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Review
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Elinogrel, an orally and intravenously available ADP-receptor
antagonist
How does elinogrel affect a personalized antiplatelet
therapy?
K. A. L. Müller; T. Geisler; M. Gawaz
Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Universitätsklinikum Tübingen
Keywords
Schlüsselwörter
Elinogrel, reversible P2Y12 ADP receptor
antagonist, antiplatelet therapy
Elinogrel, reversibler P2Y12-ADP-Rezeptorantagonist, antithrombozytäre Therapie
Summary
Zusammenfassung
The antiplatelet therapy with aspirin and the
ADP-receptor blocker clopidogrel is currently
the standard medication after coronary intervention or after acute coronary syndrome to
prevent recurrent ischemic events and reduce
mortality. However, high interindividual response variability to antiplatelet treatment is
described in up to 44% of treated patients. A
poor response to clopidogrel is caused by
multifactorial mechanisms. Individual risk assessment including platelet function testing
(PFT) can help to identify high risk patients, although recent randomized trials to investigate effects of PFT-guided therapy have failed
to detect an impact on prognostic outcome.
Poor response to standard antiplatelet agents
can be overcome by switching to alternate
substances. Elinogrel is a novel competitive,
reversible ADP-receptor antagonist available
in oral and intravenous formulation. Additional treatment with elinogrel showed advantages over clopidogrel, including more
rapid, less variable, and more complete inhibition of platelet function without significantly increased bleeding complications. This
review gives an overview over the investigational drug elinogrel for use in a personalized antiplatelet approach.
Die duale antithrombozytäre Therapie mit
Aspirin und dem ADP-Rezeptor-Inhibitor Clopidogrel gehört zur Standardmedikation nach
Koronarintervention oder akutem Koronarsyndrom, um das Auftreten kardiovaskulärer
Ereignisse zu verringern. Jedoch ist eine hohe
Variabilität in der Ansprechrate bei bis zu 44%
aller behandelten Patienten beschrieben. Ein
geringes Ansprechen auf Clopidogrel ist durch
verschiedene Faktoren bedingt, weshalb eine
individuelle Risikostratifizierung erfolgen sollte. Einer hohen residuellen Plättchenaktivität
kann durch Anpassen der antiaggregatorischen Therapie begegnet werden.
Elinogrel, ein kompetitiver, reversibler ADPRezeptor-Antagonist wurde als begleitende
Medikation zu einer plättchenhemmenden
Therapie mit Clopidogrel eingesetzt und untersucht. Elinogrel ist sowohl zur intravenösen
als auch zur oralen Gabe verfügbar. Der zusätzliche Einsatz von Elinogrel führte zu einer
schnelleren maximalen und weniger variablen Plättchenhemmung als eine ClopidogrelMonotherapie ohne signifikante Erhöhung
von Blutungskomplikationen. Dieser Übersichtsartikel befasst sich mit dem Einsatz von
Elinogrel in einer individuell angepassten antithrombozytären Therapie.
Correspondence to:
Prof. Dr. med. Meinrad Gawaz
Medizinische Klinik III, Abteilung für Herz- und
Kreislauferkrankungen, Eberhard-Karls-Universität
Otfried-Müller-Straße 10, 72076 Tübingen
E-Mail: [email protected]
Elinogrel, ein oral und intravenös verfügbarer
ADP-Rezeptorantagonist – In welcher Weise
beeinflusst Elinogrel die personalisierte Antithrombozytentherapie?
Hämostaseologie 2012; 32: 191–194
doi:10.5482/ha-1192
received: June 1, 2012;
accepted: June 4, 2012;
prepublished online: July 5, 2012;
Personalized antiplatelet
therapy after individual
risk assessment
Dual antiplatelet therapy with aspirin and
the irreversible ADP-receptor blocker
clopidogrel is currently the standard medication after coronary intervention (PCI) or
acute coronary syndrome (ACS). Dual
antiplatelet medication at optimal dosing
and timing has lowered the risk of recurrent ischaemic events and reduced mortality significantly in randomized clinical
trials (1). Hence, a high interindividual response variability to clopidogrel is described which is associated with insufficient inhibition of platelet aggregation and
worse clinical outcome in patients with
coronary artery disease (CAD). Mechanisms leading to poor response are multifactorial including
● drug interactions,
● polymorphisms of cytochrome P450
isoform CYP 2C19 and
● clinical factors like diabetes mellitus,
renal insufficiency, age>65 years, reduced left ventricular function, and ACS
(PREDICT-Score) (2).
Therefore, an individual risk assessment is
needed before choosing the appropriate
antiplatelet therapy for each patient considering cardiovascular risk factors, bleeding risks and interventional issues. Platelet
function testing can be helpful to further
identify high risk patients with high ontreatment platelet reactivity.
The release of new antiplatelet agents
like ticagrelor and prasugrel and their
recommendation over clopidogrel in the
treatment of ACS in the updated guidelines
by the AHA and ESC guidelines has imHämostaseologie 3/2012
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192
K. A. L. Müller; T. Geisler; M. Gawaz: Elinogrel
Tab.
