Tailored Antiplatelet Therapy Versus Recommended Dose of Prasugrel (ANTARCTIC)

• ClinicalTrials.gov Identifier: NCT01538446
• Recruitment Status: Completed
• First Posted: February 24, 2012
• Last Update Posted: January 11, 2017
• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Eli Lilly and Company; Daiichi Sankyo, Inc.; Allies in Cardiovascular Trials Initiatives and Organized; Accumetrics, Inc.; Stentys
• Information provided by (Responsible Party): Assistance Publique - Hôpitaux de Paris

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Acute Coronary Syndrome	Drug: Modification of Prasugrel based on a biological assay; Drug: prasugrel / clopidogrel; Device: Verify Now	Phase 4

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 880 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: March 2012
• Actual Primary Completion Date: May 2016
• Actual Study Completion Date: May 2016

Arms and Interventions

Arm	Intervention/treatment
Experimental: 1: Monitoring Arm; Monitoring Arm: dose adjustment of prasugrel with down-adjustment of the dose of prasugrel in high responders and up-adjustment of the dose of prasugrel in low responders	Drug: Modification 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); Device: Verify 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)
Active Comparator: 2: Conventional Arm; Conventional Arm: fixed dose of prasugrel 5 mg	Drug: prasugrel / clopidogrel; fixed dose of prasugrel 5 mg

Outcome Measures

Primary Outcome Measures :

1. 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 [ Time Frame: 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 Outcome Measures :

1. 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 [ Time Frame: 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
2. CV death, MI, stroke through 12 months of randomisation [ Time Frame: through 12 months of randomisation ]
3. CV death, MI, stroke or Urgent Revascularization through 12 months of randomisation [ Time Frame: through 12 months of randomisation ]
4. CV death: any death [ Time Frame: 12 months after randomization ]
5. Any death or resuscitated cardiac death [ Time Frame: 12 months after randomization ]
6. CV death or MI [ Time Frame: 12 months after randomization ]
7. Definite stent thrombosis (ARC definition) [ Time Frame: 12 months after randomization ]
8. All types of bleeding according to the BARC definitions 1, 2, 3, 4, 5 [ Time Frame: 12 months after randomization ]
9. BARC Bleeding of type 2, 3 or 5 [ Time Frame: 12 months after randomization ]
10. Bleeding TIMI major through 12 months of randomisation [ Time Frame: through 12 months of randomisation ]
11. GUSTO severe or moderate bleeding [ Time Frame: 12 months after randomization ]
12. STEEPLE bleeding definitions (major, minor or both) [ Time Frame: 12 months after randomization ]
13. ISTH bleeding definitions (major and clinically relevant non major) [ Time Frame: 12 months after randomization ]
14. Bleeding TIMI minor [ Time Frame: 12 months after randomization ]
15. Bleeding TIMI minimal [ Time Frame: 12 months after randomization ]
16. Bleeding TIMI major, minor and combination [ Time Frame: 12 months after randomization ]

Eligibility Criteria

• Ages Eligible for Study: 75 Years and older (Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

France

CHU Caremeau à Nimes - Service de Cardiologie

Nimes, France, 30029

ACTION study group - Institut de Cardiologie- Hôpital la Pitié Salpêtrière

Paris, France, 75013

Sponsors and Collaborators

Assistance Publique - Hôpitaux de Paris

Eli Lilly and Company

Daiichi Sankyo, Inc.

Allies in Cardiovascular Trials Initiatives and Organized

Accumetrics, Inc.

Stentys

Investigators

• Principal Investigator: Gilles MONTALESCOT, MD,PhD; Assistance Publique - Hôpitaux de Paris

More Information

Publications of Results:

Cayla G, Cuisset T, Silvain J, Leclercq F, Manzo-Silberman S, Saint-Etienne C, Delarche N, Bellemain-Appaix A, Range G, El Mahmoud R, Carrié 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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Cayla G, Cuisset T, Silvain J, Henry P, Leclercq F, Carrié D, Etienne CS, Belle L, Rangé 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.

• Responsible Party: Assistance Publique - Hôpitaux de Paris
• ClinicalTrials.gov Identifier: NCT01538446 History of Changes
• Other Study ID Numbers: P110101
• First Posted: February 24, 2012
• Last Update Posted: January 11, 2017
• Last Verified: January 2017

Keywords provided by Assistance Publique - Hôpitaux de Paris:

Elderly; Acute coronary syndrome; Percutaneous coronary intervention; Prasugrel; Platelet function test

Additional relevant MeSH terms:

Prasugrel Hydrochloride; Acute Coronary Syndrome; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Clopidogrel; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs