Coronary Artery Disease Clinical Trial
Official title:
Evaluation of Platelet Aggregation and Adenosine Levels in Patients With Coronary Artery Disease and Chronic Kidney Dysfunction Taking Dual Antiplatelet Therapy With Aspirin and Clopidogrel or Ticagrelor
About 35% of patients hospitalized with Acute Coronary Syndromes (ACS) have some degree of
renal dysfunction. Chronic kidney disease (CKD) is not only associated to worse prognosis in
ACS patients, but leads also to an increased risk of bleeding, which may importantly
influence the risk-benefit ratio of antiplatelet therapy in this population. The responsible
mechanisms for increased rate of ischemic events in this population are not completely
elucidated.
Antiplatelet therapy is of paramount importance in the treatment of ACS, but its benefit in
CKD patients is not well established. This population is often excluded or underrepresented
in large clinical trials, and the indication of antiplatelet therapy is often extrapolated
from studies in patients with preserved renal function. In recent meta-analysis, Palmer et
al. sought to evaluate the benefits and risks of antiplatelet agents in patients with CKD and
concluded that in patients with ACS or scheduled for angioplasty already taking aspirin, the
addition of clopidogrel or glycoprotein IIb / IIIa inhibitors have little or no impact in
reducing the incidence of myocardial infarction, death or need for revascularization.
In the PLATO trial, ticagrelor (a new reversible inhibitor of P2Y12 receptor with faster
onset of action and greater platelet inhibition) was compared to clopidogrel in patients with
high risk ACS and was associated to a 16% risk reduction on the occurrence of death from
vascular causes, myocardial infarction, or stroke. In a pre-specified sub-analysis, data from
patients with CKD were compared to those obtained from the population with normal renal
function and suggests that the benefit of ticagrelor may be even greater in patients with
CKD. Two hypotheses were considered to explain these results:
1. Greater and more consistent platelet inhibition achieved with ticagrelor would be more
effective in reducing ischemic events in this population at increased thrombotic risk;
2. Pleiotropic effects of ticagrelor besides inhibition of the P2Y12 receptor. Ticagrelor
might be associated with an elevation in serum levels of adenosine. This could improve
myocardial perfusion through coronary vasodilation, and this effect would be more
pronounced in patients with renal dysfunction.
This project aims to validate (or not) these hypotheses, analyzing platelet aggregation and
circulating adenosine levels in patients taking dual antiplatelet therapy with aspirin and
clopidogrel or ticagrelor.
Previous publications demonstrated that about 35% to 40% of patients hospitalized with Acute
Coronary Syndromes (ACS) have some degree of renal dysfunction. On the other hand, chronic
kidney disease (CKD) is not only associated to worse prognosis in ACS patients, but leads
also to an increased risk of bleeding, which may importantly influence the risk-benefit ratio
of antiplatelet therapy in this population. Even at early stages, CKD increases the risk of
myocardial infarction and death among different spectra of ACS, and the risk increase is
directly proportional to the degree of renal dysfunction. The responsible mechanisms for the
increased rate of ischemic events in this population are not completely elucidated. However,
accelerated atherosclerosis, oxidative stress, inflammation and increased platelet
aggregation, as well as underutilization of therapies such as antithrombotic agents and
invasive procedures, are some of the proposed mechanisms.
Antiplatelet therapy is of paramount importance in the treatment of ACS, but its benefit in
CKD patients is not well established. The fact that this population is often excluded or
underrepresented in large clinical trials, makes the indication for its use be very often
extrapolated from studies in patients with preserved renal function.
In recent meta-analysis, Palmer et al. sought to summarize the benefits and risks of
antiplatelet agents in patients with CKD, focusing on the occurrence of cardiovascular events
(including mortality) and bleeding. The results led them to conclude that: 1) the evidence
for the use of antiplatelet agents in patients with CKD and cardiovascular disease is of low
quality, 2) in patients with ACS or scheduled for angioplasty already taking acetylsalicylic
acid (ASA), the addition of clopidogrel or glycoprotein IIb / IIIa inhibitors have little or
no impact in reducing the incidence of myocardial infarction, death or need for
revascularization, and 3) there was a significant 40% increase in the incidence of major
bleeding.
