Three-Dimensional Balloon Catheter Sizing Identifies Significant<br />
Underdeployed Stents Using Conventional Methods in Renal<br />
Arte

Percutaneous renal artery stenting is a well-established revascularization modality for the treatment of significant renal artery stenosis (RAS) in selected patients with uncontrolled hypertension, renal insufficiency or heart failure symptoms.^1–3 Despite improving blood pressure control and preserving renal function in some patients,^2–7 in-stent restenosis remains an important problem, as it can occur in up to 39% of patients.^2,8 Optimal stent deployment defined by the poststenting minimal lumen area (MLA) or minimal lumen diameter (MLD) is an important predictor of late stent patency.^9-12 Stent diameter and cross-sectional area post deployment can be determined by visual estimation, quantitative analysis (QA) or by intravascular ultrasound (IVUS). Visual estimation is subjective and has significant inter- and intraobserver variability and inherent limitations. QA uses special software for online or offline analysis of the lesion in question and measures the two-dimensional outline of the vessel lumen to estimate its luminal diameter or area, and is also limited by side-branch overlap, foreshortening or geometric distortion.¹³ IVUS, on the other hand, provides a circumferential view of the vessel lumen and its wall, allowing a threedimensional representation of the vessel lumen with more adequate measurements of vessel diameter, cross-sectional area or volume. However, IVUS is costly, not widely available and requires operator expertise for its use and accurate interpretation of results.¹⁴ The Metricath^™ (MC) system (Angiometrx, Inc., Vancouver, British Columbia, Canada) is a novel, lowpressure balloon catheter connected to an external console that derives vessel lumen diameter and cross-sectional area from measurements of volume of fluid and pressure within the balloon.¹⁴ The aims of this study were to assess the feasibility of using the MC system during renal artery stenting and its role in guiding optimal stent deployment.

Methods
Patients. The study population consisted of 16 patients who were referred for renal artery stenting for uncontrolled hypertension despite medical therapy and who had de novo RAS (diameter stenosis) ≥ 50% and/or ≥ 10 mmHg pressure gradient across the lesion. Patients were excluded from the study if they had calcified or complex lesions. The study was approved by our institutional review board and all patients signed an informed consent before participating in the study.
The Metricath system. The MC system consists of a lowpressure balloon (250 mmHg or ≈1/3 atm) catheter similar to a conventional balloon catheter and an external console. The catheter shaft has a lumen for balloon fluid infusion, a second lumen for measuring balloon fluid pressure and a third lumen for the guidewire.¹⁴ The external console is comprised of a syringe pump, pressure transducer, printer, display screen, computer and related hardware.^13,14 The MC balloon catheter is first calibrated ex vivo to record the volume and pressure of the unconstrained balloon. The balloon catheter isthen placed at the measurement site and automatically inflated to the measurement pressure where it conforms to the size and shape of the vessel lumen. The volume of fluid and the pressure in the balloon are used by the console software to calculate the pressure-volume curve and compare it to the calibration pressure-volume curve. The MC system then uses the measurement and calibration curves to precisely calculate the cross-sectional area averaged over the balloon length and derive from it an average luminal diameter that are both digitally displayed on the console’s screen.^13,14 We utilized either of 2 balloons: the first has a length of 10 mm and a measuring diameter range of 4–8 mm, and the second a length of 7 mm and a measuring diameter up to 3.5 mm.
Procedure. Before referral for renal artery stenting, selective renal artery angiography was performed in the anteriorposterior projection using a 6 Fr Judkins right catheter (Cordis Corp., Miami, Florida). A pressure gradient across the lesion was obtained whenever feasible. During the renal stenting procedure, an 8 Fr RDC1 guiding catheter (Cordis) was used to engage the renal artery. Intravenous heparin (3000–6000 units) was administered to maintain an activated clotting time > 250 seconds throughout the procedure. The lesion was then crossed with a 0.018 inch SV8 guidewire (Cordis). The balloon and stent sizes were determined by the operator based on visual estimation of the reference renal artery. Angioplasty and stenting was performed using standard techniques whereby the lesion was predilated with a balloon and then a stent was deployed and postdilated based on the compliance chart provided by the stent’s packaging information. Once successful stent implantation and optimal angiographic results were achieved based on the operator’s visual assessment, and before terminating the procedure, the MC balloon catheter was advanced to its target site using standard interventional techniques and was then inflated to measure the MLD and MLA at the lesion site and at the distal end of the stent. Adjunctive balloon postdilatation was performed using higher pressures and/or larger balloons based on a ratio of MC lesion MLD to nominal stent diameter of < 85% as deemed appropriate by the operator. Reassessment with the MC balloon catheter was performed after each additional interventional step.
Angiographic analysis. Lesions were considered ostial if they were within 5 mm from the aorta. A single operator who was blinded to the results of the MC measurements performed offline QA using electronic calipers with the contrast-filled catheter as the calibration standard. The MLD was measured at the narrowest segment of the renal artery, and the reference diameter at the most normal-appearing segment after the stenosis excluding post-stenotic dilated segments. After stent deployment, the MLD was measured at the narrowest segment inside the stent (the stent waist) and at the distal end of the stent corresponding to the sites of the MC measurements. The measured diameters were used to calculate the corresponding areas, assuming the area of a circle (π. diameter²/ 4).

