Risk of cardiovascular events and mortality among elderly patients with reduced GFR receiving direct oral anticoagulants

Rationale and Objective — Evidence for efficacy of direct oral anticoagulants (DOACs) to prevent cardiovascular events and mortality in older individuals with a low estimated glomerular filtration rate (eGFR) is lacking. We sought to characterize the association of oral anticoagulant use with cardiovascular morbidity in elderly patients with or without reductions in eGFR, comparing DOACs to vitamin K antagonists (VKA).

Study Design — Population-based retrospective cohort study.

Settings and Participants — All individuals 66 years of age or older with an initial prescription for oral anticoagulants dispensed in Ontario, Canada from 2009-2016.

Exposure — DOACs (apixaban, dabigatran and rivaroxaban) compared to VKAs by eGFR group (≥60, 30-59, <30 ml/min/1.73m2).

Outcomes — The primary outcome was a composite of a cardiovascular event (myocardial infarction, revascularization, ischemic stroke) or mortality. Secondary outcomes were CV events alone, mortality, and hemorrhage requiring hospitalization.

Analytical Approach — High dimensional propensity score matching of DOAC- to VKA-users and Cox proportional hazards regression.

Results — 27,552 new DOAC users were matched to 27,552 new VKA users (median age, 78 years; 49% women). There was a significantly lower risk of cardiovascular events or mortality among DOAC users compared to VKA users (event rates 79.78 vs 99.77 per 1,000 person-years, respectively, hazard ratio HR 0.82 95%CI 0.75-0.90) and a lower risk of hemorrhage (event rates 10.35 vs. 16.77 per 1000 person-years, respectively, HR 0.73 95%CI 0.58-0.91). There was an interaction between eGFR and the association of anticoagulant class with the primary composite outcome (P < 0.02): for eGFR ≥60 ml/min/1.73m2, HR 1.01 95%CI 0.92-1.12, for eGFR 30-59 ml/min/1.73m2, HR 0.83 95%CI 0.75-0.93, for eGFR <30 ml/min/1.73m2 HR 0.75 95%CI 0.51-1.10. No interaction was detected for the outcome of hemorrhage.

Limitations — Retrospective observational study design limits causal inference; dosages of DOACs and INR values were not available; low event rates in some subgroups limited statistical power.

Conclusions — DOACs compared to VKAs were associated with lower risk of the composite of cardiovascular events or mortality, an association whose strength was most apparent among those with reduced eGFR. The therapeutic implications of these findings await further study.