CLINICAL STUDY
A Randomized Prospective Study Comparing Outcomes of Angioplasty versus VIABAHN Stent-Graft Placement for Cephalic Arch Stenosis in Dysfunctional Hemodialysis Accesses Dheeraj K. Rajan, MD, FRCPC, and Abigail Falk, MD
ABSTRACT Purpose: To determine if postintervention cephalic arch stenosis (CAS) primary patency and access circuit patency are superior with the VIABAHN stent graft compared with angioplasty at 3, 6, and 12 months. Materials and Methods: All patients presenting with dysfunctional hemodialysis accesses with CAS over a 4-year period were assessed for inclusion in a randomized prospective study. A total of 14 patients were recruited across three centers. All patients had mature brachiocephalic fistulae. Five were randomized to undergo percutaneous transluminal angioplasty and nine to undergo stent-graft placement. Patency of the treated cephalic arch was assessed with transonic flow and/or follow-up fistulography. Variables assessed were diabetes, previous interventions performed on the access, access age and side, and sex. Patency was determined with Kaplan–Meier estimation. Results: Anatomic and clinical success was obtained in all interventions. Mean patency intervals were 100 days in the PTA group and 300 days in the stent-graft group. Primary access circuit patency rates at 3, 6, and 12 months were significantly different: 20%, 0%, and 0% for PTA and 100%, 67%, and 22% for stent grafts (P o .01). Primacy target lesion patency rates at 3, 6, and 12 months were also significantly different: 60%, 0%, and 0% for PTA and 100%, 100%, and 29% for stent grafts (P o .01). No complications or adverse events were observed. Conclusions: Treatment of CAS with the VIABAHN stent graft appears to provide statistically superior primary patency rates compared with balloon angioplasty.
ABBREVIATIONS CAS = cephalic arch stenosis, CI = confidence interval, PTA = percutaneous transluminal angioplasty
Percutaneous transluminal angioplasty (PTA) is the primary technique for treatment of neointimal stenoses From the Division of Vascular and Interventional Radiology (D.K.R.), Department of Medical Imaging, University of Toronto, University Health Network, 585 University Ave., NCSB 1C-553, Toronto, ON, Canada M5G 2N2; and Fresenius Vascular Care (A.F.), Berwyn, Pennsylvania. Received October 26, 2014; final revision received and accepted May 1, 2015. Address correspondence to D.K.R.; E-mail: [email protected] From the SIR 2015 Annual Meeting. Research support was provided by W.L. Gore & Associates (Flagstaff, Arizona) in the form of the VIABAHN devices being supplied for the study at no cost. & SIR, 2015 J Vasc Interv Radiol 2015; XX:]]]–]]] http://dx.doi.org/10.1016/j.jvir.2015.05.001
associated with hemodialysis access dysfunction. It remains the standard treatment against which other percutaneous techniques are compared. Although an angioplasty procedure can provide an excellent immediate result, the long-term patency rates are less than satisfactory. Cephalic arch stenosis (CAS) is a common problem that shows poorer patency with angioplasty than other venous stenoses found in autogenous fistulae (1,2). There are limited endovascular studies examining outcomes with this specific lesion; among those of which we are aware, all but one are retrospective studies (2–6). One randomized study (3) examined outcomes between bare metal stents and stent grafts and found superior outcomes with stent grafts. Limited available data suggest that bare metal stents themselves are not
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associated with improved outcomes versus angioplasty (3,6). Stent grafts appear to be a viable solution to overcome the limitations of metal stents, and provide an effective treatment for recalcitrant and/or recurring stenoses. The graft material serves as an occlusive barrier to prevent ingrowth of neointimal tissue and redevelopment of an obstructive stenosis. Given relatively few published outcomes, we sought to determine prospectively if there was a difference in patency between angioplasty and stent-graft placement within the cephalic arch. The VIABAHN stent graft (W.L. Gore & Associates, Flagstaff, Arizona) was chosen in view of its increased compliance compared with other stent grafts used for peripheral interventions.
MATERIALS AND METHODS The present investigator-driven randomized prospective single unblinded study (clinicaltrials.gov identifier NCT01200914) was conducted at three centers, two in Canada and the other in the United States, over a 4-year period. Ethics board approval was obtained for all sites, with approval from the US Food and Drug Administration and Health Canada. Stent-graft devices used in the study were provided by the manufacturer at no cost.
Patients All patients had mature functioning fistulae with no thrombosis at the time of treatment. Inclusion and exclusion criteria are presented in Table 1. Antiplatelet therapy such as clopidogrel or aspirin was permitted under the study protocol but was not required, and was administered based on the site investigator’s standard practice. A total of 14 patients were recruited over a 4year period. Five received PTA alone and all others received stent grafts. Six were male, and the average age was 61 years. All patients had mature brachiocephalic fistulae, and three had bare metal stents previously placed within the cephalic arch. Stent-graft sizes used were 8 50 mm in two patients, 8 100 mm in three, 9 100 mm in one, and 10 100 mm in three.
Study Design This was a randomized unblinded study with 1:1 randomization. All groups (those with de novo stenoses and those with in-stent restenosis) underwent PTA of the CAS with randomization such that 50% of patients from each group would receive a stent graft in addition to PTA if technically successful. Patients were followed at 3-, 6-, and 12-month intervals following the procedure. Follow-up was conducted with angiographic and/or transonic measurements. Repeat interventions were performed if access dysfunction was present, and any adverse events or complications were recorded over the follow-up period.
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Lesions randomized had 4 50% stenosis and were no longer than 3 cm (Fig 1). Native cephalic arch lesions or cephalic arch lesions previously implanted with a bare metal stent were treated with angioplasty alone rather than angioplasty and covered stent placement. If multiple lesions were present and stenosed 4 50% on the initial angiogram, all lesions were to be treated and the patient was included in the study. If there was angiographic evidence of angioplasty failure (4 30% residual stenosis), repeat angioplasty with an ultra–high-pressure balloon (if not used primarily) or a larger balloon catheter was performed with inflation times as long as 120 seconds. If residual stenosis 4 30% persisted in the angioplasty group, the procedure would constitute an anatomic failure and the treating interventionalist would continue to treat the lesion at his or her discretion. However, these patients were terminated from the study (with no angioplasty failures observed in the recruited patients).
