LDL-CHOLESTEROL AND CV RISK IN CKD: EPIDEMIOLOGY VS. CLINICAL TRIALS David Wheeler, London, UK

Chairs: Maurice Laville, Lyon, FranceErling B. Pedersen, Holstebro, Denmark

Prof. David WheelerCentre for Nephrology Royal Free Campus University College London Medical School

London, UK

Slide 1

So, these are my disclosures and I don't think any of them are particularly relevant to thetalk.

Slide 2

So, my topic is LDL cholesterol and cardiovascular risk in CKD and I was asked to compare theepidemiological data with the data that we've obtained recently from randomised controlledtrials.

Slide 3

So these are the latest data I could find from 2009 looking at the epidemiological associationbetween here non-HDL cholesterol, which you can read as LDL cholesterol, and the hazardsratio for coronary heart disease. You'll see here adjusted data, adjusted for age and sex incircles and further adjusted for other cardiovascular risk factors in squares in 300.000patients or people rather who didn't have vascular disease or didn't have overt vasculardisease at the time these cholesterol measurements were taken. So, these individuals werethen followed up and this is the hazards ratio for coronary heart disease events during thefollow-up period. You can see as we're all well aware that the higher the baseline cholesterolconcentration, that's the non-HDL or LDL cholesterol concentration, the greater the hazardsratio for a coronary heart disease event.

Slide 4

If we look at these data more closely, we can calculate that for a 1 mmol reduction in LDLcholesterol, we would see or

Slide 5

we would expect to see a 40% reduction in the hazards ratio for a coronary heart diseaseevent, this is what the epidemiology tells us.

Slide 6

The reality from clinical trials is not quite the same. So, what you're looking at here is a plot ofdata from all the major statin studies. The bigger the study, the larger the square and we'recomparing here the proportional risk reduction for major coronary events in these trialsagainst the reduction in LDL cholesterol that was achieved. You can see here a very nicerelationship. The bigger the reduction in LDL cholesterol, the bigger the proportional risk ofcoronary heart disease events.

Slide 7

Remember the 40% from the last slide that we expected from the epidemiology, if you look atthe clinical trials from 1 mmol reduction in LDL cholesterol we actually see a 22% reduction inthe risk of coronary heart disease events. So, something like half the reduction that wepredicted from the epidemiological relationship which isn't perhaps surprising because ofcourse, these trials treated patients for only around 5 years and the exposure to the LDLcholesterol in the epidemiological studies lasts a lifetime. But these trials, of course,encouraged us to use statins in patients who are at high risk of major coronary events andmore recently, we've extended the use of stains into primary prevention based on the resultsof some of these studies.

Slide 8

Now the situation in patients with kidney disease is slightly different and the epidemiologylooks rather different. So, you're looking here at data from the UK Renal Registry that collectsbiochemical information from now all patients dialysed in the UK and you're looking at therelationship between serum cholesterol and the hazard of death. So this isn't specificallycardiovascular death but it is death. But what this shows us is a reverse relationshipbetween serum cholesterol and the hazard of mortality. This holds both in haemodialysispatients and in peritoneal dialysis patients, the lower the LDL cholesterol, the higher thehazard of death.

Slide 9

This is the wrong way round. O.K. you may say but we're looking at total mortality here butthen let's look at cardiovascular death and here are data from 3 studies of dialysispopulations again examining the relationship between total cholesterol and the relative riskfor a cardiovascular death. Again, we see this reverse relationship. Certainly, in this study byKilpatrick and this study by Degoulet the higher the cholesterol, the lower the risk ofcardiovascular death and the lower the cholesterol, the higher the risk of cardiovasculardeath. This is the wrong way round. This might discourage us from lowering cholesterol inpatients who are receiving dialysis.

Slide 10

How about patients who are not on dialysis but have CKD? The data are not so good. This isa small study from Birmingham of patients who attended a nephrology clinic and had stages3-5 of CKD but were not on dialysis. This is a relationship between the quintile of baselinecholesterol and the mortality both from cardiovascular disease in blue and non-cardiovasculardisease in yellow. You'll see here no clear relationship between the higher levels ofcholesterol and cardiovascular death. I accept that this is a small study but as I say, there arefew studies that look at the relationship between cholesterol and cardiovascular diseaseevents in non-dialysed CKD patients.

