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Introduction: Cardiovascular (CV) morbidity and mortality are excessively high among hemodialysis (HD) patients. Anemia is a common complication of chronic kidney disease (CKD) and a known risk factor for CV events. To understand the impact of the recent regulatory and guideline changes in anemia management, we examined regional CV event rates in high-risk and erythropoiesis-stimulating agent (ESA)−hyporesponsive HD patients. Methods: A prospective cohort study including 16,560 HD patients, 8660 CV high-risk, and 884 hyporesponsive to ESAs, from the Dialysis Outcomes and Practice Patterns Study (DOPPS) phase 4 (2009−2011) and phase 5 (2012−2015) was conducted to quantify all-cause mortality, major adverse cardiovascular events (MACE), and MACE plus heart failure and thromboembolic events (MACE+). Results: The MACE+ rates (per 100 patient-years) were highest in North America (NA) (19.4; 95% CI = 18.2−20.7), followed by Europe (EU) (17.4; 95% CI = 16.6−18.1) and lowest in Japan (7.5; 95% CI = 6.9−8.1). When restricted to the high CV risk population, rates increased by 36% in NA, 45% in EU, and 72% in Japan. Mortality accounted for >74% of MACE+ events. MACE+ rates in ESA-hyporesponsive patients and high CV risk patients were similar in NA and EU cohorts. There were minimal differences in outcomes between the DOPPS phases 4 and 5. Conclusion: Cardiovascular event rates are high in the HD population, vary by geographic region, and are substantially higher in high CV risk patients and ESA-hyporesponsive patients; however, the rates appear not to be affected by anemia guideline changes. The findings from this study will be essential to contextualize the design of future CV anemia-related outcome studies and clinical trials. Keywords: cardiovascular events, cohort study, DOPPS, ESA hyporesponsivness, hemodialysis