Procedure After access was obtained, fistulography was performed in the standard fashion per each institutional practice. CAS, when observed, was measured compared with the next normal segment of cephalic vein. Computer calibers were used to ensure that 4 50% stenosis was present. At this time, the randomization envelope was opened, which determined the treatment to be administered. If angioplasty was to be performed, the balloon size chosen was 0–1 mm larger than the diameter of the next adjacent normal cephalic vein. Balloon type was at the discretion of the treating physician. Balloon inflation was for a minimum of 45 seconds. Moderate sedation with midazolam and fentanyl citrate and heparin was administered at the discretion of the treating physician. No prophylactic antibiotic agents were administered before the interventions. For stent-graft deployment, an appropriate obliquity was chosen to properly profile the junction of the cephalic vein with the axillary vein. After the junction point was properly profiled, over a 0.035-inch wire, predilation was performed by using a PTA balloon sized to the normal cephalic vein. Following technically successful angioplasty (o 30% residual stenosis), the stent graft was deployed. The device used was the same diameter as the angioplasty balloon and was postdilated after deployment. If the stenosis extended to the junction point, the stent graft would be extended into the axillary vein by no more than 1–2 mm so as not to occlude the axillary vein and maintain its patency (Fig 1). In addition, the length of the device was chosen so that the distal end or peripheral end of the device would not terminate in the genu of the cephalic arch but project beyond this point to allow for a smooth transition through the arch.
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Table 1 . Inclusion and Exclusion Criteria Inclusion Criteria Clinical
1. Hemodialysis recipient with mature forearm or upper-arm access created 4 2 mo before study enrollment. 2. Patient is Z 18 y of age. 3. Patient is competent and able to sign informed consent. 4. Patient is willing to comply with protocol. 5. Patient has a reasonable expectation of remaining on hemodialysis for 12 mo. 6. Patient or his or her legal guardian understands the study and is willing and able to comply with follow-up requirements. 7. Patient or his or her legal guardian is willing to provide informed consent. 8. Patient has lesions that meet angiographic inclusion/exclusion criteria and induce clinical, hemodynamic, or functional abnormality. Angiographic
1. Target lesion starts r 30 mm from cephalic arch. 2. Target lesion has 4 50% stenosis as measured per protocol. 3. Target lesion is o 30 mm in length. 4. Patient may have one or more secondary stenoses if the following criteria are satisfied: a. Secondary stenosis can be located in the graft or peripheral vein. b. Secondary stenosis must be r 50 mm in length. c. Secondary stenosis must be located Z 30 mm away from the edge of target lesion. d. Secondary lesion causes 4 50% stenosis and induces clinical symptoms. e. Secondary lesion is treated before randomization by using a conventional angioplasty balloon. f. Treatment of secondary lesion with conventional angioplasty is successful with o 30% residual stenosis and no complications. Exclusion Criteria Clinical
1. Heparin-induced thrombocytopenia. 2. Contrast agent allergy not controlled with prophylactic steroids. 3. Thrombosed access. 4. Indwelling catheters (dialysis, pacemakers, ports). 5. Access infection. 6. Systemic bacteremia or sepsis. 7. Planned access abandonment within 1 y (eg, peritoneal dialysis or transplant). 8. Complete vessel occlusion. 9. Patient enrolled in another access maintenance trial. 10. Presence of second lesion in access circuit o 3 cm from the edges of the primary lesion, with Z 30% stenosis. 11. Rupture of vein segment during angioplasty. 12. Flow-limiting dissection after angioplasty. Angiographic
1. Secondary lesion is an occlusion. 2. Patient has a symptomatic central venous stenosis. 3. Physician is unable to fully inflate a conventional PTA balloon at target lesion (ie, focal waist remains in balloon upon inflation). 4. There is an angioplasty-induced rupture that is unresponsive to balloon tamponade. PTA ¼ percutaneous transluminal angioplasty.
Follow-up Surveillance was conducted after percutaneous therapy with the use of ultrasound (US) dilution technique (Flow-QC; Transonic Systems, Ithaca, New York) at monthly intervals during routine dialysis treatment sessions and by observing dialysis flow rates when available (one center). One criterion for angiographic evaluation for repeat intervention was that total access blood flow rate was less than 500 mL/min by US
dilution. The other criterion was that blood flow decreased by more than 20% from baseline blood flow and one of the following occurred: (i) fistula recirculation was more than 5% by US dilution, (ii) cannulation was difficult, (iii) directly measured venous pressures exceeded threshold levels three consecutive times, or (iv) other clinical or hemodynamic findings suggested fistula dysfunction, including variable pump speeds, arm swelling, and extremity pain. Surveillance was also
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Figure 1. (a) Initial fistulogram demonstrates focal stenosis 4 50% near the junction of the cephalic vein with the axillary vein in a 65year-old woman with right brachiocephalic fistula who presented with decreased access blood flow. (b) After placement of an 8-mm 60-mm stent graft in this patient, a fistulogram demonstrates preservation of flow in the axillary vein. Arrows mark the end point of the stent graft. (c) In another patient, fistulography 8 months after stent-graft placement demonstrates focal stenosis adjacent to the edge (arrow) of the stent graft.
conducted with clinical evaluation for evidence of access dysfunction according to Kidney Disease Outcomes Quality Initiative criteria (7) or angiographic follow-up at 3-month intervals per institutional protocol. Patients underwent angiographic repeat evaluation if access dysfunction was suspected. The indication for repeat intervention was any stenosis 4 50% within the access circuit identified by angiography.
