Restenosis after renal artery angioplasty and stenting: Incidence and risk factors

Similar documents
Early duplex predicts restenosis after renal artery angioplasty and stenting

A Closer Look: Renal Artery Stenosis. Renal artery stenosis (RAS) is defined as a TOPICS FROM CHEP. Shawn s stenosis

Atherosclerotic Renovascular Hypertension : Lessons from Recent Clinical Studies

Current Role of Renal Artery Stenting in Patients with Renal Artery Stenosis

Predicting blood pressure response after renal artery stenting

Ultrasound velocity criteria for renal in-stent restenosis

Life After CORAL: What Did CORAL Prove? David Paul Slovut, MD, PhD Co-director TAVR, Dir of Advanced Intervention

Effective Health Care

Natural history and progression of atherosclerotic renal vascular stenosis

Renal ischemia resulting from stenosis of the renal artery

CORAL Trial Aftermath: What Do We Do Now? Renal Revascularization in Perspective

JOURNAL OF VASCULAR SURGERY Volume 50, Number 3 Davis et al 565 no CHS participant demonstrated severe hypertension or renal insufficiency consistent

Pre-and Post Procedure Non-Invasive Evaluation of the Patient with Carotid Disease

Duplex Ultrasound of the Renal Arteries. Duplex Ultrasound. In the Beginning

Coral Trials: A personal experience that challenges its results in patients with uncontrolled blood pressure.

PCI for Renal Artery stenosis

Hypothesis: When compared to conventional balloon angioplasty, cryoplasty post-dilation decreases the risk of SFA nses in-stent restenosis

Comparison Of Primary Long Stenting Versus Primary Short Stenting For Long Femoropopliteal Artery Disease (PARADE)

Renal artery stenosis

Carotid Artery Disease and What s Pertinent JOSEPH A PAULISIN DO

Treatment of renal artery in-stent restenosis with sirolimus-eluting stents

Progression of atherosclerotic renovascular disease: a prospective population-based study

Renal Artery Stenosis: Insights from the CORAL Trial

Accurate Vessel Sizing Drives Clinical Results. IVUS In the Periphery

Evaluation of the Safety and Effectiveness of Renal Artery Stenting After Unsuccessful Balloon Angioplasty The ASPIRE-2 Study

Carotid Artery Stenting (CAS) Pathophysiology. Technical Considerations. Plaque characteristics: relevant concepts. CAS and CEA

RAS Epidemiology. Renal Artery Stenosis. Pathophysiology of RAS. Disclosure of Potential Conflicts. Background Pathophysiology of RAS.

Management of In-stent Restenosis after Lower Extremity Endovascular Procedures

Case 8038 Renal allograft complicated with renal artery stenosis

Disclosure of Potential Conflicts. Renal Artery Stenosis. RAS Epidemiology. Road Map. Background. ASDIN 7th Annual Scientific Meeting

Fibromuscular Dysplasia (FMD) of the renal arteries Angiographic features and therapeutic options

RENAL ARTERY PTA. JH PEREGRIN IKEM, Prague

Peripheral Arterial Disease: Who has it and what to do about it?

NOT FOR PUBLICATION, QUOTATION, OR CITATION RESOLUTION NO. 22

Renal Artery Stenting

Beyond Stenosis Severity: Top 5 Important Duplex Characteristics to Identify in a Patient with Carotid Disease

CIC Edizioni Internazionali. original article

Endovascular treatment

PCI for Left Anterior Descending Artery Ostial Stenosis

Incidence and Prevalence of Atherosclerotic Renal Artery Stenosis (RAS) in Patients with Coronary Artery Disease (CAD)

Supplementary Appendix

RENAL AND MESENTERIC ARTERY STENTS Are There Standard Velocity Criteria for Restenosis?

Recommendations for Follow-up After Vascular Surgery Arterial Procedures SVS Practice Guidelines

Impaired Chronotropic Response to Exercise Stress Testing in Patients with Diabetes Predicts Future Cardiovascular Events

Should Mesenteric Revascularization Be Staged: Report of 3 Cases One With Reperfusion Hemorrhage

The Accuracy of a Volume Plethysmography System as Assessed by Contrast Angiography

Assessing outcomes to determine whether symptoms related to hypertension justify renal artery stenting

Renal Artery Stenting With Embolic Protection

The ACC 50 th Annual Scientific Session

KEY WORDS: Bilateral Renal Artery Stenosis, Cardiac Catherization, Incidental Findings, Associated Co- morbidity

Prospective, randomized controlled study of paclitaxel-coated versus plain balloon angioplasty for the treatment of failing dialysis access

Serum Creatinine and Blood Urea Nitrogen Levels in Patients with Coronary Artery Disease

