syndromes and atrial fibrillation:
rivaroxaban shown to reduce cardiovascular deaths in STEMI
patients
The addition of rivaroxiban to dual
therapy for ST-elevation myocardial
infarction (STEMI) patients has been
shown to reduce recurrent cardiovascular
events and cardiovascular death without
increasing fatal bleeding, although TIMI
non-coronary artery bypass graft (CABG)
major bleeding was increased.
Presenting the results of this
pre-specified sub-group of the ATLAS
ACS 2-TIMI 51 trial,
1
at the 2012 ESC
congress, Dr Jessica Mega, Brigham
and Women’s Hospital, Boston,
USA, noted that the primary-efficacy
benefit, a significant 19% reduction in
cardiovascular (CV) death, myocardial
infarction (MI) or stroke emerged early in
the first two to three weeks of rivaroxaban
therapy. These results are consistent with
the results from the overall ATLAS ACS
2-
TIMI 51 phase III study. ‘The value
of rivaroxaban relates to the blocking of
excess thrombin generation, not only at
the time of the index event but also over
time’, Dr Mega said.
In the overall ATLAS ACS 2-TIMI
trial, more than 15 000 patients with
the whole spectrum of acute coronary
syndrome (ACS) were recruited; 50.3%
of patients presented with STEMI, 25.6%
with non-STEMI (NSTEMI) and 24%
with unstable angina. The 7 817 STEMI
patients were stabilised according to
the study design after a median of 4.7
days and stratified by thienopyridine use
according to the attending physician’s
discretion, given aspirin 75–100 mg/day
and randomised to placebo, or rivaroxaban
2.5
or 5 mg bid; 97% of patients were on
either clopidogrel or ticlopidine, although
some stopped taking this medication over
the course of the study.
The primary efficacy endpoint
was cardiovascular death, myocardial
infarction (MI) or stroke. Safety was
according to TIMI major bleeding not
associated with CABG.
There was no reduction in
cardiovascular death in patients receiving
the 5-mg dose but there was a 40%
reduction in CV deaths and a significant
reduction in all-cause mortality in patients
receiving the 2.5-mg dose of rivaroxaban.
There was an increase in TIMI major
and minor bleeding, with fewer bleeds
on the lower dose. There was no increase
in fatal bleeding on either dose. Dr
Mega concluded that very low doses of
rivaroxaban (2.5 mg twice daily) offer
an effective treatment strategy to reduce
thrombotic events in patients following
STEMI (Table 1).
The use of the 2.5-mg bid rivaroxaban
dose has been taken up in the new ESC
guidelines on STEMI with a class IIa,
level 1B recommendation as follows: ‘In
selected patients who do receive aspirin
and clopidogral, lower-dose 2.5-mg
rivaroxaban may be considered if the
patient is at low bleeding risk.’
Taking clinical studies in stroke
prevention in atrial fibrillation
into practice
There is a high level of evidence to
support the use of the new anticoagulants
in stroke prevention in atrial fibrillation
(
AF). This has been taken up by the ESC
in their newly released guidelines, which
recommend the use of these novel agents
as being broadly preferable to vitamin
K antagonists for the majority of AF
patients (level 1B recommendation).
This view was substantiated by Prof
Robert M Califf, primary co-investigator
of the ROCKET studies of rivaroxaban at
a special symposium at the ESC, which
evaluated the three series of studies in
RE-LY, ROCKET and ARISTOTLE,
involving dabigatran, rivaroxaban and
apixaban, respectively. ‘Fundamentally,
in my view, the data for these agents
look more similar than different and
without head-to-head comparisons in
large populations, we will have to make
appropriate decisions for individual
patients based on our interpretation of the
available data.’
The RE-LY study had the advantage
of examining two doses of dabigatran
compared to warfarin and was able to
show equivalence at the lower dose (110
mg twice daily), with less bleeding than
with warfarin. The higher dose (150 mg
twice daily) was shown to be superior
to warfarin in stroke prevention with the
same level of bleeding complications but
with fewer life-threatening major bleeds
and somewhat higher gastrointestinal
bleeding rates.
The ROCKET-AF trial was based on a
single, once-daily dose of rivaroxaban (20
mg daily), which showed non-inferiority
to warfarin with regard to the reduction
of stroke and non-central nervous system
embolism, with a decrease in serious
bleeds such as intracranial and fatal
bleeding, although overall bleeding rates
were the same. It is important to note that
the ROCKET trial intentionally included
patients at considerable risk of stroke, and
the overall risk score in ROCKET was
much higher than in the other two trials.
Prof Werner Hacke, neurologist from
Heidelberg University, Germany pointed
out that the CHADS
2
score for ROCKET
was 3.5, while average risk scores for
RE-LY and ARISTOTLE were much
lower at 2.1. Focusing on the neurologist’s
experience of encountering AF patients
only after they have experienced their first
stroke, Prof Hacke presented important
insights from the published data of the
three trials in the pre-specified patient
sub-group with prior stroke or transient
ischaemic attack (TIA).
This evaluation of secondary
prevention shows that in prior stroke
patients in RE-LY and ARISTOTLE,
some 20% of patients had higher CHADS
scores and were more comparable to
the overall ROCKET experience with
its inclusion of patients at higher stroke
risk. ‘In this group of patients who are
more vulnerable to a further stroke and
TABLE 1. ATLASACS 2-TIMI 51 RESULTS IN STEMI PATIENTSAT TWOYEARS
Rivaroxaban 2.5 mg
Placebo
CV death/MI/stroke
8.7
10.6
CV death
2.5
4.2
All-cause death
3.0
4.7
TIMI non-CABG major bleeding
1.7
0.6