Slide 11

Now we see this reverse relationship between cholesterol and mortality in other populations.As you can see from the scan here, the quality of the scan this is an old study from 1997 butlooked at the relationship between total cholesterol and relative risk of coronary heartdisease in a very elderly population. You'll see here a fairly flat relationship but with a higherrisk among the elderly people who had the lower plasma cholesterol concentrations. It wasspeculated by these investigators that this was due to confounding. This was due to otherfactors, for example, malnutrition that both led to low cholesterol and a high risk of mortality.

Slide 12

In fact, when these investigators corrected for these factors, they restored the expectedrelationship between cholesterol and the risk of cardiovascular or coronary heart diseasedeaths. So the reverse relationships certainly in this elderly population is probably due toconfounding and when you correct for confounding, you restore the normal relationship. Wecan do this in dialysis populations.

Slide 13

So you saw these data on a composite graph a few slides back. The relationship betweencardiovascular mortality and blood cholesterol in a dialysis population. These investigatorsshowed a fairly flat relationship with the suggestion of a reverse trend here, lowercholesterol, higher risk. This is their cohort overall.

Slide 14

When they looked at those patients who had elevated inflammatory markers, high CRPs, theirinflamed patients showed a similar relationship. But when they took those who had normallevels of inflammatory markers, so normal CRPs,

Slide 15

they saw the expected relationship between total cholesterol and cardiovascular mortality inthese dialysis patients. Suggesting that inflammation is confounding the relationship betweencholesterol and cardiovascular events.

Slide 16

So we argued some time ago that the only way to really untangle the relationship betweencholesterol and vascular events in CKD patients in whom there are many confounding factorsthat make these epidemiological studies unreliable is to randomise patients and that meansconducting randomised controlled trials, which of course we have done over the last fewyears. I'm going to show you the results of these trials and how they compare with theepidemiological predictions.

Slide 17

So, if we look at statin studies from the 1990s, these are data from 3 studies that usedpravastatin in different populations of patients with vascular disease and these data this is apost hoc analysis extracting from the datasets those patients who went into these trials withstage 3 CKD. So retrospective analysis of a large dataset from 3 statin studies. But, I thinkwhat's important here is that if you look at the patients with CKD and if you look at whathappens during the trials, certainly in the secondary prevention setting here that is in thosewho'd already had a cardiovascular event there's a clear suggestion here that these patientsbenefitted from statin therapy. So lowering their cholesterol with pravastatin despite thepresence of stage 3 CKD was associated with fewer further cardiovascular events andmortality during the follow-up period. Not quite such a clear relationship here in a primaryprevention setting here and here. So, basically looking back through the datasets from thelarge statin studies, and this has been done in many of these studies, patients with stage 3CKD seem to behave in the same way as the non-CKD population in these studies.

Slide 18

Now in the late 1990s we set out to address the hypothesis that LDL lowering using a regimeincluding a statin would reduce the risk of atherosclerotic vascular events in patients withCKD. I will come back to atherosclerotic vascular events in a minute. This was, of course, theorigins of the SHARP study.

Slide 19

The primary outcome in SHARP was vascular events driven by the process we know asatherosclerosis, the occlusion of arteries by lipid plaque in the intima. So, we chose our endpoints to reflect this pathology. Death due to occlusion of coronary arteries by atheroma.Non-fatal acute myocardial infarction due to plaque rupture. Non-haemorrhagic stroke and arevascularisation procedure, which is, of course, preformed to open up artery blocked byatherosclerosis. So, the primary outcome in SHARP was a composite of these atheroscleroticvascular events. We did of course, look at other vascular events in the subsidiary outcomesincluding death due to any cardiac cause and any form of stroke including haemorrhagicstroke. We had other outcomes including progression of kidney disease that I'm not going totalk about today.