Michael Meuse, M.D. Vascular and Interventional Radiology

Treatment Considerations for Carotid Artery Stenosis. Danielle Zielinski, RN, MSN, ACNP Rush University Neurosurgery

03/30/2016 DISCLOSURES TO OPERATE OR NOT THAT IS THE QUESTION CAROTID INTERVENTION IS INDICATED FOR ASYMPTOMATIC CAROTID OCCLUSIVE DISEASE

The present status of selfexpanding. for CLI: Why and when to use. Sean P Lyden MD Cleveland Clinic Cleveland, Ohio

Low fractional diastolic pressure in the ascending aorta increased the risk of coronary heart disease

Surgical Options for revascularisation P E T E R S U B R A M A N I A M

Outcome and cost comparison of percutaneous transluminal renal angioplasty, renal arterial stent placement, and renal arterial bypass grafting

Ahigh prevalence of obstructive renovascular disease in

Imaging Strategy For Claudication

Atherosclerotic renovascular disease

Beta-blockers in Patients with Mid-range Left Ventricular Ejection Fraction after AMI Improved Clinical Outcomes

Delay of dialysis in end-stage renal failure: Prospective study on percutaneous renal artery interventions

Disclosures. State of the Art Management of Carotid Stenosis. NIH funding for clinical trials Consultant for Scientia Vascular and Medtronic

2010 Korean Society of Cardiology Spring Scientific Session Korea Japan Joint Symposium. Seoul National University Hospital Cardiovascular Center

Vascular Imaging Original Research

ORIGINAL INVESTIGATION. Carotid and Lower Extremity Arterial Disease in Patients With Renal Artery Atherosclerosis

after treatment of Renal duplex sonography renovascular disease

Preoperative risk factors for carotid endarterectomy: Defining the patient at high risk

The Role of LUTONIX 035 DCB in AV Fistula Dysfunction Management in our Practice

Renal artery stenosis treated with stent deployment: Indications, technique, and outcome for 108 patients

Subclavian artery Stenting

Paclitaxel-coated versus Plain Balloon Angioplasty in the Treatment of Infrainguinal Vein Bypass Stenosis

Supplementary Online Content

Chronic renal artery occlusion: Nephrectomy versus revascularization

The Management and Treatment of Ruptured Abdominal Aortic Aneurysm (RAAA)

MORTALITY AND MORBIDITY RISK FROM CAROTID ARTERY ATHEROSCLEROSIS. 73 year old NS right-handed male applicant for $1 Million life insurance

Corporate Medical Policy

SAMMPRIS. Stenting and Aggressive Medical Management for Preventing Recurrent Stroke and Intracranial Stenosis. Khalil Zahra, M.D

How to assess the hemodynamic importance of a renal artery stenosis. Felix Mahfoud, MD Saarland University Hospital Homburg/Saar, Germany

egfr > 50 (n = 13,916)

Vasile Goldiş Western University of Arad Faculty of Medicine, Pharmacy and Dental Medicine, Arad, Romania

Abdominal Aortic Doppler Waveform in Patients with Aorto-iliac Disease

Natural history of atherosclerotic renal artery stenosis: A prospective study with duplex ultrasonography

In-stent Restenosis: the Achille's Heel of SFA Stenting

Treating In-Stent Restenosis with Brachytherapy: Does it Actually Work?

Disclosures. Carotid artery stenting. Surveillance after Endovascular Intervention: When to Re-Intervene and What s the Evidence

Effects of Kidney Disease on Cardiovascular Morbidity and Mortality

Index. interventional.theclinics.com. Note: Page numbers of article titles are in boldface type.

Arterial stenting and balloon angioplasty in ostial atherosclerotic renovascular disease: a randomised trial

Medical management of abdominal aortic aneurysms

Impact of coronary atherosclerotic burden on clinical presentation and prognosis of patients with coronary artery disease

GALECTIN-3 PREDICTS LONG TERM CARDIOVASCULAR DEATH IN HIGH-RISK CORONARY ARTERY DISEASE PATIENTS

Vascular disease. Structural evaluation of vascular disease. Goo-Yeong Cho, MD, PhD Seoul National University Bundang Hospital

MORTALITY AND MORBIDITY RISK FROM CAROTID ARTERY ATHEROSCLEROSIS. 73 year old NS right-handed male applicant for $1 Million Life Insurance

Supplementary Online Content

The Struggle to Manage Stroke, Aneurysm and PAD

Clinical Data Update for Drug Coated Balloons (DCB) Seung-Whan Lee, MD, PhD

Transcription:

