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

Treatment of renal artery in-stent restenosis with sirolimus-eluting stents Vascular Medicine 15(1) 3 7 The Author(s) 2009 Reprints and permission: http://www. sagepub.co.uk/journalspermission.nav DOI: 10.1177/1358863X09106897 http://vmj.sagepub.com Thomas J Kiernan, Bryan P Yan, Jonathan D Eisenberg, Nicholas J Ruggiero, Vishal Gupta, Douglas Drachman, Robert M Schainfeld, Michael R Jaff, Kenneth Rosenfield and Joseph Garasic Abstract The objective of this study was to analyze the use of sirolimus-eluting stent (SES) placement for the treatment of renal artery in-stent restenosis (RA-ISR). The optimal treatment of RA-ISR has not been fully elucidated to date. We retrospectively analyzed consecutive patients from our institution who underwent treatment of RA-ISR with a SES from May 2004 to June 2006. Using duplex ultrasound, RA-ISR (> 60% diameter) was determined by peak systolic velocity (PSV) > 300 cm/s and renal aortic ratio (RAR) > 4.0. Renal function (creatinine) and blood pressure were measured at baseline and follow-up. SESs were implanted in 16 patients (22 renal arteries) during the study period. The study cohort was predominantly female (75%) with a mean age of 68 ± 12 years. RA-ISR was treated with SESs with a mean diameter of 3.5 mm and mean length of 17.9 ± 3.8 mm. The mean post-dilation balloon diameter was 4.8 ± 0.6. The baseline renal artery PSV was 445 ± 131 cm/s with a mean RAR of 5.0 ± 1.6. Follow-up information was available in 21 renal arteries. During a median follow-up of 12 months (range: 9 15 months), 15 renal arteries (71.4%) developed recurrence of ISR by ultrasonographic criteria. Univariate analysis revealed that female sex was an independent predictor of recurrence of ISR after SES implantation (p < 0.05). In conclusion, placement of a SES for the treatment of ISR in renal arteries is associated with high initial technical success but significant restenosis on duplex ultrasonography at follow-up. Keywords hypertension; in-stent restenosis; renal artery stenosis; sirolimus Introduction Percutaneous renal artery intervention with balloon angioplasty and stent implantation has become the treatment of choice for atherosclerotic renal artery stenosis. However, renal artery in-stent restenosis (RA-ISR) still remains a limitation, especially in renal arteries of less than 4.5 mm. Lederman and colleagues found an incidence of RA-ISR of 36% in patients with renal vessels < 4.5 mm. 1 The optimal treatment of RA-ISR has not yet been established. Various methods including traditional or cutting balloon angioplasty, 2 or the placement of additional bare-metal, 3 drug-eluting, 4 or covered stents 5 have been used with high initial technical success, but long-term patency data are lacking. The success of drug-eluting stent (DES) technology in inhibiting neointimal hyperplasia and resultant restenosis in the coronary arteries 6 has led to enthusiasm for their use in the renal arteries. However, the larger diameter of the renal artery poses one potential limitation in the use of currently available DESs designed and approved for smaller coronary vessels. Zeller and colleagues have previously discussed the potential indications and advantages of DES technology in the renal vasculature; namely their use in renal vessels of a small vessel diameter, the presence of a single kidney (or functional), bilateral renal artery stenosis (RAS) with small vessels and ISR that responds unfavorably to plain balloon angioplasty. 7 White et al. have previously reported that in their series of renal artery stenting, the only procedural variable that was related to angiographic restenosis was the post-stent minimal luminal diameter. 8 We report a series of consecutive patients with RA-ISR treated with sirolimus-eluting stent (SES) placement (Cypher; Cordis, J&J, Miami, FL, USA) with renal artery duplex ultrasound follow-up. Department of Interventional Cardiology and Vascular Medicine, Massachusetts General Hospital, Boston, MA, USA Corresponding author: Thomas J Kiernan Department of Interventional Cardiology and Vascular Medicine Massachusetts General Hospital Boston, MA 02114, USA Email: tom_kiernan@hotmail.com

