Primary stenting for atherosclerotic renal artery stenosis

Primary stenting for atherosclerotic renal artery stenosis Olivier Steichen, Laurence Amar, Pierre-François Plouin To cite this version: Olivier Steichen, Laurence Amar, Pierre-François Plouin. Primary stenting for atherosclerotic renal artery stenosis. Journal of Vascular Surgery, Elsevier, 2010, 51 (6), pp.1574-1580.e1. <10.1016/j.jvs.2010.02.011>. <hal-01171785> HAL Id: hal-01171785 https://hal.sorbonne-universite.fr/hal-01171785 Submitted on 6 Jul 2015 HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Abstract and Title Page Primary Stenting for Atherosclerotic Renal Artery Stenosis Authors: Olivier Steichen, a MD, Laurence Amar, b MD, Pierre-François Plouin, b MD a Assistance Publique - Hôpitaux de Paris, Centre d Investigations Cliniques, Hôpital Européen Georges Pompidou, Paris, France ; Université Paris Descartes, Faculté de Médecine, Paris, France b Assistance Publique - Hôpitaux de Paris, Service d Hypertension Artérielle, Hôpital Européen Georges Pompidou, Paris, France ; Université Paris Descartes, Faculté de Médecine, Paris, France Corresponding author: Professeur Pierre-François Plouin Service d Hypertension Artérielle Hôpital Européen Georges Pompidou 20 40 rue Leblanc 75015 Paris, France pierre-francois.plouin@egp.aphp.fr Abstract word count: 146

Abstract Introduction: Endovascular treatment for atherosclerotic renal artery stenosis (ARAS) was first performed over 30 years ago and its number is increasing rapidly since then. However, only recently have large randomized trials rigorously evaluated its clinical benefit. Methods: We performed a systematic review of controlled studies on primary stenting for atherosclerotic renal artery stenosis. Studies were included if they compared the outcome of stenting and other treatments, or the outcome associated with different stent characteristics or stenting methods. Results: Stenting is preferred over angioplasty alone and over surgery when revascularization is indicated for ostial ARAS, except in cases of coexistent aortic disease indicating surgery. Randomized controlled trials showed no significant benefit and substantial risk of renal artery stenting over medication alone in patients with atherosclerotic ARAS without compelling indication. Procedure improvements, like distal embolic protection devices and coated stents, are not associated with better clinical outcomes after stent placement for ARAS. Conclusion: Recent evidence shows that impaired renal function associated with ARAS is more stable over time than previously observed. Optimal medical treatment should be the preferred option for most patients with ARAS. Only low level evidence support compelling indications for revascularization in ARAS, including rapidly progressive hypertension or renal failure, and flash pulmonary edema.

*Manuscript 1 Primary Stenting for Atherosclerotic Renal Artery Stenosis Authors: Olivier Steichen, a MD, Laurence Amar, b MD, Pierre-François Plouin, b MD a Assistance Publique - Hôpitaux de Paris, Centre d Investigations Cliniques, Hôpital Européen Georges Pompidou, Paris, France ; Université Paris Descartes, Faculté de Médecine, Paris, France b Assistance Publique - Hôpitaux de Paris, Service d Hypertension Artérielle, Hôpital Européen Georges Pompidou, Paris, France ; Université Paris Descartes, Faculté de Médecine, Paris, France Corresponding author: Professeur Pierre-François Plouin Service d Hypertension Artérielle Hôpital Européen Georges Pompidou 20 40 rue Leblanc 75015 Paris, France pierre-francois.plouin@egp.aphp.fr Abstract word count: Manuscript word count:

2 Introduction Atherosclerotic renal artery stenosis (ARAS) may lead to hypertension, impaired renal function and cardiac disorders (flash pulmonary edema, uncontrolled heart failure or unstable angina pectoris). Since the first report of ARAS angioplasty more than 30 years ago, endovascular approaches have supplanted surgical approaches for revascularization. However, few data are available to guide medical decisions in the treatment of ARAS. The objective of this review is to summarize the available evidence on primary stent placement for ARAS. Methods Many uncontrolled retrospective and prospective cohort studies of stent placement for atherosclerotic RAS have been published. However, due to the lack of control groups, their results fail to provide a sound basis for medical decision making. We therefore limited our review to studies comparing renal artery stenting with other treatment options for atherosclerotic RAS, or comparing different procedural strategies. We searched Medline, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov with combinations of the following keywords: renal artery obstruction, renal artery stenosis, renovascular disease, renovascular hypertension, ischemic nephropathy, stent, and endovascular. We also screened reference lists of original articles, guidelines and reviews. Levels of evidence were rated using a scale provided by the Journal of Vascular Surgery (Web Appendix 1).

