Navigating the renal stent empirical maze

The 17th century philosopher, Francis Bacon, challenged Aristotle’s thoughts on scientific inquiry in the “Novum Organum” and ultimately his works laid the foundation for the scientific method. Bacon described in his writings how the mind can be fooled by the distorted reflected image from an uneven mirror and this was his metaphor for how initial scientific observations are not always as they appear to be. Renal artery stenting (RASt) is now entering the third decade of maturation yet level I data confirming enhanced blood pressure (BP) control remains elusive and nonrandomized positive data continues to be counterbalanced by disappointing randomized trial results. The finding of improved BP in the pooled RASt data from five US pivotal trials reported by Weinberg and colleagues in the Journal is a case-in-point and mirrors many previous nonrandomized series. However, should these findings be completely eclipsed by the negative results of the recently published, highly awaited, randomized RASt versus medical therapy trial (CORAL) and what patients, if any, should undergo RASt today [1]? Advocates for conservative treatment of atherosclerotic renal artery stenosis (ARAS) will point out the pooled Weinberg data lacks a control arm and remind us the recent CORAL trial showed surprising improvement of BP in the medical therapy arm [1]. In addition, the authors acknowledged all five pooled studies were designed to show 9-month patency rather than hypertension (HTN) response thus may have lacked the needed rigorous assessment of BP before and after intervention. In addition, it is unclear how HTN medical therapy failure was defined in these trials and how many patients were on maximal therapy as well as receiving a thiazide diuretic. Finally, the title suggests there is analysis of 901 patients but complete data was only available on 527 patients and the smaller number of patients coupled with the heterogeneity of each individual pivotal trial design may have further weaken the conclusions and assertions regarding HTN benefit. We agree the Weinberg paper is weighted down by some limitations but also noted this is the first large RASt pooled series involving patients undergoing FDA monitored follow-up and core laboratory adjudication. Perhaps the most noteworthy observation by Weinberg is the conclusion baseline systolic blood pressure >150 mm Hg was a predictor of BP response following RASt. This is particularly relevant, since the CORAL trial launched as RASt volume was contacting, in the wake of other negative randomized trials, and slow enrollment problems led the CORAL trialists to seek creative solutions to avoid declaring futility [2]. Ultimately, the statistical type II boundaries in CORAL were crossed by extension of patient follow-up to 3 years and loosening the BP entry criteria threshold to include some well-controlled patients with azotemia. The latter changes shifted the study population away from the current strict HTN treatment criteria used by many multidiscipline academic centers. More importantly, the average CORAL trial baseline SBP was 150 mm Hg (compared to 164 mm Hg reported in the pooled series) and thus a large number of the CORAL trial patents were below the ideal SBP treatment benefit window suggested by Weinberg today. In addition, some CORAL trial operators may have been biased by personal RASt experience coupled with compelling nonrandomized data and struggled with the ethical dilemma of withholding treatment in ideal RASt patients. Finally, there is no immediate clinical renal feedback (pain) during RASt procedure-induced embolization and a sensitive biomarker surrogate for renal biopsy documentation of procedure-induced atheroembolization does not exist. Thus, it is possible we have underestimated the importance of RASt technique and the need for embolic protection before embarking on randomized studies.