Author + information
- Received May 25, 2011
- Revision received August 10, 2011
- Accepted September 5, 2011
- Published online January 3, 2012.
- Atsushi Tosaka, MD⁎,⁎ (, )
- Yoshimitsu Soga, MD⁎,
- Osamu Iida, MD†,
- Takayuki Ishihara, MD†,
- Keisuke Hirano, MD‡,
- Kenji Suzuki, MD§,
- Hiroyoshi Yokoi, MD⁎,
- Shinsuke Nanto, MD∥ and
- Masakiyo Nobuyoshi, MD⁎
- ↵⁎Reprint requests and correspondence:
Dr. Atsushi Tosaka, Department of Cardiology, Kokura Memorial Hospital, 1-2-3 Asano, Kokurakita-ku, Kitakyushu 802-8555, Japan
Objectives The purpose of this study was to investigate the relationship between angiographic patterns of in-stent restenosis (ISR) after femoropopliteal (FP) stenting and the frequency of refractory ISR.
Background In-stent restenosis after FP stenting is an unsolved problem. The incidence and predictors of refractory restenosis remain unclear.
Methods This study was a multicenter, retrospective observational study. From September 2000 to December 2009, 133 restenotic lesions after FP artery stenting were classified by angiographic pattern: class I included focal lesions (≤50 mm in length), class II included diffuse lesions (>50 mm in length), and class III included totally occluded ISR. All patients were treated by balloon angioplasty for at least 60 s. Recurrent ISR or occlusion was defined as ISR or occlusion after target lesion revascularization. Restenosis was defined as >2.4 of the peak systolic velocity ratio by duplex scan or >50% stenosis by angiography.
Results Sixty-four percent of patients were male, 67% had diabetes mellitus, and 24% underwent hemodialysis. Class I pattern was found in 29% of the limbs, class II in 38%, and class III in 33%. Mean follow-up period was 24 ± 17 months. All-cause death occurred in 14 patients; bypass surgery was performed in 11 limbs, and major amputation was performed in 1 limb during the follow-up. Kaplan-Meier survival curves showed that the rate of recurrent ISR at 2 years was 84.8% in class III patients compared with 49.9% in class I patients (p < 0.0001) and 53.3% in class II patients (p = 0.0003), and the rate of recurrent occlusion at 2 years was 64.6% in class III patients compared with 15.9% in class I patients (p < 0.0001) and 18.9% in class II patients (p < 0.0001).
Conclusions Restenotic patterns after FP stenting are important predictors of recurrent ISR and occlusion.
- endovascular therapy
- femoropopliteal arterial disease
- in-stent restenosis
- target vessel revascularization
Endovascular therapy for peripheral artery disease has become a widespread technique, and has been recognized as a common treatment (1). The patency rate of the femoropopliteal (FP) artery has been improved through use of the self-expanding nitinol stent (2), and the clinical outcome and patency of nitinol stent has already been reported (3,4). Although the favorable patency rate of the nitinol stent, as the population with FP stenting continues to increase, occurrence of refractory restenosis has become a serious problem. In the case of the coronary artery, angiographic patterns of in-stent restenosis (ISR) is prognostically important, and the risk factors of refractory restenosis are well established (5,6).
The purposes of this study were to investigate the incidence and predictors of refractory restenosis after FP stenting and to determine the relationship between angiographic patterns of ISR and the frequency of refractory restenosis.
This was a multicenter, retrospective observational study. From September 2000 to December 2009, a total of 738 patients (915 limbs) underwent successful FP stenting with nitinol stents for de novo lesions. Two types of nitinol stents were used: Luminexx (Bard, Murray Hill, New Jersey) and S.M.A.R.T. (Cordis J&J, Miami, Florida). Of these patients, 137 (157 limbs) underwent successful repeat angioplasty because of ISR. We excluded patients if they were treated with laser angioplasty, additional stenting, or had <3 months of follow-up after repeat angioplasty. The remaining 116 patients (133 limbs) were enrolled in this study (Fig. 1).