Statistical analysis. Statistical analysis was performed using SPSS (Version 11.5, SPSS Inc., Chicago, Illinois) and MedCalc (Version 9.3, MedCalc Software, Mariakerke, Belgium). Categorical variables are presented as percent frequency. Continuous variables are presented as mean ± 1 standard deviation (SD), and comparison between groups was performed using the paired t-test. Linear regression analysis was performed to determine the relationship between the QA and MC measurements. The Bland and Altman method¹⁵ was used to assess the agreement between QA and MC measurements. A p-value < 0.05 was considered statistically significant.

Results

A total of 16 patients underwent angioplasty and stenting of 20 renal lesions. The baseline patient characteristics are listed in Table 1 and the renal intervention procedural characteristics are listed in Table 2. Adjunctive intervention was performed on 18 of the 20 lesions (additional balloon dilation at higher pressures [range 10–14 atm] in 18 lesions, and upgrade to larger balloons in 2 lesions) despite an adequate visual angiographic result. Tables 3 and 4 show the results before and after adjunctive interventions on 18 lesions based on the MC measurements (Figure 1). The QA measurements were significantly higher than the MC measurements at the lesion site, and both measurements were significantly lower than the corresponding nominal stent measurements (Table 3). The MC lesion MLD to the nominal stent diameter ratio post stenting was ≥ 85% in 2 of the 20 lesions, and was ≥ 90% only in 1 lesion. An MC MLD to nominal stent diameter ratio ≥ 85% occurred in 10% of lesions before adjunctive intervention, and in 65% of lesions after adjunctive intervention (Table 4). The stent expansion was more pronounced at its distal site compared to the lesion site (Table 3). The MC and QA measurements were significantly different at the lesion and distal stent sites before adjunctive intervention and became less different after adjunctive intervention (Table 3 and Figure 2). The difference was more pronounced at the lesion site compared to the distal stent site, with a tendency for QA to overestimate the MLD and MLA (Figure 2). There was a significant correlation between the MC and QA measurements that was modest before adjunctive intervention and became stronger after adjunctive intervention (Figure 3). The best correlation was present between the MC and QA measurements at the distal stent site after adjunctive intervention (Figure 3). The time needed to do the MC measurements was around 1–2 minutes per lesion. There were no complications during the procedures (Table 5). Figure 4 shows the angiographic results of 2 patients who underwent adjunctive intervention based on the results of their MC measurements.

