Darren Grabe, BSPharm, PharmD: Welcome to this CME-accredited program entitled "Therapeutic Advances in Chronic Kidney Disease (CKD) Management of Anemia and the Role of Pharmacy." I am Dr. Darren Grabe, Associate Professor of Pharmacy Practice Department at the Albany College of Pharmacy in Albany, New York, and I'll be your moderator for today's program.

I am pleased to have with me today 2 key thought leaders to discuss some very important issues. First, we have Dr. Harold Manley, who is an Associate Professor at Albany College of Pharmacy in Albany, New York. And we have Dr. Amy Barton Pai, Assistant Professor of Pharmacy and Nephrology at the University of New Mexico Health Sciences Center, College of Pharmacy.

At the end of today's program, you should be able to do the following: examine the pathophysiology and epidemiology of anemia in chronic kidney disease; discuss the clinical impact of higher targeted hemoglobin levels; review current therapeutic agents for the management of anemia and the potential impact of emergent agents to stimulate red blood cell production; and, finally, describe the pharmacist's role in anemia management.

First, Harold will discuss the pathophysiology and epidemiology of anemia in chronic kidney disease.

Harold Manley, BS, PharmD: Thank you, Dr. Grabe, for a nice introduction. Over the next couple of minutes, I'd like to cover 3 major points: discuss the increasing prevalence of anemia in CKD; discuss the pathophysiology of anemia in CKD; and examine the impact of anemia on patient outcomes specifically in patients with CKD. So with that backdrop, I think it's important to set the stage as to what exactly is chronic kidney disease.

The National Kidney Foundation has published the Kidney Disease Outcome Quality Initiative (KDOQI) guidelines on what defines a CKD patient, and those are patients with kidney damage for greater or more than 3 months with structural or functional abnormalities with or without a decrease in glomerular filtration rate (GFR) or in patients who have a GFR of less than 60 mL/minute with or without kidney damage for at least 3 months.

Using those definitions for chronic kidney disease, you can further classify patients in one of 5 stages, stage I through stage V. And as the stages increase in number, the degree of kidney damage or reduction of glomerular filtration rate occurs. For example, patients who are stage III patients have a GFR between 30 and 59 mL/min, and patients in stage V, or patients commonly on dialysis, have a GFR of less than 15 mL/min.

So with the various stages of CKD, thinking about the size of the CKD population, the majority of the patients with CKD are within the first 3 stages, stages I through III, and few patients have actually stage V. Relatively about 400,000 patients are stage V.

But more simply put, if you think about chronic kidney disease, in the entire US population, approximately 1 in 9 adults in the United States has some form or some stage of chronic kidney disease.

So now that we have an understanding of what kidney disease is and staging of patients, if you look at the prevalence of anemia in the various stages, you also note that as the stage of CKD increases or, conversely, the amount of GFR a patient has, the more prevalent the anemia can be found. On this slide on the x-axis, you will see that in stage III patients, for example, 12% of the patients have a hemoglobin less than 13 if they're male or hemoglobin less than 12 if they're female. And as you go to stage V, up to 75% of the patients can be defined as having anemia. Specifically, in stage V, anemia was defined as a hemoglobin less than 11.

So patients with CKD oftentimes experience anemia, and the ultimate cause of anemia in many of these patients is the inability of the kidney to produce enough erythropoietin, because the kidney is responsible for about 90% of the erythropoietin that is produced in the body.

Under this next slide, "Normal Red Blood Cell Production," you will see that as oxygen concentration in the blood declines, the kidney responds by increasing more erythropoietin, which in turn goes to the bone marrow to aid in the production of red blood cells, or erythrocytes, thus raising the concentration of oxygen in the blood.

So as kidney function declines over time, the kidney's ability to produce erythropoietin also declines; therefore, there is less erythropoietin to stimulate the bone marrow to make red blood cells. In addition, EPO is actually important in red blood cell lifespan, so with less erythropoietin around, the red blood cell does not live as long. Also, patients with chronic kidney disease may potentially have bone marrow fibrosis due to separate systems involving parathyroid hormone in these patients, with elevated sustained levels of parathyroid hormone ultimately leading to renal osteodystrophy, bone marrow fibrosis. The bone marrow itself is less responsive to any erythropoietin that the patient may have.

