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

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: 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

Tracking Information
First Submitted Date  ICMJE July 31, 2015
First Posted Date  ICMJE August 11, 2015
Last Update Posted Date May 2, 2018
Study Start Date  ICMJE September 2015
Actual Primary Completion Date June 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 10, 2015)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02519608 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 10, 2015)
  • on-treatment platelet reactivity [ Time Frame: 1 month ]
    reduction of platelet reactivity (PR) as measured by P2Y12 and Aspirin VerifyNow System.
  • 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
  • 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
  • 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)
  • ischemic adverse events [ Time Frame: 1 month ]
    Cumulative incidence of ischemic adverse events (death, myocardial infarction, stent thrombosis).
  • bleeding adverse events [ Time Frame: 1 month ]
    Composite BARC 2-3-5 bleeding according to BARC definition
  • quality of life [ Time Frame: 1 month ]
    Quality of life related to respiratory symptoms (COPD assessment test)
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: August 10, 2015)
  • 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.
  • 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.
  • 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
  • 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)
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE ComparisoN of ticAgrelor vs. Clopidogrel in endoTHeliAl Function of COPD patieNts
Official Title  ICMJE 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
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.

Detailed Description
  • Epidemiology Ischemic heart disease (IHD) and chronic obstructive pulmonary disease (COPD) are respectively the first and fourth cause of death in industrialized countries accounting for 10-15% of total disability adjusted life year (DALY). COPD is common in IHD patients, ranging from 5% to 18%, with a high prevalence of under diagnosis (until 87%). At the same time, one third of COPD patients' deaths are attributable to IHD and for every 10% decrease in forced expiratory volume in one second (FEV1), cardiovascular (CV) mortality rises by 28%.
  • Prognostic implication of IHD-COPD comorbidity Presence of concomitant COPD and IHD has a negative impact on quality of life, disease progression and short and long-term outcome. After coronary revascularization patients with COPD are at higher risk of recurrent myocardial infarction (MI), heart failure (HF) and bleeding complications if compared to patients without COPD. Consequently, COPD is an independent predictor of mortality in MI patients (HR 1.4; 95%CI 1.2-1.6). In a retrospective study, including patients undergoing percutaneous coronary intervention (PCI) with a 4-years follow-up, COPD was an independent risk factor for all-cause mortality (odds ratio [OR], 1.79; 95%CI, 1.63-1.96), cardiac mortality (OR 1.57; 95%CI, 1.35-1.81), and occurrence of MI (OR 1.3; 95%CI, 1.14-1.47). Another prospective study on 5000 consecutive patients with coronary artery disease (CAD) evaluated the in-hospital period after PCI. Patients with COPD experienced a significantly higher incidence of angina (p<0.001), arrhythmias (p<0.001), composite major adverse cardiac events (p<0.001) and longer hospital stay (p<0.001) than patients without COPD. The analysis of Charlson index for stable CAD patients confirmed that the presence of COPD was strongly related with long-term survival.
  • Inflammation, hypoxia and endothelial dysfunction COPD is characterized by a state of chronic inflammation of airways and vessels. Interleukin-6, C-reactive protein (CRP) and fibrinogen are often elevated in COPD and they facilitate both endothelial dysfunction and atherosclerosis progression. Fibrinogen induces plaque growing, stimulates platelets and white blood cells adhesion to vessels wall and promotes muscle cell proliferation and migration. Higher plasma levels of fibrinogen are directly related to a higher risk of acute coronary syndrome (ACS). CRP facilitates the production of interleukins and promotes the inflammatory state. Chronic hypoxia, contributing to endothelial dysfunction and increasing arterial stiffness, triggers, in vulnerable subjects, the growth and destabilization of atherosclerotic plaques.
  • Platelet reactivity Heightened on-treatment PR is a well-known determinant of poor prognosis in PCI patients and it is significantly higher in COPD patients. In COPD patients, platelets' count tents to be higher, and thrombocytosis is associated with increased 1-year mortality (OR 1.53; 95% CI 1.03 to 2.29, p=0.03).
  • Ticagrelor Ticagrelor is a direct-acting reversely binding inhibitor of P2Y12 platelets' receptor. Dual antiplatelet therapy (DAPT) with aspirin plus ticagrelor, as compared to aspirin plus clopidogrel, significantly reduces the rate of CV death, myocardial infarction, and/or stroke. Accordingly, DAPT with ticagrelor is guideline's recommended treatment (class I) in patients with ACS. On the contrary, DAPT with ticagrelor in stable CAD patients is not recommended. Dyspnea is a well-established ticagrelor potential side effect and it could be related to circulating increased adenosine levels after ticagrelor administration. A recent study by Alexopoulos et al. reported that COPD is a major determinant of poor/absent prescription of ticagrelor. Of note, Butler et al. demonstrated that ticagrelor administration does not alter pulmonary function at rest and during exercise in patients with COPD. Furthermore, ticagrelor-induced higher adenosine concentrations are considered the main mechanism of its "pleiotropic" effects (such as prevention of ADP-induced contraction of vascular smooth muscle cells, improvement of peripheral endothelial function and increase of endothelial nitric oxide synthase phosphorylation, reduction of pro-inflammatory thrombin-induced cytokines and chemokine's production during inflammation and coagulation activation).
  • Research hypothesis and Rationale for conducting this study:

