Creation/Revision Date: July 16, 2010
Centers for Medicare and Medicaid Services
Mail Stop C1-09-01
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Baltimore, MD 21244-1850
Re: NCA Tracking Sheet for Erythropoiesis Stimulating Agents (ESAs) for Treatment of Anemia in Adults with CKD Including Patients on Dialysis and Patients not on Dialysis (CAG-00413N)
Dear Ms. Long:
The Renal Physicians Association (RPA) is the professional organization of nephrologists whose goals are to ensure optimal care under the highest standards of medical practice for patients with renal disease and related disorders. RPA acts as the national representative for physicians engaged in the study and management of patients with renal disease.
We are writing to provide comments on the recently requested national coverage determination (NCD) for recombinant human erythropoietin (ESAs) for treatment of chronic kidney disease (CKD) and dialysis-related anemia. RPA affirms that ESA-treatment studies in nondialysis CKD have resulted in a solid body of evidence that is helpful for guiding patient care, but that, like all studies of heterogeneous populations, the conclusions drawn do not necessary reflect the advantages and disadvantages of ESA use for any particular individual. RPA strongly believes that while practitioners should rely on guidelines as a general basis for treatment,care decisions should be individualized based on the characteristics of the specific patient.
Since FDA approval in 1989, nephrologists have used ESAs to treat anemia in dialysis patients and in pre-dialysis patients with chronic kidney disease. While appropriate use of ESAs and iron have reduced substantially the numbers of patients with profound anemia, RPA recognizes that recent studies have raised substantial concern about the safety of ESAs when they are used to raise hemoglobin (Hb) concentrations to the normal or near normal range of Hb greater than 12 grams per deciliter (Gm/dL).
To gain greater clarity on the issues of survival/cardiovascular risk, and patient-perceived quality of life (QoL)/exercise tolerance, RPA convened a workgroup of experts in the treatment of anemia in CKD and dialysis to review the literature and to help give our members guidance in the safe and effective use of these agents. The efforts of the workgroup shaped the RPA positions in these two areas as presented below.
Survival and Cardiovascular Risk
RPA concurs that the evidence is strong at high levels of Hb: targeting Hb at 13 Gm/dL and achieving Hb over 12 by use of ESAs for both dialysis and pre-dialysis CKD patients increases risk of death and cardiovascular complications like stroke. Furthermore, we also agree that there is reasonably strong evidence that high ESA dose in patients with resistance to ESAs is a risk for these same complications.
However, it is also RPA’s opinion that the evidence is less clear at lower levels of Hb. In a study published in March 2010 in the Journal of the American Medical Association (JAMA) by Brookhart and colleagues, data from the United States Renal Data System (USRDS) were analyzed by examining ESA prescription patterns in dialysis facilities. Since patients do not select dialysis facilities according to their ESA prescribing patterns, the authors called this a “natural experiment,” subject to less confounding than other retrospective studies, and more similar to most of the major trials of ESAs. They found that when patients had hematocrit (Hct) levels of less than 30%, centers using higher doses of ESAs and those using more frequent doses of iron had lower mortality. Since a prospective trial of ESAs for patients with significant anemia will probably never be done, RPA believes that this study provides reasonably strong evidence that ESA and iron use are associated with improved survival when Hb is less than 10.
Patient-Perceived QoL and Exercise Tolerance
With regard to patient-perceived quality of life (QoL) and exercise tolerance, RPA suggests that two reviews published in March 2010 in the American Journal of Kidney Diseases (AJKD) deserve attention. Gandra and colleagues performed a systematic literature review of prospective studies examining the impact of ESAs on energy and physical function in non-dialysis CKD patients. These 2 measures of QoL, rather than the less-specific general QoL tools, may be of more focused importance for CKD patients. They found in patients with Hb levels between 8.8-11.9, ESA use correlated with higher energy or less fatigue, and with better physical function. In the second study, Johansen and co-authors did a systematic review and meta-analysis of exercise tolerance and physical functioning in dialysis patients treated with ESA. They also found a correlation between ESA treatment, higher Hb levels, and exercise capacity and physical functioning.
