American Journal of Kidney Diseases
Volume 56, Issue 2 , Pages 259-263, August 2010

Is There Any Reason to Stent Atherosclerotic Renal Artery Stenosis?

  • Lance D. Dworkin, MD

      Affiliations

    • Corresponding Author InformationAddress correspondence to Lance D. Dworkin, MD, Department of Medicine, Alpert Medical School of Brown University, Rhode Island Hospital, 593 Eddy St, Providence, RI 02903
    • ,
  • Timothy Murphy, MD

Alpert Medical School of Brown University, Providence, Rhode Island

published online 28 June 2010.

Article Outline

 

Commentary on ASTRAL Investigators. Revascularization versus medical therapy for renal artery stenosis. N Engl J Med. 2009;361(20):1953-1962.

Renal artery stenosis, defined as a narrowing of one or both renal arteries or their branches,1 most commonly is caused by atherosclerosis. The incidence of clinically evident atherosclerotic renal artery stenosis in the Medicare population is 0.5% overall and 5.5% in those with chronic kidney disease.2 Because patients often are asymptomatic, the true incidence undoubtedly is higher, with one population-based study of older individuals in North Carolina showing a prevalence of 7%.3 Although renal artery stenosis is relatively common, the prevalence of hypertension or decreased kidney function caused by renal artery stenosis is unknown,4, 5 and <10% to 15% of patients with atherosclerotic renal artery stenosis develop intractable hypertension or progressive loss of kidney function.6, 7, 8 Although renal artery lesions tend to progress, this may occur in the absence of worsening of hypertension or kidney function, and complete occlusion of renal arteries is uncommon.6, 9

Coronary artery disease, cerebrovascular disease, and peripheral vascular disease are common in patients with atherosclerotic renal artery stenosis.2 Patients with renal artery stenosis also have worse outcomes from cardiovascular disease. In unselected patients who underwent renal arteriography at the time of cardiac catheterization, the incidence of subsequent adverse cardiovascular events was much higher in those with renal artery stenosis, and there was a direct correlation between stenosis severity and survival.5 Decreased glomerular filtration rate at the time of presentation also adversely affects survival.10 The explanation for the increased risk of cardiovascular disease in patients with atherosclerotic renal artery stenosis is uncertain, but may result from activation of the renin-angiotensin-aldosterone and sympathetic nervous systems, decreased glomerular filtration rate,11, 12, 13, 14, 15, 16, 17, 18, 19 or concomitant atherosclerosis in other vascular beds.20, 21, 22, 23, 24, 25, 26 Regardless of cause, the relatively poor prognosis of patients with renal artery stenosis provides a compelling reason to determine the most effective therapy to prevent adverse cardiovascular and renal events. However, the nature of this therapy is hotly debated. Specifically, whether angioplasty and stent placement improve outcomes for patients with atherosclerotic renal artery stenosis is not known, and there is no test that reliably identifies patients who will improve after revascularization.

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What Does This Important Study Show? 

Conducted in the United Kingdom, Australia, and New Zealand, the ASTRAL (Angioplasty and Stenting for Renal Artery Lesions) trial27 randomly assigned 806 participants with renal artery stenosis to renal artery stent placement plus medical therapy or medical therapy alone. The primary end point was the mean slope of decrease in reciprocal creatinine level at up to 5 years of follow-up, which correlates with mean rate of glomerular filtration rate decrease. Although the rate of decrease in inverse creatinine in the medical group was nearly double that in the stent group, the rate was much lower than expected in both groups, the difference was not statistically significant (P = 0.06; Fig 1), and there was no significant difference in serum creatinine levels between groups at any time during the study or from baseline to study completion. Even if the difference had been significant, it would have had little clinical relevance because total change in kidney function during the course of the study was minimal. Differences in blood pressure, kidney and cardiovascular events, mortality, and subgroup analyses between groups were all similarly unimpressive, even in the highest risk groups, which included patients with global ischemia or impaired or rapidly decreasing kidney function. There also were serious complications associated with the stent procedure, including cholesterol embolism leading to amputations in 3 patients and 2 deaths. The investigators concluded that revascularization was associated with “substantial risks but no evidence of a worthwhile clinical benefit.”27

  • View full-size image.
  • Figure 1. 

    Serum creatinine levels for participants in the ASTRAL (Angioplasty and Stenting for Renal Artery Lesions) trial. Contrary to investigators' expectations, kidney function in this population did not deteriorate overall up to 5 years after randomization.

Reproduced from ASTRAL Investigators27 with permission of the Massachusetts Medical Society.

There are several important caveats associated with the ASTRAL trial, and among the most significant is selection bias. Eligibility for the study was subjective in that potential participants were considered for inclusion only if their physician believed that the patient would not definitely benefit from revascularization. Accordingly, although baseline characteristics of the study population appear similar to those often treated clinically with stent placement, they were selected specifically because they were believed to be less likely to benefit from revascularization. The investigators state that this approach was based on the principle of equipoise, which requires uncertainty regarding the relative merits of the treatments being compared. However, in our view, the ethical issue of equipoise is satisfied if the evidence for or against a particular intervention is inconclusive28, 29 and does not have to be considered individually by every investigator for each patient. The approach in the ASTRAL trial might be considered less ethical because it severely limits our ability to draw meaningful conclusions from the data. As a result, participants were subjected to risk with less probability of generating data that are conclusive or, even worse, that support an incorrect result, thereby jeopardizing management of the entire affected population.

