CARDIOVASCULAR JOURNAL OF AFRICA • Vol 22, No 2, March/April 2011
AFRICA
107
Prasugrel offers consistent platelet control in appropriate
patients requiring treatment
Lilly launches prasugrel (Efient) in South Africa
Prasugrel represents a major breakthrough
in anti-platelet therapy for patients with
acute myocardial infarction (AMI), offer-
ing significant benefits over the past
decade’s mainstay therapy of clopido-
grel and aspirin in percutaneous coronary
interventions (PCI).
Supporting his view, Prof Jean-Pierre
Bassand of the University of Besancon,
France, described the development of
prasugrel, which is a third-generation
thienopyridine and a powerful inhibitor of
ADP-induced platelet aggregation (IPA).
‘The defining difference between pras-
ugrel and clopidogrel is that prasugrel
provides more consistent inhibition and
a faster onset of action, achieving 70 to
80% inhibition of platelet activity within
one hour compared to clopidogrel’, Dr
Bassand noted.
The active metabolites of prasugrel
and clopidogrel are virtually identical
regarding liver metabolism; but clopi-
dogrel requires a two-step process, which
includes a cytochrome P450-dependent
process. This has resulted in less anti-
platelet function and lower levels of the
active metabolite in patients with defined
genetic polymorphisms. Also, consider-
able opportunity exists for drug interac-
tions with clopidogrel, leading to exces-
sive levels of clopidogrel and an increased
hazard of bleeding.
In the development of prasugrel, the
double-blind phase II trial (JUMBO) in
acute coronary syndromes (ACS) defined
the most effective dose of prasugrel as
a 60-mg daily loading dose, followed
by a 10-mg maintenance dose, with the
least incurred hazard of bleeding in PCI
patients, compared to clopidogrel.
1
The primary end-point of the trial
was the prevalence of clinically signifi-
cant (TIMI major plus minor) non-
CABG-related bleeding events in prasu-
grel- versus clopidogrel-treated patients.
Haemorrhage complications were infre-
quent with no significant bleeding differ-
ences between prasugrel- and clopido-
grel-treated patients in this trial.
‘The TRITON-TIMI-38 trial followed
and was a very large trial of patients with
acute coronary syndromes, undertaken
to prevent thrombotic complications of
scheduled PCI. It must be emphasised
that this was a PCI trial with all the typi-
cal complications of this procedure’, Dr
Bassand stressed.
2
South Africa participated in this study,
submitting some 400 patients of the
total of 13 600 patients recruited in the
trial. Patients were randomly assigned to
receive prasugrel (60-mg loading and a
10-mg maintenance dose) or clopidogrel
(300-mg loading and 75-mg maintenance
dose).
‘It is important to stress the timing
of the prasugrel intervention. After the
anatomy was known, a loading dose was
given before PCI in only a quarter of the
patients; 75% received the therapy during
PCI or later’, remarked Dr Bassand.
The efficacy of prasugrel was clear,
with a 19% relative risk reduction (RRR)
in cardiovascular death, myocardial
infarction (MI) and stroke at a year or
more (450 days), compared to clopido-
grel. This benefit was largely driven by
the reduction in all forms of MI.
‘The benefit of prasugrel over clopi-
dogrel occurred very early, in the first
three days following PCI’, Dr Bassand
noted, ‘and the curves continued to diverge
over time. Benefits in the reduction of
stent thrombosis (absolute risk reduction
2.4 vs 1.1%, relative risk reduction 52%)
was also significant in this population of
mainly NSTEMI (unstable angina/non-
ST-segment elevation myocardial infarc-
tion) and STEMI patients.’ There was an
increased risk of major bleeding, includ-
ing fatal bleeding with prasugrel over
clopidogrel but overall mortality did not
differ significantly between the treatment
groups.
‘Some patients, the STEMI patients
and the diabetic patients with acute coro-
nary syndromes, derived more benefit
from prasugrel. Further evidence has
highlighted these patients as being the
most suitable for prasugrel intervention as
they show benefits without the increased
major bleeding in the larger TRITON-
TIMI group’, Dr Bassand stressed.
3,4
‘Prasugrel treatment is clearly to be
favoured above clopidogrel in STEMI
patients. In diabetic patients of which
there were 3 146 in TRITON-TIME 38,
there was a 30% RRR without any excess
of bleeds and no major CABG bleeds.’
‘There were some patients in whom
the powerful prasugrel anti-platelet effect
was accompanied with a higher bleeding
risk. Clopidogrel was better in patients
with prior stroke/TIA, in patients over the
age of 75 years and in patients with a low
body weight, below 60 kg. In the older
patient over 75 years without co-morbid-
ities, you can however, still consider the
use of prasugrel’, Dr Bassand noted
The increase in spontaneous bleeding,
which is the major category of prasugrel-
induced bleeding, is dominated by gastro-
intestinal bleeds, and the use of proton
pump inhibitors (PPI) is advocated in the
maintenance period of prasugrel use.
Prasugrel addresses gaps in clopi-
dogrel efficacy in acute coronary
syndromes
‘While clopidogrel is an excellent drug
that has changed the landscape of cardi-
ology by enabling PCI and reducing
thrombotic complications, its efficacy
‘Switching from clopidogrel to prasugrel is
possible, with improved platelet inhibition
without additional risk. However, switch-
ing from prasugrel to clopidogrel reduces
effective inhibition of platelet aggregation
and may increase thrombotic and ischaemic
risk’ –
Prof Jean-Pierre Bassand
Timing of prasugrel administration
inACS
• Primary PCI – at presentation
• Stent thrombosis – at presentation
• Diabetic patients – at time of PCI
‘In simple, practical terms, prasugrel is
good at stopping re-occlusion and stent
thrombosis’ –
Dr Tony Dalby, Johannes-
burg
‘In patients weighing less than 60 kg,
prasugrel, in my view, is not completely
contra-indicated. A maintenance dose of
5 mg could be given based on pharmaco-
kinetic studies’ –
Dr Lev
