Acute ST-elevation Myocardial Infarction Clinical Trial
Official title:
On-treatment PLAtelet Reactivity-guided Therapy Modification FOR ST-segment Elevation Myocardial Infarction (PLATFORM)
Adequate platelet inhibition with dual antiplatelet therapy is a key therapeutic goal after
primary percutaneous coronary intervention (PPCI), aimed at protecting against stent
thrombosis and increased mortality. Recent aggregometric assays have shown that up to one
third of acute coronary syndrome patients treated with clopidogrel have incomplete inhibition
of adenosine diphosphate(ADP)-induced platelet aggregation while the number of patients
treated with aspirin who have incomplete inhibition of thromboxane A2-induced platelet
aggregation (ASPI)is much lower. High on-treatment platelet reactivity (HTPR) has been
associated with an increased rate of ischemic events after PCI. However, recent large trials
did not show a clinical benefit of TPR-guided therapy modification in acute coronary syndrome
patients treated by PCI.
On-treatment PLAtelet reactivity-guided Therapy modification FOR ST-segment elevation
Myocardial infarction (PLATFORM) is an investigator-initiated, prospective, randomized,
parallel-group, controlled clinical trial designed to test the hypothesis that antiplatelet
therapy modification is superior to standard antiplatelet regimen among intermediate to
high-risk STEMI patients undergoing PPCI. The safety hypothesis is that compared with control
arm, interventional study arm will have similar rates of non-coronary artery bypass graft
surgery-related bleeding. Approximately 632 ST-elevation myocardial infarction (STEMI)
patients with intermediate to high-risk (RISK-PCI score >3) clinical features undergoing PPCI
will be randomly allocated to treatment modification or standard treatment. Low responders to
aspirin will receive 200 mg aspirin for 30 days. Low responders to clopidogrel will receive
180 mg ticagrelor for 1 year. Patients will be followed up to 1 year after PPCI.
On-treatment PLAtelet reactivity-guided Therapy modification FOR ST-segment elevation
Myocardial infarction (PLATFORM) is an investigator-initiated, prospective, open-label,
randomized, parallel-group, actively controlled single-centre clinical trial. The research
protocol has been approved by the Ethics Committee of the Clinical Centre of Serbia. All
participants will have to provide their informed consent in writing. The trial design will
ensure that all participants abide by good clinical practice and the ethical principles of
the Declaration of Helsinki II. Patients will be randomly allocated to antiplatelet regimen
modification (ARM, interventional arm) or standard treatment (control arm) using a
computer-generated 1:1 simple randomization scheme. TPR will be assessed in patients enrolled
in the intervention arm of the trial. Low responders to aspirin will receive 200 mg aspirin
for 30 days. Low responders to clopidogrel will receive 180 mg ticagrelor for 1 year.
Patients enrolled in the control arm will receive standard antiplatelet regimen including 100
mg aspirin and 75 mg clopidogrel without assessment of TPR. The treating physicians will not
be blinded to the intervention since an open design will make it possible for investigators
to perform necessary adjustments of the antiplatelet regimen in accordance with TPR status.
To minimize any possible bias inherent in the open design, endpoints will be evaluated by a
blinded endpoint committee. Enrollment will start in June 2013. Recruitment will continue
until 632 patients have been randomized. The end of the recruitment period is planned for
June 2015. The trial will continue until all available survivors have been followed for at
least 1 year.
Aspirin 300 mg and clopidogrel 600 mg loading doses will be administered as early as possible
before PPCI. Primary PCI will be performed via femoral or radial approach, using standard 6
French-7 French guiding catheters. The Thrombolysis in Myocardial Infarction (TIMI) blood
flow will be measured by two experienced observers blinded to identity and the order of
angiograms. Any disagreement will be resolved by a third observer. Unfractionated heparin
will be started as 100 IU/kg bolus (60 IU/kg if glycoprotein (GP)IIb/IIIa receptor inhibitor
was used); the 12 IU/kg/h infusion will follow if clinically indicated. Proton-pump inhibitor
pantoprazole or H2-blocker ranitidine will be given to selected patients at risk for
gastrointestinal hemorrhage. GP IIb/IIIa receptor inhibitor tirofiban will be administered
during the procedure in patients with evidence of high intracoronary thrombus burden
according to the European Society of Cardiology guidelines.
Multiple electrode aggregometry will be performed using the impedance aggregometer and under
the monitoring of an official representative of the manufacturer (Multiplate analyzer,
Verum-Diagnostics, Munich, Germany). TPR results will be evaluated by 2 investigators who
will be blinded to patient's identity and treatment. Whole blood will be sampled 24 hours
after the loading dose. In patients who received IIb/IIIa inhibitor tirofiban blood samples
will be obtained at least 24 hours after the completion of tirofiban infusion. On-treatment
platelet reactivity (TPA) above 50%, compared to the basal value estimated by TRAP test, will
be linked with low responsiveness.
Patients will be followed-up after discharge from hospital for net adverse events up to 1
year after enrolment by scheduled telephone interviews and outpatient visits. Interviewers
will be blinded to the randomization scheme and to the results of platelet aggregation. An
independent Clinical Event Committee, composed of 3 cardiologists and 1 neurologist and
blinded with respect to randomization allocation will review and adjudicate the occurrence of
each suspected clinical end point. Interim analyses of efficacy and futility, using
O'Brian-Fleming guidelines for group sequential design, are planned when one fourth, one half
and three fourths of the maximum number of the 632 patients had been followed-up for 30 days.
Interim analyses and all safety data will be reviewed by an independent Data Safety and
Monitoring Committee, composed of a chairman, a statistician, and 2 physician members.
;
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