Elinogrel: clinical trials
trial
patients
study design
centers
patient
number
treatment groups
ERASE-MI
STEMI
randomized,
double-blind,
placebocontrolled
pilot trial
70
● n = 34
elinogrel
● n = 36
placebo
elinogrel with escalating doses (10, 20, 40, 60 mg) as a single
intravenous bolus before the diagnostic angiogram preceding
primary PC and 600-mg clopidogrel loading dose, followed by
a second 300-mg clopidogrel loading dose four hours after PCI
versus placebo
INNOVATE-PCI
stable CAD
undergoing
non-urgent PCI
randomized,
double-blind,
triple-dummy
652 centers
in
five countries
616
● n = 408
elinogrel
● n = 208
clopidogrel
elinogrel loading dose 80 or 120 mg intravenously followed
by 50, 100 or 150 mg orally or clopidogrel loading dose with
300 to 600 mg and maintenance dose 75 mg/day
proved patient treatment as the response
variability is not as high as under clopidogrel due to different metabolic mechanisms
and the effect on the ADP-receptor.
Low response can also be overcome by
other adjustments of the antiplatelet therapy, for example, with an additional treatment of novel substances like elinogrel, a
competitive and reversible ADP-receptor
antagonist that is available in an oral and
intravenous formulation.
Novel P2Y12 antagonists like elinogrel show
advantages over a single treatment with
clopidogrel, comprising more rapid, less
variable, and more complete inhibition of
platelet function without a significant increase of haemorrhagic complications.
This review gives an overview of the investigational drug elinogrel and the options of
an additional treatment with elinogrel for
personalized antiplatelet therapy.
Impact of switching to
alternate P2Y12 receptor
inhibitors in poor
responders to standard
antiplatelet therapy?
Inadequate response to clopidogrel can be
overcome by dose increase or adminis-
tration of more potent P2Y12 inhibitors.
The clinical impact of a platelet function
guided antiplatelet approach remains unclear though. The GRAVITAS study (5429
patients, 2214 with high platelet reactivity
after 600 mg clopidogrel loading dose, LD,
VerifyNow to measure ADP-induced platelet aggregation) randomized patients
either to a
● high-dose clopidogrel arm (600 mg LD
followed by 150 mg daily maintenance
dose, MD) or to a
● standard dose arm (no additional LD
followed by 75 mg daily MD) for six
months.
Primary endpoint (cardiovascular death,
non fatal myocardial infarction, or stent
thrombosis) were not different among the
cohorts after 30 days and six months. Despite GRAVITAS being the largest randomized trial to date of individualized antiplatelet dosing, it did not discern a significant
effect of clopidogrel dose intensification.
The occurrence of primary endpoints was
not reduced whereas better inhibition of
platelet aggregation was achieved in the
high dose group (3).
Another option to overcome poor response to antiplatelet therapy with clopidogrel is an additional medication with
novel drugs like the third generation P2Y12
receptor antagonist elinogrel.
Elinogrel, mode of action
Elinogrel, a quinazoline-2,4-dione, is a potent, reversible, ADP receptor antagonist
that is available in an oral and intravenous
formulation (4). Elinogrel has a plasma
half-life of approximately 12 hours. Its direct mode of action does not require metabolic activation or conversion into an active
drug leading to reduced variability in drug
response compared to clopidogrel. Polymorphisms of genes codifying hepatic cytochrome P450 isoenzymes do not seem to
play a role in the elinogrel response rate
(5–8). The compound is cleared to a similar
extent through the kidney and the liver.
Elinogrel is a reversible and competitive
inhibitor of the P2Y12 receptor. This results
in a direct dose-action relationship with fast
on- and offset of action, thus being advantageous in bleeding situations when fast recovery of platelet function is desirable (9).
Maximum platelet inhibition is achieved within 15 minutes of intravenous administration resulting in more rapid platelet inhibition effects than any other oral
antiplatelet drugs. This approach is of potential clinical benefit in the setting of primary/urgent PCI or in ACS. For maintainance therapy the oral formulation was developed allowing for witching to oral medication after PCI using the same compound
an thus avoiding drug-drug interactions
and rebound phenomenon (10). Elinogrel
has been evaluated for its effects as adjunc-
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K. A. L. Müller; T. Geisler; M. Gawaz: Elinogrel
outcome measures
results
primary
percentage ST-segment resolution before first device
activation during primary PCI
corrected TIMI frame count before PCI
percentage ST-segment resolution 30 minutes after
completion of the PCI procedure
primary
no differences in serious adverse events
TIMI and GUSTO major and minor bleeding
intracranial haemorrhage through 30 days
safety
incidence of bleeding events infrequent and
similar in elinogrel arm vs placebo
troponin elevation,
death, MI, stroke,
GP IIb/IIIa bailout,
stent thrombosis
primary
no significant differences for the
primary end points, no deaths, strokes, or stent
thromboses at 24 h/discharge
TIMI major or minor bleeding
clinically relevant bleeding
safety
no significant differences with respect to TIMI
major or minor bleeding
●
●
●
safety
●
●
primary
●
●
●
●
safety
●
●
tive therapy in phase-2 clinical trials including moderate to high risk patients for
whom a short onset of platelet inhibition
was required.
