Erythropoiesis stimulating agents, blood transfusion, and the practice of medicine
Authors: Lawrence Tim Goodnough, Aryeh S. Shander
Journal: American Journal of Hematology (2010)

In July 2007, Centers for Medicare and Medicaid services (CMS) issued a National Coverage Decision (NCD), restricting reimbursement for erythropoiesis-stimulating agents (ESAs) to treat chemotherapy-induced anemia in cancer patients, only to cases in which hemoglobin (Hgb) levels before initiation of ESA are less than 10 g/dl [1]. In this issue of the American Journal of Hematology, Hess et al. [2] evaluated patterns for utilization of ESAs and red blood cell (RBC) transfusion in a large number of cancer patients who developed chemotherapy-induced anemia, before and after this change took effect. The CMS decision was in the context of a series of revisions by the Food and Drug Administration (FDA) on the label for ESAs [3, 4], following a number of clinical trials that showed increased adverse events and higher mortality in cancer patients who were treated with ESAs when targeted Hgb levels were in excess of 12/g/dl [5-11]. Adverse events have similarly been demonstrated in patients with chronic kidney disease who were treated with ESAs to target Hgb levels of greater than 13 g/dl [12]. The NCD restrictions for reimbursement of ESAs in this setting may be confusing to physicians, as they seem to suggest a Hgb level of 10 g/dl as both a therapy start and stop point for treatment. Some clarification can be helpful: as per the NCD and in this patient population, ESAs will be covered for 4 weeks if initiated when the Hgb is <10g/dl; a Hgb >10 g/dl after 4 weeks of treatment would mean that no further reimbursement will be authorized beyond the first 4 weeks. The restriction becomes more confusing when the effect of various rates of change in Hgb levels on coverage is described. The practice of medicine to stay within these narrow margins may be easier said than done. FDA approval of ESAs in cancer patients with chemotherapy-induced anemia was (and continues to be) primarily based on their demonstrated benefit of reducing/averting the need for RBC transfusions (and ignoring other possible/established benefits such as improved quality of life) [13]. One main concern has been that if ESA utilization is reduced significantly, then rate of RBC transfusions in patients will increase in this setting. The prospect of increased RBC transfusion rates should be taken very seriously, given the large body of evidence linking blood transfusions with potentially untoward patient outcomes as well as the negative and potentially destabilizing effect of the increased demand on blood inventory. Notably, data indicate a less than 10% margin between the total numbers of blood units collected and transfused in the United States [14]. Several lines of evidence (e.g., from the randomized, placebo-controlled trials that served as the basis of FDA approval) have demonstrated beyond doubt the transfusion-sparing effect of ESAs in patients with chemotherapy-induced anemia [15-17]. Nonetheless, what happens in the environment of a controlled therapeutic trial (i.e., the efficacy) can be quite different from the real-world consequences. A study by Hershman et al. using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database reported that while ESA utilization in cancer patients increased from 4.8% in 1991 to 45.9% in 2002, transfusion rates during the same period remained constant at around 22% [18]. However, analysis of the data from an on-going registry (Dose and Outcomes Study of ESAs; DOSE) demonstrated that a lower mean achieved Hgb level while on ESAs was associated with higher transfusion rates: among patient groups achieving mean Hgb levels of 9.1–10, 10.1–11, and 11.1–12 g/dl, the respective transfusion rates were 40%, 23%, and 18% [15]. Similarly, in this study [2], RBC transfusions did increase after implementation of the NCD: for patients aged 65 and older, transfusion rates increased significantly by 31% (absolute increase 2.1%, from 6.7% to 8.8%) concomitant with a 29% decrease (absolute decrease 13.4%, from 46% to 32.6%) in utilization of ESA. Several factors can be suggested to explain the contradictory results. Although the patients in the study by Hershman et al. [18] were comparable with the patients aged 65 or older in the study by Hess et al. [2], the former study analyzed the patients by cancer diagnosis (breast, colon, nonsmall cell lung, or diffuse large B-cell lymphoma), in contrast to the latter study that analyzed all patients undergoing a defined high or moderate myelosuppressive chemotherapy; in addition to a broad range of cancer diagnoses, 20% of these patients were classified as "other" tumor types. Thus, any analysis of ESA utilization rates, RBC transfusion rates, and projected impact on marginal blood supply is affected by and must be interpreted in the context of the patient populations being studied. Another important issue to consider is the complex nature of transfusion decisions. Indications of RBC transfusion