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Slide 1. Anemia Management Today: Blood Conservation, Transfusion, & New Options

Amir Jaffer, MD: Good evening, everyone, and welcome to the program. The program this evening is on Anemia Management Today: Blood Conservation, Transfusion, & New Options.

Slide 2. Introduction

My name is Amir Jaffer. I am actually a hospitalist at the Cleveland Clinic. I am the associate section head for hospital medicine and I also direct the preoperative center called the IMPACT Center.

Slide 3. Outcomes of Anemia Treatment Options in Oncology and Chronic Kidney Disease

What I would like to do is introduce our first speaker, who is going to be talking about Outcomes of Anemia: Treatment Options in Oncology and Chronic Kidney Disease. That is Tim Goodnough, who is a professor of pathology and medicine at Stanford. He is the director of transfusion services at Stanford Medical Center, as well as the associate director at the Stanford Blood Center.

Slide 4. Anemia and Transfusion: Impact on Surgical Outcomes

Our second speaker this evening is Lena Napolitano. She is an expert in critical care and a surgeon at the University of Michigan, and she is going to be talking to us about anemia and transfusion and its impact on surgical outcomes. She is also the director of surgical critical care at the University of Michigan Health System in Ann Arbor.

Slide 5. Blood Conservation Protocol: A Case Study

Our third speaker is a colleague and friend, Dr. Ajay Kumar, who is the assistant director of the IMPACT Center and is a colleague of mine. He is also a clinical assistant professor of medicine at Cleveland Clinic Lerner College of Medicine at Case Western Reserve University.

Slide 6. The Hospitalist Today

Before Tim gets started, some quick points about anemia and the hospitalist. Some of you spend time in the critical intensive care unit (ICU). Many of you take care of just medically ill patients. There are some of us who are involved in the perioperative arena, taking care of surgical patients, and there are some of us who also take care of patients in the rehabilitation unit. It is important to recognize that anemia is prevalent in all these different settings, and I am hoping that by the end of this session you will get a very good appreciation of the impact of this important medical condition.

Slide 7. Prevalence of Anemia & Blood Transfusions

If you will look at the ICU, for example, and you look at the percentage of patients who receive transfusions in the ICU, approximately 44% of patients in the ICU receive at least one unit of blood. Data that Dr. Napolitano will go over suggests that patients receiving transfusions in the ICU have longer ICU and hospital stays, may have increased mortality, and more complications.

Slide 8. Patients Receiving Blood Products at a Tertiary Care Center in New Jersey

If you will look at this tertiary care center in New Jersey, notice the amount of blood products that were utilized at that particular center. What they noted was 60% of the patients who received blood were in the nonsurgical setting, while 40% or so were surgical patients.

Slide 9. Economic Burden of Anemia

There is a significant burden of anemia—these are data from an administrative database—that looked at the impact of anemia in 3 different diseases. If you look at heart failure patients, if they have anemia, the total cost of managing them over an annual basis is about $30,000 more. If you look at chronic kidney disease patients, the cost may be about $20,000 more per year, if they have concomitant anemia. And if you look at cancer patients, the cost may be about $18,000 extra, if in fact they have anemia on top of their other comorbidity.

Slide 10. Anemia: A Potent Multiplier of Mortality

If you will look at mortality, and you look at this particular administrative database, looking at about a million Medicare beneficiaries, what you note is that if patients have anemia, the relative risk for 2-year mortality goes up about 2-fold, with just anemia alone. If you look at the relative risk of mortality, it continues to increase with a combination of these various medical conditions, and if you look at patients who have chronic kidney disease, heart failure, and anemia, the relative risk for mortality may go up as much as 6-fold.

So, it is important to recognize that anemia, especially in combination with a lot of the other chronic morbidities that we see in today's hospital practice, may significantly increase patients' mortality rates, and Dr. Goodnough is now going to spend more time going over a lot of the data in kidney disease, as well as cancer patients. Thank you.

Slide 1. Outcomes of Anemia Treatment Options in Oncology & CKD

L. Tim Goodnough, MD: Thank you. As was mentioned, I am director of the blood bank at Stanford, but I come to you as a hematologist/oncologist and I have had 25 years of experience with patients with solid tumors and leukemias, stem cell transplantation, including the intensive care unit, and operating room privileges going in and doing bone marrow harvests. So I have hung my share of blood, and I would like to think I know what goes on at the bedside.

Paradoxically, even though I sell blood for a living, my academic interest has been in devising strategies for patients to avoid a blood transfusion, and so the topic that I would like to share with you tonight, sort of at the 30,000-foot view, is the prevalence of anemia in certain clinical conditions, and the relationship between anemia and clinical outcomes. We will be focusing on chronic kidney disease and cancer tonight.

Slide 2. People 65 Years & Older Who Are Anemic by Race/Ethnicity

Now, I just want to start first with a so-called elderly population. I used to think 65 and older was elderly, but it is not so old to me now, and as shown here, the prevalence of anemia is quite high, approaching 11%, for all patients over the age of 65, and even more so in minority populations such as non-Hispanic blacks and Mexican-Americans.

Slide 3. Distribution Percentage of Anemias

Now, if you do a workup of these patients who are anemic, it is informative to understand that a third is going to have nutritional deficiencies, and so this is, I think, an important take-home message, that the first thing we should be thinking about is iron deficiency in the elderly who are anemic, either because of gastrointestinal (GI) blood loss or nutritional causes, but also B₁₂ and folate or combinations of these have to be considered.

The second largest category of anemia, besides nutritional, would be chronic diseases, either chronic kidney disease, or the anemia of chronic inflammation, together comprising about 30%, again about a third of the patients, and then the remaining third are classified as what we would call undifferentiated. My bias is that a lot of these may in fact be chronic kidney disease because it is underappreciated that a normal creatinine level in an elderly individual with a low body mass may in fact represent pretty significant renal dysfunction, and you have to go through glomerular filtration rate calculations to be sure, and also primary hematologic diseases such as myelodysplastic syndrome. So, I think that anemia is greatly underappreciated in the population as a whole, but certainly in the elderly in particular.

Slide 4. Impact of Anemia in the Elderly

It has significant clinical impacts, as you might imagine, in the ability of the elderly or the extreme elderly, over the age of 75, in terms of maintaining their mobility and physical performance, and actually their survival, so it does not take much for an ambulatory extreme-elderly patient to become nonambulatory because of reversible causes such as anemia, and this should receive careful consideration.

Slide 5. Evolving Questions in Anemia in the Elderly

Evolving questions in this setting are substantial and the National Institutes of Health (NIH) in particular has a series of funding initiatives to address these issues, such as should there be a different biologic definition of anemia in the elderly compared to the nonelderly, and what would be the pathophysiology of the unexplained anemia in the elderly? Would it be because of decreased marrow cellularity; impaired erythropoietin response; ineffective erythropoiesis, such as myelodysplastic syndromes; or inflammatory mediators? Is aging itself an inflammatory state, and most importantly, can anemia management improve clinical outcomes in this group?

Slide 6. Anemia of Chronic Disease (ACD)

I next want to turn to the pathophysiology of the anemia of chronic disease, and this has been a very fertile area of advancement in the last several years. As you know, it is a multifactorial process, and certainly there is diminished erythropoietin production in the anemia of chronic inflammation.

Slide 7. Characteristics of ACD

There is direct inhibition of erythroid progenitor cell production, and most tellingly, impairment in iron metabolism, and it is this third symptom where there has been the most advancement in our knowledge of the anemia of chronic disease.

Slide 8. Serum Levels That Differentiate ACD from Iron-Deficiency Anemia

This is a complicated table from a New England Journal of Medicine review that we published two years ago with the title, "Anemia of Chronic Disease" emphasizing how difficult it is for clinicians to sort out patients who have chronic disease alone, or in combination with iron deficiency. So if you take a look at traditional biochemical parameters, such as iron, transferrin, transferrin saturation, and ferritin, in the anemia of chronic disease, and compare them to patients who have chronic disease and iron deficiency, it is very difficult to sort these 2 categories out, and as a hematologist, I would not be able to tell you the iron status of your patient with chronic disease, short of doing a bone marrow and looking for stainable iron. And there have been various schemes to try to get around this by looking at an assay called soluble transferrin receptor and taking the ratio of that to the log of ferritin. As you would imagine, this is not very practical for the practicing physician—getting a laboratory report that does not go through these calculations for them—but this has been postulated as one way to separate out anemia of chronic disease versus chronic disease in the presence of iron deficiency.

