ASTRAL Findings Published

November 12, 2009—In the New England Journal of Medicine, the ASTRAL (Angioplasty and Stenting for Renal Artery Lesion) investigators have published findings from their study of revascularization versus medical therapy for renal artery stenosis (2009;361:1953–1962). The background of the study is that percutaneous revascularization of the renal arteries improves patency in atherosclerotic renovascular disease, but evidence of a clinical benefit is limited.

According to the investigators, the randomized, unblinded trial assigned 806 patients with atherosclerotic renovascular disease to undergo either revascularization in addition to receiving medical therapy or to receive medical therapy alone. The primary outcome was renal function as measured by the reciprocal of the serum creatinine level (a measure that has a linear relationship with creatinine clearance). Secondary outcomes were blood pressure, the time to renal and major cardiovascular events, and mortality. The median follow-up was 34 months.

The investigators reported that during a 5-year period, the rate of progression of renal impairment (as shown by the slope of the reciprocal of the serum creatinine level) was –0.07 X 10^–3 L/µmol/y in the revascularization group as compared with –0.13 X 10^–3 L/µmol/y in the medical therapy group, a difference favoring revascularization of 0.06 X 10^–3 L/µmol/y (95% confidence interval [CI], –0.002–0.13; P = .06). During the same amount of time, the mean serum creatinine level was 1.6 µmol/L (95% CI, –8.4–5.2 [0.02 mg/dL; 95% CI, –0.1–0.06]) lower in the revascularization group than in the medical therapy group. There was no significant between-group difference in systolic blood pressure; the decrease in diastolic blood pressure was smaller in the revascularization group than in the medical therapy group. The two study groups had similar rates of renal events (hazard ratio [HR] in the revascularization group, 0.97; 95% CI, 0.67–1.4; P = .88), major cardiovascular events (HR, 0.94; 95% CI, 0.75–1.19; P = .61), and death (HR, 0.9; 95% CI, 0.69–1.18; P = .46). Serious complications associated with revascularization occurred in 23 patients, including two deaths and three amputations of toes or limbs. The investigators concluded that there are substantial risks but no evidence of a worthwhile clinical benefit from revascularization in patients with atherosclerotic renovascular disease.

However, the trial has been criticized in the endovascular community. Michael R. Jaff, DO, provides some counterpoints to the ASTRAL investigators' methods and findings. Dr. Jaff is Associate Professor of Medicine, Harvard Medical School, and Medical Director, Vascular Center, Massachusetts General Hospital in Boston. He is the Medical Director of the Vascular Ultrasound Core Laboratory for the CORAL trial, which he discussed in the August 2009 issue of Endovascular Today that focused on renal artery interventions.

Challenging the Design and Conclusions of the Astral Trial

In an interview with Endovascular Today, Dr. Jaff critiqued the ASTRAL trial's design, inclusion criteria, clinical endpoints, complications, and the investigators' conclusions.

Trial Design
Dr. Jaff noted that the ASTRAL study was designed to include patients with renal artery stenosis, hypertension or unexplained chronic kidney disease, and those whose physician was uncertain about the value of endovascular revascularization for renal artery stenosis. This excludes the patients who clearly need to be included in randomized trials, he said.

“In the ASTRAL trial, a patient with severe unilateral renal artery stenosis and hypertension suboptimally controlled on three antihypertensive agents, seen by an interventionist, would potentially be advised that renal artery stent revascularization is indicated; a hypertension expert would potentially be advised that adjustment in pharmacotherapy is indicated,” observed Dr. Jaff. “And since both clinicians felt confident about their recommendations, this patient would not have been eligible for ASTRAL!”

Inclusion Criteria
Dr. Jaff stated that although 59% of patients included in ASTRAL had significant renal artery stenosis (> 70%), 41% did not have hemodynamically significant stenosis. Given that the primary endpoint of the trial was the impact of the randomized therapy on renal function, no one would ever expect a positive impact on the reciprocal of the serum creatinine, Dr. Jaff asserted.

Endpoints
Dr. Jaff observed that despite equivalence in the primary endpoint, the trend in reciprocal of the serum creatinine seemed to favor the revascularization arm (P = .06). In addition, other important surrogate endpoints representing meaningful outcomes, such as the number of antihypertensive pharmacologic agents required at 1 year of follow-up, demonstrated a statistically significant reduction in the revascularization arm (P = .03).

Complications
Dr. Jaff pointed out that although 403 patients were randomized to revascularization, only 83% actually had the procedure attempted. There were a large number of periprocedural complications noted within 30 days of the procedure, 106 events in 85 patients, representing a significant increase in procedural risk compared to other published series. Furthermore, 20% of patients treated with endovascular therapy suffered a serious adverse event between 24 hours and 30 days of treatment.

Conclusions
Dr. Jaff challenged the ASTRAL investigators' conclusion that renal revascularization carries significant risk without any real benefit. He said that this is a broad generalization that is not supported by the design and results of the trial and provides an inaccurate and damaging conclusion.

“Given the large proportion of patients who were included with hemodynamically insignificant stenoses, a lack of beneficial effect on renal function is unrealistic,” Dr. Jaff asserted. “This is not the fault of the therapy, but rather, of patient selection. In addition, important patients whose treatment with endovascular revascularization for renal artery stenosis is uncertain were most certainly not included in this trial.”

Therefore, Dr. Jaff said, the only rational and reasonable conclusion that can be drawn from this trial is that in unselected patients with mild, moderate, and severe renal artery stenosis and varying degrees of hypertension and chronic kidney disease, renal artery stent revascularization did not result in preservation of renal function compared to medical therapy. Further studies are needed on a more homogeneous patient population that would likely benefit from renal artery endovascular therapy, stated Dr. Jaff.