4 Vascular Medicine 15(1) Figure 1. Angiographic in-stent restenosis of a bare-metal stent within the right renal artery. Figure 2. Angiographic result after SES implantation for in-stent restenosis of the right renal artery. Methods We retrospectively analyzed consecutive patients from our institution who underwent percutaneous treatment of RA- ISR with SES placement (Cypher) at the discretion of the primary operator from May 2004 to June 2006. The sole indication for intervention was poorly controlled hypertension in the presence of significant RA-ISR documented on renal artery duplex ultrasonography in all patients. We defined poorly controlled hypertension as systolic blood pressure > 160 mmhg, despite the use of three or greater antihypertensive medications in the presence of significant RA-ISR on duplex ultrasonography. Blood pressure measurements were based on inpatient and clinic measurements, not measurements recorded in the cardiac catheterization laboratory. The study was approved by the institutional review board. procedure, all patients were given a bolus of heparin intravenously (50 U/kg body weight). A SES (Cypher, J&J) was deployed with the length and diameter of the stent used, based on the length of the ISR, the diameter of the initial stent, and the diameter of the non-diseased artery distal to the stenosis. Procedural success was defined by residual stenosis of < 30% by angiography. Routine follow-up renal angiography was not performed in the study cohort. Instead, followup surveillance was carried out with duplex ultrasonography as discussed below. Pressure gradients were obtained only if there was a question of lesion severity. A translesional gradient of 20 mmhg was defined as significant. 9 Clopidogrel was initiated on the day of the procedure for those patients not already on this medication. Aspirin (ASA) was continued indefinitely and clopidogrel was recommended for 1 year post intervention. Technical procedure The right common femoral artery was accessed using the modified Seldinger technique with an 18-gauge, 7-cm angiographic needle (Cook, Bloomington, IN, USA). A 6-Fr 11-cm brite tip vascular sheath (Cordis, J&J) was placed in the artery over a 0.035-inch Wholey guide wire (Mallinckrodt, Hazelwood, MO, USA). Based on operator discretion, a 6-Fr internal mammary guide catheter (Boston Scientific, Natick, MA, USA) or a hockey stick 6-Fr guide catheter (Boston Scientific) was used to engage the origin of the renal artery. The no-touch technique was used in all patients. Angiography was performed using iodixanol contrast Visipaque 320 (GE Healthcare, Princeton, NJ, USA). An Asahi Prowater 0.014 wire or a 0.014 Spartocore wire was placed in the renal artery for the intervention (Figures 1 and 2). During the Duplex ultrasonography Using appropriate duplex techniques, including accurate Doppler angle correction, the peak systolic velocity (PSV) within the stent, waveform analysis distal to the stent, and renal-to-aortic ratio (RAR) were used as diagnostic criteria. The endpoint of ultrasonographic RA-ISR (> 60% diameter) was determined by PSV > 300 cm/s and RAR > 4.0. 10 Baseline patient and procedural demographics were described. Renal function (serum creatinine) and blood pressure were measured at baseline and follow-up. Follow-up was advised at 6, 12, and 24 months after the procedure. Duplex ultrasonography was performed prior to discharge of the index procedure and at each visit along with blood pressure measurement and laboratory renal profile.

