Will ASTRAL do for the renal arteries what COURAGE did for the coronary arteries? The first large, randomized trial to compare renal revascularization to medical therapy found no sign of benefit, and increased risk, for the interventional approach. The results of the ASTRAL trial are published today in the New England Journal of Medicine.

Investigators randomized 806 patients with atherosclerotic renovascular disease to either revascularization plus medical therapy. After 34 months of followup, there were no significant differences between the two groups in the rates of renal events, major cardiovascular events, or death. However, 23 patients in the revascularization arm experienced serious complications, including 2 deaths and 3 amputations.

“Data from studies in the United States have indicated that revascularization is performed in 16% of patients with newly diagnosed atherosclerotic renovascular disease. Since endovascular interventions are associated with substantial morbidity, inconvenience, and cost, with little apparent benefit, the widespread use of such procedures outside of clinical trials can now be questioned. A related implication is that there seems to be little value in screening asymptomatic patients who have atherosclerosis and chronic renal disease or hypertension for evidence of renovascular disease,” the authors write in their report.

One important criticism of the study, the authors acknowledge, is that the patient population enrolled in the trial may not have had renal artery stenosis as severe as generally seen in clinical practice, since the more high risk patients may not have been randomized.

William Boden, PI of the COURAGE study, noted that ASTRAL and COURAGE  had the “same overall result” in a “different vascular bed.” Although it was  ”tempting to draw parallels to both COURAGE and BARI-2D,” Boden noted that “these trials were designed and powered as clinical event reduction trials while ASTRAL was designed and powered for a surrogate endpoint of renal function (reciprocal of a serum creatinine level).” Boden continued:

“I think another potential design issue was that the investigators only enrolled those patients with renovascular disease who the investigators were uncertain as to whether the patients would derive clinical benefit from revascularization. Such a “principle of equipoise” was, in many respects, the inverse of what was used in SYNTAX and BARI-2D, in that they also used the principle of equipoise but the uncertainty was whether or not patients would do better with PCI vs CABG. So, in those 2 trials, the feeling was revascularization would benefit the patient (uncertainty of which procedure was better) whereas ASTRAL enrolled patients where there wasn’t felt to be benefit from revascularization. So, I don’t know if the two designs are comparable.

“Nonetheless, we have yet another RCT where it’s difficult to demonstrate prophylactic benefit of catheter-based revascularization. With only 800 patients, critics will argue that the study is simply non-definitive, under-powered for clinical endpoints, and unable to address whether revascularization of patients with renovascular disease who are likely to derive clinical benefit with PCI were enrolled to begin with. It adds to mounting evidence that a catheter-based revascularization approach to treat demonstrable stenoses that are amenable to stenting actually do benefit.

“But, ASTRAL is an important step in the growing arena of peripheral catheter-based intervention. Clearly, additional studies will be needed before this important clinical question will be addressed and settled.”

Commenting on ASTRAL on behalf of SCAI, Christopher White provided the following comment to CardioBrief:

The ASTRAL Trial authors draw overbroad conclusions about the risks and benefits of renal revascularization vs. medical therapy in treatment of renal artery stenosis. It’s true that stenting intervention in renal stenosis is only marginally likely to benefit patients with mild lesions.

The authors reach the far broader – and misleading – conclusion that there is limited benefit from intervention to improve renal function in anyone. That sweeping interpretation oversteps the evidence on several accounts, diluting the benefits of stents for patients who do benefit.

Among the reasons for questioning this trial’s conclusions:

• The trial’s heavy focus on mild blockages (four in 10 subjects had < 70% narrowing, which probably shouldn’t be treated with stenting anyway).
• Only patients deemed “uncertain” of needing renal intervention were randomized, a bias against enrolling severe lesions that clearly need intervention. Not surprisingly, the progression of disease in the control group receiving medical therapy was much milder than expected, tilting comparisons unfairly in favor of medical therapy.
• There were positive outcomes in the intervention group, including better renal function (p = 0.06) and statistically significant reduction in blood pressure medications.

Finally, I am concerned about the high complication rate seen in ASTRAL, which is much higher than the 2% serious complications seen in published reports of U.S. investigators. In addition, the success rate for renal stenting (83% in ASTRAL) is not nearly as good as we see in the U.S. (98%). This is why it’s imperative that ASTRAL findings, while informative in patients with mild lesions, must only be applied to the very narrow set of patients studied in the trial.

Franz and Adrian (Franz’s son) Messerli provided the following comment:

Yet another negative trial and just as with COURAGE showing that the benefits of drug therapy and the risks of revascularization are under appreciated, whereas the benefits of revascularization are overblown. However, the crucial issue here is the definition of “renovascular” hypertension and/or ischemic kidney.  In ASTRAL patients were eligible to participate “if they had substantial anatomic atherosclerotic stenosis in at least one renal artery that was considered potentially suitable for endovascular revascularization.”  Clearly the suitability here is very much in the eye of the beholder i.e., the interventional cardiologist or radiologist, neither one of which is immune to the occulo-stenotic reflex.  In other words, most of these revascularization decisions are based on angiographic severity – a criterion, which we know from coronary and peripheral vascular experience is too simplistic.  Revascularization of an angiographic 60% stenosis (which may well be physiologically insignificant) will only expose a patient to the procedural risk but not confer any benefits.  Little wonder that in many of these cases medical therapy turns out to be superior to intervention.  The bottom line with intervention in renal arterial disease is that we are doing a exceedingly poor job in identifying the right kidney or the right patient.  The ASTRAL study is no exception in this regard.

See also Schwarzwälder U, Zeller T. Critical review of indications for renal artery stenting: do randomized trials give the answer? Catheter Cardiovasc Interv. 2009 Aug 1;74(2):251-6.