ANAEMIA MANAGEMENT: HOW AND WHY DOES ERBP DIFFER FROM KDIGO Francesco Locatelli, Lecco, Italy

Transcription

1 ANAEMIA MANAGEMENT: HOW AND WHY DOES ERBP DIFFER FROM KDIGO Francesco Locatelli, Lecco, Italy Chair: Kai- Uwe Eckardt, Erlangen, Germany Pierre- Yves Martin, Geneva, Switzerland Prof. Francesco Locatelli A. Manzoni Hospital Lecco, Italy Slide 1 Thank you very much for this presentation. My personal point of view is related to the fact that when the organizers invited me to give this talk the KDIGO guidelines were supposed to be published and the European renal best practice point of view already ready for publication but it s not the case. So the only possibility for me is to give my

2 personal opinion on the previous draft of the KDIGO guidelines because we ve realized in my opinion they ve improved a lot now underlining the possibility of individualized treatment; thus this is the major message of the KDIGO guidelines. Slide 2 So partial anaemia correction Slide 3 from the data of our previous speaker Patrick Parfrey clearly underline in this metaanalysis when you have severe anaemia at this line and the lower haemoglobin target, you can have the possibility of ameliorating, there is a clear association with amelioration of left ventricular mass index.

3 Slide 4 Of course, the question is very clear that international trials of complete anaemia correction unfortunately did not give the expected results. Slide 5 We mainly want to discuss the problem of TREAT because as Patrick Parfrey underlined before this was the major trial for the new KDIGO guideline to be considered. Slide 6

4 You can very clearly see that the trial was neutral, no positive, no negative effects in the primary endpoint related to the cardiovascular composite endpoint and the same is true if you are considering the renal outcomes. I think the starting point is there are no differences between the two targets of the haemoglobin level. So there is no reason for giving the patient a large amount or doubling ESA for correcting anaemia if the final results are the same. Slide 7 But of course, many years ago when we had the revised version of the European Best Practise Guidelines Slide 8

5 We were suggesting to have a target haemoglobin level for diabetic patients between 11 and 12 g/dl. It was a little bit more conservative than in the general population because we consider the diabetic patients at risk, at greater risk for this kind of situation. Slide 9 Also the KDOQI guidelines in 2007 you can see here the chair was our chairman Kai-Uwe Eckhardt and also there are liaison members for Europe, Ian Macdougall and myself so it s already a sort of internalization of the guidelines. Slide 10

6 I think that the conclusion of the working group was to have a haemoglobin level in the range of g/dl and again as the KDIGO guidelines have concluded now I think it is important to be aware of the fact that the target should not be above 13 g /dl to avoid any risk. I think the difference is that in those days there was moderately strong evidence and now in the new guidelines there is strong evidence and I fully agree with that. Slide 11 Of course we have to take into consideration many aspects. Again, doctor Parfrey published this trial, a double blind comparison of full and partial anaemia correction and again you can see here the major aim was related to compare patients with an haemoglobin level between 9.5 g/dl and 11.5 g/dl and 13.5 g/dl and 14.5 g/dl, what is

7 important to underline is that again there is a clear trend in increase the serum vascular disorders in randomised to the higher targets. Slide 12 So I think that you should be absolutely aware that the data are very consistent in underlining the risk of having cerebrovascular complications but let me underline very clearly here that in the higher haemoglobin group the target was very high indeed but now we have a general agreement that we should absolutely not have a target above 13 g/dl in our patient population. Slide 13 Of course, the major concern was related to the risk of stroke which was already

8 Of course, the major concern was related to the risk of stroke which was already underlined between the two groups with a 92% of higher relative risk of strokes in patients of the higher haemoglobin level and this was particularly true for patients with a previous history of stroke. Slide 14 So I think that even if you have to take into consideration the general population but for sure for patients with history the risk is higher for having this kind of complication. Slide 15 So I think that in general it is also important to try to clarify the difference between