Kiernan TJ et al. 5 Table 1. Baseline clinical characteristics of study cohort Patient cohort Percentage Number (n = 16) Female 75% 12 Age > 65 years 69% 11 BMI > 25 81% 13 LVEF < 35% 19% 3 Diabetes 50% 8 Hypertension 100% 16 Hyperlipidemia 94% 15 Current smoker 13% 2 Ex-smoker 63% 10 CRF (Cr > 2.0) 31% 5 BMI, body mass index; LVEF, left ventricular ejection fraction; CRF, chronic renal failure. Endpoints The primary endpoint observed in this study was RA-ISR as measured by duplex ultrasonographic criteria. Secondary endpoints included changes in serum creatinine and blood pressure measurement pre- and post-renal artery intervention. Statistical analysis Continuous variables are expressed as mean ± standard deviation and categorical variables as percentages. Statistical analysis was performed with the chi-squared or the Fisher s exact test for categorical variables. The t-test was used for the continuous variables. A significance level of 0.05 was used and the two-tailed test was applied. Analyses were performed using the Statistical Package for Social Scientists (SPSS Inc, 15.0 for Windows). Quantitative angiographic analysis was performed using Quantcor QCA (version 5; Pie Medical Imaging, Maastricht, The Netherlands). Results Patient demographics DESs were implanted in 16 patients (22 renal arteries) during the study period for the indication of poorly controlled hypertension in the presence of significant RA-ISR on duplex ultrasonography. The study cohort was predominantly female (75%) with a mean age of 68 ± 12 years. The majority (94%) of patients had hyperlipidemia and 50% had diabetes mellitus (Table 1). Interventional findings Twenty-one of the renal arteries treated were main renal arteries with only one accessory renal artery undergoing stenting with a SES. A total of 90% of lesions were aortoostial in location and the remaining 10% were in the proximal third of the renal artery. All renal arteries had previously undergone stenting with bare-metal stents with a mean diameter of 5.2 ± 0.8 mm and mean length of 15.9 ± 3.1 mm. RA-ISR was treated with sirolimus-eluting balloon expandable stents with a mean diameter of 3.5 mm and mean length of 17.9 ± 3.8 mm. The mean post-dilation balloon diameter was 4.8 ± 0.6 mm. The ratio of bare-metal stent post-deployment diameter to SES post-deployment stent diameter was 1:0.92, reflecting an almost final 1:1 ratio. All patients were taking ASA at the time of the procedure and 60% were also taking clopidogrel at this time. Clopidogrel was initiated on the day of the procedure for those patients not already on this medication. ASA was continued indefinitely and clopidogrel was recommended for 1 year post intervention at the discretion of the operator. At the time of follow-up duplex ultrasonography (median follow-up of 12 months), 19 renal arteries (90.4%) were still on dual anti-platelet therapy. Duplex ultrasonography follow-up The baseline renal artery PSV was 445 ± 131 cm/s with a mean RAR of 5.0 ± 1.6. Procedural success was achieved in all cases. There were no major in-hospital complications. Duplex ultrasonography follow-up was available in 15 (94%) patients and 21 renal arteries. During a median follow-up of 12 months (range: 9 15 months), 15 renal arteries (71.4%) developed recurrence of ISR after SES implantation by renal artery duplex ultrasonography criteria as defined above. No patients died during the followup period. Univariate analysis revealed that female sex was an independent predictor of recurrence of ISR after DES implantation (p < 0.05). There was a trend towards higher rates of recurrence of ISR in older patients, arteries in which longer SESs were used, and smaller post-dilatation balloon diameters; however, these did not reach statistical significance. In patients who developed recurrence of ISR by duplex ultrasonography criteria, the mean PSV was 376 ± 79 cm/s with a mean RAR of 5.1 ± 1.4. A mean PSV of 151 ± 31 cm/s and mean RAR of 1.9 ± 0.5 were recorded in patients who did not have a recurrence of ISR by duplex criteria. Target lesion revascularization was performed in six arteries (28.6%) for the indication of persistent sub-optimally controlled blood pressure despite adequate medical management. The mean time to target lesion revascularization was 12 ± 3 months. Revascularization modalities included balloon angioplasty only (one lesion), cutting balloon angioplasty (one lesion), covered stent grafts (three lesions) and use of another DES (one lesion). The remaining 10 patients (10 arteries) with RA-ISR by duplex criteria did not undergo further invasive angiography as blood pressure remained satisfactorily controlled with medical management in six patients, two patients refused the option of further invasive percutaneous revascularization despite sub-optimal blood pressure control, one patient was diagnosed with a late stage GI malignancy and one patient developed a myeloproliferative condition.