So there are several reasons why a patient with kidney disease can develop anemia over time, and when I think about anemia overall, I think of 3 major reasons -- patients either lose, destroy, or have inadequate red blood cell production, and patients with chronic kidney disease have multiple reasons under each of the 3 major categories. Patients may be bleeding naturally because of menstrual cycles or having GI bleeds. Patients specifically on dialysis are anticoagulated frequently, so they may have bleeds associated with anticoagulation, so loss of red blood cells. Patients have decreased red blood cell survival. They may be having hemolysis occurring in them. And, again, thinking about EPO production in particular, patients with chronic kidney disease have decreased EPO production. They may have bone marrow infiltration, which I kind of alluded to, due to secondary hyperparathyroidism. And patients, specifically the dialysis population, may be considered a chronically inflamedpopulation because of increased cytokine production, which may ultimately affect the body's ability to produce red blood cells.

So having multiple reasons to be anemic in the chronic kidney disease patients, what happens to these patients or in these patients? Well, there is this triad, if you will, between worsening of chronic kidney disease and how it affects worsening of anemia and worsening of congestive heart failure and how the congestive heart failure, worsening CKD, and worsening anemia all interplay with one another. Patients kind of enter this vicious circle, so these patients may have left ventricular hypertrophy. Anemia precipitates CHF in patients. They can have exacerbations of their angina. They will have reductions in their aerobic capacity and multiple quality-of-life parameters, like overall well-being, cognition, and sexual function in patients.

And if you think about the specifically dialysis population, the cardiovascular mortality in these patients is much, much more than the general population. On this figure here, on the x-axis, you can see as we age, going from left to right, the annual mortality rate, cardiovascular mortality, on the y-axis, you can see in the general population, which is the lower curves. As we age, the cardiovascular mortality increases -- clearly well understood and well appreciated. But in the dialysis population, which is the top curves, which kind of superimpose one another, regardless of age, those patients have a high cardiovascular mortality rate. And you will see that that curve is relatively flat as well. It does not rise at the same rate as you see in the general population. For example, a patient on dialysis age 35 to 44, their annual mortality rate from cardiovascular event is similar to a general population 85-year-old plus individual. So they have a high cardiovascular mortality ratein the dialysis population.

And on this next slide by Levin and colleagues, you see that for every 1-g decrease in hemoglobin, there is an increased risk of left ventricular hypertrophy by 6%, and these are in patients with CKD.

If you are using schema there looking specifically in patients with dialysis, for every 1-g decrease in hemoglobin, it confers a 42% increase in left ventricular dilation.

So it's not surprising to look at the overall mortality and hospitalization in patients as described by hemoglobin range on the x-axis from less than 8 to greater than 12. This is from an analysis of a Dialysis Outcomes Practice Pattern Study of a number of countries, and you can see the referent range between 11 and 12. As hemoglobins decline, less than 11, the rate of hospitalization and mortality increases in these patients.

And from a separate analysis by Ofsthun and colleagues in this one aspect that was presented at a Nephrology Dialysis Transplantation meeting, they analyzed the Fresenius Medical Care of North America database over a 2-year period and looked at the mortality in dialysis patients when their hemoglobin was less than 11 g/dL. And as you can see here, the more time that you are below 11 g/dL hemoglobin concentration, from less than 20% up to 100%, the mortality hazard ratio increases significantly. For those patients who are always below 11 g/dL, you can see their mortality hazard ratio is 1.8, so lower hemoglobins are clearly correlated with adverse events in these patients.

So it makes sense, when you treat anemia, that the beneficial outcomes seen are not only higher quality-of-life scores. They have less fatigue, fewer fatigue symptoms, overall well-being is improved, increased activity. But [with] the maintenance of hemoglobin levels, you will actually decrease the amount of LVH and decrease the hospitalization and mortalities observed in this population.

So at this time, I think it makes sense that clearly we have discussed the impact of hemoglobin concentrations less than 11 and their outcomes, but the effect of hemoglobin concentrations at higher targeted levels is what Dr. Grabe is to discuss with the more recent information.