3 Results Benefit of renal artery stenting over angioplasty ARAS predominantly involves the proximal third of the artery and is prone to restenosis after angioplasty alone. Primary stenting in ARAS was compared to the use of angioplasty alone in both a non-randomized study 1 and a randomized controlled trial 2 (RCT) (Table 1). The results were consistent with those of a meta-analysis indirectly comparing these two treatment strategies 3 : procedural success was higher and restenosis rate lower with stenting than with angioplasty alone, but clinical outcome did not differ significantly. Findings from the RCT suggest that, in order ensure long term patency, reintervention would be needed in 57% of patients after angioplasty alone, but only in 12% of patients after primary stenting. 2 Primary stent placement thus seems to show a more favorable cost-efficacy profile and lower riskbenefit ratio than angioplasty alone for ARAS that require intervention. 4 Benefit of renal artery stenting over surgery One RCT compared endovascular stenting with open surgical reconstruction in ARAS patients without concurrent aortic disease. 5 No significant difference in treatment outcome was found but surgery was associated with a longer initial hospitalization period (Table 1). This study thus suggests that stenting should generally be the preferred revascularization technique and that surgery should be limited to cases needing concomitant aortic reconstruction. 4 Comparison of renal artery stenting with medication alone Two small non-randomized studies 6, 7 and two RCTs of limited power 8, 9 compared stent placement with secondary prevention treatment alone (antihypertensive agents, statins and

4 aspirin) in ARAS patients with difficult-to-treat hypertension or unexplained renal function impairment. Overall, these studies did not show a clinically meaningful improvement in blood pressure control or renal function stabilization in patients receiving stents (Table 2). The results of the much larger ASTRAL RCT further question the benefit of ARAS stenting over medical therapy. 10 Improvement in renal function and renal event-free survival did not differ significantly between the two strategies. Numbers of deaths and cardiovascular events were also similar in both study groups, but the confidence intervals (CI) of hazard ratios cannot exclude relevant differences in clinical outcome: 0.90 [95% CI: 0.69 to 1.18] for overall survival and 0.94 [95% CI: 0.75 to 1.19] for cardiovascular event-free survival. A cohort study evaluated the change in left ventricular mass (LVM) after stent placement in patients with ARAS and hypertension or impaired renal function. 11 Patients with essential hypertension were used as controls. After adjustment for various potential confounding variables, the results suggested a beneficial effect of stent placement on LVM, which could not be fully accounted for by the observed reduction in blood pressure. A comparative study in patients with ARAS was unable to confirm this benefit, but it was grossly under-powered, with only eight patients in the stent group. 12 The undergoing ASTRAL-heart sub-study 13 and RADAR study 14 were designed to properly assess cardiac outcomes after stent placement. Stent placement is a minimally invasive procedure but patients with ARAS are frail and prone to complications. In ASTRAL, the proportion of patients experiencing at least one adverse event was 9% during the first 24 hours following stent placement and 20% between the 2 nd and 30 th days; overall, 6% experienced serious complications related to revascularization. 10

5 The Web Appendix 2 lists the adverse events reported in 22 large prospective cohorts (3453 patients) after stent placement for ARAS 15 and in the ASTRAL trial. Procedure improvements In some patients, acute deterioration of renal function may be due to contrast-induced nephropathy and atheroembolism. Prophylactic treatment for contrast-nephropathy should therefore be considered. Effective antithrombotic treatment and use of distal embolic protection devices during the procedure could prevent the consequences of atheroembolism. However, a comparative study 16 and a RCT 17, 18 did not find any convincing beneficial effect of protection devices on clinical outcome (Table 3). In the RCT, no change was seen in glomerular filtration rate following intervention in a small patient subgroup receiving both abciximab and a distal protection device, whereas glomerular filtration rate declined in the three other groups. Restenosis occurred in 10% to 21% of cases studied over a follow-up period of 3 to 40 months after stent placement for ARAS. 15 Optimal long-term antithrombotic treatment and coated stents may improve these rates. Patients usually receive long-term treatment with antiplatelet agents following stent placement. The US multicenter trial found no beneficial effect of three-month warfarin treatment following the procedure. 19 Four comparative studies showed no improvement in restenosis rate and clinical outcome with gold-, carbon- or sirolimus-coated stents 20-23 (Table 3). Discussion The past decade has seen the development of highly effective treatment regimens in patients with atherosclerosis, also exerting a protective effect on renal function in patients with ARAS.

