ANAEMIA MANAGEMENT: THE KDIGO RECOMMENDATIONS
Patrick S. Parfrey, St. John’s, Canada
Chair: Kai-Uwe Eckardt, Erlangen, Germany
Pierre-Yves Martin, Geneva, Switzerland
Prof. Patrick S. ParfreyDivision of Nephrology
The Health Sciences CentreMemorial UniversitySt John's, Canada
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So as many of you know, this is a committee of people with multiple different talentsand who did the review in association with the Netherlands Review team from Boston.
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I’m only going to focus on the management issues of the guidelines which were dividedamongst the use of iron, ESAs and transfusion. Much of the data that was used by thecommittee has already been discussed by Ian and the previous speakers.
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I’m not even going to bother with the non-graded statements because non-gradedstatements are common sense on how to be a good doctor. So let’s just deal with thegraded statements. So the second statement here for the use of iron agents says for that adult CKDpatients with anaemia not on iron or ESA therapy we suggest a trial of IV iron, or in ourCKD dialysis patients alternatively a 1-3 month trial on oral iron therapy, these arepretty important previsors, if an increase in haemoglobin concentration without startingESA treatment is desired, which should be based on patient symptoms and overallclinical goals including avoidance of transfusion and improvement of anaemia relatedsymptoms and after exclusion of active infection. So these are very clinically drivendecisions. Then based on the iron status test if the TSAT is less than 30% and theferritin is less than 500 ng/ml which is a change from previous guidelines and lessconservative.
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So then if you go down to the second statement here for paediatric patients, for allpaediatric CKD patients with anaemia not on iron or ESA therapy we recommend oraliron or IV iron in CKD haemodialysis patients when the TSAT is less than 20% and theferritin is less than 100 ng/ml. So there is a direct difference between the paediatricand the adult recommendations. It’s related to the fact that it’s been knowninflammation arising in children and paediatricians did not want to change the oldguidelines so they wanted to stay conservative. So for all paediatric CKD patients onESA therapy who were not receiving iron supplementation we recommend oral iron or IV
iron in haemodialysis patients to maintain a TSAT greater than 20% and a ferritingreater than 100 ng/ml.
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Now for the adult patients the guideline was driven by this information whichdemonstrates that whatever the iron status test that the proportion of respondersfrequently had a level that would be considered to be in the normal range. So if youlook here on the left hand column for a TSAT less than 20%, you can see that 50%were responders and 50% were not responders or 50% had a TSAT of greater than20%. The same goes for the other markers of iron deficiency even if the marrow iron is takenas the arbiter of iron deficiency. You can see here that in those responders with amarrow iron score of 1, 63% of the marrow score of 1 whereas the remaining the 37%had a score of 1, i.e. the markers for iron deficiency are not very good diagnostic testsfor telling us the response to giving intravenous iron.
The response that was looked for was a gram of IV iron given in 8 doses and it was judged by an
increase in haemoglobin of greater than 1 g/dL. So that’s the reason for us having less
conservative iron status test triggers.
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The other piece of information that was pretty relevant in terms of the use of iron isthat most of the studies done and that examined the use of IV iron have been verysmall. For instance, if you take Coyne’s paper, the DRIVE paper, there are only 130patients randomised and they’re only followed for about 6 weeks so the capacity tounderstand what the benefits and harms associated with IV iron is very limited. Sowhat we’re recommending is give a trial of IV iron, see the response, if there’s actuallya good response give the iron but be cautious because the long-term effects of IV ironare unknown.
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So go down to these cautions regarding iron therapy. Go down to the statement 2.4avoid administering IV iron to patients with active infection. This is not graded because
the data is divergent and there’s very little information available to educate you onthis.
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So if we move on to the ESA guidelines,
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there’s much more data about cost and benefits. The second recommendation herestates that initiating and maintaining ESA therapy we recommend balancing thepotential benefits of reducing blood transfusions and anaemia related symptoms againstthe risks of harm in individual patients such as stroke, vascular access, loss andhypertension. We recommend using ESA therapy with great caution, if at all in VCKD
patients with active malignancy in particular when cure is the anticipated outcome. Ahistory of stroke or a history of malignancy. I’ll briefly look at some of that information.