Discussion
The main finding of this study is that the MC system can be safely used to guide stent deployment during renal artery interventions. The MC measurements showed suboptimal stent deployment compared to nominal stent dimensions in 18 of 20 lesions that otherwise would have been left alone based on satisfactory visual assessment. The stents were underdeployed at the distal site and more so at the lesion site. Adjunctive intervention with dilatation at higher pressures and/or with larger balloons resulted in significant gains in MLD and MLA at lesion and distal stent sites.

The MC system has been validated in a stented porcine model and has been used to measure coronary stent dimensions in humans.^13,14 The human study involved 21 patients who underwent coronary artery stenting. MC-obtained diameters were not significantly different from IVUS diameters and were significantly different from QCA diameters. MC-obtained cross-sectional areas correlated best with offline IVUS analysis performed by an independent core lab (R² = 0.81, p < 0.001).
Most of the atherosclerotic renal artery lesions are usually located at the ostium or in the proximal portion of the artery and the renal arteries are usually large in caliper. Angiographic evaluation of renal lesions, visually or quantitatively, is further limited and made less accurate by difficultto- obtain orthogonal views of the lesion, accurate definition of a normal reference segment, or assessment of complex and eccentric lesions.³ The correlation between visual and QA assessments of renal artery lesions was modest (r = 0.51, p < 0.001), with a tendency of overestimation by visual analysis compared to QA.³ The correlation between QA- and IVUS-measured reference vessel and lesion MLD was in the range of 0.63–0.72 (p < 0.001), with a tendency of the QA measurements to overestimate the IVUS measurements.¹⁶ In our study, there was a significant modest-tostrong correlation between the MC and QA measurements, with a tendency for QA to overestimate the MC results, giving a false impression about the stent size. These differences were more pronounced at the lesion site where the stent was more underexpanded. QA measures the outer diameters of the stent in a single plane, while the MC system confirms to the inner dimensions of the stent dimensions, giving a more accurate three-dimensional measurement.