6 Renal function decline was very gradual in patients in ASTRAL, even in those with severe anatomical disease. 10 Optimal medical treatment without stent placement should be the preferred option for asymptomatic patients or for patients who do not have a compelling clinical indication for revascularization, like accelerated hypertension, unexplained rapidly declining renal function, declining renal function after the administration of angiotensinconverting-enzyme (ACE) inhibitors, or flash pulmonary edema. Outcome following renal artery stenting in specific subgroups However, the basis for this recommendation comes from comparative studies that included heterogeneous populations, including some patients with stenosis of debatable hemodynamic significance. Overall negative results do not exclude the possibility that several subgroups of patients may benefit from stenting. There are clues suggesting that hypertension or impaired renal function in a patient are consequences of ARAS rather than merely associated essential hypertension or nephrosclerosis. As such, rapidly deteriorating renal function or worsening hypertension control, low renal resistance index, low proteinuria, and severe stenosis, particularly affecting either both renal artery or a solitary kidney, are considered to be predictors of good outcome after stent placement. However, these predictive factors were established from cohort studies, often with defective methods and showing conflicting results. Moreover, even if they truly predict a better response to stent placement, they may also predict a better response to optimized medical treatment. Only comparative studies can definitely assess the relative efficacy of both treatment strategies in specific subgroups.

7 For example, severe stenosis is thought to justify a more aggressive approach than moderate stenosis. However, ASTRAL showed no difference in outcome between ARAS subgroups of varying severity. 10 Furthermore, a post hoc analysis showed very gradual renal function decline in 163 patients with 70% ARAS on both sides or affecting a solitary kidney, with a similar outcome observed for patients treated medically and those treated with stent placement. Similarly, a high renal resistance index (RI) is considered as a marker of severe nephrosclerosis. An often cited study found that a RI 0.8 was associated with poor blood pressure and renal outcome in ARAS treated by revascularization, predominantly involving angioplasty alone. 24 However, more recent prospective studies of ARAS treated with stent placement were unable to replicate this finding. 25, 26 Some studies even showed improved renal function 27 or blood pressure 28 after stent placement in patients with a high RI. The ongoing CORAL study should provide a definitive answer to this issue. 29 The benefit of stenting still has to be properly evaluated in patients with the aforementioned compelling indications, who have been explicitly or implicitly excluded from randomized trials. Cohort studies strongly suggest that ARAS patients with deteriorating renal function after the administration of ACE inhibitors or angiotensin-receptor blockers may tolerate them better after stent placement if they are necessary. 30-33 There are no published reports comparing current optimized medical treatment to stent placement in patients with flash pulmonary edema, uncontrolled heart failure or unstable angina pectoris; however, a pathophysiological rationale and the dramatic results of small series 30, 34, 35 have provided the basis for recommendation for stent placement. 4

8 Perspectives CORAL 29 and RADAR 14 are the two largest ongoing RCTs registered under ClinicalTrials.gov evaluating the benefit of stent placement over current best medical treatments. CORAL plans to enroll 1080 patients with ARAS 60% and with hypertension or renal dysfunction. The primary endpoint is cardiovascular and renal event-free survival; secondary endpoints include evaluation of the renal resistance index as an outcome predictor after stent placement and the benefit of stent placement in important patient subgroups (women, African-Americans, diabetics, bilateral stenosis). RADAR plans to recruit 300 patients with impaired renal function and ARAS estimated at 70%, using Doppler indices. The primary endpoint will be the change in renal function; clinical and echographic cardiac outcomes are secondary endpoints of the study. Conclusion Impaired renal function associated with ARAS is probably more stable over time than previously thought. On the opposite, potential complications of stent placement for ARAS are often underestimated. According to the results of recent RCTs, optimal medical treatment should be the preferred option for most patients with ARAS: antihypertensive agents including ACE inhibitors or angiotensin-receptor blockers, statins, and antiplatelet agents. Results of ongoing trials are awaited to properly address the role of stenting in patients with severe anatomical disease and to look for an effect of stent placement on left ventricular hypertrophy, beyond blood pressure lowering. Only pathophysiological rationale and anecdotal evidence support compelling indications for revascularization in ARAS, including rapidly progressive hypertension or renal failure, and flash pulmonary edema.

