COMPARE: prospective, randomized, non-inferiority trial of high- vs. low-dose paclitaxel drug-coated balloons for femoropopliteal interventions.

AIMS: Drug-coated balloons (DCBs) for femoropopliteal interventions have not been tested against each other. We aimed to directly compare efficacy and safety of a high-dose (In.Pact™) vs. low-dose (Ranger™) DCB with nominal paclitaxel densities of 3.5 vs. 2.0 µg/mm2. METHODS AND RESULTS: Within a prospective, multicentre, non-inferiority, clinical trial 414 patients with symptomatic femoropopliteal lesions (Rutherford classification 2-4) were randomly assigned in a 1:1 ratio to endovascular treatment with either high- or low-dose DCB after stratification for lesion length. Primary efficacy and safety endpoints comprised primary patency and freedom from major adverse events (i.e. device and procedure-related deaths through 1 month, major amputations, and clinically driven target lesion revascularization through 12 months). We set a non-inferiority margin of -10% at 12 months. Total occlusions were observed frequently (>40%) and provisional stenting was performed in every fourth intervention. Non-inferiority was determined for both primary efficacy and safety endpoints at 12 months. Primary patency was 81.5% in the high-dose and 83.0% in low-dose DCB group {difference: 1.5% [lower bound of the 90% two-sided confidence interval (CI) -5.2%]; Pnon-inferiority < 0.01}. Freedom from major adverse events was determined in 92.6% in high-dose and in 91.0% in low-dose DCB group [difference -1.6% (lower bound of the 90% two-sided CI -6.5%); Pnon-inferiority < 0.01]. Overall death rate was low (2.0%) and no major amputation occurred. CONCLUSION: Two DCBs with different coating characteristics exhibited comparable results with excellent effectiveness and safety through 12 months for femoropopliteal interventions including a wide range of lesion lengths. CLINICAL TRIAL REGISTRATION: The trial is registered with ClinicalTrials.gov (NCT02701543).

Primary Self-EXPANDing Nitinol Stenting vs Balloon Angioplasty With Optional Bailout Stenting for the Treatment of Infrapopliteal Artery Disease in Patients With Severe Intermittent Claudication or Critical Limb Ischemia (EXPAND Study).

PURPOSE: To compare primary placement of a self-expanding nitinol stent to percutaneous transluminal angioplasty (PTA) with bailout stenting in infrapopliteal arteries of patients with severe intermittent claudication or critical limb ischemia (CLI). METHODS: In the EXPAND trial (ClinicalTrials.gov; identifier NCT00906022), 92 patients (mean age 72.9±9.5 years; 62 men) undergoing treatment for infrapopliteal stenosis in 11 European centers were randomized 1:1 to either self-expanding nitinol stenting with the Astron Pulsar/Pulsar-18 nitinol stent or PTA with bailout stenting. The primary endpoint was sustainable clinical improvement after 12 months, defined as a ≥1-category increase for Rutherford category 3 patients or a ≥2-category increase for CLI patients (Rutherford categories 4/5) compared with baseline. Furthermore, target lesion revascularization (TLR), mortality, and amputation were assessed after 12 months. RESULTS: Sustained clinical improvement at 1 year was observed in 74.3% of the patients treated with primary stenting and in 68.6% of the patients treated with PTA and bailout stenting (p>0.05). Kaplan-Meier estimates of freedom from TLR (76.6% and 77.6%), mortality (7.4% vs 2.1%), and amputation [8.9% (major 6.7%) vs 13.2% (major 8.7%)] at 1 year were not significantly different. CONCLUSION: Primary self-expanding nitinol stenting did not show statistically different clinical outcomes compared to angioplasty with bailout stenting for infrapopliteal lesions.

MISAGO 2: one-year outcomes after implantation of the Misago self-expanding nitinol stent in the superficial femoral and popliteal arteries of 744 patients.

PURPOSE: To evaluate the safety and efficacy of the Misago self-expanding rapid-exchange nitinol stent system for the treatment of femoropopliteal occlusive disease in a prospective multicenter observational trial (ClinicalTrials.gov; identifier NCT01118117). METHODS: Between April and October 2008, the registry enrolled 744 patients (496 men; 69 ± 10 years) who had symptomatic ≥ 70% stenosis or occlusion of the superficial femoral or popliteal arteries treated with the Misago stent. Mean length of the 750 lesions was 63.9 mm; 282 (37.6%) vessels were completely occluded. Primary study endpoints were the need for target lesion revascularization (TLR) and event-free survival rates for the assessment of efficacy and safety, respectively. At 6 and 12 months post intervention, clinical symptoms of recurrent ischemia and/or claudication, Rutherford category, and ankle-brachial index (ABI) at rest were assessed. RESULTS: In the study period, 945 stents were successfully deployed in the 750 lesions. The overall TLR rate was 10.1% among 671 (90.3%) patients evaluated at 1 year [3.1% among 709 (95.3%) patients at 6 months]. Event-free survival at 12 months was 84.9%. Mean ABIs improved by ≥ 0.1 in three quarters of the patients (76.0%) over 12 months. The Rutherford grade improved or remained stable in the majority of patients (95.5%) after 1 year. Stent fractures (13 grade 1, 2 grade 2) in 3.1% of stents examined radiographically (n=484) at 1 year were not related to any clinical events. Primary patency was recorded in 574 (87.6%) patients evaluated at 1 year post procedure. CONCLUSION: The Misago rapid-exchange nitinol stent showed promising efficacy and safety results, with a low stent fracture rate, in patients with femoropopliteal disease, making it a safe and reliable treatment option.