Slide 20

At the time that we wrote the SHARP protocol eGFR reporting was not widely available andstaging of CKD hadn't been invented. So, we took a fairly pragmatic approach and decided torecruit patients coming to clinic with elevated serum creatinine concentrations on twooccasions. For men that meant a serum creatinine of 150 µmol/l and for women 130 µmol /l.We also recruited patients on dialysis and out of the 9.000 or so patients we recruited at thestart of the study 6.000 had CKD and were not on dialysis and 3.000 had CKD and werereceiving dialysis. Patients needed to be greater than 40 years of age to increase the riskand from the coronary artery perspective this was a primary prevention study. So patientsdidn't go into SHARP if they'd already had a myocardial infarction or contrary revascularisationfor seizure, although we did allow other revascularisation procedures for example ofperipheral arteries and this was not an exclusion criteria. But, from the cardiac perspective

this is a primary prevention study.

Slide 21

You'll know the result of SHARP, the combination of simvastatin 20 mg and Ezetimibe 10 mg.This is a cholesterol absorption inhibitor that augments the action of the statin and reducesthe risk of the atherosclerotic events endpoint that I've just shown you by 16.5%. So takingthis result how does this compare with the statin studies in the general population?

Slide 22

So, I'm taking you back to this graph where we plotted the statin studies and we plotted the

proportional reduction in risk against the reduction in LDL cholesterol.

Slide 23

The average reduction of LDL cholesterol in SHARP was 0.84 mmol/l and we saw a 16.5%reduction in the major coronary events endpoint. As you'll see this is pretty much what wewould have expected from the other statin studies. This result falls pretty much on this linedrawn from this relationship based on the statin studies today. So in our patient populationthat was largely populated by patients who had CKD but who were not on dialysis the statinand Ezetimibe combination did what we expected it to do in the SHARP study.

Slide 24

Of course, I can hear you telling me that there are two studies in dialysis patients, whichdidn't show a benefit of statins therapy. Here they are the 4D study from Germaninvestigators led by Christophe Wanner and the AURORA study led from Scandinavia by BengtFellström. Both of these studies used a statin, atorvastatin 20 mg in the 4D study,rosuvastatin 10 mg in the AURORA study. In both studies the LDL cholesterol was reduced byaround about 0.9 mmol/l, so about the same as in SHARP but in neither study was there aclear benefit on cardiovascular events. So we have to work out why we've got differentresults from different studies. I would say up front that these studies both included acomposite cardiovascular endpoint but these endpoints were slightly broader than in SHARPand included events that you could argue were not the direct result of the atheroscleroticprocess.

Slide 25

When you look at the SHARP data, here's the result, a 16.5 % reduction in the risk of majoratherosclerotic events favouring the lipid lowering intervention. You divide the patientsbetween those who were not on dialysis and those who were on dialysis at the start of thestudy. You will see that the effect was less obvious in the patients who started the study ondialysis. Now, I should make a few points here. Firstly, if you do a statistical test to ask ifthese two are different, a test of heterogeneity, the answer is no. Statistically these tworesults are compatible. Secondly, I should point out that although these patients started thetrial not on dialysis, about a third of these patients ended up in this dialysis category by theend of the study. So there's intermixing between the two populations here. I should alsopoint out that SHARP was not powered to address the issue as to whether lipid-loweringintervention was beneficial in this smaller dialysis population. So the SHARP study was notreally powered to separately analyse these two groups but there is this suggestion here thatthese patients who are on dialysis benefited less from the intervention.

Slide 26

But let me just make another point. The dialysis patients were less likely to comply with theirtherapy. The compliance in this population was undoubtedly poorer and we collected data oncompliance throughout the study. So, if you look at the mean LDL difference between thetreated and the untreated group in the patients who started the trial not on dialysis it wasnearly 1 mmol/l but in those patients who started the trial on dialysis the mean difference inLDL was much less, almost half that 0.6 mmol/l. This if you like lines up with the risk reductionthat we saw in these two patient groups.