9 References 1. Baumgartner I, von Aesch K, Do DD, Triller J, Birrer M, Mahler F. Stent placement in ostial and nonostial atherosclerotic renal arterial stenoses: a prospective follow-up study. Radiology 2000;216:498-505. 2. van de Ven PJG, Kaatee R, Beutler JJ, Beek FJ, Woittiez AJ, Buskens E, et al. Arterial stenting and balloon angioplasty in ostial atherosclerotic renovascular disease: a randomised trial. Lancet 1999;353:282-6. 3. Leertouwer TC, Gussenhoven EJ, Bosch JL, van Jaarsveld BC, van Dijk LC, Deinum J, et al. Stent placement for renal arterial stenosis: where do we stand? A meta-analysis. Radiology 2000;216:78-85. 4. Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL, et al. ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. Circulation 2006;113:e463-654. 5. Balzer KM, Pfeiffer T, Rossbach S, Voiculescu A, Modder U, Godehardt E, et al. Prospective randomized trial of operative vs interventional treatment for renal artery ostial occlusive disease (RAOOD). J Vasc Surg 2009;49:667,74; discussion 674-5. 6. Arthurs Z, Starnes B, Cuadrado D, Sohn V, Cushner H, Andersen C. Renal artery stenting slows the rate of renal function decline. J Vasc Surg 2007;45:726,31; discussion 731-2. 7. Zalunardo N, Rose C, Starovoytov A, Djurdjev O, Fox R, Taylor P, et al. Incidental atherosclerotic renal artery stenosis diagnosed at cardiac catheterization: no difference in kidney function with or without stenting. Am J Nephrol 2008;28:921-8. 8. Bax L, Woittiez AJ, Kouwenberg HJ, Mali WP, Buskens E, Beek FJ, et al. Stent placement in patients with atherosclerotic renal artery stenosis and impaired renal function: a randomized trial. Ann Intern Med 2009;150:840-8. 9. Ziakka S, Ursu M, Poulikakos D, Papadopoulos C, Karakasis F, Kaperonis N, et al. Predictive factors and therapeutic approach of renovascular disease: four years' follow-up. Ren Fail 2008;30:965-70.

10 10. Wheatley K, Ives N, Gray R, Kalra PA, Moss JG, Baigent C, et al. Revascularization versus medical therapy for renal-artery stenosis. N Engl J Med 2009;361:1953-62. 11. Zeller T, Rastan A, Schwarzwalder U, Muller C, Frank U, Burgelin K, et al. Regression of left ventricular hypertrophy following stenting of renal artery stenosis. J Endovasc Ther 2007;14:189-97. 12. Wright JR, Shurrab AE, Cooper A, Kalra PR, Foley RN, Kalra PA. Progression of cardiac dysfunction in patients with atherosclerotic renovascular disease. QJM 2009;102:695-704. 13. Hegarty J, Wright JR, Kalra PR, Kalra PA. The heart in renovascular disease--an association demanding further investigation. Int J Cardiol 2006;111:339-42. 14. Schwarzwalder U, Hauk M, Zeller T. RADAR - A randomised, multi-centre, prospective study comparing best medical treatment versus best medical treatment plus renal artery stenting in patients with haemodynamically relevant atherosclerotic renal artery stenosis. Trials 2009;10:60. 15. Balk E, Raman G, Chung M, Ip S, Tatsioni A, Alonso A, et al. Effectiveness of management strategies for renal artery stenosis: a systematic review. Ann Intern Med 2006;145:901-12. 16. Singer GM, Setaro JF, Curtis JP, Remetz MS. Distal embolic protection during renal artery stenting: impact on hypertensive patients with renal dysfunction. J Clin Hypertens (Greenwich) 2008;10:830-6. 17. Cooper CJ, Haller ST, Colyer W, Steffes M, Burket MW, Thomas WJ, et al. Embolic protection and platelet inhibition during renal artery stenting. Circulation 2008;117:2752-60. 18. Kanjwal K, Haller S, Steffes M, Virmani R, Shapiro JI, Burket MW, et al. Complete versus partial distal embolic protection during renal artery stenting. Catheter Cardiovasc Interv 2009;73:725-30. 19. Rees CR. Stents for atherosclerotic renovascular disease. J Vasc Interv Radiol 1999;10:689-705. 20. Zeller T, Muller C, Frank U, Burgelin K, Sinn L, Horn B, et al. Gold coating and restenosis after primary stenting of ostial renal artery stenosis. Catheter Cardiovasc Interv 2003;60:1,6; discussion 7-8. 21. Zeller T, Rastan A, Kliem M, Schwarzwalder U, Frank U, Burgelin K, et al. Impact of carbon coating on the restenosis rate after stenting of atherosclerotic renal artery stenosis. J Endovasc Ther 2005;12:605-11. 22. Zahringer M, Sapoval M, Pattynama PM, Rabbia C, Vignali C, Maleux G, et al. Sirolimus-eluting versus bare-metal low-profile stent for renal artery treatment (GREAT Trial): angiographic follow-up after 6 months and clinical outcome up to 2 years. J Endovasc Ther 2007;14:460-8. 23. Nolan BW, Schermerhorn ML, Powell RJ, Rowell E, Fillinger MF, Rzucidlo EM, et al. Restenosis in goldcoated renal artery stents. J Vasc Surg 2005;42:40-6.

