Impact of hemoglobin on cardiovascular events varies based on intradialytic weight gain
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An analysis of Japanese Dialysis Outcomes and Practice Pattern Study data indicated that the association between hemoglobin concentration and major adverse cardiovascular events varies across categories of intradialytic weight gain.
In addition, risk for major adverse cardiovascular events (MACE) may be greater for patients who have high intradialytic weight gain and hemoglobin concentrations in the upper limits, according to investigators.
These findings led Takashi Hara, MD, of Kyoto University and the Institute for Health Outcomes and Process Evaluation Research, and colleagues to recommend special consideration be placed on hemoglobin concentration in patients with high intradialytic weight gain, even if the concentration “falls within the target ranges of the guidelines” (clinical practice guidelines in Japan provide a target of 10 g per dL [to] 12 g per dL).
“Hemoglobin concentration varies dynamically depending on measurement timing because of body fluid volume changes,” the researchers wrote. “Although pre-dialysis hemoglobin concentration is mainly affected by interdialytic weight gain (IDWG), the interaction between these parameters is not well understood ... On the assumption that the measured pre-dialysis hemoglobin concentration reflects the true hemoglobin concentration is diluted with IDWG, we hypothesized that high IDWG as extracellular fluid and high levels of hemoglobin in blood vessels in the closed system of dialysis patients would synergistically promote a volume load, and as a consequence, have a synergistic interaction with the risk of cardiovascular events.”
A total of 8,234 patients on maintenance hemodialysis were included in the study. Hemoglobin concentration was placed into one of four categories by 1 g per dL increments (ranging from < 9 g per dL to < 12 g per dL) and IDWG was placed into one of six categories by 1% increments (ranging from < 2% to 6% or greater).
The primary outcome of the study was the occurrence of MACE, including acute myocardial infarction, stroke and all-cause mortality. Researchers noted they included mortality here because a large proportion of deaths in this patient population can be attributed to cardiovascular causes.
Patients were followed for a median of 2.1 years. During this time, 12.9% of patients experienced MACEs.
Researchers observed the “lowest point estimation in each IDWG category tended to shift to the lower hemoglobin concentration categories” with increasing IDWG.
In IDWG categories of 6% or greater, point estimation of MACEs with hemoglobin concentration of between 10 g per dL and 11 g per dL was higher than that with hemoglobin concentration between 9 g per dL and 10 g per dL.
The relative excess risk due to interaction (RERI) was 1.28 between the IDWG category of 6% or greater and hemoglobin categories between 10 g per dL and 11 g per dL. According to the researchers, this is indicative of a synergistic interaction.
“These results support the concept of ‘volume first,’ whereby volume control is considered the primary goal of dialysis care,” Hara and colleagues concluded of the findings. “This study did not directly establish this priority between hemoglobin concentration and IDWG, but interpretation of hemoglobin concentration is facilitated under good fluid management. Hemoglobin concentration management is mainly performed by dialysis physicians, whereas IDWG management predominantly depends on patients. Although the RERI estimate was not large, it would be undesirable for hemoglobin treatment by dialysis physicians’ practices to lead to patient harm. Attention should be paid to IDWG before attempting to control hemoglobin concentration within guideline target ranges.”
Perspective
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As this is an observational study, it can only show an association between higher Hb levels, high interdialytic weight gains, known as IDWG, and adverse cardiovascular outcomes. As such, it is hypothesis generating, but still worthy of consideration in clinical practice.
As post hoc analyses of Hb target trials with ESAs in CKD (eg, Normal Hematocrit Study, CHOIR and TREAT) attribute associated adverse cardiovascular outcomes as much (if not more) to ESA dose than to achieved Hb level, it is notable that the patients with the highest Hb levels in this study had the lowest erythropoietin resistance index, suggesting the Hb level rather than the ESA dose is at play. It is plausible that the combination of high (pre-dialysis) Hb level and high IDWG leads to an unsafe true Hb level that, by rheological factors, increases risk for cardiovascular events.
This study should still be viewed in the light that multiple studies have reported the lowest cardiovascular events and greatest survival among patients with Hb levels greater than 12 g/dL requiring no ESAs, so this study should not be interpreted as a mandate to decrease the Hb levels (as with phlebotomy) among patients with such Hb levels and high IDWG. Nonetheless, it might be prudent to aim for slightly lower Hb levels (such as 9.5 g/dL to 11 g/dL rather than 10 g/dL to 11.5 g/dL) among patients receiving ESAs with high IDWG.
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