Slide 27

So going back to this graph if you separately plot the patients who started the trial offdialysis, so these are the CKD patients not on dialysis at the start of the study, 22%reduction and if we look at those who started the trial on dialysis who had a lesser reductionin LDL cholesterol, we see a 10% reduction both in line with the data from the other statinstudies. So you get a lesser reduction in LDL in the dialysis patients, you see a lesser benefit.So I would make the argument that in SHARP separate analysis of these two populationsshow that we get the expected result in both.

Slide 28

One other point to make is that if we look at specific endpoints in the 4D, the AURORA and inthe SHARP study, we see a homogeneity in terms of the outcome. So what I've plotted on thisgraph here and this was published in the SHARP paper is a composite plot of data looking atcoronary revascularisation procedures in 4D, ALERT which was a transplant study, AURORAand SHARP. To the left of the neutrality line LDL lowering was better in terms of this outcomeand to the right of this line LDL lowering was not beneficial. You can see clearly here that in4D and in AURORA, although not statistically significant, the lipid lowering therapy that was

given in these studies produced a benefit in terms of coronary revascularisation. It's just thatthese results aren't statistically significant, whereas the SHARP result for this endpoint wasstatistically significant. If you do a meta-analysis and line these up, you see a clear benefitwith a p value of 3 noughts and then with 4, so highly statistically significant. So, I guess thepoint I'm trying to make here is that if you take atherosclerotic endpoints from these trialsthat have involved dialysis patients and you plot these together, the data are prettycompatible. The test for heterogeneity here once again shows that these results are similar,they're not statistically different. So had 4D and AURORA looked at atherosclerotic endpoints,rather than broader cardiovascular endpoints, there's a possibility that the results of thesestudies might have been different.

Slide 29

So, this is my summary slide. I hope I've shown you that the epidemiological relationshipbetween total and LDL cholesterol and cardiovascular risk, particularly atherosclerotic events,is confounded in patients with advanced CKD. I've suggested that the only way to establish acausal role between LDL cholesterol and cardiovascular events in these patients because ofthis confounding is to conduct randomised controlled trials. I've shown you that when weconducted those trials, when we've lowered LDL and looked at the relevant endpoint that wewould expect to change, then we see the expected reductions in relative risk associated withthat endpoint. But I would concede that the value of LDL lowering in dialysis patients remainscontroversial despite the three trials to date that I've described and that could be a topic fordiscussion if we want. Thank you very much for listening to me.

Slide 30

Chairman: Thank you Doctor Wheeler. The paper is now open for discussion. Please go to oneof the mikes and start to identify yourself. Please Locatelli?

Question: My question is from a practical point of view how many patients do we have totreat in order to save one in the different populations, in CKD not on dialysis and in patientson dialysis? Because this is for us as a clinician major information to be known.

Prof. Wheeler: Ok so in SHARP it's 40 patients with CKD over 5 years to prevent one event.It's pretty similar to the data from the general population studies. So 30-40 patients, 5 yeartreatment prevents one major cardiovascular event in the context of SHARP. As I've shownyou, that pretty much aligns with data from the other populations suggesting that thatbenefit is similar. In the dialysis population in SHARP you have to treat more patients to getthat benefit. So, you're looking at 50-60 patients treated for 5 years to prevent one event inSHARP. So, in the dialysis population in SHARP more patients treated to prevent an eventwhich you would expect from the relationship I showed you.

Question: Is this number according to the guidelines something you suggest we do?

Prof. Wheeler: Well is it worth doing? I guess is what you're asking me well that's thequestion. My own personal belief is that in younger patients this is well worth doing. So, ifyou have a young dialysis patient who is going to go on and get a transplant, whose life youknow is going to be limited eventually by cardiovascular disease, then it makes completesense to treat that patient's LDL cholesterol to reduce that risk. I think the situation is slightlydifferent in the elderly dialysis patient who has a box full of pills and can't remember which totake in whom perhaps the atherosclerotic disease is a less important factor in the eventualoutcome. So, you could argue that you should be targeting those patients, you know, whoare most likely to benefit from this intervention.

Question: Doctor Wheeler treatment is one thing monitoring is another thing. There has beensome discussion about how to monitor treatment. If you decide to treat, would you use a 'fireand forget' strategy as has been suggested or treatment-to-target? Please comment on that.

Prof. Wheeler: So 'fire and forget'. So you'll be aware that we've had a discussion in theproduction of the latest KDIGO guidelines about the value of repeated measurements of LDLcholesterol after you've treated. There is a view that whatever your risk of coronary heartdisease, you will have a lower risk if you lower LDL cholesterol. Therefore, a number of peoplehave suggested that if you simply put everybody just on the effective therapy on the statin,know you've done what you can, then you can forget about that risk factor and move on toworrying about the others. So, there is a suggestion that one of our approaches should besimply to say this is a high risk patient, I'm going to put this patient on a statin in areasonable dose that is tolerated by the patient and is safe and then I'm not going to worryabout that risk factor anymore because I've done what I can about it. There's another reviewfrom perhaps a slightly more obsessional people who argue that what you want to do isknow that you've reduced your LDL and know that if it's only so low, you might be able toreduce it further by increasing the dose of the statin of adding in Ezetimibe. So the big debatenow is after you've started the treatment do you need to monitor the effect and titrate up ordo you simply say I've treated it, I've done my best, I've given a reasonable dose of statin,I'm a busy nephrologists I'm going to move on and do something else a little bit more

interesting. I think this is the debate that we've had and it's a debate that will be reflected inthe forthcoming KDIGO guideline on the management of dyslipidaemia in CKD which we hopewill be published in June or July as a Kidney International supplement.

Chairman: Please.

Question: --- Manheim Germany. We have shown in the 4D study, I guess that you are awareof that publication, that the LDL cholesterol level at baseline determines the clinical outcomein other words that you get a highly significant reduction in events if you look into the fourthquartile which starts at an LDL cholesterol of 140, so have you done the same things inSHARP?

Prof. Wheeler: Yes.

Question: And in particular what happens to the dialysis patients? Do they show the samephenomenon, a larger relative risk reduction at high baseline LDL cholesterol levels?

Prof. Wheeler: Yes so we have to done that analysis in SHARP, it's actually in the paper butit's hidden in then paper. We see the same trend, so the higher the start in LDL cholesterol,the greater if you like there is a trend towards a greater benefit of statin therapy. We havenot done that separately for the dialysis population and the CKD populations in SHARP. I thinkour argument would be that the numbers are smaller and that the trial wasn't powered to dothat but we certainly see the expected trend across the starting LDL cholesterol categories.As in the general population your risk is higher if your starting LDL is higher and theproportional benefit is greater in those patients who have the higher starting LDL cholesterol.

Question: One could easily increase the power to look at dialysis patients separately if onelumped together AURORA, SHARP and dialysis subgroup and the 4D study.

Prof. Wheeler: So there have been plans for a patient level meta-analysis of the dialysis datain the relevant studies. I'm not quite sure where that's got to but it involves quite a lot ofwork as you'll appreciate but that's a good idea and it has been thought through andsuggested and it may happen.

Chairman: A last question for Doctor Wheeler.

Question: Chris – from Bristol. David should we risk stratify the CKD patients or shouldeverybody other than those with awful prognosis be on statins?

Prof. Wheeler: So should we risk stratify the CKD patients? I think it depends on yourphilosophy, so I think the message from the general population is if that whatever yourstarting LDL cholesterol, you will benefit by reducing that to a lower level with a statin. So ifwe were going to ration our care, if we had a budget which we do in the NHS and we wantedto target the therapy perhaps at the most relevant patients, then I think yes, it's veryreasonable to risk stratify. How we risk stratify is slightly more complicated because of coursethe epidemiological data as I've shown you don't always tell us the patients at highest risk.But my view is that here we have a therapy that's effective in patients with CKD that reducesan endpoint that's relevant. The therapy is safe and it's cheap. I would argue that this issomething we should be spending some time on rather than giving something like folic acid,which doesn't have an evidence base to support it. So I'm not in favour of risk stratification,I'm in favour of getting the effect of therapy to the maximum number of patients who will seethe greatest benefit. Sorry the maximum number of patients, all of whom will benefit I believe.

Chairman: Ok thank you very much Doctor Wheeler.