Costs and Outcomes of ESA Treatment for Non-dialysis Patients

According to the Prevalence of Anemia in Early Renal Insufficiency study, anemia occurs in 47% of patients with chronic kidney disease (CKD). Anemia of CKD is frequently associated with adverse cardiovascular events, mortality, and substantial healthcare costs. However, many studies have shown benefits of treating anemia of CKD with erythropoiesis-stimulating agents (ESAs), including improved clinical outcomes and reduced healthcare costs. In particular, dialysis patients with no predialysis treatment incurred higher healthcare costs during the first month of treatment compared to patients treated with ESAs before dialysis onset. A recent observational study by Maddux et al examined anemic CKD patients not on dialysis, and compared clinical outcomes and healthcare costs for patients receiving or not receiving ESAs.

The study utilized a large U.S. health plan database to identify 26,244 patients with CKD. Of these patients, 31.2% were anemic, with 14.6% of anemic patients receiving ESA treatment. Significantly fewer ESA-treated patients died during the study period than untreated patients. Also, compared to those not receiving ESA treatment, ESA users had longer mean and median time before dialysis onset, significantly fewer inpatient and emergency room visits, but, experienced more adverse cardiovascular events. ESA use also predicted lower total monthly anemia-related healthcare costs, although it was not a strong predictor of total monthly healthcare costs. In addition, ESA users experienced more adverse cardiovascular events.

The results of this study indicate that ESA-treated patients experience reduced anemia-related healthcare costs and longer times to dialysis onset. Despite these benefits, only 14.6% of study patients received ESAs, suggesting significant undertreatment of clinically-recognized anemia. However, not all patients may have had indications for ESA treatment, and regional variations may reflect different health plan guidance and practice patterns. Furthermore, the increase in adverse cardiovascular events that ESA-treated patients experienced may be explained by hemoglobin levels of greater or equal to 13 g/dL. Some studies have shown that targeting hemoglobin concentrations above target levels (11-12 g/dL) increases the risk for cardiovascular problems. Overall, more studies are needed to assess the potential of ESA treatment and optimize the benefits for patients with anemia of CKD.

Please reference the source article:
Effect of Erythropoiesis-stimulating Agents on Healthcare Utilization, Costs, and Outcomes in Chronic Kidney Disease. Maddux FW, Shetty S, del Aguila MA, Nelson MA, Murray BM. Ann Pharmacother. 2007 Nov;41(11):1761-9. Epub 2007 Sep 25.

NAAC Expert Commentary:
Anemia remains one of the most common and morbid complications of chronic kidney disease (CKD). It begins early in the course of the disease, when GFR drops below 60 ml/min and becomes increasingly prevalent with more severe CKD. For a multitude of reasons, few patients seem to receive treatment despite this high prevalence and availability of effective therapy with iron and/or erythropoiesis-stimulating agents (ESAs). The current study, emphasizes these points. In addition, the authors attempt to look at costs and outcomes of care as well, utilizing claims data from healthplan members.

The association of ESA use and lower overall costs attributable to improved clinical outcomes is of interest, but must be interpreted cautiously. First, as pointed out by the authors, claims data is likely to understate key diagnoses like CKD or anemia and because of a lack of laboratory data does not permit staging of CKD or an analysis of the severity of anemia. Second and more importantly, the associations shown may not be causal. That is, patients who received ESAs may have had better overall medical care that contributed to the improved outcomes independent of anemia treatment. Nevertheless, this study, along with others in the literature, permit the generation of testable hypotheses about the overall value, clinically and financially, of early anemia identification and treatment in patients with CKD.

Anemia Management with Erythropoietin in Diabetic Patients

Erythropoietin (EPO) is produced in the kidneys and naturally stimulates red blood cell production in the body. Patients with diabetes mellitus (DM) often experience renal tubular and interstitial damage, leading to a decreased production of EPO. In turn, patients with DM frequently experience anemia. Studies have shown anemia to be an independent risk factor for progression of diabetic retinopathy, vascular damage, and other adverse events. However, EPO administration has shown valuable therapeutic potential in anemic DM patients. In this review, Khoshdel et al summarize recent studies to propose potential roles for EPO in the management of anemia and other complications of DM.