9 So I think that in general it is also important to try to clarify the difference between the ischemic and haemorrhagic stroke in order to see if there are any differences between the two possibilities according to the treatment but you can see here, in general the percentage between the two possibilities is the same. It doesn t matter if you re looking at the patients treated with darbopoietin or placebo. So there is no specific risk but risk is related to both the complications. Slide 16 But what is important is to try to clarify the risk is to take into consideration at the multivariate,the predictor of strokes in the TREAT study and I think they have very important information here because for sure darbopoietin alpha treatment was associated with the risk. The same is true for history of stroke, also for the log protein/creatinine ratio, insulin use so you can see here there are many factors affecting the risk of stroke in this patient population. What is strange, at least at a first look is strange, if you have a haemoglobin level of 1g/dL down, you have an increase in the risk. So it s exactly the opposite to what you re expecting according to the first interpretation of the KDIGO of the TREAT. The same is true if you are looking at the BMI. You can see again if the BMI is decreasing there is a higher risk. So I think that altogether these data should be, at least in my view, interpreted as an inflammation related risk. So in case you are unable to increase the haemoglobin level and we have a very low decrease in BMI for sure this is because the patients have a lot of comorbidities. So I fully agree with doctor Parfrey s interpretation that inflammation is a very important point to take into consideration. Slide 17

10 So I think that also considering the post- randomisation factor and the risk of stroke, you can see strangely enough you can t find any difference as far as systolic and diastolic pressurel values are concerned. Also you can see here no difference at all between the haemoglobin levels between the two groups so it is completely again in the range of in the two groups. So haemoglobin per se is not a factor or a cause of stroke in the patients in the TRERAT trial. Also you can see that the darbopoietin doses were absolutely the same. So these underline the difficulties in interpreting the data because if you try to find out the reason for these differences, I think it is very difficult to find out a very clear situation. Again if you are considering the placebo group, the situation is the same. Very good blood pressure control systolic and diastolic, the haemoglobin levels again were the same and also the platelet counts questioned before were absolutely the same and also of course, the ESA dose in this case by definition was very close to zero. Slide 18

11 So the problem is the difficulties in interpreting the cause of strokes in this patient population. So it s a sort of smoking gun. Slide 19 English people know very well the meaning of this word but I think that at the end of the day if you are looking at the stroke incidence in the different trials, you can see here only in the TREAT trial the difference between the strokes was very clear between the two target levels of haemoglobin levels, while for the other ones it was not the case. Of course we have to take into consideration the follow-up and the follow-up was particularly long in the TREAT trial, 29 months but I think that another important point to take into consideration is the percentage of diabetes patients : in the NHT trial it was 44%, in the CREATE only 25% in the CHOIR 50% and in the TREAT trial by

12 definition 100%. So I think apparently it could be something related to the diabetes status. Slide 20 So the question is who is the culprit of this situation? For sure a question mark related to diabetes, a question mark related to ESA resistance and maybe haemoglobin variability but we have no data on that and on the level of renal function deterioration Slide 21 but I think that it is important to consider this interpretation of the data considering that for sure there is a clear association between the CRP level, you can see there is an increase in cardiovascular mortality as soon as the CRP levels are increased. The

13 same is true if you are considering the proteinuria in this patient population. So what does it mean? Does it mean that for sure inflammation seems to be very important and also the activity of the disease seems very important? If you have very active disease and proteinuria for sure is a marker for this activity, you can see you have a clear association between higher levels of CRP and higher levels of proteinuria and the risk of cardiovascular events. Slide 22 So another problem is why is the cardiovascular risk particularly increased in nondialysis patients? Because we are expecting exactly the opposite because in nondialysis patients normally the ESA doses are lower than in dialysis patients for sure and haemodialysis patients have higher post- dialysis haemoglobin values due to the hemoconcentration related to dialysis particularly in some patients. Of course, normally haemodialysis patients receive more IV iron and for sure we are aware of the fact that the patients on haemodialysis have more comorbidities than the other ones. Slide 23