From the Southern Association for Vascular Surgery Restenosis after renal artery angioplasty and stenting: Incidence and risk factors Matthew A. Corriere, MD, MS, a Matthew S. Edwards, MD, MS, a Jeffrey D. Pearce, MD, a Jeanette S. Andrews, MS, b Randolph L. Geary, MD, a and Kimberley J. Hansen, MD, a Winston-Salem, NC Background: Management of renal artery stenosis (RAS) with primary renal artery percutaneous angioplasty and stenting (RA-PTAS) is associated with a low risk of periprocedural death and major complications; however, restenosis develops in a subset of patients and repeat intervention may be required. We examined the incidence of restenosis after RA-PTAS and associations with clinical factors. Methods: Consecutive patients undergoing RA-PTAS for hemodynamically significant atherosclerotic RAS associated with hypertension or ischemic nephropathy, or both, between October 2003 and September 2007 were identified from a registry. Restenosis was defined using duplex ultrasound (DUS) imaging as a renal artery postintervention peak systolic velocity (PSV) >180 cm/s. The incidence and temporal distribution of restenosis was analyzed using survival analysis based on treated kidneys. Associations between clinical factors and recurrent stenosis were examined using proportional hazards regression. Results: RA-PTAS was performed on 112 kidneys for atherosclerotic RAS during the study period. Initial postintervention renal artery DUS imaging confirming PSV <180 cm/s in 101 kidneys, which formed the basis of this analysis. Estimated restenosis-free survival was 50% at 12 months and 40% at 18 months. Decreased risk of restenosis was associated with preoperative statin use (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.16-0.74; P.006) and increased preoperative diastolic blood pressure (DBP; HR, 0.70 per 10-mm Hg increase in preoperative DBP; 95% CI, 0.49-0.99; P.049). No other factors assessed were associated with restenosis. Conclusion: Restenosis occurs in a substantial number of patients treated with RA-PTAS. Preoperative statin medication use and increased preoperative DBP are associated with reduced risk of restenosis. In the absence of contraindications, statins should be considered standard therapy for patients with atherosclerotic renal artery stenosis. (J Vasc Surg 2009; 50:813-9.) Atherosclerotic renal artery stenosis (RAS) may cause severe hypertension or renal dysfunction, or both, and is associated with an increased risk for cardiovascular events. 1 Patients with atherosclerotic RAS who have poorly controlled hypertension or progressive deterioration of renal function, or both, despite appropriate medical management, often are treated with renal artery revascularization, although the benefits associated with treatment remain controversial. Renal artery percutaneous angioplasty and stenting (RA-PTAS) has become the most common method of renal artery intervention. Unfortunately, restenosis has been reported in 17% to 44% of arteries after RA-PTAS 2-8 and may From the Departments of Vascular and Endovascular Surgery a and Biostatistical Sciences, b Wake Forest University School of Medicine. Dr Edwards is supported by the American Vascular Association and Lifeline Foundation Research Career Development Award. Grant support was also provided by The National Heart, Lung, and Blood Institute of the National Institutes of Health to Dr Edwards (Grant 1K23HL083981-01), Dr Geary (Grant R01 HL57557), and Dr Hansen (Grant 5K12HL083763-02). Competition of interest: none. Presented at the Thirty-third Annual Meeting of the Southern Association of Vascular Surgery, Tucson, Ariz, Jan 14, 2009. Additional material for this article may be found online at www.jvascsurg. org. Reprint requests: Kimberley J. Hansen, MD, Department of Vascular and Endovascular Surgery, Medical Center Blvd, Winston-Salem, NC 27157-1095 (e-mail: mcorrier@wfubmc.edu). 0741-5214/$36.00 Copyright 2009 by the Society for Vascular Surgery. doi:10.1016/j.jvs.2009.05.019 be associated with recurrent clinical symptoms despite an initial treatment response. Analyses to date have identified associations between restenosis after RA-PTAS and renal artery diameter, 5,9 stent diameter, 10 weight/body mass index, 11 and smoking. 12 The purpose of this study was to determine the frequency and predictors of restenosis after primary RA- PTAS in a single-center cohort of adult patients with atherosclerotic RAS. METHODS Study population. This investigation was conducted with the approval of the Wake Forest University Health Sciences Institutional Review Board. Consecutive primary RA-PTAS procedures performed for hemodynamically significant atherosclerotic RAS were identified from a procedure registry. All treated patients had hypertension with or without renal dysfunction, and indications for RA-PTAS were determined by individual operators. The analysis excluded RA-PTAS performed for restenosis or fibromuscular dysplasia. All procedures were performed by vascular surgeons at the Wake Forest University School of Medicine between October 2003 and September 2007. Standard preparation, procedural management, and follow-up for patients treated with RA-PTAS at our center have been described previously. 13,14 Balloon-mounted stents were used in all patients and sized to match the diameter of the distal, 813