Many studies show that patients with COPD undergoing PCI and stent implantation are at higher risk of adverse events (death, MI and stent thrombosis, ST). This is true both for patients with ACS and stable coronary artery disease (SCAD). Many factors may explain this finding. First, COPD patients have a higher on-treatment (both aspirin and clopidogrel) platelet reactivity (PR). Second, inflammation profile is significantly enhanced in COPD, contributing to higher PR and endothelial dysfunction. Third, endothelial dysfunction due to hypoxia, abnormal shear stress and inflammation is common in COPD and may explain the increase of acute events after stent implantation. Patients receiving PCI and stent implantation must be treated with DAPT to minimize the risk of ST and recurrent MI. According current guidelines, DAPT should be started as soon as possible in patients with ACS and at the timing of PCI in patients with SCAD. Current guidelines recommended the association of aspirin and newer P2Y12 inhibitors (ticagrelor or prasugrel) for ACS patients, whereas aspirin and clopidogrel for SCAD patients. 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. These findings support a possible positive effect of ticagrelor in COPD patients undergoing PCI for SCAD. Due to their comorbidity, COPD patients undergoing PCI for SCAD may be considered similar to ACS patients (higher platelet reactivity, chronic inflammatory response, heightened endothelial dysfunction). Accordingly, COPD patients undergoing PCI for SCAD may obtain a stronger benefit by ticagrelor when compared to clopidogrel. The aim of this study is to evaluate whether ticagrelor is superior to clopidogrel in reducing endothelial dysfunction, PR and inflammation profile of patients with stable CAD and COPD.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Coronary Artery Disease
  • Chronic Obstructive Pulmonary Disease
Intervention  ICMJE
  • 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
  • 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
Study Arms  ICMJE
  • Active Comparator: Aspirin 100 mg + Clopidogrel 75 mg
    dual antiplatelet therapy as suggested by guidelines with aspirin 100 mg and clopidogrel 75 mg daily
    Interventions:
    • Drug: Aspirin 100 mg
    • Drug: Clopidogrel
  • Experimental: Aspirin 100 mg + Ticagrelor 90 mg x2
    dual antiplatelet therapy with aspirin 100 mg and ticagrelor 90 mg x 2 daily
    Interventions:
    • Drug: Aspirin 100 mg
    • Drug: Ticagrelor
Publications * Campo G, Vieceli Dalla Sega F, Pavasini R, Aquila G, Gallo F, Fortini F, Tonet E, Cimaglia P, Del Franco A, Pestelli G, Pecoraro A, Contoli M, Balla C, Biscaglia S, Rizzo P, Ferrari R. Biological effects of ticagrelor over clopidogrel in patients with stable coronary artery disease and chronic obstructive pulmonary disease. Thromb Haemost. 2017 Mar 23;117(6):1208-1216. doi: 10.1160/TH16-12-0973. Epub 2017 Mar 23.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 29, 2016)
44
Original Estimated Enrollment  ICMJE
 (submitted: August 10, 2015)
40
Actual Study Completion Date  ICMJE January 2017
Actual Primary Completion Date June 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Italy
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02519608
Other Study ID Numbers  ICMJE 150497
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Gianluca Campo, University Hospital of Ferrara
Study Sponsor  ICMJE University Hospital of Ferrara
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account University Hospital of Ferrara
Verification Date May 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP