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ComparisoN of ticAgrelor vs. Clopidogrel in endoTHeliAl Function of COPD patieNts (NATHAN-NEVER)

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ClinicalTrials.gov Identifier: NCT02519608
Recruitment Status : Completed
First Posted : August 11, 2015
Last Update Posted : May 2, 2018
Sponsor:
Information provided by (Responsible Party):
Gianluca Campo, University Hospital of Ferrara

Brief Summary:

This is an investigator-initiated, prospective, single-centre, randomised, phase II, open-label study, testing the superiority of ticagrelor, as compared to clopidogrel, in modulating on-P2Y12 treatment platelet reactivity, endothelial dysfunction and inflammation in chronic obstructive pulmonary disease (COPD) patients receiving scheduled percutaneous coronary intervention (PCI) for stable coronary artery disease. Subjects that meet the inclusion criteria and have provided informed consent will be randomly assigned in a 1:1 fashion to one of the two dual antiplatelet therapy (DAPT) regimen: aspirin + clopidogrel (standard of care) vs. aspirin + ticagrelor (experimental arm).

DAPT with aspirin and clopidogrel for at least 6 months (preferably 12 months) is the current gold-standard for patients receiving PCI and drug eluting stent implantation for SCAD. No data supports a different strategy and/or approach in COPD patients undergoing PCI. Ticagrelor, a new P2Y12 inhibitor, showed a significantly higher platelet inhibition as compared to clopidogrel. Recently, ticagrelor administration has been associated with a positive effect on endothelial function and a modulation of proinflammatory signalling. These actions are mediated by a significant influence of adenosine uptake. Higher platelet reactivity, chronic inflammatory response, heightened endothelial dysfunction characterized COPD patients with concomitant coronary artery disease (CAD). The investigators speculated that COPD patients undergoing PCI for stable CAD (SCAD) had a risk profile similar to that of acute coronary syndromes (ACS) patients. Accordingly, COPD patients undergoing PCI for SCAD may obtain a stronger benefit by ticagrelor as compared to clopidogrel. The aim of this study is to evaluate whether ticagrelor, is superior to clopidogrel, in reducing endothelial dysfunction , platelet reactivity (PR) and inflammation profile of patients with stable CAD and COPD. Ticagrelor will be administered according PLATO trial and international guidelines (180 mg as loading dose, 90 mg x 2 daily as maintenance dose). As suggested by international guidelines, the control group will be patients with current gold standard treatment for SCAD treated with PCI (aspirin + clopidogrel 75 mg daily). The evaluation of endothelial dysfunction, PR and inflammation profile will be repeated after 30 days and will be compared to baseline values.


Condition or disease Intervention/treatment Phase
Coronary Artery Disease Chronic Obstructive Pulmonary Disease Drug: Aspirin 100 mg Drug: Ticagrelor Drug: Clopidogrel Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 44 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Comparison Between Ticagrelor and Clopidogrel Effect on Endothelial, Platelet and Inflammation Parameters in Patients With Stable Coronary Artery Disease and Chronic Obstructive Pulmonary Disease Undergoing PCI
Study Start Date : September 2015
Actual Primary Completion Date : June 2016
Actual Study Completion Date : January 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Aspirin 100 mg + Clopidogrel 75 mg
dual antiplatelet therapy as suggested by guidelines with aspirin 100 mg and clopidogrel 75 mg daily
Drug: Aspirin 100 mg
Patients with COPD and SCAD undergoing PCI and stent implantation will receive aspirin
Other Name: baseline background treatment

Drug: Clopidogrel
Patients with COPD and SCAD undergoing PCI and stent implantation will receive according randomization aspirin + clopidogrel (loading dose 600 mg + maintenance 75 mg)
Other Name: gold standard P2Y12 treatment

Experimental: Aspirin 100 mg + Ticagrelor 90 mg x2
dual antiplatelet therapy with aspirin 100 mg and ticagrelor 90 mg x 2 daily
Drug: Aspirin 100 mg
Patients with COPD and SCAD undergoing PCI and stent implantation will receive aspirin
Other Name: baseline background treatment

Drug: Ticagrelor
Patients with COPD and SCAD undergoing PCI and stent implantation will receive according randomization aspirin + ticagrelor (loading dose 180 mg + maintenance 90 mg x2)
Other Name: new hypothesis group




Primary Outcome Measures :
  1. apoptosis rate in HUVEC [ Time Frame: 1 month ]
    reduction of the rate of apoptosis in human umbilical vein endothelial cells (HUVEC) incubated with serum from patients enrolled in the study.


Secondary Outcome Measures :
  1. on-treatment platelet reactivity [ Time Frame: 1 month ]
    reduction of platelet reactivity (PR) as measured by P2Y12 and Aspirin VerifyNow System.

