Spotlight on Evidence-based Synthesis Program- 12 -Department of Veterans Affairs

**Department of Veterans Affairs**

**Spotlight on Evidence-based Synthesis Program**

**Cyberseminar 04-16-2012**

**Treatment of Anemia in Patients with Heart Disease**

**Dr. Devan Kansagara**

**Dr. Ed Dyer**

**Dr. David Kagen**

Mollie:  As we are at the top of the hour, I now would like to introduce our presenters for today.  First we have Dr. Devan Kansagara, he is an assistant professor of medicine at Oregon Health and Science University.  He is also the director of the Evidence-based Synthesis Program at Portland VA Medical Center and a staff physician also at Portland VA Medical Center.  

Joining him today is Dr. Ed Dyer, he is a clinical informatics fellow, Department of Health Services Research and Development at the Portland VA Medical Center.  Also joining him is Dr. David Kagen, he is the director of the hospitalist group, section of general internal medicine at Portland VA Medical Center and an assistant professor of medicine at Oregon Health Science University.  At this time, I would like to check in with Dr. Kansagara.   

Dr. Devan Kansagara:  Hello, everyone.  I'm here with Ed Dyer and David Kagen, we're going to talk about the treatment of anemia in patients with heart disease, reviewing a systematic review we just completed of the evidence.  Before we get rolling here, just to acknowledge our co-authors, Dr. Honora Englander, Michele Freeman and Rose Relevo, who provided research librarian assistance for us.  Then we've got our technical expert panel members listed.

I will just roll through these evidence-based synthesis program slides very, very quickly.  They're here for your reference, if you would like.  There is a link at the bottom of this slide for the topic nomination process, if there's new topics of interest to stakeholders out there.  This slide has some further details.

In terms of the talk, we'd actually like to start off with some poll questions, which we'll ask you and then we'll talk briefly about the epidemiology of anemia and heart disease.  The bulk of the time will be spent summarizing our systematic review findings of anemia treatment efficacy.  We'll take a few moments to describe our research methods and then we'll roll through the results.  Ed Dyer will talk about the findings for erythropoiesis stimulating agents and iron and David Kagen will talk about the findings for red blood cell transfusion and then I'll talk about some of the implications and then we should have some time for questions at the end.  We do have a lot to get through, so some of these slides we may roll through fairly quickly.  Here's the first poll question.

Molly:  Thank you.  I'm going to pulling that up in one second.  Okay.  So our audience members, please do select the response that describes your primary responsibility and we will give you just a few short moments to answer that.  [Pause]  Okay.  It looks like we have had about 50 percent of our attendees already respond, I'm just going to give it a few more seconds and then I will close the poll and share the results with everyone.  I am now closing the poll and I'm going to share the results with everyone.  About 75% of our audience has voted, if you do still want to submit a response, please do so at this time.  Dr. Kansagara, you should be able to see the results now, if you'd like to speak through those real quick.   

Dr. Devan Kansagara:  It looks like nearly half the respondents are mainly outpatient clinicians and then a smattering of the other categories.  Okay.  Thank you.  We'll move on to the next question here.  Here's the second question: "Do you believe erythropoiesis stimulating agents, for example, EPO or erythropoietin or darbepoietin should be used to treat anemia in patients with congestive heart failure?  [Pause]  So about two-thirds of the respondents are unsure and presumably is one of the reasons people are interested in our findings.  

Molly:  I can launch the third one now if you're ready?

Dr. Devan Kansagara:  Yeah.  

Molly:  I'm launching that poll question now, it is up on our attendee screens.  [Pause]  And the answers are coming right in.  It looks like almost two-thirds of people have voted, but the responses are still coming in, so I'm going to give it a few more seconds.  Okay.  We have a 75% response rate and I'm going to go ahead and close the poll and share the results with everyone and you should be able to see those now.

Dr. Devan Kansagara:  Interesting, a pretty evenly distributed set of answers here, about a quarter said, "Yes, they have used iron supplementation," about a quarter said, "No, but they've been familiar with it or seen it used at their institution," about a quarter said, "No." and about  a quarter are unsure.  Okay.  Thank you for those responses.  We can move to the fourth one here, this is a case-based scenario.  It says a 68 year old male is hospitalized after sustaining a hip fracture and is awaiting surgery--

Molly:  Devan?

Dr. Devan Kansagara:  Yes.

Molly:  Sorry to interrupt, I apologize.  We have had just one technical difficulty.  You can go ahead and read through the case study, it's going to take me just a second to correct the poll.

