Age Modifies Intracranial and Gastrointestinal Bleeding Risk from P2Y12 Inhibitors in Patients Receiving Dialysis

Background: Individuals 75 years or older are the fastest-growing population starting dialysis for end-stage kidney disease (ESKD) due to living longer with coronary artery disease. ESKD alone can increase bleeding risk, but P2Y12 inhibitor (P2Y12-I) antiplatelet medications prescribed for cardiovascular treatment can exacerbate this risk in patients with ESKD. The age-specific rates of bleeding complications in dialysis patients with ESKD on P2Y12-I remain unclear, as does how age modifies the bleeding risk from P2Y12-I use in these patients. Methods: In a retrospective cohort study, we collected data on 40,972 patients receiving maintenance hemo- or peritoneal dialysis who were newly prescribed P2Y12-I therapy between 2011 and 2015 from the USRDS registry. We analyzed the effect of age on the time-to-first bleed, and the interactions between age and P2Y12-I type on modifying effects of bleed. Results: 19.8% of the cohort was 75 years or older. There were 3,096 (7.6%) gastrointestinal (GI) and 1,298 (3.2%) intracranial (IC) bleeding events during median follow up of 1.0 year. Annual incidence rates for IC bleeds were 1.9% in the age-group <55 years and 3.0% in the age-group 75 years or older. Rates for GI bleeds were 3.8% in the age-group <55 years and 8.5% in the age-group 75 years or older. On clopidogrel, prasugrel and ticagrelor, for every decade increase in age of the cohort members, risk of IC bleed increased by 9%, 55% and 59%, and of GI bleed increased by 21%, 28% and 39%, respectively. At age 75 and beyond, prasugrel was associated with greater risk of IC bleed than clopidogrel. At age 60 and beyond, ticagrelor was associated with greater risk of GI bleed than clopidogrel. Conclusions: More potent P2Y12-Is (prasugrel and ticagrelor) were associated with disproportionately higher risk of intracranial bleed with increasing age compared to that of clopidogrel - prasugrel was much worse than clopidogrel at 75 years and beyond. All 3 drugs were associated with only modest increase in the risk of GI bleed with every decade increase in age - ticagrelor was much worse than clopidogrel at 60 years and beyond. These results highlight the need for head-to-head clinical trials for use of P2Y12-Is in patients with ESKD to determine age cutoffs where the risk of bleeding outweighs the benefits of thrombosis prevention.