11 24. Radermacher J, Chavan A, Bleck J, Vitzthum A, Stoess B, Gebel MJ, et al. Use of Doppler ultrasonography to predict the outcome of therapy for renal-artery stenosis. N Engl J Med 2001;344:410-7. 25. Rivolta R, Bazzi C, Stradiotti P, Paparella M. Stenting of renal artery stenosis: is it beneficial in chronic renal failure?. J Nephrol 2005;18:749-54. 26. Rocha-Singh K, Jaff MR, Lynne Kelley E. Renal artery stenting with noninvasive duplex ultrasound followup: 3-year results from the RENAISSANCE renal stent trial. Catheter Cardiovasc Interv 2008;72:853-62. 27. Zeller T, Frank U, Muller C, Burgelin K, Sinn L, Horn B, et al. Stent-supported angioplasty of severe atherosclerotic renal artery stenosis preserves renal function and improves blood pressure control: long-term results from a prospective registry of 456 lesions. J Endovasc Ther 2004;11:95-106. 28. Garcia-Criado A, Gilabert R, Nicolau C, Real MI, Muntana X, Blasco J, et al. Value of Doppler sonography for predicting clinical outcome after renal artery revascularization in atherosclerotic renal artery stenosis. J Ultrasound Med 2005;24:1641-7. 29. Cooper CJ, Murphy TP, Matsumoto A, Steffes M, Cohen DJ, Jaff M, et al. Stent revascularization for the prevention of cardiovascular and renal events among patients with renal artery stenosis and systolic hypertension: rationale and design of the CORAL trial. Am Heart J 2006;152:59-66. 30. Gray BH, Olin JW, Childs MB, Sullivan TM, Bacharach JM. Clinical benefit of renal artery angioplasty with stenting for the control of recurrent and refractory congestive heart failure. Vasc Med 2002;7:275-9. 31. Gross CM, Kramer J, Waigand J, Uhlich F, Olthoff H, Luft FC, et al. Ostial renal artery stent placement for atherosclerotic renal artery stenosis in patients with coronary artery disease. Cathet Cardiovasc Diagn 1998;45:1-8. 32. Khosla S, Ahmed A, Siddiqui M, Trivedi A, Benatar D, Salem Y, et al. Safety of angiotensin-converting enzyme inhibitors in patients with bilateral renal artery stenosis following successful renal artery stent revascularization. Am J Ther 2006;13:306-8. 33. van de Ven PJG, Beutler JJ, Kaatee R, Beek FJ, Mali WP, Geyskes GG, et al. Transluminal vascular stent for ostial atherosclerotic renal artery stenosis. Lancet 1995;346:672-4. 34. Bloch MJ, Trost DW, Pickering TG, Sos TA, August P. Prevention of recurrent pulmonary edema in patients with bilateral renovascular disease through renal artery stent placement. Am J Hypertens 1999;12:1-7. 35. Khosla S, White CJ, Collins TJ, Jenkins JS, Shaw D, Ramee SR. Effects of renal artery stent implantation in patients with renovascular hypertension presenting with unstable angina or congestive heart failure. Am J Cardiol 1997;80:363-6.

