Percutaneous revascularization of the renal arteries offers no evidence of clinical benefit in patients with atherosclerotic renal artery stenosis—the astral trial

Authors

  • Michael J. Bloch MD,

    1. From the Division of General Internal Medicine/Division of Cardiology, University of Nevada School of Medicine;
    2. the Risk Reduction Center, Saint Mary’s, Regional Medical Center, Reno, NV;
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  • Jan N. Basile MD

    1. Seinsheimer Cardiovascular Health Program, Division of General Internal Medicine/Geriatrics, Medical University of South Carolina;
    2. the Primary Care Service Line, Ralph H. Johnson VA Medical Center, Charleston, SC
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Michael J. Bloch, MD, Risk Reduction Center, Saint Mary’s Regional Medical Center, 645 North Arlington Street, Suite 460, Reno, NV 89503
E-mail: mbloch@aol.com

Percutaneous revascularization by angioplasty and stenting is associated with a high rate of technical success and artery patency; however, evidence of meaningful clinical benefit has been limited. The Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) trial was a multicenter, randomized, unblinded, clinical endpoint study designed to determine whether, in addition to aggressive medical therapy, revascularization offered any important clinical benefit on renal function and other outcomes in patients with established renovascular disease.

Patients were screened for enrollment in the study if clinical findings, including refractory hypertension or unexplained renal dysfunction, suggested a diagnosis of atherosclerotic renal disease. These potential subjects underwent renal artery imaging by intra-arterial angiography, computed tomographic angiography, magnetic resonance angiography, or duplex ultrasonography at the discretion of the treating physician. Patients were eligible to participate if they had evidence of significant atherosclerotic renal artery stenosis in at least one renal artery, the lesion was considered by the treating physician to be suitable for potential percutaneous intervention, and in the opinion of the treating physician the evidence for clinical benefit was uncertain. Exclusion criteria included: previous revascularization for renal artery stenosis, known significant nonatheromatous cardiovascular disease, need for surgical renal artery revascularization, or belief on the part of the treating physician that the patient would have a high likelihood of definitely needing renal artery revascularization within 6 months. Eligible patients were randomized to receive percutaneous revascularization plus medical therapy vs medical therapy alone. Randomization stratified according to the serum creatinine level, estimated glomerular filtration rate (eGFR), severity of renal artery stenosis, kidney length on noninvasive imaging, and rate of progression of renal dysfunction over the previous year.

For patients assigned to undergo revascularization, the procedure was generally performed within 4 weeks of randomization. The precise revascularization procedure, including whether it was performed by angioplasty alone or with additional placement of a stent, was determined by the treating interventionalist. Distal protection devices were not used. Patients in both groups received aggressive medical therapy aimed at controlling the progression of atherosclerosis and renal dysfunction. While the exact protocol was set by the local practitioner, in general, medical treatment included use of statin-based lipid lowering therapy, optimal blood pressure control, and antiplatelet agents. Follow-up visits were scheduled at 1–3 months, 6–8 months, at 1 year, and yearly thereafter for 5 years. The primary outcome was the change in renal function, assessed by measuring the mean slope of the reciprocal of the serum creatinine over time. Secondary and other tracked outcomes included: blood pressure, time to first renal event (new onset of acute kidney injury, initiation of dialysis, renal transplantation, nephrectomy, or death from renal cause), time to first cardiovascular event (myocardial infarction, stroke, hospitalization for cardiovascular cause, intervention for peripheral artery disease, or death from cardiovascular cause), total mortality, treatment complications, and serious adverse events. All analyses were performed according to intention-to-treat principle with the use of all available data through the maximum follow-up of 5 years.

From September 2000 through October 2007, 806 participants (mean age 70 years) were randomized at 57 hospitals (53 in the United Kingdom, 3 in Australia, and 1 in New Zealand). Overall, 59% of patients had renal artery stenosis of at least 70%, and 60% had a serum creatinine of at least 1.7 mg/dL. Mean baseline eGFR was about 40 mL/min, mean urinary protein was approximately 500–700 mg/d, and mean blood pressure was approximately 150/76 mm Hg on a mean of 2.8 antihypertensive medications. Overall, about 92% of subjects were on antiplatelet agents, and 80% were on lipid lowering therapy (96% of whom were on a statin).

In the revascularization group, the procedure was attempted in 335 of the 403 enrolled (83%) patients and was considered a technical success in 95% of procedures attempted. The vast majority of revascularized patients (95%) received a stent. In the medical therapy alone group, 24 patients (6%) required revascularization after a mean of 601 days. After 1 year in both the revascularization plus medical therapy and the medical therapy alone group, the proportion of patients receiving lipid lowering medications and antiplatelet agents was similar to baseline. After a year, the average number of antihypertensive agents used was somewhat higher for patients in the medical therapy alone group (2.97 vs 2.77 medications [P=.03]). In addition, slightly more patients in the revascularization group were receiving renin-angiotensin blockers both at baseline (47% vs 38%, P=.02) and after 1 year (50% vs 43%, P=.05).