814 Corriere et al JOURNAL OF VASCULAR SURGERY October 2009 Table I. Candidate covariates for Cox proportional hazards modeling Preoperative factors Age Race Gender Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Estimated glomerular filtration rate Number of antihypertensive medications Current smoker Medication use Aspirin Clopidogrel Statin Personal history of diabetes Ipsilateral renal artery peak systolic velocity (cm/s) Resistive index Procedural factors Renal artery diameter Stent diameter Stent/artery diameter ratio Distal protection (complete distal renal artery balloon occlusion) Predilation before stent deployment Unilateral vs staged bilateral RA-PTAS Incomplete revascularization (ie, unilateral RA-PTAS in the setting of bilateral RAS) RA-PTS, Renal artery renal artery percutaneous angioplasty and stenting. normal-caliber renal artery as measured by angiography at the time of treatment. Renal duplex ultrasound (DUS) imaging was performed before the intervention and 24 hours after RA-PTAS. Thereafter, routine DUS surveillance of the renal artery was conducted at 1 and 6 months, and then at 6-month intervals. Data collection and management. Clinical data, including patient demographics, comorbidities, and laboratory results, were retrospectively collected from the electronic medical record. Presence of left ventricular hypertrophy was determined by baseline electrocardiography. Renal DUS data, including peak systolic velocity (PSV), resistive index, acceleration time, and kidney length, were collected from a prospectively maintained clinical vascular laboratory database. Anatomic information was retrospectively collected from angiograms performed during RA-PTAS by manual electronic caliper measurement of archived images. All measurements were performed in a nonblinded fashion by a single individual. Angiographic percentage of RAS was determined by measuring the smallest luminal diameter at the point of maximal stenosis and comparing it with the lumen of the main renal artery distal to the lesion and any poststenotic dilatation, if present. Anatomic locations of stenotic lesions were classified as described by Baumgartner et al. 3 Estimated glomerular filtration rate (egfr) was calculated from the serum creatinine level using the abbreviated Modification of Diet in Renal Disease formula. 15 Renal dysfunction was categorized as severe for patients with an egfr 30 ml/min/1.73 m 2, moderate for patients with egfr of 30 to 60 ml/min/1.73 m 2, and none for patients with an egfr 60 ml/min/1.73 m 2. Renal artery resistive index was calculated from segmental velocities as [1 (end diastolic velocity/peak systolic velocity)]. 16 Assessment of restenosis. Hemodynamically significant recurrent RAS was identified using DUS imaging. Patients underwent routine DUS examinations immediately after treatment and then at 1, 3, and 6 months. DUS studies were performed using a 5.2-MHz curvilinear probe with Doppler color flow, with either a Philips IU22 (Philips Healthcare, Andover, Mass) or an ATL HDI 5000 (Advanced Technology Laboratories, Bothell, Wash) US system using a previously described technique. 17 Restenosis was defined as renal artery PSV 180 cm/s in a stented artery previously documented as free of restenosis. This DUS criterion for renal artery restenosis has been used by others 18-20 and was internally validated at our center (Fig 1, online only). Renal artery PSV 180 at the time of the first postintervention DUS study was considered residual stenosis and not interpreted as restenosis. Repeat renal artery angiography or intervention, or both, was undertaken at the discretion of individual operators in the setting of hemodynamically significant restenosis on follow-up DUS imaging accompanied by deterioration of renal function after initial postintervention improvement or worsening of hypertension (eg, increased number of antihypertensive agents, increase in blood pressure, or hypertensive emergency) after an initial hypertension response to RA-PTAS. Statistical analysis. Data on baseline patient comorbid medical conditions, blood pressure, medication use, renal function data, and demographics are reported using mean standard deviation for continuous variables and count (%) for categoric variables. Restenosis was assessed for the kidneys using models controlling for withinsubject correlation, and data are reported using modelbased mean standard error. The incidence and temporal distribution of recurrent RAS were analyzed using survival analysis based on treated kidneys. Associations between clinical factors and time to restenosis were examined using Cox proportional hazards regression. Both of these methods accounted for correlated observations. Cox proportional hazards regression modeling was performed using stepwise selection (P.10 for model entry). Candidate covariates for model selection are listed in Table I. Results were evaluated for significance using 0.05, and hazard ratios (HR) are expressed with 95% confidence intervals (CI). Statistical analyses were performed using SAS 9.1 software (SAS Institute, Cary, NC). RESULTS Incidence of restenosis and associations with clinical factors. Primary RA-PTAS for atherosclerotic RAS was attempted in 112 kidneys during the study period. Of these, eight were excluded due to residual stenosis on initial postintervention renal artery DUS imaging, two were excluded due to lack of renal artery DUS follow-up data, and one was excluded as a technical failure related to inability to