Statistical Methodology and Definitions Randomization was performed by using computergenerated random numbers in blocks of 10. Randomization codes of stent graft or no stent graft were placed in sequentially numbered, opaque, sealed envelopes at each treatment site. When a patient had been recruited and given consent, the next numbered envelope was to be opened by the operator, who had no knowledge of the randomization code just before intervention. Sample size calculations for the study were based on the primary efficacy endpoint of time to event of loss of target lesion primary patency. Power Analysis and Sample Size software (Number Cruncher Statistical Systems, Kaysville, Utah) was used to determine that a sample size of 34 subjects was required to be recruited into the study, or approximately 17 per treatment group, to obtain an 80% power. The following assumptions were used in this computation: primary efficacy outcome was time to loss of target lesion primary patency allowing for censoring statistical test with a one-sided log-rank test of superiority; stent-graft primary patency rate of 82% at 6 months (3); PTA primary patency rate of 42% at 6 months (2); and loss to follow-up of 5% for each 6-month period. Definitions used were based on Society of Interventional Radiology (SIR) reporting standards for dialysis access interventions (8). Briefly, anatomic success was defined as residual stenosis o 30% following study treatment. Clinical success was defined as the resumption of normal dialysis for at least one session. Circuit primary patency was defined as the time interval from initial study treatment to the next access thrombosis or intervention performed within the
vascular access circuit. Postintervention lesion patency (primary target lesion patency) was defined as the time interval from initial study treatment of the original treatment site until the next repeat intervention at or adjacent to the original treatment site. Complications were monitored and categorized per SIR categories. Patency was estimated by Kaplan–Meier technique by using SAS software (version 9.3; SAS, Cary, North Carolina). Recorded variables were examined to determine if any influenced patency, with a P value o .05 considered significant. Continuous variables were assessed with the Wilcoxon rank-sum test, and discrete variables were assessed with the Fisher exact test.
RESULTS Anatomic and clinical success was obtained in all interventions. Mean patency durations were 100 days (range, 56–154 d) in the PTA group and 300 days (range, 201–504 d) in the stent-graft group. Primary access circuit patency rates at 3, 6, and 12 months were significantly different: 20% (95% confidence interval [CI], 4%–100%), 0%, and 0% for PTA and 100%, 67%, and 22% (95% CI, 42%–100%; 6%–75%) for stent-graft placement (P o .01; Fig 2). Primary target lesion patency rates at 3, 6, and 12 months were also significantly different: 60% (95% CI, 29%–100%), 0%, and 0% for PTA and 100%, 100%, and 29% (95% CI, 9%–93%) for stent-graft placement (P o .01; Fig 3). The common failure pattern with the stent-graft device was edge stenosis or focal in-stent stenosis within 5 mm of the edge of the stent graft (Fig 1). For stent grafts placed for in-stent stenosis within the cephalic arch (n ¼ 3), median primary access survival was 95 days, versus 232 days for stent grafts placed for non–stent-implanted CASs. This finding was not statistically significant (P ¼ .6). None of the patients had other areas of stenosis within the access circuit that required angioplasty. No complications or adverse events were observed for angioplasty or stent-graft placement. No stent grafts were placed for flow-limiting dissection or venous rupture.
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Figure 2. Primary access circuit patency estimated with Kaplan–Meier methodology.
Figure 3. Primary target lesion patency estimated with Kaplan–Meier methodology.
There was no significant difference in categoric variables between the two groups (Table 2). No patients were lost to follow-up. One patient’s fistula developed thrombosis at 6 months after stent-graft placement and could not be salvaged. Another patient died 4 months after stent-graft insertion with no evidence of access dysfunction.
DISCUSSION We hypothesized that the VIABAHN device, with its helically wound nitinol wire frame, would be more flexible
than other devices and would conform to the arch of the cephalic vein. In addition, the Fluency stent graft (C. R. Bard, Tempe, Arizona) is not to be placed across joints or in vessels with tight bends, as mentioned in the manufacturer’s instructions for use, whereas the VIABAHN device may be placed across the antecubital fossa according to the instructions for use. A balloon-expandable expanded polytetrafluoroethylene stent graft would be considered a poor choice in this location in view of the lack of flexibility when expanded. In addition, the device was extended 1–2 mm into the axillary vein centrally and
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Table 2 . Variables Examined between the Two Treatment Groups Variable
No Stent (n ¼ 5)
Stent (n ¼ 9)
52.2 ⫾ 11.4
66.6 ⫾ 11.3
53.0 35.0–67.0
65.0 50.0–84.0
4 (80) 1 (20)
2 (22.2) 7 (77.8)
2 (40) 3 (60)
3 (33.3) 6 (66.7)
1 (20) 1 (20)
5 (55.6) 2 (22.2)
Age Mean ⫾ SD Median Range
.0712
Sex Male Female
.0909
Diabetes No Yes
1.0
Race White Black
.5205
Hispanic
2 (40)
1 (11.1)
Asian Access side
1 (20)
1 (11.1)
2 (40)
2 (22.2)
3 (60)
7 (77.8)
2 (40)
3 (33.3)
3 (60)
6 (66.7)
At junction
1 (20)
1 (11.1)
Through arch
4 (80)
8 (88.9)
Right Left Lesion type Focal (o 1 cm length) Diffuse (4 1 cm and o 3 cm length) Location
P Value
.5804
1.0
1.0
Note–Values in parentheses are percentages. SD ¼ standard deviation.
