Yoshimitsu Soga

Long-term results of direct and indirect endovascular revascularization based on the angiosome concept in patients with critical limb ischemia presenting with isolated below-the-knee lesions

OBJECTIVE We compared clinical outcomes between limbs with and without achievement of feeding artery flow by endovascular therapy (EVT) based on the angiosome concept in critical limb ischemia (CLI) patients with isolated below-the-knee (BTK) lesions and assessed factors influencing major amputation (MA). METHOD We analyzed 369 limbs from 329 consecutive patients (224 men; age, 70 ± 11 years) with ischemic ulceration or gangrene, or both, presenting with isolated BTK lesions (Rutherford class 5, 270 limbs; class 6, 99 limbs) with a pretreatment ankle-brachial index of 0.79 ± 0.26. Patients underwent successful EVT, without bypass surgery. Limbs were classified into direct (n = 200) and indirect (n = 169) groups by whether feeding artery flow to the site of ulceration or gangrene was successfully achieved, based on the angiosome concept. Unadjusted and adjusted (by propensity score matching) between-group rates of amputation-free survival (AFS) and freedom from major amputation (MA) and major adverse limb event (MALE) were compared by Kaplan-Meier analysis and the log-rank test. The independent determinants of MA in the direct and indirect groups were explored by multivariable analysis. RESULTS During follow-up (mean, 18 ± 16 months), the overall limb salvage rate was 81% (300 of 369), death occurred in 36% (119 of 329), and the reintervention rate was 31% (114 of 369). After propensity score adjustment, the estimated (± standard error) rates for AFS (49% ± 8% vs 29% ± 6%; P = .0002), freedom from MALE (51% ± 8% vs 28% ± 8%, P = .008), and major amputation (82% ± 5% vs 68% ± 5%, P = .01) were significantly higher in the direct group than in the indirect group for up to 4 years after the index procedure. After multivariable Cox proportional analysis, the independent factors associated with major amputation were hemoglobin A(1c) level (hazard ratio [HR], 1.4; 95% confidential interval [CI], 1.1-1.9; P = .006) and cilostazol administration (HR, 0.28; 95% CI, 0.11-0.70; P = .006) in the direct group, and C-reactive protein level (HR, 1.2; 95% CI, 1.1-1.4; P = .002) in the indirect group. CONCLUSION Achieving direct flow by angioplasty based on the angiosome concept in CLI patients with isolated BTK lesions is clinically important for AFS and freedom from MA and MALE. Limb salvage factors appear to differ between patients with and without direct flow from the feeding artery after EVT.

Classification and Clinical Impact of Restenosis After Femoropopliteal Stenting

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.

Mid-term clinical outcome and predictors of vessel patency after femoropopliteal stenting with self-expandable nitinol stent.

BACKGROUND Long-term clinical outcomes after femoropopliteal (FP) stenting with nitinol stents have not yet been clear. We investigated the mid-term efficacy of FP stenting with nitinol stents. METHODS This study was a multicenter retrospective study. From April 2004 to December 2008, 511 consecutive patients (639 limbs; mean age 71 +/- 7 years; 71% male) who underwent successful FP stenting with nitinol stents for de novo lesions were retrospectively selected and analyzed in this multicenter study. All patients had a minimum follow-up of 6 months. Restenosis was defined as >2.4 of peak systolic velocity ratio by duplex or >50% stenosis by angiogram. Primary patency was defined as treated vessels without restenosis and repeat revascularization. Secondary patency was defined as target vessels that become totally occluded and are reopened by repeat revascularization. RESULTS Sixty-one percent of the patients had diabetes, 76% were claudicant, and 20% were on hemodialysis. Mean lesion length was 151 +/- 75 mm. Mean follow-up period was 22 +/- 11 months. Primary patency was 79.8%, 66.7%, and 63.1%, and secondary patency was 90.4%, 87.3%, and 86.2% at 1, 3, and 5 years, respectively. During the follow-up period, 53 patients (10%) died. Of them, cardiovascular death was 38% and stent fracture had occurred in 14%. On multivariate analysis by Cox proportional hazard ratio, cilostazol administration (hazard ratio [HR], 0.52;P < .0001), stent fracture (HR, 1.6; P = .03), hemodialysis (HR, 1.7; P = .01), and Trans Atlantic Inter-Society Consensus (TASC) II class C/D (HR, 2.4; P < .0001) were the independent predictors of primary patency after successful FP stenting. CONCLUSION Clinical efficacy of nitinol stent implantation for FP disease was favorable for up to 5 years.

