Clinical trial NCT01538446: Tailored Antiplatelet Therapy Versus Recommended Dose of Prasugrel
Official title: The ANTARCTIC Study - Assessment of a Normal Versus Tailored Dose of Prasugrel After Stenting in Patients Aged > 75 Years to Reduce the Composite of Bleeding, Stent Thrombosis and Ischemic Complications
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Acute Coronary Syndrome
Keywords: Elderly
Acute coronary syndrome
Percutaneous coronary intervention
Prasugrel
Platelet function test
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Eli Lilly and Company
name: Daiichi Sankyo
name: Allies in Cardiovascular Trials Initiatives and Organized
name: Accumetrics, Inc.
name: Stentys
First posted: 2012-02-24
Enrollment: 880
Sex: ALL
Minimum age (years): 75
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: through 12 months of randomisation
Secondary outcomes:
measure: 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
timeFrame: through 12 months of randomisation
measure: CV death, MI, stroke through 12 months of randomisation
timeFrame: through 12 months of randomisation
measure: CV death, MI, stroke or Urgent Revascularization through 12 months of randomisation
timeFrame: through 12 months of randomisation
measure: CV death: any death
timeFrame: 12 months after randomization
measure: Any death or resuscitated cardiac death
timeFrame: 12 months after randomization
measure: CV death or MI
timeFrame: 12 months after randomization
measure: Definite stent thrombosis (ARC definition)
timeFrame: 12 months after randomization
measure: All types of bleeding according to the BARC definitions 1, 2, 3, 4, 5
timeFrame: 12 months after randomization
measure: BARC Bleeding of type 2, 3 or 5
timeFrame: 12 months after randomization
measure: Bleeding TIMI major through 12 months of randomisation
timeFrame: through 12 months of randomisation
measure: GUSTO severe or moderate bleeding
timeFrame: 12 months after randomization
measure: STEEPLE bleeding definitions (major, minor or both)
timeFrame: 12 months after randomization
measure: ISTH bleeding definitions (major and clinically relevant non major)
timeFrame: 12 months after randomization
measure: Bleeding TIMI minor
timeFrame: 12 months after randomization
measure: Bleeding TIMI minimal
timeFrame: 12 months after randomization
measure: Bleeding TIMI major, minor and combination
timeFrame: 12 months after randomization
Other outcomes:
Locations:
city: Nimes
country: France
facility: CHU Caremeau à Nimes - Service de Cardiologie
city: Paris
country: France
facility: ACTION study group - Institut de Cardiologie- Hôpital la Pitié Salpêtrière
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Gilles MONTALESCOT, MD,PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cayla G, Cuisset T, Silvain J, Leclercq F, Manzo-Silberman S, Saint-Etienne C, Delarche N, Bellemain-Appaix A, Range G, El Mahmoud R, Carrie D, Belle L, Souteyrand G, Aubry P, Sabouret P, du Fretay XH, Beygui F, Bonnet JL, Lattuca B, Pouillot C, Varenne O, Boueri Z, Van Belle E, Henry P, Motreff P, Elhadad S, Salem JE, Abtan J, Rousseau H, Collet JP, Vicaut E, Montalescot G; ANTARCTIC investigators. Platelet function monitoring to adjust antiplatelet therapy in elderly patients stented for an acute coronary syndrome (ANTARCTIC): an open-label, blinded-endpoint, randomised controlled superiority trial. Lancet. 2016 Oct 22;388(10055):2015-2022. doi: 10.1016/S0140-6736(16)31323-X. Epub 2016 Aug 28.
citation: Lattuca B, Cayla G, Silvain J, Cuisset T, Leclercq F, Manzo-Silberman S, Saint-Etienne C, Delarche N, El Mahmoud R, Carrie D, Souteyrand G, Kerneis M, Hauguel-Moreau M, Zeitouni M, Guedeney P, Diallo A, Collet JP, Vicaut E, Montalescot G; ACTION Study Group. Bleeding in the Elderly: Risk Factors and Impact on Clinical Outcomes After an Acute Coronary Syndrome, a Sub-study of the Randomized ANTARCTIC Trial. Am J Cardiovasc Drugs. 2021 Nov;21(6):681-691. doi: 10.1007/s40256-021-00468-8. Epub 2021 Jun 30.
citation: Cayla G, Cuisset T, Silvain J, Henry P, Leclercq F, Carrie D, Etienne CS, Belle L, Range G, Pouillot C, Varenne O, Van Belle E, Boueri Z, Motreff P, Elhadad S, Delarche N, El Mahmoud R, Vicaut E, Collet JP, Montalescot G; ANTARCTIC investigators. Platelet function monitoring in elderly patients on prasugrel after stenting for an acute coronary syndrome: design of the randomized antarctic study. Am Heart J. 2014 Nov;168(5):674-81. doi: 10.1016/j.ahj.2014.07.026. Epub 2014 Aug 7.