ANAEMIA MANAGEMENT: THE KDIGO RECOMMENDATIONS Patrick S. Parfrey, St. John s, Canada

Transcription

1 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. Parfrey Division of Nephrology The Health Sciences Centre Mem orial University St John's, Canada Slide 1 Slide 2

2 So as many of you know, this is a committee of people with multiple different talents and who did the review in association with the Netherlands Review team from Boston. Slide 3 I m only going to focus on the management issues of the guidelines which were divided amongst the use of iron, ESAs and transfusion. Much of the data that was used by the committee has already been discussed by Ian and the previous speakers. Slide 4

3 I m not even going to bother with the non- graded statements because non- graded statements are common sense on how to be a good doctor. So let s just deal with the graded statements. So the second statement here for the use of iron agents says for that adult CKD patients with anaemia not on iron or ESA therapy we suggest a trial of IV iron, or in our CKD dialysis patients alternatively a 1-3 month trial on oral iron therapy, these are pretty important previsors, if an increase in haemoglobin concentration without starting ESA treatment is desired, which should be based on patient symptoms and overall clinical goals including avoidance of transfusion and improvement of anaemia related symptoms and after exclusion of active infection. So these are very clinically driven decisions. Then based on the iron status test if the TSAT is less than 30% and the ferritin is less than 500 ng/ml which is a change from previous guidelines and less conservative. Slide 5

4 Slide 6 So then if you go down to the second statement here for paediatric patients, for all paediatric CKD patients with anaemia not on iron or ESA therapy we recommend oral iron or IV iron in CKD haemodialysis patients when the TSAT is less than 20% and the ferritin is less than 100 ng/ml. So there is a direct difference between the paediatric and the adult recommendations. It s related to the fact that it s been known inflammation arising in children and paediatricians did not want to change the old guidelines so they wanted to stay conservative. So for all paediatric CKD patients on ESA therapy who were not receiving iron supplementation we recommend oral iron or IV

5 iron in haemodialysis patients to maintain a TSAT greater than 20% and a ferritin greater than 100 ng/ml. Slide 7 Now for the adult patients the guideline was driven by this information which demonstrates that whatever the iron status test that the proportion of responders frequently had a level that would be considered to be in the normal range. So if you look 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 than 20%. The same goes for the other markers of iron deficiency even if the marrow iron is taken as the arbiter of iron deficiency. You can see here that in those responders with a marrow 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 tests for 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. Slide 8

6 The other piece of information that was pretty relevant in terms of the use of iron is that most of the studies done and that examined the use of IV iron have been very small. For instance, if you take Coyne s paper, the DRIVE paper, there are only 130 patients randomised and they re only followed for about 6 weeks so the capacity to understand what the benefits and harms associated with IV iron is very limited. So what we re recommending is give a trial of IV iron, see the response, if there s actually a good response give the iron but be cautious because the long-term effects of IV iron are unknown. Slide 9 So go down to these cautions regarding iron therapy. Go down to the statement 2.4 avoid administering IV iron to patients with active infection. This is not graded because

7 the data is divergent and there s very little information available to educate you on this. Slide 10 So if we move on to the ESA guidelines, Slide 11 there s much more data about cost and benefits. The second recommendation here states that initiating and maintaining ESA therapy we recommend balancing the potential benefits of reducing blood transfusions and anaemia related symptoms against the risks of harm in individual patients such as stroke, vascular access, loss and hypertension. We recommend using ESA therapy with great caution, if at all in VCKD

8 patients with active malignancy in particular when cure is the anticipated outcome. A history of stroke or a history of malignancy. I ll briefly look at some of that information. Slide 12 For adult CKD non-dialysis patients with a haemoglobin of greater than 10 g/dl we suggest ESA therapy not be initiated. For adult CKD patients with haemoglobin below 10 g/dl we suggest the decision be individualized based on the clinical status of the patient outlined here the things you need to take into account. For CKD patients who are on dialysis we suggest that ESA therapy be used to avoid having the haemoglobin level fall below 9 g/dl by starting ESA therapy when the haemoglobin is between 9 g/dl and 10 g/dl. Slide 13

9 Individualisation of therapy is reasonable if some patients may have improvements in quality of life at higher haemoglobin concentrations and the ESA therapy may be started above 10 g/dl. Again it was felt that children should be treated somewhat differently from adults because there are different considerations and target haemoglobins may actually be a bit higher. Slide 14 So I m not going to spend a lot of time on the data because some of it has already been presented other than to say that in the management of severe anaemia when the haemoglobin is below 10 g/dl the baseline haemoglobin is below 10 g/dl there are no randomised controlled trials telling us about the benefit and harms ratio. There are small studies, they initiated the ERA use of ERA and people jumped into it because it prevented transfusions and improved quality of life. However, there s much better data for those people whose baseline haemoglobins are greater than 10 g/dl what I m calling moderate anaemia. Slide 15

10 Slide 16 You ve already heard about the Besarab study which demonstrated harm because vascular access was lost in patients in the intervention compared to the control arm. Slide 17

