Use of Registries to Complement Clinical Trials in Renal Artery Stenting

The role of renal artery stenting in the treatment of atherosclerotic lesions of renal artery remains intensely debated.^1,2 There were similar debates several times in interventional cardiology arena, and interestingly the data in renal artery stenting have followed the same footsteps. Use of registry data helped in the debate on many issues in cardiology, ³ and we make a case for use of registries to complement clinical trials in renal artery stenting.

Rapid developments followed after Dr Gruntzig pioneered treatment of atherosclerotic blockages in coronary and renal arteries with angioplasty.^4,5 Results in the first 50 patients who underwent percutaneous transluminal coronary angioplasty (PTCA), the primary success rate was only 64%, and emergency coronary bypass surgery (CABG) was required in 14%, with a periprocedural myocardial infarction (MI) rate of 6%. ⁶ Subsequently, as a result of greater operator experience and refinements in catheter and imaging technology, acute complication rates of balloon angioplasty steadily decreased. ⁷ However, restenosis and the need for repeat intervention remained a severe limitation, occurring in up to 40% of cases. ⁷ An alternative strategy evolved and in 1986, Sigwart ⁸ performed first stent implantation in a human coronary artery. Restenosis was soon recognized to be a major problem that found viable solution in the form of drug-eluting stents, first of which was approved by the Food and Drug Administration (FDA) in 2003.

Initial treatment of ostial renal atherosclerotic lesions was limited by a low acute technical success rate of 50% to 62% and a high restenosis rate of up to 47% in the long term due to dissections, elastic recoil, and rigidity of the lesion in calcified stenoses.^9;–11 Single-center reports of stenting started trickling in 1990s.^12–17 Two randomized studies proved the superiority of stenting over conventional balloon angioplasty in terms of acute treatment success and technical durability^9,18 of the endovascular treatment of atherosclerotic ostial renal artery stenosis (RAS). Larger clinical trials were required to define the indications for interventional treatment of RAS. Unfortunately, 3 prospective randomized controlled clinical trials (RCTs) that have been published on the subject thus far have failed to provide clear answers.^19–22 With the exception of Stenting for Renal Artery Lesions (ASTRAL) trial,^20,21 the studies were underpowered to provide meaningful answers. All the trials enrolled patients with limited disease burden (stenosis <70%) and who had little plausible survival benefit from intervention versus medical therapy. Large number of patients did not receive the intended treatment and the statistical analysis was performed on intention-to-treat basis that could never account for high crossover rates. A large national institute of health funded Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial ²³ that will randomize over 900 participants with greater than 60% stenosis to stenting and optimal medical therapy or medical therapy alone is underway. Recruitment for this trial has also been slow and research protocol has undergone multiple revisions to ease the recruitment process. The primary end point is survival free of cardiovascular and renal adverse events. The results of this trial are awaited.

Sketching parallels, Taggart ²⁴ elaborated that trials evaluating the use of drug-eluting stents in multivessel coronary disease faced similar problems. The trials systematically enrolled patients with limited disease burden and who had little plausible survival benefit from surgery versus medical therapy. In the mentioned trials, ²⁴ more than 90% of screened patients were excluded from randomization as they did not meet the inclusion criteria. ²⁴ The investigations only represented a small portion of the spectrum of multivessel disease, but their results were used to justify percutaneous coronary intervention (PCI) in much more anatomically complex patients without corroborating evidence. Evidence from total population-based studies such as the New York State registry indicates that when all patients are considered, CABG provides superior survival in the setting of all patients with left anterior descending coronary artery disease and at least 1 other diseased vessel. ²⁵

Our intention is not to challenge the role of clinical trials and the educational activities they generate, as these are well established, important, and desirable. However, they could be complemented with additional data that appropriately address the problem in a community setting. Nonrandomized prospective registries document the treatment and outcomes for consecutive patients in clinical practice. Therefore, data are gained from a “real-world” selection of patients, many of whom would be excluded from RCTs. Also, RCTs are usually performed in high-volume, experienced centers and enroll highly selected patient populations. Indeed, it is estimated that less than a third of patients in a clinical cardiology practice would actually qualify for inclusion in various RCTs.^26,27 Prospective registries can be used to assess whether RCT findings are indeed applicable to general population in 2 ways: first, the characteristics of patients included in registries can be assessed to determine whether they are similar to those included in clinical trials; and second, they can show whether RCT findings are maintained in the unselected (or excluded) clinical population. Due to the above limitations of RCTs, the FDA recognizes the importance of integrating registries into their adverse event reporting systems. ²⁸

We acknowledge the limitation that prospective registry populations are not randomized, and without an appropriate control group, a registry cannot evaluate efficacy findings. We recognize that unless a standardized data collection with accurate definitions and reporting is implemented, the registry data lacks provisions to assure the quality, accuracy, and completeness of data. Also, participation of investigators and patients involves some selection process, usually keeping in mind the best interests of patients. The sites that might be involved in proposed registries may be biased toward trying to demonstrate a benefit to stenting. This can be addressed during the design of the potential registry by creating mandatory fields that capture the intention to treat prior to the intervention and actual treatment performed. Studies of large registry populations are also ideally placed to assess the incidence of rare adverse events that might not be identified by RCTs that will include relatively small numbers of patients because of the nature of the disease, particularly within high-risk groups.

In summary, we acknowledge the role of RCTs in renal artery stenting; they are very reliable in establishing the proof of concept and efficacy in the ideal patient population. In our opinion, creating national and or state registries may be more suited to assessing the efficacy and broad applicability of stenting of renal arteries to the real-world community setting. Just like postmarketing surveillance is very important given the short duration and specialized settings of RCTs, complementing an RCT with establishment of registries at the centers participating in trials might provide clinicians with more definite approach to renal artery atherosclerotic disease management at relatively low cost. Such a registry may also set guidelines regarding best medical therapy (BMT). This, in turn, may raise the standard of care and result in more homogeneity within the registry population.