Clinical trial NCT00827411: Double Randomization of a Monitoring Adjusted Antiplatelet Treatment Versus a Common Antiplatelet Treatment for DES Implantation, and Interruption Versus Continuation of Double Antiplatelet Therapy
Official title: Double Randomization of a Monitoring Adjusted Antiplatelet Treatment Versus a Common Antiplatelet Treatment for DES Implantation, and a Interruption Versus Continuation of Double Antiplatelet Therapy, One Year After Stenting
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Coronary Artery Disease
Acute Coronary Syndrome
Keywords: Drug Eluting Stent
Percutaneous coronary intervention
Oral antiplatelet therapy
Clopidogrel/Aspirin
Acute Coronary Syndrome
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Allies in Cardiovascular Trials Initiatives and Organized
name: Institut National de la Santé Et de la Recherche Médicale, France
name: Sanofi
name: Bristol-Myers Squibb
name: Medtronic
name: Cordis Corporation
name: Fondation de France
name: Diagnostica Stago
name: Boston Scientific Corporation
First posted: 2009-01-22
Enrollment: 2500
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Our first hypothesis is that dose adjustment of aspirin and clopidogrel based on biological monitoring reduces the rate of severe cardiovascular complications compared to a conventional strategy in patients scheduled for drug eluting stent implantation and followed up for one year. Our second hypothesis is that interruption of clopidogrel / Prasugrel after one year of a combined therapy of clopidogrel/Prasugrel and aspirin is associated with a higher rate of severe cardiovascular complications as compared with patients in whom aspirin and clopidogrel / Prasugrel is maintained during the subsequent 6 months of follow-up.

Detailed description: Participating Centers : 38 french high PCI volume (\>700) centers Rationale: Clopidogrel / Prasugrel (75 mg/day), in combination with aspirin (75 mg/day), is currently the antiplatelet treatment of choice for prevention of stent thrombosis, and clinical trials have shown that, in high-risk patients, prolonged dual antiplatelet treatment is more effective than aspirin alone in preventing major cardiovascular events. However, despite the use of clopidogrel, a considerable number of patients continue to have cardiovascular events. Numerous in VITRO studies have shown that individual responsiveness to clopidogrel but also to aspirin is not uniform in all patients and is subject to inter- and intraindividual variability. The recent possibility of bedside monitoring of oral antiplatelet therapy offers the unique opportunity of tailoring antiplatelet therapy. However, the relevance of such strategy has never been evaluated in a randomized prospective adequately powered study having long term follow-up (rationale 1). Late state stent thrombosis, especially in the era of drug eluting stent and after interruption of OAT, is another important safety issue raising the questions of the modalities of interruption of dual OAT after one year according to the most recent updated recommendations. Can we switch from dual to single OAT after one year? If so, what is the ischemic hazard? (Rational 2) Our first hypothesis is that a strategy of dose adjustment of OAT based on biological monitoring reduces the rate of the combined ischemic endpoints of death, urgent revascularization, stent thrombosis and stroke as compared to a conventional strategy (local practice without monitoring) in patients scheduled for DES implantation and followed up for one year. Our second hypothesis is that interruption of clopidogrel after one year of dual OAT is associated with a higher rate of the same combined ischemic endpoints as compared with patients in whom dual OAT is maintained during the subsequent 6 months of follow-up. Objectives: 1) To demonstrate the superiority of the strategy of monitoring with dose adjustment in suboptimal responders (Monitoring Arm) as compared to a more conventional strategy (Conventional Arm) with fixed dose regimen of both oral antiplatelet agents in all patients as defined by the international guidelines to reduce the primary endpoint evaluated one year after DES implantation. 2) to demonstrate the superiority of a strategy of pursuit of a dual OAT beyond one year (Pursuit Arm) as compared to a strategy of interruption (Interruption Arm).

Duration of the participation : from 18 up to 30 months according to the time delay from study start to randomization. No participants will be excluded from the study at the exception of consent withdrawal. However, participants who have not been randomized for interruption or continuation of DAPT at the 12 month follow up visit will terminate the study

Number of patients: 2500 patients. This number was obtained for the demonstration of the superiority of the strategy of monitoring (Monitoring Arm) over the conventional strategy (Conventional Arm) to reduce the primary endpoint by 33% (relative risk reduction).

Expected results: The ARCTIC study will provide answers to two major clinical challenges. It will also give a unique opportunity to assess the prevalence and the associated risk factors of suboptimal answers to OAT, but also to improve a suboptimal biological response. Finally, the economic impact of both strategies of monitoring and of interruption will be evaluated.

Eligibility criteria: Inclusion Criteria:

* Patients (≥18 years) in whom elective DES stent placement is scheduled after diagnostic angiography
* Patients not treated by GPIIb/IIIa inhibitors prior to randomization.
* Provided written consent for participation in the trial prior to any study-specific procedures or requirements.

