Abstract: Background. We present the results of a patient-level meta-analysis of the two currently completed and core-lab adjudicated prospective trials of Jetstream atherectomy system (Boston Scientific) in femoropopliteal in-stent restenosis (FP-ISR) and compare the findings to a published, prespecified 6-month performance goal of target-lesion revascularization (TLR) with angioplasty alone. Methods. The JETSTREAM-ISR (n = 29 patients; n = 32 lesions) was a two-center feasibility study that evaluated Jetstream atherectomy in FP-ISR. The JET-ISR (n = 60 patients; n = 60 lesions) was a 10-center investigational device exemption study that evaluated the same. Both trials were investigator-initiated, prospective, single-arm designs, with core lab assessments of stent-device interaction and with nearly identical inclusion/exclusion criteria and data definitions. The primary endpoint was TLR, which was analyzed using proportional and Kaplan-Meier analyses. Results. A total of 92 lesions were treated in 89 patients. Kaplan-Meier freedom from TLR at 6 months was 78.5% (95% confidence interval, 69.9-87.1). Proportional TLR was 21.2% (18/85 limbs). The performance goal of TLR (bailout stent included as TLR) was set at 37.9% at 6 months with balloon angioplasty alone. TLR rate derived from the meta-analysis was significantly lower than the TLR rate set for the historic control accounting for the 95% confidence interval lower bound (P<.01). There was no device-stent interaction and no amputation. Distal embolization occurred in 11/92 (12.0%) (filters used in 76.1% of all cases) and bailout stenting was performed in 8.7%. Conclusion. In this meta-analysis, Jetstream atherectomy in treating FP-ISR had a high freedom from TLR despite no adjunctive drug-coated balloon use. Randomized trials are needed to confirm these findings.
J INVASIVE CARDIOL 2020;32(8):289-294.
Key words: femoropopliteal, in-stent restenosis, Jetstream atherectomy, rotational atherectomy, superficial femoral artery, target-lesion revascularization
Treatment of femoropopliteal in-stent restenosis (FP-ISR) with balloon angioplasty (PTA) is suboptimal, leading to high rates of restenosis and bailout stenting.1-5 Debulking has been shown to be effective in reducing FP-ISR as an adjunctive treatment to PTA.5-13 The Jetstream atherectomy device (Boston Scientific) is a rotational cutter with aspiration capacity and has been shown to be effective in debulking de novo and restenotic tissues.15-18
The JETSTREAM-ISR (n = 29 patients; n = 32 lesions) was a two-center feasibility study that evaluated Jetstream in FP-ISR.18 The JET-ISR (n = 60 patients; n = 60 lesions), a 10-center investigational device exemption study that evaluated the same, was recently presented.19 Both trials were investigator-initiated, prospective, single-arm design, adjudicated with core lab assessments of stent-device interaction with nearly identical inclusion/exclusion criteria and data definitions. Both trials evaluated the 6-month target-lesion revascularization (TLR) rate. In this study, we performed a patient-level meta-analysis of JET-ISR and JETSTREAM-ISR and compared the 6-month TLR to a published performance goal of PTA in FP-ISR.20
Data extraction and methodology. The following information from the JET-ISR trial and the JETSTREAM-ISR study was extracted: number of participants and limbs treated; patient and target-vessel inclusion/exclusion criteria; and variable definitions for demographic, clinical, procedure-related and study endpoint outcomes.
Definition of variables that varied between the JET ISR trial and the JETSTREAM-ISR study were adjusted as follows: chronic renal insufficiency (creatinine >1.5 mg/dL was used); Rutherford-Becker categories (0-1 mild, 2-3 claudication, ≥4 limb ischemia); lesion length and treated length (investigator estimate was used as the JETSTREAM-ISR did not have these parameters core-lab analyzed); device outcome (atherectomy success definition in JETSTREAM-ISR was used); procedure outcome (procedure success in JETSTREAM-ISR was used); ankle-brachial index (ABI) (resting ABI was used); and patency (peak systolic velocity ratio [PSVR] ≤2.5).
There were 29 patients (32 limbs) in the JETSTREAM-ISR study and 60 patients (60 limbs) in JET-ISR. Both studies were investigator-initiated and directed by the same sponsor at the Midwest Cardiovascular Research Foundation. Five patients were included in JET-ISR after they have completed follow-up in JETSTREAM-ISR. The demographic variables from the most current study (JET-ISR) were used.
Definitions. Device outcome was categorized by <50% residual stenosis following Jetstream atherectomy alone and without additional adjunctive PTA or bailout procedures, as determined by the angiographic core laboratory. Procedural success was defined as ≤30% residual diameter stenosis following Jetstream + PTA without provisional or bailout procedures. Target-lesion revascularization (TLR) at 6 months and 1 year (with or without bailout stent considered as TLR) was defined as retreatment of the index lesion (extended 1 cm proximal and distal to the lesion). Clinical patency at 6 months and 1 year was defined as PSVR ≤2.5 at the treated site in the absence of TLR, amputation, and/or surgical bypass (the evaluation of patency is extended to 1 cm proximal and 1 cm distal to the target lesion).