Renal artery in-stent restenosis, as in coronary artery instent restenosis, is related to acute gain and late loss.³ Smaller postprocedural MLD or smaller acute gain, smaller stent diameters, and smaller renal artery reference diameters have been shown to be significant predictors of renal artery instent restenosis.^5,6,17–19 The mean renal artery in-stent restenosis rates from 2 meta-analyses were 17% at 17 months (range 0–39%) in one study,² and 16% at 6–12 months (range 0–39%) in another.8 The in-stent restenosis rate can be improved to 9–12% with the use of optimal deployment techniques.^3,4,20,21 In one study, the angiographic (> 50% diameter) restenosis rate was 19% at 8.7 months. The poststent MLD was 4.9 ± 0.9 mm in the patent renal arteries compared to 4.3 ± 0.7 mm in renal arteries with in-stent restenosis (p = 0.025), with a late loss of 3.0 ± 1.4 mm for the restenotic arteries compared to 1.3 ± 0.9 mm for the patent arteries (p < 0.001).⁵ In another study, the 10-month angiographic restenosis rate was 36% for renal arteries with a reference diameter (RD) < 4.5 mm compared to 12% in renal arteries, with a RD > 4.5 mm (p < 0.01).⁶ The post-stent MLD was 4.7 ± 1.1 mm in renal arteries with restenosis compared to 5.6 ± 1.2 mm in those without restenosis (p = 0.01).⁶ Shammas et al found a 40% restenosis rate when the vessel RD was ≤ 4 mm compared to 18.4% when the vessel RD was > 4 mm.¹⁸ The percent residual stenosis was a sole significant predictor of restenosis using multiple regression analysis.¹⁸ The risk of in-stent restenosis was significantly lower when stents ≥ 6 mm in diameter and < 20 mm in length were used in one study¹⁹ and when a final stent diameter > 5 mm was achieved in another study.²² In the current trial, the MC lesion MLD improved from 4.40 ± 0.77 mm to 5.17 ± 0.82 mm (p < 0.05), a value which, based on what was discussed above, should translate into an improvement in restenosis rates of these stents.
Optimal stent deployment and expansion are thus important to improve long-term stent patency. Reliance on visual or even quantitative assessment of lesions is not very accurate, as it tends to overestimate the diameter measurements and underestimate the real diameter gains as shown by the MC system in our study and by IVUS studies. MC-guided renal artery stenting showed that 90% of the stents were underdeployed by reliance on manufacturers’ stent deployment compliance charts and visual assessment of angiographic results. In an IVUS-guided study of stent deployment in coronary arteries, only 29% achieved optimal stent deployment, which was further improved with adjunctive balloon postdilatation.²³ Higher deployment pressures were predictors of optimal deployment, whereas stent type and nominal stent size were not.²³ Failure to achieve optimal stent deployment was not related to undersizing the stent, but to failure of the stent delivery balloon to fully expand the stent to its nominal size.²³ In an IVUS-guided renal artery stenting study, IVUS guidance after stent deployment warranted the use of additional balloon dilatation in 5 of 18 patients, additional stent deployment in 1 of 18 patients and use of a larger balloon in 3 of 18 patients.²⁴ In another IVUS-guided renal artery stenting study, angiographic success was achieved in all patients, though IVUS guidance dictated additional balloon inflations in 24% of cases to optimize stent deployment despite adequate apparent angiographic results.¹⁶ However, IVUS use is not widespread for assessing stent deployment for various technical and cost-related issues. The MC system could be an alternative, as it is simpler to use, cheaper and can provide an adequate assessment of stent dimensions. The results of our study emphasize the importance of high-pressure inflations in renal stenting, similar to coronary artery stenting. The MC technique can aid in selecting those patients who will benefit from high-pressure inflations or who may need larger balloons. However, the results of our study cannot be extrapolated to patients with calcified or complex lesions who were excluded from this study.
Study limitations. This study is limited by its small number of patients and by the fact that it was a single-center, single-operator study. The results of the MC were not compared to IVUS, which is considered the gold standard. Furthermore, IVUS has an advantage over the MC system in its ability to provide an inside view of the stent. However, prior studies showed excellent correlations between MC and IVUS measurements in coronary arteries.^13,14 We did not test the reproducibility of the MC measurements, though in one study there was a strong linear relationship between repeated MC measurements (r = 0.99, p < 0.001).¹⁴

Conclusions
MC guidance during renal interventions revealed a large proportion of underdeployed stents, despite optimal visual angiographic and QCA results which were further optimized by adjunctive postdilatation with larger-sized balloons or higher pressures. Our study expanded the use of the MC system to the renal arteries and showed its safety and feasibility. Future studies need to focus on the long-term effects of using such a strategy, particularly its effect on restenosis and its clinical sequelae.