During the 5 years of follow-up, the overall mean slope of the reciprocal of the serum creatinine concentration (primary endpoint) was not significantly different between the two groups, and there was no difference in change in serum creatinine over time between the two groups. Even when per protocol analysis compared only those who actually had revascularization vs those who did not, there was no difference in the primary outcome. There were also no differences in the primary endpoint in any of the protocol specified subgroups, including those defined by renal function, degree of stenosis, kidney length, and previous rate of renal function deterioration. In terms of blood pressure, over the 5-year follow-up period, systolic blood pressure decreased in both groups, without any significant difference between groups, and diastolic blood pressure actually decreased to a somewhat greater degree in the medical therapy alone group. During follow-up, the number of renal events and the time to first renal event were not different between the two groups; the incidence of new end-stage renal disease was 8% in both groups. Finally, there was no significant difference in the incidence of cardiovascular events or total mortality (103 deaths in the revascularization group vs 106 deaths in the medical therapy alone group). In total, there were 31 serious complications (in 23 patients) within 1 month of revascularization.

In patients with documented atherosclerotic renal artery stenosis receiving aggressive medical therapy, there is no discernable clinical benefit associated with percutaneous revascularization with respect to renal function, blood pressure, renal or cardiovascular events, or mortality. In addition, revascularization carries with it significant risk.—ASTRAL Investigators. Revascularization versus medical therapy for renal-artery stenosis. N Engl J Med. 2009;361(20):1953–1962.

Comment

Renal artery stenosis is increasingly recognized as a potential contributing factor for hypertension and renal dysfunction. There are two principal causes of renal artery stenosis, fibromuscular dysplasia (FMD) and atherosclerosis. The treatment of renal artery stenosis due to FMD, which tends to be more common in younger patients, is relatively straightforward; percutaneous intervention in FMD usually leads to a significant improvement and often a cure of hypertension. Renal artery stenosis due to atherosclerosis is a much more difficult clinical conundrum.

Certainly, atherosclerotic renal artery stenosis can lead to increased blood pressure (renovascular hypertension) and decreased renal function (ischemic nephropathy) and has been associated with an increased risk of cardiovascular events and even mortality. But, while some patients with atherosclerotic renal artery stenosis will have refractory hypertension and progress to late stage kidney disease, these outcomes appear to be relatively uncommon in patients on appropriate medical management. And, while atherosclerotic renal artery disease traditionally has been considered a progressive condition, it is now generally thought that, perhaps in part due to the more wide-spread use of aggressive medical management, the incidence of progression may be lower. Most recent studies have suggested that the risk of progression to complete occlusion of the renal artery is <15%.1

Over the past two decades, multiple nonrandomized observational studies have suggested that percutaneous renal artery angioplasty (PTRA) and subsequently renal artery stenting leads to improvements in blood pressure and “stabilization” of renal function in patients with atherosclerotic renal artery disease. However, the relevance of these results has been repeatedly questioned based not just on the lack of randomization, but also the lack of appropriate antiatherosclerotic medical therapy used in these series. Despite the limitations of the available data, many clinicians have become quite aggressive in performing renal artery interventions in these patients with a substantial increase in the number of these procedures performed over the past decade. Some interventionalists have even promoted “drive by angioplasty” in some settings, whereby renal artery intervention is performed in patients undergoing angiography for other reasons even without symptoms of refractory hypertension or worsening renal function.

More recently, a metaanalysis of 3 small randomized studies of PTRA vs medical therapy and another small study of renal artery stenting vs medical therapy have demonstrated no, or at most modest, clinical benefit from percutaneous intervention.2,3 In this context, the null result of the ASTRAL study is not terribly surprising.

ASTRAL, like many previous studies in this difficult to study population, has some potential limitations that should be considered. First it was nonblinded. However, the endpoints studied were objective and not subject to potential bias, and it did not appear that, with the exception of the number of antihypertensive medications required, there was any difference in the medical management between the two groups. Second, since patients with normal renal function and stenosis of 50%–70% (which may not be hemodynamically significant) were included, the ability to identify a beneficial effect of percutaneous intervention may have been diminished. However, the subsets of patients with more significant stenosis (>70%), bilateral renal artery stenosis, and worse baseline renal function did not appear to get any additional benefit from renal artery intervention. Finally, exclusion criteria for ASTRAL included belief on the part of the treating physician that the patient would probably not have a high likelihood of needing renal artery revascularization in the near future. As the authors discuss, this criteria for equipoise leaves unresolved the question as to whether or not there is a subset of patients that may receive benefit from these procedures, but were not included in the clinical trial.

There appears to be no benefit from or indication for routine percutaneous intervention for atherosclerotic renal artery stenosis, even in the presence of hypertension or chronic kidney disease. The mainstay of therapy for these patents should be aggressive medical management, including appropriate antihypertensive therapy (including agents that block the renin-angiotensin system if indicated and tolerated), statin-based lipid lowering therapy, and antiplatelet therapy. Although there is a paucity of supporting data, we would also recommend careful surveillance of renal function, kidney size and degree of stenosis with frequent measurement of eGFR and occasional, perhaps yearly, renal artery duplex scanning. Pending the results of future clinical trials, renal artery intervention for atherosclerotic disease should be limited to the small number of patients with the type of high-risk characteristics that may have led clinicians to exclude their patients from the ASTRAL study. These potential characteristics include: flash pulmonary edema or recurrent decompensated heart failure, very high grade lesions (perhaps >90%) where the risk of progressing to complete occlusion may be high, hypertension truly refractory to aggressive multi-agent antihypertensive therapy, unexplained progression of renal dysfunction, and progressive decrease in kidney size.

We eagerly await the results of the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) study, which is a large, prospective, multicenter, randomized controlled clinical trial comparing the cardiovascular and renal outcomes of optimal medical therapy plus stent revascularization vs optimal medical therapy alone. Pending results of CORAL, expected in 2011, the utility of renal artery revascularization should continue to be viewed with skepticism for most patients with atherosclerotic renal artery disease.

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