beyond the curve of the arch into the nonangled part of the cephalic vein peripherally. The latter was performed to adequately cover stenosis at the junction of the cephalic vein and axillary vein and to distally avoid having the distal end of the device stick up or “tent” the cephalic vein. The later concern was to avoid a potential focus of intimal hyperplasia from focal irritation of the vein wall. Sustained successful outcomes for endovascular interventions within the cephalic arch are limited. Patency and complications are unique for CAS, as alluded to in an initial study of this lesion (2). CAS is associated with poorer patency, higher inflation pressures to obtain anatomic success, and a higher rupture rate. In addition, the location of stenosis is sometimes at the junction of the cephalic vein with the axillary vein. If stent or stent-graft placement is contemplated, there is the risk of extending the device into the axillary vein, thereby inhibiting venous drainage from the axillary vein (5). In a single randomized study of recurrent CAS in autogenous arteriovenous access for hemodialysis (3), bare metal stent placement was compared versus Fluency stent-graft placement in 21 patients. Although the study demonstrated statistically superior patency of stent-graft placement, no sample size calculation before the initiation of the study was determined, and, in many cases, the devices were extended to the subclavian vein, thereby
excluding the axillary vein. Despite these shortcomings, one important observation was that stent placement had a similar patency outcome as angioplasty: 39% versus 42% at 6 months (2,3). In another retrospective study of 45 CASs (6), median PTA patency interval was 91.5 days, with a suggestion of improved bare metal stent patency, with a median patency interval of 152 days. Although patency appeared improved with bare metal stents for CASs in this study (6), no description of intervention, follow-up methodology, points of censure, or definitions and estimation of patency were provided, making any comparison problematic. However, as observed by Shemesh et al (3), patency with stent grafts exceeds that observed with bare metal stents. We prospectively observed 67% and 22% primary access circuit patency rates at 6 and 12 months with the VIABAHN device. In a retrospective study in which 11 VIABAHN devices were placed (5), 82% and 73% primary access circuit patency rates were observed at 6 and 12 months, respectively. Although our 6-month patency rate was similar, we had considerably lower 12month patency rates. This is possibly explained by our study design, in which patients were assessed routinely with objective measures, as opposed to the single retrospective study using VIABAHN devices, in which there was no description of follow-up methodology (5). In the study by Shemesh et al (3), which used the Fluency stent
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graft (C. R. Bard), 82% and 32% primary lesion patency rates were observed at 6 months and 1 year, respectively. Our results are somewhat similar, as we observed 100% and 29% respective primary lesion patency rates. Although our 6-month lesion primary patency rate was superior to that observed with the Fluency device, it was worse at 12 months. A conclusive reason for this difference cannot be provided, with the exception that three of the patients who received stent grafts had them placed for in-stent stenosis rather than native lesions. We observed poor patency in this subgroup, although this finding was insignificant, likely in view of the small sample size. The Kidney Disease Outcomes Quality Initiative suggests a 50% primary patency rate after PTA at 6 months, with this recommendation based on retrospective data (7). In two randomized prospective studies (9,10) performed in patients with dialysis grafts, PTA treatment area primary patency rates were found to be lower at 23%–40%. In the present prospective study, we observed 0% primary treatment area patency and 0% primary circuit access patency with PTA at 6 months. Although other studies (2,6) observed a 42% rate and a median 91-day access circuit patency period after PTA for CASs, these studies were retrospective (2,6). Even compared with these retrospective outcomes, we observed a 100% 6-month primary access circuit patency with stent-graft placement. Our primary purpose in the present study was to determine if there was superiority of postintervention target lesion primary patency and access circuit patency with the VIABAHN stent graft compared with angioplasty in the treatment of CAS. Therefore, in view of our original intention and small sample size, secondary outcomes from stent graft in-stent stenoses were not fully analyzed. The present study was terminated before complete enrollment as a result of poor recruitment over an extended period of time. The reasons are multifactorial, but the most frequently observed factor was that this was an investigator-driven study with no compensation for investigational sites beyond the devices being provided by the manufacturer. We conducted the study without industry support beyond the devices to remove possible industry bias. Seven sites received institutional review board approval, with three sites not recruiting a single patient. At one site, the investigator only wanted to place stent grafts and hence opened the blinded envelopes to select the envelopes indicating stent-graft placement. This alone resulted in elimination of data from the study owing to selection bias. At one site considering the study, despite the fact that this was a physician-driven, non–industry-supported study, the
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chair of the ethics board insisted on standard industry fee payment for review of the study. Despite multiple attempts to enroll other sites within the study, there was no interest in participating. Beyond these points, there was no funding to support individuals to oversee and drive study site recruitment, follow-up, and study documentation. Case report forms had to be filled out by investigators directly, which in itself was a barrier. There are multiple other limitations to the present study in addition to the prominent limitation that we did not complete enrollment in the study to reach the estimated sample size required to prove significance. This limits our examination of variables against patency, assessment of assisted and secondary patency outcomes, and observed results of significance and nonsignificance may be a result of this. Second, randomization was not on a one-to-one basis as a result of asymmetric recruitment across the sites and small sample size. In addition, different types of stent grafts for CAS were not compared. Given these shortcomings, it was observed that the VIABAHN stent graft appears to provide statistically superior primary patency rates in the treatment of CAS compared with balloon angioplasty. Further investigation is needed to corroborate this observation.
REFERENCES 1. Rajan DK, Bunston S, Misra S, Pinto R, Lok CE. Dysfunctional autogenous hemodialysis fistulas: outcomes after angioplasty–are there clinical predictors of patency? Radiology 2004; 232:508–515. 2. Rajan DK, Clark TW, Patel NK, Stavropoulos SW, Simons ME. Prevalence and treatment of cephalic arch stenosis in dysfunctional autogenous hemodialysis fistulas. J Vasc Interv Radiol 2003; 14:567–573. 3. Shemesh D, Goldin I, Zaghal I, Berlowitz D, Raveh D, Olsha O. Angioplasty with stent graft versus bare stent for recurrent cephalic arch stenosis in autogenous arteriovenous access for hemodialysis: a prospective randomized clinical trial. J Vasc Surg 2008; 48:1524–1531, 31 e1-2. 4. Heerwagen ST, Lonn L, Schroeder TV, Hansen MA. Cephalic arch stenosis in autogenous brachiocephalic hemodialysis fistulas: results of cutting balloon angioplasty. J Vasc Access 2010; 11:41–45. 5. Shawyer A, Fotiadis NI, Namagondlu G, et al. Cephalic arch stenosis in autogenous haemodialysis fistulas: treatment with the viabahn stentgraft. Cardiovasc Intervent Radiol 2013; 36:133–139. 6. Dukkipati R, Lee L, Atray N, Kajani R, Nassar G, Kalantar-Zadeh K. Outcomes of cephalic arch stenosis with and without stent placement after percutaneous balloon angioplasty in hemodialysis patients. Semin Dial 2015; 28:E1–E7. 7. Clinical practice guidelines for vascular access. Am J Kidney Dis 2006; 48 (Suppl 1):S176–S247. 8. Gray RJ, Sacks D, Martin LG, Trerotola SO. Reporting standards for percutaneous interventions in dialysis access. Technology Assessment Committee. [see comments]. J Vasc Interv Radiol 1999; 10:1405–1415. 9. Haskal ZJ, Trerotola S, Dolmatch B, et al. Stent graft versus balloon angioplasty for failing dialysis-access grafts. N Engl J Med 2010; 362: 494–503. 10. Vesely TM, Siegel JB. Use of the peripheral cutting balloon to treat hemodialysis-related stenoses. J Vasc Interv Radiol 2005; 16:1593–1603.