Slide 9. IL-6 Mediates Hypoferremia of Inflammation by Inducing Hepcidin

The story that is most interesting to me is the hepcidin story, and this was identified by Elizabeth Nemeth and John Gantz, from the University of California at Los Angeles not so many years ago, where they demonstrated in a rodent model that if you give a rodent an infusion of interleukin-6 (IL-6), which is an inflammatory cytokine, over 3 hours, shown here with peak levels, very shortly after that, hepcidin, which is an inflammatory peptide, is produced very quickly, measurably, in the urine, within 2 hours of this infusion. And it is accompanied by an acute reduction in serum iron, hypoferremia, and reduced iron saturation, and teleologically, having anemia of chronic disease in inflammation has been explained as a defense mechanism to deny iron to pathogens.

Slide 10. Anemia of Chronic Disease or "Anemia of Inflammation"

This is a picture from our review in the New England Journal of Medicine showing how this works in the setting of a pathogen, which will set off a cascade of inflammatory cytokines, such as gamma interferon, tumor necrosis factor, IL-1, and IL-6, which I showed you in the previous slide. IL-6, for example, is stimulating hepcidin. It was demonstrated to be produced by the liver, which is why it is called hepcidin, and along with tumor necrosis factor, inhibiting erythropoietin production, and also inhibiting red blood cell precursors, leads to a direct inflammatory suppression of red blood cell production.

What hepcidin does is act at 2 sites. It gives you an immediate reduction in iron absorption and an immediate sequestration of iron in the macrophages, which is why we have this acute hypoferremia, and this presumably denies iron from pathogens as a defense mechanism.

Slide 11. Algorithm for the Differential Diagnosis Among Iron-Deficiency Anemia, ACD, & ACD With Iron-Deficiency

We were asked by the New England Journal of Medicine to come up with an algorithm for the lay physician on how to approach anemia in their patients, and this is what we tried to illustrate. If you have anemia in the setting of inflammation, either by diagnosis or with some kind of a biochemical marker, and you have a low transferrin saturation and you have ruled out other causes of anemia, next go to your ferritin. In the setting of a patient, if the ferritin is less than 30 ng/mL, almost certainly your patient is iron deficient. If the patient has a ferritin of more than 100 ng/mL—and I have been criticized that perhaps this is too low, and some people advocate 200 ng/mL—if it is more than 100 to 200 ng/mL, you are probably pretty sure that you are not dealing with iron deficiency, although you can not absolutely rule that out because ferritin is an acute-phase reactant, and in the setting of inflammation, you lose it as a road map as a marker for storage iron, but if your ferritin is more than 100 to 200 ng/mL, think anemia of chronic disease. Between 300 and 100 to 200 ng/mL, think of a combination of chronic disease and iron problems, and you can either go through a transferrin receptor assay and divide it by the log ferritin, or more probably, in my view, an empiric trial of iron, not forgetting to rule out colon cancer and other things that need to be entertained, but in terms of anemia management probably the most intelligent way to approach this would be an empiric trial of iron to see if the anemia is improved.

Slide 12. Therapeutic Options for the Treatment of Patients With ACD

Now, we also were asked to give a table on the therapeutic options for treating the anemia of chronic disease, and it is important to remember that you need to treat the underlying disease. This was illustrated in rheumatoid arthritis, which is your classic prototype for inflammatory disease, and antitumor necrosis factor, or infliximab, has been available, and when you give that to patients with rheumatoid arthritis, their anemia corrects, and when you address the inflammation, that is part of anemia management. Transfusions are indicated if the patient is unstable or has symptoms or is severely anemic, for example, less than 6 g/dL, and that would be appropriate both in the anemia of chronic disease, and the anemia of chronic disease with true iron deficiency. I almost cringe to say this—to me a transfusion is contraindicated when a patient has iron deficiency—but if they are unstable, transfuse.

Iron supplementation should be given if you are convinced they are iron deficient. It should not be given in the setting of chronic disease alone although this, I think, deserves further study. The question is, should we be treating anemia of chronic disease and iron sequestration syndrome, with a combination of iron and erythropoietic agents, and I think that that is an area that has been investigated in oncology and needs to be investigated in other inflammatory states, such as chronic heart failure and in the critical care setting, which you will hear about later.

Erythropoietic agents are indicated, as you all know, for certain diagnoses in chronic disease, and you should also use these in chronic disease after you have ruled out a response to iron.

Slide 13. Anemia & Outcomes

I have tried to make the case over the last several years that anemia should not be an abnormal lab value. My view on this is that it is an unmet medical need with serious clinical consequences, and needs to be paid attention to and needs to be corrected. What I would like to do is go through the data to try to convince you of that.

Slide 14. Anemia & Outcomes

The adverse outcomes in patients with anemia are, first and foremost, blood transfusions. I have not yet met a patient who is excited about getting a blood transfusion. This is a very patient-friendly thing to do, to devise strategies to help them avoid blood transfusions, and interestingly enough, in the whole field of blood conservation, as you are aware, the Food and Drug Administration (FDA) has always bought into the fact that if you can show a blood transfusion-sparing effect, that is an indication for a label for that agent in a particular clinical setting.

But increasingly we are learning, and I will go through some of this data with you, and there are adverse effects on cardiac function, and morbidity and mortality in patients with impaired cardiac function. Quality of life has been well documented to be improved with anemia management in patients with chronic kidney disease and patients with cancer, and for a while we were hoping to be able to demonstrate that with anemia management you could fundamentally affect disease progression, and improve patient survival. As you are all aware, in the last several months, there have been some clinical trials that have demonstrated that is probably not the case and I will be addressing that towards the end of the session.

Slide 15. Anemia in Chronic Kidney Disease (CKD)

Let's first turn our attention to the anemia of chronic disease.

Slide 16. The Impact of Severity of Disease Management & Hct Levels on Mortality Risk in Hemodialysis Patients

These are data from Medicare—this is a Medicare registry study, published in the late 1990s, but it is actually data from the early 1990s—and what they looked at was all-cause deaths, deaths from cardiac, and deaths from infectious disease, the 2 most common causes for death in the dialysis population, and they looked at 1992 and 1993, and stratified the odds adjusted ratio of death, according to the hematocrit cohort that year. So they set at one the likelihood of death for the hematocrit cohort from 30% to 33%. And as you can see, with increasing degrees of anemia, there was a 12% and a 33% increase in mortality. Now obviously this is a retrospective observational study, but it was an enormous Medicare database, and it was highly statistically significantly different. They were not able to show a reduction in mortality that was statistically significantly different at higher levels of hemoglobin because of the relatively small number, but when they combined 1992 and 1993, they were able to show a reduction in mortality that was statistically significant and so it was this that led the National Kidney Foundation (NKF) to develop guidelines, first in 1994, updated in 1997, and again last year, to actually lead their field in anemia management.

Slide 17. Anemia in Patients With Chronic Kidney Disease (CKD)

Why did they do this? It is because it was an underrecognized problem. Eight percent of the US population has abnormal serum creatinines; from some studies we know this. At the time, only 7% of chronic kidney disease was treated with erythropoietin therapy and we now know that long-term anemia is a risk factor for surrogate markers, such as left ventricular hypertrophy, which itself is a risk factor for mortality.

Slide 18. Anemia in CKD

The anemia affects approximately 20 million adults in the United States, and a large US multicenter study of predialysis chronic kidney disease is the kind of patients you are going to be seeing, or you do see, of 5000 patients found that anemia was present in half of these cases.