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For adult CKD non-dialysis patients with a haemoglobin of greater than 10 g/dL wesuggest ESA therapy not be initiated. For adult CKD patients with haemoglobin below 10g/dL we suggest the decision be individualized based on the clinical status of thepatient outlined here the things you need to take into account. For CKD patients whoare on dialysis we suggest that ESA therapy be used to avoid having the haemoglobinlevel fall below 9 g/dL by starting ESA therapy when the haemoglobin is between 9 g/dLand 10 g/dL.
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Individualisation of therapy is reasonable if some patients may have improvements inquality of life at higher haemoglobin concentrations and the ESA therapy may bestarted above 10 g/dL. Again it was felt that children should be treated somewhatdifferently from adults because there are different considerations and targethaemoglobins may actually be a bit higher.
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So I’m not going to spend a lot of time on the data because some of it has alreadybeen presented other than to say that in the management of severe anaemia when thehaemoglobin is below 10 g/dL the baseline haemoglobin is below 10 g/dL there are norandomised controlled trials telling us about the benefit and harms ratio. There are smallstudies, they initiated the ERA use of ERA and people jumped into it because itprevented transfusions and improved quality of life. However, there’s much better datafor those people whose baseline haemoglobins are greater than 10 g/dL what I’m callingmoderate anaemia.
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You’ve already heard about the Besarab study which demonstrated harm becausevascular access was lost in patients in the intervention compared to the control arm.
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In the Canada Europe study which even though was an echocardiographic outcomestudy
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there was a higher risk of stroke in the high haemoglobin arm compared to the lowhaemoglobin arm.
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In CREATE there was an increased risk of going on dialysis earlier in the highhaemoglobin arm compared to the low haemoglobin arm
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and one needed to question the relevance of it clinically because the eGFR dropped atthe same rate in both groups.
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There was a high risk of composite cardiovascular events in CHOIR which was notconfirmed in TREAT.
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So if the data that influenced our group most was clearly the data that came fromTREAT 4,000 patients in this study. It was in fact a placebo controlled trial and inrelationship to the hyporesponsiveness story one must remember that TREAT testedthe hypothesis whether treating anaemia with darbepoetin could prevent cardiovascularevents and the answer was it didn’t. This is what this slide shows here.
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There’s no difference between the intervention arm and the control arm in terms ofcardiovascular outcomes or in terms of renal outcomes in diabetic nephropathypatients.
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The biggest concern that arose was that there was an increased incidence of stroke. Of influence was that the risk of stroke attributable to the intervention, attributable todarbepoetin was substantially higher in those with a prior history of stroke 8% overapproximately 4 years compared to those who had no history of stroke which was 2%over approximately 4 years. So you could identify a group in whom there was a muchhigher risk of stroke attributable to the intervention.
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If you go to the lower half of this study, this is familiar information but there was asignal that those patients who had a baseline history of malignancy were more likelyto have a death from cancer here in the intervention arm i.e. those given darbopoietinthan those in the placebo arm. When this signal was matched with data that camefrom randomised controlled trials in the oncology literature, it stimulated us to believethat the use of ESAs in people with a history of malignancy was not a good thing.
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I’ll briefly mention quality of life because that actually was associated with a largeamount of discussion because nephrologists think that patients feel better when theirhaemoglobins are higher. But when you get down to the data on quality of life, it’sactually difficult to interpret. There seems to be little doubt that clinically important
improvements in fatigue and in physical function occur when treating haemoglobinsbelow 9 ng/ml.
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But when you end up and examine the effect of treating haemoglobin in patients whosebaseline haemoglobin is greater than 10 ng/ml there’s very diverse data. In our studythe Canada-Europe study we found critically important changes in fatigue scores over
many weeks in those people who were randomly allocated to a high haemoglobincompared to a low haemoglobin.
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However TREAT showed a very, very modest impact on fatigue it was statisticallysignificant but it was not clinically significant.
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So based on that background in terms of maintenance therapy we suggest that ESAsnot be used to maintain haemoglobin concentrations above 11.5 g in adult patient.However we strongly recommend individualization of therapy as it will be necessary insome patients who feel they’ve had an improvement in quality of life at a haemoglobin
greater than 11.5 and are prepared to accept the increased risks. In all adult patientswe recommend that ESAs not be used to intentionally increase the haemoglobin above13 g/dL and in paediatric patients the selected haemoglobin range is a bit higher thanan adult’s 11-12 g/dL.