Dr. Grabe: Thank you, Harold.

I will now discuss the clinical impact of the higher targeted hemoglobin levels. This is certainly an issue that has come up of late with several studies that have documented that perhaps targeting higher hemoglobin levels is actually the wrong thing to do. This is borne out by several studies in the oncology population, about 4 particular trials and 2 specific trials that were identified in the nephrology population back in November. The outcome of this has led the FDA to issue a warning regarding the erythropoiesis-stimulating agents (ESAs) and their concern over the fact that higher target hemoglobins might relate to higher cardiovascular death as well as an increased risk of death, which is certainly a little bit different from what Dr. Manley has already identified, that certainly we know that lower hemoglobin targets are associated with poor outcomes. Now we are also perhaps finding out that higher hemoglobin targets may also be associated with poor outcomes. So it becomes anissue of what the optimum target hemoglobin is, and that is certainly unknown at this point in time.

The 2 chronic kidney disease trials that I'd like to discuss today are the CREATE and the CHOIR studies.

The first one is the CREATE study, and this is a study that had a little over 600 patients with stage III and stage IV CKD. These patients were randomized to 1 or 2 hemoglobin targets. One was a normalization, if you will, of hemoglobin; the goal hemoglobin was 13 to 15. The second group was a partial correction, and that is a hemoglobin target range of 10.5 to 11. 5. They started these patients on erythropoietin beta. This was a European trial, not done in the United States, so they used erythropoietin beta, which is available in the European countries, and they started at a fairly low dose actually, at 2000 units subQ weekly. They reviewed that dose every 4 weeks, and depending on what the hemoglobin was at that particular interval, they either increased or decreased the dose by 25% to 50%. Again, that depended on the rate of hemoglobin rise. If the hemoglobin rose less than 0.5 g/dL in that timeframe, they increased the dose by 25% to 50%. Conversely, if the hemoglobin increasedmore than 1 g/dL in that time period, they decreased the dose 25% to 50%.

The patients were provided oral or IV iron, and they visited the clinic frequently over the first 3 months, every 2 weeks, and then every 3 months thereafter.

The primary end point for this particular trial was a composite of cardiovascular events, and by the study's end, there was really no difference between groups in the primary end point. However, there was the suggestion or trend that there was a higher composite end point in the group that was randomized to the normalization of hemoglobin. Also, there was a significant increase in the quality of life in both groups, which is an important thing to remember.

Now the opposite trial was the CHOIR trial, and this is perhaps the one that has raised the most issue with the community at large. This is larger trial. It had over 1400 patients with stage III and stage IV CKD. They again were randomized very similarly to the CREATE trial to 1 of 2 hemoglobin targets. The higher hemoglobin target was 13.5 g/dL, and the second group was randomized to a target of 11.3 g/dL. The primary end point for this particular trial was a composite of death, myocardial infarction, hospitalization for congestive heart failure, and stroke. Now compared with the CREATE trial, they actually started their EPO doses a little bit higher at 10,000 units subQ weekly. They adjusted their doses every 2 weeks, but it's a little unclear on the details of this dosing algorithm. If you visit The New England Journal site, you will find some supplementary material for this particular trial; they mention the algorithm, but they are not as clear as the CREATE trial as faras what they did with the doses and changing doses. What they, however, did also say is if a particular patient was stable on their EPO dose for one month, they were then changed to a biweekly dose of EPO; the dose was doubled essentially. If they were on 10,000 subQ weekly for a month, they were then switched over to 20,000 units every other week. Now that's a little bit different from perhaps some other studies that have come out.

This was a US study, as compared with the CREATE study, which was a little different. There were 130 centers that were involved. What was interesting about this study is that the higher hemoglobin group had a little bit different baseline characteristics than the lower hemoglobin group. Of particular significance was increased rate of CABG and hypertension at baseline, and the end result of this study was that there was a higher rate of composite end point in the higher hemoglobin group. This is really a cause for concern for many nephrologists and certainly the general population that targeting at a higher hemoglobin level might increase your risk of death, higher risk of cardiovascular end points. But I think it's important to consider some of these other issues with the study and the fact that perhaps group 1, the group that was randomized to the higher hemoglobin target, had some important baseline characteristic differences.

