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PRotective Effect on the Coronary Microcirculation of Patients With DIabetes by Clopidogrel or Ticagrelor (PREDICT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02698618
Recruitment Status : Unknown
Verified February 2016 by Javier Escaned, Hospital San Carlos, Madrid.
Recruitment status was:  Not yet recruiting
First Posted : March 4, 2016
Last Update Posted : March 4, 2016
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
Javier Escaned, Hospital San Carlos, Madrid

Study Description
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Brief Summary:
The purpose of this study is to determine whether Ticagrelor has a protective effect on microcirculation during percutaneous coronary interventions in patients with Diabetes mellitus type II or in a pre-diabetic status.

Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 2 Procedure: Diagnostic Drug: Randomization Procedure: PCI Phase 4

Detailed Description:

Introduction:

Patients with Diabetes Mellitus (DM) Type 2 still consistently perform worse than their non-diabetic counterparts especially in the setting of Percutaneous Coronary Intervention (PCI). The abnormal coronary microcirculation along with the higher risk of distal embolization of particles released from the PCI target lesion constitutes the main cause of peri-procedural microcirculatory damage.

New antiplatelet agents, in particular Ticagrelor, might also play a protective role on microcirculation. Ticagrelor inhibits cellular uptake of adenosine, increasing the circulating levels of adenosine through the inhibition of its physiological clearance. Adenosine may protect the myocardium from both ischemic, and reperfusion injury via its potent vasodilatory effects and possibly by anti-inflammatory and antiplatelet properties.

Additionally previous research have identified a more profound effect of adenosine on microcirculatory resistance associated to obesity and diabetes and a higher myocardial protective effect of Ticagrelor during PCI might be expected in this high risk subgroup of patients.

The purpose of PRotective Effect on the Coronary Microcirculation of Patients With DIabetes by Clopidogrel or Ticagrelor (PREDICT) trial was designed to investigate the protective effect of Ticagrelor on microcirculation during PCI in stable diabetic patient

Rationale:

  1. Coronary plaques at high risk for distal embolization during PCI, like the one with thin-cap fibroatheroma (TCFA), are more prevalent in patient with DM. Thus, this population is at high risk to develop myocardial injury and microcirculation impairment subsequent to PCI.
  2. By blocking the Adenosine transporter (ENT) 1 nucleoside cell membrane transporter, Ticagrelor inhibits cellular uptake of adenosine, increasing the circulating levels of adenosine through the inhibition of its physiological clearance. Adenosine may protect the myocardium from both ischemic, and reperfusion injury via its potent vasodilatory effects and possibly by anti-inflammatory and antiplatelet properties. This translates into an adenosine-mediated vasodilatory effect of ticagrelor that takes place soon after loading dose.
  3. Previous research from our group have identified a more profound effect of adenosine on microcirculatory resistance associated to obesity and diabetes and a higher myocardial protective effect of Ticagrelor during PCI might be expected in this high risk subgroup of patients. (enhanced microcirculatory response to raised adenosine levels).

Giving these premises in diabetics or pre-diabetics patients, Ticagrelor treatment pre-PCI might improve microcirculatory parameters (lower resistance) compared with clopidogrel (secondary hypothesis). Ticagrelor might be superior to clopidogrel in providing microcirculatory protection during PCI procedures in the same subgroup of patients (primary hypothesis).

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: PRotective Effect on the Coronary Microcirculation of Patients With DIabetes by Clopidogrel or Ticagrelor
Study Start Date : March 2016
Estimated Primary Completion Date : March 2017
Estimated Study Completion Date : March 2017

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Ticagrelor
A loading dose of Ticagrelor 180mg followed by a dose of 90mg b.i.d. (during 48 hours)
 Procedure: Diagnostic

Pre-PCI and treatment:

  1. At hospital admission: all consecutive patients referred for coronary angiography in stable ischemic heart disease will undergo a complete physical examination, Electrocardiogram (ECG) and laboratory blood testing including cardiac troponin and kinase mioband. Subjects will be investigated to confirm or diagnose existing diabetic or pre-diabetic status.
  2. At the time of diagnostic catheterization After informed consent, diabetic or pre-diabetic patients with at least one stenosis with a Fractional Flow Reserve value (FFR) ≤ 0.80 fulfilling all the inclusion/exclusion criteria will be included in the trial.At the same time, a multimodal physiology assessment, including Coronary Flow Reserve (CFR) and Index of Microcirculatory Resistance (IMR) will be measured.

Drug: Randomization
Randomization: patients will be randomly assigned (with 1:1 ratio) to receive either Clopidogrel or Ticagrelor before their clinically-indicated Percutaneous Coronary Intervention (PCI). Either a loading dose of Ticagrelor 180mg followed by a dose of 90mg b.i.d. (during 48 hours) or a loading dose of Clopidogrel 600mg followed by a daily dose (during at least 48 hours) of 75mg will be administered according to their randomization. Additionally the groups will be balanced according to obesity prevalence [Body Mass Index (BMI) ≥30 kg/m2] with the implementation of a dedicated randomization list.

