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The Need for Randomized Trials to Prove the Safety and Efficacy of Parachutes, Bulletproof Vests, and Percutaneous Renal Intervention

  • Christopher J. White
    Correspondence
    Address correspondence to Christopher J. White, MD, Department of Cardiovascular Diseases, John Ochsner Heart and Vascular Institute and Ochsner Clinical School-The University of Queensland School of Medicine, 1514 Jefferson Hwy, New Orleans, LA 70121
    Affiliations
    Professor of Medicine Department of Cardiovascular Diseases John Ochsner Heart and Vascular Institute and Ochsner Clinical School-The University of Queensland School of Medicine New Orleans, LA
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      In this issue of Mayo Clinic Proceedings, the informative review on atherosclerotic renal artery stenosis (ARAS) by Lao et al
      • Lao D
      • Parasher PS
      • Cho KC
      • Yeghiazarians Y
      Atherosclerotic renal artery stenosis—diagnosis and treatment.
      reminds us of the uncertainty and confusion regarding treatment with percutaneous renal intervention (PRI). Before we can consider treatment outcomes, however, it is necessary to appreciate the complexity of ARAS. It is not a single entity but manifests as 3 clinical conditions that may overlap: (1) renovascular hypertension, (2) ischemic nephropathy, and (3) the cardiac destabilization syndromes of flash pulmonary edema, refractory heart failure, and unstable angina.
      The debate over the effectiveness of PRI has been confused by a paradigm shift in treatment techniques. In the past, small randomized trials of balloon angioplasty for ARAS and renovascular hypertension had slightly positive outcomes favoring angioplasty,
      • Webster J
      • Marshall F
      • Abdalla M
      • et al.
      Scottish and Newcastle Renal Artery Stenosis Collaborative Group
      Randomised comparison of percutaneous angioplasty vs continued medical therapy for hypertensive patients with atheromatous renal artery stenosis.
      • Plouin PF
      • Chatellier G
      • Darné B
      • Raynaud A
      • Essai Multicentrique Medicaments vs Angioplastie (EMMA) Study Group
      Blood pressure outcome of angioplasty in atherosclerotic renal artery stenosis: a randomized trial.
      • van Jaarsveld BC
      • Krijnen P
      • Pieterman H
      • Dutch Renal Artery Stenosis Intervention Cooperative Study Group
      • et al.
      The effect of balloon angioplasty on hypertension in atherosclerotic renal-artery stenosis.
      as did a cohort-controlled study
      • Losito A
      • Errico R
      • Santirosi P
      • Lupattelli T
      • Scalera GB
      • Lupattelli L
      Long-term follow-up of atherosclerotic renovascular disease: beneficial effect of ace inhibition.
      and 2 meta-analyses.
      • Ives NJ
      • Wheatley K
      • Stowe RL
      • et al.
      Continuing uncertainty about the value of percutaneous revascularization in atherosclerotic renovascular disease: a meta-analysis of randomized trials.
      • Nordmann AJ
      • Logan AG
      Balloon angioplasty versus medical therapy for hypertensive patients with renal artery obstruction.
      During the past 15 years, treatment of ARAS has evolved from simple balloon angioplasty, which was marginally effective, to the current strategy of balloon-expandable stent placement, which reliably (>95%) yields patent renal arteries. Renal stent placement has been proven superior to balloon angioplasty in a randomized trial
      • van de Ven PJ
      • Kaatee R
      • Beutler JJ
      • et al.
      Arterial stenting and balloon angioplasty in ostial atherosclerotic renovascular disease: a randomised trial.
      and a meta-analysis.
      • Leertouwer TC
      • Gussenhoven EJ
      • Bosch JL
      • et al.
      Stent placement for renal arterial stenosis: where do we stand? A meta-analysis.
      Multiple clinical series and meta-analyses have demonstrated the safety and efficacy of renal stents for lowering blood pressure,
      • Leertouwer TC
      • Gussenhoven EJ
      • Bosch JL
      • et al.
      Stent placement for renal arterial stenosis: where do we stand? A meta-analysis.
      and multiple convincing nonrandomized studies and case series have shown the safety and efficacy of renal stenting for ischemic nephropathy.
      • Isles CG
      • Robertson S
      • Hill D
      Management of renovascular disease: a review of renal artery stenting in ten studies.
      Such an investigational history will lead many to wonder whether more prospective, randomized trials are needed.
      Contemporary medicine's indiscriminate desire for randomized controlled trials to assess treatment efficacy needs to be more carefully considered. No reasonable person would argue that randomized trials are needed to prove the efficacy of parachutes, bicycle helmets, or bulletproof vests,
      • Smith GCS
      • Pell JP
      Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials.
      ie, situations in which ethical and other reasons would hinder participation in a control vs a treatment group. But, what if—in these highly divergent situations—we specified that treatment results would be analyzed only in “borderline situations”? What if we wanted to understand the benefit of a parachute when jumping from a footstool, from a second story window, or from an airplane at 10,000 feet? At some point, we reach a situation of uncertainty (second story window) between the certainty that the parachute is not helpful (footstool) and the certainty that the parachute is helpful (10,000 feet from an airplane).
      The same argument can be made for renal stents. There are conditions for which reasonable persons would agree that renal stents are not useful (eg, <50% stenosis without a translesional pressure gradient). Conversely, there are ARAS conditions for which most would agree that renal stents are useful (eg, bilateral 90% ARAS and flash pulmonary edema).

