Hemoglobin level variability: associations with mortality

Abstract

Background/objectives: Awareness of hemoglobin level variability in dialysis patients is increasing, as is interest in its potential implications. In this retrospective, national study of associations between the degree of hemoglobin level variability in the first 6 mo of 2004 and subsequent mortality rates in the following 6 mo, 159,720 hemodialysis patients receiving epoetin therapy were studied.

Design, setting, participants, measurements: Monthly hemoglobin values were categorized as low (L; < 11 g/dl), intermediate (I; 11 to 12.5 g/dl), and high (H; >12.5 g/dl). Variability groups were classified on the basis of the lowest and highest hemoglobin categories seen during the 6-mo observation period: low-low (L-L), 1.4%; intermediate-intermediate (I-I), 6.0%; high-high (H-H), 2.3%; low-intermediate (L-I), 18.3%; intermediate-high (I-H), 31.7%, and low-high (L-H), 40.2%.

Results: On multivariate analysis, adjusted hazards ratios for subsequent mortality events were as follows: I-I, 1.0 (reference category); I-H, 1.02 (95% confidence interval [CI] 0.95 to 1.11); H-H, 1.06 (95% CI 0.93 to 1.21); L-H, 1.19 (95% CI 1.10 to 1.28); L-I, 1.44 (95% CI 1.33 to 1.56), and L-L, 2.18 (95% CI 1.93 to 2.45). Persistently and transiently low hemoglobin levels and highly variable hemoglobin levels were associated with increased risk of death; transiently and persistently high hemoglobin levels were not associated with increased risk of death. Bayesian modeling indicated that > or =3 mo with hemoglobin levels <11 g/dl may be associated with of increased risk of death.

Conclusions: Number of months with hemoglobin values below the target range, rather than hemoglobin variability itself, may be the primary driver of increased risk of death. Further research is needed to distinguish cause from effect and to understand the underlying mechanisms.

Figure 1.

Hazard ratios for mortality based on the first classification system. Monthly hemoglobin values were categorized as low (L, <11 g/dl), intermediate (I, 11 to 12.5 g/dl) and high (H, >12.5 g/dl); variability groups were classified on the basis of the lowest and highest categories seen in the 6-mo observation period. Each P value tests the corresponding variability group hazard ratio compared with the reference group (consistently intermediate).

Figure 2.

Hazard ratios for mortality based on the second classification system. Number of months with hemoglobin <11 g/dl and first or second half of the 6-mo exposure period. For example, 2-F represents 2 mo with hemoglobin <11 g/dl during the first 3 mo; 4-F-S represents 4 mo with hemoglobin <11 during both the first and the second 3-mo periods. I-I, consistently intermediate (11 to 12.5 g/dl), represents the reference group.

Figure 3.

Interval Poisson model examining the change in hazard ratios over follow-up time. Number of months with hemoglobin <11 g/dl and first or second half of the 6-mo exposure period, as explained in Figure 2. I-I, consistently intermediate (11 to 12.5 g/dl), represents the reference group.