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

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.