It has been said that half of all medical knowledge will be proven wrong. The problem is that we don’t know which half.

It has also been said that the half-life of medical knowledge is around seven years. The story of anemia management in patients with kidney disease is a good example. It took about nine years, from the U.S. Food and Drug Administration’s approval of recombinant human erythropoietin (EPO) in 1989 to the publication of the Normalization of Hematocrit Trial in 1998, for the nephrology community to discover that EPO was not the risk-free, totally physiologic panacea for erythropoietin deficiency that it was thought to be.

(Find more articles from “Controversies in anemia management”)

The cardiovascular risks of EPO therapy in kidney disease patients were more dramatically demonstrated eight years later in the 2006 CHOIR study, resulting in hearings by the U.S. House Ways and Means Healthcare Subcommittee and actions by the FDA and the Centers for Medicare & Medicaid Services to limit erythropoiesis-stimulating agent use. It is now seven years since the publication of the CHOIR study, and, to paraphrase the Declaration of Independence, even fewer truths about anemia management are self-evident.

Truth vs. hypothesis

As Dr. Szczech points out in the first article in this supplement, medical “truth” comes from the intention-to-treat (ITT) analysis of randomized controlled trials (RCTs) that demonstrate cause and effect. All other conclusions from clinical research, whether the secondary analyses of RCTs or the analyses of prospective or retrospective non-randomized studies, are hypothesis generating (“what we think we know”), no matter how tempting it may be to use them as evidence.

To our shame, nephrology has among the fewest RCTs in its literature base compared to other medical subspecialties. The ITT analyses of the major RCTs in anemia management are remarkably consistent in their conclusion: higher target hemoglobin (Hb) levels in patients receiving ESA therapy are associated with more cardiovascular events and not necessarily associated with improved quality of life (QOL). All other conclusions from these and other studies are hypothesis generating: Higher ESA doses are associated with poorer outcomes, and higher achieved Hb levels among ESA responders are associated with better outcomes.

Is the risk of higher target Hb levels linear? This hypothesis prompted the FDA to require ESA makers to state, “No trial has demonstrated a target Hb level, ESA dose or dosing strategy that does not increase these risks” in their product information. Such a trial would require stratification to multiple target Hb levels and would require thousands of patients to achieve the needed statistical power. It is too expensive to ever be done. This is an example of what we don’t know. However, there is another category that Donald Rumsfeld, the Secretary of Defense during the Reagan Administration, pointed out: “What we don’t know we don’t know,” meaning we haven’t even framed the questions or the studies to elucidate those truths, Unfortunately, there are still likely to be many issues regarding anemia management that fall into this category.

Physiology vs. pharmacology

One of the undeniable assets of EPO in 1989 was its homology to the native hormone. How could this be a problem? That cognitive dissonance probably led to the marginalization of the safety signal in the higher hematocrit arm of the Normal Hematocrit Trial, and it wasn’t until the publication of CHOIR and CREATE in 2006 did this safety signal get the attention it deserved. As Dr. Besarab notes in his article, it’s not only about quality but also about quantity. The vascular effects of erythropoietin are well documented now, but were poorly understood in 1989 when it was thought that erythropoietin had only one receptor on the bone marrow stem cell. In physiologic doses (small amounts released continuously), the vascular effects of erythropoietin are but one component of overall vascular homeostasis. With pharmacologic doses of ESAs (large amounts delivered intermittently), the ESAs destabilize vascular homeostasis as their high blood levels overwhelm the small physiologic levels of other vasoactive hormones. This has led to research into agents, such as the orally administered hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors (PHIs), that induce a more physiologic continuous lower level of native erythropoietin production to stimulate red blood cell synthesis, theoretically without the adverse vascular effects of pharmacologic doses of exogenous ESAs. Whether this desirable benefit-to- risk ratio will be borne out in large clinical trials remains to be seen.

Similarly, Drs. Fishbane and Shah point out the theoretical benefits of a longer-acting ESA on iron utilization. Studies have suggested that similar increases in Hb can be achieved with higher TSAT and lower serum ferritin levels; the more physiologic continuous stimulation of the erythropoietin receptor will lead to a more physiologic, rather than episodic, release of iron from stores in the reticuloendothelial system to circulating transferrin and from transferrin to the bone marrow. Thus there is less mismatch between iron supply and demand as with shorter-acting ESAs (functional iron deficiency) and lower exogenous iron requirements to maintain adequate bone marrow iron delivery.