Exclusion Criteria:

* Oral anticoagulation (Vitamin K Antagonists).
* Contraindication for aspirin and/or clopidogrel/Prasugrel or GPIIb/IIIa inhibitors or to increasing dose of clopidogrel or aspirin
* Ongoing or recent bleeding and/or recent major surgery (\<3 weeks)
* Severe liver dysfunction
* Thrombocytopenia (Platelet count \<80000/µl).
* IIb/IIIa inhibitors within a week prior to randomization
* STEMI presentation
* Patient at risk of poor compliance to the study
* Patient not affiliated to social security
* Pregnant women, no signed inform consent
* Any invasive or surgical planned intervention during the year after stent placement

Primary outcomes:
measure: Composite endpoint of death, myocardial infarction, stroke, urgent coronary revascularization, stent thrombosis assessed at one year for the first hypothesis and between 6 up to 18 months of follow-up for the second hypothesis
timeFrame: during the study (one year in both " monitoring " and " conventional " arms and during the periode from 6 up to 18 months in the "interruption" and "pursuit" arms)
Secondary outcomes:
measure: Stent thrombosis and urgent coronary revascularization
timeFrame: at month 12 and month 30
measure: Rate of individual event at one year follow-up in both " monitoring " and " conventional " arms but also during the period from one year up to 24 months in the " interruption " and " pursuit " arms.
timeFrame: at month 12 and month 30
measure: Time delay from treatment interruption (randomization 2) to any thrombotic event (stent thrombosis, urgent revascularization, acute myocardial infarction, cardiac death) treatment interruption(randomisation 2)
timeFrame: at month 12 and month 30
measure: Treatment compliance evaluated by the number of oral antiplatelet treatment in both arms and with respect to all individual events of the primary composite endpoint
timeFrame: at month 12 and month 30
measure: Rate of use of GP IIb/IIIa receptor antagonists in both " monitoring " and " conventional " arms before percutaneous coronary intervention and in bail out situations and in both.
timeFrame: at month 12 and month 30
measure: Rate of suboptimal responders as defined by ARU>550 for aspirin or by a % of inhibition <15% and or a PRU<235) and the average dosage of aspirin and clopidogrel (in mg) will evaluated before and after dose adjustment (J0) and after each dose adjustment
timeFrame: at month 12 and month 30
measure: Net clinical benefit (death, myocardial infarction, urgent revascularization, stent thrombosis, stroke, major bleeding)
timeFrame: at month 12 and month 30
measure: Medico-economic evaluations will be performed for both hypotheses. The rate of rehospitalisation and the length of stay will be used as economic indicators
timeFrame: at month 12 and month 30
Other outcomes:
Locations:
city: Paris
country: France
facility: Institut de Cardiologie- Hopital la Pitié Salpétrière
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Gilles Montalescot, PUPH
role: PRINCIPAL_INVESTIGATOR
affiliation: Assistance Publique - Hôpitaux de Paris
name: Jean-Philippe Collet, PH
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Collet JP, Cayla G, Cuisset T, Elhadad S, Range G, Vicaut E, Montalescot G. Randomized comparison of platelet function monitoring to adjust antiplatelet therapy versus standard of care: rationale and design of the assessment with a double randomization of (1) a fixed dose versus a monitoring-guided dose of aspirin and clopidogrel after DES implantation, and (2) treatment interruption versus continuation, 1 year after stenting (ARCTIC) study. Am Heart J. 2011 Jan;161(1):5-12.e5. doi: 10.1016/j.ahj.2010.09.029.
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citation: Collet JP, Hulot JS, Cuisset T, Range G, Cayla G, Van Belle E, Elhadad S, Rousseau H, Sabouret P, O'Connor SA, Abtan J, Kerneis M, Saint-Etienne C, Barthelemy O, Beygui F, Silvain J, Vicaut E, Montalescot G; ARCTIC investigators. Genetic and platelet function testing of antiplatelet therapy for percutaneous coronary intervention: the ARCTIC-GENE study. Eur J Clin Pharmacol. 2015 Nov;71(11):1315-24. doi: 10.1007/s00228-015-1917-9. Epub 2015 Aug 13.
citation: Collet JP, Silvain J, Barthelemy O, Range G, Cayla G, Van Belle E, Cuisset T, Elhadad S, Schiele F, Lhoest N, Ohlmann P, Carrie D, Rousseau H, Aubry P, Monsegu J, Sabouret P, O'Connor SA, Abtan J, Kerneis M, Saint-Etienne C, Beygui F, Vicaut E, Montalescot G; ARCTIC investigators. Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomised trial. Lancet. 2014 Nov 1;384(9954):1577-85. doi: 10.1016/S0140-6736(14)60612-7. Epub 2014 Jul 15.
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