Acute Coronary Syndrome
Conditions
Keywords
Elderly, Acute coronary syndrome, Percutaneous coronary intervention, Prasugrel, Platelet function test
Brief summary
The purpose of this study is to demonstrate the superiority of a strategy of platelet monitoring (Monitoring Arm) with down-adjustment of the dose of prasugrel in high responders and up-adjustment of the dose of prasugrel in low responders as compared to a more conventional strategy of a fixed dose of 5 mg to every patient without monitoring (Conventional Arm) as measured by a reduction in the composite endpoint of, cardiovascular (CV) death, myocardial infarction (MI) , stroke, stent thrombosis (ARC definition type definite), urgent revascularisation or bleeding (BARC definition type 2, 3 or 5).
Detailed description
Objective: To demonstrate the superiority of a strategy of platelet monitoring (Monitoring Arm) with down-adjustment of the dose of prasugrel in high responders and up-adjustment of the dose of prasugrel in low responders as compared to a more conventional strategy of a fixed dose of 5 mg to every patient without monitoring (Conventional Arm).Rationale: Prasugrel 10 mg is superior to clopidogrel in patients with acute coronary syndrome treated by percutaneous coronary intervention, reducing significantly the rates of ischemic events. Elderly patients appear to be at higher risk of bleeding events and pharmacokinetic data suggests that elderly patients are exposed to a higher concentration of the active metabolite of prasugrel. A reduced dose of 5 mg of prasugrel is therefore proposed to these patients to limit the risk of bleeding. On the other hand, the elderly have also a higher ischemic risk and higher levels of platelet aggregation under treatment than younger patients and may deserve stronger protection from antiplatelet therapy. Platelet function testing appears to be of particular interest in patients at high risk of both ischemic and bleeding events like the elderly. Too intense platelet inhibition may expose the elderly patients to an excessive bleeding risk. Too low platelet inhibition may expose them to recurrent cardiovascular ischemic events. The possibility of bedside monitoring of oral antiplatelet therapy offers the opportunity of tailoring prasugrel therapy in elderly patients to optimize their risk/benefit ratio. Such strategy has never been evaluated in a randomized and adequately powered study. Population: Acute coronary syndrome (STEMI and NSTEMI) treated by PCI-stent (bare metal stent or drug eluting stent) in patients aged 75 ≥ year. Methods: Monitoring with VerifyNow P2Y12, 2 weeks after initiation of 5 mg of maintenance dose of prasugrel, reduction of antiplatelet therapy if there is high on-treatment platelet inhibition (HPI) or increase in dosing if there is high on-treatment platelet reactivity (HPR). Patients will be monitored again 2 weeks later, only if they do not meet the Verifynow P2Y12 targets at the first assessment. Primary endpoint net clinical benefit at 12 months:Composite of Cardiovascular death, myocardial infarction, stroke, urgent revascularisation, stent thrombosis and bleedings according to the BARC definitions (type 2, 3 or 5) Centers: Approximately 40 French high volume PCI centers
Interventions
DRUGModification of Prasugrel based on a biological assay
Monitoring with VerifyNow P2Y12, 2 weeks after initiation of 5 mg of maintenance dose of prasugrel, reduction of antiplatelet therapy if there is high on-treatment platelet inhibition (HPI) or increase in dosing if there is high on-treatment platelet reactivity (HPR) Device: VerifyNow point of care assay VerifyNow (ACCUMETRICS San Diego USA)
DRUGprasugrel / clopidogrel
fixed dose of prasugrel 5 mg
DEVICEVerify Now
Monitoring with VerifyNow P2Y12, 2 weeks after initiation of 5 mg of maintenance dose of prasugrel, reduction of antiplatelet therapy if there is high on-treatment platelet inhibition (HPI) or increase in dosing if there is high on-treatment platelet reactivity (HPR) Device: VerifyNow point of care assay VerifyNow (ACCUMETRICS San Diego USA)
Sponsors
Eli Lilly and Company
Daiichi Sankyo
Allies in Cardiovascular Trials Initiatives and Organized
Accumetrics, Inc.
Stentys
Assistance Publique - Hôpitaux de Paris
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
75 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Acute coronary syndrome (STEMI and NSTEMI) treated by PCI * Stent (bare metal stent or drug eluting stent) regardless of the regime of thienopyridines administered before randomisation * Age ≥ 75 years. * Aspirin dose of 75 mg will be recommended but study authorizes doses ranging from 75-160 mg * Ability to understand and to comply with the study protocol. * Written informed consent
Exclusion criteria
* Prior history of ischemic or hemorrhagic stroke or transient ischemic attack, or sub-arachnoids haemorrhage * Have received fibrinolytic therapy within 48 hours of entry or randomisation into the study * Are receiving vitamin K antagonist * Concomitant medical illness (terminal malignancy) that is associated with reduced survival over the expected study treatment period. * History of intolerance or allergy to ASA or approved thienopyridines (ticlopidine, clopidogrel, or prasugrel) * Have active pathological bleeding or history of bleeding diathesis * Thrombocytopenia \< 100 000 µL * Severe hepatic impairment (Child Pugh class C). * Have a condition associated with poor treatment compliance, including dementia or mental illness
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite of Cardiovascular death, myocardial infarction, stroke, urgent revascularisation, stent thrombosis and bleedings according to the BARC definitions (type 2, 3 or 5) through 12 months of randomisation | through 12 months of randomisation | Composite of Cardiovascular death, myocardial infarction, stroke, urgent revascularisation, stent thrombosis and bleedings according to the BARC definitions (type 2, 3 or 5) through 12 months of randomisation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| CV death, MI, stroke through 12 months of randomisation | through 12 months of randomisation | — |
| CV death, MI, stroke or Urgent Revascularization through 12 months of randomisation | through 12 months of randomisation | — |
| CV death: any death | 12 months after randomization | — |
| Any death or resuscitated cardiac death | 12 months after randomization | — |
| CV death or MI | 12 months after randomization | — |
| Definite stent thrombosis (ARC definition) | 12 months after randomization | — |
| All types of bleeding according to the BARC definitions 1, 2, 3, 4, 5 | 12 months after randomization | — |
| Evaluation of the benefice of prasugrel adjustment on the composite ischemic endpoint of cardiovascular (CV) death, MI, definite stent thrombosis and Urgent revascularisation through 12 months of randomisation | through 12 months of randomisation | The key secondary objective is to evaluate the benefice of prasugrel adjustment on the composite ischemic endpoint of cardiovascular (CV) death, MI, definite stent thrombosis and Urgent revascularisation through 12 months of randomisation |
| Bleeding TIMI major through 12 months of randomisation | through 12 months of randomisation | — |
| GUSTO severe or moderate bleeding | 12 months after randomization | — |
| STEEPLE bleeding definitions (major, minor or both) | 12 months after randomization | — |
| ISTH bleeding definitions (major and clinically relevant non major) | 12 months after randomization | — |
| Bleeding TIMI minor | 12 months after randomization | — |
| Bleeding TIMI minimal | 12 months after randomization | — |
| Bleeding TIMI major, minor and combination | 12 months after randomization | — |
| BARC Bleeding of type 2, 3 or 5 | 12 months after randomization | — |
Countries
France
Outcome results
None listed