CAN WE PREDICT THE RISK FOR ADVERSE EVENTS? Andrzej Wiecek, Katowice, Poland

Transcription

1 CAN WE PREDICT THE RISK FOR ADVERSE EVENTS? Andrzej Wiecek, Katowice, Poland Chair: Kai- Uwe Eckardt, Erlangen, Germany Pierre- Yves Martin, Geneva, Switzerland Prof. Andrzej Więcek Departm ent of Nephrology, Endocrinology and Metabolic Diseases Medical University of Silesia Katowice, Poland Slide 1 Slide 2

2 This is a nice overview prepared and published by Ian Macdougall showing the history and development of erythropoiesis- stimulating agents through more than 20 years. I had the pleasure and also performe some activity working with this new compounds from the very beginning since the end of the 80s when the first erythropoietin alpha and beta were introduced into the market. Slide 3 As you are probably aware, the new erythropoiesis- stimulating agents is also licensed, at least in the United States, for haemodialysis patients, is peginesatide which will have the name OMONTYS. (ATTENTION!!! This drug was already withdrawn from the market because of severe, life-threatening adverse reactions) So as you see there is a long history and we were very happy and proud to have this

3 new compound because we were able to treat anaemia, one of the most important and severe conditions in patients with CKD. Slide 4 However, even for experienced doctors treatment of anaemia with erythropoiesisstimulating agents is still a big challenge and as you can see it is not always very fortunate. Slide 5 What do we know about the treatment of anaemia nowadays in 2012? First, that treatment with erythropoiesis stimulating agents is relatively well- tolerated and the most important thing is that using ESAs we can reduce the need for blood transfusion

4 which was quite nicely presented by Professor Ian MacDougall before. However, we also know that higher haemoglobin concentration obtained with higher erythropoiesis- stimulating agents may lead to increased risk of adverse events, especially related to cardiovascular events. The second problem is the improvement of the patient s quality of life. We were at the beginning quite certain that this is true. However, now we know that the relationship for most subscales, particularly those like vitality, exercise capacity is sigmoid. So the major increases, major improvements of the quality of life occur between haemoglobin concentrations of 7 to 9-10 g/dl and then this is not so obvious, especially at the high levels. Slide 6 So from the observational studies we know that with improving of the haemoglobin or haematocrit level we can reduce the risk of mortality and reduce the risk of cardiovascular complications. This was presented in many publications and in many ways from different registries but it was just based on observational studies. However, in the prospective randomised clinical trials these results were not so obvious, not so clear. Slide 7

5 You see here there s a list of 5 larger prospective trials: Normal Haematocrit Clinical Trial, the Canadian Trial, CREATE, CHOIR and TREAT and in each of these prospective studies both in haemodialysis patients and non- dialysis patients with the increase of haemoglobin concentration or haematocrit there was increased risk of cardiovascular risk, thrombotic risk, also a possible effect on cancer development and even a possible increase of death. Slide 8 So you can see here for example the Besarab Normal Haematocrit Trial with haematocrit 42 as a target. The risk of obtaining the primary endpoint was not significantly higher but it was higher. Slide 9

6 But it was significantly higher in the CHOIR study in non-dialysis patients. You see here there s a composite endpoint obtained in these patients treated with erythropoietin and it was significantly higher in those targeted to haemoglobin 13.5 g/dl in comparison to those with lower target of haemoglobin concentration. It was quite surprising that this study was terminated before the end because of this unexpected increase of complications mostly from the cardiovascular system. Slide 10 Another prospective trial the CREATE trial did not show any difference between the higher haemoglobin as a target in comparison to the lower haemoglobin as a target. Slide 11

7 So the question arose what are the potential mechanisms of increased cardiovascular risk in patients treated as a target higher haemoglobin levels? So there are probably several potential pathomechanisms of this increased risk. Of course, one of the most important is the increase of blood pressure and I will go a little bit later into the details. Increased blood viscosity, post dialysis hemo concentration in haemodialysis patients with a large weight gain, oxidative stress from intravenous iron which normally also is present with high doses of EPO and high target haemoglobin and finally the direct effect of erythropoietin or other erythropoiesis- stimulating agents directly on the cardiovascular system. Slide 12 The hypertension has been described many times and it s a symptom which occurs during the treatment of ESAs in all subjects also in normal subjects, first phase II trials

