New York, NY (June 26, 2007) - The National Kidney Foundation (NKF) is America's oldest and largest voluntary health agency serving the needs of kidney patients and the professionals who care for them. As we will demonstrate, NKF appreciates and shares the Committee's interest in ensuring that kidney patients receive safe and appropriate anemia management care and in reviewing the relationship between reimbursement policy and quality improvement. This statement updates and supplements the testimony that NKF provided to the Committee for its hearing on December 6, 2006, on the subject of "Patient Safety and Quality Issues in End Stage Renal Disease Treatment," which specifically addresses payment reform issues.
Anemia commonly contributes to poor quality of life in patients with chronic kidney disease (CKD). Fortunately, among the many disorders that may afflict patients with CKD, anemia is perhaps the most responsive to treatment. For this reason, anemia was the subject of one of the first efforts of NKF to improve patient outcomes: the development, dissemination, and implementation of NKF's Dialysis Outcomes Quality Initiative (DOQI) Clinical Practice Guidelines, in 1997. Those guidelines have been revised several times over the last decade, to reflect the latest scientific evidence. In addition, DOQI has evolved into KDOQI. (Kidney Disease Outcomes Quality Initiative) as the focus of this program has expanded to embrace all stages of CKD. The goal of the NKF's clinical practice guideline development program has remained constant since it began in 1995: to promote improvement in the quality and safety of care for all patients with kidney disease by providing information to clinicians and patients that can assist decision making, taking into consideration the needs of individual patients and unique clinical situations. Our guidelines take into account safety of the treatment as well as potential quality of life benefits which may be important considerations for patients with kidney disease. While the NKF's clinical practice guidelines do not include reimbursement recommendations, reimbursement policy should support informed decision making that KDOQI facilitates. The goal of NKF's clinical practice guideline development program is supported by the rigorous methodology of the KDOQI process, which involves an expert work group; a separate and independent evidence review team, currently based at Tufts New England Medical Center; and opportunity for public review of draft guidelines and practice recommendations before final publication. It is widely acknowledged that, since their initial publication in 1997, the DOQI guidelines have had a significant and measurable impact on the care and outcomes of dialysis patients. Most recently, in keeping with the KDOQI process, the decision to update the May 2006 KDOQI Anemia Guidelines on hemoglobin target was undertaken, since new information, published in November of 2006, changed the evidentiary base. Therefore, the substance of some of the guidelines and clinical practice recommendations, particularly related to safety concerns, were revised. A new KDOQI Clinical Practice Recommendation will be published in the September 2007 issue of the American Journal of Kidney Diseases, acknowledging that judgments regarding benefits and harm in anemia therapy may vary from patient to patient, and for the same patient, under different conditions. Limitations of the current evidence base, differences in individual clinical judgments, and variable responsiveness to therapy between patients, and within a patient, argue for maintaining flexibility when addressing erythropoiesis stimulating agents (ESA) therapy.
Benefits of Anemia Therapy
Improvement in quality of life and avoidance of transfusion are the most likely benefits of anemia therapy. Quality of life is an outcome of direct importance to kidney patients and should be valued accordingly. In research studies, measurement of Health Related Quality of Life is performed using standardized instruments that have been validated in a range of target populations, including patients with CKD requiring or not requiring dialysis. Results yielded by these instruments achieve levels of reliability and precision that are comparable to those seen with other commonly-used clinical tests. Health Related Quality of Life has been examined in several randomized clinical trials, comparing lower and higher hemoglobin targets in CKD patients receiving ESA for anemia. Most studies show some quality of life improvement in patients assigned to higher hemoglobin (Hb) targets when compared to those assigned to lower Hb targets. Higher Hb targets lead to improvements in both physical and mental health domains. This is not to say that all patients should be treated to higher Hb levels, but to provide patients with full disclosure on the potential harms as well as benefits given the survival expectations of the ESRD population.
