Slide 1

Thank you Professor Zoccali. It’s a pleasure to be in this symposium and to share with Doctor Port’s group, the DOPPS and the COSMOS. The COSMOS, as you see here in the name is the acronym of Current Management Of Secondary Hyperparathyroidism Multicentre Observational Study. It’s a study supported by AMGEN and Instituto of Renal Investigacion in Spain and it’s a study that really I will try to describe as preliminary data from the study because we studied it last year.

Slide 2

I will try to divide my presentation in two parts, a very short part about the consequences of inadequate control of mineral metabolism and the need for studies such as COSMOS and other studies that now are in progress. Then I will show you characteristics of the design, first baseline results from part of the cohort of this COSMOS.

Slide 3

Well as you know, PTH increases early in the course of chronic kidney disease.

Slide 4

And this gets much worse in the second part when patients are on dialysis where really numerous events of molecular changes and irreversible genetic changes occur.

Slide 5

We are all aware of these things and then we are aware about also the influence about this high level of PTH in bone, in heart and also we are aware that the poor control, inadequate control of these mineral metabolism parameters and the vitamin D, calcium and phosphorous produces irreversible molecular changes as I said and poor clinical outcomes. We learned recently that poor clinical outcomes are very important, we learned first about vascular calcification and in relation with fractures.

Slide 6

New recent studies have demonstrated this relationship but we also learned recently that these 2, vascular calcifications and fractures independently are related with mortality. That means that it’s quite a vicious circle that we have to study.

Slide 7

Why COSOMOS then? Well, because really now new drugs are available to treat secondary hyperparathyroidism and all these related disorders and we are thinking that this may change the scenario and we are looking for better clinical outcome, we are using new drugs and we are looking for better outcomes. Then we need, as was said before, prospective studies to know the impact of these new strategies in current practice because really this is an observational study just in current practice for 3 years.

Slide 8

Then the COSMOS was designed as a prospective multicentre observational non-interventional cohort study. This is the real life what we are doing with our patients throughout the next 3 years. As Professor Zoccali said it is a web-based database, there is no paper there, it’s all electronic and we’re going to collect clinical parameters and outcomes from about 5700 patients who were randomised selected according to the number of haemodialysis per country from 20 countries. I’m trying to make a homogenous distribution, for example, huge country, I would say Italy is a large country and then it is not maybe the same in the North and in the South, we try to make the randomised in 3 areas and the same for Spain, the same for France, the same for all big countries, Germany and so on. Then we’ll have participating 285 centres is there. The number of sites in the 20 countries are here. Of course, the countries with a greater population of patients on dialysis have more sites than countries with less patients on dialysis.

Slide 9

The main objective of the study is going to be to investigate the K/DOQI target achievements in this representative sample of the Pan European Population on dialysis by type of dialysis, type of centre and time on dialysis. We are trying to divide and I’ll show you some of the preliminary results about prevalent patients or say less than one year and patients with more than 1 year on dialysis and as I said before the duration of the study is 3 years.

Slide 10

Another primary objective that is quite important I mean that is needed is to estimate the association between these K/DOQI target achievements with 2 very important outcome parameters, mortality and overall cardiovascular hospitalisation. Also to characterise the longitudinal changes in bone markers we are going to measure every 6 months and describe the patterns able to predict these outcomes. That means using these repeated measurements on individuals over time we’re trying to see if some of them will help us to prevent or to know in advance data related with outcomes.

Slide 11

Secondary objectives are to estimate also the association between K/DOQI target achievements and specific cardiovascular outcomes. We are all interested in parathyroidectomies, relevant bone diseases including Symptomatic Bone Fractures because it’s the only thing we can collect. You do not need a special study to study morphometrically bone fractures. Hospitalisation and vascular access. Also what is very important to evaluate the additional value of albumin and haemoglobin levels together with bone mineral markers in the prediction of mortality and clinical events.

Slide 12

The study was designed at the end of 2004 and at the beginning of 2005. The first patients were included in the Spring of 2005 and the first set of patients recruited that I’m going to show you the data of are from these 6 months until September last year but really now and we’re going to present this if we can in the American Society of Nephrology, we’ve got almost 80% of the sample completed and then we hope to have all the samples completed quite soon, maybe in Autumn.

