To assess the efficacy, safety and cost-effectiveness of the CYP2C19 genotype guided antiplatelet treatment strategy, using clopidogrel or prasugrel/ticagrelor.
ID
Source
Brief title
Condition
- Coronary artery disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To determine whether the CYP2C19 genotype guided antiplatelet treatment
strategy is not inferior to a treatment strategy with the newer antiplatelet
drugs i.e. ticagrelor and prasugrel in terms of the composite of death,
recurrent myocardial infarction (MI), definite stent thrombosis, stroke and
PLATO major bleeding at 1 year, in patients undergoing primary PCI for STEMI.
If non-inferiority is proven, analysis will be performed for superiority.
To determine whether the CYP2C19 genotype guided antiplatelet treatment
strategy is superior to a treatment strategy with the newer antiplatelet drugs
i.e. ticagrelor and prasugrel in terms of a composite endpoint of PLATO major
and minor bleeding.
To assess the quality of life of patients and health-care resource use in both
treatment groups i.e. the CYP2C19 genotype guided antiplatelet treatment and
the treatment strategy with the newer antiplatelet drugs i.e. ticagrelor and
prasugrel, to calculate Quality Adjusted Life Years (QALY*s) and net costs per
life-year and QALY.
Secondary outcome
Secondary objectives:
To compare the efficacy of the CYP2C19 genotype guided antiplatelet treatment
strategy versus the treatment strategy with the newer antiplatelet drugs i.e.
ticagrelor and prasugrel in terms of clinical outcome parameters taken
separately or combinations of parameters i.e. death, cardiovascular death,
cerebrovascular death, recurrent myocardial infarction (MI), definite stent
thrombosis, probable stent thrombosis, possible stent thrombosis, urgent target
vessel revascularisation (TVR), hospital admission for ACS or stroke at 30 days
and 1 year, in patients undergoing primary PCI for STEMI.
To compare the safety of the CYP2C19 genotype guided antiplatelet treatment
strategy to the treatment strategy with the newer antiplatelet drugs i.e.
ticagrelor and prasugrel in terms of safety outcome parameters taken separately
or combinations of these parameters i.e. (non-)CABG-related major bleeding,
major bleeding, minor bleeding, life threatening bleeding, fatal bleeding,
intracranial bleeding, bleed requiring transfusion at 30 days and 1 year in
patients undergoing primary PCI for STEMI. Different bleeding classifications
will be used i.e. TIMI, PLATO and BARC bleeding scales to make the study
comparable to previous and future publications.
To compare the CYP2C19 genotype guided antiplatelet treatment strategy
(subdivided into patients included before protocol version 05, 16-02-2012 and
patients included starting with protocol version 05, 16-02-2012) to a treatment
strategy with either clopidogrel in all patients or a treatment strategy with
the newer antiplatelet drugs i.e. ticagrelor and prasugrel in terms of the
composite of death, recurrent myocardial infarction (MI), definite stent
thrombosis, stroke and PLATO major and minor bleeding at 30 days and 1 year, in
patients undergoing primary PCI for STEMI.
To compare the efficacy and safety of CYP2C19 genotype guided antiplatelet
treatment strategy to the treatment strategy with the newer antiplatelet drugs
i.e. ticagrelor and prasugrel in subgroups (subgroups are described in the
protocol) in terms of death, recurrent myocardial infarction (MI), definite
stent thrombosis, stroke and PLATO major and minor bleeding (or one of the
other bleeding classifications, i.e. TIMI, BARC) and net adverse clinical
events , in-hospital, at 30 days and at 1 year in patients undergoing primary
PCI for STEMI.
To compare the efficacy and safety of using a loading dose of clopidogrel
versus not using a loading dose of clopidogrel in the CYP2C19 genotype guided
antiplatelet group in terms of the composite death, recurrent myocardial
infarction (MI), definite stent thrombosis, stroke and PLATO major and minor
bleeding (or one of the other bleeding classifications, i.e. TIMI, BARC) at 30
days and 1 year, in patients undergoing primary PCI for STEMI.
To compare the efficacy and safety of using glycoprotein IIB/IIIA inhibitors
(GPI) in patients undergoing primary PCI for STEMI in terms of death, recurrent
myocardial infarction (MI), definite stent thrombosis, stroke and PLATO major
and minor bleeding (or one of the other bleeding classifications, i.e. TIMI,
BARC) and net adverse clinical events , in-hospital, at 30 days and at 1 year
in patients undergoing primary PCI for STEMI. The use of GPI will be compared
between patients on ticagrelor with GPI versus ticagrelor without GPI, in
patients on ticagrelor with GPI versus clopidogrel with GPI and there will be
further sub-group analysis based on the CYP2C19 genome.
To compare the number of patients in whom the antiplatelet drug is prematurely
discontinued or switched to another drug in the CYP2C19 genotype guided
antiplatelet treatment versus the treatment strategy with the newer
antiplatelet drugs i.e. ticagrelor and prasugrel.