11 In the Canada Europe study which even though was an echocardiographic outcome study Slide 18 there was a higher risk of stroke in the high haemoglobin arm compared to the low haemoglobin arm. Slide 19

12 In CREATE there was an increased risk of going on dialysis earlier in the high haemoglobin arm compared to the low haemoglobin arm Slide 20 and one needed to question the relevance of it clinically because the egfr dropped at the same rate in both groups. Slide 21

13 There was a high risk of composite cardiovascular events in CHOIR which was not confirmed in TREAT. Slide 22 So if the data that influenced our group most was clearly the data that came from TREAT 4,000 patients in this study. It was in fact a placebo controlled trial and in relationship to the hyporesponsiveness story one must remember that TREAT tested the hypothesis whether treating anaemia with darbepoetin could prevent cardiovascular events and the answer was it didn t. This is what this slide shows here. Slide 23

14 There s no difference between the intervention arm and the control arm in terms of cardiovascular outcomes or in terms of renal outcomes in diabetic nephropathy patients. Slide 24 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 to darbepoetin was substantially higher in those with a prior history of stroke 8% over approximately 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 much higher risk of stroke attributable to the intervention. Slide 25

15 If you go to the lower half of this study, this is familiar information but there was a signal that those patients who had a baseline history of malignancy were more likely to have a death from cancer here in the intervention arm i.e. those given darbopoietin than those in the placebo arm. When this signal was matched with data that came from randomised controlled trials in the oncology literature, it stimulated us to believe that the use of ESAs in people with a history of malignancy was not a good thing. Slide 26 I ll briefly mention quality of life because that actually was associated with a large amount of discussion because nephrologists think that patients feel better when their haemoglobins are higher. But when you get down to the data on quality of life, it s actually difficult to interpret. There seems to be little doubt that clinically important

16 improvements in fatigue and in physical function occur when treating haemoglobins below 9 ng/ml. Slide 27 Slide 28 But when you end up and examine the effect of treating haemoglobin in patients whose baseline haemoglobin is greater than 10 ng/ml there s very diverse data. In our study the Canada- Europe study we found critically important changes in fatigue scores over

17 many weeks in those people who were randomly allocated to a high haemoglobin compared to a low haemoglobin. Slide 29 However TREAT showed a very, very modest impact on fatigue it was statistically significant but it was not clinically significant. Slide 30 So based on that background in terms of maintenance therapy we suggest that ESAs not 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 in some patients who feel they ve had an improvement in quality of life at a haemoglobin

18 greater than 11.5 and are prepared to accept the increased risks. In all adult patients we recommend that ESAs not be used to intentionally increase the haemoglobin above 13 g/dl and in paediatric patients the selected haemoglobin range is a bit higher than an adult s g/dl. Slide 31 Now in terms of the hyporesponsiveness that was discussed earlier there certainly seems to be a feeling that it s a waste of money giving high doses in hyporesponsive patients. So in patients with ESA hyporesponsiveness we suggest avoiding repeated escalations in ESA dose beyond double the initial weight based dose. Slide 32 We wanted to classify patients similar to TREAT. So they were classified as having

19 We wanted to classify patients similar to TREAT. So they were classified as having acquired ESA hyporesponsiveness if after treatment with stable doses of ESAs that acquired two increases in ESA doses of up to 50% beyond the dose at which they d been stable and been able to maintain a stable haemoglobin concentration. This is a definition for subsequent acquired ESA hyporesponsiveness. Again, in these people who have acquired ESA hyporesponsiveness following association we suggest avoiding repeated 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 double the dose and then if they acquire hyporesponsiveness double the dose. So it s such that the maximum dose that we re suggesting based on weight based doses is four times higher than the initial dose, initial weight based dose. Slide 33 Certainly the presence of hyporesponsiveness at the beginning subsequently requires investigation. Slide 34

20 Now I m just going to mention this data again this is from TREAT and it s the interpretation of the data that I m kind of more concerned about because it clearly demonstrates that every trial of high haemoglobin levels have demonstrated an inverse relationship between hyporesponsiveness and outcome. Slide 35 However, TREAT demonstrated that there is no difference in the cardiovascular outcome using darbepoetin compared to placebo and the biggest issue was stroke. There is in fact, no relationship between hyporesponsiveness and stroke. So my feeling is that this cardiovascular relationship between hyporesponsiveness and cardiovascular outcome is driven by the pre- existing comorbidity and that it s a dose targeting bias that s occurring as a result of us trying to drive EPO doses in people who already have got a comorbid illness.