Efficacy of cilostazol after endovascular therapy for femoropopliteal artery disease in patients with intermittent claudication.

OBJECTIVES The purpose of this study was to investigate whether cilostazol reduces restenosis and revascularization after endovascular therapy (EVT) for femoropopliteal lesions. BACKGROUND Cilostazol improves walking distance in patients with intermittent claudication and reduces restenosis after coronary intervention, but its efficacy remains unclear after EVT for femoropopliteal disease. METHODS This study was performed as a multicenter, randomized, open-label clinical trial. Eighty patients (mean age 70.7 +/- 6.2 years, 84% men) with intermittent claudication due to a femoropopliteal lesion were randomly assigned to receive or not receive cilostazol in addition to aspirin. The primary end point was freedom from target vessel revascularization, and the secondary end points were the rate of restenosis and freedom from target lesion revascularization and major adverse cardiovascular events, defined as all-cause death, myocardial infarction, stroke, repeat revascularization, and leg amputation. RESULTS Clinical follow-up information was obtained in all patients. Patient, lesion, and procedural characteristics did not differ significantly between the 2 groups. Stenting was performed in 36 patients (cilostazol, 16; control, 20; p = 0.36). Freedom from target vessel revascularization at 2 years after EVT was significantly higher compared with the control group (84.6% vs. 62.2%, p = 0.04). The rate of restenosis was lower in the cilostazol group (43.6% vs. 70.3%, p = 0.02), and freedom from target lesion revascularization and major adverse cardiovascular events was higher in the cilostazol group (87.2% vs. 67.6%, p = 0.046, 76.8% vs. 45.6%, p = 0.006, respectively). There was no major bleeding in either group during follow-up period. CONCLUSIONS Cilostazol reduced restenosis and repeat revascularization after EVT in patients with intermittent claudication due to femoropopliteal disease.

Angiographic Restenosis and Its Clinical Impact after Infrapopliteal Angioplasty

OBJECTIVE To assess 3- and 12-month angiographic restenosis rates and their clinical impact after infrapopliteal angioplasty. DESIGN Prospective multicenter study. MATERIALS AND METHODS We analyzed 68 critical ischemic limbs (tissue loss: 58 limbs) from 63 consecutive patients due to isolated infrapopliteal lesions who underwent angioplasty alone. Primary endpoint was 3-month angiographic restenosis rate; secondary endpoints were 12-month angiographic restenosis rate, and 3- and 12-month rates of mortality, major amputation and reintervention. Three- and 12-month frequency of ambulatory status and of freedom from ischemic symptoms, and time to wound healing in the ischemic wound group, were compared between restenotic and non-restenotic groups. Angiographic restenosis predictors were assessed by multivariable analysis. RESULTS 95% of cases had 3-month angiography; restenosis rate was 73%: 40% restenosis and 33% re-occlusion. Twelve-month follow-up angiography was conducted for the patients without 3-month angiographic restenosis, and restenosis rate at 12 months was 82%. Non-administration of cilostazol and statin, and chronic total occlusion were 3-month angiographic restenosis predictors. Three- and 12-month mortality was 5% and 12%, respectively. Despite no patients having undergone amputation, 15% had persistent ischemic symptoms, and 48% of limbs underwent reintervention within 12 months. During the same study period, ambulatory status and limbs with complete healing were more frequently observed in the non-restenosis group than in the restenosis group. In the tissue loss group, time to wound healing in the restenosis group was longer than in the non-restenosis group (127 days vs. 66 days, p = 0.02). CONCLUSION The extremely high angiographic restenosis rate after infrapopliteal angioplasty may adversely impact clinical status improvement.