In several recent studies, EPO administration effectively corrected renal anemia in DM patients compared to patients without diabetes. Although only short-term studies were carried out, patients reported improved quality of life and well-being, as well as improvement of cardiac function. Additionally, EPO administration has been shown to protect against myocardial cell apoptosis, improve left ventricle function, and increase exercise capacity. Other significant advantages of EPO administration include neuroprotection, cell-to-cell junction maintenance, and improved insulin resistance.

Despite the possible benefits of EPO administration, some adverse effects have been reported. In particular, progressive worsening of hypertension is a common side effect in patients with chronic kidney disease. Thus, EPO use on hypertensive patients is often contraindicated. Also, studies have found EPO-receptors on several malignant cell lines including ovarian, uterine, and prostate. However, the results from these studies are contradictory, and do not consistently show regression or proliferation of malignant cell lines.

Because of the therapeutic potential of EPO administration, more longitudinal studies are needed to assess long-term effects in anemic DM patients. Optimal time and duration of treatment also needs to be determined by more randomized clinical trials. In addition, developing non-erythropoietic analogues of EPO will greatly enhance therapeutic efficacy. Currently, an EPO mutant is being developed with neuroprotective effects against stroke and diabetic nephropathy. Mutant analogues such as these have the potential for longer half-lives and only need to be administered once a month. The authors concluded further advances of molecular research, along with more comprehensive clinical trials like those referenced in the commentary, will help physicians make better treatment decisions for anemic DM patients.

Please reference the source article:
Potential roles of erythropoietin in the management of anaemia and other complications diabetes. Khoshdel, A. Carney, S. Gillies, A. Mourad, A. Jones, B. Nanra, R. Trevillian, P. Diabetes Obes Metab. 2008 Jan;10(1):1-9. Epub 2007 Jul 21.

NAAC Expert Commentary:
In this comprehensive review, Khoshdel et al highlights the reasons that persons with diabetes get anemia earlier in the course of their kidney disease. This occurs because interstitial fibrosis often accompanies glomerular lesions. Anemia is more prevalent among persons with diabetes than those with other forms of CKD. The importance of a thorough work-up is stressed so that nutritional and other deficiencies can be managed early. Khoshdel et al summarize data from studies that show erythropoietin has receptors on many cells and tissues in the body, and may have divergent effects on tissues other than hematopoietic stem cells. Many clinical effects are speculative, such as neuroprotection and cardioprotection.

Since this article was accepted for publication, two large trials using erythropoietin therapy to drive hemoglobin levels to normal versus below normal levels were published. CHOIR(1) tested whether epoetin alpha, given to CKD patients weekly to achieve higher hemoglobin targets, would result in less cardiovascular morbidity and mortality. The study was negative, suggesting that a low-normal hemoglobin level was more appropriate for CKD patients. Of note, about half of the patients in CHOIR had diabetes. A companion study, CREATE(2), tested whether early versus late treatment with epoetin beta would reduce cardiac morbidity and mortality. The higher hemoglobin group had a non-significant increase in CV events and mortality, but reported a better quality of life.

These studies have caused clinicians, policy groups and major medical payers to take another look at erythropoiesis-stimulating agents (ESAs) in general, and to recommend more modest targets. Still ongoing is a much larger clinical trial, TREAT(3), which aims to show that treatment of anemia with darbepoetin alpha in patients with type 2 diabetes and CKD will reduce CV events and mortality. This study already has more patient years studied than CHOIR or CREATE, and is still ongoing. TREAT should add clarity to the effective use of ESA in patients with type 2 diabetes and CKD.

Reference in the commentary:
(1) Correction of anemia with epoetin alfa in chronic kidney disease. Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, Reddan D; CHOIR Investigators. N Engl J Med. 2006 Nov 16;355(20):2085-98.
(2) Normalization of hemoglobin level in patients with chronic kidney disease and anemia. Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, Burger HU, Scherhag A; CREATE Investigators. N Engl J Med. 2006 Nov 16;355(20):2071-84.
(3) Rationale--Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT): evolving the management of cardiovascular risk in patients with chronic kidney disease. Mix TC, Brenner RM, Cooper ME, de Zeeuw D, Ivanovich P, Levey AS, McGill JB, McMurray JJ, Parfrey PS, Parving HH, Pereira BJ, Remuzzi G, Singh AK, Solomon SD, Stehman-Breen C, Toto RD, Pfeffer MA. Am Heart J. 2005 Mar;149(3):408-13.

