Platelet Aggregation in Patients With Coronary Artery Disease and Kidney Dysfunction Taking Clopidogrel or Ticagrelor

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.

Inclusion Criteria:

• Patients in use of aspirin for at least 7 days prior to randomization;
• Documented obstructive coronary artery disease by angiography;
• At least 12 months from the last episode of myocardial infarction (MI);
• Agree to sign the Informed Consent.

Exclusion Criteria:

• Prior ischemic or hemorrhagic stroke;
• Prior intracranial bleeding;
• Use of oral anticoagulant in the past month;
• Use of dual antiplatelet therapy in the last 30 days;
• Use of NSAIDs and / or dipyridamole in the past month;
• Mandatory use of proton pump inhibitor;
• Known platelet dysfunction or platelets <100,000 or >450,000/μL;
• End-stage renal disease undergoing hemodialysis;
• Terminal illness;
• Known liver disease or coagulation disorder;
• Known pregnancy, breast-feeding, or intend to become pregnant during the study period;
• Hypersensitivity to clopidogrel, ticagrelor or any excipients;
• Refusal to sign the Informed Consent;
• Active pathological bleeding.