Dr. Devan Kansagara:  Okay.  So a 68 year old male is hospitalized after sustaining a hip fracture and is awaiting surgery.  He has hip pain, but is otherwise asymptomatic, he has a history of MI, myocardial infarction 1 year ago.  I would transfuse him if the hemoglobin were less than--and there's four options there.  Ten grams per deciliter, or approximately a hematocrit of 30, 9 grams per deciliter or a hematocrit of 27, 8 grams per deciliter or a hematocrit of 24 and 7 or a hematocrit of 21.  

Molly:  Thank you for that.  I'm going to put up the answer choices now.   We're seeing about 50 percent response rate, we'll give it a few more seconds.  [Pause]  Not quite as high a response rate on this one, maybe people are taking a second to think about it, so we'll give them a little bit more time.  It looks like we're only going to get about two-thirds percent of people responding.  So I'm going to go ahead and close that and share the results now.

Dr. Devan Kansagara:  Okay.  So thank you for responding.  Again it's a distribution of results, but the majority would transfuse at lower hemoglobin targets.  There is a range here.  We'll just run through the last one here quickly and again there's no right or wrong answer here.  A 60 year old male was admitted with unstable angina and underwent successful stent placement today.  He is not bleeding, but his hemoglobin is slightly lower at 9 grams per deciliter, would you transfuse him?

Molly:  If you could read through the responses, while I get those up on the screen.

Dr. Devan Kansagara:  The responses are 1) Yes, you would transfuse him.  2)  Only if he had symptoms.  3)  No.  4)  Unsure.  

Molly:  Thank you.  I'm going to go ahead and post those right now.  We do have the final poll question up on the screen at this time, if I can get our attendees to respond.  [Pause]  Okay.  It looks like we've got about three-fourths of people, so I'm going to go ahead and close the poll now and I'll share the results.

Dr. Devan Kansagara:  Thanks.  A minority said, "Yes, they would transfuse, about 40 percent said only if the patient had symptoms, about 40 percent said they would not transfuse and 13 percent said they were unsure.  Okay.  Thanks for taking the time to respond to those, this just gives us a sense of what people are doing out there.  Without further ado, we'll just launch into the talk.  [Pause]

Molly:  Thank you to our audience members for your patience.  This is still a relatively new software we're dealing with, so we're all getting used to how it works.  [Pause]

Dr. Devan Kansagara:  As many of you are familiar with, the prevalence of anemia in heart disease is quite high, 10 to 20% of coronary heart disease patients are anemic.  About a third of congestive heart failure patients have anemia and then iron deficiency which may or may not be associated with anemia is also very common.  

Anemia is associated with poor outcomes in congestive heart failure and there's some illustrative statistics listed here.  For instance, for each 1% point lower hematocrit, there's a 2 percentage increase in 1 year mortality.  In stable CHF patients-- that development of new anemia is frequent and portends a poor prognosis that is associated with increasing risk of death and hospitalization.  It's interesting that the mechanism for the link between anemia and poor outcomes in congestive heart failure is not entirely accounted for by underlying coronary heart disease and myocardial ischemia.

Speaking of coronary heart disease, anemia, as we have said, is also common in coronary heart disease patients and lower hemoglobin is associated with higher mortality risk after both STE segment elevation and non ST segment elevation MI and part of the pathophysiology here is thought to be that anemia can decrease myocardial oxygen delivery, distal to a stenosis and also increase myocardial oxygen demand.

This is a diagram of some postulated mechanisms by which congestive heart failure can lead to anemia.  If you look on the left-hand side, chronic heart failure is a proinflammatory state, which can lead to blunted erythropoietin production, direct suppressive effects on the bone marrow and decreased incorporation of iron into red blood cells.  Congestive heart failure is also associated with worsening kidney disease, which itself can lead to a decreased epo production and then through the [inaudible] system, there may also be additional effects.

So you can see here where some of the treatment targets might be, so one potential option is just to directly give erythropoietin, another option would be to give iron treatments and lastly an option would be to simply give red cells back to the patient.  Here are those potential treatments listed.

So in terms of work others have already done, people have looked at the role of erythropoiesis stimulating agents in congestive heart failure.  There was a recent Cochrane review which found that ESAs improve anemia, exercise tolerance, quality of life and reduced symptoms of in heart failure patients with mild anemia.  They may also reduce hospital admission, improve survival and they found few side effects.  They go on to say that further study is needed.  So we looked at this and thought that this was interesting and warranted a further look at the literature.  We also noted in our own clinical practice and in the literature that there's quite a variation in transfusion practice as is partially evidenced in the poll questions we had conducted.  