Now when you sit down and compare the 2 trials head-to-head, again, the sample sizes were a bit different. However, in the CHOIR trial, I think there were only about 700 patients that were included in the final analysis, so even though 1400+ were randomized, only about 700 or so patients were actually included in the final analysis as compared with 603 that were in the CREATE trial. The age, the baseline age characteristics were different. The CREATE trial had a bit of an older population. The CHOIR trial had a younger population. Another important difference between these 2 trials was the fact that the diabetic population was different in terms of the cause of CKD. In the CREATE trial, about 20% of their patient population had diabetes as the cause of CKD as compared with the CHOIR trial, which had about a rate of 50% of their patient population with a diabetic cause of CKD. Hypertension was also different; about 19% to 23% of the patients in CREATE had hypertension as the causeof CKD compared with CHOIR, which had about 28% to 30%. So, again, different populations that were looked at in these 2 trials.

As mentioned earlier, the EPO starting dose was also different. The starting dose for the CREATE trial was 2000 and the end dose of EPO in the normalization group was 5000 compared with 2000 as a final dose for those who targeted the lower hemoglobin target in CREATE. Compare this to CHOIR, where the starting dose was 10,000. The final dose for the higher hemoglobin group was 11,000+ and about 6300 for the lower hemoglobin target group. Now it's interesting that the lower hemoglobin group in the CHOIR group was 6300, which is still above the 5000-unit dose that was achieved for the CREATE trial. So, again, some interesting differences as far as what the dose of EPO was to get to the particular target.

And then the last interesting comparison was that the CREATE trial showed that there was an increasing quality of life in both groups; however, CHOIR, being a little bit larger, showed that there was no change in quality of life. And this is a bit different from other trials that have shown that quality of life does increase with correction of anemia. So there is a bit of a controversy regarding the quality-of-life outcomes in this particular trial.

Now again, as I mentioned earlier, the FDA certainly took this and released a public health warning late in November of 2006. What they essentially said was that the hemoglobin targets that are greater than 12 g/dL may increase the risk for cardiovascular events and death. They also state that the lowest dose of ESAs should be used and that hemoglobin should be gradually raised to avoid the need for transfusion.

The recommendations that they make are interesting as well and certainly have impact, I think, on clinical practice. They recommend that hemoglobin be measured twice a week for 2 to 6 weeks after any dose adjustment to ensure that the hemoglobin has stabilized in response to whatever that change in the dose was. They also recommend -- which is different from, I think, clinical practice -- that the dose should be withheld of the ESA if the hemoglobin exceeds 12 or rises by 1 g/dL in a 2-week period. So, again, a little bit different from perhaps what is recommended by Kidney Disease Outcomes Quality Initiative (K/DOQI).

I think the clinical impact of all of this is the fact that more attention is required to mange anemia. Without a doubt, the starting dose is an issue. I think in many clinics in the United States, a starting dose of 10,000 units is not unheard of, and comparing to the CREATE trial, perhaps the stage III/IV patients require less EPO and the starting doses should be tailored for the individual patient. The titration of the dose has to be very deliberate, and the frequency of hemoglobin measurements, I think, is a little bit different from perhaps what is done in several clinics across the United States. Twice-a-week hemoglobin measurements for 2 to 6 weeks is a lot of bloodletting perhaps for a patient. If that's the recommendation, however, it's going to be something that nephrology or CKD clinics are going to have to consider. And obviously, routine outcome monitoring is going to be an important aspect of this.

Keeping in mind that these patients are complicated, anemia is only one complication of many that exist in patients as they lose their kidney function as well as the other comorbidities that these patients have. These patients require a lot of individuals to perhaps help manage this, and it obviously requires an interdisciplinary team. I think that pharmacists are crucial and certainly can help play a key role in this arena. The anemia management is very similar, I think, at this stage of this game to warfarin therapy or Coumadin therapy. It has been demonstrated many times in many different journals that pharmacists can effectively manage a Coumadin therapy clinic, and I think that's very similar to what we are going to see with anemia.