Slide 19. NKF K/DOQI Clinical Practice Guidelines for Anemia of CKD: Upgraded Guidelines – 2000

The NKF's Disease Outcomes Quality Initiative (DOQI) guidelines, which is sort of a manual from A to Z on how to take care of dialysis patients and patients with chronic kidney disease, were upgraded this last year for both predialysis and dialysis patients. They said hemoglobin should be maintained between 11 g/dL to 12 g/dL in this setting, and I think this is a wonderful example of who to lead a field instead of simply sitting back and reflecting what the practice is. When they first started out in 1994, very few nephrologists were maintaining their dialysis patients between 11 g/dL to 12 g/dL, and subsequently they have demonstrated that this is a benefit in the predialysis population also.

Slide 20. Percentage of CKD Patients Maintaining Hb Levels >11.0 g/dL During Extended Epoetin Alfa Dosing

What is noteworthy is that you can get to this level with a variety of dosing strategies, so this is the percentage of patients on the Y axis who successfully maintained hemoglobins greater than 11 g/dL by the dosing strategy on the X axis. So the first bar shows that when you take all dosing strategies together, 80% of patients with chronic kidney disease can be maintained at hemoglobins of greater than 11 g/dL. Probably the least effective way to do this is once-weekly dosing strategies, but as you can see, these bar graphs range between 70% and 90% and the message is that you can treat patients weekly, you can treat them every 2 or 3, or every 4 weeks, or even less often than that, and with the proper dose, with these intervals, you can get to where you want to go.

Slide 21. Extended Dosing Regimens for Initiation of Epoetin Alfa for Treatment of Anemia of CKD

Here is one such study, for example, from Spinowitz, that was just presented as a poster last month. It examined at the value of an extended dosing regimen for the initiation of epoetin alfa for the treatment of anemia of chronic kidney disease, and again, on the Y axis they looked at the percentage of patients who could be maintained at hemoglobins of greater than 11 g/dL, or an increase of greater than 1 g/dL from baseline. As you can see— the yellow bar is representing hemoglobins greater than 11 g/dL—they were able to successfully extend the dosing interval all the way out to every 4 weeks and maintain the efficacy of getting to a hemoglobin of 11 g/dL.

Slide 22. Anemia: A Continuing Problem Following Kidney Transplantation

The other thing that you should know is that even when you transplant patients with chronic kidney disease, there is a certain percentage of patients who continue to have problems with anemia posttransplant, so this is a retrospective cohort study of about 240 patients. The proportion of patients, for example, with hemoglobins of less than 9 were 76% at transplantation, went down to 21% 1 year after transplant, and back up to 36% 4 years posttransplant, for a variety of reasons: chronic inflammation, myelosuppressive or immunosuppressive therapy and so forth. I think what we need in this population is continued vigilance, better anemia screening, and long-term management, even after transplant.

Slide 23. Anemia in Congestive Heart Failure (CHF)

What about anemia and congestive heart failure? We know that anemia is associated with worse symptoms, greater impairment in functional capacity, and a significant increase in mortality in patients with advanced heart failure. When you manage the anemia by increasing the hemoglobin as little as 1 g, this is associated with a reduction in length of stay, decreased hospital charges, and a reduction in mortality. Every 1 g decrease in admission hemoglobin values, in patients with significant heart failure, is associated with a corresponding increase in death or rehospitalization, so I think that there is a growing awareness that anemia is again not an abnormal lab value, but a serious comorbidity and needs to be incorporated into heart failure treatment guidelines, which to my knowledge are not yet part of the heart failure guidelines. If you take a look at the guidelines, getting a hemoglobin and paying attention to the hemoglobin is simply not on the radar, and that needs to be addressed.

Slide 24. Survival Analysis for the Entire Cohort by Quartile of Hb Level

Here is an example of how interesting this is from a hematologic point of view. This is the survival over 1 year of class III/class IV New York Heart Association heart failure patients by quartile of hemoglobin. The pink is the upper most quartile, the yellow is the lowest most quartile, and as a hematologist, I would not even regard the upper 3 quartiles as anemic. But, with reduction in hemoglobin by quartile, there is a substantial reduction in survival from 80%, with hemoglobins of more than 14.8 g/dL to 60% in hemoglobins of less than 12 g/dL.

Slide 25. Impact of Hemoglobin Level & Age on Length of Stay (LOS) in Patients With Heart Failure

Is this true and unrelated or is it cause and effect? We do not know from studies like this, but we do know that when you look at the impact of hemoglobin level and age on length of stay in patients with heart failure there is a direct correlation, so these are bar graphs of patients aged less than 70 years, 70-79 years, and greater than 80 years, and all ages here, and this is mean adjusted length of stay. As you can see, for those who are least anemic or not anemic, this would be the length of stay and there is a corresponding increase with increasing degrees of anemia.

Slide 26. Impact of Hemoglobin Level & Age on Charges in Patients With Heart Failure

And it has a corresponding effect on patient charges shown here.

Slide 27. Anemia As a Predictor of Death or Rehospitalization in Patients With Decompensated Heart Failure

Anemia has also been shown to be a predictor of death or rehospitalization in patients who do have decompensated heart failure, so this would be death or rehospitalization, the rates with normal hemoglobins or increasing degrees of anemia.

Slide 28. Clinical Outcomes by Hemoglobin Level in Patients With Decompensated Heart Failure

Clinical outcomes by hemoglobin in patients with decompensated heart failure are shown here by hemoglobin level, normal, and increasing degrees of anemia, and this is inpatient, in-hospital patient mortality, also for 60-day mortality and for rehospitalization.

Slide 29. The Effect of Correction of Mild Anemia in Severe, Resistant CHF Using Subcutaneous EPO & Intravenous Iron: A Randomized, Controlled Study

We have looked at this and the question is, is this an association or cause and effect? So this study attempted to address this by randomizing patients to no anemia management versus an anemia-management strategy.

Slide 30. The Effect of Correction of Anemia in Patients With CHF

This is a relatively small study from Israel. This is the control group. Look at the hemoglobin levels in these patients with class III/class IV heart failure. The severely anemic, compared to the Horwich study I showed you by quartile. So when you do nothing over 9 months, in terms of anemia management, the hemoglobin does not change. The left ventricular ejection fraction, if anything, goes down. The need for Lasix® (furosemide) therapy goes up, and the number of hospital days goes up. When you treat these patients with a combination of intravenous iron and epoetin alfa your hemoglobin goes from 10 g/dL to 13 g/dL, or left ventricular ejection fraction, if anything, goes up, the need for Lasix® (furosemide) therapy goes down, and the number of days in hospital goes down. There were mortalities in this group over 9 months. There were zero mortalities in this group. It was a relatively small study—I can not say too much about the statistical association—but in terms of proof of principle, when you manage anemia I think clearly there is an indication that you reduce morbidity and perhaps mortality, and this is being followed up with randomized controlled clinical trials to demonstrate that point.

Slide 31. Anemia in Myocardial Infarction

Anemia in myocardial infarction.

Slide 32. Blood Transfusion in Elderly Patients With Acute Myocardial Infarction

There was a very large Medicare registry study by Wu published in the New England Journal of Medicine. The next slide is very complicated, but I want to walk you through this.

Slide 33. Patient Hospital Course & Mortality

When you do a retrospective observational study and you compare transfused patients to nontransfused patients, transfused patients always do worse, no matter how carefully you control for the known comorbidities as a physician, when you make a decision to transfuse that patient, but not that one, my view on this is the transfused patient was inherently sicker.