Major adverse event during the in-hospital period and up to 30 days was defined as amputation (major and minor unplanned), death, significant distal embolization requiring the use of pharmacologic or mechanical means to treat (other than a vasodilator), perforation (extravasation of blood outside the vessel wall), major bleeding (drop of hemoglobin by 3 g/dL with a source of bleed, transfusion of 2 units of blood, bleed in a critical organ or fatal bleed), non-fatal myocardial infarction (defined as the occurrence of >20 minutes of chest pain post procedure with an increase in troponin), bailout stenting (type C dissection or residual narrowing of ≥30%), and acute renal failure (drop in creatinine clearance by >25% from baseline). Major adverse events at 6 months and 1 year was defined as major unplanned amputation of the treated limb, all-cause mortality or TLR at 6 months and 1 year (with or without bailout stenting in the vascular lab included as TLR).
Change in Rutherford clinical category at 30 days, 6 months, and 1 year was defined as the change in clinical status indicated by the change in Rutherford category compared to baseline, that is attributable to the treated limb. Change in ABI at 30 days, 6 months, and 1 year was defined as the change in the ABI compared to baseline in subjects with compressible arteries and baseline ABI <0.9.
Statistical analysis. A one-stage meta-analysis was conducted with raw individual participant data obtained from the JET-ISR trial and the JETSTREAM-ISR study. Continuous variables are presented as mean ± standard deviation and dichotomous variables as count/sample (percentage). The difference between 30-day ABI and 6-month ABI compared to baseline was done with the one-sample T-test. The Wilcoxon signed-rank test and confidence interval (CI) were used to compare category changes in the Rutherford-Becker between 30 days and 6 months to baseline. Freedom from TLR at 6 months and 1 year was estimated using Kaplan-Meier method. The comparator arm for Jetstream was historic PTA derived from a meta-analysis of three published and adjudicated randomized trials in the field (EXCITE-ISR, RELINE, FAIR).19 The performance goal was set at 37.9% at 6-month follow-up with bailout stenting considered as TLR. One-sample proportion and CIs were performed to test whether TLR with bailout stenting was less than the historic control of 37.9%. The I2 test for heterogeneity was done to evaluate inconsistency between studies. Cochran-Mantel-Haenszel risk ratio, CI, and forest plot were performed across treatment sites. The threshold of statistical significance was P<.05. Analyses were performed using Minitab 17 (Minitab), Cytel Studio 11 (Cytel) and Comprehensive Meta-Analysis Software (Biostat).
Table 1 shows demographics and clinical variables. The mean age was 68.4 ± 14.8 years (58.3% men). Diabetes and history of smoking were present in 45.2% and 72.6% of patients, respectively. Critical limb ischemia was present in 17.4% of patients. Table 2 illustrates procedure-related and angiographic variables. Lesion length was 17.9 ± 12.6 cm and total treated length was 19.0 ± 12.5 cm. Chronic total occlusion was present in 44.6% of patients. Embolic filter protection was used in 76.1% of the limbs. Debris was noted in 49/70 patients (70.0%). Adjunctive balloon angioplasty following atherectomy was performed at a mean pressure of 10.7 ± 3.2 atm. Stenosis severity was significantly reduced from a mean of 84.3% to 51.9% (P<.001) after Jetstream runs and to 23.8% (P<.001) after adjunctive balloon angioplasty. Acute device success was achieved in 47/74 patients (63.5%). No stent fractures or deformities were seen per core lab analysis in both JET-ISR and JETSTREAM-ISR.
Core-lab analyzed immediate procedure success (Table 3) was obtained in 65/84 limbs (77.4%). Distal embolization requiring treatment occurred in 11/92 cases (12.0%). Bailout stenting was performed in 8/92 patients (8.7%), 4 of which were related to the presence of a type C or higher dissection and the other 4 related to a residual narrowing of more than 30%. At 30-day follow-up, there was no TLR post hospital discharge. At 6-month and 1-year follow-up, proportional TLR rates (with bailout stenting as TLR) were 21.2% and 42.7%, respectively. When bailout stenting was not considered as TLR, the TLR rates at 6 months and 1 year were 11.9% and 37.0%, respectively. Clinical patency rates at 6 months and 1 year were 75.4% and 51.1%, respectively. Kaplan-Meier for TLR (with and without bailout stenting considered as TLR) is shown in Figure 1. At 6-month and 1-year follow-up, Kaplan-Meier freedom from TLR rates (with bailout stenting considered as TLR) were 79.7% and 58.9%, respectively. When bailout stenting was not considered as TLR, freedom from TLR rates at 6 months and 1 year were 88.4% and 63.8%, respectively. Mortality occurred in 9/89 patients (10.1%) at 1-year follow-up. The relative risk of using Jetstream with adjunctive PTA vs PTA alone is shown in Figure 2. The relative risk reduction in TLR with the use of Jetstream assuming the number of deaths would remain constant between the study and the historic control was 40% (95% CI, 5.0-62.0; P=.03) (Figure 2). When proportional TLR of 21.4% (95% CI, 0.0-32.4) (bailout stenting considered as TLR) was compared to the historic performance goal of 37.9%, the TLR rate was significantly less than the historic control (P<.01).