There are a number of other notable flaws in the ASTRAL trial. Both the method of revascularization and medical therapy regimen were left to local practitioners and consequently were varied and poorly defined. Although it is well known that local investigators routinely overestimate stenosis severity, there was no central core laboratory that reviewed the angiographic studies. Even interpreted locally, 40% of participants included in the study had stenoses of 50%-70%, which may not be hemodynamically significant. The inclusion of many patients with mild stenoses might explain the slower than expected decrease in kidney function. In the group randomly assigned to stent placement, the procedure was attempted in only 83% and was successful in only 79% of patients. Approximately 6% of patients randomly assigned to medical therapy crossed over and underwent revascularization on average within the first 2 years of follow-up. Cross-contamination of the groups by patients treated according to the protocol for the other treatment group further compromised the power of the study. Finally, although hard clinical end points such as mortality and cardiovascular events were examined, the study was not adequately powered to detect differences in these important outcomes.

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How Does This Study Compare With Prior Studies? 

Since 1998, five randomized clinical trials have compared percutaneous renal artery revascularization with medical therapy.7, 30, 31, 32, 33 Consistent with results in the ASTRAL trial, none have reported a benefit of renal artery angioplasty with or without stent placement. At best, a meta-analysis suggested a small potential blood pressure benefit of questionable clinical relevance34; namely, a decrease in the number of medications needed to control blood pressure. Paradoxically, during this same interval, there has been a considerable increase in the frequency of renal artery stent procedures.35 This may reflect the observation that some patients appear to benefit clinically and also because serious method problems in all the previous trials have caused physicians to doubt the validity of their findings. These include imprecise definitions of renal artery stenosis, likely leading to the inclusion of large numbers of unaffected patients; inadequate interventions, such as angioplasty without stent placement; crossovers; and lack of an intensive medical intervention. A review of percutaneous renal artery revascularization in 2006 concluded that “The evidence from direct comparisons of interventions is sparse and inadequate to draw robust conclusions.”36

The STAR (Stent Placement and Blood Pressure and Lipid-Lowering for the Prevention of Progression of Renal Dysfunction Caused by Atherosclerotic Ostial Stenosis of the Renal Artery) trial, the largest and most recent of these studies before the ASTRAL trial, included 140 patients with creatinine clearance <80 mL/min and renal artery stenosis ≥50% who were randomly assigned to stent placement versus medical therapy.33 The primary end point was a ≥20% decrease in creatinine clearance, which occurred in 22% of those in the medical treatment group compared with 16% in the stent group33 (P = 0.06). Again, interpretation of even this equivocal result was compromised further because of problems in the design and conduct of the trial; for example, 12 of 64 patients in the stent group had stenosis <50% and did not undergo revascularization. Accordingly, the investigators concluded that the study was inconclusive.

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What Should Clinicians and Researchers Do? 

Up to and including publication of the ASTRAL trial results, data for renal artery revascularization remain insufficient to draw definite conclusions. In this context, there is little justification for widespread screening of at-risk populations for renal artery stenosis or performing interventions in individuals with anatomic stenoses that are clinically stable. The CORAL (Cardiovascular Outcomes With Renal Atherosclerotic Lesions) study is a large, prospective, randomized, multicenter clinical trial that is still ongoing. CORAL will enroll 900 patients and compare the effects of medical therapy plus stent placement with medical therapy alone on a composite end point of important clinical events, including heart attack, heart failure, kidney failure, stroke, and death. CORAL is rigorously determining patient eligibility using imaging core laboratories and centrally managing medical therapy according to current guidelines. At present, referring patients into this or a similar randomized clinical trial makes sense to definitively answer this important question.

Absent entry into a clinical trial, it is our opinion that based on present data, revascularization should be reserved for patients with severe (>70%) renal artery stenosis associated with refractory hypertension or deteriorating kidney function for whom medical therapy has failed. Even in this context, the potential risks and uncertain benefits of revascularization should be clearly discussed with the patient. Medical management also is a reasonable option for even clinically unstable patients until convincing data indicate otherwise. Regardless of whether revascularization is performed, patients with renal artery stenosis require intensive medical therapy, including tight control of blood pressure. This typically will require administration of multiple agents and should include a drug that blocks the renin-angiotensin-aldosterone system. Serum creatinine and potassium levels should be monitored closely when treatment with these agents is initiated and dosages should be titrated in patients with renal artery stenosis because a significant decrease in kidney function or serious hyperkalemia infrequently may occur. Administration of a statin and an antiplatelet agent also is indicated, as are treatment of diabetes and sequelae of chronic kidney disease to current guidelines, if present. Patients treated in this manner can achieve good blood pressure control and be remarkably stable, even in the presence of persistent high-grade stenosis.

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Acknowledgements 

Financial Disclosure: Dr Dworkin is an investigator on several industry-funded multicenter clinical trials in the areas of hypertension and cardiovascular disease and receives grant support for his work on these trials. He is the study chair of the CORAL trial, which is funded primarily by the National Heart, Lung and Blood Institute, but also supported by Johnson & Johnson, AstraZeneca, and Pfizer. Dr Murphy is the co-principal investigator of the CORAL trial.

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 Originally published online as doi:10.1053/j.ajkd.2010.04.005 on June 28, 2010.

PII: S0272-6386(10)00726-2

doi:10.1053/j.ajkd.2010.04.005

American Journal of Kidney Diseases
Volume 56, Issue 2 , Pages 259-263, August 2010

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