CARDIOVASCULAR JOURNAL OF AFRICA • Vol 22, No 2, March/April 2011
AFRICA
109
is hampered by its wide variability in
platelet inhibition, with consequent risk
of stent thrombosis and MI in poor-
responders, and its slow onset of action,
which is particularly relevant to PCI in
STEMI patients.’ Dr Eli Lev, director of
the Cardiac Catheterisation Laboratory,
Petah-Tikva, Israel, an active researcher in
the field of platelets and anti-coagulation,
presented this view at the Lilly-sponsored
symposium held in Cape Town recently.
The main reason for the variability
of the clopidogrel response lies in its
complex metabolism from pro-drug to
active metabolite and the many enzymes
that can be affected. It has been shown
that 30% of Caucasians are carriers of the
CYP
2
C
19
reduced-function allele, which
results in low metabolism of clopidogrel
to the active metabolite.
Numerous studies and meta-analy-
ses have shown that being a low/non-
responder to clopidogrel is a significant
risk factor for suffering a catastrophic
event. A study by Buonamici
et al
. on
the effects of non-response to clopidogrel
in patients receiving drug-eluting stents
showed a very significant increase in the
incidence of stent thrombosis of 8.6%
in non-responders compared to 2.3%
in responders.
5
The overall rate of stent
thrombosis was 3.1% over the six-month
period of this prospective study in an
American academic hospital.
Various meta-analyses have shown a
three to four-fold increase in stent throm-
bosis in clopidogrel low responders and
a moderate but significant increase in
mortality.
In a Xhosa population, unique genetic
profiles with novel CYP
2
C
19
allelles have
been found which can influence clopi-
dogrel responses.
6
‘This is certainly an
interesting field which warrants further
research’, Dr Lev noted.
Prasugrel’s metabolism is much more
efficient and studies have shown that
carriers of the clopidogrel reduced-
function CYP
2
C
19
alleles do not show
altered metabolism of prasugrel, nor are
prasugrel’s platelet aggregation or cardio-
vascular event rates affected.
7
‘This is
because prasugrel’s metabolism is only
a one-step process with little opportunity
for the genetic make-up of the patient to
influence prasugrel’s anti-platelet action.
Even patients who are non-responders to
clopidogrel are responsive to prasugrel’,
Dr Lev noted.
Efforts to increase platelet inhibition
by increasing the clopidogrel dose to
higher than the approved levels of 600
mg loading dose and 150 mg daily main-
tenance dose have been compared to the
standard prasugrel therapy in patients
undergoing cardiac catherterisation for
planned PCI.
8
This PRINCIPLE-TIMI 44
study showed that the 60-mg prasugrel
loading dose and 10-mg maintenance
dose resulted in a greater anti-platelet
effect, which was consistent with that of
the high clopidogrel treatment.
Implications of TRITON-TIMI
38 for the interventionist
You can count on Efient
‘The importance of the TRITON-TIMI
38 trial is also its very effective preven-
tion of stent thrombosis regardless of
the type of intracoronary stent used’, Dr
Lev stressed.
9
Ninety-six per cent of the
patients (12 844) in TRITON-TIMI 38
received at least one coronary stent, with
approximately equal distribution of drug-
eluting and bare-metal stents.
‘Stent thrombosis is “the perfect plate-
let storm” with very catastrophic conse-
quences and a 20 to 30% mortality rate,
even though it is a relatively rare occur-
rence (1% of patients)’, Dr Lev noted.
‘Prasugrel invites the use of personalised
and tailored medicine where the clinician
should risk-stratify his patient to optimise
anti-platelet therapy’, Dr Bassand and Dr
Lev concluded.
J Aalbers, Special Assignments Editor
1. Wiviott SD, Cannon CP, Morrow DA, Ray
KK, Pfeffer MA,
et al
. Randomised compari-
son of prasugrel (cs-747 LY640315) a novel
thienopyridine P2Y12 antagonist with clopi-
dogrel in PCI intervention –JUMBO-TIMI
26 trial.
Circulation
2005;
111
(25): 3366–
3373.
2. Wiviott SD, Braunwald E, McCabe CH,
Montalescot G, Ruzyllo W,
et al
. Prasugrel
versus clopidogrel in patients with acute
coronary syndromes.
N Engl J Med
2007;
357
(20): 2001–2015.
3. Wiviott SD, Braunwald E, Angiolillo DG,
Meisel S, Dalby AJ, Verheugt VW,
et al
.
Greater clinical benefit of more intensive
oral antiplatelet therapy with prasugrel in
patients with diabetes mellitus in the trial to
assess improvement in therapeutic outcomes
by optimising platelet inhibition with prasu-
grel-thrombolysis in Myocardial Infarction
38.
Circulation
2008;
118
(16): 1626–1636.
Epub Aug 31.
4. Montalescot G, Wiviott SD, Braunwald E,
Murphy SA, Gibson CM, McCabe CH,
et
al
. Prasugrel compared with clopidogrel in
patients undergoing percutaneous coronary
intervention for ST-elevation myocardial
infarction (TRITON-TIMI 38): double-blind,
randomised controlled trial.
Lancet
2009;
373
(9665): 723–731.
5. Bounamici P,
et al
. Impact of platelet reactiv-
ity after clopidogrel administration on drug-
eluting stent thrombosis.
J Am Coll Cardiol
2007;
49
(24): 2312–2317.
6. Dogemoller BI. Characterisation of the
genetic profile of CYP
2
C
19
in the two South
African populations.
Pharmacogenetics
2010;
11
(8): 1095–1103.
7. Mega JL,
et al
. Cytochrome p450 genetic
polymorphisms and the response to prasu-
grel: relationship to pharmacokinetics,
pharmacodynamic and clinical outcomes.
Circulation
2009;
119
(19): 2553–2560.
8. Wiviott SD,
et al
. Prasugrel compared
with high loading and maintenance-dose
clopidogrel in patients with planned
PCI-PRINCIPLE-TIMI 44 trial.
Circulation
2007;
116
(25): 2923–2932.
9. Wiviott SD, Braunwald E, McCabe CH,
Horvath I, Keltai M, Herrman JP,
et al.
Intensive oral antiplatelet therapy for reduc-
tion of ischaemic events including stent
thrombosis in patients with acute coro-
nary syndromes treated with percutaneous
coronary intervention and stenting in the
TRITON-TIMI 38 trial: a subanalysis of a
randomised trial.
Lancet
2008;
371
(9621):
1353–1363.
Surgery in the face of prasugrel
pre-treatment
In patients on prasugrel, as for clopidogrel,
surgery should be delayed for at least seven
days. If the CABG/surgery cannot wait,
platelet transfusion is necessary. Platelet
function tests can also add useful informa-
tion on risk of bleeds.
Key take-home messages
• Prasugrel has been shown to be an
effective inhibitor of platelet aggre-
gation.
• The FDA has approved prasugrel.
• Prasugrel significantly reduces isch-
aemic events.
• It has an especially marked reduc-
tion in stent thrombosis.
• It has stronger benefits in patients
with STEMI, stent thrombosis and
diabetes.