There are a number of pharmacist clinics that are now publishing their data that this is a worldwide phenomenon. Certainly, in Japan, the impact of a pharmacist clinic was published a couple years ago. Dr. To and her colleagues showed that the pharmacist is effective in managing anemia in a hemodialysis unit. And most recently, Dr. Joy and her colleagues showed that the management of anemia is a possibility with a pharmacist's involvement. I think that is certainly an important aspect as we carry forth.

There are a number of new agents that are certainly on the horizon, and Amy will now discuss some of the emerging agents to stimulate red blood cell production.

Overall, I think when we consider the goals for new ESA products, we are really as clinicians looking for several things. We want convenient dosing. It has become quite evident, especially in CKD 3 and 4 that we need convenient dosing for the patient to enhance compliance and achieve hemoglobin targets consistently. I think also we are looking for improved hemoglobin stability. Now whether this is achieved through alteration of the pharmacokinetic and pharmacodynamic profile or potentially through some amelioration of the hyperresponsiveness process that is probably related to inflammation, it remains to be seen what the best approach would be.

What I'd like to do in the next few minutes or so is talk about 3 new agents that are on the horizon. The first is Mircera, and that's the proprietary name given to CERA, which is manufactured by Hoffmann-La Roche. Hoffmann-La Roche initiated probably the largest registration program in the renal anemia area, and it consisted of over 2700 patients from 29 countries. And recently, on May 18, the FDA provided them with an approvable letter. The final label, of course, and the final approval will be relying on the meeting from the Cardiovascular and Renal Drugs Advisory Committee, so likely we will see final approval in the fall. But this agent is interesting. It's essentially a pegylated epoetin beta, and it has been pretty clear that enlarging the molecular weight of the compound reduces systemic clearance and extends half-life. That was certainly seen in the preclinical data with CERA. In their phase 3 trials, they essentially dosed the agent every 2 weeks or every month,and with those phase 3 data, it was clear that both dosing strategies were able to achieve hemoglobin targets.

To date, one of the emerging concerns with these agents has been pure red cell aplasia (PRCA). To date with this agent, there has been no documentation of any autoantibodies. But, again, with its similar structure to the native EPO, we should certainly do some postmarketing surveillance in that area. And I surmise that the FDA will request such. Another interesting thing about CERA, in addition to its pegylated compound, is really I think there are some data that will be emerging on hemoglobin stability compared with its EPO comparator, so I'm excited to sort of look for that.

Also on the horizon in phase 3, I believe, trials is Hematide. This is a new class of agents, a novel class of ESAs. They are typically called peptidic ESAs or have been also called EPO mimetics. These agents bind to the EPO receptor and do activate the same intracellular signaling pathways but quite interestingly are completely structurally dissimilar to the native EPO compound, the 165-kilodalton protein, and bear no similar homology. So they do stimulate the receptor in the same way, activate the same pathways. There have been several generations. Hematide I believe is second-generation, and what they have done with the compound, again in order to extend its half-life, is they've pegylated it, increasing its molecular weight and decreasing its systemic clearance. Potential advantages of this agent would include low immunogenicity because, again, it bears no structural homology to the endogenous or other current ESA compounds. It actually, in terms of a logisticstandpoint and a pharmacy standpoint, is able to be stored at room temperature, which has been somewhat of an issue in patients, especially CKD patients 3 and 4, in terms of stability of the ESA compound. And, again, because it's so long acting and because of the pegylated molecule, I believe they're going to be trying to do every-month administration with this agent, which would be similar to the CERA compound. This product is being developed by Affymax in Palo Alto, California. There is certainly going to be more data needed to see if this agent would offer significant pharmacodynamic advantages, and we'll talk more about that.

