Investigating Factors of Hemoglobin Variability in Nondialysis CKD Patients

Hemoglobin (Hb) variability, which is the oscillation or fluctuation of an individual’s Hb levels over time, has been associated with adverse outcomes in anemic patients and was recently identified as a potential therapeutic target. Currently, clinical research has not determined a clear method to define or measure Hb variability and its relationship to adverse outcomes, nor have studies assessed this relationship outside of dialysis patient populations. Therefore, the study by Boudville et al examined the relationship of Hb variability and mortality in nondialysis chronic kidney disease (CKD) patients receiving erythropoiesis-stimulating agents (ESAs), and aimed to identify specific factors that are associated with Hb variability.

The study included 6,165 nondialysis CKD patients, half of whom were receiving ESA treatment. These patients were enrolled at various healthcare centers from seven countries between January 2003 and October 2005, and received at least three Hb measurements within a 6-month base-line period during enrollment. To consistently evaluate and establish a definition of Hb variability, a number of study parameters were used including the mean change and standard deviation of the fluctuation in Hb between measurements, Hb amplitude between the highest and lowest measurement, and a classification system of patient Hb levels.

Using these parameters, as well as descriptive statistics that adjusted for factors such as age and gender, the study revealed that Hb variability is increased in nondialysis CKD patients and is associated with an increased risk of death. In addition, patients using ESAs showed a higher rate of Hb variability compared to those not using ESAs. Furthermore, a significant number of patients (31.7%) who used ESAs throughout the entire base-line period died by the completion of follow-up, consistent with previous studies.

Although patients in the ESA group showed higher risk for mortality, patients not using ESAs also showed a significant risk for death with increased Hb variability. This finding raises many questions about whether Hb variability can causally affect mortality or if it is simply an epiphenomenon. For example, age, male gender, and presence of diabetes were found to be the most significant predictors of mortality in the ESA group, suggesting that multiple factors, rather than ESA treatment by itself, are involved in Hb variability and mortality. However, because the ESA group showed higher Hb variability and greater risks for mortality, the authors concluded that researchers should consider ESA treatments as a focal point for future studies so that Hb variability can be better understood as a marker of illness and comorbidity.

Boudville NC, Djurdjev O, Macdougall IC, de Francisco AL, Deray G, Besarab A, Stevens PE, Walker RG, Ureña P, Iñigo P, Minutolo R, Haviv YS, Yeates K, Agüera ML, Macrae JM, Levin A. Hemoglobin Variability in Nondialysis Chronic Kidney Disease: Examining the Association with Mortality. Clin J Am Soc Nephrol. 2009 May 7.

NAAC Expert Commentary:
Variability in Hb levels from day to day and even hour to hour has been documented in normal individuals and likely reflects non-constant erythropoietin (EPO) output, bone marrow response, and fluid status. However, there has been little work done on the clinical implications of such variability in normal patients. In patients with chronic kidney disease (CKD) on dialysis, Hb variability has been described in many studies, work driven primarily by reimbursement policies for recombinant erythropoietin that set limits on Hb values that are acceptable to allow for payment for ESAs. Such studies have demonstrated substantial Hb variation and attempts have been made to correlate such variation with clinical outcomes, with conflicting results. The myriad factors that may contribute to Hb variability in this complex, ill population is the likely explanation for the difficultly in demonstrating cause and effect. The current study attempts to look at a less complex population, those with CKD not yet on dialysis, including patients not yet receiving ESAs. The results suggest an association between Hb variability and adverse clinical outcomes, with a greater effect in patients receiving ESAs. The study design precludes cause and effect conclusions, but is hypothesis generating – that is, it is plausible that Hb variability is itself a contributor to poor outcomes. An equally plausible hypothesis is that Hb variability is a marker of severity of illness – sicker patients have more variability and therefore poorer outcomes. Only carefully designed controlled trials will provide answers that are more definitive.

Comparing Effects of Anemia Treatments on Cancer Patient Survival

Erythropoiesis-stimulating agents (ESAs) have been shown to provide many benefits to cancer patients, including increased Hb levels, reductions in red blood cell transfusions, and improved quality of life. However, despite these benefits, many questions remain concerning the safety and efficacy of ESAs. Some studies have shown increased risk of thromboembolic events or tumor growth with ESA treatment. Further, the studies that have addressed these concerns have been small in scale. Therefore, a recent study examined the effects of two ESAs – epoetin and darbepoetin – on the survival of cancer patients through a comprehensive meta-analysis based on individual patient data from randomized controlled trials.