Procedure: PCI
  1. Pre-PCI: multimodal physiological evaluation: FFR, CFR, IMR will be repeated
  2. PCI: For all the patients undergoing PCI, the use of unfractioned heparin (UHF) will be allowed at the time of PCI; UFH be administered with a target on Activated Clotting Time (ACT) of 200-250 s. The PCI procedures will be performed by standard technique using only second generation Drug Eluting Stents (DES). In all cases, balloon pre-dilatation will be performed before stent implantation using a semi-compliant balloon with a diameter lower than a 75% of the distal reference diameter of the vessel to avoid confounders Post-dilation will be performed according to clinical practice although it will be not mandatory.
  3. Post-PCI: After stent implantation/s, multimodal physiological evaluation will be re-performed (FFR, CFR, IMR).
Active Comparator: Clopidogrel
A loading dose of Clopidogrel 600mg followed by a daily dose (during at least 48 hours) of 75mg
 Procedure: Diagnostic

Pre-PCI and treatment:

  1. At hospital admission: all consecutive patients referred for coronary angiography in stable ischemic heart disease will undergo a complete physical examination, Electrocardiogram (ECG) and laboratory blood testing including cardiac troponin and kinase mioband. Subjects will be investigated to confirm or diagnose existing diabetic or pre-diabetic status.
  2. At the time of diagnostic catheterization After informed consent, diabetic or pre-diabetic patients with at least one stenosis with a Fractional Flow Reserve value (FFR) ≤ 0.80 fulfilling all the inclusion/exclusion criteria will be included in the trial.At the same time, a multimodal physiology assessment, including Coronary Flow Reserve (CFR) and Index of Microcirculatory Resistance (IMR) will be measured.

Drug: Randomization
Randomization: patients will be randomly assigned (with 1:1 ratio) to receive either Clopidogrel or Ticagrelor before their clinically-indicated Percutaneous Coronary Intervention (PCI). Either a loading dose of Ticagrelor 180mg followed by a dose of 90mg b.i.d. (during 48 hours) or a loading dose of Clopidogrel 600mg followed by a daily dose (during at least 48 hours) of 75mg will be administered according to their randomization. Additionally the groups will be balanced according to obesity prevalence [Body Mass Index (BMI) ≥30 kg/m2] with the implementation of a dedicated randomization list.

Procedure: PCI
  1. Pre-PCI: multimodal physiological evaluation: FFR, CFR, IMR will be repeated
  2. PCI: For all the patients undergoing PCI, the use of unfractioned heparin (UHF) will be allowed at the time of PCI; UFH be administered with a target on Activated Clotting Time (ACT) of 200-250 s. The PCI procedures will be performed by standard technique using only second generation Drug Eluting Stents (DES). In all cases, balloon pre-dilatation will be performed before stent implantation using a semi-compliant balloon with a diameter lower than a 75% of the distal reference diameter of the vessel to avoid confounders Post-dilation will be performed according to clinical practice although it will be not mandatory.
  3. Post-PCI: After stent implantation/s, multimodal physiological evaluation will be re-performed (FFR, CFR, IMR).


Outcome Measures
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Primary Outcome Measures :
  1. Delta IMR post-PCI [ Time Frame: at least 48 hours after randomization, just after PCI and stenting. ]
    Absolute difference in the IMR value associated to PCI ["Delta IMR Post-PCI" = (IMR value post-PCI) minus (IMR value pre-PCI)]

  2. Delta IMR pre-PCI [ Time Frame: at least 48 hours after randomization, just before PCI and stenting. ]
    Absolute difference in the IMR value associated to PCI ["Delta IMR Pre-PCI" = (IMR value pre-PCI) minus (IMR value at baseline)]


Secondary Outcome Measures :
  1. Myocardial necrosis associated to PCI damage [ Time Frame: at least 72 hours, at the time of hospital discharge. ]
    Myocardial necrosis associated to PCI damage, assessed by cardiac markers (troponin rise > 5 times 99th percentile of upper reference limit or as elevation of CK-MB 3 times the upper limit of normal

  2. IMR post-PCI [ Time Frame: at least 48 hours after randomization, just after PCI and stenting. ]
    Absolute resistance value after PCI

  3. Severe microcirculatory impairment [ Time Frame: at least 48 hours after randomization, just after PCI and stenting. ]
    Incidence of severe microcirculatory impairment defined as Index of Microvascular Resistance > 29 after PCI