A Randomized Prospective Study Comparing Outcomes of Angioplasty versus VIABAHN Stent-Graft Placement for Cephalic Arch Stenosis in Dysfunctional Hemodialysis Accesses Dheeraj K. Rajan, MD, FRCPC, and Abigail Falk, MD
ABSTRACT Purpose: To determine if postintervention cephalic arch stenosis (CAS) primary patency and access circuit patency are superior with the VIABAHN stent graft compared with angioplasty at 3, 6, and 12 months. Materials and Methods: All patients presenting with dysfunctional hemodialysis accesses with CAS over a 4-year period were assessed for inclusion in a randomized prospective study. A total of 14 patients were recruited across three centers. All patients had mature brachiocephalic fistulae. Five were randomized to undergo percutaneous transluminal angioplasty and nine to undergo stent-graft placement. Patency of the treated cephalic arch was assessed with transonic flow and/or follow-up fistulography. Variables assessed were diabetes, previous interventions performed on the access, access age and side, and sex. Patency was determined with Kaplan–Meier estimation. Results: Anatomic and clinical success was obtained in all interventions. Mean patency intervals were 100 days in the PTA group and 300 days in the stent-graft group. Primary access circuit patency rates at 3, 6, and 12 months were significantly different: 20%, 0%, and 0% for PTA and 100%, 67%, and 22% for stent grafts (P o .01). Primacy target lesion patency rates at 3, 6, and 12 months were also significantly different: 60%, 0%, and 0% for PTA and 100%, 100%, and 29% for stent grafts (P o .01). No complications or adverse events were observed. Conclusions: Treatment of CAS with the VIABAHN stent graft appears to provide statistically superior primary patency rates compared with balloon angioplasty.
ABBREVIATIONS CAS = cephalic arch stenosis, CI = confidence interval, PTA = percutaneous transluminal angioplasty
Percutaneous transluminal angioplasty (PTA) is the primary technique for treatment of neointimal stenoses From the Division of Vascular and Interventional Radiology (D.K.R.), Department of Medical Imaging, University of Toronto, University Health Network, 585 University Ave., NCSB 1C-553, Toronto, ON, Canada M5G 2N2; and Fresenius Vascular Care (A.F.), Berwyn, Pennsylvania. Received October 26, 2014; final revision received and accepted May 1, 2015. Address correspondence to D.K.R.; E-mail: [email protected] From the SIR 2015 Annual Meeting. Research support was provided by W.L. Gore & Associates (Flagstaff, Arizona) in the form of the VIABAHN devices being supplied for the study at no cost. & SIR, 2015 J Vasc Interv Radiol 2015; XX:]]]–]]] http://dx.doi.org/10.1016/j.jvir.2015.05.001
associated with hemodialysis access dysfunction. It remains the standard treatment against which other percutaneous techniques are compared. Although an angioplasty procedure can provide an excellent immediate result, the long-term patency rates are less than satisfactory. Cephalic arch stenosis (CAS) is a common problem that shows poorer patency with angioplasty than other venous stenoses found in autogenous fistulae (1,2). There are limited endovascular studies examining outcomes with this specific lesion; among those of which we are aware, all but one are retrospective studies (2–6). One randomized study (3) examined outcomes between bare metal stents and stent grafts and found superior outcomes with stent grafts. Limited available data suggest that bare metal stents themselves are not
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associated with improved outcomes versus angioplasty (3,6). Stent grafts appear to be a viable solution to overcome the limitations of metal stents, and provide an effective treatment for recalcitrant and/or recurring stenoses. The graft material serves as an occlusive barrier to prevent ingrowth of neointimal tissue and redevelopment of an obstructive stenosis. Given relatively few published outcomes, we sought to determine prospectively if there was a difference in patency between angioplasty and stent-graft placement within the cephalic arch. The VIABAHN stent graft (W.L. Gore & Associates, Flagstaff, Arizona) was chosen in view of its increased compliance compared with other stent grafts used for peripheral interventions.
MATERIALS AND METHODS The present investigator-driven randomized prospective single unblinded study (clinicaltrials.gov identifier NCT01200914) was conducted at three centers, two in Canada and the other in the United States, over a 4-year period. Ethics board approval was obtained for all sites, with approval from the US Food and Drug Administration and Health Canada. Stent-graft devices used in the study were provided by the manufacturer at no cost.
Patients All patients had mature functioning fistulae with no thrombosis at the time of treatment. Inclusion and exclusion criteria are presented in Table 1. Antiplatelet therapy such as clopidogrel or aspirin was permitted under the study protocol but was not required, and was administered based on the site investigator’s standard practice. A total of 14 patients were recruited over a 4year period. Five received PTA alone and all others received stent grafts. Six were male, and the average age was 61 years. All patients had mature brachiocephalic fistulae, and three had bare metal stents previously placed within the cephalic arch. Stent-graft sizes used were 8 50 mm in two patients, 8 100 mm in three, 9 100 mm in one, and 10 100 mm in three.
Study Design This was a randomized unblinded study with 1:1 randomization. All groups (those with de novo stenoses and those with in-stent restenosis) underwent PTA of the CAS with randomization such that 50% of patients from each group would receive a stent graft in addition to PTA if technically successful. Patients were followed at 3-, 6-, and 12-month intervals following the procedure. Follow-up was conducted with angiographic and/or transonic measurements. Repeat interventions were performed if access dysfunction was present, and any adverse events or complications were recorded over the follow-up period.
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Lesions randomized had 4 50% stenosis and were no longer than 3 cm (Fig 1). Native cephalic arch lesions or cephalic arch lesions previously implanted with a bare metal stent were treated with angioplasty alone rather than angioplasty and covered stent placement. If multiple lesions were present and stenosed 4 50% on the initial angiogram, all lesions were to be treated and the patient was included in the study. If there was angiographic evidence of angioplasty failure (4 30% residual stenosis), repeat angioplasty with an ultra–high-pressure balloon (if not used primarily) or a larger balloon catheter was performed with inflation times as long as 120 seconds. If residual stenosis 4 30% persisted in the angioplasty group, the procedure would constitute an anatomic failure and the treating interventionalist would continue to treat the lesion at his or her discretion. However, these patients were terminated from the study (with no angioplasty failures observed in the recruited patients).