8 also in haemodialysis patients, non- dialysis or PD patients. This is very common that the blood pressure is increasing during the treatment. Slide 13 It was even observed in the pre-esa era, as you see from Neff who increased the haematocrit using the blood transfusion and when he increased the haematocrit up to 43, he reduced the cardiac index and at the same time significantly increased in this situation diastolic blood pressure. So it was just obtained with the blood transfusion. Normally the increase of the haematocrit was associated with an increase of blood pressure. Slide 14 What he stated at that time, it was 1971, that anaemia of chronic renal failure may

9 What he stated at that time, it was 1971, that anaemia of chronic renal failure may actually serve to protect patients from the effects of otherwise devastating hypertension. Slide 15 So therefore, when you normalize anaemia, you increase the blood pressure. There are several pathomechanisms which clarify why the blood pressure is increased when you normalise haematocrit. You see for example, in anaemic states the blood viscosity is decreased, vascular resistance is also decreased because of the hypoxia- induced vasodilatation and the cardiac output is increased. The blood pressure is relatively low. When you correct anaemia, you increase the blood viscosity, you eliminate this vasodilatation related to anaemia, so the vascular resistance is increased and at the same time cardiac output is decreased but finally the blood pressure is increased. Slide 16

10 So there is a nice scheme showing what the pathomechanisms of cardiovascular risk are. It is increased viscosity, loss of hypoxic vasodilatation, activation of several neurohumoral systems and also direct effects on the vascular wall, mitogenic effects, platelet- dependent mechanism, increased calcium uptake and endothelial release. So different pathomechanisms induced by EPO or other ESAs related to increased blood pressure. Slide 17 It is known now that when you activate the receptor with EPO, this is the activation, you activate at least some thousands of different pathways. Slide 18

11 So it is difficult to predict what the final effect of the stimulation of EPO receptor is. Of course, we would like to activate the erythrocytes proliferation and finally increase the number of erythrocytes and also haemoglobin concentration. Slide 19 However, we also induce other effects activating the receptors which are located on endothelial cells, cardiac tissue, renal tissue etc.. so the erythropoietin receptors are located everywhere almost, also in the brain therefore you receive also another effect not only activation of the erythrocyte proliferation. Slide 20

12 So therefore, you see here that when you treat the patients with erythropoietin, especially with the high doses, you obtain different effects, as I already mentioned, resulting in hypertension, resulting in thrombosis and also increasing the proproliferative situation in the retina also giving the risk of tumour growth. Slide 21 In the TREAT study for example it was clearly shown that patients who were already with a history of malignancy developed, during the treatment with darbepoietin, cancer much more frequently than those treated with placebo. Slide 22

13 So we know already that the treatment of anaemia with ESAs is not quite safe, especially when you use highest doses. Slide 23 When do we use highest doses of ESA? We use highest doses of erythropoiesisstimulating agents when we have hyporesponsiveness. There are a lot of documents showing that the hyporesponsiveness is associated with adverse events and comorbidities. For example, the re- analysis of the Anatole Besarab study, the Normal Haematocrit study for the FDA revealed this very nice --- those patients treated with erythropoietin alpha and who needed higher doses of erythropoietin alpha, the survival was significantly lower in comparison to those who needed lower doses of ESAs and they reacted much better.

14 Slide 24 So highest doses of ESA, less ESA responsiveness was associated with poor survival. Slide 25 Also the renal analysis of the CHIOR study by Linda Szcezch pointed out exactly the same that those patients who were treated with lower erythropoietin alpha doses, had less cardiovascular events. Slide 26

15 Even our speaker Ian Macdougall published in 2002 a study with a relatively low number of subjects but with exactly the same conclusion that in those who were poor responders to erythropoietin the survival was significantly lower. Slide 27 Again Solomon did the re-analysis of the TREAT results and when he divided these patients into four quartiles, in this one the patient needed highest doses of darbepoetin and the effect was significantly lower and the haemoglobin concentration was lower and that in this quartile the patients received less darbepoetin but these effects were significantly better and the haemoglobin concentration was better. Slide 28

16 So there are non-responders and the good responders and in the good responders the survival was absolutely identical to placebo and as you remember, the TREAT study there were much more cardiovascular complications especially stroke and in the poor responders the survival was significantly lower. So it means that again the re- analysis of the TREAT showed the same, the poor responders have poor prognosis. Slide 29 Why are they poor responders? What are the conditions for poor response to ESA therapy? You know this is very well known, there is iron deficiency, inflammation, infection underdialysis that are the main factors and also a lot of less common factors listed on this slide.