Slide 13

You can see here, this is the data I’m going to show you comes almost for 50% of the sample because comes from the patients analysed until the end of last year and then it’s about 50% of the total population we want to have from 143 facilities and from 16 European countries because some of the 20 European countries started later and the data were not available when we decided to do it. As you can see here, this is the number of patients and of course, big countries, for example, like Spain entering at the beginning and completed the study have 400 patients but also Germany and France a lot of patients but with half of the sample completed by now. This is just an estimate about the progress of this study.

Slide 14

We’re going to analyse some of the details about the baseline demographic characteristics of the study. You can see here this data will maybe appear later on but I will try to point out just those data I consider important because they are preliminary data and then if we look at the age and we’ll see now that this is more than 1 year and less than 1 year we’ve got a cohort that is 20% of new patients and the other 80% are old patients on dialysis, patients with more time on dialysis and we will see that there are some differences in these 2 cohorts. Also we’re looking at the age, we’ll see that there are no great differences between the patients with more time on dialysis, less time on dialysis roughly we’ve got 55% of patients older than 65 like other studies have shown.

Slide 15

What about other variables like diabetes? Again this is quite an interesting result. The mean is 30% but you can see here you divided more than 1 year and less than 1 year the patients who started dialysis recently 40% the number of diabetics that is an important number to mention. Also when we go to the type of calcification, you see that as we expected vascular calcification were the more common being around 65% independently of the time on dialysis and it was by far more common than the other type of calcification like valvular and soft tissue calcification.

Slide 16

Now, I’m sorry I have to tell you that before the less than 1 year was on the right, I’m sorry, less than 1 year now is on the left and you’ve got here less than 1 year more divided between 1-5 years on dialysis and more than 5 years on dialysis. You will see here that we are having progressively less men, at the beginning was 55-60 and 63, that was significant.

Slide 17

And we’ll see body mass index, we are clearly seeing that new patients, less percentage of patients with less than 20 meanwhile according to dialysis time is passing the number of patients with less than 20 is increasing and it’s exactly the reverse for those more than 30 of body mass index.

Slide 18

What about haemoglobin and serum albumin? O.k. both are significant. It’s clear that patients are new patients have a lower level of haemoglobin than those stable on dialysis that means that there’s an indirect message that we have to do work of course in predialysis in this issue. We are really in the level we know that it is important to have patients but lower than the others and serum albumin even though it’s significant I think it’s maybe clinically irrelevant from 3.7-3.8 is really a small difference really in the amount of serum albumin.

Slide 19

Even though the study was not powered to compare countries and it is not the idea of the study, just to see if there are differences in the world, we called before Western countries and Eastern countries there are 7 out of the 20 countries are from the Eastern countries and here we’ve got the age at baseline in the Western countries and less than 65 and we’ve got 40% and as we expected in the Eastern countries and younger people are less than 65, we’ve got 60% of people there are more younger people in this cohort that started a bit later in the study.

Slide 20

What about diabetes? Again similar features maybe also related with the age of course. The diabetes is 32 overall in the West what you see the Eastern countries is 23 that must be partially or importantly driven by the age also. 

Slide 21

What about the typical figures we are seeing in many, many studies about K/DOQI achievements? Well, we tried to do exactly the same with them before about K/DOQI achievements at baseline and the 50% of the sample for example and as you can see here the PTH is about 28% achievement. Calcium phosphorous product 66%, calcium 55% and phosphorous 50% and all four 9% as usual. The question is well, this data has been shown many times in other studies carried out throughout the last 6 years. Can we compare this data? And I will put here the data. Again these are the oldest data as from one Spanish study it is 1998, that’s seven years from this and this and look that really the figures are almost the same. The only small difference is a better control of PTH but similar control and calcium phosphate, phosphorous really well. It was worse here the four parameters together but there was despite we started here with guidelines, the European guideline was 2000, no big changes in the control of these metabolic parameters. Again if we go back with American data 5 years later 2003, again similar figures that means that despite as I said the guidelines are in use, both the European guidelines and the K/DOQI guidelines still we don’t have really positive results in this we say one shot look for the study.

Slide 22

What about other things? We’re collecting several data, for example, medication. I’m just curious because we have been saying many, many times throughout the last 5 years that we have to increase the level of 25 hydroxy in our patients and we were positively surprised that at least 15% of patients are receiving any form of 25 hydroxy.