If you take a look at all patients and you set the odds adjusted ratio of in-hospital mortality at 1, and these are patients over 65, in the coronary care unit, with a primary diagnosis of MI, nobody went to surgery, those were excluded, so we are excluding surgical blood loss, and you look at the transfused versus the nontransfused cohorts, there was a 48% increase in mortality in the patients transfused. And if you now look at it by admission hematocrit—these are the patients who came in not anemic, again, the transfused patients did worse than the nontransfused. With increasing degrees of anemia, these mortalities are still higher in the transfused versus the nontransfused, but it is starting to telescope together here, and with admission hematocrits that are significantly anemic at admission, with a transfusion, you have a substantial reduction in mortality compared to those not transfused. Now, there are a lot of problems with this study and Lena would be happy to help you understand that in the question/answer period, but for example, there is a lot we do not know. We do not know what the hemoglobins were at the time of the transfusion. We do not know why they were transfused, how much blood they transfused, and there is apparently an imbalance in the percentage of patients who are in Inderal® (propanolol) therapy in the one cohort versus the other, but I think it is instructive that this is the only observational retrospective trial I am aware of where it shows that a transfusion is actually associated with a better outcome than not getting transfusion. So I think we need to be cautious about patients with acute coronary syndromes in the coronary care unit, with transfusion trigger philosophies, and I think that the other speakers are going to be addressing this in their talks.

Slide 34. Anemia in Cancer & Cancer Therapy

What can we say about the relationship between anemia and cancer and cancer chemotherapy?

Slide 35. Anemia Before & During Radiation Therapy (RT) by Site

If you take a look at radiation therapy patients, for example, by category of disease, many of them are anemic at baseline, before radiation therapy, and then during radiation therapy the prevalence of anemia goes up. So it is a common clinical problem.

Slide 36. Hypoxia & Radiation Therapy in Patients with Cervical Cancer

Previous studies had demonstrated that in patients who can be demonstrated to have oxygenated tumors versus hypoxic tumors, there is a much better disease-free survival at 1 year. That goes along with how we understand the clinical benefit of radiation therapy requiring oxygen radicals for benefit.

Slide 37. Anemia & Prognosis

They were able to tie this together in patients with cervical cancer by level of hemoglobin at the time of radiation therapy and the likelihood of recurrence. So if they had hemoglobins of more than 12 g/dL during treatment, their local recurrence rate was much lower than if they were anemic, as was survival.

Slide 38. Impact of Anemia on Survival

Here is another clinical setting, in squamous cell carcinoma of the head and neck, where the 2- and 5-year survival was very much affected by whether the patient had normal hemoglobin levels, higher survival rates, than the patients who were anemic.

Slide 39. EPO in Cancer Patients Receiving Chemotherapy

And correspondingly, in the chemotherapy literature, Littlewood demonstrated in a very large study of a variety of solid and liquid tumors, that if you randomized patients to placebo versus epoetin alfa and raised hemoglobin levels, the probability of survival over time was actually better in the erythropoietic agent group than in the placebo group. It is these 2 clinical observations in radiation therapy and chemotherapy that led to a series of clinical trials in an attempt to normalize hemoglobin and have an impact on overall survival.

Slide 40. Cochrane Review

There is a recent Cochrane analysis on a large number of randomized clinical trials, a systematic review and an economic evaluation of the erythropoietic agents in cancer to see whether there was efficacy and safety. What they demonstrated was that yes, the erythropoietic agents, in cancer-induced anemia, reduce blood transfusion by an estimated 18%, and if you remember, this is why we received the labeled indication for these agents as a blood transfusion-sparing event. So they concluded that erythropoietic agents are effective in improving hematologic response and red blood cell transfusion requirements, and appear to have a positive effect on health-related quality of life.

Slide 41. FDA Alert Regarding ESAs

As you are all aware, over the last 3 to 4 months, there has been a flurry of interest in these series of clinical trials I alluded to. There are 6 of them in a variety of settings—including breast cancer, non–small-cell lung cancer, undifferentiated cancer not receiving chemotherapy, and chronic kidney disease—in an attempt to show, with normalization of hemoglobin, that you can improve survival. To make a long story short, they were unsuccessful at showing that, and in fact, the data seems to indicate the opposite. So as of March 9, there have been new black box warnings in cancer and chronic kidney disease, and other speakers will address perioperative surgery.

To make a long story short, if you remember nothing else from tonight's symposium from my summary, the hemoglobin levels should be less than or equal to 12 g/dL and no higher, and the FDA is very concerned that we not go above that level, and reminds everybody that the reason why these agents should be used is a blood transfusion sparing effect. Overcorrection of anemia above these levels is associated with adverse outcomes.

Slide 42. Danish Head & Neck Cancer Trial

I am not going to go through the 6 studies, but I just want to just briefly mention 2 of the studies just to give you a flavor for where we are coming from. You have probably read about these studies in the New York Times and the Wall Street Journal, which is where I get all of my news. One of them was in head and neck cancer, it was an open-labeled randomized trial, comparing radiation therapy alone to radiation therapy plus darbepoetin alfa in the treatment of advanced head and neck cancer, trying to build on those preliminary studies I had shown you, indicating that you can improve survival and disease progression.

They corrected the hemoglobin to 14 g/dL to 15.5 g/dL, a very high target range, with the idea that an oxygenated tumor is going to respond to radiation therapy better than a nonoxygenated tumor. What they found, however, was that the 3-year locoregional control in subjects treated with the erythropoietin level—I am sorry, with darbepoetin alfa—to these levels was significantly worse than those who did not receive the erythropoietic agent, and it was statistically significantly different. And also, overall survival also favored those not treated with the erythropoietic agent, that is, treated with placebo, although this did not reach statistical significance so that is one of the clinical trials that you have been reading about.

Slide 43. Primary Composite End Point

The second clinical trial I want to show you is one that was published last winter from Singh in CKD, and these would be patients who are predialysis with the hypothesis that if you normalized hemoglobin, the high hemoglobin group, the target being 13.5 g/dL and the low hemoglobin group, the target being 11.3 g/dL, so that is a 2-g difference, a clinically important difference, the hypothesis being, if you could normalize the hemoglobin in predialysis patients, somehow you would improve survival. They found the opposite. And this is the published data. The probability of a composite event being either mortality or hospitalization because of heart failure, myocardial infarction, cerebrovascular accident, serious cardiovascular complications, or death. A higher rate in the high hemoglobin group, 25% to 30% over more than 3 years, compared to about 20% in the low hemoglobin group.

Slide 44. Summary Anemia: Anything But An Innocent Bystander

In summary, my view on this is that anemia does remain an underrecognized and undertreated disease. I think in patients with chronic kidney disease, long-term anemia is a risk factor for left ventricular hypertrophy and mortality, but so far to date, the idea that you normalize hemoglobins is not a good idea, so stick with the National Kidney Foundation guidelines of 11 g/dL to 12 g/dL, and these may be revised going forward. We know that anemia does increase the cost of delivering health care in the chronic inflammatory state across the board, and most importantly, effective treatment of anemia should not be solely based on achieving an optimal hemoglobin level, but primarily as a blood transfusion sparing effect. Thank you very much.

Slide 1. Anemia & Transfusion: Impact on Surgical Outcomes

Lena Napolitano, MD: My task is to talk about critical care and surgery; so we are going to look at data from a number of trials that really investigate this area.

Slide 2. ABC: Anemia & Blood Treatment in the Critically Ill and CRIT: Characterization of ICU-Acquired Anemia

We are very fortunate that there are 2 large prospective trials that were cohort studies to evaluate anemia in the ICU setting. One of these trials, the ABC Trial, published by Jean-Louis Vincent, was done in western Europe over a period of about 2 weeks, with the total sample size of about 3500 patients. The CRIT trial, on the other hand, was a United States-based study—Howard Corwin was the lead investigator—was done over about a year, in 213 institutions—almost 300 ICUs—and enrolled almost 5000 patients.

Slide 3. Blood Transfusion in the ICU

I am going to put these studies side by side because the data are intriguingly similar. If you look at the data carefully overall, patients in the ICU spent about a week. On average, the ICU mortality was 13%; hospital mortality 20%; and virtually all patients were anemic on admission to the ICU with a hemoglobin of 11 g/dL. But what is striking is approximately 40% of patients in the ICU setting get transfused, and on average get transfused with 4.5 to 5.0 units of blood per patient. Very strikingly similar results. Both of these trials, as part of their primary analysis, did a propensity matched cohort analysis to look at the effect of blood transfusion on outcome, on survival and mortality. And as Tim has already mentioned, we have to be careful about the evaluation of these, because although it does stratify for severity of illness, there may be some factors that we are not capturing in these analyses.