Table 4 shows the significant improvement in ABI and Rutherford Becker category from baseline. There was a statistical mean difference between the 30-day, 6-month, and 12-month vs baseline for ABI (P<.001, P<.001, and P<.01, respectively). With 95% confidence, the mean increase in ABI is at least 0.21, 0.09, and 0.09 for each of the respective comparisons. Also, there was a significant difference in the median classification change on the Rutherford Becker between baseline vs 30 days, baseline vs 6 months, and baseline vs 12 months (P<.001 for all). With 95% confidence, the estimated median classification changes between baseline and follow up visits are (1.5, 2.0), (1.0, 1.5), and (1.5, 2.5) for 30 days, 6 months, and 12 months, respectively.
Balloon angioplasty is suboptimal in treating FP-ISR with high TLR (31%-47%) and reduced patency rates (28%-37%)at 1 year.1-5 Multiple predictors of PTA failure in treating FP-ISR have been identified, including long lesions, TASC II D lesions, total occlusions, diabetes mellitus, and stent underexpansion.21,22 Debulking of restenotic tissue with excimer laser has been shown to offer superior results to PTA alone in treating FP-ISR.5 Also, rotational atherectomy using the Rotarex S had a 1-year patency rate of 81.6% in treating FP-ISR, which appears to be higher than historic controls.23 In addition, Jetstream atherectomy had TLR rates of 13.8% and 41.4% at 6 months and 1 year, respectively, in treating long FP-ISR lesions (mean of 19.5 cm)18 with results comparable to what had been observed with excimer laser. Finally, the multicenter JET-ISR study20 showed similar results and suggested that the Jetstream is superior to historic PTA. This study, however, did not enroll all its intended patients because of slow enrollment. In this patient-level meta-analysis, we combined data from two prospective studies, JET-ISR20 and JETSTREAM-ISR.18 Combining these two similar studies provided a more robust number to compare the 6-month TLR rate with the prespecified historic control. This study demonstrated that Jetstream atherectomy resulted in statistically lower TLR rates than PTA. Although randomized trials are more conducive to determine this finding, operators are unlikely to randomize against PTA, which is an inferior therapy to approved treatments with excimer laser, covered stents, and drug-coated balloons.
Distal embolization occurs frequently with atherectomy. The use of embolic protection devices is variable among operators, but they are not infrequently used during infrainguinal interventions.5,24-27 FP-ISR is a strong predictor of distal embolization with atherectomy devices as well as PTA, particularly in total occlusions.24-29 In the EXCITE trial,5 distal embolization occurred in 8.3% of FP-ISR patients treated with the laser despite the use of distal protection in 40.2% of cases. In the WISE LE trial,29 which used the Wirion filter (Cardiovascular Systems, Inc) with various atherectomy devices (and with the Jetstream being the dominant device used in this patient cohort), debris of <1 mm, 1-2 mm, and >2 mm diameter were found in 98%, 22%, and 9% of patients, respectively.
Core laboratory analysis (VAMC core lab in Dallas, Texas for JET-ISR, and Brigham and Women’s angiographic core lab for JETSTREAM-ISR) showed no adverse device-stent interaction with the Jetstream in interpretable cine angiograms. There was no stent integrity disruption or stent deformation following Jetstream and adjunctive balloon angioplasty. It should be noted, however, that high-grade index stent fractures (class 3 and 4) were excluded from both studies.
Bailout stenting was 8.7% with Jetstream in treating FP-ISR. In the EXCITE-ISR trial,5 bailout stenting rate with PTA alone was 11.1%. Both JETSTREAM-ISR and JET-ISR were not randomized to determine whether bailout stenting was reduced with Jetstream vs PTA. However, when compared to published data, bailout stenting appears numerically lower with Jetstream than PTA alone.
Study limitations. The study is limited by the overall small number of patients derived from only two non-randomized studies. Randomized trials are needed to confirm these findings.
In this meta-analysis, Jetstream atherectomy in FP-ISR has significantly lower TLR rates than historic PTA data when compared with a prespecified performance goal and despite no drug-coated balloons. Stent integrity was demonstrated by core lab with no deformities or new fractures.
From the Midwest Cardiovascular Research Foundation, Davenport, Iowa.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr N. Shammas is a trainer on the Jetstream device and a consultant to Boston Scientific; he reports educational and research grants to the Midwest Cardiovascular Research Foundation from Boston Scientific; research/educational grants and consultant from Angiodynamics; research grants from Philips, Intact Vascular, and Shockwave Medical; research/educational grants from Bard and VentureMed Group. The remaining authors report no conflicts of interest regarding the content herein.
Funding: This work was supported by an unrestricted grant from Boston Scientific.
Manuscript accepted April 21, 2020.
Address for correspondence: Nicolas W. Shammas, MD, MS, FACC, FSCAI, Research Director, Midwest Cardiovascular Research Foundation, 1622 E. Lombard Street, Davenport, IA 52803. Email: Shammas@mchsi.com
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