17 Slide 30 I will show you several examples from the literature mostly as results from registries not prospective studies. Unfortunately we don t have prospective studies yet on this showing the same that with high doses of ESAs here for example, a large number of patients 58,000, exactly the same reaction large doses, higher mortality and higher cardiovascular complications. Slide 31 Also patients who developed cancer were treated with larger doses of erythropoietin alpha or darbepoetin Slide 32

18 in this case although those patients who developed cancer received significantly higher ESA doses. Slide 33 You know that this problem is especially important in the United States Slide 34

19 where the dose of erythropoietin is significantly higher than the other countries in order to obtain the same haemoglobin concentration. Slide 35 This is also an interesting study recently published based on the US renal data system where the patients were divided into diabetic and non- diabetic. This situation where the patients needed higher EPO were under the risk of cardiovascular complications was present only in diabetic patients. Slide 36

20 This is also a quite recent publication based on a Japanese study. In those patients with low haemoglobin who need higher ESA doses were at higher risk than those with high haemoglobin that need lower ESA dose. Slide 37 It was not related to age and the same results were obtained in younger and older subjects. Slide 38

21 Slide 39 It is interesting to show that these results are mostly related to haemodialysis patients and are not related to PD patients. Slide 40

22 So it s also interesting to say that the combination between the iron dose and the erythropoiesis- stimulating agents doses is important Slide 41 and especially on this slide you see that patients who need less erythropoietin and less iron survive better than those who need more erythropoietin and more iron. Slide 42

23 Interesting also to say is that patients who are obese with insulin resistance are also under the risk of cardiovascular complications and there was an inverse relation to HOMA index to adiponectin concentration. Slide 43 The increase of the risk related to the dose was not so clear when we used peginesatide and this poster was presented during the congress that the risk of cardiovascular complication was not so strongly related to the dose of peginesatide as to erythropoietin. (ATTENTION!!! This drug was already withdrawn from the market because of severe, life-threatening adverse reactions) Slide 44

24 Therefore, the new guidelines will be presented by Professor Patrick Parfrey. They put the attention to hyporesponsiveness and because I also was a collaborator of this new guidelines we created a definition of the hyporesponsiveness and we would like to prevent the escalation of the dose in order to reduce the risk. Slide 45 So I would like to conclude. The question was can we predict the risk for adverse events? I would like to say yes, we can predict adverse events in patients treated with ESA when?, because we should use lower doses of ESA. So the patients who need high doses are at risk. The patients who are treated also with high iron IV are at risk so we should reduce that treatment as much as possible and also patients who have cancer / malignancy or who have tumours are at risk we also should not treat these patients.

25 Slide 46 But we need prospective trials in order to clarify whether the exposure of CKD patients to high doses is really harmful and this trial is already settled, there is an acronym of the trial, 2 doses 4,000, 18,000 after randomisation and the prospective study will be evaluated. Slide 47 Thank you. Slide 48

26 Chairman: Thank you very much we have time for one or two questions. I would like to go further. Sorry. Excuse me. Question: George from Romania, Fresenius Medical Care. Do you think that reactive thrombocytosis induced by EPO was neglected in the CHOIR and TREAT study? Reactive thrombocytosis, was it neglected? Prof. Wiecek: Was reactive thrombocytosis neglected? There is no increase of thrombocyte count during ESA therapy. The pathomechanisms of increased thrombosis during ESA which is reported is related to other mechanism not only increased number of thrombocytes. There are no receptors according to my knowledge on the megakaryocytes which are stimulated by ESA. So therefore, there is no significant increase in the number of thrombocytes. Question: By the high dose of EPO? Prof. Wiecek: By the high dose. I don t have data on the high dose or the number of thrombocytes but this is a good question of course. Question: By iron deficiency, anaemia, so it leads to the active thrombocytosis, do you think it was neglected in the CHOIR and TREAT study? Prof. Wiecek: Yes we can say that it was neglected because at least to my knowledge it was not the one outcome, the one point which was analysed during this high dose treatment. Yes. Chairman: Are there any other questions? No, so thank you very much we can go further.