Procedure After access was obtained, fistulography was performed in the standard fashion per each institutional practice. CAS, when observed, was measured compared with the next normal segment of cephalic vein. Computer calibers were used to ensure that 4 50% stenosis was present. At this time, the randomization envelope was opened, which determined the treatment to be administered. If angioplasty was to be performed, the balloon size chosen was 0–1 mm larger than the diameter of the next adjacent normal cephalic vein. Balloon type was at the discretion of the treating physician. Balloon inflation was for a minimum of 45 seconds. Moderate sedation with midazolam and fentanyl citrate and heparin was administered at the discretion of the treating physician. No prophylactic antibiotic agents were administered before the interventions. For stent-graft deployment, an appropriate obliquity was chosen to properly profile the junction of the cephalic vein with the axillary vein. After the junction point was properly profiled, over a 0.035-inch wire, predilation was performed by using a PTA balloon sized to the normal cephalic vein. Following technically successful angioplasty (o 30% residual stenosis), the stent graft was deployed. The device used was the same diameter as the angioplasty balloon and was postdilated after deployment. If the stenosis extended to the junction point, the stent graft would be extended into the axillary vein by no more than 1–2 mm so as not to occlude the axillary vein and maintain its patency (Fig 1). In addition, the length of the device was chosen so that the distal end or peripheral end of the device would not terminate in the genu of the cephalic arch but project beyond this point to allow for a smooth transition through the arch.
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Table 1 . Inclusion and Exclusion Criteria Inclusion Criteria Clinical
1. Hemodialysis recipient with mature forearm or upper-arm access created 4 2 mo before study enrollment. 2. Patient is Z 18 y of age. 3. Patient is competent and able to sign informed consent. 4. Patient is willing to comply with protocol. 5. Patient has a reasonable expectation of remaining on hemodialysis for 12 mo. 6. Patient or his or her legal guardian understands the study and is willing and able to comply with follow-up requirements. 7. Patient or his or her legal guardian is willing to provide informed consent. 8. Patient has lesions that meet angiographic inclusion/exclusion criteria and induce clinical, hemodynamic, or functional abnormality. Angiographic
1. Target lesion starts r 30 mm from cephalic arch. 2. Target lesion has 4 50% stenosis as measured per protocol. 3. Target lesion is o 30 mm in length. 4. Patient may have one or more secondary stenoses if the following criteria are satisfied: a. Secondary stenosis can be located in the graft or peripheral vein. b. Secondary stenosis must be r 50 mm in length. c. Secondary stenosis must be located Z 30 mm away from the edge of target lesion. d. Secondary lesion causes 4 50% stenosis and induces clinical symptoms. e. Secondary lesion is treated before randomization by using a conventional angioplasty balloon. f. Treatment of secondary lesion with conventional angioplasty is successful with o 30% residual stenosis and no complications. Exclusion Criteria Clinical
1. Heparin-induced thrombocytopenia. 2. Contrast agent allergy not controlled with prophylactic steroids. 3. Thrombosed access. 4. Indwelling catheters (dialysis, pacemakers, ports). 5. Access infection. 6. Systemic bacteremia or sepsis. 7. Planned access abandonment within 1 y (eg, peritoneal dialysis or transplant). 8. Complete vessel occlusion. 9. Patient enrolled in another access maintenance trial. 10. Presence of second lesion in access circuit o 3 cm from the edges of the primary lesion, with Z 30% stenosis. 11. Rupture of vein segment during angioplasty. 12. Flow-limiting dissection after angioplasty. Angiographic
1. Secondary lesion is an occlusion. 2. Patient has a symptomatic central venous stenosis. 3. Physician is unable to fully inflate a conventional PTA balloon at target lesion (ie, focal waist remains in balloon upon inflation). 4. There is an angioplasty-induced rupture that is unresponsive to balloon tamponade. PTA ¼ percutaneous transluminal angioplasty.
Follow-up Surveillance was conducted after percutaneous therapy with the use of ultrasound (US) dilution technique (Flow-QC; Transonic Systems, Ithaca, New York) at monthly intervals during routine dialysis treatment sessions and by observing dialysis flow rates when available (one center). One criterion for angiographic evaluation for repeat intervention was that total access blood flow rate was less than 500 mL/min by US
dilution. The other criterion was that blood flow decreased by more than 20% from baseline blood flow and one of the following occurred: (i) fistula recirculation was more than 5% by US dilution, (ii) cannulation was difficult, (iii) directly measured venous pressures exceeded threshold levels three consecutive times, or (iv) other clinical or hemodynamic findings suggested fistula dysfunction, including variable pump speeds, arm swelling, and extremity pain. Surveillance was also
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Figure 1. (a) Initial fistulogram demonstrates focal stenosis 4 50% near the junction of the cephalic vein with the axillary vein in a 65year-old woman with right brachiocephalic fistula who presented with decreased access blood flow. (b) After placement of an 8-mm 60-mm stent graft in this patient, a fistulogram demonstrates preservation of flow in the axillary vein. Arrows mark the end point of the stent graft. (c) In another patient, fistulography 8 months after stent-graft placement demonstrates focal stenosis adjacent to the edge (arrow) of the stent graft.
conducted with clinical evaluation for evidence of access dysfunction according to Kidney Disease Outcomes Quality Initiative criteria (7) or angiographic follow-up at 3-month intervals per institutional protocol. Patients underwent angiographic repeat evaluation if access dysfunction was suspected. The indication for repeat intervention was any stenosis 4 50% within the access circuit identified by angiography.