Incidence and Clinical Impact of Stent Fracture After Everolimus-Eluting Stent Implantation

Background—Stent fracture (SF) after drug-eluting stent implantation has recently become an important concern because of its potential association with in-stent restenosis and stent thrombosis. However, the incidence and clinical impact of SF after everolimus-eluting stent implantation remain unclear. Methods and Results—A total of 1035 patients with 1339 lesions undergoing everolimus-eluting stent implantation and follow-up angiography 6 to 9 months after index procedure were analyzed. SF was defined as complete or partial separation of the stent, as assessed by plain fluoroscopy or intravascular ultrasound during follow-up. We assessed the rates of SF and major adverse cardiac events, defined as cardiac death, myocardial infarction, stent thrombosis, and clinically driven target lesion revascularization within 9 months. SF was observed in 39 of 1339 lesions (2.9%) and in 39 of 1035 patients (3.8%). Ostial stent location and lesions with hinge motion, tortuosity, or calcification were independent predictors of SF. The rate of myocardial infarction and target lesion revascularization were significantly higher in the SF group than in the non-SF group (5.1% versus 0.4%; P=0.018 and 25.6% versus 2.0%; P<0.001, respectively). Stent thrombosis was more frequently observed in the SF group than in the non-SF group (5.1% versus 0.4%; P=0.018). Major adverse cardiac events within 9 months were significantly higher in the SF group than in the non-SF group (25.6% versus 2.3%; P<0.001). Conclusions—SF after everolimus-eluting stent implantation occurs in 2.9% of lesions and is associated with higher rate of major adverse cardiac events, driven by higher target lesion revascularization and stent thrombosis.

Cilostazol Reduces Angiographic Restenosis After Endovascular Therapy for Femoropopliteal Lesions in the Sufficient Treatment of Peripheral Intervention by Cilostazol Study

Background— It remains unclear whether cilostazol, which has been shown to improve the clinical outcomes of endovascular therapy for femoropopliteal lesions, also reduces angiographic restenosis. Methods and Results— The Sufficient Treatment of Peripheral Intervention by Cilostazol (STOP-IC) study investigated whether cilostazol reduces the 12-month angiographic restenosis rate after percutaneous transluminal angioplasty with provisional nitinol stenting for femoropopliteal lesions. Two hundred patients with femoropopliteal lesions treated from March 2009 to April 2011 at 13 cardiovascular centers were randomly assigned 1:1 to receive oral aspirin with or without cilostazol. The primary end point was 12-month angiographic restenosis rate. Secondary end points were the restenosis rate on duplex ultrasound, the rate of major adverse cardiac events, and target lesion event-free survival. Researchers evaluated all follow-up data and assessed the end points in a blinded fashion. The mean lesion length and reference vessel diameter at the treated segment were 128±86 mm and 5.4±1.4 mm, respectively. The frequency of stent used was similar between groups (88% versus 90% in the cilostazol and noncilostazol group, respectively, P=0.82). During the 12-month follow-up period, 11 patients died and 152 patients (80%) had evaluable angiographic data at 12 months. The angiographic restenosis rate at 12 months was 20% (15/75) in the cilostazol group versus 49% (38/77) in the noncilostazol group (P=0.0001) by intention-to-treat analysis. The cilostazol group also had a significantly higher event-free survival at 12 months (83% versus 71%, P=0.02), although cardiovascular event rates were similar in both groups. Conclusions— Cilostazol reduced angiographic restenosis after percutaneous transluminal angioplasty with provisional nitinol stenting for femoropopliteal lesions. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00912756; and URL: https://www.umin.ac.jp. Unique identifier: UMIN000002091.