      Messerli FH, Bangalore S, Makani H, et al. Flash pulmonary oedema and bilateral renal artery stenosis: the Pickering Syndrome [published online ahead of print March 15, 2011]. Eur Heart J. doi: 10.1093/eurheartj/ehr056.

      Finally, there are borderline ARAS conditions, eg, mild to moderate lesions with mild to moderate translesional pressure gradients, for which most of us are uncertain regarding the efficacy of PRI. These borderline conditions will, by definition, meet criteria for clinical equipoise, which is necessary for ethical randomization.
      Two recently published randomized trials, Angioplasty and Stenting for Renal Artery Lesions (ASTRAL)
      • Wheatley K
      • Ives N
      • Gray R
      • et al.
      Revascularization versus medical therapy for renal-artery stenosis.
      and Stent Placement and Blood Pressure and Lipid-lowering for the Prevention of Progression of Renal Dysfunction Caused by Atherosclerotic Ostial Stenosis of the Renal Artery (STAR),
      • Bax L
      • Woittiez AJ
      • Kouwenberg HJ
      • et al.
      Stent placement in patients with atherosclerotic renal artery stenosis and impaired renal function: a randomized trial.
      showed no benefit for renal stenting in mild to moderate ARAS. However, there is good reason to doubt the validity of the studies' conclusions. Major problems included the involvement of renal interventionists whose experience was minimal and who generated unacceptably high procedure complication rates and the indiscriminate enrollment of patients with mild ARAS who would not have benefitted from PRI.
      • White CJ
      Kiss my ASTRAL: one seriously flawed study of renal stenting after another [editorial].
      The reliance on visual angiographic assessment of severity of ARAS lesions and failure to ensure competence of renal interventionists are important flaws that corrupted the results of ASTRAL
      • Wheatley K
      • Ives N
      • Gray R
      • et al.
      Revascularization versus medical therapy for renal-artery stenosis.
      and STAR.
      • Bax L
      • Woittiez AJ
      • Kouwenberg HJ
      • et al.
      Stent placement in patients with atherosclerotic renal artery stenosis and impaired renal function: a randomized trial.
      The efficacy of renal artery stenting depends on our ability to identify which patients with ARAS are likely to respond to revascularization.
      • White CJ
      Optimizing outcomes for renal artery intervention.
      A meta-analysis suggests that only 60% to 70% of hypertensive patients with ARAS will clinically improve after renal stenting.
      • Losito A
      • Errico R
      • Santirosi P
      • Lupattelli T
      • Scalera GB
      • Lupattelli L
      Long-term follow-up of atherosclerotic renovascular disease: beneficial effect of ace inhibition.
      Why would a procedure with such a high technical success rate (>95%) result in such a modest clinical response? The answer is that we are likely treating some patients who do not have obstructive ARAS. The visual estimation of mild to moderate ARAS is an inadequate method to select patients for PRI.
      When determining the efficacy of any treatment, it is critically important to carefully define the population being studied. It is becoming clear that the “Achilles heel” of renal artery stenting is the inaccuracy of the traditional criterion standard of diagnosis, angiographic determination of ARAS severity. The visual estimation of lesion severity by angiography, the so-called oculostenotic reflex, has been shown repeatedly to overestimate the severity of arterial stenoses. Even with quantitative measurement, angiography is unable to discriminate between nonobstructive and significant ARAS (Figure).
      • Subramanian R
      • White CJ
      • Rosenfield K
      • et al.
      Renal fractional flow reserve: a hemodynamic evaluation of moderate renal artery stenoses.
      One solution that would improve patient selection for PRI is hemodynamic assessment of ARAS. Hemodynamic confirmation of severity of angiographic lesions can be accomplished by placing a small nonobstructive catheter (≤3 F) or a micromanometertipped pressure measuring guidewire (0.014-in) across the renal artery stenosis to measure a simultaneous translesional pressure gradient.
      • Mitchell JA
      • Subramanian R
      • White CJ
      • et al.
      Predicting blood pressure improvement in hypertensive patients after renal artery stent placement.
      • Mangiacapra F
      • Trana C
      • Sarno G
      • et al.
      Translesional pressure gradients to predict blood pressure response after renal artery stenting in patients with renovascular hypertension.
      Figure thumbnail gr1
      FIGUREThere is a poor correlation of quantitative angiographic diameter stenosis with baseline mean translesional pressure gradient (BPG) (left), hyperemic mean translesional pressure gradient (HPG) (middle), and renal fractional flow reserve (FFR) (right).
      From Catheter Cardiovasc Interv,
      • Subramanian R
      • White CJ
      • Rosenfield K
      • et al.
      Renal fractional flow reserve: a hemodynamic evaluation of moderate renal artery stenoses.
      with permission.
      Unfortunately, the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial, which has recently completed enrollment, is unlikely to settle this dispute or help to clarify which patients, lesions, and clinical conditions will benefit from renal stent placement. Once again, the investigators relied on angiographic criteria to select ARAS lesions for treatment. The inability of angiography to differentiate the severity of lesions will be problematic for the final analysis, particularly for intermediate ARAS lesions.
      Percutaneous renal intervention with renal artery stenting has benefitted many patients. It is important that we not throw the renal artery stent “baby” out with the bath water. Emotions run high on both sides of this argument, polarizing practitioners along specialty lines. Clearly, we need a better understanding of the value of PRI for “borderline conditions.” Angiographers and interventionists need to accept the fact that using hemodynamic criteria (translesional pressure gradient), not angiography, is the best way to determine the severity of ARAS. Because PRI clinical data have relied on angiographic selection criteria, we currently lack the evidence required to resolve these questions. What is needed, going forward, is less debate and more rational investigation.

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