14 So the FDA clearly modified the level according to the results of the TREAT trial so I don t want to go into detail because my topic is mainly related to the interpretation of the KDIGO guidelines Slide 24 but in general I think that the FDA clearly underlined the differences between the patients on dialysis and non- dialysis and of course the treatment with ESA should be considered only when the haemoglobin level is less than 10 g/dl. Slide 25

15 I think that maybe according to the results of the TREAT the approach in my opinion is a little bit strange, more conservative in patients not on dialysis than in patients on dialysis. This is a strange point considering the hemoconcentration that the patient has on dialysis. So at the end of dialysis you can have very high levels of haemoglobin with the same pre-dialysis level as in patients not on dialysis. Slide 26 So, I think my comments were related to the first draft Slide 27

16 and I have told you already that in my view I don t know the final guidelines because are not available but according to Doctor Parfrey s presentation I think that the guidelines are much closer to the European point of view than before. You know that the grade related to level 1 is we recommend and to level 2, we suggest. Slide 28 Also grading the recommendation, level A is high quality level, high quality of evidence and B is moderate, while for C and D you know it is low or very low. So I think that is important to take into consideration. Slide 29

17 We have already the major points of these guidelines and of course, we fully agree that before starting the treatment we should take into consideration all these aspects together. So I don t think there is disagreement on that because this is common sense. We agree particularly to take into consideration caution when the patients have a history of stroke or history of malignancy. Slide 30 I think that in general you can see here the recommendation is not to have Hb above 11.5 g/dl but I think in general it s a good recommendation so there s not too much to discuss.

18 Slide 31 There is full agreement to avoid haemoglobin level above 13 g/dl and this is absolutely important. Slide 32 This is the reason why in the previous position statement related to TREAT the European Renal Best Practise Group underlined that the target between 11 g/dl and 12 g/dl should be maintained avoiding to intentionally reach the target above 13 g/dl. Slide 33

19 So this was already the opinion of the European Renal Best Practise Group. You can see here the many comments we made mainly related to avoid the risk of stroke. This is absolutely important. Avoiding these transfusions is important. Let me underline that very recently there was information,i would like to underline this point, that now transfusions in the United States are increasing again after many years of decreasing the transfusions and possibly this is related to the new FDA level and this is something that we have to follow with great caution in order to avoid this problem. Slide 34 I don t want to discuss this point too much because there is a general agreement about the risk of transfusion because it was already underlined by the previous speaker. Slide 35

20 But it is important to be aware of the fact that even in the randomised controlled trials, the percentage of the transfusion was higher in the lower haemoglobin level than in the higher haemoglobin target. You can see here also in the TREAT 14.8 g/dl versus 24.5 g/dl. In the CREATE it was almost more or less the same; different in BESARAB trial. Slide 36 So I think this risk is very well-known Slide 37

21 and particularly you can see that if you don t treat the patient, the risk of transfusion increases when the haemoglobin level decreases below 10 g/dl Slide 38 and of course, if you treat the patient with iron, Slide 39

22 with ESA, Slide 40 with the combination of both you are able to reduce dramatically the need for transfusions. So I think this is absolutely important to take into consideration. Slide 41

23 Ian MacDougall very clearly underlined the potential hazard of blood transfusion, so I don t want to discuss this too much. Slide 42 Unfortunately the instruments that we have for measuring the quality of life are not so good. So all the results related to the quality of life are someway jeopardized by the instruments that they are using to measure that. So because we do not have the right instruments you can t say that the quality of life was not different between the two groups. Slide 43

24 Possibly we were unable to catch what the patients everyday are telling us, doctor I m feeling much better than before and No, you are wrong because the instruments are saying the level of quality of life is the same. So I think we should try to improve these aspects. Slide 44 Also in the TREAT trial there was a statistical significant difference between the two groups favouring the high haemoglobin level but from the clinical point of view that is the relevance of these results is matter of discussion. Slide 45