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Table 1 Table 1. Studies comparing stent placement with other interventions for atherosclerotic renal artery stenosis Reference Primary stent vs Angioplasty alone Design Years LOE Inclusion criteria % stenosis Mean renal function Mean blood pressure Bilateral treatment Number of patients Mean follow up Outcomes Van de Ven RCT 1999 2 1993-1997 I Hypertension + positive renography or a rise in Creatinin 20% on ACEI Stenosis > 50% Creatinine 1.8 mg/dl 186/103 mmhg 21% 41 patients (stent); 40 patients (angioplasty) 6 months 65% relative reduction in risk of restenosis with stents at 6 months angiography (p<0.001 No difference in blood pressure or renal outcome Baumgartner Prospective 2000 1 1994-1998 II-2 Hypertension Stenosis > 60% Creatinine 2.0 mg/dl 179/95 mmhg 37% 163 patients; 70 arteries (stent); 130 arteries (angioplasty) 9 months 70% relative reduction in risk of restenosis with stents for ostial stenoses at 12 months ultrasound study (p=0.002) No comparative data on blood pressure and renal outcome Stent vs Surgery Balzer 2009 5 RCT 1998-2004 I Hypertension Stenosis > 70% Creatinine 1.45 mg/dl 170/88 mmhg 22% (stent), 81% (surgery) 22 patients (stent); 27 patients (surgery) from 54 to 96 months Initial hospitalization: 10 days for stenting and 18 days for surgery No difference in frequency of complications, in long-term patency, blood pressure or renal outcome LOE: level of evidence; RCT: randomized-controlled trial; ACEI: angiotensin-converting-enzyme inhibitors

Table 2 Table 2. Studies comparing stent placement with medication alone for atherosclerotic renal artery stenosis Reference Design Years LOE Inclusion criteria % stenosis Renal function Mean blood pressure Bilateral treatment Intervention; Control Number of patients Mean follow up Outcomes ASTRAL RCT 2009 10 2000-2007 I Uncontrolled hypertension or unexplained impaired renal function Stenosis > 50% GFR 40 151/76 mmhg (or solitary kidney) 20% Stent; Discretionary medication 403 patients (stent); 403 patients (no stent) 34 months No difference in renal function decline, renal event-free survival, BP, cardiovascular event-free survival or overall survival, regardless of baseline GFR, baseline GFR decline rate, severity of renal artery stenosis, and severity of anatomical disease STAR RCT 2009 8 2000-2005 I Impaired renal function but stable BP Stenosis > 50% GFR 45 160/82 mmhg 46% Stent; Semistandardized medication 45 patients (stent); 46 patients (no stent) 24 months No difference in renal event-free survival, in blood pressure outcome or overall survival Ziakka RCT 2008 9 Not stated II-1 Hypertension Mean stenosis 74% Creatinine 2.3 mg/dl 176/89 mmhg 34% (+ 5% solitary kidney) Stent; Discretionary medication 46 patients (stent); 36 patients (no stent) 48 months Renal function improved in 31% with stent vs 0% with medication (p<0.001), but improved or stabilized in 64% with stent vs 70% with medication (not significant) Zalunardo Retrospective 2008 7 2001-2005 II-2 Coronarography and uncontrolled hypertension, Stenosis > 50% GFR 55 158/73 mmhg (stent), 40% (stent), 21% Stent if uncontrolled hypertension, 67 patients (stent); 38 months (stent); 27 months No difference in renal function decline