In the PLATO trial - "Ticagrelor versus Clopidogrel in Patients with Acute Coronary
Syndromes" - ticagrelor, a new reversible inhibitor of the P2Y12 receptor with faster onset
of action and greater platelet inhibition power was compared to clopidogrel in over 18,000
patients with high risk ACS. In this publication, patients receiving ticagrelor had a 16%
risk reduction on the occurrence of primary composite endpoint (death from vascular causes,
myocardial infarction or stroke) without significant increase in the incidence of major
bleeding. In a secondary outcome analysis, it was found a significant reduction in mortality
from vascular causes and mortality from any cause in patients treated with ticagrelor. Among
the high-risk criteria used in the selection of patients for this study, a creatinine
clearance <60 ml/min/1.73 m2 was included.
In a following article, considering a pre-specified sub-analysis from the PLATO trial, the
results of 3,237 patients who had this high-risk criterion were compared to those obtained
for the population with normal renal function. The developed comparisons suggest that the
benefit of ticagrelor may be even greater in patients with CKD: when considering the MDRD
equation to estimate renal function, the hazard-ratio (HR) for the primary outcome of the
study was 0.71 for patients with renal impairment (creatinine clearance <60 ml/min/1.73m2)
and 0.90 for those without renal dysfunction (p = 0.03 for interaction). Furthermore, the HRs
for mortality were, respectively, 0.79 and 0.91 for patients with and without renal
dysfunction (P = 0.02 for interaction). Interestingly, no significant difference between
groups relatively to major bleeding was observed, and the incidence of dyspnea was higher in
the population without renal dysfunction.
Two hypotheses were considered to explain these results. The first suggests that a greater
and more consistent platelet inhibition achieved with ticagrelor would be more effective in
reducing ischemic events in this population at increased thrombotic risk. The second
hypothesis considers possible pleiotropic effects of ticagrelor besides the reversible
inhibition of the P2Y12 receptor. Ticagrelor might be associated with an elevation in serum
levels of adenosine through the inhibition of its reuptake by erythrocytes and by increased
release of adenosine triphosphate (ATP) from the same erythrocytes, subsequently converted in
adenosine by ecto-ATPases. An increase in the concentrations of circulating adenosine could
improve myocardial perfusion through coronary vasodilation, and this effect would be more
pronounced in patients with renal dysfunction.
Thus, this project aims to validate (or not) these hypotheses, analyzing platelet aggregation
and circulating adenosine levels in patients taking dual antiplatelet therapy with aspirin
and clopidogrel or ticagrelor.
# Safety: as this protocol was designed for a short-term duration, we do not expect to have
many adverse events (AE). An AE is any untoward medical occurrence in a participant that does
not necessarily have a causal relationship with the study intervention. An AE can therefore
be any unfavorable or unintended sign (including an abnormal laboratory finding), symptom or
disease temporally associated with the use of a medical treatment or procedure regardless of
whether it is considered related to the medical treatment or procedure. AEs will be reported
as soon as possible.
Serious adverse events (SAE) are defined as any untoward medical occurrence that meets any
one of the following criteria:
1. Results in death or is life-threatening at the time of the event;
2. Requires inpatient hospitalization, or prolongs a hospitalization;
3. Results in a persistent or significant disability/incapacity;
4. Is a congenital anomaly/birth defect (in a participants offspring); or
5. Is medically judged to be an important event that jeopardized the subject and, for
example, required significant measures to avoid one of the above outcomes.
SAEs will be reported within 24 hours of its information received. The causality of SAEs
(their relationship to all study treatment/procedures) will be assessed by the
investigator(s) and the investigator is responsible for informing the local authorities and
ethical committees, of any serious adverse events as per local requirements.
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