Statistical Methodology and Definitions Randomization was performed by using computergenerated random numbers in blocks of 10. Randomization codes of stent graft or no stent graft were placed in sequentially numbered, opaque, sealed envelopes at each treatment site. When a patient had been recruited and given consent, the next numbered envelope was to be opened by the operator, who had no knowledge of the randomization code just before intervention. Sample size calculations for the study were based on the primary efficacy endpoint of time to event of loss of target lesion primary patency. Power Analysis and Sample Size software (Number Cruncher Statistical Systems, Kaysville, Utah) was used to determine that a sample size of 34 subjects was required to be recruited into the study, or approximately 17 per treatment group, to obtain an 80% power. The following assumptions were used in this computation: primary efficacy outcome was time to loss of target lesion primary patency allowing for censoring statistical test with a one-sided log-rank test of superiority; stent-graft primary patency rate of 82% at 6 months (3); PTA primary patency rate of 42% at 6 months (2); and loss to follow-up of 5% for each 6-month period. Definitions used were based on Society of Interventional Radiology (SIR) reporting standards for dialysis access interventions (8). Briefly, anatomic success was defined as residual stenosis o 30% following study treatment. Clinical success was defined as the resumption of normal dialysis for at least one session. Circuit primary patency was defined as the time interval from initial study treatment to the next access thrombosis or intervention performed within the
vascular access circuit. Postintervention lesion patency (primary target lesion patency) was defined as the time interval from initial study treatment of the original treatment site until the next repeat intervention at or adjacent to the original treatment site. Complications were monitored and categorized per SIR categories. Patency was estimated by Kaplan–Meier technique by using SAS software (version 9.3; SAS, Cary, North Carolina). Recorded variables were examined to determine if any influenced patency, with a P value o .05 considered significant. Continuous variables were assessed with the Wilcoxon rank-sum test, and discrete variables were assessed with the Fisher exact test.
RESULTS Anatomic and clinical success was obtained in all interventions. Mean patency durations were 100 days (range, 56–154 d) in the PTA group and 300 days (range, 201–504 d) in the stent-graft group. Primary access circuit patency rates at 3, 6, and 12 months were significantly different: 20% (95% confidence interval [CI], 4%–100%), 0%, and 0% for PTA and 100%, 67%, and 22% (95% CI, 42%–100%; 6%–75%) for stent-graft placement (P o .01; Fig 2). Primary target lesion patency rates at 3, 6, and 12 months were also significantly different: 60% (95% CI, 29%–100%), 0%, and 0% for PTA and 100%, 100%, and 29% (95% CI, 9%–93%) for stent-graft placement (P o .01; Fig 3). The common failure pattern with the stent-graft device was edge stenosis or focal in-stent stenosis within 5 mm of the edge of the stent graft (Fig 1). For stent grafts placed for in-stent stenosis within the cephalic arch (n ¼ 3), median primary access survival was 95 days, versus 232 days for stent grafts placed for non–stent-implanted CASs. This finding was not statistically significant (P ¼ .6). None of the patients had other areas of stenosis within the access circuit that required angioplasty. No complications or adverse events were observed for angioplasty or stent-graft placement. No stent grafts were placed for flow-limiting dissection or venous rupture.
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Figure 2. Primary access circuit patency estimated with Kaplan–Meier methodology.
Figure 3. Primary target lesion patency estimated with Kaplan–Meier methodology.
There was no significant difference in categoric variables between the two groups (Table 2). No patients were lost to follow-up. One patient’s fistula developed thrombosis at 6 months after stent-graft placement and could not be salvaged. Another patient died 4 months after stent-graft insertion with no evidence of access dysfunction.
DISCUSSION We hypothesized that the VIABAHN device, with its helically wound nitinol wire frame, would be more flexible
than other devices and would conform to the arch of the cephalic vein. In addition, the Fluency stent graft (C. R. Bard, Tempe, Arizona) is not to be placed across joints or in vessels with tight bends, as mentioned in the manufacturer’s instructions for use, whereas the VIABAHN device may be placed across the antecubital fossa according to the instructions for use. A balloon-expandable expanded polytetrafluoroethylene stent graft would be considered a poor choice in this location in view of the lack of flexibility when expanded. In addition, the device was extended 1–2 mm into the axillary vein centrally and
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Angioplasty versus VIABAHN Stent Grafts for Cephalic Arch Stenosis
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Table 2 . Variables Examined between the Two Treatment Groups Variable
No Stent (n ¼ 5)
Stent (n ¼ 9)
52.2 ⫾ 11.4
66.6 ⫾ 11.3
53.0 35.0–67.0
65.0 50.0–84.0
4 (80) 1 (20)
2 (22.2) 7 (77.8)
2 (40) 3 (60)
3 (33.3) 6 (66.7)
1 (20) 1 (20)
5 (55.6) 2 (22.2)
Age Mean ⫾ SD Median Range
.0712
Sex Male Female
.0909
Diabetes No Yes
1.0
Race White Black
.5205
Hispanic
2 (40)
1 (11.1)
Asian Access side
1 (20)
1 (11.1)
2 (40)
2 (22.2)
3 (60)
7 (77.8)
2 (40)
3 (33.3)
3 (60)
6 (66.7)
At junction
1 (20)
1 (11.1)
Through arch
4 (80)
8 (88.9)
Right Left Lesion type Focal (o 1 cm length) Diffuse (4 1 cm and o 3 cm length) Location
P Value
.5804
1.0
1.0
Note–Values in parentheses are percentages. SD ¼ standard deviation.