Slide 4. ABC Trial: 28-Day Mortality Rates Propensity-Matched ICU Patients

This is the propensity analysis from the ABC trial and you can see that blood transfusion was associated with a higher mortality rate, 23% versus 17% for the nontransfused cohort.

Slide 5. CRIT Trial: 30-Day Mortality Rates Propensity-Matched ICU Patients

In the CRIT trial, in the United States trial, very similar findings. Again, by propensity matching a higher risk for mortality in the patient group that was transfused. So we have before us, I think, a good evidence and good data to assure us that any ways that we can reduce blood transfusion may potentially be beneficial in the ICU environment.

Slide 6. Table

This is a very large table. It demonstrates the 2 trials we have just talked about, the ABC and the CRIT trial, but I wanted to show you that there has been a wealth of other studies now that have demonstrated very similar findings, findings from Canada, findings from the United Kingdom, with again on average 4 to 6 units of blood transfused per ICU patient, and the very first trial, from the American Burn Association (ABA), that shows that burn patients get administered, on average, 14 units of blood per patient during their ICU time. So this is clearly a patient population that warrants great care in determining how we can potentially reduce blood transfusion.

Slide 7. CRIT Results: Trauma Patients

A cohort analysis of the trauma patients of the CRIT trial showed that these patients are exposed to an even greater degree of blood transfusion—on average approximately 6 units of blood per patient—and overall, their hemoglobin on admission was also low at 11 g/dL, and they spent a longer time in the ICU—about 9 days—and once again, red blood cell transfusion was associated with higher mortality, increased length of stay in the ICU, and higher organ failure rates.

Slide 8. Anemia in the ICU

Why are patients anemic in the ICU? Dr. Goodnough has already shared with you those issues related to chronic kidney disease and related to anemia of chronic inflammation or anemia of chronic disease. This is a little complex. This is a study that identified that 95% of patients in the ICU are anemic on day 3 in the ICU, but only 9% were found to be iron deficient, and another 6% were found to have other nutritional deficiencies, such as B₁₂ and folate. But again, 95% manifest anemia. What is this due to?

Slide 9. Causes of Anemia in ICU Patients

The bottom line is that it is very similar to the anemia of chronic disease that was already talked about by Dr. Goodnough. Some of our patients are exposed to hemorrhage in the ICU, either they have upper or lower GI hemorrhage, or trauma. Hemolysis can occur, sometimes due to disease states or drugs. Bone marrow dysfunction clearly occurs, and we will review why that is, and one of the preventive strategies that we can utilize is actually to reduce phlebotomy. Phlebotomy accounts for a significant proportion of anemia. And then the comorbid conditions that Dr. Goodnough has already reviewed are present in many of our ICU patients.

Slide 10. Blood Loss Due to Phlebotomy

Let us look at blood loss due to phlebotomy. This is an interesting finding. About a decade ago, the blood loss due to phlebotomy was 90 cc to 100 cc per day in the ICU environment, and we have actually made some progress. These are data from the ABC trial by Vincent and colleagues, and on average, in the ICU, they phlebotomize patients 40 cc of blood per day with an average of 4.6 blood draws and 10 cc per blood draw. But that is a significant amount when a patient stays in the ICU for a long period of time.

Slide 11. Decreasing Phlebotomy Blood Loss

There are a number of simple strategies that utilize either a venous arterial blood management protection (VAMP) system or a syringe system where the waste blood is drawn up into that VAMP or that syringe, the sampling port is utilized to get your diagnostic test, and the waste blood is sterilely re-infused. Clearly, these systems are now utilized in less than 20% of ICUs in the US, and it is a very simple strategy that reduces blood transfusion requirements.

Slide 12. Decreasing Phlebotomy Blood Loss Low-Volume Adult Blood Collection Tubes

Another strategy is to utilize pediatric blood sampling tubes, but many times the laboratory cannot actually facilitate that transfer over to pediatric tubes. Another simple strategy is to go to low-volume adult sampling tubes where they can actually sample 1.8 mL to 2.7 mL instead of the requisite 5 mL to 11 mL in the large adult-volume tubes, and again, this can create a significant reduction in blood transfusion requirements. So preventive strategies are very important.

Slide 13. Blunted Erythropoietin Response

Let us get again to the pathophysiology of anemia in the ICU setting. Clearly, it was relayed already that reduction in endogenous erythropoietin is the main cause of anemia of chronic disease, and that is true as well for ICU patients. ICU patients have a defective or blunted endogenous erythropoietin response, approximately 10-fold lower than the same response for the degree of anemia in a normal individual.

Slide 14. Anemia in the ICU

Why do we produce less endogenous erythropoietin? It is actually a very interesting question, and not one, but many studies now have validated the finding that not only our erythropoietin levels are low on initial admission to the ICU, but after week 1, week 2, week 3, and week 4 in the ICU, we do not see any recovery of endogenous erythropoietin. The erythropoietin levels stay low, they stay below 100, and they do not increase, actually even when anemia worsens, when the hemoglobin falls further. This study was done in 184 patients, and again reflect that only 9% of these patients had iron deficiency.

Slide 15. Blunted EPO Response in Critically Ill Patients

This gets back to what Dr. Goodnough has already mentioned and his review in the New England Journal of Medicine is a wonderful review on the anemia of chronic disease, or the anemia of inflammation. This is the same in the critical care setting. Many of our patients in the ICU environment have an inflammatory response with release of proinflammatory mediators, and the clear consequence to that is a significant inhibition of erythropoietin gene transcription in the renal juxtaglomerular cells. That causes a reduction in endogenous erythropoietin. More importantly, there is a direct inhibition of the erythroid precursor cells' response to erythropoietin, so we need to use higher doses in an inflammatory environment. There is also a direct inhibition of red blood cell production by the bone marrow, and finally, that same response that occurs in anemia of chronic disease occurs in the anemia of inflammation. There is a limitation of iron availability because of sequestration in the macrophages.

Slide 16. Anemia in the ICU

This is our baseline ICU patient that is inflamed at baseline and they are anemic at baseline, and when we utilize them, a unit of blood to actually transfuse the patient to treat anemia, we transiently cause an increase in inflammatory response again, and we may actually be further downregulating their endogenous production of erythropoietin, and hence I really believe strongly that to try to get out of this cycle, to try to make our patients less inflamed, I think it is important to try to avoid transfusion, because this is an immune and inflammatory stimulus.

The bottom line is that anemia in the ICU is quite complex. It is a mix of a number of factors, but clearly the blunted endogenous erythropoietic response is central to the pathophysiology, but there are patients who have combined pathophysiology related to bleeding, their endogenous erythropoietic production that is reduced, inflammatory mediators, and again, very importantly that hypoferremic state mediated by hepcidin.

Slide 17. CRIT Study: Transfusion Triggers

Let us look at the CRIT study again in a little bit of a different way. Remember, the CRIT study documented that, on average, we use 4 units to 5 units of blood per patient in the ICU, and it also captured data—how many of our hospitals actually have transfusion protocols in the ICU environment—and only 29% of hospitals in the US at the time of the study had any standardized transfusion protocol. At the time of the study, the most common trigger for the general ICU patient was to transfuse blood if the hemoglobin was less than 8 g/dL, and if the patient had cardiovascular disease, we transfused blood if the hemoglobin was less than 10 g/dL. We felt uncomfortable with letting our cardiac patients stay anemic.

Slide 18. Pretransfusion Hb Concentration: CRIT Study (US)

About 35% of the patients that were transfused blood in the CRIT study in the United States were transfused when their hemoglobin was greater than 9, and these patients were not transfused for bleeding, they were transfused for anemia, so clearly, education and having policies and protocols for transfusion and guidelines can be helpful in the ICU environment.

Slide 19. Anemia & Blood Transfusion in the Critically Ill

And we have learned a couple of other things from the CRIT study. We have identified that the amount of transfusion that is received in the ICU setting is inversely related to the hemoglobin on admission. That makes sense. The more anemic they are, the larger the number of total transfusions they receive. It is directly related to age, so the older you are, the more blood you receive, and that is because they are usually more anemic.