Low-Dose vs High-Dose Paclitaxel-Coated Balloons for Femoropopliteal Lesions: 2-Year Results From the COMPARE Trial.

BACKGROUND: So far only 1-year data have been reported for direct comparisons of paclitaxel-coated balloons (PCBs) using different coating technologies. OBJECTIVES: The aim of this study was to report the 24-month results on the efficacy and safety of low-dose vs high-dose PCBs with nominal paclitaxel densities of 2.0 and 3.5 µg/mm2 and different coating technologies for femoropopliteal interventions from the COMPARE (Compare I Pilot Study for the Treatment of Subjects With Symptomatic Femoropopliteal Artery Disease) trial. Procedural characteristics of clinically driven (CD) target lesion revascularization (TLR) were analyzed. METHODS: Within a prospective, multicenter, clinical trial, 414 patients with symptomatic femoropopliteal lesions (Rutherford categories 2-4, maximum lesion length 30 cm) were randomly assigned in a 1:1 ratio to endovascular treatment with either a low-dose (Ranger) or a high-dose (IN.PACT) PCB after stratification for lesion length. Two-year follow-up included assessment of primary patency (defined as absence of CD TLR or binary restenosis with a peak systolic velocity ratio >2.4 by duplex ultrasound), safety, and functional and clinical outcomes. RESULTS: At 2 years, the Kaplan-Meier estimates of primary patency were 70.6% and 71.4% for the low-dose and high-dose PCBs (log-rank P = 0.96), respectively. One major amputation occurred in the high-dose group, and rates of all-cause mortality (3.6% vs 2.2%; P = 0.55) and CD TLR (17.3% vs 13.0%; P = 0.31) were similar between the groups. Among a total of 57 CD TLRs, 44.6% were performed for reocclusion and 28.1% for in-stent restenosis. Functional and clinical benefits over baseline were sustained in both groups. CONCLUSIONS: The 2-year results of the COMPARE trial demonstrate a sustained treatment benefit of both low-dose and high-dose PCBs for femoropopliteal interventions including a wide range of lesion lengths. (Compare I Pilot Study for the Treatment of Subjects With Symptomatic Femoropopliteal Artery Disease; NCT02701543).

The Real-World CONSEQUENT ALL COMERS Study: Predictors for Target Lesion Revascularization and Mortality in an Unselected Patient Population.

We evaluated the safety and efficacy of a resveratrol-paclitaxel-coated peripheral balloon catheter in an all-comer patient cohort undergoing endovascular treatment of above-the-knee and below-the-knee peripheral artery disease. CONSEQUENT ALL COMERS (Clinical Post-Market Clinical Follow-up [PMCF] on Peripheral Arteries treated with SeQuent Please OTW [Over-the Wire]) is a prospective, single-arm, multicenter observational study (ClinicalTrials Identifier: NCT02460042). The primary end point was the 12-month target lesion revascularization (TLR) rate. Secondary end points included vessel patency, target vessel revascularization, and all-cause mortality. A total of 879 lesions in 784 consecutive patients (71.3 ± 10.4 years old, 57.7% male) were analyzed; 53.3% had claudication, whereas the remaining 46.7% exhibited critical limb ischemia (CLI). Substantial comorbidities were present, including diabetes mellitus (41.2%), smoking (66.1%), and coronary artery disease (33.9%). Lesion length (879 lesions) was 12.0 ± 9.3 cm and 31.8% were Transatlantic Inter-Society Consensus II C/D lesions. The overall technical success rate of the 1269 drug-coated balloon (DCB)'s used was 99.6% (1.60 ± 0.79 DCB's/patient). At 12 months, the TLR rates were 6.3% in patients with CLI and 9.6% in claudicants, with a primary patency rate of 89.9% and 87.1%, respectively. All-cause mortality was 4.3% (28/658). The most important predictors for TLR were female gender, in-stent restenosis at baseline and lesion length.

Directional Atherectomy Followed by a Paclitaxel-Coated Balloon to Inhibit Restenosis and Maintain Vessel Patency: Twelve-Month Results of the DEFINITIVE AR Study.

