A longitudinal analysis of haemoglobin levels and major cardiovascular events

Abstract

Background and hypothesis: Standard approach to anaemia in non-dialysis chronic kidney disease (CKD) does not account for potential age- or sex-specific related risks. We assessed differences in the association between haemoglobin and major cardiovascular events (MACE+) in men and women with CKD, by age groups.

Methods: Using 5-year longitudinal data from the CKD-REIN cohort, we studied patients with CKD stage 2-5 not treated with erythropoiesis stimulating agents (ESA). The main outcome was MACE+, defined as cardiovascular death, myocardial infarction, stroke or hospitalization for acute heart failure. Competing events were initiation of kidney replacement therapy and non-cardiovascular death. In each of the 4 predefined subgroups by sex and age (≤ 70 versus > 70 years at baseline), we estimated hazard ratios (HR) of current values of haemoglobin using a cause-specific Cox model adjusted for current values of glomerular filtration rate and transferrin saturation. All current values of biomarkers were first estimated in a multivariate-shared random effect joint model.

Results: Analyses considered 29 042 haemoglobin measurements from 2791 patients, and 364 MACE + . The association between current haemoglobin and log hazard of MACE + was linear in men and J-shape in women. For a haemoglobin of 10.5 g/dL, as compared to 11.5 g/dL, the hazard of MACE + at any time was increased by 60% in younger women (HR = 1.6, 95%CI 1.1-2.4), 70% in older women (HR = 1.7, 95%CI 1.3-2.4), 30% in younger men (HR = 1.3 95%CI 1.1-1.5) and 20% in older men (HR = 1.2 95%CI 1.1-1.4). Results were similar in the sensitivity analysis not censoring at the first ESA treatment.

Conclusion: Our longitudinal analysis in patients with CKD not on ESA therapy highlights a stronger association between anaemia and increased hazard of MACE + in women than in men. This sex-difference should inform the design of trials addressing anaemia correction in CKD.

Keywords: age and sex specificity; anaemia; haemoglobin; longitudinal association; major adverse cardiovascular event.