JOURNAL OF VASCULAR SURGERY Volume 50, Number 4 Corriere et al 815 Table II. Demographics of the 91 study patients Variable No. (%) or mean SD Age, y 68.8 10.1 White race 79 (86.8) Female 48 (52.8) Weight, kg 75.9 15.9 Smoking Never 22 (24.4) Former 45 (50.0) Current 23 (25.6) Diabetes 29 (31.9) Stroke 24 (26.4) Coronary artery disease 39 (42.9) COPD 14 (15.4) History of hypertensive emergency 13 (14.3) Left ventricular hypertrophy (ECG) 34 (37.4) Serum creatinine, mg/dl 1.5 0.6 egfr, a ml/min/1.73m 2 50.9 23.1 Renal insufficiency, egfr None, egfr 60 25 (27.5) Moderate, egfr 30-60 53 (58.2) Severe, egfr 30 13 (14.3) Ischemic nephropathy (Cr 1.8 mg/dl) 29 (31.9) Resistive index b 0.75 0.08 Pre-op blood pressure Systolic, mm Hg 161.7 26.2 Diastolic, mm Hg 79.1 13.1 Antihypertensive agents 3.3 1.3 Pre-op renal artery PSV, cm/s 269.8 101.0 Significant contralateral RAS c 29 (39.7) Resistive index 0.8 21 (24.4) Pre-intervention medications ACE inhibitor or ARB 57 (62.6) -blocker 63 (69.2) Calcium channel blocker 55 (60.4) Diuretic 52 (57.1) Aspirin 61 (67.0) Clopidogrel 22 (24.2) Statin 54 (59.3) Fibrate 4 (4.4) ACE, Angiotensin-converting enzyme; ARB, angiotensin receptor blocker; COPD, chronic obstructive pulmonary disease; ECG, electrocardiogram; PSV, peak systolic velocity; RAS, renal artery stenosis; SD, standard deviation. a Estimated glomerular filtration rate using abbreviated modification of diet in renal disease formula. b Resistive index from the side with the higher B segment renal artery peak systolic velocity. c Significant contralateral RAS defined as PSV / 180 cm/s on preintervention duplex ultrasound imaging. access the target renal artery. The remaining 101 kidneys in 91 patients form the basis of this analysis. Mean preintervention angiographic RAS was 79.1% 12.9%. Of these stenotic lesions, 73% were categorized as ostial, 18% involved the proximal renal artery, and 9% involved the truncal renal artery. Distal renal artery balloon occlusion was used for embolic protection during 90% of procedures. Patient baseline demographics are reported in Table II. Mean patient age was 68.8 10.1 years, all patients had hypertension, 53% were women, and 87% were white. According to the egfr, moderate or severe renal insufficiency was observed in 72% of patients. The mean preintervention renal artery diameter was 5.6 0.1 mm, and mean stent diameter was 5.7 0.1 mm. There were no periprocedural deaths. Estimated restenosisfree survival adjusted for within-subject correlation was 50% at 12 months and 40% at 18 months (Fig 2). Proportional hazards regression analysis demonstrated decreased risk for restenosis associated with preoperative statin use (HR, 0.35; 95% CI, 0.16-0.74; P.006) and preoperative diastolic blood pressure (DBP; HR, 0.70 per 10-mm Hg increase in preoperative DBP; 95% CI, 0.49-0.99; P.049). No other covariates assessed (Table I) were associated with restenosis-free survival. Predicted restenosis-free survival stratified by statin medication use is displayed graphically in Fig 3. Clinical manifestations and management of restenosis. Clinical manifestations and management of restenosis are summarized in Table III. At a mean postintervention interval of 5.5 months, 28 recurrent lesions were identified in 27 patients. Bilateral restenosis developed in one patient managed with staged bilateral primary RA-PTAS, whereas the remaining restenoses were unilateral. In 17 of 27 patients (63%) with restenosis, there were no associated clinical manifestations such as worsening of hypertension, need for resumption of previously discontinued antihypertensive agents, or decline in egfr after an initial improvement. In the setting of improvement after RA-PTAS in hypertension control or renal function, or both, these patients were managed with continued medical therapy and DUS surveillance without repeat angiography. The remaining 10 patients (37%) with restenosis identified by DUS imaging had associated hypertension or a decline in egfr, or both, prompting repeat intervention. Angiography findings in these patients confirmed the presence of 60% diameterreducing in-stent restenosis in all arteries. Among individuals who underwent repeat intervention for restenosis, procedural management initially consisted of surgical revascularization in one patient and repeat angioplasty in nine; four of the nine repeat angioplasties were performed using cutting balloons. A second restenosis developed in one patient managed with repeat angioplasty and was later treated with aortic endarterectomy plus renal artery bypass. One patient with restenosis was hospitalized for an acute hypertensive emergency associated with pulmonary edema and improved clinically with aggressive medical management. A DUS examination after discharge from the hospital revealed interval progression of the restenosis to occlusion. DISCUSSION This analysis represents an attempt to characterize the incidence of restenosis after RA-PTAS documented by DUS follow-up and to characterize associated risk factors. In a kidney-based analysis of primary RA-PTAS for atherosclerotic disease, estimated risk of restenosis was 50% at 12 months and 60% at 18 months. Clinical manifestations, including worsening of hypertension or decline in egfr, or both, were observed frequently in patients with restenosis, and these patients were most often managed with repeat