References

1. van de Ven PJ, Kaatee R, Beutler JJ, et al. Arterial stenting and balloon angioplasty in ostial atherosclerotic renovascular disease: A randomised trial. Lancet 1999;353:282–286.
2. Leertouwer TC, Gussenhoven EJ, Bosch JL, et al. Stent placement for renal arterial stenosis: Where do we stand? A meta-analysis. Radiology 2000;216:78–85.
3. White CJ. Catheter-based therapy for atherosclerotic renal artery stenosis. Circulation 2006;113:1464–1473.
4. Blum U, Krumme B, Flugel P, et al. Treatment of ostial renal-artery stenoses with vascular endoprostheses after unsuccessful balloon angioplasty. N Engl J Med 1997;336:459–465.
5. White CJ, Ramee SR, Collins TJ, et al. Renal artery stent placement: Utility in lesions difficult to treat with balloon angioplasty. J Am Coll Cardiol 1997;30:1445–1450.
6. Lederman RJ, Mendelsohn FO, Santos R, et al. Primary renal artery stenting: Characteristics and outcomes after 363 procedures. Am Heart J 2001;142:314–323.
7. Balk E, Raman G, Chung M, et al. Effectiveness of management strategies for renal artery stenosis: A systematic review. Ann Intern Med 2006;145:901–912.
8. Isles CG, Robertson S, Hill D. Management of renovascular disease: A review of renal artery stenting in ten studies. QJM 1999;92:159–167.
9. Hoffmann R, Mintz GS, Mehran R, et al. Intravascular ultrasound predictors of angiographic restenosis in lesions treated with Palmaz-Schatz stents. J Am Coll Cardiol 1998;31:43–49.
10. van der Lugt A, Gussenhoven EJ, Pasterkamp G, et al. Intravascular ultrasound predictors of restenosis after balloon angioplasty of the femoropopliteal artery. Eur J Vasc Endovasc Surg 1998;16:110–119.
11. Fitzgerald PJ, Oshima A, Hayase M, et al. Final results of the Can Routine Ultrasound Influence Stent Expansion (CRUISE) study. Circulation 2000; 102: 523– 530.
12. de Feyter PJ, Kay P, Disco C, Serruys PW. Reference chart derived from post-stentimplantation intravascular ultrasound predictors of 6-month expected restenosis on quantitative coronary angiography. Circulation 1999; 100: 1777– 1783.
13. van der Giessen WJ, Carlier SG, Regar E, et al. A new intracoronary measurement catheter, MetriCath, compared to intravascular ultrasound and quantitative coronary angiography in a stented porcine coronary model. Catheter Cardiovasc Interv 2002;57:2–9; Discussion 10–11.
14. van der Giessen WJ, Regar E, McFadden E, et al. Assessment of stent dimensions with a novel intracoronary balloon-based system: Comparative study versus intravascular ultrasound and quantitative coronary angiography. The CAMUS — coronary angioplasty metricath vs ultrasound trial. Eurointervention 2005: 239- 246.
15. Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986; 1: 307– 310.
16. Dangas G, Laird JR Jr, Mehran R, et al. Intravascular ultrasound-guided renal artery stenting. J Endovasc Ther 2001; 8: 238– 247.
17. Zeller T, Muller C, Frank U, et al. Gold coating and restenosis after primary stenting of ostial renal artery stenosis. Catheter Cardiovasc Interv 2003;60:1–6; Discussion 7–8.
18. Shammas NW, Kapalis MJ, Dippel EJ, et al. Clinical and angiographic predictors of restenosis following renal artery stenting. J Invasive Cardiol 2004; 16: 10– 13.
19. Vignali C, Bargellini I, Lazzereschi M, et al. Predictive factors of in-stent restenosis in renal artery stenting: A retrospective analysis. Cardiovasc Intervent Radiol 2005; 28: 296– 302.
20. Henry M, Amor M, Henry I, et al. Stents in the treatment of renal artery stenosis: Long-term follow-up. J Endovasc Surg 1999; 6: 42- 51.
21. Rocha-Singh KJ, Mishkel GJ, Katholi RE, et al. Clinical predictors of improved long-term blood pressure control after successful stenting of hypertensive patients with obstructive renal artery atherosclerosis. Catheter Cardiovasc Interv 1999; 47: 167– 172.
22. Bates MC, Rashid M, Campbell JE, et al. Factors influencing the need for target vessel revascularization after renal artery stenting. J Endovasc Ther 2006; 13: 569– 577.
23. Brodie BR, Cooper C, Jones M, et al. Is adjunctive balloon postdilatation necessary after coronary stent deployment? Final results from the POSTIT trial. Catheter Cardiovasc Interv 2003; 59: 184– 192.
24. Leertouwer TC, Gussenhoven EJ, van Overhagen H, et al. Stent placement for treatment of renal artery stenosis guided by intravascular ultrasound. J Vasc Interv Radiol 1998; 9: 945– 952.