Hemodialysis patients lose blood from frequent blood tests, trapped blood in the dialyzer and tubing, and increased risk for GI bleeding from anticoagulants. Replacing these losses via transfusion, unfortunately, carries many risks that are specific to kidney patients, in addition to the risk of exposure to blood borne pathogens that transfusions present. In the presence of severe chronic anemia, transfusion may lead to congestive heart failure, particularly in the elderly. The administration of many red blood cell transfusions over a prolonged period can eventually lead to iron overload. Blood transfusions can also induce antibodies to histocompatibility leukocyte antigens that interfere with kidney transplantation; thus, transfusions generally should be avoided in patients awaiting a kidney transplant. In the current era, transfusing dialysis patients has become more complex in that the payment system does not allow for red blood cell transfusions at the time of outpatient dialysis treatments, thereby increasing the complexity and safety of administering transfusions. It is important to remember transfusion of stored blood carries a risk of potassium overload or hyperkalemia, since the packed cells release potassium from the red blood cells over time. The volume changes are equally important when blood is transfused off dialysis, because many patients gain fluid in between dialysis sessions pre-disposing individuals to further risk of congestive heart failure as transfused blood will expand their intravascular volume. Therefore, the choice for dialysis patients must balance the safety of anemia treatment with ESAs, transfusion risks, and the potential quality of life issues.
Potential Harm from Anemia Therapy
The KDOQI Anemia Work Group met in Dallas, Texas, on February 4, 2007, to review published trials that reported results of all-cause mortality and adverse cardiovascular events in patients assigned to higher compared to lower Hb targets. With regard to mortality, the Work Group found no statistically significant difference for assignment to higher versus lower Hb in either subgroup of dialysis or non-dialysis patients. However, the Work Group rated the evidence showing a trend toward greater cardiovascular events in dialysis and non-dialysis patients assigned to Hb targets greater than 13.0 g/dL of moderately high quality for showing harm. The Work Group concluded that the possibility of harm with Hb targets above 13.0 g/dL weighs more heavily than the potential to improve quality of life and reduce transfusions. Therefore, clinicians should minimize the exposure of patients with kidney disease to Hb levels of 13 gm/dl or more for safety considerations. The exact methods to achieve these desired results are lacking and require more study.
At the same time the NKF fully supports the FDA's recent alerts on the safety of ESA and the concerns that doctors practice within the recommended label. The only difference between our recommendations and the FDA's centers on the potential for a quality of life benefit with a Hb range of 11-12 gm/dl, since the FDA does not specify a lower hemoglobin target, but rather the use of the lowest ESA dose necessary to avoid red blood cell transfusions. The FDA's upper Hb recommendation with ESA (12 gm/dl) is the same as NKF's. We look forward to the ongoing dialog over the safety and efficacy of ESA treatment since patients need to understand the potential risks and benefits related to the primary indications for ESA treatment, namely to reduce blood transfusions and to improve quality of life, while recognizing the risks with Hb levels that reach 13 gm/dl noted in the recent clinical trails.
Implementation Issues and Measuring Performance
Aiming for a Hb target within narrow boundaries in ESA-treated patients requires frequent dose adjustments in many patients. Only 30% of patients at any one point in time have an actual Hb level in the Hb target range of 11.0 and 12.0 g/dL when targeted to that range. Over 60% of patients receiving ESA therapy with Hb targets between 11.0 and 12.0 g/dL require between 6 and 9 dose changes per year. The necessary dose adjustment frequency may differ between initiation and maintenance of ESA therapy. Studies suggest that when the target Hb is 11.0-12.0 g/dL, variability of achieved Hb around the target is high, the fraction of prevalent patients with achieved Hb within the target range is low, and ESA dose titration is required frequently during maintenance therapy. Clinical evidence is lacking about how to respond to achieved Hb levels above target range. Holding ESA doses may lead to steep downward Hb excursions and high amplitude Hb cycling. On the other hand, flexibility in determining the size of the dose adjustment may be needed. Unfortunately, there are little data to guide clinicians on different dose adjustment methods, even withholding of the ESA dose, so as to maximize the number of patients within the desired Hb range. In short, measures of clinical performance, to be clinically useful, must account for a high degree of within-patient and between- patient variability, and the difficulty in maintaining the Hb within the desired range.
The National Kidney Foundation thanks the Committee for the opportunity to provide this statement and offers its assistance to the Committee and its staff with regard to deliberations concerning anemia therapy for kidney patients.