Thomas A Sos, interventional radiologist from New York-Presbyterian Hospital, Weill-Cornell, New York, USA, critiqued the STAR and ASTRAL trials at the recently held VEITHsymposium, in New York. His presentation was titled ‘The pseudoscience of prospective randomised trials, embolic protection devices and other myths which prevent the rational use of renal artery stenting.’ He said, “The results of the STAR and ASTRAL trials show that it is the study design and the operator, rather than the procedure, which might be the problems.”
The ASTRAL (Angioplasty and stent for renal artery lesions) trial is the largest ever randomised study to evaluate the effectiveness of catheter-based interventions in patients with renal artery stenosis. The results were published in the 12 November 2009 issue of The New England Journal of Medicine.
Jon Moss, one of the ASTRAL principal investigators wrote in the last issue of Vascular News, a sister pubication of Interventional News, that ASTRAL could find no additional clinical benefit from renal artery stenting over and above best medical treatment, at least in the short term. Also, he pointed out that there was a small and not insignificant morbidity and mortality associated with renal stenting in arteriopathic patients.
Similarly the STAR, a much smaller randomised trial including fewer than 150 patients (published in the 16 June 2009 issue of the Annals of Internal Medicine), compared medical treatment of renal artery stenosis with medical treatment and stenting in 10 European centres. The objective of the study was to determine the efficacy and safety of stent placement in patients with atherosclerotic renal artery stenosis and impaired renal function.
“Investigators in both trials found that patients who underwent stenting experienced no clear benefits, and several experienced complications, including in STAR two (probably three) procedure-related deaths. As the abdominal aorta is a very hostile environment for endovascular intervention, it is important to take into account thatoperator competence/experience varies widely in large multicentre trials. On the other hand it is relatively easier to standardise optimal therapy,” said Sos.
“Unfortunately the results of ASTRAL and STAR probably do represent real world experience. They show the results of poorly selected patients, poorly documented physiology and variable levels of technical proficiency of interventionalists,” he told delegates.
Sos argues that the biggest flaws in ASTRAL’s trial design were in patient selection. Firstly, patients were excluded from the study if their physician thought that they might benefit from intervention; indeed, of 508 patients presented to the study centre that recruited the largest number of patients, 283 patients had renal-artery stenosis >60%. Seventy one underwent randomisation in ASTRAL, but 24 underwent revascularisation outside the trial for poorly controlled hypertension, rapidly declining renal function, and to participate in another study; these are the very patients that ideally would have been included in the trial, but their results are not reported. “This is also a major potential pitfall of the CORAL trial, where patients whose physicians expect them to benefit from intervention are not excluded from the trial by design, but who may refuse to be included, because they do not want to take the chance of losing the benefit of intervention,” he said.
Secondly, Sos continued, of the 403 patients randomised to stenting, two had less than 50% stenoses and other 159 (39%) had 50–70% stenoses. Visual estimates of stenosis severity are notoriously unreliable and stenoses less than 70% are unlikely to be haemodynamically significant especially without confirmatory pressure gradients which were not measured in any of the ASTRAL and STAR patients. Hence in ASTRAL 40% of the stented group were unlikely to have benefited even from a successful intervention without complications, since they probably did not have the disease, “ischaemic nephropathy”, in the first place.
Another major flaw in the ASTRAL study is the variability of operator (in)experience – there were at least 56 participating centres, but as of March 2006 of 648 patients enrolled, only five centres entered more than 30 patients, half of whom would have been randomised to medical therapy only, and half to intervention, while 45 centres enrolled 10 or fewer with only half of these patients randomised to intervention.
STAR had similar, but more extreme problems. Sixty four patients were randomised to stenting. Of these 18 (28%) had no possible benefit since they were not stented – 12 because they had stenoses <50% and six for other reasons. An additional 22 (34%) with stenoses 50–70% had only doubtful potential benefit since they had no gradients to establish haemodynamic significance of the stenoses.
Sos emphasised that some argue that pressure gradients are not important to measure; but if they are not important, why bother to eliminate the stenoses?
Referring to excerpts from the NEJM paper reporting on the ASTRAL trial, Sos emphasised the trial design limitations. He quoted from the original paper a paragraph that said “There is a consensus, which is not evidence-based that certain groups of patients, with severe renal artery stenosis (eg those presenting with acute kidney injury or flash pulmonary oedema) should be treated with revascularisation, and such patients were unlikely to have been included in our trial. These are the very patients who should undergo stenting,” Sos said.
Sos told Interventional News, “ASTRAL and STAR demonstrate that prospective randomised studies show the results in the ‘real world’. However, combined with more successful large single centre results they also argue that renal artery stenting should be performed in only relatively few centres by very experienced operators with better results; it is probably not the procedure, but the operators that are the problem.” He told VEITH attendees that renal artery stenosis is a “portable” condition to the nearest experienced centre; procedure-related renal failure is with the patient for their entire short remaining life.