816 Corriere et al JOURNAL OF VASCULAR SURGERY October 2009 Fig 2. Estimated restenosis-free survival. The estimation method accounts for the correlated data. The standard error of the survival estimate is 0.1 for the displayed postintervention interval. endovascular treatment. In multivariable proportional hazards analysis, use of statin medications and preintervention DBP were both associated with decreased risk of restenosis. DUS imaging has demonstrated validity for identification of restenosis after RA-PTAS at a number of centers. 18-21 Among patients studied with renal DUS imaging before digital subtraction angiography, Bakker et al 18 observed a 100% sensitivity and 74% specificity for PSV 180 cm/s in determining the presence of restenosis after RA- PTAS. Using this criterion, the incidence of restenosis reported in this study is comparable with the incidence reported by others using DUS imaging for surveillance of stented renal arteries, 6-8 although our validation analysis (Fig 1, online only) shows PSV 180 cm/s may underestimate the true incidence of anatomic restenosis. In the current study, restenosis was diagnosed at a relatively early interval after primary RA-PTAS of 5.5 months and was associated with hypertension or decline in egfr, or both, in 37% of patients. The poor primary patency of RA-PTAS for atherosclerotic RAS and the frequent need for repeat intervention underscore the current controversy regarding benefits of percutaneous treatment of RAS, particularly when considering the modest hypertension and renal function benefits observed with this method. 14 Previously described associations with restenosis or the need for repeat intervention after RA-PTAS include body weight and body mass index, 11 renal artery diameter, 5 stent diameter, 9,10 and smoking. 12 We were unable to specifically evaluate body mass index as a predictor of restenosis due to incomplete patient height data, but did not observe a significant relationship between weight or any of these other factors and restenosis in the present study. Post hoc power analysis confirmed 80% power to detect hazard ratios 3 for these variables, but power to detect smaller effect sizes was limited and may have resulted in a type II statistical error. Statin use was associated with a significant reduction in restenosis risk, however, and patients not treated with statin medications had a nearly threefold increase in estimated risk for restenosis over time. Although an association between statin use and restenosis after RA-PTAS has not been described previously, to our knowledge, reduction in coronary artery restenosis associated with statin use has been observed, 22 and similar effects on postinjury renal artery remodeling would therefore seem plausible. Potential mechanisms

JOURNAL OF VASCULAR SURGERY Volume 50, Number 4 Corriere et al 817 Fig 3. Time to restenosis stratified by statin medication use. Estimation method accounts for correlated data. Line becomes broken when the standard error of the survival estimate is 0.1. Table III. Clinical manifestations and procedural management of renal artery stenosis after renal artery percutaneous angioplasty and stenting No. (%) Clinical manifestations Absent 17 (63) Present 10 (37) Hypertension a 6 (60) Renal dysfunction a 5 (50) Hypertensive emergency a 3 (30) Management Medical (without procedural intervention) 17 Repeat intervention 10 Repeat angioplasty 8 Surgical revascularization 1 Repeat angioplasty followed by surgical revascularization 1 a Percentage calculated based on 10 patients with clinical manifestations. through which statin use may have reduced the risk of restenosis include effects on serum cholesterol or the composition and morphology of atheromatous plaques, or both. Unfortunately, lipid data within this retrospectively collected data set was incomplete, precluding meaningful interpretation of cholesterol values in relationship to statin use or restenosis. Beneficial pleiotropic effects of statins include favorable influences on atherosclerotic plaque stability, inflammation, endothelial function, matrix metalloproteinase activity, and nitric oxide bioavailability. 23,24 Decreased incidence of anatomic progression of atherosclerotic RAS was observed with statin use by Cheung et al. 25 Presumably, this beneficial effect on natural disease history might also translate into protection against secondary progression of atherosclerosis after RA-PTAS. The relatively rapid development of restenosis we observed after intervention, however, seems more consistent with neointimal hyperplasia rather than secondary progression of atherosclerotic disease as the responsible pathophysiologic mechanism. Inhibition of vascular smooth muscle cell migration and proliferation, along with induction of neointimal smooth muscle cell apoptosis, are previously described in vitro statin effects 26,27 that make protection against neointimal hyperplasia after RA-PTAS a plausible hypothesis. Statin-induced plaque stabilization resulting from increased collagen and reduced lipid content has also been characterized 28 and may contribute to a more favorable interface between the stent and the stenotic lesion, theoretically reducing odds of plaque rupture through stent interstices at the time of deployment. We also observed an association between increasing preintervention DBP and freedom from restenosis. Unlike