And then finally, in the ICU setting, the longer you are in the ICU, the more blood you receive. If you are there for longer than 2 weeks, almost 80% of patients received on average 6.2 units of blood. So we have learned quite a bit from these prospective observational studies.

Slide 20. Canadian Critical Care Trials Group Blood Transfusion in the ICU

Now let's move to the Hébert trial, the TRICC (Transfusion Requirements in Critical Care) trial. This is the only trial, which I am sure you are all aware of, that is a prospective randomized study that compared a restrictive transfusion trigger—do not transfuse blood unless the hemoglobin goes below 7 g/dL versus a liberal trigger—do not give blood unless the hemoglobin goes below 10 g/dL. This study was done by the Canadian Critical Care Trials group and enrolled over 800 patients in multiple ICUs in Canada and followed them over time.

Slide 21. Canadian Critical Care Trials Group

As we look at the data for the entire cohort of this very important prospective randomized trial, you can see that overall there was no difference in total survival rate for the group that was restrictive transfusion strategy versus the liberal transfusion strategy. Absolutely no difference in overall outcome, and this led us to conclude that it is safe to allow our critically ill patients to remain anemic and use a trigger of 7.0 g/dL. Not necessarily have to use 7.0, but that it was safe to go as low as 7.0 g/dL.

Slide 22. Canadian Critical Care Trials Group

There were 2 cohorts, in a post hoc analysis, that demonstrated actually a survival benefit in the restrictive transfusion strategy cohort, those that got less blood. Those who received less blood and were less severely ill, had an APACHE score less than 20, had a higher survival rate, and those who received fewer blood transfusions and were younger than 55 years had a better survival rate and a lower mortality rate. So, if anything, there were some cohorts that actually did better with less blood.

Slide 23. Limitations of Anemia in Cardiovascular Disease (CVD)

The one clear factor that we are all uncomfortable with is this issue about cardiovascular disease. My patient that might be having an acute myocardial infarction (MI) might actually be demonstrating some signs of cardiac ischemia. We know that when you acquire anemia in the ICU setting, the first thing you have to do is increase your cardiac output and increase your coronary circulation by vasodilation of the coronary circulation in order to prevent cardiac ischemia and in order to tolerate anemia. And if a patient has fixed cardiovascular disease, this may not be possible. We also know from some older studies that anemia itself, in cardiovascular disease patients, was associated with a higher mortality rate.

Slide 24. Canadian Critical Care Trials Group Patients With CVD

Let's look at the Hébert trial, the TRICC trial, from the Canadian Critical Care Trials Group. They did a subsequent post hoc analysis where they pulled out just their patients with cardiovascular disease. They had over 350 patients who had a history of cardiovascular disease. And what they saw was in the group that was randomized to the restrictive strategy, they received, on average, about 2.5 units of blood, compared to 5 units of blood in the liberal group. How did they fare? Mortality rate was absolutely no different: 23%. And what was interesting was their degree of multiple organ dysfunction was actually higher in the group that received more blood transfusion, liberal transfusion strategy.

Slide 25. Canadian Critical Care Trials Group Patients with CVD – Conclusions

Their conclusion was a restrictive transfusion strategy generally appears to be safe for most critically ill patients with cardiovascular disease, with the possible exception of those with acute MI and unstable angina. And I think that is what most of us are going on these days, clearly if I have somebody who is having an acute MI, all bets are off, whatever the clinician feels we should do at the bedside we do, and we do not worry about following a protocol or a guideline.

Slide 26. Blood Transfusion in Elderly Patients with AMI Associated with Lower Short-Term Mortality

Dr. Goodnough showed you this study and I am not going to show you that big long table, I am going to show it to you in a figure format, because it is important to reflect that the Wu study, which showed that if your hematocrit was 33% or lower, in this retrospective cohort study, and you received a blood transfusion, the blood transfusion was actually associated with improved outcome, better survival. If you gave blood and the hematocrit was 33% or greater, blood transfusion was associated with worse survival, higher mortality. Now that is one side of the equation.

Slide 27. Blood Transfusion and Clinical Outcome in Acute Coronary Syndrome

You have to reflect as well that there is another published study by Rao and colleagues that also has some limitations to its study design. It utilized already completed prospective randomized studies in patients who had acute coronary syndrome, and of those studies, asked the simple question of if blood transfusion was associated with outcome after regression analysis for stratifying for specific factors. And in this study, exactly the opposite finding was identified. Patients who were exposed to blood transfusion over the period of the study period, which was up to 30 days, had a higher mortality compared to patients that were not exposed to blood transfusion. Clearly again, these 2 studies contradict each other, and this is an area where we need more intense investigation, particularly in the form of prospective randomized trials.

Slide 28. Functional Outcomes of CVD Patients Undergoing Surgical Repair of Hip Fracture (FOCUS)

So we are all awaiting the completion of this trial. Jeff Carson and colleagues are in the midst of completing this very important study that is called the FOCUS study, for Functional Outcomes of Cardiovascular Disease Patients Undergoing Surgical Repair for Hip Fracture. This is funded by the National Heart, Lung, and Blood Institute and is going to enroll over 2000 patients in a number of medical centers in the US and Canada.

Slide 29. FOCUS (cont'd)

The inclusion criteria is patients have to undergo surgery for hip fracture, have a history of cardiovascular disease, and be anemic, with hemoglobin less than 10 g/dL. And then they are randomized to keep their hemoglobin greater than 10 g/dL with blood transfusion or to transfuse if the hemoglobin falls below 8 g/dL, or to not transfuse, if a clinician feels comfortable letting them be more anemic. What is very different in this study is they are not only looking at overall survival and overall mortality, they are actually looking at a functional outcome of being able to walk unassisted at 60 days.

Slide 30. FOCUS (cont'd)

It is important as well to reflect that the negative outcome in this study will be postoperative unstable angina, MI, or death, and in addition to that they are going to look at 30- and 60-day functional outcome and overall long-term mortality. So be on the watch for the completion of this study. Dr. Carson did publish their study design just a couple of months ago, which is a wonderful review.

Slide 31. Do Blood Transfusions Improve Outcome in Mechanical Ventilation?

Let‘s ask another question in the ICU environment: If I have a patient on mechanical ventilation, does blood transfusion improve outcome? And clearly, this is again a post hoc analysis of the TRICC trial, restrictive versus liberal transfusion strategy in over 700 patients of the TRICC trial, and as you see here again, in the restrictive transfusion strategy group, they were exposed, on average, to about 2.5 units of blood, and in the liberal group, 5.5 units of blood. Any difference in ventilator weaning? None. About 80%. Any different in vent-free days? None. Sixteen to 17 days. So there was no clear evidence that a liberal red blood cell-transfusion strategy decreased the duration of mechanical ventilation, and I think again this is an important study that many are not aware of. It does have the limitation of being a post hoc analysis.

Slide 32. Erythropoietin & Multiple Organ Failure

Let's talk about erythropoietin and critical care. Clearly, one of the very first studies that looked at erythropoietin in critical care was in a trauma patient population, and it was a very small study of 19 patients with multiple organ failure and trauma, and they did show that with dosing erythropoietin 3 times weekly, that they were able to actually increase the reticulocyte count and the hematocrit and reduce blood transfusion, and that study was published quite some time ago in 1998.

Slide 33. Clinical Studies With rHuEPO in the Critically Ill

Since that time, we now have 3 prospective randomized trials, utilizing recombinant erythropoietin in critical care. So, we have EPO I, which was a small study in 160 patients that dosed erythropoietin daily for 5 days at 20,000 units daily and then every other day. That is a high dosing strategy. We then have EPO II, which enrolled over 1300 patients, had an expanded site size, followed patients for 28 days instead of 42 days, and used the more standard and traditional erythropoietin dosing strategy of 40,000 units weekly, which is very commonly used in multiple patient populations.