The third new class of compounds, which is actually different mechanistically, is the hypoxia-inducible factor (HIF) stabilizers. These factors are induced under hypoxia. The alpha form of it is actually inducible while the beta is constitutive. What these agents essentially do is drive endogenous EPO production. What's interesting in these compounds is in patients who have CKD, we presume they have very low capacity to produce endogenous EPO because of either fibrotic or reduced functional renal mass; however, they have demonstrated that these patients are able to produce additional endogenous EPO, so it's likely from an extrarenal source, perhaps the liver. Another interesting and potentially beneficial property of these compounds is because they're not peptides, they are orally active; and, as we know presently, some of the barriers in the outpatient population with CKD 3 and 4 is training patients to use subcutaneous injections. And this would be an orally active compound thatcould circumvent that. These preliminary studies of the HIF stabilizers again show that they can increase hemoglobin but potentially at lower levels of EPO, endogenous EPO, that are produced, so the potential benefit there is that if we're talking about dose relationships, as Dr. Grabe was alluding to, that again you might have a more physiologic red blood cell production and not have to use suprapharmacologic doses of ESA compounds and still get some benefit of the red blood cell production. And, as we'll talk more about pharmacodynamics, in terms of the dose concerns, there are some mechanistic data and in vitro data that suggest that the compounds may induce vascular reactivity or increases in vascular reactivity. So I think we will be seeing some additional work on whether this is a dose-related phenomenon, whether there are other risk factors that would impart an increased risk of these agents with increased doses. So as these new agents emerge, this may be one of ourconsiderations in the future.

I'll turn it over to Dr. Grabe. I think we're going to have some dialogue about our discussion today.

Dr. Grabe: Thank you, Amy. That was very helpful and certainly will be exciting, I think, in the next several years to see the emergence of these newer agents that certainly, I think, have some significant advantages over perhaps what we have currently available to us. I'd like to now perhaps have an opendiscussion on some of the things that we each have discussed.

The first one I think we need to address up front -- and I'll turn this over to perhaps Dr. Manley, and then when Dr. Manley is finished Dr. Pai can comment -- and that would be, what is the pharmacist's role in effective anemia management?

Dr. Manley: I think pharmacists clearly could be used in, one, I think first and foremost, identifying patients with chronic kidney disease and addressing the multitude of issues that these patients have in addition to anemia. So aid in identifying patients with chronic kidney disease, realizing that 1 in 9 adults have it and realizing that if we can identify these patients we can identify patients with anemia. Making sure that hemoglobins are being obtained in patients with chronic kidney disease, and if we are recognizing lower hemoglobins in these patients, effectively treating them to, I guess, target ranges between 11 and 12 as the data support because clearly under 11 there are adverse outcomes and it appears over 12, adverse outcomes. So the pharmacist could help identify and help with the pharmacotherapy with the existing agents, with the various ESAs and iron products, and help managing these patients, because as you had mentioned earlier, Darren, I thinkpharmacists are very good at helping patients obtain therapeutic goals or outcomes by being vigilant about the pharmacotherapy that's employed in these patients. So I think pharmacists definitely have a role in anemia management.

Dr. Pai: I would certainly echo your thoughts, Harold, and I really do believe that the key role of the pharmacist is optimizing therapy. It's clear that clinicians are using ESAs and are treating anemia, but certainly at many institutions not optimally. So the pharmacist has a key role in monitoring and allowing the therapy to be optimized and, importantly, looking at other drug factors that are often overlooked, like hyporesponsiveness, and also facilitating potentially intravenous iron, if necessary. These are logistic conundrums in the health system setting, and pharmacists can certainly play a pivotal role in expediting these processes and making them happen and again optimizing therapy and having the patient achieve target hemoglobin levels.

Dr. Grabe: Now in relation to monitoring and optimization of therapy, the CREATE and CHOIR trials are certainly something that no one can escape at this point in time. However, these are obviously very selected populations and very controlled environments. What do you think the true clinical significance of this recent trial data is?

Dr. Manley: I guess I'll jump in. I think clinically now physicians and pharmacists and even nurses managing these patients and the anemia treatment of these patients can't escape the data that show that there are adverse outcomes with higher hemoglobin. The reasons for those adverse outcomes could be, I guess, debated further, but nonetheless, having elevated hemoglobins, we've all -- I guess the data are more sound -- they say definitely keep it less than 12 and keep it above 11. So I think the clinical significance of these 2 trials, even with some older data -- I'm thinking of the Besarab New England Journal of Medicine in dialysis patients -- so the emerging data are beginning to confirm each other, if you will, that higher hemoglobin isn't necessarily safe for patients with chronic kidney disease. I think what pharmacists, nurses, physicians, all of us as healthcare providers, we have to be that much more vigilant in making sure we stay within the acceptableranges for these patients.

