ComparisoN of ticAgrelor vs. Clopidogrel in endoTHeliAl Function of COPD patieNts
Information source: University Hospital of Ferrara
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Coronary Artery Disease; Chronic Obstructive Pulmonary Disease
Intervention: Aspirin 100 mg (Drug); Ticagrelor (Drug); Clopidogrel (Drug)
Phase: Phase 2
Status: Not yet recruiting
Sponsored by: University Hospital of Ferrara Overall contact: Veronica Lodolini, BSc, Phone: +390532236450, Email: veronica.lodolini@student.unife.it
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.
Clinical Details
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 design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: apoptosis rate in HUVEC
Secondary outcome: on-treatment platelet reactivityNO intracellular levels ROS production inflammation markers levels ischemic adverse events bleeding adverse events quality of life
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.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
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
Locations and Contacts
Veronica Lodolini, BSc, Phone: +390532236450, Email: veronica.lodolini@student.unife.it
University Hospital of Ferrara, Cona, Ferrara 44124, Italy
Additional Information
Starting date: September 2015
Last updated: August 10, 2015
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