Randomised controlled trials, including CORAL and ASTRAL, have failed to demonstrate benefit of renal artery stenting over optimal medical therapy. However, a new expert consensus developed by the Society for Cardiovascular Angiography and Interventions (SCAI) and published online in Catheterization and Cardiovascular Interventions states that there are patients whose condition might be improved by stenting who were excluded from the trials. Sahil A Parikh, assistant professor of Medicine, Case Western Reserve University School of Medicine, Cleveland, USA, and the paper’s lead author, spoke to Vascular News about the recommendations.
Why was there a need to develop new recommendations for the treatment of patients with renal artery disease?
The motivation for the society [SCAI] was the emerging data in the field—not just for renal artery disease but also for other areas of peripheral arterial disease. There are few guidelines that focus not only on indications but also on best practices for the performance of the procedures. While in the United States we have appropriate use criteria for coronary intervention, there is a vacuum in the arena of peripheral arterial intervention. We reviewed all of the available data and guidelines and organised them in a single document to make them accessible for clinicians. We tried to capture what we see in clinical practice, with a focus on addressing potential gaps. Our focus was on when renal intervention represents appropriate care. The second point was to delineate the current knowledge base in these areas and try to identify the scenarios that are frequently encountered in clinical practice. And of course we wanted to present our expert consensus on how to perform the procedure safely.
What group of patients would benefit from stenting?
CORAL adds a lot to our knowledge base. And what the trial says is what the guidelines said all along: that patients should be treated with optimal medical therapy. One can argue that CORAL shows that patients who are not refractory to optimal medical therapy will not benefit from revascularisation. That is the takeaway from that study, which was done in a rigorous way. We all accept and believe its results. The problem is that there are patients who are refractory to medical therapy, and who might have been excluded from CORAL—those with progressive nephropathy that results in end-stage renal disease, or those patients with truly resistant hypertension. We can see from the curves that both the medical therapy and revascularisation arms have marked reductions in blood pressure once patients are enrolled in the trial. Whether that is a bias of patients taking part in a trial, or because medical therapy was not optimal before they were enrolled in the trial, it is hard to discern. For example, in SYMPLICITY HTN-3, where the results were surprisingly neutral, both groups showed benefit in reduction of blood pressure. So maybe there is more to it.
The patients who experience the greatest benefit, both anecdotally and in case series, are those with real “flash” pulmonary oedema. These patients frequently were excluded from CORAL. So there are gaps. In addition, the trial did not include global renal ischaemia, meaning bilateral disease, and we feel that global renal ischaemia certainly has the highest level of benefit as the stakes are higher in those patients.
The definitions of significant renal lesions have also changed. While initially in CORAL a significant lesion was 80% stenosis assessed by angiography or 60% or greater with haemodynamic confirmation, that was relaxed during the trial due to slow enrolment. Subsequently it included duplex ultrasound, CT and MRA, and those are not as accurate and have lower sensitivity and specificity compared to direct translesional mean pressure measurement or more stringent criteria, and this is something we say in the document. First, global renal ischaemia, and second, patients with certain conditions that were CORAL exclusion criteria. For example, this would include the mandate to be on three or four medications at maximal doses (as opposed to only two) with systolic blood pressure greater than 160mmHg.
CORAL has set the bar, and the guidelines go in line with the trial. You have to do a good job to evaluate the patient and identify renal artery disease in a rigorous manner. If you do that, and separate those patients out, they are the ones likely to benefit, but there is no individual randomised controlled trial data that supports that.
And we cannot forget that this is a highly complex field. If you read only the headline from CORAL, it is that renal stenting is not valuable. But when you dig into the details, there are clear areas where patients would have benefited if they had not been excluded.
How should heamodinamically significant stenosis be determined?
The major point in the document that is not commonly known is renal fractional flow reserve (FFR), as used in the coronary arteries. De Bruyne and colleagues have shown that renal FFR (Pd/Pa) correlates with physiological renin secretion and probably would allow us to discern those lesions that are haemodynamically significant from those that are not. There is a table in the manuscript that is useful to physicians—it shows that if the stenosis is lower than 50%, it is not significant. In fact there were many patients with less than 50% stenosis in ASTRAL, and those patients should never have been treated.
A stenosis of 50–70% (intermediate) can be a grey zone, and we recommend evaluation by one of three methods: measuring the pressure gradient at rest, and if the mean is >10mmHg then you have a significant stenosis; the second would be to induce hyperaemia as we do with FFR except that adenosine is not the right agent, we use dopamine or papaverine, and you have a hyperemic systolic pressure gradient >20mmHg, that also would be a significant lesion; and the last would be those with Pd/Pa of 0.8 or lower. If the stenosis is greater than 70% it is reasonable to assume that it is a haemodynamically significant stenosis. This algorithmic approach will allow us to say “Yes, there is existing atherosclerosis”, and “No, it is not haemodynamically significant”, or conversely “It is significant and therefore in the right clinical context it may be appropriate for therapy”.
Are many patients who do not fall into the category of significant stenosis receiving stents?
While that may have been a concern previously, now we have a strong reluctance to treat some patients who may benefit from revascularisation. I think many of us have patients who we have treated after careful evaluation, in whom we intervened upon and saw improvement in their clinical status. But we have to be rigorous about it. Some would argue that we have gone too far and are being too restrictive with those patients that might benefit from therapy.
In the document, what does each level of evidence category encompass?
This is an expert consensus document, so that is a level evidence C. On the other hand, we review data from clinical trials and other datasets. The problem is that for many of the scenarios there is a paucity of data. There are certain scenarios, particularly those that are in the “may be” appropriate care category, where clinical discretion is applied and patients may or may not benefit but it is reasonable to consider renal intervention when the appropriate steps are taken. And those scenarios are not adequately assessed in clinical trials. For the ones included in the appropriate care category, we would support patient inclusion, and primarily those in the category of case series where there has been corelab control. That leads us to another problem with the original, early trials: the lack of core laboratory. They were basically based on investigator report of angiographic stenosis, for example, and lead to the same conundrum of what a significant lesion is.
Are there any trials underway in the USA looking at renal artery stenting?
To my knowledge there is not an active randomised controlled trial. In truth, I doubt that there will be again after the duration of time that took for CORAL to be completed. The appetite for that kind of study is increasingly going away.
For patients in whom stenting is recommended, what technique should be used?
This paper reviews a good deal about optimal technique for renal stenting. We recommend the use of a no-touch technique whenever possible, or a telescoping catheter, to safely engage the renal artery for multiple reasons but mainly to limit trauma at the time of engagement. We do talk about using selective angiography with appropriate catheters; we talk about the techniques to measure gradients; we review what data there are regarding embolic protection devices and adjunctive medical therapies.
SCAI aims to develop documents that are accessible to physicians, that can help organise their thoughts about a specific disease entity, in this case renal artery disease, which has a great deal of controversy after some of the randomised controlled trial data. We wanted to put it in a way that is digestible and easy to understand, and can also help to identify that subset of patients who might benefit. We did not want the baby to be thrown out with the bathwater.
To read the statement:
The SCAI Expert Consensus Statement for Renal Artery Stenting Appropriate Use and other SCAI documents can be downloaded at www.scai.org/guidelines