Effects of Hemoglobin Stability on Mortality of Hemodialysis Patients

Clinical treatment for anemic patients on hemodialysis (HD) has significantly improved since the introduction of erythropoiesis-stimulating agents, such as epoetin alfa (EPO). Treatment with EPO is effective in raising hemoglobin (Hb) levels in anemic patients to the target range (10-12 g/dL) determined by the United States Food and Drug Administration. However, maintaining a target Hb level during EPO treatment is difficult. Some studies have indicated that only 10% of HD patients receiving EPO treatment are able to maintain stable target levels from month to month. Recently, a national, retrospective study examined the relationship between Hb variability and mortality.

The study assessed 159,720 HD patients who had EPO claims in each of the first six months of 2004. This time frame was considered the study’s exposure assessment period during which Hb levels were monitored. After these six months, patients were followed until the end of 2004, or until death or change in dialysis treatment. The study utilized two classification systems to define Hb variability; one based on monthly Hb values, and the other based on the lowest and highest Hb values observed during the exposure assessment period. Hemoglobin categories within each system were defined as follows: low (Hb < 11 g/dL), intermediate (Hb = 11-12.5 g/dL), and high (Hb > 12.5 g/dL). Descriptive statistics were used to assess the classification system’s various categories, with adjustments made for demographic and comorbidity characteristics.

Patients with Hb values in the intermediate and high ranges showed no increased risk for death, while patients consistently in the low category had the highest risk of death. Also, patients with low Hb levels in the first 3 months of the assessment period and higher Hb levels (> 11 g/dL) in the second 3 months had lower mortality risk than patients with low levels in the second 3 months. In general, more patients with low Hb levels in the second 3 months indicated a higher risk of mortality.

These results suggest the number and timing of low Hb levels are the most important factor in terms of mortality risk. Patients who experienced falling levels during the latter months of the assessment period were at a significantly higher risk for death than patients whose Hb levels were increasing in the latter months. In general, the model indicated that > 3 months with Hb levels < 11 g/dL may be associated with increased risk of death. The results also address concerns about mortality risk with Hb levels above the target range. Gilberson et al concluded this study did not find increased mortality associations with higher Hb levels in patients, and indicates the need for future trials to examine optimal EPO dosing for HD patients.

Please reference the source article:
Hemoglobin Level Variability: Associations with Mortality. Gilbertson DT, Ebben JP, Foley RN, Weinhandl ED, Bradbury B, Collins AJ. Gynecol Oncol. 2007 Nov 23.

NAAC Expert Commentary:
Anemia management is a key component of chronic kidney disease care and one that has undergone substantial scrutiny. Whereas target hemoglobin (Hb) ranges have been recommended for patients receiving erythropoiesis-stimulating agents (ESAs), there is prior evidence that patients regularly experience fluctuations outside the range, so-called hemoglobin cycling. In this retrospective study, the authors sought to better define the impact of fluctuating Hb values. The findings which ultimately proved most interesting were the very frequent nature of Hb cycling and the association between Hb values below the K/DOQI target and the risk of mortality in patients receiving hemodialysis.

The implications of the data are that recognition of Hb cycling should be incorporated into the design of quality improvement projects tied to anemia management, and that clinicians should follow current treatment recommendations regarding the lower limit Hb target value. The absence of an association between either Hb cycling or a high Hb value and patient mortality, despite previous publications which have suggested otherwise, highlights the need for additional studies on these issues and others (e.g. impact of ESA dosage vs. Hb achieved on patient morbidity and mortality), in the dialysis population.

As with any observational study, limitations must be considered when applying relevance to the results; in this case those limitations which could help explain the Hb variability. Limitations recognized by the authors included the likely presence of confounding-by-indication biases, the exclusion of patient data from all those who did not have a complete dataset, and the lack of complete comorbidity profiles addressing issues such as hospitalization and infection. These factors will undoubtedly be addressed in future prospective clinical trials intended to help optimize the treatment of anemia.