Baseline clinical characteristics and procedural data were collected from hospital medical records or databases. The study protocol was approved by the hospital ethics committees, and the study was performed in accordance with the Declaration of Helsinki. Written informed consent was obtained from every patient.
Classification of ISR
The ISR lesions were classified by visual estimate on angiography (Fig. 1): class I, the focal (≤50 mm in length) ISR group, included lesions positioned at the stent body, the stent edge, or a combination of these sites; class II, the diffuse (>50 mm in length) ISR group, includes not only stent body lesions, but also stent edge lesions; and class III is the totally occluded ISR group.
Angioplasty procedure for ISR
All patients had taken dual-antiplatelet therapy (aspirin 100 mg/day plus clopidogrel 75 mg/day or ticlopidine 200 mg/day) from >2 days before the procedure. Unfractionated heparin was injected intra-arterially before the intervention at a dose of 3,000 to 5,000 IU and was added as required to maintain the active clotting time at ≥200 s. The target lesion was passed with a 0.035-, 0.018-, or 0.014-inch guide wire. All patients were treated by balloon angioplasty for at least 60 s, and the diameter and length of the balloon was determined by the surgeon on the basis of angiography. After the procedure, all patients were prescribed lifelong aspirin (100 mg/day), and clopidogrel or ticlopidine was stopped on or after the day of the procedure.
Clinical follow-up was performed with office visits or telephone contacts at least every 6 months after the procedure. Clinical examinations, duplex ultrasonography scan of the stented vessel, and occurrence of major late clinical events (including all-cause death, surgical revascularization, and leg amputation) were recorded.
Restenosis was defined as >2.4 of the peak systolic velocity ratio by the duplex scan (7,8) or >50% stenosis by angiography. An undetectable signal in stented segments by the duplex scan was graded as a complete occlusion. Early ISR was defined as ISR within 6 months after stenting. Recurrent ISR or occlusion was defined as ISR or in-stent occlusion after target lesion revascularization. Stent fractures were classified as minor (single strut fracture), moderate (fracture of >1 strut), and severe (complete separation of stent segments) (9). Coronary artery disease (CAD) was defined as stable angina with documented CAD, history of percutaneous coronary intervention, history of coronary artery bypass graft surgery, or previous myocardial infarction. Cerebrovascular disease (CVD) was defined as a hospital or neurologist report with the diagnosis of transient ischemic attack or ischemic stroke. Below-the-knee runoff was assessed by angiography before or after the procedure. Leg amputation was defined as amputation above the ankle.
Values are expressed as mean ± SD. Continuous variables were examined by the unpaired t test or analysis of variance. Categorical variables were compared by the chi-square test. Survival curves were estimated by the Kaplan-Meier method and compared with the log-rank test. Cox multivariate regression analysis was used to determine predictors for recurrent ISR. A probability value of p < 0.05 was considered statistically significant.
Patients and lesion characteristics
Initial clinical and angiographic characteristics are shown in Tables 1 and 2.⇓⇓ Of the 133 limbs analyzed, 29% were class I (focal ISR), 38% class II (diffuse ISR), and 33% class III (totally occluded ISR). Balloon angioplasty was performed in all cases. Early ISR was shown in 20% of limbs. Presence of CVD, lesion length, and total stent length were significantly different among the ISR classes. Compared with stenotic ISR group (classes I and II) and class III, presence of CVD and lesion length were significantly different.
