Dr. Jay Wish (00:05): Hello, I'm Dr. Jay Wish, Professor of Clinical Medicine at the Indiana University School of Medicine in Indianapolis, Indiana. Welcome to this program titled Anemia of CKD: Consequences of Missing the Boat. This is episode three of six podcasts in the Updates and Advances in Anemia of Chronic Kidney Disease series. Joining me today is Dr. Frederick Finklestein, who is Clinical Professor of Medicine at Yale University School of Medicine in New Haven, Connecticut. Welcome, Fred. Dr. Fredric Finkelstein (00:37): Hi, nice to be here. Dr. Jay Wish (00:40): By means of introduction, anemia is a common complication of chronic kidney disease or CKD. The prevalence of anemia in patients with CKD increases as the disease progresses. About 50% of all patients with stage five CKD have associated anemia. In this episode, we'll focus on how anemia has been managed, where there are gaps in managing anemia patients with CKD, and what can happen when anemia is poorly controlled, especially in terms of the quality of life of our patients. (01:13): Let's start by diving into the history of how anemia in patients with CKD has been treated. Previous to the 1989 approval of Epoetin by the FDA to treat anemia in dialysis patients, these patients typically had hemoglobin levels in the 78 grams per DL range and were transfused so often they frequently developed iron overload. Epoetin not only decreased transfusion requirements but improved the quality of life of these patients by increasing hemoglobin levels to around 10. Fred, what are the data regarding improved quality of life in this population? Dr. Fredric Finkelstein (01:51): Any nephrologist or caregiver looking after patients with chronic kidney disease or end-stage kidney disease was well aware of the positive impact that ESAs had on the health-related quality of life of these patients in a wide variety of domains, including overall quality of life, patient's perception of their quality of life, energy, fatigue, symptoms of congestive heart failure, sexual dysfunction, psychosocial functioning such as depression, et cetera. The impact was clearly traumatic and thus ESAs appropriately became incorporated into the routine care of patients with chronic kidney disease and anemia. (02:33): In the contemporary era, patients routinely defeated with ESAs and we do not usually see CKD or ESKD patients with hemoglobin levels of 78 as we did in the 1980s. If we do see them, they have started on therapy ESAs. The debate in the contemporary era is not whether ESA therapy should be used because it certainly should be, but rather to what level of hemoglobin should these patients be treated. Dr. Jay Wish (03:03): The three major post-approval trials of ESAs, the normal hematocrit study, CHOIR and TREAT compare the effects of ESA dosing to higher target hemoglobin levels in the 13 to 14 range versus standard treatment to hemoglobin levels in the nine to 11 range. Those studies demonstrated cardiovascular risk in the higher target hemoglobin groups. What were the effects of the higher target hemoglobin levels on health-related quality of life in these studies? Dr. Fredric Finkelstein (03:33): The answer really requires that a careful review of these studies be done, which I think are often misinterpreted. For example, in the CHOIR study, the two treatment groups had baseline hemoglobin levels of 10.1 and were randomized to higher hemoglobin levels at average 11.3 in the low group and 12.6 in the high group. These studies suggested there was not a statistically significant difference in the low and the high groups in terms of quality of life measures. But importantly, both the SF-36 physical functioning and vitality scores increased in both the low and the high groups. For example, the vitality scores increased 8.2 points in the low group and 10.6 in the high group, substantial increments. So raising the hemoglobin from 10.1 to the mid-11s or 12.6 really did result in significant improvements in physical functioning vitality scores. (04:32): In the CREATE study when hemoglobin levels were increased from baselines of 11.6 to 13.3, SF-36 physical functioning and vitality scores increased 5.5 and 4.5 points respectively, again, statistically significant increases. And in the TREAT study, hemoglobin levels were increased from 10.6 to 12.5 and fact fatigue scores increased by 1.4 points, which was statistically significant. But the 1.6 increment did not meet the predetermined significant increases of three points that were suggested by the study investigators. However, a significantly greater number of patients in the treated group had a three point increase versus the control group. (05:23): This brings up the question of individualization of care focusing on the individual patient rather than the statistics in a given study. If the mean average patient has an improvement in symptoms but this does not reach statistical significance as determined by study investigators, what does that really mean for the individual patient? And that's an important thing to keep in mind as we think about using ESAs to treat the anemia of patients with chronic kidney disease. Dr. Jay Wish (05:55): So showing an association between low hemoglobin and poor health-related quality of life is not the same as showing that pharmacologically raising the hemoglobin level improves quality of life. Fred, can you explain this disconnect? Dr. Fredric Finkelstein (06:10): The problem is that the cause of the anemia needs to be put in the context of the individual patient. For example, a patient who is anemic because of systemic illness inflammatory condition may feel poorly not only because of anemia but also because of the underlying disease. Thus, simply treating the anemia without addressing the underlying problem may not result in improvement of symptoms. But raising the hemoglobin in the studies which we just discussed with the ESAs did result in improvements in various health-related quality of life measures. So from my perspective, there's no question that the treatment of anemia does result in improvement in health-related quality of life. Dr. Jay Wish (06:57): Fred, can you comment on patient report outcome data such as the SONG or SONG initiative that shows that reducing the symptom burden from anemia, particularly poor energy and vitality and physical functioning is a high priority for patients? Dr. Fredric Finkelstein (07:13): The SONG initiative wanted to determine which symptoms and areas of difficulty were most important for patients with CKD and the SRD. These studies clearly showed that fatigue and impaired physical functioning was of major concern for these patients