Part of this is a relic of an old dogmatic rule that dates back to 1942 called the 10/30 rule, in which it was thought that patients with heart disease or perioperative patients as well should have transfusions to keep their hemoglobins above 10 or their hematocrit above 30.  This rule has been bandied about for many decades and we continue to hear it, when we're all attending on the wards.  Despite some more evidence within the last 15 years or so RBC transfusions have remained at peak level throughout the last decade and survey studies suggest that folks do use higher thresholds in coronary heart disease patients.  Cohort studies, some of which Dave will talk about, suggest that people have used hemoglobin triggers ranging from 8 to 10.  

So that leads us to our systematic review.  In order to further explore these issues, we asked the following questions: "In patients with congestive heart failure or coronary heart disease, what are the health outcome benefits and harms of treating anemia with erythropoiesis-stimulating agents?  Two, what are the health outcome benefits and harms of using iron to treat iron deficiency with or without anemia in these patients?  Three, what are the health outcome benefits and harms of treating anemia with red blood cell transfusions?"

In order to answer those questions, we looked at studies with the following characteristics: Studies including patients with congestive heart failure and these are adult patients with congestive heart failure or coronary heart disease and the definitions are listed there.

We are, as we've already said, interested in the following interventions: ESAs, iron and red blood cell transfusions and we looked at studies comparing these intervenions to usual care or placebo.  

Outcomes included a broad variety of mortality, hospitalization, exercise tolerance or duration and we didn't prespecify what metric that would be.  Often it was NYHA class, quality of life, cardiovascular events in harms.  So, for harms we would report any harms that were reported in the studies themselves and we also did separate analyses for erythropoiesis stimulating agents, looking specifically at the harms of hypertension, venous [thromboembolic] disease and cerebrovascular event.

Of note, for the transfusions literature, we recognized during a preliminary search that the trial literature--especially when we had started this review a while ago that there wasn't much trial literature.  In our own clinical experience, there's quite a variation in practice, owing to different understandings of what the observational literature suggested.  So we also looked at observational studies for the transfusion literature, with the exception of cardiac surgery trials in [inaudible] section was because cardiac surgery--anemia associated with cardiac surgery--the mechanisms underlying it are quite different and we felt the confounding factors would be too broad to make meaningful conclusions.

So we searched MEDLINE and Cochran databases up through November, 2010, although we have looked at trials that have been reported since then and we plan on doing an updated search this summer.  We also looked at ClinicalTrials.gov for in-progress trials and we also directly contacted drug companies.

Our findings in terms of article yield are listed here.  We looked at nearly 2,500 abstracts--from these found 320 potentially relevant full text articles and from these, we culled 16 randomized control trials for ESAs, 3 randomized controls for Iron, 9 randomized control trials for RBC transfusion and 24 observational studies in 26 publications.  I'm going to turn it over to Ed Dyer here, who will talk about the erythropoiesis stimulating agent findings.

Dr. Ed Dyer:  Thank you, Devan.  Ed Dyer here.  As Devan was referring to earlier, erythropoiesis stimulating agents or ESAs have had some appeal in the treatment of anemia and both heart failure and heart disease patients, owing to the reasons he gave earlier.  This prompted our key question No. 1 and the search he was describing earlier yielded 16 randomized control trials.  As you can see here, about two-thirds of those exclusively looked at a heart failure population, the remainder typically looked at a combination of heart failure and heart disease patients.

If I can just draw your attention to the third arrow there, the mean GFR.  We discovered that in the majority of these studies, there was a significant degree of comorbid chronic kidney disease.  Based on this and all of our clinical anecdotal experience in that patients frequently have both heart failure and kidney disease, we elected to include two trials that actually had a primary population of chronic kidney disease patients, but analyzed a subgroup of patients with heart disease and that's a subgroup of the TRICC trial and a subgroup of the CHOIR trial, which I'll refer to briefly later.  

To get right into our results, [inaudible] did look at two outcomes that are related to activity tolerance, as Devan was describing earlier.  Right here you can see the NYHA class and a meta-analysis of the 9 trials that included this outcome, showed a .77 improvement in NYHA class.  So, for instance, that might mean that the mean NYHA class went from Class III to 2.23 and that favored treatment, favoring darbpoietin.

