Clinical trial NCT01477775: Customized Choice of Oral P2Y12 Receptor Blocker
Official title: Customized Choice of P2Y12 Oral Receptor Blocker Based on Phenotype Assessment Via Point of Care Testing
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Acute Coronary Syndrome
Coronary Angioplasty
Keywords: myocardial infarction
coronary stent
Oral P2Y12 receptor blocker
Platelet reactivity units (PRU)
Lead sponsor: Italian Society of Invasive Cardiology
Sponsor class: OTHER
Collaborators: name: Eustrategy
First posted: 2011-11-23
Enrollment: 4000
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: A subset of patients recruited in the main MATRIX study will be randomized after intervention but before discharge to standard of care (the treating physician will decide which oral P2Y12 inhibitor will be added on top of aspirin) versus a customized approach based on an algorithm which integrates phenotypic information, including but not limited to residual on-treatment platelet reactivity assessed via VerifyNow P2Y12 Assay.

Detailed description: Up to 20-30% of clopidogrel treated patients do not adequately respond to the drug and are at higher risk for ischemic events including death, myocardial infarction, stroke and stent thrombosis.

Residual high on-treatment platelet reactivity while the patient is on clopidogrel depends on a complex interplay of phenotypic (spontaneous platelet reactivity, inflammatory status, acuity of the clinical presentation, age, renal function) and genetic variables.

Two main Loss of function alleles have been identified: 1) CYP450 2C19\*2 is present in around 25% of the Caucasian population and result in a lower amount of clopidogrel active metabolite. Carriers of 2C19\*2 are at higher risk for death or MI and 2.7 fold increase in the risk of stent thrombosis if treated with conventional clopidogrel; 2) ABCB-1 C carriers have reduced clopidogrel absorption and they have similarly been shown to be at higher risk for ischemic adverse events if treated with clopidogrel. Many investigators have recently shown however, that the positive predictive value of genetic testing alone at the time of PCI is limited and the knowledge of genetic status alone with respect to the two previously described loss of function alleles is only poorly able to identify to long-term clopidogrel poor responders. An Algorithm has therefore been developed, combining phenotype information which has been shown to risk stratify both ischemic and bleeding events up to one year follow-up in PCI patients.

This algorithm has been developed from a single center retrospective registry. To prospectively validate it in the context of a prospective multicenter study, the first 320 patients recruited in the present study will undergo phenotype at discharge and at 30 days and genotype assessment at the time of randomization, irrespective of the group which they have been assigned to (i.e. standard of care or gene and phenotype). The hypothesis behind this mechanistic sub-study is that the use of this combined phenotype-genotype algorithm will increase the proportion of patients at 30 days who will be in the therapeutic range according to PRU values from 50% in the standard of care versus 70% in the gene and phenotype group.

Eligibility criteria: Inclusion Criteria:

* patients recruited in the main MATRIX study who underwent coronary angioplasty with stent placement.

Exclusion Criteria:

* unwillingness to sign this sub study specific informed consent

Primary outcomes:
measure: Cardiovascular death, myocardial infarction, stroke or BARC defined bleeding type 2, 3 or 5
timeFrame: 1 year
measure: Proportion of patients in the therapeutic range for residual P2Y12 pathway activity according to PRU values.
timeFrame: 30 days
Secondary outcomes:
measure: Overall death
timeFrame: 1
measure: cardiovascular death
timeFrame: 1 year
measure: myocardial infarction
timeFrame: 1 year
measure: stroke
timeFrame: 1 year
measure: BARC bleeding type 2
timeFrame: 1 year
measure: BARC bleeding type 3
timeFrame: 1 year
measure: BARC bleeding type 5
timeFrame: 1 year
measure: Bleeding classified according to the Bleedscore
timeFrame: 1 year
measure: Stent thrombosis
timeFrame: 1 year
Other outcomes:
Locations:
city: Catanzaro
country: Italy
facility: Azienda Ospedaliera Pugliese Ciaccio
state: Calabria
city: Milano
country: Italy
facility: Azienda Ospedaliera Fatebenefratelli e Oftalmico
state: MI
city: Brescia
country: Italy
facility: Spedali Civili di Brescia
city: Carbonia
country: Italy
facility: Azienda USL Sirai
city: Ferrara
country: Italy
facility: University Hospital of Ferrara
city: Lodi
country: Italy
facility: Ospedale di Lodi
city: Naples
country: Italy
facility: Ospedale dei Colli, Cardiologia SUN
city: Rimini
country: Italy
facility: Ospedale degli Infermi di Rimini
city: Torino
country: Italy
facility: Ospedale San Giovanni Bosco
city: Vimercate
country: Italy
facility: A. O. Ospedale Civile di Vimercate
city: Zingonia
country: Italy
facility: Policlinico San Marco
Study officials:
affiliation: University Hospital of Ferrara
name: Marco Valgimigli, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Campo G, Parrinello G, Ferraresi P, Lunghi B, Tebaldi M, Miccoli M, Marchesini J, Bernardi F, Ferrari R, Valgimigli M. Prospective evaluation of on-clopidogrel platelet reactivity over time in patients treated with percutaneous coronary intervention relationship with gene polymorphisms and clinical outcome. J Am Coll Cardiol. 2011 Jun 21;57(25):2474-83. doi: 10.1016/j.jacc.2010.12.047.
citation: Campo G, Ferraresi P, Marchesini J, Bernardi F, Valgimigli M. Relationship between paraoxonase Q192R gene polymorphism and on-clopidogrel platelet reactivity over time in patients treated with percutaneous coronary intervention. J Thromb Haemost. 2011 Oct;9(10):2106-8. doi: 10.1111/j.1538-7836.2011.04457.x. No abstract available.
citation: Campo G, Miccoli M, Tebaldi M, Marchesini J, Fileti L, Monti M, Valgimigli M, Ferrari R. Genetic determinants of on-clopidogrel high platelet reactivity. Platelets. 2011;22(6):399-407. doi: 10.3109/09537104.2011.579648. Epub 2011 May 31.
citation: Valgimigli M, Campo G, de Cesare N, Meliga E, Vranckx P, Furgieri A, Angiolillo DJ, Sabate M, Hamon M, Repetto A, Colangelo S, Brugaletta S, Parrinello G, Percoco G, Ferrari R; Tailoring Treatment With Tirofiban in Patients Showing Resistance to Aspirin and/or Resistance to Clopidogrel (3T/2R) Investigators. Intensifying platelet inhibition with tirofiban in poor responders to aspirin, clopidogrel, or both agents undergoing elective coronary intervention: results from the double-blind, prospective, randomized Tailoring Treatment with Tirofiban in Patients Showing Resistance to Aspirin and/or Resistance to Clopidogrel study. Circulation. 2009 Jun 30;119(25):3215-22. doi: 10.1161/CIRCULATIONAHA.108.833236. Epub 2009 Jun 15.