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Now in terms of the hyporesponsiveness that was discussed earlier there certainlyseems to be a feeling that it’s a waste of money giving high doses in hyporesponsivepatients. So in patients with ESA hyporesponsiveness we suggest avoiding repeatedescalations in ESA dose beyond double the initial weight based dose.
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We wanted to classify patients similar to TREAT. So they were classified as having
We wanted to classify patients similar to TREAT. So they were classified as havingacquired ESA hyporesponsiveness if after treatment with stable doses of ESAs thatacquired two increases in ESA doses of up to 50% beyond the dose at which they’dbeen stable and been able to maintain a stable haemoglobin concentration. This is adefinition for subsequent acquired ESA hyporesponsiveness. Again, in these people whohave acquired ESA hyporesponsiveness following association we suggest avoidingrepeated escalations in dose beyond double the dose at which they’d been stable. So in fact then we’re saying those starting ESA therapy and they’re hyporesponsive doublethe dose and then if they acquire hyporesponsiveness double the dose. So it’s suchthat the maximum dose that we’re suggesting based on weight based doses is fourtimes higher than the initial dose, initial weight based dose.
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Certainly the presence of hyporesponsiveness at the beginning subsequently requiresinvestigation.
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Now I’m just going to mention this data again this is from TREAT and it’s theinterpretation of the data that I’m kind of more concerned about because it clearlydemonstrates that every trial of high haemoglobin levels have demonstrated an inverserelationship between hyporesponsiveness and outcome.
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However, TREAT demonstrated that there is no difference in the cardiovascularoutcome using darbepoetin compared to placebo and the biggest issue was stroke.There is in fact, no relationship between hyporesponsiveness and stroke. So my feelingis that this cardiovascular relationship between hyporesponsiveness and cardiovascularoutcome is driven by the pre-existing comorbidity and that it’s a dose targeting biasthat’s occurring as a result of us trying to drive EPO doses in people who already havegot a comorbid illness.
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I’m just briefly going to finish off with the transfusions.
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Iain has presented nearly all the data in transfusions that we discussed. In fact, werecommend avoiding when possible red blood cell transfusions to minimize the generalrisks related to their use. In patients eligible for organ transplantation we specificallyrecommend avoiding when possible red cell transfusions to minimize the risk ofallosensitisation. When managing chronic anaemia we suggested the benefits of redblood transfusions may outweigh the risks in certain groups of patients, those in whom
it’s ineffective the ESA and the risks may outweigh the benefits in those with aprevious or current malignancy or with prior stroke.
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We suggested the decision to transfuse the CKD patients with non-acute anaemiashould not be based on an arbitrary haemoglobin threshold but should be determined bythe occurrence of symptoms caused by anaemia. In fact, we want people toindividualise therapy and not be driven by numbers. Thank you.
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Chairman: Thank you Patrick thank you also for keeping so well within the time framewhich gives us plenty of time I must say actually to discuss this guideline. Are there
any questions about specific statements and recommendations? It’s still an earlymorning. Let me start off with the matter of hyporesponsiveness and recommendationnot to over-escalate those adjustments because this is something which is new whichis different from previous guidelines. I’m still slightly confused and I guess people maybe slightly confused about how you actually do it. If I understand the statementcorrectly it implies that if you’ve chosen a specific dose based on patient weight, youshould not go beyond two times this dose, is that correct?
Prof. Parfrey: This is correct initially once you’ve escalated the dose on two occasionsand you’re still finding no response try and find the cause for the lack of response.Then we’re suggesting that going further to drive the ESA dose is unlikely to lead toany increased benefit. You’re going to spend money on ESAs and it has the potentialto be toxic even though we don’t know the answer to that.
Question: Doctor Cassiz from Barcelona Spain I have just a question. We don’t havesafety studies on long-term use of IV iron. The recommendations are right now toincrease with the ferritin levels that I think are quite high because some studies havedemonstrated accumulation of iron when you have ferritin levels higher than 400 forexample. What’s the opinion of the panel of the KDIGO guidelines about this issue?
Prof. Parfrey: I think that we’ve been extremely careful to try and say that there’sbeen no data on benefits versus terms on the use of IV iron. That there the ironstatus tests are poor diagnostic tests for iron deficiency and giving a trial of IV iron 1g once or twice to try and see its effect on raising the haemoglobin level is areasonable pathway but then the subsequent decision to provide substantial long-termiron is going to be individualized and one must take into account that the data on harmis not there and that we should not be using IV iron in the same ways we did ESAswhich is that every year we escalated the use of ESAs in the mistaken belief that wewere providing benefit. I personally would not be very aggressive with IV iron until weget the evidence that it’s not harmful but I think we’re pushing the belief that a trial ofthe IV arm is a useful diagnostic test for iron deficiency.