This is pretty similar to what was seen in the Cochran systematic review, published in 2010.  However, we sort of extended beyond that review in several ways.  One of which was that we performed a risk of bias assessment for each of the trials that we included in our systematic review.  We used the grade working groups criteria for this and in doing so we analyzed each study and gave them a score of very low risk, low, moderate or high risk of bias and we then repeated our meta-analysis, looking only at the very low and low risk studies, excluding the moderate high risk studies.  We can see that reduced those 9 studies down to 4 and significantly attenuated the results.  You can see the combined results here was a 0.15 improvement in NYAH score, not a 0.77 NYHA score and in fact that 0.15 is now at nonsignificant between treatment and control groups.

We did similar analysis for our other outcomes, here I'm showing the mortality stuff another [inaudible] plot and you can see looking at mortality in studies that gave this outcome and if we excluded the moderate high risk studies, we see again a nonsignificant difference between the control and treatment group.

I want to make two further points on this slide, the first of which, is that, in fact, it's not just not significant, it may be that there's a small trend favoring the control group, which is to say that potentially treatment with darbepoeitin or other ESAs may in fact increase mortality.

The second thing I just wanted to draw attention to is you can see that as with a lot of our meta-analyses, they were somewhat dominated by two of the larger studies, the Besarab 2008 at the top of the [inaudible] and Pfeiffer 2009 at the bottom of the [forest] plot and Pfeiffer 2009, is in fact that subgroup analysis of the [TREAT] trial of kidney patients.

We performed a similar analysis for cardiovascular outcomes, similar to the mortality stuff and that also showed a nonsignificant difference between treatment and controls.  Here I'm showing the Forest plot for the side effects of ESA treatment, hypertensive events and again you can see nonsignificant differences, but similar to the mortality there seems to be a trend favoring controls, suggesting that ESAs may in fact actually increase the risk of hypertensive events.

I'm just going to go briefly into looking at those two larger trials I talked about earlier the Pfeiffer 2009, the subgroup analysis of TREAT and the Besarab 2008 because those two really dominated the mortality data on the hypertensive events.  You can see that based on the patient population in each that they made up about 75 percent of the total patients we were looking at in our systematic review.

The TREAT trial was a multicenter randomized control trial and it was blinded and compared [inaudible] to placebo in anemic, diabetic patients with kidney disease.  The treatment group targeted the hemoglobin of 13 and the control group allowed--[inaudible] whatever unless is drifted below the 9 in which case they received some erythropoietin in order to boost it back above 9.  The actual TREAT trial itself enrolled 4,000 patients and eventually would show no difference in the primary endpoint of cardiovascular events, but as I specified earlier, Pfeiffer did this [nice] analysis of a previously defined subgroup that had cardiovascular disease, including 2,600 patients and I'll show you those results next.  Actually they are almost identical to what was in the overall greater population in the TREAT trial, that is a nonsignificant difference between groups in the mortality and risk of cardiovascular events.  

Maybe more interesting and concerning was that we actually saw a significant difference in cerebral vascular events and venous thromboembolisms, both of which favored the control group so that there was a higher incidence of these events with dabeopoeitin treatment.  

Going into the other trial, the second largest, Besarab, this was a nonblinded randomized trial--I'm sorry, it says RCT there, it's actually a controlled trial because it's a comparative dose trial.  This looked at Epoeitin at varying doses in patients with end stage renal disease on dialysis, who had either heart disease or heart failure.  

The more intensive therapy group targeted hematocrit of 42, the lower intensity group targeted 30, and this actually had to be ended early due to increased mortality in the higher intensity group, so the group that they were targeting a normal hematocrit in actually relative risk, 1.2 of death during the study.  They intended to go for 30 months and they ended early with a median duration of 14 months.  

I'm going to switch gears now and switch to our key Question No. 2 on iron and as Devan showed earlier, there are only really 3 randomized control trials found in our literature search.  You can see here, based on the size, that the FAIR-HF study by Anker really dominated that analysis--I'm sorry systematic review--we were unable to form a meta-analysis with those few studies.

To go briefly into Anker's work, again multicenter, international randomized control trial, blinded, looking at IV iron versus placebo in patients with heart failure and iron deficiency.  They had an outward [inaudible] iron deficiency, which was interesting in that, although they were all iron deficient, you can see the mean ferritin in 55, but actually 50% of the patients were not anemic, they had a fairly high mean hemoglobin level of around 12.  Because their algorithms somewhat [intended] and they prespecified that they would look at the subgroup of anemic and a subgroup of non-anemic patients as part of their study.  You can also see that they only recruited NYHA Class 11 and 111 patients and it was largely NYHA Class 111, 80%. 

