American journal of nephrology · 2026
Prognostic Relevance of Erythropoiesis-Stimulating Agent Dose Requirements in PIVOTAL and Its Implications for the Potential Mechanisms of Intravenous Iron Benefit in Maintenance Haemodialysis Patients.
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Oliveira Benjamin A, Barakat Mohamad F, Macdougall Iain C, Okonko Darlington O
Аннотация
INTRODUCTION: Decreased erythropoiesis-stimulating agent (ESA) requirements might explain the benefits of high-dose intravenous (IV) iron in PIVOTAL. However, as iron can be beneficial via non-erythropoietic pathways, higher iron doses might relate to better outcomes independently of ESA doses. This post hoc analysis examines whether reductions in ESA exposure were associated with the benefits of IV iron, and whether IV iron doses remained associated with outcomes after accounting for ESA exposure and haemoglobin (Hb) levels in PIVOTAL.
METHODS: We analysed data from 2,141 participants in the PIVOTAL trial. Primary endpoint was all-cause mortality (ACM) or nonfatal myocardial infarction, nonfatal stroke, or heart failure hospitalization.
RESULTS: Baseline median (IQR) ESA dose was 8,000 (5,000, 10,000) IU/week and similar in both treatment arms. Over 24 (10, 33) months, 658 (31%) patients met the primary endpoint, and ACM occurred in 515 (24%) patients. In adjusted Cox models, higher baseline ESA doses (per 10,000 IU/week) were associated with increased risks (primary endpoint: HR: 1.31 [95% confidence interval [CI]: 1.16, 1.49], p < 0.001; ACM: HR: 1.33 [95% CI: 1.15, 1.53], p < 0.001) in reactive patients. Over time, proactive patients had lower ESA (25,980 [17,320, 43,300] vs. 34,640 [25,980, 56,290] IU/month) and higher iron (250 [193, 300] vs. 127 [88, 171] mg/month) doses. In adjusted Cox models with time-varying covariates, higher ESA doses (≥34,640 IU/month) were associated with increased risks (primary endpoint: HR: 1.58 [95% CI: 1.34, 1.86], p < 0.001; ACM: HR: 1.83 [95% CI: 1.51, 2.20], p < 0.001), while higher iron doses (≥200 mg/month) were linked to reduced risks (primary endpoint: HR: 0.78 [95% CI: 0.67, 0.92], p = 0.002; ACM: HR: 0.78 [0.65, 0.93], p = 0.001) in the total population.
CONCLUSION: Lower ESA requirements predicted better outcomes in PIVOTAL, but higher IV iron doses remained associated with better outcomes even after accounting for ESA dose requirements and Hb levels. These findings suggest that some of the benefits of proactive IV iron in PIVOTAL may not be fully mediated by reductions in ESA exposure alone, supporting the possibility of non-erythropoietic mechanisms.
METHODS: We analysed data from 2,141 participants in the PIVOTAL trial. Primary endpoint was all-cause mortality (ACM) or nonfatal myocardial infarction, nonfatal stroke, or heart failure hospitalization.
RESULTS: Baseline median (IQR) ESA dose was 8,000 (5,000, 10,000) IU/week and similar in both treatment arms. Over 24 (10, 33) months, 658 (31%) patients met the primary endpoint, and ACM occurred in 515 (24%) patients. In adjusted Cox models, higher baseline ESA doses (per 10,000 IU/week) were associated with increased risks (primary endpoint: HR: 1.31 [95% confidence interval [CI]: 1.16, 1.49], p < 0.001; ACM: HR: 1.33 [95% CI: 1.15, 1.53], p < 0.001) in reactive patients. Over time, proactive patients had lower ESA (25,980 [17,320, 43,300] vs. 34,640 [25,980, 56,290] IU/month) and higher iron (250 [193, 300] vs. 127 [88, 171] mg/month) doses. In adjusted Cox models with time-varying covariates, higher ESA doses (≥34,640 IU/month) were associated with increased risks (primary endpoint: HR: 1.58 [95% CI: 1.34, 1.86], p < 0.001; ACM: HR: 1.83 [95% CI: 1.51, 2.20], p < 0.001), while higher iron doses (≥200 mg/month) were linked to reduced risks (primary endpoint: HR: 0.78 [95% CI: 0.67, 0.92], p = 0.002; ACM: HR: 0.78 [0.65, 0.93], p = 0.001) in the total population.
CONCLUSION: Lower ESA requirements predicted better outcomes in PIVOTAL, but higher IV iron doses remained associated with better outcomes even after accounting for ESA dose requirements and Hb levels. These findings suggest that some of the benefits of proactive IV iron in PIVOTAL may not be fully mediated by reductions in ESA exposure alone, supporting the possibility of non-erythropoietic mechanisms.