Dr. Pai: I would certainly concur with Harold. I think these trials are certainly compelling and should prompt certainly more extensive research into why these patients aren't benefiting from the higher hemoglobin levels, and we certainly don't know conclusively why that is. But, again, I think there should be an increased level of vigilance from all practitioners about achieving the target hemoglobin concentration, and I think the large amount of attention to this topic has really propelled that, at least at our institution.

Dr. Grabe: Now, Amy, you had mentioned some potential pharmacodynamic advantages for the new agents. Do you think that is really where their impact will be in regards to the management of anemia, or do you think that they will have another advantage beyond that?

Dr. Pai: I think it will ultimately be related to the pharmacodynamics, and that could be done either through modifying the PK profile and delivering what might be more physiologic concentrations of such drug to the bone marrow to stimulate red blood cell production, or it could be mechanistic. But I think largely we've been sort of cavalier about how we're administering these agents and perhaps not looking closely enough at certain dose relationships, and I think there are some urgent data that are needed in this area.

Dr. Grabe: And the Hematide or the peptidic ESAs, what do you think the population should be? Who is the right person for that particular therapy?

Dr. Pai: I think at the present moment, certainly someone who's developed pure red cell aplasia. Although rare, we did have a spike of it after 1998, and we could perhaps continue to see it with some of these agents that bear similar homology to the parent protein. But certainly it's an extremely viable option for someone with pure red cell aplasia as they are typically going to be managed transfusion dependent. There have been some investigations of immunosuppressants with some success, but largely these patients will be transfusion dependent. So certainly it's a viable option for someone who develops PRCA.

Dr. Grabe: If I can follow that up with the other new class that you discussed, and that was the HIF stabilizers, there were some issues perhaps with their safety. Obviously, being orally active, I think, offers a significant advantage as you mentioned, but perhaps you can just elaborate on some of the safety concerns with these agents?

Dr. Pai: I think we've largely had good experience with the safety profiles of these agents overall, but when we consider how this agent is working and that the hypoxia-inducible factor is a transcription factor that affects many target genes, including some of those that may be involved with neoangiogenesis, this prompts some concerns out there long term about possible development of malignancies, so we'll await certainly some long-term trial data with this class of agents.

Dr. Manley: One concern I have with, I guess, the oral agents is I think pharmacists need to be aware of patients with chronic kidney disease in the earlier stages, say stages III and IV. They are on, on average, say, 6 to 8 different medications. When they get to dialysis, they are on 10 to 12 different medications. So introduction of yet another agent orally, patients' medication regimens become so complex that the rate of nonadherence to medication regimens increases clearly. So my concern is not -- so say the drugs are perfectly safe, wonderful drugs, but every time you introduce another agent into the already complex regimens, you run the risk of nonadherence, and with nonadherence you aren't going to meet the goals that you set out to meet with these agents, in other words, treatment of their anemia. So I would be, I guess, I won't say skeptical, but I would be at least that much more vigilant if I have a patient on oral therapy to treat their anemia. We want to makesure that they are going to be adherent to it because if they're not, what comes to mind is the poor outcomes associated with lower hemoglobin. I think with the introduction of oral agents to treat anemia, although it saves an injection for these patients, I think adherence is something that definitely needs to be assured when using those agents.

Dr. Grabe: It's certainly a challenge in regards to managing these patients.

Dr. Grabe: Harold, what other challenges do you think are there in terms of managing these patients who have CKD and anemia?

Dr. Manley: Other challenges. I think -- I guess I was alluding to the complexity of the regimens that these patients already have. They have 3 to 4 other chronic conditions. They're taking multiple, multiple medications, and anything that we can do to give them medications that have great pharmacokinetic profiles or pharmacodynamic profiles to diminish the amount of complexity in their regimens is a true benefit for them. The challenges that we oftentimes encounter are nonadherence in this patient population, so the issues surrounding their disease states -- for example, anemia and low hemoglobins -- don't necessarily go away. So we have to be that much more vigilant and assure that our patients are meeting the outcomes that we need with target hemoglobins through their medications that we give them.