6 Vascular Medicine 15(1) Kidney function and blood pressure The mean systolic blood pressure was 170 ± 33 mmhg and serum creatinine was 1.9 ± 0.7 mg/dl at baseline. At followup, a mean serum creatinine of 1.7 ± 0.5 mg/dl (p = 0.14) and mean systolic blood pressure of 148 ± 23 mmhg (p < 0.001) was noted. No patients in the study cohort developed contrast-induced nephropathy post procedure. Complications There were no deaths recorded during follow-up but two patients developed groin hematomas as a result of the intervention. Both hematomas were managed conservatively. Discussion In large study cohorts, the overall restenosis rate following stenting of renal artery stenosis is significant, regardless of the threshold used to define restenosis. 11,12 However, there remain patients who appear to be at higher risk for restenosis. Lederman et al. have studied patients undergoing stenting of renal arteries and found a strong correlation between vessel diameter and ISR: < 36% for vessels < 4.5 mm diameter, 15.8% for vessels > 4.5 6.0 mm, and 6.5% for vessels > 6.0 mm. 1 It has been suggested that patients with small renal arteries in particular might benefit from the use of DES if they offer the same magnitude of reduction in restenosis as demonstrated in the coronary arteries. 13 Despite limited data regarding the use of DES in renal arteries, potential scenarios in which DES may be useful include small vessel diameter, the presence of a single kidney (or a solitary functioning kidney), bilateral renal artery stenosis, and in-stent restenosis. Our study cohort is interesting in that it represents a series of predominantly female (75%) patients with atherosclerotic RA-ISR. Optimal treatment of RA-ISR is not established, with therapeutic options including balloon angioplasty, cutting balloon angioplasty, stent-in-stent angioplasty, covered stent placement, and intra-vascular radiation therapy. Each of these modalities has only been studied in small single-center series or case reports and not in randomized trials. The GREAT (Palmaz Genesis Peripheral Stainless Steel Balloon Expandable Stent, comparing a Sirolimus Coated with an Uncoated Stent in REnal Artery Treatment) trial was a randomized prospective, multicenter study of angiographic patency of renal artery stents placed in patients with de novo atherosclerotic renal artery stenosis. 14 This study randomized patients to bare metal versus SES stents. Angiographic assessment was performed at baseline and 6 months, and clinical follow-up visits were performed up to 24 months. At the 1-year follow-up, the clinical patency rate was 98.1% in the SES group with a target lesion revascularization rate of only 1.9%. Our study demonstrated an ISR rate by duplex ultrasonography of 71.4% at 12 months. The Palmaz-Genesis SES used in the GREAT trial was very different from the Cypher SES stents used in our series. The Genesis stent has higher radial strength compared to the thin strut Cypher coronary stent and thus may lack the radial strength required to overcome elastic recoil in the aorto-ostial location. Second, the GREAT trial used 5.0 mm and 6.0 mm stents compared to the 3.5 mm stents in our study, the largest Cypher SES currently commercially available. The Cypher SES can be post-dilated to a maximum of 4.0 4.5 mm, which may be inadequate for renal artery stenosis or RA-ISR, which may require 5 7 mm in diameter. Expansion of the Cypher SES to above 4.5 mm can distort the architecture of the stent, including the thin profile strut, and may damage the pharmacokinetics of the drug-elution system and allow areas of diminished drug delivery between stent struts, potentially contributing to the high rate of ISR demonstrated in our study. Zeller and colleagues studied 31 consecutive patients (33 lesions) in a non-randomized prospective design presenting with their at least second ISR following renal artery stenting (mean follow-up 36 ± 25 months, range 1 85). The primary endpoint of the study was the reoccurrence rate of ISR after primarily successful treatment of ISR as determined by duplex ultrasound. Seven lesions were treated with balloon angioplasty (21%), seven lesions with stentin-stent placement (21%,), six lesions with placement of a covered stent (18%), three lesions with a cutting balloon (9%), and 10 lesions with placement of a drug-eluting stent (sirolimus and