beyond the curve of the arch into the nonangled part of the cephalic vein peripherally. The latter was performed to adequately cover stenosis at the junction of the cephalic vein and axillary vein and to distally avoid having the distal end of the device stick up or “tent” the cephalic vein. The later concern was to avoid a potential focus of intimal hyperplasia from focal irritation of the vein wall. Sustained successful outcomes for endovascular interventions within the cephalic arch are limited. Patency and complications are unique for CAS, as alluded to in an initial study of this lesion (2). CAS is associated with poorer patency, higher inflation pressures to obtain anatomic success, and a higher rupture rate. In addition, the location of stenosis is sometimes at the junction of the cephalic vein with the axillary vein. If stent or stent-graft placement is contemplated, there is the risk of extending the device into the axillary vein, thereby inhibiting venous drainage from the axillary vein (5). In a single randomized study of recurrent CAS in autogenous arteriovenous access for hemodialysis (3), bare metal stent placement was compared versus Fluency stent-graft placement in 21 patients. Although the study demonstrated statistically superior patency of stent-graft placement, no sample size calculation before the initiation of the study was determined, and, in many cases, the devices were extended to the subclavian vein, thereby
excluding the axillary vein. Despite these shortcomings, one important observation was that stent placement had a similar patency outcome as angioplasty: 39% versus 42% at 6 months (2,3). In another retrospective study of 45 CASs (6), median PTA patency interval was 91.5 days, with a suggestion of improved bare metal stent patency, with a median patency interval of 152 days. Although patency appeared improved with bare metal stents for CASs in this study (6), no description of intervention, follow-up methodology, points of censure, or definitions and estimation of patency were provided, making any comparison problematic. However, as observed by Shemesh et al (3), patency with stent grafts exceeds that observed with bare metal stents. We prospectively observed 67% and 22% primary access circuit patency rates at 6 and 12 months with the VIABAHN device. In a retrospective study in which 11 VIABAHN devices were placed (5), 82% and 73% primary access circuit patency rates were observed at 6 and 12 months, respectively. Although our 6-month patency rate was similar, we had considerably lower 12month patency rates. This is possibly explained by our study design, in which patients were assessed routinely with objective measures, as opposed to the single retrospective study using VIABAHN devices, in which there was no description of follow-up methodology (5). In the study by Shemesh et al (3), which used the Fluency stent
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graft (C. R. Bard), 82% and 32% primary lesion patency rates were observed at 6 months and 1 year, respectively. Our results are somewhat similar, as we observed 100% and 29% respective primary lesion patency rates. Although our 6-month lesion primary patency rate was superior to that observed with the Fluency device, it was worse at 12 months. A conclusive reason for this difference cannot be provided, with the exception that three of the patients who received stent grafts had them placed for in-stent stenosis rather than native lesions. We observed poor patency in this subgroup, although this finding was insignificant, likely in view of the small sample size. The Kidney Disease Outcomes Quality Initiative suggests a 50% primary patency rate after PTA at 6 months, with this recommendation based on retrospective data (7). In two randomized prospective studies (9,10) performed in patients with dialysis grafts, PTA treatment area primary patency rates were found to be lower at 23%–40%. In the present prospective study, we observed 0% primary treatment area patency and 0% primary circuit access patency with PTA at 6 months. Although other studies (2,6) observed a 42% rate and a median 91-day access circuit patency period after PTA for CASs, these studies were retrospective (2,6). Even compared with these retrospective outcomes, we observed a 100% 6-month primary access circuit patency with stent-graft placement. Our primary purpose in the present study was to determine if there was superiority of postintervention target lesion primary patency and access circuit patency with the VIABAHN stent graft compared with angioplasty in the treatment of CAS. Therefore, in view of our original intention and small sample size, secondary outcomes from stent graft in-stent stenoses were not fully analyzed. The present study was terminated before complete enrollment as a result of poor recruitment over an extended period of time. The reasons are multifactorial, but the most frequently observed factor was that this was an investigator-driven study with no compensation for investigational sites beyond the devices being provided by the manufacturer. We conducted the study without industry support beyond the devices to remove possible industry bias. Seven sites received institutional review board approval, with three sites not recruiting a single patient. At one site, the investigator only wanted to place stent grafts and hence opened the blinded envelopes to select the envelopes indicating stent-graft placement. This alone resulted in elimination of data from the study owing to selection bias. At one site considering the study, despite the fact that this was a physician-driven, non–industry-supported study, the
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chair of the ethics board insisted on standard industry fee payment for review of the study. Despite multiple attempts to enroll other sites within the study, there was no interest in participating. Beyond these points, there was no funding to support individuals to oversee and drive study site recruitment, follow-up, and study documentation. Case report forms had to be filled out by investigators directly, which in itself was a barrier. There are multiple other limitations to the present study in addition to the prominent limitation that we did not complete enrollment in the study to reach the estimated sample size required to prove significance. This limits our examination of variables against patency, assessment of assisted and secondary patency outcomes, and observed results of significance and nonsignificance may be a result of this. Second, randomization was not on a one-to-one basis as a result of asymmetric recruitment across the sites and small sample size. In addition, different types of stent grafts for CAS were not compared. Given these shortcomings, it was observed that the VIABAHN stent graft appears to provide statistically superior primary patency rates in the treatment of CAS compared with balloon angioplasty. Further investigation is needed to corroborate this observation.
REFERENCES 1. Rajan DK, Bunston S, Misra S, Pinto R, Lok CE. Dysfunctional autogenous hemodialysis fistulas: outcomes after angioplasty–are there clinical predictors of patency? Radiology 2004; 232:508–515. 2. Rajan DK, Clark TW, Patel NK, Stavropoulos SW, Simons ME. Prevalence and treatment of cephalic arch stenosis in dysfunctional autogenous hemodialysis fistulas. J Vasc Interv Radiol 2003; 14:567–573. 3. Shemesh D, Goldin I, Zaghal I, Berlowitz D, Raveh D, Olsha O. Angioplasty with stent graft versus bare stent for recurrent cephalic arch stenosis in autogenous arteriovenous access for hemodialysis: a prospective randomized clinical trial. J Vasc Surg 2008; 48:1524–1531, 31 e1-2. 4. Heerwagen ST, Lonn L, Schroeder TV, Hansen MA. Cephalic arch stenosis in autogenous brachiocephalic hemodialysis fistulas: results of cutting balloon angioplasty. J Vasc Access 2010; 11:41–45. 5. Shawyer A, Fotiadis NI, Namagondlu G, et al. Cephalic arch stenosis in autogenous haemodialysis fistulas: treatment with the viabahn stentgraft. Cardiovasc Intervent Radiol 2013; 36:133–139. 6. Dukkipati R, Lee L, Atray N, Kajani R, Nassar G, Kalantar-Zadeh K. Outcomes of cephalic arch stenosis with and without stent placement after percutaneous balloon angioplasty in hemodialysis patients. Semin Dial 2015; 28:E1–E7. 7. Clinical practice guidelines for vascular access. Am J Kidney Dis 2006; 48 (Suppl 1):S176–S247. 8. Gray RJ, Sacks D, Martin LG, Trerotola SO. Reporting standards for percutaneous interventions in dialysis access. Technology Assessment Committee. [see comments]. J Vasc Interv Radiol 1999; 10:1405–1415. 9. Haskal ZJ, Trerotola S, Dolmatch B, et al. Stent graft versus balloon angioplasty for failing dialysis-access grafts. N Engl J Med 2010; 362: 494–503. 10. Vesely TM, Siegel JB. Use of the peripheral cutting balloon to treat hemodialysis-related stenoses. J Vasc Interv Radiol 2005; 16:1593–1603.