The mean follow-up period was 24 ± 17 months. The recurrent ISR rate was 49.9% in class I, 53.3% in class II, 84.8% in class III, and 52.0% in the stenosis group at 2 years (Figs. 2 and 3)⇓⇓; the recurrent occlusion rate was 15.9%, 18.9%, 64.6%, and 17.6%, respectively (Figs. 4 and 5)⇓⇓. There were significant differences between classes I and III (recurrent ISR, p < 0.0001; recurrent occlusion, p < 0.0001), between classes II and III (recurrent ISR, p = 0.0003; recurrent occlusion, p < 0.0001), and between the stenosis group and class III (recurrent ISR, p < 0.0001; recurrent occlusion, p < 0.0001). All-cause death occurred in 14 patients; bypass surgery was performed on 11 limbs, and major amputation was performed on 1 limb during the follow-up. Although the difference in survival rate was not significant among the classes, the bypass surgery rate (Figs. 6 and 7)⇓⇓ was significantly high for class III cases (class I vs. class II, p = 0.0077; class II vs. class III, p = 0.0025; stenosis group vs. class III, p = 0.0001).
Risk factors for recurrent ISR and occlusion were examined using the Cox hazard model. Clinically pre-specified predictors (age, sex, hypertension, hyperlipidemia, diabetes mellitus, current smoker, hemodialysis, CAD, CVD, critical limb ischemia, statin administration, warfarin administration, cilostazol administration, ISR classification, lesion length, reference vessel diameter, type of nitinol stent, stent fracture, below-the-knee run-off, early restenosis, and TransAtlantic Inter-Society Consensus [TASC] II classification before stenting) with p < 0.05 on Cox univariate models were entered into the multivariable Cox regression model (Tables 3 and 4).⇓ Multivariate analysis showed that ISR class III (hazard ratio [HR]: 2.44; 95% confidence interval [CI]: 1.33 to 4.48, p = 0.004) and reference vessel diameter (HR: 0.63, 95% CI: 0.44 to 0.89, p = 0.008) were independent predictors of recurrent ISR, and that ISR class III (HR: 4.06, 95% CI: 1.79 to 9.24, p = 0.0008) and reference vessel diameter (HR: 0.60, 95% CI: 0.36 to 0.99, p = 0.049) were independent predictors of recurrent occlusion.
This study represents the progress after balloon angioplasty for FP ISR. Class III (totally occluded ISR group) is associated with increased risks of recurrent ISR, recurrent occlusion, and surgical revascularization. Unlike the established Mehran classification for coronary ISR (5), there is no prognostic difference between class I (focal ISR group) and class II (diffuse ISR group), even if the cut-off point is changed from 50 mm to 30 or 80 mm. Compared to the Mehran classification, the mean stent length of the focal ISR group was significantly longer in this study (143.6 mm in FP ISR, 18.3 mm in coronary ISR). Occurrence of new restenosis in another stent segment after angioplasty for focal ISR may participate in the similar prognosis of these classes. Conversely, similar to coronary drug-eluting stent data (10), the recurrent ISR rate of the nonfocal ISR group (classes II and III) is significantly high compared with that of the focal ISR group (68.7% in nonfocal ISR group, and 49.9% in focal ISR group at 2 years; p = 0.023).
The freedom from the recurrent restenosis rate of infrainguinal vein bypass grafts revised with balloon angioplasty and open surgical techniques for stenotic lesion has been reported to be 56.6% and 43.0% to 61.2% at 2 years, and that from the recurrent occlusion rate to be 84.5% and 78.8% to 87.7%, respectively (11). In this study, the freedom from recurrent ISR and occlusion rate after balloon angioplasty for stenotic ISR was 46.7% to 50.1% and 81.1% to 84.1% at 2 years, respectively. The results of this study show that the progress after balloon angioplasty for stenotic ISR of FP artery is acceptable.