and are, in fact, one of the top concerns for these patients. Addressing these domains, fatigue and physical functioning, are difficult, but certainly the treatment of anemia is one of the most important and easiest therapies we can offer. In fact, excellent studies by Kristen Johansen several years ago showed that the treatment of anemia results in significant improvements of both physical functioning vitality scores and, in fact, those are the domains that are most impacted by the treatment of anemia with ESAs. Dr. Jay Wish (08:04): Based on safety issues with higher hemoglobin targets in ESA doses, our use of ESAs for anemia in patients with CKD is guided by the FDA label and the KDIGO anemia guidelines, which recommend a target hemoglobin level of 10 to 11 in the case of the FDA label and 10 to 11.5 in the case of the KDIGO recommendations. Do you think it's realistic to expect a health-related quality of life improvement in patients whose hemoglobin level starts in the nine to 10 range with these target ceilings? Dr. Fredric Finkelstein (08:38): Let's go back and review exactly what the KDIGO guidelines say. These were published in 2012, but let me quote what they actually say. "First, individualization of care is necessary as some patients may have improvements of quality of life at hemoglobin and concentrations above 11.5 grams per deciliter and will be prepared to accept the risks." They further state that, and again, I quote, "Individualization of therapy is reasonable as some patients may have improvements in quality of life at higher hemoglobin concentrations and ESA therapy may be started above 10 grams per deciliter." (09:19): My interpretation of the CHOIR, CREATE and TREAT studies is that individual responses to anemia treatment vary, but clearly some patients respond to increases in hemoglobin concentrations even when ESAs are started above 10 and to targets above 11.5 grams per deciliter. The important point here is to see each patient as an individual. Dr. Jay Wish (09:44): In an abstract presented at ASN 2021 Kidney Week, non-dialysis CKD patients with baseline hemoglobin in the 8.5 to 10 range were randomized to placebo or active treatment with anemia agent to target hemoglobin in the 11 to 12 range. Those receiving active treatment demonstrated increased SF-36 vitality score versus placebo. Does this help inform us as to the magnitude of the hemoglobin rise that may be needed to improve health-related quality of life? Dr. Fredric Finkelstein (10:18): This important study which you're referring to clearly demonstrated that anemia treatment can improve selected health-related quality of life domains, particularly vitality and physical functioning. I would like to refer it to two often overlooked papers from 2009 that address the relationship with hemoglobin level to fatigue and physical functioning. The first is the Leaf and Goldfarb Review article published in Kidney International which showed that these domains, physical functioning and vitality, increased as hemoglobin levels increased from eight to 14, although the improvement flattened above 12 and was most dramatic in the nine to 10 rage. (11:01): And the results of the cryo study published in [inaudible 00:11:05] that showed significant improvements in these domains from hemoglobin levels below 11 to 11.12 with continued improvement of O flatter the hemoglobin levels over 13. These same findings were confirmed in another study of over 5,000 patients by [inaudible 00:11:25] published in BMG Nephrology in 2020 using the visual analog scale of the EQ 5-D assessing overall health status. This study showed a linear increase in patient's perception of the health status as hemoglobin levels increased from eight to 14. Dr. Jay Wish (11:49): Fred, do you think that patients who experience improved quality of life at hemoglobin levels greater than 11 which is actually off-label for ESAs in the United States should be offered higher doses of anemia treatment drugs to a hemoglobin target as high as 13 if they understand and accept the risks? Dr. Fredric Finkelstein (12:08): So my answer to that would be definitely yes. You have basically defined what patient-centered care is all about. Explaining the risks and benefits of treatment to patients and letting them decide how they would like to be treated is not for us as physicians to make that decision for patients. Patients should be informed of the potential benefits of treatment to the higher hemoglobin levels, for example, they should be aware of what the risks are of that treatment, and then they should make the decision about what they would like to do. It's important to be clear what the data shows, both the benefits as well as risks, and that decision then should be made by the patient, not by the physician, not by the FDA, and perhaps not by international guidelines. Dr. Jay Wish (12:58): Fred, do you have any final comments? Dr. Fredric Finkelstein (13:00): Well, I think this is a fascinating area. I think the role of the treatments of anemia has an important impact on patients' health-related quality of life, and I think the care of patients has been too much driven by guidelines set up internationally, nationally, and by the FDA and by dialysis providers. I think we need to take a broader view and incorporate the treatment of anemia into a patient-centered care worldview. Dr. Jay Wish (13:31): So just to kind of summarize, although the FDA approved label for anemia treatment drug such as ESAs recognizes only transfusion reduction as a benefit of therapy, most of us treating these patients recognize that many of them report improvement in fatigue and functional status with an increase in hemoglobin level. The degree of symptom improvement in hemoglobin level at which that occurs varies from patient to patient and underscores the importance of individualizing therapy of this condition. Since reduction in fatigue and physical impairment is a high priority for patients with CKD and ESKD based on survey data, it is important for practitioners who treat these individuals to discuss with them an anemia treatment strategy that best suits their unique benefit and risk situation. (14:20): I'd like to thank Fred for this great discussion. I really appreciate your sharing your expertise, and thanks to our audience for participating in this activity. Please join us for the remaining five podcasts in this series, Updates in Advances in Anemia of Chronic Kidney Disease. We hope you enjoy the rest of your day and please continue on to answer the questions that follow and complete the evaluation. We really appreciate your feedback as it helps us develop future educational programs.