Bare Metal Stent Thrombosis and In-Stent Neoatherosclerosis

Background— Very late stent thrombosis (VLST) was reported to occur even in patients with bare metal stent (BMS) implantation, although the annual incidence of VLST after BMS was much lower than that after drug-eluting stent implantation. Pathophysiologic mechanisms of VLST after BMS implantation remain largely unknown. Methods and Results— From September 2002 to February 2010, we identified 102 patients with definite stent thrombosis (ST) of BMS and 42 control patients with acute coronary syndrome (ACS) unrelated to ST who underwent thrombus aspiration with histopathologic evaluation. There were 40 patients with early ST (EST, within 30 days), 20 patients with late ST (LST, between 31–365 days), and 42 patients with VLST (>1 year). Evidence for fragments of atherosclerotic plaques, such as foamy macrophages, cholesterol crystals, and thin fibrous cap, was more commonly seen in patients with EST (23%) and VLST (31%), whereas these findings were rarely observed in patients with LST (10%). Atherosclerotic fragments were predominantly seen in patients who had EST within 7 days or VLST beyond 3 years. The aspirated thrombi harvested from patients with ST and those with ACS were histologically indistinguishable from each other. Eosinophils were very rarely observed. Plasma level of total cholesterol and triglyceride were significantly higher in VLST cases with atherosclerotic fragments as compared with those without. Conclusions— Fragments of atherosclerotic plaque were highly prevalent in patients with VLST beyond 3 years. Disruption of in-stent neoatherosclerosis could play an important role in the pathogenesis of VLST of BMS occurring beyond 3 years after implantation.

Timing of the restenosis following nitinol stenting in the superficial femoral artery and the factors associated with early and late restenoses.

Objectives: We sought to investigate the timing of restenosis and the restenosis factors following nitinol stenting in the superficial femoral artery (SFA). Background: Restenosis following nitinol stenting in the SFA remains unsolved. Methods: We analyzed 742 limbs in consecutive 585 patients who underwent successful endovascular therapy for de novo SFA lesions. Patency was assessed by duplex ultrasonography. Primary patency was defined as treated vessels without restenosis and secondary patency was defined as target vessels reopened by repeat revascularization. Receiver‐operating characteristic (ROC) analysis was performed to delineate the timing of restenosis. Patients were subsequently classified into three groups: no restenosis, early restenosis, and late restenosis. Cox proportional hazard regression analyses were performed to explore the determinants of restenosis in each restenosis group. Results: Primary and secondary patency was 67 and 86% at 6 years, respectively. ROC curves indicated the 369th day was the best cutoff point distinguishing the early (144 limbs) and the late (42 limbs) restenoses. Sustained patency was observed in 556 limbs. After multivariate analysis, cilostazol (P = 0.0007) was negatively associated; female gender (P = 0.0071), diabetes mellitus (P = 0.0428), critical limb ischemia (P = 0.0435), and stent fracture (P = 0.0004) were positively associated with the early restenosis. Trans Atlantic Inter‐Society Consensus II C/D was positively associated with both the early (P = 0.0017) and the late (P = 0.0359) restenoses. Conclusions: Restenosis predominantly occurred within a year following nitinol stenting in the SFA, and the factors associated with the early restenosis were different from those with the late restenosis.

1-Year Results of the ZEPHYR Registry (Zilver PTX for the Femoral Artery and Proximal Popliteal Artery): Predictors of Restenosis.

OBJECTIVES This study sought to assess the rate and predictors of 1-year restenosis after drug-eluting stent implantation for femoropopliteal (FP) lesions in patients with peripheral arterial disease. BACKGROUND Zilver PTX, a paclitaxel-eluting stent for FP lesions, provides superior outcomes to angioplasty and bare-metal stents in clinical trials. However, its real-world outcomes and the associated features remain unclear. METHODS This was a prospective multicenter study enrolling 831 FP lesions (797 limbs, 690 patients) treated by Zilver PTX implantation. The primary endpoint was 1-year restenosis. Secondary endpoints included major adverse limb event and stent thrombosis. RESULTS Mean lesion length was 17 ± 10 cm. One-year restenosis, major adverse limb event, and stent thrombosis rates were 37%, 22%, and 2%, respectively. The generalized linear mixed model showed that lesion length ≥16 cm assessed by angiography and distal external elastic membrane area ≤27 mm(2) and minimum stent area ≤12 mm(2) assessed by intravascular ultrasound were independent risk factors for restenosis. One-year restenosis rates were 15% in cases with none of these risk factors and 50% in those with ≥2 risk factors. CONCLUSIONS The current study demonstrated 1-year real-world outcomes after drug-eluting stent treatment for FP lesions, including challenging ones in clinical practice. Lesion length, external elastic membrane area, and minimum stent area were independent predictors for restenosis. (Zilver PTX for the Femoral Artery and Proximal Popliteal Artery-Prospective Multicenter Registry [ZEPHYR]; UMIN000008433).