Chairman: Next question?
Question: Yes – from Japan I have a question. Previously I noted that duration of thehaemoglobin level below 11 g /dl is a great risk for the survivor but now KDIGO guidelines recommend a haemoglobin below 11.5 g/dL. But patients with haemoglobinlevel of 11 g/dl patients are more at risk of death or cardiovascular disease becauseprevious guidelines show that we should keep the haemoglobin level 11 g/dL over butnow new KIDGO guidelines show that haemoglobin level should be below 11 g/dL. Maybesome patients with haemoglobin between 10 and 11 g/dL. Sorry I’m Japanese and myEnglish .. maybe you’re haemoglobin guidelines KDIGO guidelines shows haemoglobinlevels lower than the previous ones. We previously studied you said the haemoglobinshould be between over 11 g/dL but now you should say most of the patients should bebelow 11 g/dL of haemoglobin but maybe some patients have lower haemoglobin levelsmore severe anaemia such patients are at more risk of survival I think what do youthink?
Prof. Parfrey: To be honest I could barely understand a word you said because of thesound system but what I would try and state is that we do not believe in targets, thatthere are certain ranges that patients should be kept at. We believe that in providing atherapy you would like to demonstrate a clinical benefit to the patient and not just animprovement in the number and that should drive your decisions at the range you’retrying to get, at the levels you’re trying to get to achieve. So, in fact we’re sayingthat up to 13 going beyond 13 is dangerous. Between 11.5 and 13 the danger isrelatively unknown but the belief that it is accumulating risk avoid 11.5 – 13. Thenyou’ve got a range in 9 and 11.5 in fact 9 and 11.5 in which you’re treating thepatients. We feel that these therapies whether it’s IV iron whether it’s ESAs or whetherit’s blood transfusions blood transfusions should be driven by the clinical needs of thepatient and not by the number.
Question: Coming back to the iron issue previous guidelines gave a corridor of TSATvalues and ferritin concentrations that should be aimed for. This guideline is slightlydifferent in this respect.
Prof. Parfrey: Yes it is because the data that educating the use of iron status tests asgood diagnostic tests is awful. So there was feeling from some people that wouldn’t itbe good to tell nephrologists that the maximum art status tests you should be aimingfor should be? There’s no data there is in fact a drive study demonstrated that youcould increase the haemoglobin level and ESA therapy by giving IV iron in people with aferritin level between I think it’s 600 and 1200 units. So there’s a lot of opportunity ofdoing research to tell us better how to manage IV iron but the iron status tests arevery poor tests in which to guide the management of IV iron therapy.
Chairman: One more question.
Question: Good morning I’m doctor – from Sheffield UK I just want to ask you wouldyou agree with the recommendation to keep the haemoglobin target in diabetics a bitless compared to the non-diabetics?
Prof. Parfrey: It’s very difficult. I think personally I don’t differentiate the diabetic from the non-diabetic particularly. --- treat diabetic patients and that’s what the data’sderived from. But I’m more inclined to deal with the patients in terms of symptomsthey’ve got and the comorbidities they’ve got. Have they got stroke, have they gotcancer, have they got fatigue and weakness, have they got symptoms that arepotentially attributable to anaemia? If treat anaemia whatever agent I use am I goingto benefit the patient? Or am I going to cause increased risk? That’s the way my mindwould be working rather than say are they diabetic or non-diabetic. Even though thevasculature of the diabetics is certainly probably different from the vasculature of thenon-diabetics.
Chairman: Would you like to make a final comment about the necessity of futuretrials? What would be at the top of your priority list in terms of additional trials that weneed for anaemia management?
Prof. Parfrey: Well, personally I think there’s an awful lot of baloney talking aboutdose because the relationship between hyporesponsiveness and cardiovascularoutcome is so strong people are now implying that dose is the toxic thing. I think that atrial based on the high dose and the low dose is probably the most important trial thatwe can get and try and answer that question about dose. Our discussions abouthyporesponsiveness are similar to the discussions we had years ago about Kt/V and wedid a trial and we found it to be baloney.
Chairman: Ok I see no further questions thank you so much.