RPA also believes the evidence is reasonably strong that treating anemia in non-dialysis CKD patients and hemodialysis patients when their Hb is less than10 improves survival, patient-perceived quality of life and exercise tolerance. We also believe that hemodialysis patients are different than non-dialysis CKD patients, and that it is prudent to follow the KDOQI guidelines to target Hb at 10 – 12 Gm/dL in those patients.
It is important to remember that evidence-based medicine is designed for use at the individual patient level. We too often forget that “Evidence-based medicine is the integration of best research evidence with clinical expertise and patient values” as formulated by Sackett in 1996 [Sackett DL, et al. Evidence based medicine: what it is and what it isn’t. BMJ 1996;312:71] As CMS examines the strength of the evidence and considers its coverage policies, we trust the agency will preserve the ability of doctors and patients together to consider risks and benefits, the uniqueness of each patient’s conditions and each patient’s preferences, and make decisions about ESA or other therapies one patient at a time at the bedside.
Reduction in Transfusion Requirements
The evidence appears to be excellent that ESA use in patients with Hb less than 10 reduces transfusion requirements. This may be particularly important for patients awaiting kidney transplantation since it minimizes the likelihood of sensitization (from preformed antibodies) that can preclude successful transplantation.
RPA offers the following recommendations for ESA use in the patient with CKD/ESRD and anemia:
|CMS and practitioners should recognize that ESA treatment in nondialysis CKD patients to a target Hb greater than13 gm/dl has been found to increase cardiovascular and other risks, without consistent signs of benefit.
|ESA treatment in nondialysis CKD to target Hb between 10-13 gm/dl has not been adequately tested. Since this limits the ability of clinicians to balance risk against benefit, RPA feels that no clear treatment recommendations can be made in this range. RPA recommends that CMS develop policies that allow practitioners to consider their patient's clinical characteristics, and include the patient in consideration of potential benefits and risks of ESA treatment in this range.
||ESA use for nondialysis CKD patients with Hb less than 10 gm/dl reduces the need for transfusions and may improve patient reported outcomes. As such, RPA urges CMS to recognize that particularly for patients who are candidates for kidney transplantation, avoidance of blood transfusions may reduce pre-sensitization and improve the likelihood of finding a good donor-recipient match.
||While there are no good, modern era studies of CKD patients with profound anemia, older, less rigorous studies show impairment in physical functioning and quality of life when ESRD patients have profound anemia. Since it is unlikely that rigorous studies of CKD/ESRD patients with profound anemia will be performed, RPA suggests that CMS develop policies that will facilitate the nephrologist’s ability to consider treatment for patients with symptomatic anemia with these steps:
- Evaluate patients with anemia to exclude and treat causes of anemia other than CKD.
- Always measure iron status during anemia evaluation and replete iron when deficiency is diagnosed. ESAs should not be administered until the effect of iron repletion is assessed after 6-8 weeks.
- Consider the risks and benefits of blood transfusions and ESAs and treat anemia to achieve adequate Hb levels.
- Monitor carefully all patients treated for anemia, particularly to avoid high doses of ESAs to achieve a target Hb.
||RPA urges CMS to account for the fact that the CKD population has differences from the patients who have reached ESRD and are treated with hemodialysis. Hemodialysis patients often have more co-morbidities and are sicker than nondialysis CKD patients. Hemodialysis is associated with its own unique clinical problems. The hemodialysis procedure itself causes chronic blood loss and may reduce the quality of life. Therefore, the benefits of ESAs are likely to be valued more in this population. Moreover, studies of ESA treatment in hemodialysis have been more consistent in indicating improved quality of life. Thus, RPA believes that hemodialysis represents a different clinical setting than nondialysis CKD, and that the current target hemoglobin range of 10.0 to 12.0 gm/dl represents a prudent range for these patients. Especially large doses of ESA should be avoided because of possible increased risk.
As always, we welcome the opportunity to work collaboratively with CMS in its efforts to improve the quality of care provided to the nation’s kidney patients, and we stand ready as a resource to CMS in its future endeavors. Any questions or comments regarding this correspondence should be directed to RPA’s Director of Public Policy, Rob Blaser, at 301-468-3515, or by email at firstname.lastname@example.org
Edward R. Jones, M.D.