Double Randomization of a Monitoring Adjusted Antiplatelet Treatment Versus a Common Antiplatelet Treatment for DES Implantation, and Interruption Versus Continuation of Double Antiplatelet Therapy

Condition(s) targeted: Coronary Artery Disease; Acute Coronary Syndrome

Intervention: Aspirin and clopidogrel (Drug); VerifyNow (Device); Aspirin and clopidogrel (Drug); Aspirin and clopidogrel (Drug); Aspirin (Drug)

Phase: Phase 4

Status: Recruiting

Sponsored by: Assistance Publique - Hôpitaux de Paris

Official(s) and/or principal investigator(s):
Gilles Montalescot, PUPH, Principal Investigator, Affiliation: Assistance Publique - Hôpitaux de Paris
Jean-Philippe Collet, PH, Principal Investigator, Affiliation: Assistance Publique - Hôpitaux de Paris

Overall contact:
Gilles Montalescot, PUPH, Phone: (33) 1 42 16 30 06, Email: gilles.montalescot@psl.aphp.fr

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 after one year of a combined therapy of clopidogrel and aspirin is associated with a higher rate of severe cardiovascular complications as compared with patients in whom aspirin and clopidogrel is maintained during the subsequent 6 months of follow-up.

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 design: Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Efficacy Study

Primary outcome: 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

Secondary outcome:

Stent thrombosis and urgent coronary revascularization

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.

Time delay from treatment interruption (randomization 2) to any thrombotic event (stent thrombosis, urgent revascularization, acute myocardial infarction, cardiac death) treatment interruption(randomisation 2)

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

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.

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

Net clinical benefit (death, myocardial infarction, urgent revascularization, stent thrombosis, stroke, major bleeding)

Medico-economic evaluations will be performed for both hypotheses. The rate of rehospitalisation and the length of stay will be used as economic indicators

Detailed description: Participating Centers : 30 french high PCI volume (>700) centers Rationale: Clopidogrel (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).

Study duration (FPI-LPO) : 30 months 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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Patients >18 year old who already underwent coronary angiography and who is scheduled

for elective percutaneous coronary intervention with at least one drug eluting stent were scheduled for coronary angiography.

- Patients who had coronary angiography with immediate PCI following 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 or GPIIb/IIIa inhibitors or to

increasing dose of clopidogrel or aspirin

- Patient with recent bleeding or surgery (<3 weeks)

- Administration of GPIIb/IIIa inhibitors prior the randomization

- Acute Coronary Syndrome with ST- segment elevation

- Personal history of Haematological disorders (bleeding disorders,haemorrhage..)

- Severe chronic liver disease

- Primary angioplasty

- Thrombocytopenia (Platelet count <80000/µl).

- Patients scheduled for surgery during the first year of follow-up-Patient with a

prior history of haemorrhagic peptic ulcers

- Patient at risk of poor compliance to the study

- Patient not affiliated to social security

- Pregnant women, no signed inform consent

Gilles Montalescot, PUPH, Phone: (33) 1 42 16 30 06, Email: gilles.montalescot@psl.aphp.fr

Institut de Cardiologie- Hopital la Pitié Salpétrière, PARIS 75013, France; Recruiting
Gilles Montalescot, PUPH, Phone: + 33 (0) 1 42 16 30 06, Email: gilles.montalescot@psl.fr

Starting date: January 2009
Ending date: July 2011
Last updated: January 28, 2009