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

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

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.

Study Overview

• Status: Completed
• Conditions: Coronary Artery Disease; Chronic Obstructive Pulmonary Disease
• Intervention / Treatment: Drug: Aspirin 100 mg; Drug: Clopidogrel; Drug: Ticagrelor

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: Interventional
• Enrollment (Actual): 44
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Ferrara
    • Cona, Ferrara, Italy, 44124
      • University Hospital of Ferrara

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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 Names: 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 Names: 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 Names: new hypothesis group

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
apoptosis rate in HUVEC	reduction of the rate of apoptosis in human umbilical vein endothelial cells (HUVEC) incubated with serum from patients enrolled in the study.	1 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
on-treatment platelet reactivity	reduction of platelet reactivity (PR) as measured by P2Y12 and Aspirin VerifyNow System.	1 month
NO intracellular levels	modulation of intracellular levels of nitric oxid (NO) in HUVECs treated with serum from patients enrolled in the study	1 month
ROS production	reduction of intracellular levels of reactive oxygen species (ROS) in peripheral blood mononuclear cells (PBMCs) isolated from patients enrolled in the study	1 month
inflammation markers levels	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)	1 month
ischemic adverse events	Cumulative incidence of ischemic adverse events (death, myocardial infarction, stent thrombosis).	1 month
bleeding adverse events	Composite BARC 2-3-5 bleeding according to BARC definition	1 month
quality of life	Quality of life related to respiratory symptoms (COPD assessment test)	1 month

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
apoptosis rate in HUVEC	rate of apoptosis in human umbilical vein endothelial cells (HUVEC) incubated with serum from patients enrolled in the study.	time between LD and end of PCI, expected average of 5 hours
on-treatment platelet reactivity	reduction of platelet reactivity (PR) as measured by P2Y12 and Aspirin VerifyNow System.	time between LD and end of PCI, expected average of 5 hours
NO intracellular levels	modulation of intracellular levels of nitric oxid (NO) in HUVECs treated with serum from patients enrolled in the study	time between LD and end of PCI, expected average of 5 hours
inflammation markers levels	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)	time between LD and end of PCI, expected average of 5 hours

Collaborators and Investigators

• Sponsor: University Hospital of Ferrara

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start: September 1, 2015
• Primary Completion (Actual): June 1, 2016
• Study Completion (Actual): January 1, 2017

Study Registration Dates

• First Submitted: July 31, 2015
• First Submitted That Met QC Criteria: August 10, 2015
• First Posted (Estimate): August 11, 2015

Study Record Updates

• Last Update Posted (Actual): May 2, 2018
• Last Update Submitted That Met QC Criteria: May 1, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: ticagrelor; inflammation; clopidogrel; platelet reactivity; endothelial function; chronic obstructive pulmonary disease; stable coronary artery disease
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; 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; Ticagrelor; Clopidogrel
• Other Study ID Numbers: 150497