Evidence and Renovascular Disease: Trials and Mistrials?

Occlusive renovascular disease presents a vexing challenge. Hypertension induced by renal artery stenosis is among the most widely studied and well-characterized causes of secondary hypertension. When arterial occlusion reaches critical levels, renal blood flow decreases and kidney function eventually deteriorates. It seems intuitive that restoring vessel patency and blood flow should provide clinical benefits both for relieving hypertension and preserving kidney function. This principle was widely accepted in the days of renovascular surgery (mainly in the 1970s) and after wider application of endovascular angioplasty and stenting (in the 1990s).¹ The value of searching for surgically curable hypertension and salvageable ischemic kidneys seemed self-evident.

Despite this history, management of the most common renovascular disease, atherosclerotic renal artery stenosis, has undergone dramatic shifts and triggered substantial controversy. Advances in anti-hypertensive drug therapy, including blockade of the renin-angiotensin system, make achieving goal blood pressures in renovascular hypertension with tolerable inexpensive regimens possible for most patients. Because atherosclerotic renal artery stenosis is associated with advancing age and multiple comorbid conditions, many patients with atherosclerotic renal artery stenosis experience unrelated disease events and now are commonly managed without revascularization. Whether this approach serves individual patients well in the long run remains controversial and has prompted several prospective randomized trials. Despite negative or ambiguous outcomes from these trials, numerous observational case series and registry data repeatedly demonstrate that some patients experience reversible kidney failure, refractory hypertension, and circulatory overload associated with atherosclerotic renal artery stenosis that can be reversed with effective revascularization. The question of how to integrate and interpret the body of data available in this field is challenging for clinicians in general and for nephrologists in particular.

What Does This Important Study SHOW?

The article by Raman et al² was commissioned through the Agency for Healthcare Research and Quality (AHRQ) and presents results of a systematic review of published reports regarding the role of renal revascularization as compared to medical therapy only for patients with atherosclerotic renal arterial stenosis. This project sought to integrate more recent prospective randomized trials (specifically ASTRAL [Angioplasty and Stenting for Renal Artery Lesions]³ and CORAL [Cardiovascular Outcomes in Renal Atherosclerotic Lesions]⁴) with previous studies the same group had summarized in 2007. It also included nonrandomized clinical trials and case reports published during the same intervals. Hence, it presents a systematic review of published literature between 1993 and 2015. More than 1,560 citations were obtained from multiple databases, of which 189 were reviewed, in addition to 54 references from the initial report from 2007. These included 15 reports specifically comparing outcomes of medical therapy as compared to percutaneous transluminal angioplasty with stenting. Thirty-nine reports focused on adverse outcomes; 28 focused on outcome predictors, subgroup, or cotreatment analyses; and 20 focused on specific high-risk patient outcomes.

Total enrolled patients in prospective randomized controlled trials (RCTs) were 2,178 (n = 7 studies). Data from n = 8 additional nonrandomized controlled studies included 1,828 patients. Importantly, decompensation (generally designated as episodes of pulmonary edema and/or rapidly progressive kidney failure) was an exclusion criterion in the prospective RCTs. Four other studies included patients with episodes of flash pulmonary edema or rapidly progressive hypertension and progressive kidney failure. Due to substantial clinical heterogeneity, no combination of data for metaanalysis was undertaken. All studies reviewed were evaluated using the risk-of-bias tools of Cochrane analysis and were examined for study, participant, and clinical atherosclerotic renal artery stenosis characteristics, as well as analytical design. The reviewers concluded that most studies were underpowered to examine mortality and other major outcomes over the time frames reported. As a result, many of the end points were considered to have low strength of evidence and identified no difference regarding mortality, progression to end-stage renal disease, or rates of cardiovascular disease events (definitions of these varied widely across different studies). Similarly, they concluded with low strength of evidence that some patients experience improved kidney function with renal revascularization and that blood pressure control was not different between those treated with medication primarily versus percutaneous transluminal angioplasty with stenting.

Remarkably, adverse events related to revascularization procedures were uncommon. (Adverse effects related to medical therapy alone were not reported for the large majority of reports). Procedure-related deaths were rare (0.5% over 3 RCTs; none in CORAL, the largest trial). Adverse events such as pseudo-aneurysm, distal embolization, and acute kidney injury were also infrequent in recent series, averaging 3.2% overall.

Analysis of participant demographic features failed to identify predictors of benefit consistently, including ethnicity, pre-existing diabetes, or bilateral disease. Most trials included patients defined simply by the presence of atherosclerotic renal artery stenosis and moderate clinical manifestations, such as hypertension or stage 3 chronic kidney disease. By contrast, observational series and case reports targeting decompensated or rapidly changing clinical syndromes identified mortality and clinical benefits for such patients. These reports underscore the limited generalizability of the prospective RCTs.

The authors conclude from these data that “overall, the evidence does not support a benefit with percutaneous transluminal angioplasty with stenting over medical therapy alone in most patients with ARAS [atherosclerotic renal artery stenosis].”^2,p9 They acknowledge that high-risk patients, namely patients who have worse kidney function or higher blood pressure (both variably defined) or flash pulmonary edema, may be more likely to experience improved kidney function and blood pressure after percutaneous transluminal angioplasty with stenting.