Clinical trials
Elinogrel has been tested in two phase 2
studies (씰Tab.) in patients with STelevation myocardial infarction (STEMI)
and in patients with stable CAD undergoing PCI.
The ERASE MI study was designed as
randomized, double blind, placebo controlled, dose escalating safety trial that assessed the effects of additional intravenous
elinogrel bolus administration in a total of
70 patients with STEMI. Patients with
STEMI were randomized to several doses of
either elinogrel (n = 34) or placebo (n =
36). Elinogrel was given with escalating
doses (10, 20, 40, and 60 mg) as a single intravenous bolus before the diagnostic angiography before PCI in subjects who received concomitant therapy with 600 mg clopidogrel LD, followed by a second 300 mg
clopidogrel LD four hours after PCI.
The primary safety endpoints of the
study were TIMI major and minor in hospital bleedings, Global Strategies to Open
Occluded Coronary Arteries (GUSTO) severe and moderate in-hospital bleedings
and intracerebral haemorrhage within 30
days.
The safety endpoints occurred in similar
frequency between the placebo arm and
across the different elinogrel dosing arms.
No major bleeding events and five minor
bleeding events were documented within
the elinogrel group. The incidence of bleeding events was similar between all tested
doses of elinogrel and the placebo group.
No differences in serious adverse events,
laboratory values, or ST resolution were
demonstrated between the elinogrel and
placebo arm. All doses were well-tolerated.
Limitations were the small patient number
of this pilot study. The trial was prematurely terminated for administrative
reasons (6).
The INNOVATE-PCI study was a multicenter, randomized, double-blind, tripledummy, active-controlled phase 2b study
of intravenously administered elinogrel
followed by an oral treatment with elinogrel in patients with CAD undergoing elective non-urgent PCI. 616 patients were assigned to receive either clopidogrel 300 or
600 mg followed by 75mg daily or elinogrel
80 or 120 mg intravenous followed by 50
mg, 100 mg or 150 mg of oral elinogrel
twice daily. Compared to clopidogrel, patients in the elinogrel arm achieved a more
rapid and potent platelet inhibition ex vivo
with a similar bleeding rate.
But there were no significant differences
in the occurrence of ischemic events between the clopidogrel and elinogrel arms at
24 hours and 120 days and no significant
differences in troponin elevation either. Although not significant, treatment with elinogrel was associated with higher rates of
bleeding at the vascular access site requiring medical intervention as well as higher
rates of serious adverse events and severe
dyspnea. Elevated liver enzymes (greater
than three times the upper limit of normal)
occurred in 1% of the clopidogrel group
and in 4.0% and 4.8% of the elinogrel 100
mg and 150 mg twice daily arms, respectively. Most cases occurred within the first
60 days, none involved serious hepatotoxicity, and all resolved even though treatment
was continued (7, 8).
The data show that elinogrel might provide
additional platelet inhibition on top of standard dual antiplatelet therapy independent
from CYP2C19 polymorphism (5).
However, larger studies are needed to prove
the superiority of this substance in patients
with loss-of-function genotypes and to
further prove the advantages of the two formulations (intravenous and oral) available
for transition from acute to subacute and
long-term therapy. Thus, elinogrel might
represent a valuable alternative in patients
in whom sufficient oral drug absorption
cannot be safeguarded. However, issues
concerning pharmacodynamic and -kinetic response, mode of action during transition phase from intravenous to oral solutions, drug monitoring and dosing have to
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193
194
K. A. L. Müller; T. Geisler; M. Gawaz: Elinogrel
be further resolved and need to be investigated in clinical trials.
The large double-blind placebocontrolled phase III trial in patients with
prior history of myocardial infarction and
chronic CAD was planned due to elinogrel's encouraging results in the phase II
trials. However, this study was currently
suspended as the production of elinogrel
was preliminary terminated by the manufacturer in January 2012.
Conclusion
The major advantage for elinogrel is its
availability as two formulations (intravenous and oral form), its fast onset and
higher maximum platelet inhibition within
15 minutes of the intravenous administration. Clopidogrel exhibits a highly variable response profile and is ineffective in a
relevant number of patients. In contrast,
elinogrel has a lower variability and a
favourable pharmacodynamic and -kinetic
profile. Both, intravenous and oral elinogrel resulted in faster and more complete
platelet inhibition than clopidogrel during
acute and long-term therapy. Optimal timing and dosing of this novel compound
warrants further clinical investigations.
Recently, the manufacturer terminated the
production of elinogrel in January 2012.
6.
Conflict of interest
The authors declare, that there are no
conflicts of interest.
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