Here are their outcomes and in brief, they looked at both activity tolerance NHYA score, self-reported patient global assessment, six-minute walk test and also quality of life scores and these are--all these outcomes were significant favoring treatment with IV iron.  When they looked at their two prespecified subgroups, anemic and non-anemic patients, who both had iron deficiency, they had similar outcomes.  So it was consistent across these two subgroups.  I'm going to turn it over now to David Kagen, to handle the transfusion part.  Thank you.

Dr. David Kagen:  As Devan already alluded, our literature search turned up 9 randomized controlled trials that examined transfusion strategies in patients with cardiovascular disease.  Of these two were in medical populations and the other 7 in the perioperative literature.  Four of those in cardiac surgery, 3 in non-cardiac surgery.  

Since our own experience suggests that the observational literature still wields a fairly significant influence on practice, we thought it would be interesting and useful as well as Devan alluded to, to discuss the observational trial literature as well.

So most folks knowledge of transfusions starts and often ends with the TRICC trial, so it makes sense to start here.  When I'm on the wards and the topic of transfusion comes up, which happens most every week, most residents I work with can cite the TRICC trials conclusions, if not where those conclusions came from, so let's talk about it.

So this landmark multicenter Canadian randomized trial was published in 1999.  So they enrolled 838 ICU patients all with a hemoglobin at 9 or less within 72 hours of admission and they were all considered euvolemic, so nobody was bleeding.  They randomized folks to a restrictive versus a liberal strategy of transfusion in the restrictive group patients were transfused only at a hemoglobin of less than 7, 1 unit at a time, with a goal of hemoglobin of 7 to 9 versus a liberal strategy, where folks were transfused at a hemoglobin of less than 10, 1 unit at a time, with a goal of hemoglobin of 10 to 12.  Long story short, the result was that there was no difference in survival between the two groups and, in fact, there was no difference among any of the outcomes they looked at, including 30-day mortality, hospital mortality, multi-organ dysfunction scores, cardiac events and so forth.

They looked actually at several subgroups, including what I've got pictured here are patients younger than 55 years and those with lower APACHE scores, they actually found a significantly lower mortality among those who were transfused more restrictively.

So their conclusion was that a restrictive transfusion policy i.e. a goal hemoglobin of at least 7 is safe in critically ill patients, including those being mechanically ventilated.  An additional subgroup analysis [inaudible] with those patients and they also faired the same.  They also concluded that withholding transfused red blood cells may actually be beneficial particularly in younger and less critically ill patients.

So that still leaves the question of cardiovascular disease, which was the main thrust of our review.  These patients presumably have a lower tolerance for anemia, since they can't augment oxygen delivery by increasing coronary flow.  So the TRICC authors actually tended to address this issue with another subgroup analysis.  In this one, they looked at the 40 odd percent of the originally enrollees, who had a primary or secondary admitting diagnosis of cardiovascular disease and these were a very critically ill patient group.  Over 85% were mechanically ventilated, over 50% had PA catheters and their average APACHE II score was 23.  Nevertheless, once again, they found no difference in survival between the two groups or in any other outcome that they examined, including length of stay and multi-organ dysfunction score.

They drilled down further still and looked at the 257 patients who had quote, unquote "known ischemic heart disease" and in this case, once again, there was no significant difference in outcomes.  As you can see, there's a little bit of separation in the two curves there, where the restrictive strategy actually seems to have perhaps a slightly lower survival, but once again, this is certainly not diminishing the key value of 0.30.

When you look at the actual numbers, you can see that the 30-day mortality was 26 percent in the restricted group versus 21 in the liberal group.  Once again with a p value of 0.38, nevertheless, the authors and many readers did see this difference and although there was no difference in any of the other outcomes that they looked at, so their conclusions from the subgroup analysis with a restrictive strategy with a goal hemoglobin of at least 7 appeared safe in patients with underlying cardiovascular disease.  The main caveat here being that it's more difficult to draw conclusions given the smaller sample size and the fact that this was a post-hoc subgroup analysis.  The question still remained about the particular subset of patients with ischemic heart disease.

So, with that in mind, is there any other data available to guide decision making in this particular patient population?  Well, there was nothing else until just about a year ago--at least in the randomized control trial literature, when the CRIT trial came out.  This study was a multicenter US trial that enrolled patients between 2003 and 2009.  This was just a pilot study there were only 45 patients enrolled.  These folks, though, were admitted with acute MI, 40% of whom had a STEMI and 56% of whom had a [percutaned] coronary intervention.  In order to take part, all patients had to have hematocrit less than 30%, without any major bleeding.  