In EPO I, there was a 50% reduction in blood transfusion. Pretty good. In EPO II, there was a 10% reduction in the number of patients that were exposed to zero blood transfusions, so actually more patients received zero blood.

Slide 34. rHuEPO in Critically Ill Patients: EPO III

The recent findings of EPO III, which were just presented at the Society of Critical Care Medicine meeting in February, and are not yet published. They have been submitted for publication and are undergoing revision at present. The national principal investigator of all of these studies is Howard Corwin. This study was completed in June 2006 and you see it took about 2.5 years to complete the trial.

Slide 35. Methods

This is an important study. It was again a randomized prospective study in ICU patients with anemia. And they were randomized to receive erythropoietin at the same dosing strategy as EPO II, 40,000 units weekly, versus placebo, and it was administered by subcutaneous injection, and they received up to 3 doses, if they were still in the ICU at 3 weeks.

What was very different about this study compared with EPO I and EPO II was that they mandated the utilization of a transfusion guideline, and here they identified that the patients in the ICU should not be transfused if they had a hemoglobin of greater than 9 g/dL, unless there was a clear indication, which was myocardial ischemia or bleeding. That was a very different experimental design.

Slide 36. Study Outcomes

The primary efficacy end point was transfusion independence, and the secondary end points were the total number of units of blood transfused, overall mortality at day 29, and they did a long-term follow up to day 140, and safety as well.

Slide 37. Primary Efficacy Endpoint – Percent Transfused Study Day 29

Let's look at the data. The data for the primary outcome measure here, percentage of patients transfused, is here. Overall, 46% to 48% of patients in the erythropoietin and placebo group received transfusion. No difference. And if you look at the data by the different cohorts of patients that were enrolled, there were three predefined cohorts: trauma, surgical nontrauma, and medical nontrauma patients. And again, there was no difference in the cohorts of patients that were transfused. Absolutely no difference in the primary outcome measure.

Slide 38. Secondary Efficacy Endpoint - RBC Transfusion Day 42

The secondary end point was the total number of red blood cell transfusions up to day 42, and this very much matches the CRIT data, that on average, patients received 4.3 to 4.5 units of blood up to day 42 in the ICU, and again no difference in the group that received erythropoietin versus placebo. And even if you look at the data transfusion rates per day alive, therefore you eliminate the deaths, the early deaths, again, there is no difference in those data.

Slide 39. Pre-Randomization RBC Transfusions

When we look at prerandomization red blood cell transfusion, this is an important finding. This study calculated the number of units of blood that were transfused before the patients were randomized to study drug, and you can see here that this is a high number—5.9 units in the placebo group, and 6.3 units in the erythropoietin group—and a lot of this is related to the large number of trauma patients that were enrolled in this trial.

Slide 40. Mortality – Study Day 29

And then finally mortality here, this is mortality on study day 29, an interesting finding in this study that was unexpected, is a reduction in mortality in the erythropoietin group, compared to the placebo group, for the total cohort, 11.4% versus 8.5%, but this change is driven by the mortality rate in the trauma cohort, which was a significant reduction of 6.7% to 3.5%.

Slide 41. EPO 3: Mortality Study Day 29 (All Subjects)

That mortality rate—these are the mortality curves by day 30—you can see it is substantially different for the entire cohort . . .

Slide 42. Adjusted Mortality – Study Day 29

. . . and when you adjust it by logistic regression, you can see the odds ratio for the trauma cohort is very significant at 0.36.

Slide 43. Mortality Study Day 140

By day 140, that finding continues to hold true, that particularly the trauma cohort that received recombinant erythropoietin had a significant reduction in mortality.

Slide 44. Why No Transfusion Benefit?

Why was there no transfusion benefit? We talked about the lower dose, and so that is clearly an issue. We talked about the transfusion guideline, and clearly our practice has changed. We are now comfortable with using a lower transfusion trigger.

Slide 45. What Is Responsible for Mortality Benefit?

What is responsible for the mortality benefit in the erythropoietin trial is of question, but clearly many people have hypothesized that it is the nonhematologic effects of erythropoietin, which are listed here, that will require further validation to make certain that these findings are correct. I will tell you that in EPO II, there was a similar reduction in mortality in the trauma cohort.

Slide 46. Preoperative Anemia: Independent Risk Factor for Infection & Resource Utilization in Surgery

Let's end up here with a word about general surgery, in a study that we did in over 6000 patients who were undergoing noncardiac surgical procedures, preoperative anemia occurred in 39% of patients and postoperative anemia in 84% of patients.

Slide 47. Blood Utilization in Surgery

There is no question that the greater your anemia is, the higher your utilization of blood transfusion.

Slide 48. Postoperative Infections

We noted an association between blood transfusion and postoperative infection.

Slide 49. Blood Transfusions & Infection, Mortality

This held true on our multivariate logistic regression analysis, that blood that was transfused intraoperatively and perioperatively, had a higher risk for both infection and for mortality.

Slide 50. Anemia in Surgery

We have tried, in many ways, to identify anemia early in our surgical patients and treat it early, since anemic patients are exposed to more blood transfusion in surgery.

Slide 51. Perioperative Period: Similar Efficacy with rHuEPO Daily & Weekly Dosing

We now know from an initial trial in 1998 that utilizing erythropoietin in 4 weekly doses, at 40,000 units per week rather than 14 daily doses before surgery is equivalent, and so many of us have done to utilizing that strategy for preoperative dosing of erythropoietin.

Slide 52. Perioperative rHuEPO in Elective Colorectal Surgery

This is one of many, many trials in surgery, this happens to be in colorectal surgery, that shows that the utilization, the proper utilization of erythropoietin preoperatively can reduce your blood transfusion requirements significantly when you are identifying anemia early and treating it appropriately.

Slide 53. Report From the STS Workforce on Evidence-Based Surgery

Finally, you should be aware that these guidelines were just published a couple of months ago by the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists, and they have carefully reviewed the evidence in surgery and their last statement here is that, "Institution-specific protocols should screen for patients at high risk for blood transfusion and available evidence-based blood conservation techniques should be utilized." And then they list all of the potential blood conservation techniques.

Slide 54. Blood Conservation Algorithm in Patients Undergoing THA

One very large study that has identified that this is efficacious in surgery, was a cluster randomized control trial in 30 hospitals that identified that patient and caregiver education, erythropoietin, institutional transfusion guidelines, and even preoperative autologous blood donation could reduce blood transfusion perioperatively from 26.1% down to 16.5%." So blood conservation strategies, I think, are here to stay.

Slide 55. Summary

To summarize, anemia is very common in surgical and ICU patients. Clearly blood transfusion are not risk-free, there is no evidence that blood transfusion improves outcomes for the treatment of anemia, and so we should be cautious and careful with blood transfusions.

Slide 56. Summary (cont'd)

From the Hébert trial we have recognized that critically ill patients can tolerate hemoglobin levels down to 7 g/dL without any adverse outcome, and that the pathophysiology of anemia in the ICU environment is partly related to reduction in endogenous erythropoietin concentrations, and in my mindset, every preventive strategy we can utilize to reduce blood transfusion we should. Thanks for your attention.

Slide 1. Blood Conservation Protocol: A Case Study

Ajay Kumar, MD: My name is Ajay Kumar. I am a hospitalist at Cleveland Clinic, and I will be talking about hospitalists' perspective on anemia management in surgical patients.

Slide 2. Overview

A background: At Cleveland Clinic, we hospitalists over there run an IMPACT clinic which sees more than 14,000 patients. We are clearly very much involved in preoperative and postoperative care of the patients, and the message today would be to get more involved in anemia management and participate as much as you can to reduce the blood consumption.

We will be talking about some of the protocols we instituted at Cleveland Clinic, the case study, and how you set up an anemia management program at your local institution.

Slide 3. Surgical Trends – 2004

It is interesting to know that we operate a lot—45 million in 2004, and it continues to rise—and we are projected to have a significant increase in operations by 2030.

