REsistance to Aspirin and Clopidogrel in acuTe Myocardial Infarction (REACT-MI)

Phase IV Study of Aspirin and Clopidogrel Therapy Tailored by Functional Thrombocyte Examination (PFA-100, LTA and VerifyNOW) in Acute Myocardial Infarction

The purpose of this study is to compare 3 point-of-care methods for monitoring antiplatelet therapy to golden standard (Light transmittance aggregometry-LTA) in high risk population of acute myocardial infarction patients. If two methods (PFA-100, VerifyNOW,Multiplate or LTA) will indicate insufficient antiplatelet blockade/high residual reactivity for aspirin, clopidogrel or both, the dose of aspirin will be increased to 200mg qd and the dose of clopidogrel will be increased to 2x75mg qd.In addition genotyping of CYP2C19 (6 alleles) will be performed.

Study Overview

• Status: Completed
• Conditions: Acute Myocardial Infarction
• Intervention / Treatment: Drug: Aspirin 200mg qd, Clopidogrel 2x75mg qd

Detailed Description

Dual antiplatelet therapy is the cornerstone of treatment of coronary heart disease after coronary stent implantation. The interindividual response to this therapy is not uniform, however. There are subgroups of patients, where no anticipated antiplatelet effect to either aspirin, clopidogrel or both is reached. The term of aspirin/clopidogrel resistance has been introduced few years ago, most recently it was substituted by more suitable term - high on-treatment residual platelet reactivity (HPR). Although there are many assays to monitor antiplatelet therapy, uncertainty still remains about the correlation of HPR with ischemic vascular events (in-stent thrombosis, myocardial infarction, etc.). Thus platelet aggregation testing is considered to be the most promising method to indicate inappropriate/low response to aspirin/clopidogrel, however the best suited method is not established yet. Up-to date light transmittance aggregometry is widely accepted as golden standard, nonetheless labour intensive and difficult to standardize. On the other hand many point-of-care aggregation testing methods like PFA-100, VerifyNOW, Multiplate etc. have been introduced, their role in clinical practice is uncertain, however. The biggest challenge of today is to determine platelet function assay, which could reliably indicate future ischemic vascular events;moreover it could be potentially used to tailor antiplatelet therapy and precede these events. It was demonstrated, that gene polymorphism - CYP2C19*2 and CYP2C9*3 loss of function is conjugated with an increased occurrence of stent thrombosis. Within the project we also plan to examine 4 alleles which have not been examined in detail before.

• Study Type: Interventional
• Enrollment (Actual): 154
• Phase: Phase 4

Contacts and Locations

Study Locations

• Czech Republic
  • Prostejov, Czech Republic, 79604
    • Departement of Laboratory Medicine, Prostejov Hospital
  • Poruba
    • Ostrava, Poruba, Czech Republic, 70852
      • University Hospital Ostrava

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• acute myocardial infarction (verified by troponin I elevation and ST-segment deviation ≥0.1mV in ≥2 contiguous ECG leads persisting for at least 20 minutes and angiographical proof of coronary stenosis )
• preceding antiplatelet medication with aspirin100mg qd/5 and more days before PCI
• pre-treatment with 600mg Clopidogrel loading dose
• preferably patients with drug eluting stent implantation
• signed informed consent

Exclusion Criteria:

• stable/unstable angina pectoris
• active malignancy
• contraindication to antiplatelet therapy
• increased risk of bleeding (trauma, surgery or non-ischemic stroke in last month)
• effective anticoagulation therapy:LMWH, Pradaxa, Xarelto, Warfarin
• known thrombophile disorder
• SIRS
• renal insufficiency (eGFR under 15ml/min)
• severe anemia (<80 g/l)
• polyglobulia (>160 g/l)
• pregnancy
• Hematocrit <0.25 > 0.55

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Standard therapy; standard dose of 100mg aspirin qd and 1x75mg Clopidogrel will be given
Active Comparator: ASA/CLP increase; According to 2 platelet monitoring assays HPR confirmation aspirin will be increased to 200mg qd, clopidogrel to 2x75mg qd	Drug: Aspirin 200mg qd, Clopidogrel 2x75mg qd; According to 2 platelet monitoring assays HPR confirmation aspirin will be increased to 200mg qd, clopidogrel to 2x75mg qd. This treatment will be given for 30 days from index event (myocardial infarction); Other Names: R-130964

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Platelet inhibition level	The main outcome measure is the difference in platelet inhibition between clopidogrel 1x75mg and 2x75mg in HPR patients	5 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bleeding Events	TIMI major/minor bleeding Bleeding prediction with Crusade bleeding score (calculator free accessible at http://www.crusadebleedingscore.org/index.html)	30 days
Stent thrombosis	In-stent thrombosis will be assessed in 30-days time-frame in all patients included in the trial. -- due to inadequate power of the trial IST cannot be primary outcome measure--	30 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ischaemic events (not IST)	unplanned targed vessel revascularisation (TVR), need for coronary - aortic by-pass graft ,myocardial infarction	30 days

Collaborators and Investigators

• Sponsor: University Hospital Ostrava
• Investigators: Principal Investigator: Jiri Plasek, MD, PhD, Department of Cardiology, University Hospital Ostrava; Study Chair: Miroslav Homza, MD, Department of Cardiology, University Hospital Ostrava; Study Chair: Jaromir Gumulec, MD, Institute of clinical Hematology, University Hospital Ostrava

Publications and helpful links

General Publications

• Marcucci R, Gori AM, Paniccia R, Giusti B, Valente S, Giglioli C, Buonamici P, Antoniucci D, Abbate R, Gensini GF. Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay: a 12-month follow-up. Circulation. 2009 Jan 20;119(2):237-42. doi: 10.1161/CIRCULATIONAHA.108.812636. Epub 2008 Dec 31.
• Cuisset T, Cayla G, Frere C, Quilici J, Poyet R, Gaborit B, Bali L, Morange PE, Alessi MC, Bonnet JL. Predictive value of post-treatment platelet reactivity for occurrence of post-discharge bleeding after non-ST elevation acute coronary syndrome. Shifting from antiplatelet resistance to bleeding risk assessment? EuroIntervention. 2009 Aug;5(3):325-9. doi: 10.4244/51.
• Sibbing D, Byrne RA, Bernlochner I, Kastrati A. High platelet reactivity and clinical outcome - fact and fiction. Thromb Haemost. 2011 Aug;106(2):191-202. doi: 10.1160/TH11-01-0040. Epub 2011 Apr 20.

Helpful Links

• Site info

Study record dates

Study Major Dates

• Study Start: May 1, 2011
• Primary Completion (Actual): June 1, 2015
• Study Completion (Actual): July 1, 2015

Study Registration Dates

• First Submitted: June 22, 2011
• First Submitted That Met QC Criteria: June 22, 2011
• First Posted (Estimate): June 27, 2011

Study Record Updates

• Last Update Posted (Estimate): October 27, 2016
• Last Update Submitted That Met QC Criteria: October 26, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: myocardial infarction; percutaneous coronary intervention (PCI); high platelet reactivity (HPR)
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Myocardial Infarction; Infarction; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Aspirin; Clopidogrel
• Other Study ID Numbers: FNO-KVO-1; plasek680 (Other Identifier: University Hospital Ostrava)