Clinical trial NCT02698618: PRotective Effect on the Coronary Microcirculation of Patients With DIabetes by Clopidogrel or Ticagrelor
Official title: PRotective Effect on the Coronary Microcirculation of Patients With DIabetes by Clopidogrel or Ticagrelor
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Diabetes Mellitus, Type 2
Keywords: Diabetes
IMR
Microcirculation
Ticagrelor
CFR
FFR
Coronary microcirculation
Lead sponsor: Fundacion Investigacion Interhospitalaria Cardiovascular
Sponsor class: OTHER
Collaborators: name: AstraZeneca
First posted: 2016-03-04
Enrollment: 50
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: 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.

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).

Eligibility 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

Primary outcomes:
measure: Delta IMR post-PCI
timeFrame: at least 48 hours after randomization, just after PCI and stenting.
measure: Delta IMR pre-PCI
timeFrame: at least 48 hours after randomization, just before PCI and stenting.
Secondary outcomes:
measure: Myocardial necrosis associated to PCI damage
timeFrame: at least 72 hours, at the time of hospital discharge.
measure: IMR post-PCI
timeFrame: at least 48 hours after randomization, just after PCI and stenting.
measure: Severe microcirculatory impairment
timeFrame: at least 48 hours after randomization, just after PCI and stenting.
Other outcomes:
measure: Delta IMR post-PCI in subject with BMI = or > 30
timeFrame: at least 48 hours after randomization, just after PCI and stenting.
measure: Delta IMR pre-PCI in subject with BMI = or > 30
timeFrame: at least 48 hours after randomization, just before PCI and stenting.
measure: Myocardial necrosis associated to PCI damage in subject with BMI = or > 30
timeFrame: at least 72 hours, at the time of hospital discharge.
measure: IMR post-PCI in subject with BMI = or > 30
timeFrame: at least 48 hours after randomization, just after PCI and stenting.
measure: Severe microcirculatory impairment in subject with BMI = or > 30
timeFrame: at least 48 hours after randomization, just after PCI and stenting.
Locations:
city: Santander
country: Spain
facility: Hospital Universitario Marqués de Valdecilla
state: Cantabria
city: Bilbao
country: Spain
facility: Hospital Galdakao-Usansolo
state: Vizcaya
city: Madrid
country: Spain
facility: Hospital San Carlos
Study officials:
affiliation: Hospital San Carlos, Madrid, Spain
name: Javier Escaned, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: San Luigi Gonzaga University Hospital, Orbassano (Turin), Italy
name: Enrico Cerrato, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cerrato E, Quiros A, Echavarria-Pinto M, Mejia-Renteria H, Aldazabal A, Ryan N, Gonzalo N, Jimenez-Quevedo P, Nombela-Franco L, Salinas P, Nunez-Gil IJ, Rumoroso JR, Fernandez-Ortiz A, Macaya C, Escaned J. PRotective Effect on the coronary microcirculation of patients with DIabetes by Clopidogrel or Ticagrelor (PREDICT): study rationale and design. A randomized multicenter clinical trial using intracoronary multimodal physiology. Cardiovasc Diabetol. 2017 May 19;16(1):68. doi: 10.1186/s12933-017-0543-5.