Ignite Creation Date:
2024-05-06 @ 7:19 AM
Last Modification Date:
2024-10-26 @ 11:47 AM
Study NCT ID:
NCT02519608
Status:
COMPLETED
Last Update Posted:
2018-05-02
First Post:
2015-07-31
Brief Title:
ComparisoN of ticAgrelor vs Clopidogrel in endoTHeliAl Function of COPD patieNts
Sponsor:
University Hospital of Ferrara
Organization:
University Hospital of Ferrara
Study Overview
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
Status:
COMPLETED
Status Verified Date:
2018-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
NATHAN-NEVER
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 11 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 andor 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
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 andor 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 14 95CI 12-16 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 179 95CI 163-196 cardiac mortality OR 157 95CI 135-181 and occurrence of MI OR 13 95CI 114-147 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 p0001 arrhythmias p0001 composite major adverse cardiac events p0001 and longer hospital stay p0001 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 153 95 CI 103 to 229 p003
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 andor stroke Accordingly DAPT with ticagrelor is guidelines 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 poorabsent 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 chemokines 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 andor 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
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 14 95CI 12-16 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 179 95CI 163-196 cardiac mortality OR 157 95CI 135-181 and occurrence of MI OR 13 95CI 114-147 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 p0001 arrhythmias p0001 composite major adverse cardiac events p0001 and longer hospital stay p0001 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 153 95 CI 103 to 229 p003
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 andor stroke Accordingly DAPT with ticagrelor is guidelines 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 poorabsent 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 chemokines 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 andor 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None