The target hemoglobin level in patients on dialysis

Epoetin is the most expensive drug in the Medicare program.1 Erythropoietin- stimulating agents (ESAs) account for more than 20% of the income of dialysis chains.2 Many dialysis chains rely on epoetin revenue for profit, and some have encouraged aggressive correction of anemia in their dialysis patients.3 Indeed, nationally there has been a steady increase in both the average hemoglobin (Hgb) of dialysis patients and a growth in the dose of Epogen used. However, emerging data suggest targeting a higher Hgb results either in no benefit or in an increased risk of death and cardiovascular complications.4-6 Recent data from a survey published by Reuters suggest that nephrologists are starting to pare back their use of ESAs.7 In the past, Medicare recommended an Hgb target level of 10–12 g/dL,8 whereas the 2000 National Kidney Foundation (NKF) Kidney Disease Outcome Quality Initiative (KDOQI) guidelines recommended an Hgb of 11–12 g/dL.9 More, recently, the KDOQI have modified the anemia guidelines.10 In April 2006 the Centers for Medicare and Medicaid Services (CMS) introduced guidelines for reimbursement that have heralded a rise in the mean Hgb in dialysis patients and resulted in an Hgb > 13 g/dL in more than 20% of dialysis patients, or approximately 65,000 patients in the United States.11 To some, this broadened range of Hgb represents a “perverse incentive” to allow Hgb values in dialysis patients to rise beyond a safe level.2 On the other hand, CMS and members of the dialysis community have argued that the wider target range is necessary because of Hgb cycling—only a minority of dialysis patients are able to be maintained within such a narrow range.12 The debate has resulted in a flurry of articles, and the NKF has decided to reopen consideration of these issues by reconvening the NKF Anemia Workgroup.14-16 The “natural variability” that CMS cites in its new policy is supported by the literature. 16-18 The results of 3 studies collectively suggest that it is difficult to maintain an Hgb level in the 11–12 g/dL range. In a study by Fishbane et al., more than 90% of the dialysis patients studied experienced Hgb cycling. These investigators reported that the mean number of Hgb excursions each year per patient was 3.1 ± 1.1. The mean amplitude per Hgb excursion was 2.51 ± 0.89 g/dL, and the mean duration of Hgb excursions was 10.3 ± 5.1 weeks. Indeed, the NKF Work Group has “rejected, identifying a target Hgb level bounded by narrow upper and lower values (e.g., 11.0 to 12.0 g/dL). Such a target affords neither clarity nor simplicity, is possible to achieve in only a minority of patients, discourages flexibility in managing individual patients, and likely promotes cycling of Hgb results greater than and less than the target.” On the other hand, others have made the point that this narrow Hgb range is achievable if anemia management is structured in the dialysis clinic, that is, achieving the tight Hgb range of 11–12 g/dL can be achieved successfully.19 However, until safety in the high Hgb range has been demonstrated, maintaining a narrow range that is limited at the upper end by 12.0 g/dL is prudent policy.20, 21 The recent May 2006 update of the NKF anemia guidelines has generated controversy. The recently published guidelines explicitly state that “no patient should be maintained intentionally at less than the lower threshold [11.0 g/dL], and patients should not be routinely maintained at greater than the upper threshold [13.0 g/dL]” and that “there is insufficient evidence to recommend routinely maintaining Hgb levels at 13.0 g/dL or greater in ESAtreated patients.” The intent of the guidelines appears to be that allowing the Hgb level to transiently exceed 13 g/dL should be discouraged. The change in the Hgb target range appears to reflect concerns about the inability to maintain patients within the narrow target range of 11–12 g/dL. Furthermore, in the guidelines document, data are cited suggesting there are quality-of-life benefits with higher Hgb levels. Using Cochrane Collaboration methodology, Stripolli et al. has been critical of the quality-of-life studies performed so far.22 A balanced view is that the quality- of-life benefits in raising the Hgb from 11 g/dL to higher levels are at best modest, and for most patients the trade-off between risk and benefit is not substantial. Even incorporating quality-of life-benefits into their analysis, Tonelli