Slide 23

What about the new products? Paricalcitol and cinacalcet was in few patients, few percent of patients were receiving these drugs although of course, as I told you this finished in the last part of 2005 and then maybe when we’ll analyse again the sample now 80% of the sample in the next 3 months, maybe we’ll have a difference here and I hope also a difference also there.

Slide 24

What about COSMOS laboratory parameters by Vintage? I mean less than 1 year, from 1-5 years and more than 5 years. The only main difference in calcium, calcium phosphate and phosphorous was in calcium. Lower calcium concentration in those patients who were less time on dialysis, less than 1 year. We call them incident patients. Similar figures for phosphorous and the difference in calcium-phosphate is driven for the difference in calcium.

Slide 25

What about parathyroidectomy? It’s obvious that patients with less time on dialysis has less percentage of parathyroidectomy from 1-5 is in the middle and more than 5 is 20% and quite similar to the results published in several papers, I remember now a paper from Doctor Malberti and similar papers showing that more than 5 years between 15-20% of parathyroidectomy in patients.

Slide 26

What about PTH? Of course, if we are performing more parathyroidectomy, it should be because the PTH is higher and here we can see that really it’s a good picture because really we can see here that as time is passing, PTH is not controlled better but controlled worse and it’s this data that really having 400 as a mean here is in keeping with some hypotheses or some concepts we try to pass over that really when you read a PTH of 400, everything is maybe reversible but when you trespass that point really things get worse. This is the reason why according to the time passing PTH is always higher despite this group of patients are those that receive more treatment.

Slide 27

What about presence of calcification just for the x-ray? Less than 1 year 31% and more than 5 years 57%. Less than we thought because some studies --- in more than 5 years around 70%. What about the history of any event of cardiovascular disease? Like other studies showing that even the new patients, those within 1-5 years, more than 5 years all of them ¾ have a clear study of cardiovascular events.

Slide 28

Well, we’ll go now to the guidelines and to make a big critic about well this baseline data can help us to know if we are following the guidelines or not. One of the questions was, are you following guidelines? There was well 63% say we’re following the K/DOQI. 19% the European guidelines, 9% the National guidelines and no guidelines 8% of the centres. If you see these 2 and we compared these 2 with this almost 82% is almost the great part of the sample, we can see that really something that surprised us was, for example well, measurements. When you meet at least calcium, phosphorous, calcium-phosphate and PTH. 83% of centres measure once monthly which is I think the most logical way to do it but we were quite surprised that 15% of centres measured even every 6 months. It’s impossible to control calcium and phosphate metabolism, if you measure every 6 months. Then there’s a great gap to fill here which is very, very important.

Slide 29

What about the comparison of the patients following the K/DOQI and the European guidelines? They are not the same because really the targets are, for example, less rigid in calcium in the European. More rigid in the phosphate. Again more rigid in the PTH and similar in calcium-phosphate.

Slide 30

Then these columns clearly show that the patients on target according to the guidelines the blue is the K/DOQI, the red the European and of course, here are the European guidelines are less strict for calcium. There are differences and all these differences you can see here are explained because of the difference of the guidelines. But the most important question is not that one because you can be biased with this.

Slide 31

The most important question is do biochemical markers at baseline differ according to the type of guideline used?

Slide 32

Which is a practical question and the answer is no because those who follow the K/DOQI here or the European here has the mean serum calcium exactly the same, the phosphorous is the same, the calcium-phosphate is the same and PTH is almost the same.

Slide 33

I mean that despite you can have the idea that because the guidelines are quite different when you look at these results you are surprised because really they are not deeply or they are not fully following the guidelines at 100%.

Slide 34

Well, and this is a summary and final slide there are significant and relevant patient differences depending on Vintage that is important I think body mass index and haemoglobin and also serum albumin but I said maybe clinically irrelevant. Serum calcium as serum calcium-phosphate product and PTH changes according to time which is something we expected and the incidence of parathyroidectomy, vascular calcifications and cardiovascular disease also increase according to time passing that is important and was known.

Slide 35

I don’t want to leave without thanking all the National coordinators of the study. Really this is a tremendous effort because this is a study that really is time consuming. There are 20 patients per centre but they have to be updated every 6 months and it is almost I would say on a voluntary basis, this thanks is a great big thanks for all of them and for all the sites, centres that are collaborating in this study. Thank you very much.