25 Of course, we have to take into consideration also the opinion of the patients and this is why I fully agree with the comments related to the new KDIGO guidelines that in order to treat the patient with a history of stroke or with a history of malignancy the opinion of the patient is of paramount importance in deciding the target to be reached. Slide 46 The problem is that before we had only one player in the field : the haemoglobin target, now we have to take into consideration at least 4 players, the haemoglobin target, the amount of ESA to reach the target, the amount of iron to reach the target and the comorbidities of the patient. Slide 47

26 I think we have to take into consideration all these aspects together in order to be sure to be in the right direction for making the right decision. Slide 48 So I think that the position statement of the KDIGO that was published in 2008 Slide 49

27 was clearly underlining to maintain the target between 9.5 g/dl and 11.5 g/dl avoiding to reach an intentional haemoglobin level above 15 g/dl. I think there is not much difference now between this approach and the previous one because the flexibility and the individualisation is in some way reducing the difference between the opinion of the KDIGO and the previous opinion of our guidelines. Slide 50 I think the major problem is related to the interpretation of the TREAT trial because it was supposed to start the treatment when the haemoglobin level was 9 g/dl but you can see here very clearly that while the experimental group reached 12.5 g/dl the control group was exactly in the level suggested by the guideline. Slide 51

28 So we have a grey area between 9 g/dl and 10.6 g/d. Slide 52 We don t know exactly what is the risk of maintaining the patient below 10.6 g/dl because it s true that almost 50% of the patients 48% of the patients received darbopoietin in the control group but the median dose was zero. So that means that the patients didn t need at all any treatment for maintaining this haemoglobin level because at the end of the trial the control group reached a haemoglobin level of 11.4 g/dl. Slide 53

29 So, I think that in general we can say that now the difference between the European point of view and KDOQI guideline are much less than before. Slide 54 So the opinion of the guidelines and the European point of view is more or less the same so we just have to discuss some details because the previous, the first draft was modified in order to try to avoid a too rigid approach and the flexibility is of paramount importance because I used to say that the guidelines are for the population while the doctor is for the patient. Thank you. Slide 55

30 Chairman: Francesco I think we have gone into all the details now. Can I just ask you a question about the process? Because I think people are getting a little bit confused about the different organisations producing guidelines KDOQI, KDIGO, ERBP and actually you took a lead in coordinating this effort and publishing the paper in KI as a first order in 2008 where everybody said we ll stop guideline production in this field we ll wait for KDIGO to take it on once TREAT has been published. Now we are there according to the timeline the workgroup submitted the draft to public review and everybody had a chance to comment it s about what we published now. Are you pleased with this process or would you like to make any comments about this? Prof. Locatelli: No as you know I am together with one of the people who initiated the process of KDIGO as a sort of internationalisation to avoid duplications of the guidelines. So I think that s of paramount importance. This is why the ERA- EDTA decided to not have I don t know if forever but not to have a guideline just to duplicate the previous guideline. So thus KDIGO is the master guideline to be followed. But of course time to time we have to look at the guidelines to see if really they are representative of the different countries point of view. So not to make new guidelines but to have a comment or the position statement saying we agree 90% but maybe this point is not the same in different countries. In Europe for example, the individualisation of the treatment is of paramount importance but now the KDIGO guidelines have received the message because the concept of individualisation is stronger than before. So I think commenting and saying we agree because if you look at the composition of the group maybe you will find too many nephrologists from the United States for example. So the European nephrologists could ask are KDIGO guidelines really representative also of the European point of view? So the position statement could say 90%, 80%, 99%, 100% whatever you want according to the analysis of the group. Chairman: You want 100% of course. Prof. Locatelli: No this 100% is something that is always suspicious. Chairman: So I thank you very much I would like to thank all the speakers because it was a tour de force to be able to speak about this subject so clearly. Thank you very much and I close the session now.