21 Slide 36 I m just briefly going to finish off with the transfusions. Slide 37 Iain has presented nearly all the data in transfusions that we discussed. In fact, we recommend avoiding when possible red blood cell transfusions to minimize the general risks related to their use. In patients eligible for organ transplantation we specifically recommend avoiding when possible red cell transfusions to minimize the risk of allosensitisation. When managing chronic anaemia we suggested the benefits of red blood transfusions may outweigh the risks in certain groups of patients, those in whom

22 it s ineffective the ESA and the risks may outweigh the benefits in those with a previous or current malignancy or with prior stroke. Slide 38 We suggested the decision to transfuse the CKD patients with non- acute anaemia should not be based on an arbitrary haemoglobin threshold but should be determined by the occurrence of symptoms caused by anaemia. In fact, we want people to individualise therapy and not be driven by numbers. Thank you. Slide 39 Chairman: Thank you Patrick thank you also for keeping so well within the time frame which gives us plenty of time I must say actually to discuss this guideline. Are there

23 any questions about specific statements and recommendations? It s still an early morning. Let me start off with the matter of hyporesponsiveness and recommendation not to over- escalate those adjustments because this is something which is new which is different from previous guidelines. I m still slightly confused and I guess people may be slightly confused about how you actually do it. If I understand the statement correctly it implies that if you ve chosen a specific dose based on patient weight, you should not go beyond two times this dose, is that correct? Prof. Parfrey: This is correct initially once you ve escalated the dose on two occasions and 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 to any increased benefit. You re going to spend money on ESAs and it has the potential to 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 have safety studies on long- term use of IV iron. The recommendations are right now to increase with the ferritin levels that I think are quite high because some studies have demonstrated accumulation of iron when you have ferritin levels higher than 400 for example. 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 s been no data on benefits versus terms on the use of IV iron. That there the iron status tests are poor diagnostic tests for iron deficiency and giving a trial of IV iron 1 g once or twice to try and see its effect on raising the haemoglobin level is a reasonable pathway but then the subsequent decision to provide substantial long- term iron is going to be individualized and one must take into account that the data on harm is not there and that we should not be using IV iron in the same ways we did ESAs which is that every year we escalated the use of ESAs in the mistaken belief that we were providing benefit. I personally would not be very aggressive with IV iron until we get the evidence that it s not harmful but I think we re pushing the belief that a trial of the 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 the haemoglobin 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 haemoglobin level of 11 g/dl patients are more at risk of death or cardiovascular disease because previous guidelines show that we should keep the haemoglobin level 11 g/dl over but now new KIDGO guidelines show that haemoglobin level should be below 11 g/dl. Maybe some patients with haemoglobin between 10 and 11 g/dl. Sorry I m Japanese and my English.. maybe you re haemoglobin guidelines KDIGO guidelines shows haemoglobin levels lower than the previous ones. We previously studied you said the haemoglobin should be between over 11 g/dl but now you should say most of the patients should be below 11 g/dl of haemoglobin but maybe some patients have lower haemoglobin levels more severe anaemia such patients are at more risk of survival I think what do you think? Prof. Parfrey: To be honest I could barely understand a word you said because of the sound system but what I would try and state is that we do not believe in targets, that there are certain ranges that patients should be kept at. We believe that in providing a therapy you would like to demonstrate a clinical benefit to the patient and not just an improvement in the number and that should drive your decisions at the range you re trying to get, at the levels you re trying to get to achieve. So, in fact we re saying that up to 13 going beyond 13 is dangerous. Between 11.5 and 13 the danger is relatively unknown but the belief that it is accumulating risk avoid Then you ve got a range in 9 and 11.5 in fact 9 and 11.5 in which you re treating the patients. We feel that these therapies whether it s IV iron whether it s ESAs or whether it s blood transfusions blood transfusions should be driven by the clinical needs of the patient and not by the number. Question: Coming back to the iron issue previous guidelines gave a corridor of TSAT values and ferritin concentrations that should be aimed for. This guideline is slightly different in this respect.

24 Prof. Parfrey: Yes it is because the data that educating the use of iron status tests as good diagnostic tests is awful. So there was feeling from some people that wouldn t it be good to tell nephrologists that the maximum art status tests you should be aiming for should be? There s no data there is in fact a drive study demonstrated that you could increase the haemoglobin level and ESA therapy by giving IV iron in people with a ferritin level between I think it s 600 and 1200 units. So there s a lot of opportunity of doing research to tell us better how to manage IV iron but the iron status tests are very 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 would you agree with the recommendation to keep the haemoglobin target in diabetics a bit less 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 s derived from. But I m more inclined to deal with the patients in terms of symptoms they ve got and the comorbidities they ve got. Have they got stroke, have they got cancer, have they got fatigue and weakness, have they got symptoms that are potentially attributable to anaemia? If treat anaemia whatever agent I use am I going to benefit the patient? Or am I going to cause increased risk? That s the way my mind would be working rather than say are they diabetic or non- diabetic. Even though the vasculature of the diabetics is certainly probably different from the vasculature of the non- diabetics. Chairman: Would you like to make a final comment about the necessity of future trials? What would be at the top of your priority list in terms of additional trials that we need for anaemia management? Prof. Parfrey: Well, personally I think there s an awful lot of baloney talking about dose because the relationship between hyporesponsiveness and cardiovascular outcome is so strong people are now implying that dose is the toxic thing. I think that a trial based on the high dose and the low dose is probably the most important trial that we can get and try and answer that question about dose. Our discussions about hyporesponsiveness are similar to the discussions we had years ago about Kt/V and we did a trial and we found it to be baloney. Chairman: Ok I see no further questions thank you so much.