Rationale for Guideline Hemoglobin Targets
Hemoglobin Targets
Contribution from the KDOQI 2006 Anemia workgroup
Source:
National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis 47:S1-S146, 2006 (suppl 3).
2.1.1. Lower limit of Hb: In patients with CKD, Hb should be 11.0 g/dL or greater. (MODERATELY STRONG RECOMMENDATION)
2.1.2. Upper limit of Hb: In the opinion of the Work Group, there is insufficient evidence to recommend routinely maintaining Hb levels at 13.0 g/dL or greater in ESA-treated patients.
Justification
Patients in the 19 randomized clinical trials (RCTs) reviewed to support the statement that Hb level should be 11.0 g/d or greater clearly are representative of the anemic patients with CKD that the statement intends to address. Ten RCTs enrolled patients with HD-CKD, 1 enrolled patients with PD-CKD, 2 enrolled patients with both HD and PD-CKD, and 9 enrolled patients with ND-CKD. Evidence supporting the statement that Hb level should be 11.0 g/dL or greater is confined to results of between- group comparisons generated by trials randomizing patients to distinct intent-to-treat Hb targets, using “ESA versus placebo” or “ESA lower Hb target versus ESA higher Hb target” designs.
Conversely, distinct target RCTs consistently show that patients assigned to a Hb value of 13 g/dL or greater show no discernable improvement in survival, hospitalization, or LVH compared with patients assigned to Hb targets less than 13 g/dL and may be prone to excess adverse cardiovascular events. Most distinct-target RCTs clearly have inadequate power to compare AE rates between patients in lower and higher Hb target groups for the key safety outcomes, mortality, MI, and cerebrovascular events. There are 2 exceptions. In patients with HD-CKD with CVD, patients assigned to a Hb target level of 14 g/dL showed increased risk for death or MI compared with patients assigned to an Hb level of 10 g/dL, [1] a finding that did not reach significance (relative risk [RR], 1.3; 95% CI, 0.9 to 1.9). However, safety concerns prompted early study termination. In a second trial of patients with HD-CKD without symptomatic heart disease or left ventricular dilation, patients assigned to a Hb target of 13.5 to 14.5 g/dL showed a greater rate of cerebrovascular events than those assigned to an Hb target range of 9.5 to 11.5 g/dL (P < 0.045). [2] The failure of observational associations to be confirmed by interventional trials renders use of observational evidence unsuitable to support the development of an intervention guideline statement. The statement that There is insufficient evidence to recommend routinely maintaining Hb levels at 13.0 g/dL or greater recognizes the concern that, for most patients, the known risks outweigh the known benefits of treating to higher Hb level. The phrase insufficient evidence reflects the finding that published results from comparative trials large enough to examine safety are relatively limited.
The Work Group considered, but rejected, identifying a target Hb level bounded by narrow upper and lower values (eg, 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, [3-5] discourages flexibility in managing individual patients, and likely promotes cycling of Hb results greater than and less than the target. [6] The Work Group chose to define a broad therapeutic range of Hb levels bounded by a discrete lower threshold above which Hb level should be maintained and a upper threshold above which Hb should not be routinely maintained. This approach makes clear to the practitioner that no patient should be maintained intentionally at less than the lower threshold, and patients should not be routinely maintained at greater than the upper threshold.
References:
- Besarab A, Bolton WK, Browne JK, et al: The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 339:584-590, 1998
- Parfrey PS, Foley RN, Wittreich BH, Sullivan DJ, Zagari MJ, Frei D: Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease. J Am Soc Nephrol 16:2180-2189, 2005
- Lacson E Jr, Ofsthun N, Lazarus JM: Effect of variability in anemia management on hemoglobin outcomes in ESRD.Am J Kidney Dis 41:111-124, 2003
- Collins AJ, Brenner RM, Ofman JJ, et al: Epoetin alfa use in patients with ESRD: An analysis of recent US prescribing patterns and hemoglobin outcomes. Am J Kidney Dis 46:481-488, 2005
- Berns JS, Elzein H, Lynn RI, Fishbane S, Meisels IS, Deoreo PB: Hemoglobin variability in epoetin-treated hemodialysis patients. Kidney Int 64:1514-1521, 2003
- Fishbane S, Berns JS: Hemoglobin cycling in hemodialysis patients treated with recombinant human erythropoietin. Kidney Int 68:1337-1343, 2005
Prepared on behalf of the National Kidney Foundation KDOQI guideline Anemia workgroup by Michael Rocco (KDOQI Vice-Chair).