paclitaxel) (31%). Twelve lesions (36%) developed reoccurrence of ISR but none of the ISR lesions (10 lesions) treated with drug-eluting stents developed ISR after a mean follow-up period of 11 ± 6 months. It is important to note that the sizes of the drug-eluting stents used in this study were not specified in the published manuscript. Treatment with a cutting balloon was the only significant predictor of ISR. 5 It must also be stated that the Cypher stents used in this study may have been somewhat undersized for renal artery use and this indeed may have also had an effect on the development of restenosis. The initial stents used in this study population were bare metal with a mean postdeployment diameter of 5.2 ± 0.8 mm, while the Cypher stents had a mean post-deployment diameter of 4.8 ± 0.6 mm. Follow-up surveillance in our study was performed primarily by the use of duplex ultrasonography. It has been previously stated in the literature that ultrasound velocity criteria for ISR is higher than for de novo lesions. This may in part be due to the lack of compliance of the stented vessel. 10 Limitations This is a single center retrospective study with small patient numbers, which may limit statistical powering and significance of the results. Selecting only patients with RA-ISR that were treated with sirolimus-eluting stents could also

Kiernan TJ et al. 7 represent a source of selection bias in our study. Comparative treatment strategies are needed to assess the efficacy of treatment of RA-ISR with DES. However, the data represents a relatively homogenous group of patients with ISR of renal arteries treated with sirolimus-eluting coronary stents with clinical and ultrasonographic follow-up information available in 94% of patients. Conclusion Placement of undersized coronary drug-eluting stents (sirolimus) for the treatment of ISR in renal arteries is associated with high initial technical success but significant restenosis on duplex ultrasonography at follow-up. Declaration of conflicting interests There are no conflicts to disclose. References 1. 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: 314 323. 2. Otah KE, Alhaddad IA. Intravascular ultrasound-guided cutting balloon angioplasty for renal artery stent restenosis. Clin Cardiol 2004; 27: 581 583. 3. Bax L, Mali WP, Van De Ven PJ, et al. Repeated intervention for in-stent restenosis of the renal arteries. J Vasc Interv Radiol 2002; 13: 1219 1224. 4. Kakkar AK, Fischi M, Narins CR. Drug-eluting stent implantation for treatment of recurrent renal artery in-stent restenosis. Catheter Cardiovasc Interv 2006; 68: 118 122. 5. Zeller T, Sixt S, Rastan A, et al. Treatment of reoccurring in-stent restenosis following reintervention after stent-supported renal artery angioplasty. Catheter Cardiovasc Interv 2007; 70: 296 300. 6. Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003; 349: 1315 1323. 7. Zeller T, Rastan A, Rothenpieler U, Müller C. Restenosis after stenting of atherosclerotic renal artery stenosis: is there a rationale for the use of drug-eluting stents? Catheter Cardiovasc Interv 2006; 68: 125 130. 8. White CJ, Ramee SR, Collins TJ, Jenkins JS, Escobar A, Shaw D. Renal artery stent placement: utility in lesions difficult to treat with balloon angioplasty. J Am Coll Cardiol 1997; 30: 1445 1450. 9. Rundback JH, Sacks D, Kent KC, et al. Guidelines for the reporting of renal artery revascularization in clinical trials. American Heart Association. Circulation 2002; 106: 1572 1585. 10. Galin I, Trost B, Kang J, et al. Validation of renal duplex ultrasound in detecting renal artery stenosis post-stenting. Presented at the American College of Cardiology Annual Scientific Meeting, Chicago, 2008. Abstract A 317. 11. Tollefson DFJ, Ernst CB. Natural history of atherosclerotic renal artery stenosis associated with aortic disease. J Vasc Surg 1991; 14: 327 331. 12. Zierler RE, Bergelin RO, Davidson RC, et al. A prospective study of disease progression in patients with atherosclerotic renal artery stenosis. Am J Hypertens 1996; 9: 1055 1061. 13. Neumann FJ, Desmet W, Grube E, et al. Effectiveness and safety of sirolimus-eluting stents in the treatment of restenosis after coronary stent placement. Circulation 2005; 111: 2107 2111. 14. Zähringer M, Sapoval M, Pattynama PMT, et al. Sirolimuseluting 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: 460 468.