Benefit vs. risk

The only FDA-approved benefit of ESA therapy is transfusion avoidance. The FDA has removed all quality of life claims from the ESA product information because they were not supported by placebo-controlled RCTs. Non-RCT studies of kidney disease and oncology patients receiving ESAs have suggested that the QOL benefit is greatest when the baseline Hb is <9 g/dL and when the Hb increase is at least 2 g/dL. The current FDA guidance that ESAs be initiated when the Hb is <10 g/dL and the dose reduced or discontinued when the Hb approaches 11 g/dL is consistent with these observations in terms of QOL benefit. Many in the nephrology community have been concerned regarding the increase in transfusions among dialysis patients since the FDA labeling change for ESAs in June 2011 and the removal of the Hb floor for the ESRD quality incentive payment announced in July 2011. As Dr. Coyne notes in his article in the February 2013 issue of NN&I, this increase in transfusions can be viewed as an acceptable trade-off from both the greater risks of higher target Hb levels and higher costs of ESAs to achieve them. Coyne presents data in this supplement suggesting that the risks of transfusion are overstated, even among potential transplant recipients in whom avoidance of allosensitization is a concern, and that targeting Hb levels higher than 11 g/dL would not have a significant impact on decreasing the transfusion rate.

In his article, Dr. Berns favors the restoration of an Hb floor for the ESRD QIP, but suggests that it should be lower than the previous 10 g/dL, perhaps 9.5 g/dL, to optimize the benefit-to-risk ratio of ESA therapy. He emphasizes that this is a population-based approach, and that the same target Hb range may not be suitable for all ESRD patients. He uses the term “optimization” of ESA therapy, which most would agree is easier said than done, and alludes to the heterogeneity of the ESRD patient population in terms of functional status, ESA responsiveness, and transplant eligibility. A dynamic tension has developed between the dialysis provider that wants to simplify anemia management with nurse-driven “one size fits all” protocols and the nephrologist who may want a more customized patient-centered approach to anemia management. How this tension can be resolved in the best interest of the patient is addressed in the final two articles.

Standardization vs. individualization

The words “individualization” and “patient-centered” are unavoidable in the current medical culture. They are aims of the Institute of Medicine, CMS, and FDA-approved product information for ESAs that recommend weighing for each patient “the possible benefits of decreasing transfusions against the increased risks of death and other serious cardiovascular events.” Although the FDA does not acknowledge a QOL benefit from ESAs, Dr. Finkelstein proposes in his article the idea of using patient-reported outcomes with a health-related quality of life (HRQOL) instrument such as the kidney disease quality of life (KDQOL) questionnaire, which has been validated in ESRD patients and includes the QOL elements that are useful in guiding the choice of a target Hb level. This may not be consistent with “a one-size fits all.” Dr. Finkelstein and the KDIGO (Kidney Disease Improving Global Outcomes) anemia guidelines published in August 2012 acknowledge that there is a subset of kidney disease patients who may experience a QOL benefit at a Hb target >11.5 g/dL, and that individualization of anemia management for such patients is appropriate.

In the final article in this supplement, Dr. Zager and his colleagues at Dialysis Clinic Inc. explain how both standardization and individualization of anemia management have been achieved through the use of a computer decision support program for ESA and iron therapy, with a user-friendly option for physician override of the algorithm in patients in whom the physician feels that individualization of therapy is indicated. DCI has found that the protocol has been adopted in 80% of the patients, which conforms to the “80/20 rule” that standardization works about 80% of the time. What results is not chaos, but validation of another rule that “consistency of process leads to consistency of outcomes” while allowing for the 20% outliers to receive the customized care that is best suited for their needs.

Have we figured it out yet?

We seem to be getting there. We are beginning to understand what is true and what is not best evidence. Unfortunately, given the poor inventory of RCTs in nephrology, there are only two recommendations from KDIGO that are based on grade A evidence: ESAs should not be used intentionally to increase the Hb concentration above 13 g/dL and that ESA therapy be stopped in patients who develop antibody-mediated pure red cell aplasia. Although many of the remaining statements from KDIGO are recommendations rather than suggestions or are not graded at all, the lack of compelling evidence supporting these recommendations underscores the need for forums for the discussion of these issues, such as this NN&I supplement.

We hope that the pipeline of new products to treat anemia will afford a more physiological approach and improve the benefit-to-risk ratio of therapy. We anxiously await the results of the phase 3 trials of these agents and we hope that, if and when they are approved, there are no unexpected adverse reactions as they are used by many thousands of vulnerable patients with kidney disease.

If there has ever been a lesson regarding benefit vs. risk, it has been with ESAs, whose promise of risk-free improvement in QOL was betrayed by aggressive use and the eventual demonstration of their untoward effects, the mechanism for which is still not completely understood. Nonetheless, this lesson has increased the awareness and emphasized the importance of weighing benefit vs. risk in all therapies and in all patients, understanding that this ratio will vary from patient to patient and even in a given patient over time. Individualization of therapy or “patient-centeredness” is more than a slogan; it is a change in medical culture that transcends anemia management. Fortunately, it is not difficult to achieve with the proper tools, the most important of which is communication.

Understanding what the patient expects from his/her anemia management using patient-reported outcome instruments will identify the 20% of patients who require deviation from protocols that work fine for everyone else.

That is the biggest step in figuring it out.

We welcome your comments on this special NN&I supplement on anemia management. Please contact editor Mark Neumann (mneumann@nephrologynews.com) with your own views on how we might improve anemia management in our CKD and ESRD population.