How Does This Study Compare With Prior Studies?

This report summarizes the published experience with percutaneous transluminal angioplasty with stenting in atherosclerotic renal artery stenosis in a more systematic fashion than the individual studies and most clinical reviews. It offers the benefit of experienced study analysis from the perspective of the AHRQ, without absolutely excluding the information available from observational and clinical reports. Several features merit particular emphasis.

First, despite the efforts to enlarge prospective RCTs, individual reports and combined series remain underpowered to detect moderate clinical benefits regarding mortality and major cardiovascular events. Hence, the authors' conclusion that there is no benefit to renal revascularization must be tempered with the caveat of the low strength of evidence.

Second, multiple observational series and case reports underscore major clinical and potential mortality benefits associated with renal revascularization in high-risk subsets. Importantly, these subsets are defined by clinical syndromes (eg, flash pulmonary edema) that are not evidently related to specific characteristics of the vascular stenosis itself, for example, the severity of occlusion or whether the vascular lesions are unilateral or bilateral.

Third, reported complications associated with percutaneous transluminal angioplasty with stenting in the recent series are appreciably lower than in many earlier reports. Previous studies of targeted renal artery stent procedures report significant clinical events averaging 9% to 15% during the early postprocedure period that may increase to as high as 20% if followed up longer.⁵ Whether these reports truly reflect improved techniques and interventional expertise or patient selection cannot be fully determined. Nonetheless, these studies suggest that percutaneous transluminal angioplasty with stenting in experienced centers using more recent low-profile systems can restore kidney blood flow at low risk.

What Should Clinicians and Researchers Do?

At face value, the data presented in this systematic review generally support the inclination to delay renal artery revascularization in the management of patients with renovascular hypertension. Without a doubt, results of these trials have reduced the frequency of renal revascularization procedures in the United States and Europe. It may be argued that many previously unwarranted referrals for stenting procedures are less likely to occur. Despite these observations, professional consensus groups argue that a subset of high-risk patients with atherosclerotic renal artery stenosis may benefit from percutaneous transluminal angioplasty with stenting. The American Heart Association/American College of Cardiology guidelines from 2005 provide a class I recommendation for percutaneous transluminal angioplasty with stenting for high-risk patients with hemodynamically significant atherosclerotic renal artery stenosis and recurrent unexplained flash pulmonary edema.⁶ This general approach has been confirmed and restated in recent consensus documents from multiple cardiovascular and interventional groups.^7,8 These recommendations take into consideration that some patients treated with optimal medical therapy nonetheless develop episodes of acute decompensation.

Recent reviews of treatment-resistant hypertension also provide guidelines stating that percutaneous transluminal angioplasty with stenting should be considered for resistant or accelerated hypertension in patients with hemodynamically significant atherosclerotic renal artery stenosis and/or intolerance to antihypertensive medication.^9,10 A recent subset analysis of more than 300 patients from CORAL with low levels of proteinuria identified a significant mortality benefit and reduction in cardiovascular event rate in patients with stents.¹¹ Importantly, patients with atherosclerotic renal artery stenosis presenting with rapidly declining kidney function with bilateral atherosclerotic renal artery stenosis or stenosis to a solitary functioning kidney should be considered for revascularization to preserve kidney function.¹²

Nephrologists need to recognize these major consequences of atherosclerotic renal artery stenosis not addressed in the RCTs: progressive deterioration of kidney function, uncontrolled hypertension, and flash pulmonary edema. Rather than pursue a single approach to patients with atherosclerotic renal artery stenosis, particular clinical conditions and changes over time need to be evaluated for each patient. Some nuances and limitations in this field extend beyond those evident in this systematic review. Serum creatinine as a marker of kidney function in atherosclerotic renal artery stenosis is flawed due to the opposing compensatory hemo-dynamics in the stenosed and contralateral kidney.¹³ Accordingly, it is sometimes difficult to gauge the effect of both progressive disease and restoring blood flow on kidney function simply based on peripheral blood values alone. Timing of vascular intervention is another critical question. At some point, renal revascularization accomplishes little if the kidney structure has been irreversibly damaged. Long-term reductions in renal blood flow associated with tissue hypoxia in an atherosclerotic milieu lead to vascular rarefaction, activation of inflammatory injury, and fibrosis.¹⁴ These are the dangers of waiting too long to restore blood flow to a critical organ. An understated corollary of depending on medical therapy primarily is the obligation to follow up individual patients for disease progression. Partly as a result of negative trials, we are encountering more patients who are referred after passing the point at which revascularization may be of benefit.

For the practicing nephrologist, it is important not to miss the forest for the trees. This includes not overlooking the patient who may benefit from renal artery revascularization. Many patients may do well with medical therapy alone for many years. Nonetheless, indications for renal artery revascularization still exist, lest we forget the individual patient in the midst of meta-analyses.