Their intervention was similar to the TRICC trial, they divided folks into the conservative versus liberal transfusion strategies.  In the conservative group they used a transfusion threshold of 24 versus 30.  So they used a slightly higher threshold in TRICC in their restrictive group.

Their outcomes you can see here, this study clearly was not powered to detect a difference in mortality, but there was no significant difference, with rates really quite low only one patient in one arm and two in the other died.  Their primary outcome was a combined outcome of death, MI or heart failure in the hospital and they did actually find some separation here that was significant, that was a potentially higher number of patients with this outcome in the liberally transfused group than in the conservative group.  This was almost entirely explained by a higher incidence of heart failure exacerbation.  

So we performed a meta-analysis of medical literature, which is limited because it only includes these two studies and it's dominated by the TRICC trial.  Nevertheless, it suggests no difference in mortality to transfusion strategies, looking at these two in an aggregate.

So let's change focus for a moment, no pun intended, and look at the perioperative literature.  So I will start again with the Landmark trial, this one just published four months ago in the New England Journal, this is a FOCUS trial that examined patients with hip fracture repair.  So this was a multicenter trial conducted in the US and Canada that enrolled patients over five years between '04 and '09.  They enrolled 2016 folks, all over the age of 50 who were undergoing hip fracture repair and who had either known cardiovascular disease, ischemic heart disease history or EKG findings, heart failure, peripheral vascular disease or prior stroke or risk factors for coronary disease and that included hypertension, diabetes, dyslipidemia, smoking or [inaudible].

They initially intended to enroll only folks with known disease, but expanded their inclusion criteria when enrollment was a little bit slower than they hoped.  They also randomized enrollees into a liberal or restrictive strategy.  Once again with transfusion thresholds of 10 versus 8.

You can see their outcomes here, their primary outcome was a combined one of death or the inability to walk 10 feet at 60 days.  They also reported individual outcomes as you can see.  There were no differences in any of the outcomes that they examined.

They also did a subgroup analyses and since we were particularly interested in the patient population with known coronary disease, it was reassuring to find that their subgroup analysis of those with known cardiovascular disease that was about 60% of the patients that they enrolled also found no difference.

In addition to the FOCUS trial, there are six other trials that have been conducted in surgical populations, two others in non- cardiac surgery and four in cardiac surgery.  Suffice it to say that they all have found no difference in outcomes between a liberal and a restrictive transfusion strategy.  Not a single one actually has found a difference and, of course, in aggregates, we also found no difference in our meta-analysis.

If you combine the two medical trials with the cardiac and non-cardiac surgery trials, once again, there's no difference in meta-analysis with a relative risk actually, 1.04.  

So, as I mentioned already, we thought it would be useful and helpful to look at the observational trials as well since they still have an influence on practice in the US and worldwide.  So I thought I'd start with the percutaneous primary intervention setting.  There were actually 9 studies that looked at outcomes with persons without transfusion in patients undergoing percutaneous coronary intervention.  

They enrolled somewhere in [2000]  39,000 patients these are registries that precluded [2000]  39,000 patients and in 8 of these 9 trials, transfusion was associated with higher mortality after multi-varied adjustments and in the 9th there was no difference at all.  This finding was consistent in both bleeding patients, bleeding being a fairly common complication among patients who had undergone PCI and in non-bleeding transfused cohorts.  In fact, the association between higher risk of mortality and transfusion status seems a little bit stronger than non-bleeding cohorts.

Looking exclusively, then, at patients who had acute coronary syndrome or acute MI, there were 12 studies.  Nine of these looked at outcomes across all hemoglobin or hematocrit levels after multi-varied adjustments and once again 8 of these 9 found a higher association or an association with higher mortality among patients who were transfused after multi-varied adjustment and once again the 9th found no difference.

Since the whole patient population isn't usually who we think about when we're trying to decide about whether to transfuse or not, we tend to use triggers like a hemoglobin of 30 or a hemoglobin of 24.  I thought it would be useful to look at the studies that actually stratified patients by hematocrit.  In fact, there were 6 studies that looked at outcomes with, versus without transfusion, among patients transfused at hematocrits less than 24 to 25.  In two of these survival appeared to improve.  There was a mixed result in one, where they actually saw better survival in a setting of ST elevation MI, but worsened survival in patients with non ST elevation [inaudible] syndrome.  

Three trials showed no difference in mortality, although two actually had a strong trend toward [inaudible] in the transfused cohort.  Similarly 6 studies also reported outcomes with, versus without transfusion, in patients transfused with hematocrits above 30.  Four of these found higher association with mortality in patients transfused and the other two had mixed results.  One with higher mortality in patients with non-ST elevation ACF, but lower with transfusion in the setting of STEMI at least with a hemoglobin less than 12.  There was no difference in outcomes when hemoglobin was above 12.  

