Customized Choice of Oral P2Y12 Receptor Blocker (PRU-MATRIX)

Customized Choice of P2Y12 Oral Receptor Blocker Based on Phenotype Assessment Via Point of Care Testing

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.

Study Overview

• Status: Unknown
• Conditions: Acute Coronary Syndrome; Coronary Angioplasty
• Intervention / Treatment: Drug: Oral P2Y12 receptor blocker; Drug: Customized choice for the oral P2Y12 receptor blocker

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.

• Study Type: Interventional
• Enrollment (Anticipated): 4000
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Marco Valgimigli, MD, PhD; Phone Number: +39 3356478877; Email: vlgmrc@unife.it
• Study Contact Backup: Name: Maria Salomone, MD; Phone Number: +39 3357378767; Email: m.salomone@dimensione-ricerca.com

Study Locations

• Italy
  • Brescia, Italy
    • Active, not recruiting
    • Spedali Civili di Brescia
  • Carbonia, Italy
    • Recruiting
    • Azienda USL Sirai
    • Contact: Salvatore Ierna, MD
    • Principal Investigator: Salvatore Ierna, MD
  • Ferrara, Italy, 44100
    • Recruiting
    • University Hospital of Ferrara
    • Contact: Marco Valgimigli, MD, PhD; Phone Number: +39 3356478877; Email: vlgmrc@unife.it
  • Lodi, Italy
    • Active, not recruiting
    • Ospedale di Lodi
  • Naples, Italy
    • Recruiting
    • Ospedale dei Colli, Cardiologia SUN
    • Principal Investigator: Paolo Calabro, MD
    • Contact: Paolo Calabrò, MD PhD
  • Rimini, Italy
    • Recruiting
    • Ospedale degli Infermi di Rimini
    • Principal Investigator: Andrea Santarelli, MD
  • Torino, Italy
    • Recruiting
    • Ospedale San Giovanni Bosco
    • Contact: Roberto Garbo, MD
    • Principal Investigator: Roberto Garbo, MD
  • Vimercate, Italy
    • Recruiting
    • A. O. Ospedale Civile di Vimercate
    • Contact: Stefano Garducci, MD
    • Principal Investigator: Stefano Garducci, MD
  • Zingonia, Italy
    • Recruiting
    • Policlinico San Marco
    • Contact: Nicoletta De Cesare, MD
    • Principal Investigator: Nicoletta De Casare, MD
  • Calabria
    • Catanzaro, Calabria, Italy, 88100
      • Active, not recruiting
      • Azienda Ospedaliera Pugliese Ciaccio
  • MI
    • Milano, MI, Italy, 20121
      • Recruiting
      • Azienda Ospedaliera Fatebenefratelli e Oftalmico
      • Contact: B. Cortese, MD; Phone Number: +393347298103; Email: bcortese@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard of Care; The treating physician will be left free to give the oral P2Y12 receptor blocker, including clopidogrel,prasugrel or ticagrelor, which according to his/her clinical judgement is most appropriate for the individual patient.	Drug: Oral P2Y12 receptor blocker; Free choice among clopidogrel, prasugrel or ticagrelor
Experimental: Customized choice of the oral P2Y12 receptor blocker; The choice of the oral P2Y12 receptor blocker will be based on an algorithm which integrates phenotype information, including but not limited to residual on-treatment platelet reactivity assessed via Verifynow P2Y12 assay.	Drug: Customized choice for the oral P2Y12 receptor blocker; one drug among clopidogrel, prasugrel or ticagrelor based on an algorithm integrating phenotype information.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiovascular death, myocardial infarction, stroke or BARC defined bleeding type 2, 3 or 5	The time to first occurrence of any of the variables listed above will be reported as primary study outcome.	1 year
Proportion of patients in the therapeutic range for residual P2Y12 pathway activity according to PRU values.	We expect that the prospective use of the previously generated combined phenotype and genotype algorithm will result in an higher proportion of patients being in the therapeutic range with respect to the P2Y12 residual activity (70%) as compared to patients in who the P2Y12 inhibitor is left to the discretion of the treating physician. The first 320 patients recruited in the present study will participate into this mechanistic sub-study.	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
myocardial infarction		1 year
stroke		1 year
cardiovascular death		1 year
Overall death		1
BARC bleeding type 2		1 year
BARC bleeding type 3		1 year
BARC bleeding type 5		1 year
Bleeding classified according to the Bleedscore		1 year
Stent thrombosis	Stent thrombosis will be reported according to the ARC classification	1 year

Collaborators and Investigators

• Sponsor: Italian Society of Invasive Cardiology
• Collaborators: Eustrategy
• Investigators: Principal Investigator: Marco Valgimigli, MD, PhD, University Hospital of Ferrara

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: January 1, 2012
• Primary Completion (Anticipated): December 1, 2014
• Study Completion (Anticipated): December 1, 2015

Study Registration Dates

• First Submitted: October 27, 2011
• First Submitted That Met QC Criteria: November 19, 2011
• First Posted (Estimate): November 23, 2011

Study Record Updates

• Last Update Posted (Estimate): September 3, 2014
• Last Update Submitted That Met QC Criteria: September 1, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Keywords: myocardial infarction; coronary stent; Oral P2Y12 receptor blocker; Platelet reactivity units (PRU)
• Additional Relevant MeSH Terms: Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Acute Coronary Syndrome
• Other Study ID Numbers: RFBU 13-I-PRU