  2. NO intracellular levels [ Time Frame: 1 month ]
    modulation of intracellular levels of nitric oxid (NO) in HUVECs treated with serum from patients enrolled in the study

  3. ROS production [ Time Frame: 1 month ]
    reduction of intracellular levels of reactive oxygen species (ROS) in peripheral blood mononuclear cells (PBMCs) isolated from patients enrolled in the study

  4. inflammation markers levels [ Time Frame: 1 month ]
    reduction of values from baseline to 1 month of the most important inflammation cytokines associated with COPD (hs-PCR, fibrinogen, IL-6, IL-1Ra, TNF-alpha)

  5. ischemic adverse events [ Time Frame: 1 month ]
    Cumulative incidence of ischemic adverse events (death, myocardial infarction, stent thrombosis).

  6. bleeding adverse events [ Time Frame: 1 month ]
    Composite BARC 2-3-5 bleeding according to BARC definition

  7. quality of life [ Time Frame: 1 month ]
    Quality of life related to respiratory symptoms (COPD assessment test)


Other Outcome Measures:
  1. apoptosis rate in HUVEC [ Time Frame: time between LD and end of PCI, expected average of 5 hours ]
    rate of apoptosis in human umbilical vein endothelial cells (HUVEC) incubated with serum from patients enrolled in the study.

  2. on-treatment platelet reactivity [ Time Frame: time between LD and end of PCI, expected average of 5 hours ]
    reduction of platelet reactivity (PR) as measured by P2Y12 and Aspirin VerifyNow System.

  3. NO intracellular levels [ Time Frame: time between LD and end of PCI, expected average of 5 hours ]
    modulation of intracellular levels of nitric oxid (NO) in HUVECs treated with serum from patients enrolled in the study

  4. inflammation markers levels [ Time Frame: time between LD and end of PCI, expected average of 5 hours ]
    reduction of values from baseline to 1 month of the most important inflammation cytokines associated with COPD (hs-PCR, fibrinogen, IL-6, IL-1Ra, TNF-alpha)



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

Type of Patients Subjects either male or female eligible for PCI and undergoing drug eluting stent implantation who have meet all inclusion criteria and did not meet any of the exclusion criteria.

Inclusion Criteria:

For inclusion in the study subjects should fulfill the following criteria:

  1. Age ≥18 years;
  2. Ability to provide informed written consent and to participate in the 6-months follow-up period;
  3. Diagnosis of SCAD requiring coronary artery angiography
  4. COPD diagnosis confirmed by spirometry in stable phase and after medical treatment from at least 3 months.

Exclusion Criteria:

Subjects should not enter the study if any of the following exclusion criteria are fulfilled:

  1. Patients hospitalized with diagnosis of acute coronary syndrome
  2. Previous chronic use of P2Y12 inhibitors
  3. Known intolerance to aspirin and/or P2Y12 inhibitors
  4. Absence of significant variation in guideline driven medical treatment in the last 15 days
  5. History of intracranial haemorrhage
  6. Known intake of a strong CYP3A4 inhibitor (e.g. ketoconazole, clarithromycin, nefazodone, ritonavir, and atazanavir),
  7. Known pregnancy, breast-feeding, or intend to become pregnant during the study period
  8. Planned surgery, including CABG as a staged procedure (hybrid) within 6 months;
  9. Known moderate to severe hepatic impairment (alanine-aminotransferase ≥ 3 x ULN);
  10. Need for chronic oral anti-coagulation therapy;
  11. Active major bleeding or major surgery within the last 30 days;
  12. Known stroke (any type) within the last 30 days;
  13. Currently participating in another trial before reaching primary endpoint;
  14. Thrombocytopenia;
  15. Increased risk of bradycardia;
  16. Known other inflammatory chronic disorders;
  17. Known or suspected malignancy
  18. Other concomitant pulmonary diseases

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): NCT02519608


Locations
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Italy
University Hospital of Ferrara
Cona, Ferrara, Italy, 44124
Sponsors and Collaborators
University Hospital of Ferrara

Publications of Results:
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Responsible Party: Gianluca Campo, Assistant Professor and Interventional Cardiologist, University Hospital of Ferrara
ClinicalTrials.gov Identifier: NCT02519608     History of Changes
Other Study ID Numbers: 150497
First Posted: August 11, 2015    Key Record Dates
Last Update Posted: May 2, 2018
Last Verified: May 2018
Keywords provided by Gianluca Campo, University Hospital of Ferrara:
chronic obstructive pulmonary disease
stable coronary artery disease
ticagrelor
clopidogrel
endothelial function
inflammation
platelet reactivity
Additional relevant MeSH terms:
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Aspirin
Clopidogrel
Lung Diseases
Lung Diseases, Obstructive
Pulmonary Disease, Chronic Obstructive
Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Respiratory Tract Diseases
Heart Diseases
Cardiovascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Ticagrelor
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Antipyretics