818 Corriere et al JOURNAL OF VASCULAR SURGERY October 2009 the protective effect associated with statin use, this relationship was unanticipated. Activation of the renin-angiotensin system is a known stimulus for neointimal hyperplasia. 29 Hypothetically, more frequent use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers, or both, among patients with higher baseline DBP might have resulted in a confounding protective effect against restenosis. However, no significant differences in baseline blood pressure, number of antihypertensive agents, ACE inhibitors, or angiotensin receptor blockers were noted between patients according to restenosis status (Table II), raising the possibility that this observation may represent a type I statistical error. In the absence of supporting data from other studies, we can only speculate about the unexpected relationship observed between baseline DBP and freedom from restenosis. This study provides novel information about factors associated with restenosis after RA-PTAS; however, several additional limitations exist that deserve comment. Although restenosis was verified with angiography among all patients undergoing repeat intervention, most patients with restenosis did not have associated clinical sequelae and therefore did not undergo additional confirmatory imaging. Increased rates of positive angiography results have been observed when patients are studied in the setting of clinical suspicion, 5 and the incidence of restenosis therefore may have been overestimated due to false-positive DUS results. Such a possibility is supported by the findings of Bakker et al, 18 who determined renal artery DUS imaging to be 100% sensitive but only 74% specific for restenosis after RA-PTAS. Analysis of clinical disease recurrence (ie, anatomic restenosis associated with worsening of hypertension or renal dysfunction), as an alternative outcome therefore might have increased the specificity of our findings and permitted angiographic confirmation of DUS results among all patients experiencing the event. We instead defined restenosis with DUS imaging given the reliability of this imaging method at our center and its widespread use as the primary postintervention surveillance method in current clinical practice. Nonrandom allocation of patients to statin therapy in this retrospective study also might have resulted in bias if statin nonuse was a global indicator of suboptimal medical management, although the stratified comparisons in Table II seem to argue against this possibility. Finally, symptoms of restenosis that occurred subsequent to development of a detectable anatomic lesion might have been missed due to the relatively short follow-up in this study, which also precluded analysis of late restenosis. CONCLUSION Restenosis after primary RA-PTAS for atherosclerotic RAS occurs frequently and is often accompanied by physiologic manifestations. Considered in combination with the beneficial extrarenal cardiovascular effects of statins, the decreased risk of restenosis associated with use of these medications supports their routine use in patients undergoing RA-PTAS. AUTHOR CONTRIBUTIONS Conception and design: MC, ME, JA, JP, RG, KH Analysis and interpretation: MC, ME, JS, KH Data collection: MC, JP, JS Writing the article: MC, ME, JS, KH Critical revision of the article: MC, ME, JA, JP, RG, KH Final approval of the article: MC, ME, JA, JP, RG, KH Statistical analysis: JA, MC Obtained funding: Not applicable Overall responsibility: MC REFERENCES 1. Edwards MS, Craven TE, Burke GL, Dean RH, Hansen KJ. Renovascular disease and the risk of adverse coronary events in the elderly: a prospective, population-based study. Arch Intern Med 2005;165: 207-13. 2. 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. 3. 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. 4. Dorros G, Jaff M, Jain A, Dufek C, Mathiak L. Follow-up of primary Palmaz-Schatz stent placement for atherosclerotic renal artery stenosis. Am J Cardiol 1995;75:1051-5. 5. Lederman RJ, Mendelsohn FO, Santos R, Phillips HR, Stack RS, Crowley JJ. Primary renal artery stenting: characteristics and outcomes after 363 procedures. Am Heart J 2001;142:314-23. 6. Nolan BW, Schermerhorn ML, Powell RJ, Rowell E, Fillinger MF, Rzucidlo EM, et al. Restenosis in gold-coated renal artery stents. J Vasc Surg 2005;42:40-6. 7. Nolan BW, Schermerhorn ML, Rowell E, Powell RJ, Fillinger MF, Rzucidlo EM, et al. Outcomes of renal artery angioplasty and stenting using low-profile systems. J Vasc Surg 2005;41:46-52. 8. Tullis MJ, Zierler RE, Glickerman DJ, Bergelin RO, Cantwell-Gab K, Strandness DE Jr. Results of percutaneous transluminal angioplasty for atherosclerotic renal artery stenosis: a follow-up study with duplex ultrasonography. J Vasc Surg 1997;25:46-54. 9. Bates MC, Rashid M, Campbell JE, Stone PA, Broce M, Lavigne PS. Factors influencing the need for target vessel revascularization after renal artery stenting. J Endovasc Ther 2006;13:569-77. 10. Vignali C, Bargellini I, Lazzereschi M, Cioni R, Petruzzi P, Caramella D, et al. Predictive factors of in-stent restenosis in renal artery stenting: a retrospective analysis. Cardiovasc Intervent Radiol 2005; 28:296-302. 11. Kane GC, Hambly N, Textor SC, Stanson AW, Garovic VD. Restenosis following percutaneous renal artery revascularization. Nephron Clin Pract 2007;107:c63-9. 12. Shammas NW, Kapalis MJ, Dippel EJ, Jerin MJ, Lemke JH, Patel P, et al. Clinical and angiographic predictors of restenosis following renal artery stenting. J Invasive Cardiol 2004;16:10-3. 13. Edwards MS, Craven BL, Stafford J, Craven TE, Sauve KJ, Ayerdi J, et al. Distal embolic protection during renal artery angioplasty and stenting. J Vasc Surg 2006;44:128-35. 14. Corriere MA, Pearce JD, Edwards MS, Stafford J, Hansen KJ. Endovascular management of atherosclerotic renal artery stenosis: early results following primary intervention. J Vasc Surg 2008;48: 580-7. 15. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461-70. 16. 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.