In the study, data from 13,933 patients were included from 53 trials, and patients receiving epoetin or darbepoetin plus red blood cell transfusion were compared to patients receiving only transfusion. Patients received 21,000 to 63,000 IU of epoetin or 100 to 157 µg of darbepoetin per week for 8 to 52 weeks, depending on a number of factors, including duration of chemotherapy. The study’s primary outcome was mortality occurring between the date of randomization and 28 days after the active trial period. Mortality was defined as death due to any cause during this period.

Statistical analyses were then used to analyze differences in baseline characteristics and follow-up times between the two study groups. After the data from these trials were analyzed, it was found that ESAs increased overall mortality by 17% in all patients compared to control groups, and by 10% in patients undergoing chemotherapy compared to control groups. Although patients undergoing chemotherapy showed a markedly smaller increase in mortality compared to patients not on chemotherapy, random variation accounted for the difference.

The results of this study are strongly supported by the large number of patients included, duplicated analyses by two independent groups, and a consistency of results among the 53 trials included. However, to further elucidate the clinical benefits of the findings, specific patient sub-groups need to be investigated, and more uniform survival endpoints need to be defined to assess the long-term effects of ESA treatment that could be confounded by the introduction of control patients that began the ESA treatment after the study. In addition, patients with a history of thromboembolic events seemed to have protection from increased mortality after treatment with ESAs, furthering the need for more research into the benefits and risks of ESA treatment in cancer patients.

Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J, Zwahlen M, Clarke M, Weingart O, Kluge S, Piper M, Rades D, Steensma DP, Djulbegovic B, Fey MF, Ray-Coquard I, Machtay M, Moebus V, Thomas G, Untch M, Schumacher M, Egger M, Engert A. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet. 2009 May 2;373(9674):1532-42.

NAAC Expert Commentary:

Because of the heterogeneity of study populations, the question of whether ESA use among certain subgroups reduces risk, particularly among chemotherapy related anemia and for lower baseline Hb (i.e., < 10 g/dL), has been controversial. The meta-analysis by Bohlius et al incorporates individual data from 13,933 patients enrolling 53 trials. Individual level data allowed the authors to look at patient specific factors such as baseline Hb, concentration of Hb achieved, or use of ESA for anemia not related to chemotherapy that might influence the outcome. The authors affirmed prior studies by showing increased mortality (HR -1.17, 95% CI: 1.06 – 1.30) among all subjects. For those receiving chemotherapy, ESA treatment was associated with increased risk of mortality that did not cross the threshold of statistical significance (HR-1.10, 95% CI: 0.98 – 1.24).

Although methodologically more rigorous, this trial shows similar results to other meta-analyses or reviews. ESAs appear to increase mortality among cancer patients, although it is important to recognize that the hazard ratio does not cross the threshold of statistical significance. Data from anemia of chronic renal insufficiency caused similar concerns about the potential for shortened survival. To mitigate harm, the updated FDA guidelines on ESA treatment include restricting the use of ESAs to chemotherapy related anemia for cancer patients, not to exceed an Hb level of 12.0 g/dL, not to exceed a rise of more than 1 g/dL over 2 weeks, and to use the lowest ESA dose possible. The authors did not find any baseline factor that significantly influenced results, such as baseline Hb, target Hb, performance status, or type of treatment; each subgroup was relatively small, leading to wide confidence intervals. It is still quite possible if not probable that some factors increase or decrease ESA risks, since subgroups were small and these were not baseline randomized factors. Despite this study, it is unclear if following the FDA guidelines mitigates risks associated with ESAs.

How should clinicians respond to this and other negative data? A very cautious approach to ESA prescribing is warranted. While we do not know if the FDA recommendations for ESA treatment of chemotherapy related anemia(1) will actually reduce risks associated with ESAs, the recommendations represent reasonable guidelines.

References

1. U.S. Food and Drug Administration. Information on Erythropoiesis-Stimulating Agents (ESAs) Epoetin alfa, Darbepoetin alfa. 2009. Accessed June 10, 2009.