Another study found no difference in mortality when folks were transfused with a hematocrit of 30 to 36, but increased morality once the initial hemoglobin rose above 36.

There, of course, remains the question of patients in that gray area between 25 and 30 hematocrit and four studies reported outcomes in this setting.  One found improved survival with transfusion at 25 to 30, one found mixed results with improved survival [inaudible] STEMI but worse with NSTE-ACS.  One was neutral and one found increased mortality, so they were sort of all over the board there.  There was actually one additional study that found a higher mortality among patients transfused at a nadir hemoglobin above 8, but didn't separate out those who had hemoglobin of 8 to 10, versus above 10.

Finally we found two studies that examined the heart failure population and these had conflicting results.  One found a higher mortality with transfusions, the lower found a lower mortality.  So once again conflicting results.

So to try to summarize this, I think we can say that there is no benefit and possible harm with transfusions in hemoglobin above 10.  There are mixed results, but no clear benefits from transfusion of hemoglobin down to 8 to 9 with non NSTE-ACS elevations.  There is consistent evidence of increased mortality with transfusion in the unselected PCI population at a mean nadir hemoglobin of 8 to 9 and there is a higher incidence of death seen in transfusion in the setting of hemorrhage but may be  higher still in non-bleeding patients, who undergo percutaneous coronary intervention.  Finally, there are not studies in stable coronary disease and conflicting results in decompensated heart failure.  All right.  I'm going to turn it back over to Devan now.

Dr. Devan Kansagara:  Thanks, Ed and Dave.  We'll just take a few moments here to summarize what we've learned.  So for ESAs or erythropoiesis stimulating agents, in summary, we found no consistent good quality evidence for improved outcomes from the use of ESAs and we also found the potential for serious harms, including thrombosis and mortality, especially in patients with chronic kidney disease.

Just to echo some of Ed's comments earlier, I think this is an opportunity to talk about how review methodology in setting up our study, the choices we make actually matter in the conclusions that are drawn.  So as we have alluded to before, the Cochran review of erythropoiesis stimulating agents came to slightly different conclusions and it probably reflects some of the methodologic choices we had made up front in designing our review.  We conducted additional analyses, evaluated impact of study quality on results and that's where a lot of the initially seen benefit kind of vanished, when we only looked at better quality studies.  We also chose to include studies of patients with advanced kidney disease if heart disease subgroup data was reported and we felt this was justifiable because chronic kidney disease is so common in folks with congestive heart failure that it's an important clinical question to answer and that the harms seen in one group would be applicable to the other group.  We also included both CHF and coronary heart disease patient populations although most studies were congestive heart failure patients.

So implications--routine use of erythropoiesis stimulating agents in patients with congestive heart failure is probably not warranted at this time and that for patients with comorbid chronic kidney disease, it might be reasonable to consider the recent FDA recommendations that if these agents are to be used at all and that's a big if, hemoglobin should be at least less than 10.  So in other words, there's really no good data that aggressive use of ESAs to increase hemoglobin to normal or near normal levels is beneficial and in fact may be harmful.

So for iron studies described, most of the information came from one large trial, which was a good quality study and showed improvement in short-term exercise tolerance and quality of life.  Of note, this data is probably most applicable to patients who had [inaudible] Heart Association Class III symptoms, so they were pretty symptomatic and who had ferritins less than 100.  Of note, the long-term effects of IV iron and the effects on mortality in cardiovascular events is unknown at this time.

So the implications of this that intravenous iron may be a promising adjunctive therapy in patients with symptomatic heart failure and low ferritin, but probably further study is needed before this could be widely implemented.

So for transfusions, the more liberal transfusion protocols meaning a triggered hemoglobin of 10 grams per deciliter or approximately a hematocrit of 30 do not improve outcomes compared to more conservative protocols.  The evidence is strongest in surgical populations and we have a weaker evidence base in medical populations and this evidence doesn't really apply to actively symptomatic or unstable patients.

So for recommendations here we actually just put up--this just came out a couple of weeks ago this is AABB Guidelines.  I guess they used to be called the American Association of Blood Banks, just issued guidelines on transfusions in general and we pulled out the ones that are applicable to our study here and we felt that these were fairly reasonable recommendations.

