BackgroundEnd-stage renal disease (ESRD) is the last stage of chronic kidney disease, mainly caused by type 2 diabetes mellitus and characterized by an increased mortality risk related to cardiovascular disease. Low-dose aspirin (acetylsalicylic acid or ASA) seems to effectively prevent cardiovascular events in patients with ESRD. However, the number of interventional studies in this population remains limited and the mechanisms of aspirin-related bleeding remain poorly understood. Aspirin’s efficacy and safety may be modified by the presence of type 2 diabetes mellitus or platelet hyperreactivity.ObjectiveThe overall objective of this protocol is to (1) evaluate aspirin’s safety and efficacy in reducing the risk of thrombotic events in patients with ESRD on hemodialysis and (2) examine whether aspirin’s efficacy is modified by the presence of type 2 diabetes mellitus or platelet hyperreactivity. Specifically, the primary objective is to compare the 12-month rate of any thrombotic event (cardiac death, nonfatal myocardial infarction, nonfatal stroke, arteriovenous fistula thrombosis) and Thrombolysis in Myocardial Infarction (TIMI) major bleeding in patients treated with aspirin compared to those on placebo. Secondary objectives are to test for effect modification of treatment by the presence of type 2 diabetes mellitus or platelet hyperreactivity and compare the rate of TIMI minor bleeding between treatment groups.MethodsWe developed a protocol for a phase 2 randomized, single-center, placebo-controlled, triple-blind, superiority clinical trial to assess the prophylactic efficacy and safety of aspirin in patients with ESRD and on hemodialysis. It follows the ethical principles of the Declaration of Helsinki of the World Medical Association. A total of 342 participants would be enrolled over 12 months at a large dialysis center. Patients will be randomized in a 1:1 ratio and stratified by presence of type 2 diabetes mellitus and platelet hyperreactivity to receive either oral aspirin (100 mg/d) or placebo for a treatment period of 12 months. An intention-to-treat statistical analysis will be performed.ResultsThe randomized clinical trial will be performed after approval by the ethical committee of the participating center and registration at ClinicalTrials.gov.ConclusionsWe provide a protocol for a randomized controlled trial to evaluate the safety and efficacy of treatment with aspirin to reduce the risk of thrombotic events. In addition, such a study would further our understanding of the mechanism of aspirin-related bleeding and help identify subgroups of best-responders and patients with a higher risk of adverse events.Registered Report IdentifierRR1-10.2196/10516

Results: we developed a protocol for a phase II randomized, single-center, placebocontrolled, triple-blind, superiority clinical trial in order to assess aspirin prophylactic efficacy and safety in ESRD patients on hemodialysis. It follows the ethical principles of the Declaration of Helsinki of the World Medical Association. Participants will be randomized (1:1 ratio) in 2 arms and orally receive acetylsalicylic acid 100mg/day or placebo, for 12 months. An intent-to-treat (ITT) statistical analysis will be performed.The primary composite outcome (12-month incidence of thrombotic events [cardiac death, nonfatal myocardial infarction, nonfatal stroke, arteriovenous fistula thrombosis] and TIMI major bleeding) will be analyzed with Kaplan Meier curves and a log-rank test to compare treatment arms. Cox proportional hazards regression will be used to adjust for covariates, if appropriate. As secondary outcomes, the same components of the primary outcome will be assessed in a subgroup analysis after patients' stratification for the presence versus absence of type-2 Diabetes Mellitus and platelet hyper-reactivity. The presence of TIMI minor bleeding will be compared between groups and tested with a Chi-square test. Conclusions:We provide a protocol for a randomized controlled trial to evaluate aspirin's prophylactic efficacy for thrombotic events and safety in ESRD patients.When conducted, such a study would further our understanding of the mechanism of aspirin-related bleeding, and would help identify best-responders and patients with a higher risk of adverse events.