Compared to the stenotic ISR group (classes I and II), the freedom from recurrent ISR and occlusion rate of class III were remarkably low (22.7% and 42.9% at 1 year, respectively). Balloon angioplasty for occluded ISR is unfavorable, except for patients who require short-term blood flow to heal an ischemic ulcer. In accordance with a previous report (12), the 1-year bypass patency rate after surgical thrombectomy or transluminal balloon angioplasty for occluded polytetrafluoroethylene bypass graft was 13.5%. As in the case of bypass graft, treatment for the occluded FP stent and prevention of stent occlusion are major concerns. Although directional atherectomy for ISR fails to show acceptable long term patency (13), drug-eluting stent implantation for ISR results in a 1-year target lesion revascularization rate of 22% (14). Furthermore, previous studies have shown good outcomes using a paclitaxel-coated balloon (15,16), excimer laser (17), and stent graft (18). The patency is likely to improve in future treatments of occluded FP stent. A recent study has reported that TASC II C and D lesions and cilostazol administration are independent predictors of stent occlusion after successful FP stenting (3). Early follow-up with duplex ultrasonography for TASC II C/D lesions and cilostazol administration may prevent stent occlusion, and consequently reduce the surgical revascularization rate.
Among ISR classes, class II was related with the highest presence of CVD. This finding may indicate that patients with severe systemic arteriosclerosis are inclined to generate diffuse ISR. In this study, stent fracture was found in 27 limbs (minor in 7 limbs, moderate in 19 limbs, and severe in 1 limb). There was no relationship between the incidence and morphology of fracture and type of nitinol stent (incidence, p = 0.224; morphology, p = 0.147). Although the incidence and morphology of stent fracture were not statistically different among ISR classes, the incidence of stent fracture tended to be low in class III. Stent facture is known to be related to patency after FP stenting (19), but the relationship with stent occlusion is unclear. Our finding may demonstrate that stent fracture is less related to stent occlusion compared to stent restenosis. Kaplan-Meier survival curves showed that the freedom from recurrent ISR was 43.0% with fracture versus 34.8% without fracture at 2 years (p = 0.148). That class III was found in 18.5% with fracture versus 36.8% without fracture (p = 0.072) may affect this result. Moreover, the freedom from recurrent ISR was not significantly different for morphology of the fracture (p = 0.384).
A previous study reported that TASC II C and D lesions, hemodialysis, stent fracture, and cilostazol administration are independent predictors of primary patency (3). However, on investigation of recurrent ISR and occlusion, our multivariate analysis suggests that ISR type III and reference vessel diameter (RVD) are strong predictors. As RVD was measured by visual estimation in this study, it may have been underestimated (20). To examine the relationship between RVD and recurrent ISR more accurately, estimation by intravascular ultrasonography is needed. In the case of coronary artery, early restenosis is an independent predictor of repeat target lesion revascularization (6). Although early restenosis was omitted from our multivariate analysis, it tends to predict recurrent ISR. In this study, early restenosis lesions were found in only 20 limbs; that is an important limitation.
First, this study involved a retrospective, nonrandomized, small-sample size analysis, despite being a multicenter study. Second, lesion characteristics were not completely confident because they were measured by visual estimation. Finally, only 2 types of nitinol bare metal stents were used because these were the only available stents in Japan at the time of the study. Therefore, further investigation of new-generation nitinol bare metal stents or drug-eluting stents is needed. Despite these limitations, the findings in this study indicate that restenotic pattern after FP stenting is a strong predictor of recurrent restenosis.
Restenotic patterns and RVD after FP stenting are independent predictors of recurrent restenosis and occlusion. Although balloon angioplasty for the stenotic ISR group is feasible, the freedom from recurrent ISR and occlusion after balloon angioplasty are remarkable low for totally occluded ISR. Whereas bypass surgery is favorable treatment for occluded ISR, the prognosis is likely to improve with future treatments, namely, drug-eluting stent, paclitaxel-coated balloon, excimer laser, and stent graft.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- coronary artery disease
- confidence interval
- cerebrovascular disease
- hazard ratio
- in-stent restenosis
- reference vessel diameter
- TransAtlantic Inter-Society Consensus
- Received May 25, 2011.
- Revision received August 10, 2011.
- Accepted September 5, 2011.
- American College of Cardiology Foundation
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