Other Outcome Measures:
  1. Delta IMR post-PCI in subject with BMI = or > 30 [ Time Frame: at least 48 hours after randomization, just after PCI and stenting. ]
    Absolute difference in the IMR value associated to PCI ["Delta IMR Post-PCI" = (IMR value post-PCI) minus (IMR value pre-PCI)] in subject with BMI = or > 30

  2. Delta IMR pre-PCI in subject with BMI = or > 30 [ Time Frame: at least 48 hours after randomization, just before PCI and stenting. ]
    Absolute difference in the IMR value associated to PCI ["Delta IMR Post-PCI" = (IMR value post-PCI) minus (IMR value pre-PCI)] in subject with BMI = or > 30

  3. Myocardial necrosis associated to PCI damage in subject with BMI = or > 30 [ Time Frame: at least 72 hours, at the time of hospital discharge. ]
    Myocardial necrosis associated to PCI damage, assessed by cardiac markers (troponin rise > 5 times 99th percentile of upper reference limit or as elevation of CK-MB 3 times the upper limit of normal in subject with BMI = or > 30

  4. IMR post-PCI in subject with BMI = or > 30 [ Time Frame: at least 48 hours after randomization, just after PCI and stenting. ]
    Absolute resistance value after PCI in subject with BMI = or > 30

  5. Severe microcirculatory impairment in subject with BMI = or > 30 [ Time Frame: at least 48 hours after randomization, just after PCI and stenting. ]
    Incidence of severe microcirculatory impairment defined as Index of Microvascular Resistance > 29 after PCI in subject with BMI = or > 30


Eligibility Criteria
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Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subject with Diabetes Mellitus (DM) Type II
  • Subject must be older than 18 years
  • Written informed consent available
  • Subject with stable ischemic heart disease referred for coronary angiography
  • Subject is eligible for PCI, and PCI target(s) have FFR≤0.80

Exclusion Criteria:

  • Prior myocardial infarction in the territory of the target vessel
  • Akinesia or dyskinesia in subtended myocardial segments
  • Severe impairment of left ventricular function (LVEF) <35%
  • PCI target is a chronic total occlusion
  • Target lesion has been treated previously (restenotic lesions)
  • Target vessel is a saphenous vein graft or a surgical graft has been anastomosed to target vessel
  • Thrombolisis in Myocardial Infarction (TIMI) flow ≤ 1 prior to guide wire crossing
  • Subject is not eligible for treatment with DES
  • Bleeding disorders or chronic anticoagulant treatment
  • Left main stenosis > 50%
  • Coronary surgery deemed more beneficial for the patient than PCI
  • Intolerance or contraindications to anti-platelet drugs
  • Contraindications for adenosine administration
  • Platelet count <75000 or >700000/mm3
  • Immunosuppressive therapy
  • Pregnant or breast feeding patient
  • History of intracranial haemorrhage
  • Severe hepatic impairment
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02698618


Contacts
Layout table for location contacts
Contact: Javier Escaned, MD, PhD +34913303438 javier.escaned@salud.madrid.org
Contact: Enrico Cerrato, MD enrico.cerrato@gmail.com

Locations
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Spain
Hospital Universitario Marqués de Valdecilla
Santander, Cantabria, Spain, 39008
Contact: José M de la Torre, MD, PhD    +34 942202520      
Principal Investigator: José M de la Torre, MD, PhD         
Hospital Galdakao-Usansolo
Bilbao, Vizcaya, Spain, 48960
Contact: José R Rumoroso, MD, PhD    +34 944007000      
Principal Investigator: José R Rumoroso, MD, PhD         
Hospital San Carlos
Madrid, Spain, 28040
Contact: Javier Escaned, MD, PhD    +34913303438    javier.escaned@salud.madrid.org   
Contact: Enrico Cerrato, MD       enrico.cerrato@gmail.com   
Principal Investigator: Javier Escaned, MD, PhD         
Sub-Investigator: Alicia Quirós, PhD         
Sponsors and Collaborators
Fundacion Investigacion Interhospitalaria Cardiovascular
AstraZeneca
Investigators
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Principal Investigator: Javier Escaned, MD, PhD Hospital San Carlos, Madrid, Spain
Principal Investigator: Enrico Cerrato, MD San Luigi Gonzaga University Hospital, Orbassano (Turin), Italy
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Javier Escaned, Unit head, Hospital San Carlos, Madrid
ClinicalTrials.gov Identifier: NCT02698618    
Other Study ID Numbers: ESR-15-10793
2015-003621-33 ( EudraCT Number )
First Posted: March 4, 2016    Key Record Dates
Last Update Posted: March 4, 2016
Last Verified: February 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by Javier Escaned, Hospital San Carlos, Madrid:
Diabetes
IMR
Microcirculation
Ticagrelor
 CFR
FFR
Coronary microcirculation
Additional relevant MeSH terms:
Layout table for MeSH terms
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases