CME Slides Forum - J.J. Beutler

A joint Congress by ERA-EDTA and ISN

RESULTS OF THE STAR STUDY

Jaap J. Beutler, 's-Hertogenbosch, Netherlands

Chair: Alain Meyrier, Paris, France

Marius Miglinas, Vilnius, Lithuania

beutler

Dr. Jaap J. Beutler
Jeroen Bosch Hospital, Den Bosch
University Medical Center
Utrecht, The Netherlands

Good morning Ladies and Gentlemen, Mr Chairman. Thank you for the opportunity to present our work here today.
What I show here is the painting from our most famous citizen, Jeroen Bosch, the name given to our hospital and this famous painting is the Last Judgement.

You don’t have to write down all the information because our study has recently been published on the website of the Annals of Internal Medicine and it will be published in print next month.

but in part of the patients the stenosis will progress to occlusion, as you can see in this slide. Also the renal failure in these patients might be progressive. In more than 50% of the patients presented to us to undergo stenting had progressive renal failure in the year preceding the stent placement.

Stenting an atherosclerotic renovascular renal failure has become booming business especially in the United States

and observational and post hoc analyses show the following results which I have reviewed for you in this systematic review. In 16% of the patients you see an improvement, it remains stable in 66% and it gets worse in 18%.

Interpretation of this data depends on how you look at it. If you have a treatment bias like most doctors you say this is a great success.

We stabilized the disease in many of them and even got an improvement in some of them. But if you look from a different angle, you can say we didn’t do anything in most of them and some of them got serious complications.

The complications are seen in some cases and this is a meta-analysis of the complication rate. Some die after stenting, some got dialysis dependent. There are a lot of other minor complications.

We are all focused on the renal artery stenosis, the so-called oculo-stenotic-stent reflex and if we see a stenosis we want to proceed to stenting.

However we forget what’s going on beyond the stenosis and in the kidney. There is segmental stenosis in the small renal arteries. In the kidney there’s nephroangiosclerosis and there’s also atheroembolisation either spontaneously or after many interventions in these patients with a high comorbidity of cardiovascular disease.

The driving forces for atherosclerosis are also the driving forces for glomerulosclerosis. Glomerulosclerosis is a renal form of atherosclerosis.

Also the targets for treatment for glomerulosclerosis are the same as for atherosclerosis as I can show here for patients with renal artery stenosis.

ACE inhibition in patients with diabetic nephropathy or proteinuria have been proven to slow down the progression as shown here also in patients with atherosclerotic renal failure, the use of ACE inhibitors is associated with a decrease in loss of renal function.

Statins. There is increasing evidence that statins can slow down the progression of renal failure in patients with atherosclerotic disease.

So all in all it was time for a randomized trial comparing stenting with medication versus medication alone.

The main objective of our study was to determine the efficacy and safety of stent placement in patients with atherosclerotic renal artery stenosis and renal impairment.

In our study 9 hospitals in the Netherlands and one in France participated. Inclusion started in 2000 and ended up in 2005.

Patients could enter the trial if they had renal failure defined as a creatinine clearance estimated by the Cockcroft-Gault method of less than 80 ml/min and had to have an atherosclerotic ostial stenosis with a computer-generated block randomization and we stratified for uni- and bilateral stenosis and for site.

The medication was the same in both groups that received up to 4 antihypertensive drugs, a fixed dose of a statin, they received aspirin and got lifestyle counselling to stop smoking. The stented patients were treated all with the same stents, the Palmaz Genesis, Balloon expandable stent. All ostial stenoses were treated with these stents and a truncal stenosis was treated alone.

The primary endpoint was a 20% decrease in creatinine clearance. That had to be confirmed within one month if they started ACE inhibitors or ARBs during the trial it had to be stopped and confirmation within 4 weeks and in the stent group it had to be persistent after a re-intervention because death and renal failure are related and early death could have influenced results.

We also looked at the following secondary endpoints and in this presentation I will not address quality of life and cost-effectiveness.

We assumed an untreated patient should have progression of the disease in 50% of the patients in two years of time and stenting could reduce it to 20%. Considering a drop out we needed 140 patients to prove efficacy of the stent.

Patients were followed up for 2 years, every 3 months we saw them on the out patient polyclinic. The analysis was predefined in subgroups, unilateral stenosis and bilateral stenosis and analysis was performed on the intention-to-treat principle.

A repeat angiography was performed for safety reasons in those patients who had therapy refractory hypertension, a 20% decrease in creatinine clearance, flash pulmonary oedema with intolerance to ACE inhibitors or a hypertensive crisis.

We started with 140 patients due to the block randomization with a slight difference in the number of patients as you can see here

and here are the baseline characteristics. As you can expect, there are all the patients at a mean creatinine clearance of 45 ml/min, slightly hypertensive of course a big vascular history a lot of current smokers and it is of note that more than 50% of the patients used already an ACE inhibitor or an ARB and 3/4 of them were already using a statin.

Prior intervention and diagnostic procedures were comparable in both groups. Unilateral and bilateral stenosis were equally distributed among the two groups. The mean degree of stenosis was 77% and 3/4 of the patients had a stenosis of more than 70% in our trial.

Of the 64 patients only 46 patients received a stent indeed. A number of stents was not placed in 80 patients because mainly the stenosis was less than 50%.

As the same in the ASTRAL study this was caused because one of the inclusion criteria were MRA and as shown on this slide you can see a MRA stenosis which could not be confirmed with standard angiography and we did not proceed to stenting.

Minor complications, we had a few and most of them were haematoma at the puncture site.

We also had major complications, we had two acute deaths one late death and one patient becoming dialysis dependent after atheroembolisation after a redo angiography. It is of note that all these major complications occurred at different sites with different radiologists and all had more than 10 years experience with renal artery stenting.

The right side tight stenosis, stent was placed successfully only one hour after the procedure he complained about abdominal pains, had extravasation of contrast, a big retroperitoneal haematoma, the patient was sent back to the -- and the artery was embolised. Unfortunately the patient died in hypovolemic shock.

In both arms we lost two patients in follow up and in the end we analyzed 74 patients in the medication group and 62 patients in the stent group.

Here’s the primary endpoint a 20% decrease in creatinine clearance no differences between the two groups. The first time to renal event was 10 months in both groups

and here they are plotted in the Kaplan-Meier estimate to endpoints over time. Also in this analysis no differences between the two groups.

Also the composite endpoint of decrease in creatinine clearance and death, we saw no statistical significant difference between the two treatment arms.

Also if we plot a Kaplan-Meier curve, no differences between stenting and medication.

As a lot of patients did not receive a stent we analyzed those patients who actually got a stent compared to those patients who did not get a stent, the by-protocol analysis. Also in this analysis we could not prove any benefit of stenting.

We had predefined subgroups, unilateral and bilateral stenosis and in our analysis the type of stenosis was not an effect modifier. However, we saw a little trend for a beneficial effect of stenting in unilateral disease.

Progressive renal failure, the so-called rapid progressors are thought to respond better to stenting than patients with stable disease so we did a subgroup analysis of those rapid progressors. Also in this subcategory of patients we could not show a beneficial effect of stenting.

The estimated creatinine clearance, in the medication group the creatinine slightly declined but stayed stable in the stenting group. As you can expect, of course, creatinine clearance is related to serum creatinine also the same pattern. Patients becoming dialysis dependent were comparable in the two groups.

Secondary endpoints there were too few to draw a firm conclusion. Only we saw three patients with therapy refractory hypertension and one with flash pulmonary oedema in the medication group leading to stenting in the end. Cardiovascular mortality and overall mortality were comparable in both arms.

Blood pressure, no differences between the two groups with a slight tendency of a little bit less medication in the stent group as compared to the medication group.

Summarizing the trial we found no clear effect of stenting on the progression of renal failure. However, we saw a small number of major complications; two acute deaths, one late death and one patient became dialysis-dependent.

The mortality rate seems high but if you look at the literature at stenting in patients with the indication of renal failure and not hypertension.

The mortality rate in the literature is also high and it ranges from 0-11% with a rated average of 3.4% comparable to our trial.

The medication group, we saw a low rate of progressors lower than anticipated, it meant that the study was underpowered which was good for the patients bad for our trial.

How can we explain the low rate of progressors? It could have been a selection bias in our trial that those patients with more severe disease were sent to other centres and not entered into the trial. It could be that the studies, the few studies about natural history were wrong, they had probably also a selection bias, they included only the worst patients that were too bad to undergo stenting operation. Or another explanation is that the natural history has improved with the widespread use of ACE inhibitors, statins, aspirin, stopping smoking and other lifestyle improvements. To my opinion it will be a combination of these things.

Making up the balance of our trial we could prove no clear benefit of stenting on renal function. However, because of the wide confidence intervals we cannot exclude a possible small beneficial effect.

However, we saw serious complications and our conclusion of our trial is that we favour a conservative approach to those patients consisting of cardiovascular factor risk management without stenting.

My overall conclusion of our trial and that from the ASTRAL reminded me of another painting of the name giver of our hospital Jeroen Bosch, here showing a quack performing an operation on this poor man who’s looking to you asking for help and this is symbolizing an allegory of Jeroen Bosch for the -- principle. This man with despair in his eyes is asking us please let this man stop doing this operation with no proven benefit, potentially harmful and costing a lot of money. Jeroen Bosch gave him a funnel on his head to symbolize the outflow of the knowledge from his brain and this empty headed man and Jeroen Bosch is telling us that if he continues these practices, the gallows will wait for him in the back.

Chairman: Well, thank you very much we have time for plenty of questions in fact.

Question: Thank you for this excellent presentation, excellent study. I just want to know how many patients got stenting in the medication group because you did intention-to-treat analysis and in the DRASTIC study we had the problem that half of the patients had stenting, so how many?

Prof. Beutler: In the medication group 16 patients had progressive disease, 11 of them underwent eventually a stent or PTA, 9 of these 11 patients had a persistent decrease of renal function despite the secondary intervention.

Question: No one in the medical arm had progressed to complete occlusion of the renal artery and if so what were the underlying risk factors? Does ACE or ARB or combined blockade of the RAS system lead to progressive complete occlusion of the atherosclerotic renal artery?

Prof. Beutler: I’m sorry the sound is directed to you and not to me, if I repeat your question, what are the factors causing progression of the stenosis?

Question: What about the incidence of complete occlusion of the atherosclerotic renal artery in your study?

Question: I’m interested in knowing what are the underlying risk factors? Does combined ACE and ARB therapy lead to progressive complete occlusion?

Prof. Beutler: Well, one patient with bilateral disease and one of the kidneys got occluded and there are too small numbers to allow any conclusion of risk factors.

Chairman: Well, I have a last question maybe, yes a last question, the whole session, I mean the last two speakers left me an impression of rather depression, rather depressing in a way, the results, I remember the papers by Novak patients being dialyzed and stenotic renal artery stenosis being diagnosed and you would uprate and the patients would recover renal function sufficient to wean them from dialysis. Now, aren’t we now encountering an ethical problem about stenting I mean the rate of complications yes is low but still I mean when you find that the mortality in dialysis patients is pretty high we know that but in fact, now if I had a renal artery stenosis and I was proposed a choice between medical treatment and stenting now I would hesitate, what is your opinion about that? Aren’t we heading towards a kind of ethical problem?

Prof. Beutler: I think both trials show there’s no benefit of stenting, they have complications. We cannot identify subgroups that might benefit from the treatment, so I would refrain from stenting patients. I don’t see any ethical problem because we have no information that it is beneficial.

Prof. Beutler: Professor Losito asked me if the treatment wasn’t aggressive enough. I think it can be more aggressive for that time; we gave a fixed dose of atorvastatin of 20 mg that was pretty high for that time. We achieved an LDL cholesterol of 2.0 mmol/l. We all gave them aspirin, they could have ACE inhibitors, you could be more aggressive. There are trials in cardiology comparing stenting with 80 mg of atorvastatin and that is probably more beneficial, but there is no proof. We wanted a 2 by 2 design to solve that question also but we didn’t get it funded.

Prof. Kalra: So just to respond to our chairman’s provocative question, these two great trials you know confirm the JAARSVELD trial early on the DRASTIC trial and give pretty good certainty that for the group as a whole stenting does not have a benefit. I don’t think it rules out the possibility that the careful selection of patients may define a group that do have a benefit. Neither of these trials has really looked at that specifically they were designed to look at the group overall and they produced these extremely important results but therefore I think I wouldn’t be totally dismissive of the future of stenting in very carefully selected groups. I mean I don’t know what the rest of you feel in the audience but in my own case I still search very carefully for a small group of patients who I believe may benefit from stenting but of course it’s against the background of your trials.

Prof. Beutler: I think the asymptomatic patients with moderate renal failure should not be treated. In my experience those patients that I treated with stenting are only those patients with flash pulmonary oedema which I cannot control with diuretics and ACE inhibitors. I saw in those patients an impressive improvement in renal function far more than I have seen in patients with renal impairment as indication alone. So I think the remaining but it is again observational trials and remember the rationale of all these trials were also all those observational post hoc analyses showing beneficial effects. So I’ve become a little bit reluctant now to rely on your own observations alone.

Prof. Kalra: Yes, I would just like to emphasize that finishing my presentation I did say that I still believe that there is a small subgroup that we should identify who do benefit. Only a year ago I had a patient who presented with a creatinine of 700 and had bilateral occlusion having known that they had an occlusion the year before and 60% stenoses on the other side and this patient went straight off dialysis with stenting and has remained with a creatinine of 120 ever since. There are innumerable anecdotal cases we have of benefit but it’s a symptomatic patient is the key point so the overall findings of big trials like ASTRAL and STAR as Professor Wilcox says in the big group of patients overall no benefit but it definitely disguises subgroups, small subgroups where there can be some benefit and the key is to find those people I think in the future.

Prof. Beutler: I think both the ASTRAL and the STAR trial because at that time some people thought it was malpractice not to treat patients with a stent, so I think it’s certainly there’s a selection bias that more asymptomatic people entered the trial and more severely affected people were not treated in this trial.

Chairman: Ok well this will be the last word of a very interesting session. Thank you all for your attention and thank you to the speakers.