JOURNAL OF VASCULAR SURGERY Volume 50, Number 4 Corriere et al 819 17. Hansen KJ, Tribble RW, Reavis SW, Canzanello VJ, Craven TE, Plonk GW Jr, et al. Renal duplex sonography: evaluation of clinical utility. J Vasc Surg 1990;12:227-36. 18. Bakker J, Beutler JJ, Elgersma OE, de Lange EE, de Kort GA, Beek FJ. Duplex ultrasonography in assessing restenosis of renal artery stents. Cardiovasc Intervent Radiol 1999;22:475-80. 19. Napoli V, Pinto S, Bargellini I, Vignali C, Cioni R, Petruzzi P, et al. Duplex ultrasonographic study of the renal arteries before and after renal artery stenting. Eur Radiol 2002;12:796-803. 20. Parenti GC, Palmarini D, Bilzoni M, Campioni P, Mannella P, Ginevra A. Role of color-doppler sonography in the follow-up of renal artery stenting. Radiol Med (Torino) 2008;113:242-8. 21. Motew SJ, Cherr GS, Craven TE, Travis JA, Wong JM, Reavis SW, et al. Renal duplex sonography: main renal artery versus hilar analysis. J Vasc Surg 2000;32:462-9. 22. Kastrati A, Schomig A, Elezi S, Schuhlen H, Dirschinger J, Hadamitzky M, et al. Predictive factors of restenosis after coronary stent placement. J Am Coll Cardiol 1997;30:1428-36. 23. Davignon J. Beneficial cardiovascular pleiotropic effects of statins. Circulation 2004;109(23 suppl 1):III39-43. 24. Calabro P, Yeh ET. The pleiotropic effects of statins. Curr Opin Cardiol 2005;20:541-6. 25. Cheung CM, Patel A, Shaheen N, Cain S, Eddington H, Hegarty J, et al. The effects of statins on the progression of atherosclerotic renovascular disease. Nephron Clin Pract 2007;107:c35-42. 26. Erl W, Hristov M, Neureuter M, Yan ZQ, Hansson GK, Weber PC. HMG-CoA reductase inhibitors induce apoptosis in neointima-derived vascular smooth muscle cells. Atherosclerosis 2003;169:251-8. 27. Erl W. Atorvastatin-induced downregulation of survivin and vascular smooth muscle cell apoptosis: a causal relationship in restenosis? Cardiovasc Drugs Ther 2007;21:141-4. 28. Crisby M, Nordin-Fredriksson G, Shah PK, Yano J, Zhu J, Nilsson J. Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization. Circulation 2001; 103:926-33. 29. Heeneman S, Sluimer JC, Daemen MJ. Angiotensin-converting enzyme and vascular remodeling. Circ Res 2007;101:441-54. Submitted Jan 10, 2009; accepted May 12, 2009. Additional material for this article may be found online at www.jvascsurg.org. COLLECTIONS OF PAPERS On the Web version of the Journal, selected articles have been grouped together for the convenience of the readers. The current collections include the following: American Board of Vascular Surgery Editorial Comments History Reporting Standards Technical Notes Basic Science Reviews Guidelines Lifeline Research Meeting Abstracts Reviews

819.e1 Corriere et al JOURNAL OF VASCULAR SURGERY October 2009 Fig 1. Validation of peak systolic velocity (PSV) 180 cm/s as indicator of renal artery restenosis. The horizontal dashed line indicates PSV of 180 cm/s, and the vertical dashed line indicates angiography-defined stenosis of 60%. In our own institutional cohort, significant agreement was observed between PSV 180 cm/s and angiographic stenosis 60% ( 0.6; P.05).