unexplained renal failure or pulmonary edema 142/73 mmhg (medic) (medic) worsening renal function, pulmonary edema, or ACEI sensitivity 73 patients (no stent) (medic) Arthurs Retrospective 2007 6 2001-2006 II-2 Uncontrolled hypertension, worsening renal function, cardiac disturbance, or ACEI intolerance Stenosis > 60% Creatinine 1.5 mg/dl (stent), 1.0 mg/dl (medic) 162/75 mmhg (stent), 142/73 mmhg (medic) 58% No stent if inadequate antihypertensive regimen, poor patient compliance, acute medical condition, resistance index > 0.80, or stenosis < 70% 18 patients (stent); 22 patients (no stent) 15 months No difference in overall and coronary event free survival No difference in 6 months blood pressure outcome Stabilization of renal function with stent, especially if preexisting renal dysfunction (p<0.05 compared to medication alone) LOE: level of evidence; RCT: randomized-controlled trial; GFR: glomerular filtration rate (in ml/min/1.72m²); ACEI: angiotensin-convertingenzyme inhibitors

Table 3 Table 3. Evaluation of procedural improvements for stent placement in atherosclerotic renal artery stenosis Reference With vs without protection device Design; Years LOE Inclusion criteria % stenosis Number of patients Mean follow up Outcomes Cooper 2008 17, 18 RCT 2002-2007 I Hypertension, renal failure, or cardiac destabilization Stenosis > 50% 100 patients randomized in 2x2 groups: with or without Angiogard (filter); with or without abciximab 1 month No difference in procedural and blood pressure outcome No overall difference in renal outcome but a significant improvement in the group randomized to Angioguard + abciximab Similar outcomes whether distal embolic protection was complete or incomplete (at least one renal artery branch not protected) Singer 2008 16 Retrospective 2002-2005 II-2 GFR < 60 and anatomic eligibility for the use of a protection device Not stated 31 patients (various protection devices); 17 patients (no protection device) 12 months No difference in blood pressure and renal outcomes at 6 or 12 months Bare stents vs coated stents Zeller 2003 20 Prospective 1996-2000 II-1 Hypertension Stenosis > 70% 54 patients (gold coated stent); 117 patients (bare metal stent) 12 months No difference in primary success rate or 12 months restenosis rate No data on blood pressure and renal outcome Zeller 2005 21 Prospective 2002-2004 II-1 Hypertension Stenosis > 70% 68 patients (carbon coated stent); 57 patients (bare metal stent) 22 months No difference in primary success or 12 months restenosis rate No data on blood pressure and renal outcome Zahringer Prospective II-1 Hypertension and Stenosis > 50% 53 patients Up to 24 No difference in 6 months restenosis rate (systematic

2007 22 2001-2003 non-severe renal failure (sirolimus-coated stent); 52 patients (bare metal stent) months control angiography) or later restenosis No difference in blood pressure or renal outcome at 6, 12 and 24 months Nolan 2005 23 Retrospective 2000-2003 II-2 Difficult to treat hypertension or chronic renal failure Stenosis > 75% or systolic transstenotic gradient over 15 mmhg 44 patients (gold coated stent); 33 patients (bare metal stent) 12 months No difference in primary success rate but significantly more restenosis with gold-coated stents after 12 months (hazard ratio 3.3 [95%CI 1.2 to 8.7]) Improved blood pressure in 77% with gold-coated stents vs 87% with bare metal stents (p=0.04); no difference in renal outcome LOE: level of evidence; GFR: glomerular filtration rate (ml/min/1.73m²)

Web Appendix 1 Web Appendix 1. System used to rate the level of evidence of individual studies. - Level I: Evidence obtained from at least one properly designed randomized controlled trial. - Level II-1: Evidence obtained from well-designed controlled trials without randomization. - Level II-2: Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group. - Level II-3: Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence. - Level III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

Web Appendix 2 Table 3. Complications of renal artery stenting Between 10 and 20% Vascular access complications, including: Groin hematoma False aneurysm Bleeding requiring transfusion Arterial injury Puncture site infection Arterial thrombosis Arteriovenous fistula Kidney injury and deterioration of renal function, including: Contrast nephropathy Cholesterol atheroembolism Renal infarction Peri-renal/retroperitoneal hematoma Between 2 and 10% Renal artery complications, including: Dissection Stent misplacement or dislodgment Early restenosis Rupture or perforation Thrombosis Spasm Periprocedural cardiovascular events, including: Non-renal arterial embolisation Pulmonary edema Myocardial infarction Venous thromboembolism Less than 2% Death by day 30, related to: Myocardial infarction Stroke Pulmonary embolism Cholesterol embolism Hemorrhage Septicemia Contrast medium allergy