Stenting for atherosclerotic renal artery stenosis: One poorly designed trial after another

THE ASTRAL TRIAL

In the Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) trial,⁸ the primary outcome measure was the change in renal function over time as assessed by the mean slope of the reciprocal of the serum creatinine. In this trial, 806 patients with atherosclerotic renal artery stenosis were randomized to either stent-based revascularization combined with medical therapy or medical therapy alone.

Authors’ conclusions

“We found substantial risks but no evidence of a worthwhile clinical benefit from revascularization in patients with atherosclerotic renovascular disease.”⁸

Despite size, flaws remain

Unlike the other trials, ASTRAL had a sample size large enough to provide an answer. However, numerous flaws in study design and implementation invalidate its results for the overall population of patients with renal artery stenosis. The major flaws in ASTRAL were:

Selection bias. For a patient to be enrolled, the treating physician had to be undecided on whether the patient should undergo revascularization or medical management alone. However, the treatment of atherosclerotic renal artery stenosis is so controversial that physicians of different specialties cannot agree on the most effective treatment strategy for most patients.^1,2 Therefore, to exclude patients when their physicians were sure they needed or did not need renal artery revascularization is incomprehensible and introduces considerable selection bias into the trial design.

Normal renal function at baseline. The primary outcome was a change in renal function over time. Yet 25% of patients had normal renal function at the outset of the trial. In addition, a significant number had unilateral disease, and 41% had a stenosis less than 70%. What made the investigators think that stent implantation could possibly be shown to be beneficial if they entered patients into a renal function study who had near-normal renal function, unilateral disease, and mild renal artery stenosis? These are patients whose condition would not be expected to worsen with medical therapy nor to improve with stenting. Most clinicians would not consider stenting a patient to preserve renal function if the patient has unilateral mild renal artery stenosis.

There was no core laboratory to adjudicate the interpretation of the imaging studies. To determine the degree of stenosis of an artery in an accurate and unbiased fashion, a core laboratory must be used.

The reason this is so important is that visual assessment of the degree of stenosis on angiography is not accurate and almost always overestimates the degree of stenosis.^12,13 In a study assessing the physiologic importance of renal artery lesions, the lesion severity by visual estimation was 74.9% ± 11.5% (range 50%–90%), which exceeded the quantitative vascular angiographic lesion severity of 56.6% ± 10.8% (range 45%–76%).¹³

Therefore, in ASTRAL, some patients in the 50%–70% stenosis group (about 40% of patients entered) actually had a stenosis of less than 50%. And some patients in the group with stenosis greater than 70% had stenosis of less than 70%. This further illustrates that, for the most part, the patients in ASTRAL had mild to moderate renal artery stenosis.

A high adverse event rate. The major adverse event rate in the first 24 hours was 9%, whereas the usual rate is 2% or less.^14–18 Of the 280 patients in the revascularization group for whom data on adverse events were available at 1 month, 55 (20%) suffered a serious adverse event (including two patients who died) between 24 hours and 1 month after the procedure. This is in contrast to a major complication rate of 1.99% in five reports involving 727 patients.⁵

The trial centers were not high-volume centers. During the 7 years of recruitment, 24 centers (42% of all participating centers) randomized between one and five patients, and 32 centers (61% of all participating centers) randomized nine patients or fewer. This means that many participating centers randomized, on average, less than one patient per year! This was not a group of high-volume operators.