The CORAL Trial: Is This the End for Renal Artery Stenting?
Abstract & Commentary
Jeffrey Zimmet, MD, PhD
Associate Professor of Medicine, University of California, San Francisco, Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center
Source: Cooper CJ, et al. Stenting and medical therapy for atherosclerotic renal-artery stenosis. N Engl J Med 2013; Nov. 18. [Epub ahead of print.]
Renal artery stenosis (RAS) caused by atherosclerosis is a common finding among
patients with vascular disease. Indeed, the prevalence of renal artery stenosis has been estimated to be as high as 7% in community studies of patients older than 65 years. Early uncontrolled studies of renal angioplasty and stenting suggested potential benefits, both in terms of blood pressure control and renal function. To date, however, randomized trials have failed to replicate these findings. Prior randomized trials have been criticized on multiple counts, including enrolling patients with relatively mild, nonsignificant disease.
In the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial, the authors sought to compare clinical outcomes in patients with RAS and either systemic hypertension or renal dysfunction who were randomized to medical therapy alone or with renal artery stenting. During the study period between May 2005 and January 2010, 947 patients were randomly assigned to stenting plus medical therapy or to medical therapy alone. The primary endpoint was a composite of hard clinical events: death from cardiac or renal causes, stroke, myocardial infarction, hospitalization for congestive heart failure, progressive renal dysfunction, or the need for permanent hemodialysis. Patients with angiographic renal artery stenosis of at least 80% could be enrolled directly. Those with stenosis between 60% and 80% could be included if a systolic pressure gradient of at least 20 mmHg was documented. Notably, in contrast to prior studies, all angiograms were evaluated by a central core laboratory. Initially, patients were required to have systemic hypertension with a systolic blood pressure (SBP) of at least 155 mmHg while on at least two medications. Subsequently, however, the minimum BP requirement was removed, and patients could be enrolled if they had chronic kidney disease, defined by a glomerular filtration rate (GFR) of < 60. All patients were treated with an aggressive medical regimen with protocol-specified medications. This included the ARB candesartan with or without the addition of hydrochlorothiazide, and the combination of amlodipine and atorvastatin. Patients were treated to a target blood pressure of 140/90, or to the lower target of 130/80 in the presence of diabetes or chronic kidney disease.
Of the 459 patients in the stent group, 434 underwent successful stenting. Of the 472 patients in the medical therapy group, 19 crossed over to stenting. In an intention-to-treat analysis, the study showed no difference in occurrence of the primary endpoint between the medical therapy and stenting groups over a mean follow-up of 43 months (35.1% and 35.8%, respectively; hazard ratio, 0.94; 95% confidence interval, 0.76-1.17; P = 0.58). There was a small but significant difference in BP between the two groups, with the stenting group showing a mean decrease of 2.3 mmHg compared with the medical therapy group. The authors concluded that in patients with atherosclerotic RAS, renal artery stenting did not reduce subsequent clinical events as compared to intensive medical therapy.
CORAL is a well-done study that contributes significantly to an important question in cardiovascular medicine. For patients with moderately severe RAS and either hypertension or chronic renal disease, stenting did not have additive value in preventing clinical events on top of good medical therapy.
A few points are worth mentioning here. First, enrolling patients in studies such as this is challenging. Indeed, it took nearly 5 years to complete enrollment in this trial, and in the end only 947 of the originally intended 1080 patients were enrolled. Modifications resulting in inclusion of less-sick patients were made after initiation of the trial, primarily to address slow enrollment issues. Notably, the initial requirement of hypertension with a SBP of at least 155 mmHg while on two or more drugs was removed, allowing patients with chronic kidney disease without hypertension to be enrolled. This reflects the real-world balance struck between defining the population with possible benefit from renal artery stenting and attaining adequate patient enrollment to complete the study. The observed event rate of 20% at 2 years in the medical therapy group was half of the expected rate. While this beneficial effect of aggressive medical therapy is encouraging, the low event rate also reduces the power of the trial to detect a difference between groups.
Were the right patients examined here? In terms of severity of RAS, CORAL did a better job than prior studies, enrolling patients with mean angiographic stenosis of 73%. In a subgroup analysis looking only at patients with stenosis > 80%, the results were unchanged, with no significant difference in outcomes between medical and stent groups. CORAL shows us that with appropriate medical therapy, the majority of patients with RAS will do well clinically. However, it does not erase the need to look at our patients individually and to recognize that not all patients fit within the study constraints. Patients in this study were on a mean of only two antihypertensive medications at the time of enrollment, and three by study end. These are clearly not the patients who are failing medical management on four or more medications. Patients with truly critical stenosis, bilateral RAS, or RAS affecting a single functioning kidney were not significantly represented. Likewise, patients presenting with critical RAS and recurrent pulmonary edema despite optimal medical therapy were not part of the study group. Whether future trials will be able to address these less-common and difficult-to-enroll populations is doubtful.