et al. advocated cost effectiveness in maintaining the Hgb in the 11–12 g/dL range.23 The FDA is independent and rigorous in its regulatory oversight of drugs. Until a future study supports the safety of a higher Hgb level in kidney patients, we should adhere to the FDA's advice. The CHOIR study reported an increased risk from targeting an Hgb of 13.5 g/dL (and achieving an Hgb of 12.6 g/dL) and no incremental quality-of-life benefit with a target of 13.5 g/dL versus the lower target of 11.3 g/dL.24 The CHOIR study enrolled 1,432 patients and randomized about half to a target Hgb of 13.5 g/dL (achieved mean 12.6 g/dL) and half to a lower target of 11.3 g/dL.7 The results showed the higher Hgb group had a significantly higher risk of the composite end point (death, myocardial infarction, heart failure, and stroke; hazard ratio of 1.34, p < 0.03). Notably, there was no benefit in quality of life using three validated quality-of-life instruments. The CREATE study of approximately 600 patients also suggested a trend toward a higher rate of cardiovascular complications for patients assigned to the higher Hgb group.25 The results were compatible with an earlier study of high-risk dialysis patients, the Normal Hematocrit study.26 However, unlike the Normal Hematocrit study, both CHOIR and CREATE studied pre-dialysis CKD patients, and so the results may not be generalizable to the dialysis community. Still, both the Normal Hematocrit and the Canada-Europe studies of dialysis patients demonstrated either no benefit or increased risk.4 The Normal Hematocrit study demonstrated a strong trend, whereas the Canada-Europe study suggested a statistically significantly higher rate of cerebrovascular accidents. Thus, the results of the CHOIR study reinforce and strengthen the observations from these other two trials of dialysis patients. It is true that dialysis patients are a different population from pre-dialysis patients, even when anemia issues are considered. In contrast to pre-dialysis patients, patients undergoing dialysis have blood loss through the dialyzer and tubing, a greater degree of iron deficiency (perhaps because of reduced absorption and mobilization of iron), and more inflammation, causing erythropoietin resistance. Generally, epoetin dose requirements appear to be higher for dialysis patients than for pre-dialysis patients. Therefore, it seems to be justified to argue that dialysis patients should be considered a distinct group. However, the significance of conceding this point should not be underestimated. Because there are no ongoing or planned randomized controlled studies evaluating Hgb target levels in dialysis patients, this means that until such a study is published, the status quo ante of aggressively treating the anemia these patients have would prevail. It would also allow CMS to provide dialysis chains the flexibility, through relaxed reimbursement policies, to drive Hgb values beyond the FDA-recommended level of 12 g/dL. However, most importantly, results looking at anemia targets have been similar between dialysis and pre-dialysis patients. Why should physicians treating their dialysis patients aim for Hgb levels < 12 g/dL? First, because the recent data from the CHOIR study indicated increased deaths and cardiovascular complications with no significant improvement in quality of life in the higher versus lower Hgb group. Second, because the data from studies of dialysis patients (Normal Hematocrit and Canada-Europe studies) and pre-dialysis patients have provided concordant results, indicating the potential for harm to both dialysis and pre-dialysis patients; thus, concerns about differences in the dialysis and pre-dialysis populations are likely exaggerated, at least as they apply to anemia. Third, several studies in cancer and other populations have reported increased risk with aiming for Hgb levels > 12 g/dL. Finally, we should defer to the FDA on safety-related issues. The FDA recently issued a black box warning that recommended that the Hgb in patients with kidney disease not rise beyond 12 g/dL.27 The black box warning is the most severe warning about the safety of a drug that the FDA issues, and it has resulted in a label change. The FDA is independent and rigorous in its regulatory oversight of drugs. Until a future study supports the safety of a higher Hgb level in kidney patients, we should adhere to the FDA's advice.

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