Dr. Pai: I totally agree with your assessment of oral medications in this population, Harold. Obviously, we've discussed quite a bit. And I would also offer up as sort of just a peripheral point that there are emerging data that these patients also have quite altered hepatic metabolism, and the clinical impact of that on drug pharmacokinetic and pharmacodynamic profiles is not clear. So it's something we should again consider and may again make a subcutaneous injection more favorable possibly.

Dr. Grabe: Now, I'd like to go back to discuss some of the CHOIR and the CREATE study details in regards to what led to the FDA warning and recommendations. Harold, how reasonable do you think -- at least in the stage III or stage IV patient -- their recommendation for frequency of hemoglobin measurements is? What they are recommending obviously is twice a week for 2 to 6 weeks after any dosage adjustment.

Dr. Manley: Logistically, that would be very difficult. As you know, trying to get a stage III or a stage IV patient who you may see in your office once a month at best, sometimes every 3 to 6 months, and depending on where they are in the therapy you could say, okay, well, I'll see you next year -- so if you have these patients on ESA therapy and you have to do much more -- to steal your term -- bloodletting, sampling, of their blood to see what their hemoglobin is, it just logistically is going to be difficult to have a number of patients coming into the clinic. It's not an insurmountable issue, but it's something that clearly needs to be thought of when having patients on ESA therapies. And I guess that's kind of my concern too. Hopefully, some clinics won't see this as an insurmountable issue because if they initiate an ESA therapy and don't monitor as appropriate, if you will, you run the risk of having hemoglobins rise too high; or the converse, if they initiate an ESAtherapy and it's still not adequate or sufficient for the patient, the patient runs the risk of having all the adverse outcomes associated with lower hemoglobins too. So I think there are a lot of logistics that need to be addressed in the ambulatory stage III/stage IV patients going to the nephrology clinic. But on the dialysis side, they come to the dialysis center 3 times a week, so you know where the patient is going to be every other day, if you will, so it's a little bit easier to monitor those patients.

Dr. Grabe: Now, Amy, the other recommendation that the FDA had made was withholding the dose of ESA if the hemoglobin rose too quickly in any 2-week period. Now, this is a little bit different from what we're used to. Do you think this is going to translate into clinical practice?

Dr. Pai: You know, at this point -- I'm sure as your practice has borne out -- we have sort of dose reductions as we approach the upper levels of hemoglobin, and there's some thought that withholding the ESA results in the bone marrow having to start over once again you reinitiate the ESA. I guess it will depend on ultimately each individual clinic's choice, but at this present time, we have stuck with our original dosing algorithm where we make basically percentage dose reductions as we approach a hemoglobin of 12.

Dr. Grabe: Harold, is that consistent with what you've seen?

Dr. Manley: Yes. It's reducing by percentage the dose that's administered as opposed to withholding the drug altogether for fear of this up and down seesaw effect that Amy was talking to because if you withhold therapy, what typically happens to these patients is the hemoglobin plummets quite quickly, and then when you reinitiate the ESA, it takes a while for it come back, and you are responding to a hyporesponsiveness, if you will. Then the patient overshoots again. So you are constantly starting and stopping doses. So it's easier to just reduce the dose as opposed to stopping and reinitiation.

Dr. Grabe: Yeah. It certainly goes back to one of the slides that you had presented earlier in regards to the percent of time below hemoglobin of 11 and what the mortality is. And I would envision, similar to what you would see, is that as you are stopping the dose, you increase perhaps the chance of greater hemoglobin variability and increase that percentage time below 11. You are going to be following that hemoglobin and trying to chase it. So I think it's consistent. What I've seen is a typical percentage reduction in dose, which is what was seen in CREATE. So it's interesting, I think, that they made that recommendation that you should stop the dose when everything else you've read is a percentage change in dose, 25% to 50% depending on what you like to do for that particular individual.

Well, with that, I thank each of you for being here, Dr. Manley, Dr. Barton Pai, and for your comments today. I think they've helped us to certainly define anemia and the current controversy as well as help our colleagues recognize a role for pharmacists in a multidisciplinary CKD clinic, and thank you to the audience for listening. We hope this discussion will prove useful.

Supported by an independent educational grant from Roche