Tertiary objectives:
To evaluate whether clopidogrel in non carriers of a reduced CYP2C19 function
allele is not inferior to prasugrel and ticagrelor in CYP2C19 reduced function
allele carriers in terms of clinical outcome and safety parameters taken
separately or combinations of these parameters i.e. death, cardiovascular
death, cerebrovascular death, recurrent myocardial infarction (MI), definite
stent thrombosis, probable stent thrombosis, possible stent thrombosis, urgent
target vessel revascularisation (TVR), hospital admission for ACS, stroke,
(non-)CABG-related major bleeding, major bleeding, minor bleeding, life
threatening bleeding, fatal bleeding, intracranial bleeding or bleed requiring
transfusion at 30 days and 1 year, in patients undergoing primary PCI for STEMI.
To evaluate the effect of genetic variants on the response to clopidogrel,
ticagrelor or prasugrel in terms of efficacy and safety in a candidate gene
approach, Genome Wide Association Study or (next generation) sequencing.
Background summary
The use of antiplatelet drugs (i.e. clopidogrel, ticagrelor or prasugrel) are
crucial as antiplatelet drug in the treatment in of patients undergoing
percutaneous coronary intervention (PCI) with stent implantation and during one
year after PCI, to prevent atherothrombotic complications. New antiplatelet
drugs, i.e. prasugrel and ticagrelor, are more effective in preventing
atherothrombotic complications, but exhibit a higher risk of bleeding
complications, compared to clopidogrel. Clopidogrel is converted into its
active metabolite by CYP2C19. Carriers of the non functional CYP2C19*2 and *3
alleles have an impaired CYP2C19 capacity, making clopidogrel less effective in
CYP2C19*2 and *3 carriers. For these subjects prasugrel orticagrelor is an
alternative, because the antiplatelet effect of those drugs is not influenced
by CYP2C19 metabolizer status. It is hypothesized that the net clinical
benefit, taking atherothrombotic and bleeding complications into account, of a
CYP2C19 guided antiplatelet strategy is not inferior to a strategy with the
newer antiplatelet drugs and reduces drug costs.
Study objective
To assess the efficacy, safety and cost-effectiveness of the CYP2C19 genotype
guided antiplatelet treatment strategy, using clopidogrel or
prasugrel/ticagrelor.
Study design
The design is a randomized, open label, multicenter study. STEMI patients who
underwent primary PCI will be randomized to the CYP2C19 genotype guided
antiplatelet treatment strategy (intervention group) or treatment with
prasugrel or ticagrelor (usual care in the control group). Patients in both
treatment groups will receive the antiplatelet drugs for the duration of one
year.
Intervention
The intervention group will be genotyped for the CYP2C19*2 and *3 alleles
within 48 hours after PCI. Carriers of a CYP2C19*2 or *3 allele will receive
prasugrel at a dosage of 10 mg once daily or ticagrelor at a dosage of 90mg
twice daily starting after PCI for one year. Patients older than 75 years or
with a body weight of less than 60 kg will receive prasugrel at a dosage of 5
mg once daily. Non-carriers will be treated with clopidogrel at a dosage of
75mg once daily. The control group receives prasugrel or ticagrelor at the same
dosage as described above. The choice for prasugrel or ticagrelor will be made
by the attending doctor. Antiplatelet therapy will be continued for one year
after PCI. Follow-up using questionnaires will be performed for one year.
Study burden and risks
The burden for patients participating in the study is that patients will be
contacted after 1,6 and 12 months to fill out a follow-up and a quality of life
questionnaire.
Depending on the randomisation result patients can be treated with prasugrel or
ticagrelor (routine treatment) or clopidogrel (if genotyping result is
'extensive metabolizer'). The use of prasugrel and ticagrelor is associated
with a decrease in atherothrombotic events, compared to clopidogrel, but with
an increase in bleeding events. Evidence suggests that by selecting patients
based on CYP2C19 metabolizer status the best net clinical benefit can be
achieved related to atherothrombotic and bleeding events.
Koekoekslaan 1
Nieuwegein 3435CM
NL
Koekoekslaan 1
Nieuwegein 3435CM
NL
Listed location countries
Age
Inclusion criteria
1) more than 21 years of age with symptoms of acute myocardial infarction of more than 30 minutes but less than 12 hours
2) performed primary PCI with stenting for STEMI
Exclusion criteria
1) unable to give informed consent or have a life expectancy of less than one year
2) active malignancy with increase in bleeding risk, in the investigator*s opinion
3) women who are known to be pregnant or who have given birth within the past 90 days or who are breastfeeding
4) having received thrombolytic therapy within the previous 24 hours or oral anticoagulants during the previous 7 days
5) severe renal function impairment needing dialysis
6) confirmed or persistent severe hypertension (Systolic Blood Pressure (SBP) > 180 mmHg and/or Diastolic Blood Pressure (DBP) >110 mmHg) at randomization
7) contraindication to anticoagulation or at increased bleeding risk, at the investigator*s opinion
8) cardiogenic shock (SBP <= 80mmHg for >30 mins) or needing Intra-Aortic Balloon Pump (IABP)
9) history of major surgery, severe trauma, fracture or organ biopsy within 90 days prior to randomisation
10) clinically significant out of range values for platelet count or haemoglobin at screening, in the investigator*s opinion.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-024667-40-NL |
| CCMO | NL35106.100.11 |
| OMON | NL-OMON24886 |