in various patient populations (including cancer patients) have been the subject of long and continuous debates. Guidelines have been proposed to ensure that only the appropriate patients receive blood, although the evidence bases of these recommendations are often shaky. Most guidelines agree that Hgb alone should not be used as the basis of transfusion decisions, but it is generally accepted across the board that RBC transfusions are not indicated if Hgb level is 10 g/dl or more [19, 20]. This study does not address the question of the Hgb levels at which RBC transfusions were given to the patients, although a previous study by the authors on apparently a related dataset provided these data [21]. It would have been interesting to see how much of the increased transfusions were occurring at Hgb levels above 10 g/dl, which would have underscored the importance of appropriate use of transfusions, particularly following issuance of the NCD. Unfortunately, the only Hgb data provided in this study is the mean nadir value, and even this was compared only between pre- and post-NCD cohorts without further delineations for ESA treatment, transfusion status, and other potentially relevant factors. Despite this limitation, this study supports the premise that decrease in ESA use is associated with a significant increase in RBC transfusion rate, albeit the old debate of statistical significance versus clinical significance lingers. Given the risks and side effects of both ESAs and RBC transfusions, the ultimate clinically relevant question here is the effect of NCD implementation on patients' clinical outcomes. Is the additional risk posed by the increased transfusion rate outweighed by the decrease in the ESA-related complications? During the process leading to the issuance of the NCD, several public comments (almost all expressing some disagreements with the proposed decision) were submitted to the CMS [1]. Regardless of their position, all parties (CMS included) seem to agree that more clinical trials are needed to answer important, outstanding questions with regards to ESA use in cancer patients. In the meanwhile, these questions will not offer much help to physicians who must make bedside decisions (the practice of medicine) on the use of these agents. As for any approved pharmacologic agent therapy, decisions to prescribe also depend on assessments of relative merits (risk versus benefit) of the alternative therapy. In this instance either untreated anemia or RBC transfusion. The substantial advances in blood safety over the last 25 years [22-24] should not subtract from the continued relevance in considering the alternatives to RBC transfusion. The Circular of Information for Blood and Blood Products states that RBC transfusion is not indicated if specific medications that promote erythropoiesis have time to serve as alternatives [25]. These recommendations are timeless in view of the inherent (known and unknown) risks of blood, including emerging pathogens [26]. Consistent with the medical/legal concepts of informed consent (a discussion of risks, benefits, and alternatives), the FDA has required that ESAs must be prescribed under a risk management program, known as a Risk Evaluation and Mitigation Strategy (REMS), to ensure the safe use of these drugs [27]. REMS programs are in place for over 95 other pharmaceuticals, including therapies used in patients with malignancies. These programs underscore the reality that the practice of medicine includes the use of FDA-approved medications beyond the more narrow specifications in the label. For ESAs, targeting and maintaining Hgb levels between 10–12 g/dl may be "'not indicated'" for all patients; but for individual patients with clinical symptoms and/or signs, or co-morbidities such as cardiovascular risk factors, management of anemia to this level may be what is necessary and desirable to minimize the likelihood of avoiding RBC transfusion. The level of Hgb necessary to achieve this goal is currently not known. A previous study by Littlewood et al. [28] found that "late-intervention" initiation of ESA therapy (when Hgb <10.5 g/dl) reduced RBC transfusion rates from 42.2% to 28.2% for placebo versus ESA, respectively; meanwhile, "early intervention"' (ESA initiation when Hgb levels were between 10.5 and 12.0 g/dl, and at least a 1.5 g/dl decrease after initiation of chemotherapy) achieved a reduction from 20% to 7.1% for placebo versus ESA, respectively (see Table I). These findings may serve to predict the consequences of the CMS decision to reimburse ESA therapy only when physicians practice "late intervention" (at Hgb less than 10 g/dl) for patients' likelihood of receiving RBC transfusion. Informed choice by patients for likelihood and risks of RBC transfusion, as summarized in the table, as well as the risks of ESA therapy, should be part of the consent process when physicians consider prescription of ESA or RBC transfusion therapy. Reimbursement constraints should not dictate these kinds of clinical decisions in the absence of conclusive evidence.