So their first recommendation was to suggest adhering to a restrictive strategy in hospitalized patients with preexisting cardiovascular disease and considering transfusion for patients with symptoms or hemoglobin level of 8 or less  This was a weak recommendation based on moderate-quality evidence.

Their second recommendation was actually a non-recommendation, they point out the lack of information with which to guide decision-making in acute coronary syndrome patients.  So this is the group in which we did find some observational study literature, but it can't be considered strong evidence because of all the confounding issues.  So it will be interesting to see what further guideline recommendations come out about this particular group, but the evidence is certainly weaker.

The third recommendation is that transfusion decisions be influenced by symptoms as well as hemoglobin concentration.  So a patient with cardiovascular disease and a hemoglobin of 8.5 or 9 who is tachycardic and having chest pain, you might consider transfusing and that might be a very different scenario from the asymptomatic patient.

Lastly, just to quickly mention that there are--one important ongoing study, the RED-HF study will hopefully provide some more definitive answers around the role of erythropoiesis stimulating agents in heart failure.  Their target is to enroll 2600 patients with symptomatic heart failure and reduce left ventricular [ejection] fraction, results won't be available until at least 2014 and the intervention in this case is darbepoetin titrated to a near normal hemoglobin of 13 or more.

We still need long-term outcomes studies for iron.  We need transfusion trials, addressing the role of transfusion in acute coronary syndrome patients.  It might be useful to consider ESA trials with less aggressive hemoglobin targets.  So there's fairly good evidence, especially in kidney disease patients again that normalizing or coming to near normal levels is unlikely to be helpful, may be harmful, but we don't know the role of less aggressive ESA use, to target hemoglobins between 10 and 12.  So that is all we have, I think we have a few moments for questions, if you have any other questions after this particular question period is over, feel free to e-mail me and our report and slides will be up at this site.

Molly:  Thank you all very much.  For those of you that joined us after the top of the hour and are wondering how to submit a question, please go to the go-to Webinar panel, located on the right-hand side of your screens and click the question section and then you can simply type your question into the bottom and press ask and I will pass it along to our presenters in the order that they arrive.  

At this time no questions have come in, so if you gentlemen would like to give a few more concluding comments, we'll give our audience members a few moments to type in any questions or comments they may have.

Dr. Devan Kansagara:  Oh, any more concluding comments?  Yeah.  I realize we kind of rolled through things pretty quickly because there was a lot to cover, but, no, I think we'll wait a few moments, see if any questions pop.

Molly:  In the meantime you will note that on the bottom of the screen now is the Web address to the published ESP report and you can find all of our previous ESP reports located on that same page.  So we do encourage you to check there for the full results and also I do--while we're waiting for questions to come in, I want to remind all of our attendees that when you do exit this session, you will be prompted after a few seconds to complete a short survey of today's presentation, it's just a few questions that help us gauge how our audience members are enjoying the presentations and it allows you to suggest further topics for HSR&D seminars and further topics for ESP program syntheses, so please do take the time to just answer those few short questions, as we really do take your opinions into consideration when we plan our future ones.

On that same note, we do have a couple Cyberseminars for the ESP program coming up shortly.  One is on family interventions in mental health and then we have two on suicidality and those will be scheduled in the coming months and they will be advertised to you.  The evidence-based synthesis program Cyberseminars do not offer CMEs or CEUs, we have not had them accredited at this time, so if you are looking for CMEs or CEUs, I'm sorry we don't provide those for this series.  You can check the HSR&D research Web site under Cyberseminars for a complete CEU frequently answered questions resource.

No questions have come in at this time, so I think we can go ahead and wrap it up.  As you can see, Devan was kind enough to make himself available for follow-up questions, so you can always contact them afterwards.  I want to thank our attendees for joining us and I'd especially like to thank our three experts for presenting for us.  Do you guys want to say anything before we sign off?

Dr. Devan Kansagara:  Thanks for listening, we enjoyed it.  Like we said the report is up on the Web site, although we will be updating our review probably in upcoming months, so once we have an updated manuscript, we'll end up posting it on the ESP site in the future, but--

Unidentified:  I'd be happy to take questions and comments off line.

Molly:  Great.  Thank you so much and everyone will receive a follow-up e-mail tomorrow with a direct link to this recording to the audio portion and to the handouts and transcript in case you'd like to pass those along to any of your colleagues who couldn't join us today or anyone you feel might be interested in this subject matter.  With that, thank you again everyone and I hope you enjoy this nice spring day.  This does conclude our HSR&D Cyberseminar for today.  

[All say thank you.]

Molly:  Thanks, guys.

**[End of Recording]**