Slide 4. Blood Supply

The only downside of that is the blood supply—the procurement rate is declining too—and we have noticed in the last 10 to 15 years that continuously it is going down. It is quite a challenge nowadays to get blood products. I learned at Cleveland Clinic all the strategies and, in fact, all the goodies they provide nowadays for people who can donate blood, which is interesting. We are forecasting about 4 million red blood cell-products shortage by 2030, so it is quite concerning.

Slide 5. Perioperative Anemia – Prevalence

Perioperative anemia, the prevalence is anywhere from 5% to 76%, and we will talk about why that is. It is kind of strange, such a variation, but definitely the postoperative anemia is significant. We have quite a sick population, complicated in many diseases nowadays, we are operating and we are doing more advanced surgery than we used to do before. One of the reasons why the prevalence has such a wide range is because the definitions in most of the studies have differed quite a bit. The patients who have different comorbidities are getting operated on at this time, so that is one of the reasons.

Slide 6. Perioperative Anemia

Perioperative anemia has been significantly related to increased risk of death, cardiac events, and cardiovascular patients, especially with a study by Carson that showed a 16-fold increase in mortality in patients, so it is concerning having anemic patients in your surgical area.

Slide 7. Perioperative Blood Transfusion

But at the same time, the easiest answer for the anemia is to give blood transfusion, but it has its own problems. It does actually increase morbidity and length of stay, which we are all concerned about as hospitalists, as well as postoperative infections, and it decreases immunosuppression and other diseases that are transmitted.

Slide 8. Blood Transfusion: An Independent Risk Factor for Infection, Mortality, & Resource Utilization in Surgery

This is a study that was quoted by Lena earlier on. Dunne had studied more than 6000 patients and found that a significant amount of preoperative anemia still exists and there is a postoperative anemia that is even more significant in this population . . .

Slide 9. Mortality Risk Associated With Hct & Blood Utilization

. . . and pretty much all the parameters—including blood utilization associated with mortality, . . .

Slide 10. Risk of Infection Associated With Hct & Blood Utilization

. . . risk of infection . . .

Slide 11. Predictors of Hospital Length of Stay

. . . and length of stay—all of them were related to increased amount of blood transfusion.

Slide 12. Transfusion Risks – Worldwide 2005

This is a busy slide, which actually talks about the different counties, the highly developed Human Development Index based on economic stability of the country, and the not-so-fortunate ones, and the blood has its own risk and so it continues to be a risky business and we have prions and other diseases, and many more coming up, actually, which we know a little bit about at this time, and there is increased concern about diseases like TRALI where it is usually under-recognized if it is found.

Slide 13. Decline in HIV, HBV, & HCV Risks of Transmission Through Transfusion

Over time, the blood has become safer. We have several more tests that have been developed for HIV, HCV, and other things, and we are actually improving our blood supply, but it is nowhere near, as you know, where we would like to see it.

Slide 14. Serious Hazards of Transfusion Spontaneously Reported Deaths & Major Complications in UK & Ireland (1996/97-2003)

This is an interesting Web site, www.shotuk.org, It actually collects information from NHS hospitals in England. More than 483 hospitals are registered and they voluntarily give information to this registry and we are talking about a very highly developed country where a significant amount of the blood errors occur because the incorrect blood has been transfused.

Slide 15. Errors in Transfusion

The errors in transfusion are not uncommon here in the US; we have a 1 in 14,000 risk of mistransfusion, and most of the errors occur in the clinical arena, but obviously labs are responsible about 30% of the time.

Slide 16. Blood Is "Unavoidably Unsafe" & Dangerous

So blood is actually very unsafe. I think we all have heard many times so far.

Slide 17. Hemoglobin Thresholds for Allogeneic Blood Transfusion: Published Guidelines

All the organizations and everybody else sat down together and tried to come up with some sort of trigger to guide us to help us streamline our blood transfusion practice. Dr. Goodnough actually told me this morning that in 1992, when he was on the panel for the American College of Physicians (ACP), they had an extremely difficult time coming to a conclusion. These guidelines actually were posted on the ACP Web site but were retracted afterwards, so we do not know when to transfuse, but we have some idea from the CRIT trial and other things, and the critically ill patients.

Slide 18. Perioperative Anemia Management

As hospitalists, we have the onus ourselves of reviewing our patients very carefully. It begins in the preoperative area and going in to the intraoperative and postoperative. Intraoperatively, as hospitalists, we do not have a whole lot of role to play except guiding people. Preoperatively, however, medication management and looking at who is getting aspirin and clopidogrel bisulfate and other medications, and offering other modalities like erythropoietin therapy. Preoperative autologous donation has been kind of a favorite for a while but it is fading away and we will talk about the reasons why. Cell Saver, definitely a very noble technology, needs to be utilized and acute normovolemic hemodilution, which has its own problems.

Slide 19. Perioperative Anemia Management (cont'd)

The surgical technique obviously plays an important role. You have two types of surgeons: bloodless, or blood less. The one who does leave blood, or one who actually gives a lot of blood. Or, the other pharmacological agents like thrombin and collagen, aprotinin has been used in cardiothoracic patients, but there have been some trials suggesting there is increased risk of renal failure. Tranexamic acid and aminocaproic acid, these are cheap and underutilized strategies and not that many hospitals utilize them.

Slide 20. Epoetin Alfa

It was interesting to know, in 1990, there was a survey done of all the hospitals in the United States. About 2% of the hospitals utilized erythropoietin [epoetin alfa] in their blood conservation protocol, although 96% of them had that in the pharmacy.

The FDA has approved erythropoietin [epoetin alfa] for noncardiac, nonvascular surgery indications, mainly the hip and knee, which is reimbursed by the Centers for Medicare and Medicaid Services (CMS), so that is usually who would be giving it. Refractory anemia in myelodysplastic syndrome, chemotherapy-related anemia, and anemia related to AZT use in HIV patients and chronic renal insufficiency.

Slide 21. Epoetin Alfa: Orthopedic Surgery

In orthopedic surgery, CMS reimburses patients with anemia of chronic disease, hemoglobin between 10 g/dL and 13 g/dL, and when there is expected blood loss of 2 units, which is because for less than 2 units they do not reimburse. That gets bundled into the diagnosis-related group, so it is a savings, and if the patient is not a candidate for autologous blood transfusion, at least you have 3 weeks of lead time before the surgery.

Slide 22. Erythropoietin [epoetin alfa] to Minimize Perioperative Blood Transfusion: A Systematic Review of Randomized Trials

This was a metanalysis that was published in 1998, which showed that EPO decreased the proportion of patients who were exposed to allogenic blood. Benefits of EPO were greatest in patients who had a high risk of transfusion, and it was effective in daily or weekly dosing, and there were no significant thrombotic events noted.

Slide 23. Epoetin Alfa: History

Erythropoietin [epoetin alfa] has been around for a while and in 1989, the US had approved it for chronic renal failure patients, and in 1996 for surgical patients. We have more than 10 years' experience with that.

Slide 24. Epoetin Alfa: Surgical Experience

There are several studies, I will not talk about details about each one of them, but it has been compared head to head with preoperative autologous donation (PAD) and placebo and has been found beneficial in increasing hemoglobin in surgical patients.

Slide 25. Selected Randomized, Controlled Clinical Trials of EPO Therapy in Patients Undergoing Non-Cardiac Surgery

This is another slide that actually summarizes some of the studies done until 1997, which showed the usefulness of EPO in the surgical patients.

Slide 26. CC - Blood Product Utilization: Jan-Dec 2005

At the Cleveland Clinic, we take pride in giving blood. We gave 142,000 units of blood in 2005. Quite a burden on Red Cross, and I think quite a burden on the whole country, actually. We cut it down to 136,000 in 2006 and I still do not have the full details about the breakdowns, but it is a significant worry. A single institution in Ohio is giving 142,000 units of blood products. That accounts to about 300 units every day transfused, if you are working 24 hours every day.

Slide 27. What Are the Barriers in Using EPO?

What is one of the barriers of using EPO? We have the modalities and why not use them? Well, it is very easy to give blood. At night, when you are on call or somebody else is on call, it is very easy to order 2 units