BACKGROUND: Studies assessing drug-coated balloons (DCB) for the treatment of femoropopliteal artery disease are encouraging. However, challenging lesions, such as severely calcified, remain difficult to treat with DCB alone. Vessel preparation with directional atherectomy (DA) potentially improves outcomes of DCB. METHODS AND RESULTS: DEFINITIVE AR study (Directional Atherectomy Followed by a Paclitaxel-Coated Balloon to Inhibit Restenosis and Maintain Vessel Patency-A Pilot Study of Anti-Restenosis Treatment) was a multicenter randomized trial designed to estimate the effect of DA before DCB to facilitate the development of future end point-driven randomized studies. One hundred two patients with claudication or rest pain were randomly assigned 1:1 to DA+DCB (n=48) or DCB alone (n=54), and 19 additional patients with severely calcified lesions were treated with DA+DCB. Mean lesion length was 11.2±4.0 cm for DA+DCB and 9.7±4.1 cm for DCB (P=0.05). Predilation rate was 16.7% for DA+DCB versus 74.1% for DCB; postdilation rate was 6.3% for DA+DCB versus 33.3% for DCB. Technical success was superior for DA+DCB (89.6% versus 64.2%; P=0.004). Overall bail-out stenting rate was 3.7%, and rate of flow-limiting dissections was 19% for DCB and 2% for DA+DCB (P=0.01). One-year primary outcome of angiographic percent diameter stenosis was 33.6±17.7% for DA+DCB versus 36.4±17.6% for DCB (P=0.48), and clinically driven target lesion revascularization was 7.3% for DA+DCB and 8.0% for DCB (P=0.90). Duplex ultrasound patency was 84.6% for DA+DCB, 81.3% for DCB (P=0.78), and 68.8% for calcified lesions. Freedom from major adverse events at 1 year was 89.3% for DA+DCB and 90.0% for DCB (P=0.86). CONCLUSIONS: DA+DCB treatment was effective and safe, but the study was not powered to show significant differences between the 2 methods of revascularization in 1-year follow-up. An adequately powered randomized trial is warranted. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique Identifier: NCT01366482.

Promising role of drug-coated balloons in the tibial vessels?

In order to assess the role of drug-coated balloons (DCB) in below-the-knee (BTK) artery interventions, we analyzed randomized trials which compare coated to non-coated balloons and additionally a direct comparison of drug-eluting stents (DES) with DCB. As angioplasty with non-coated balloons is per guideline-recommendation still standard of care for below-the-knee artery endovascular treatment, we focused on the direct comparison of efficacy and clinical outcome data of both treatment modalities. Data from peer reviewed and published trials were consulted. For each single study, primary and secondary endpoints were reported and compared. Three single-center, non-core lab adjudicated trials showed encouraging data which suggests that DCB in BTK arteries effectively inhibit the risk of early restenosis, but the pivotal, prospectively randomized, multicenter, core lab adjudicated trials failed to match with these result. Limitations of DEB treatment and trials in BTK arteries had been reported, hence a technical evaluation of possible side effects of DCB treatment and of trial design was taken into account. On the basis of the results available, the distinguishing findings of drug eluting effects in the femoropopliteal region cannot be transferred to BTK arteries. Refinement of the existing DCB technology and of future trial design should be considered. To adjudicate on DCB technology applied for BTK treatment is premature and it is mandatory to be kept under evaluation, because the potential benefit, with respect to the compelling results in the femoropoliteal arteries, could be huge to improve endovascular BTK and especially CLI treatment.

MISAGO 1: first-in-man clinical trial with Misago nitinol stent.

AIMS: To evaluate a newly developed self-expanding Misago (Terumo Corp., Tokyo, Japan) nitinol stent with rapid exchange delivery catheter for the treatment of stenotic or occluded superficial femoral (SF) or popliteal arteries. METHODS AND RESULTS: MISAGO 1 clinical trial enrolled 55 patients undergoing percutaneous intervention of totally occluded or stenotic lesions in SF or popliteal arteries treated with the implantation of 81 stents in five centres across Europe. Primary endpoint was restenosis rate at six months assessed by duplex sonography. Patients (67% male) were 68+/-9 years old, 60% were smokers and 31% had diabetes. Clinical symptoms of ischaemia were present in all patients. Average lesion length was 85+/-50 mm, 64% were totally occluded and 38% classified as TASC C or D. The technical success rate was 100% while the procedural success rate was 98.2% without death, MI, stroke, or major bleeding. At six months follow-up the restenosis rate was 8.5%. One patient (1.8%) died of bronchial carcinoma and two (3.6%) underwent target vessel revascularisation. Mean ankle brachial index improved from 0.70 at baseline to 0.95 at six months while walking capacity on treadmill test improved with an average of 147 m. Rutherford index at six months demonstrated improvement of 72%, without any patients having symptom deterioration. One case of stent fracture was observed. CONCLUSIONS: The results from this first-in-man study indicate good safety and short to medium term efficacy profile of the Misago nitinol stent.

Nitinol stent implantation in TASC A and B superficial femoral artery lesions: the Femoral Artery Conformexx Trial (FACT).

PURPOSE: To investigate the impact of nitinol stenting of superficial femoral artery (SFA) lesions with a maximum length of 10 cm (TASC-II A or B) on 1-year outcomes compared to a historical study cohort from the Femoral Artery Stent Trial (FAST). METHODS: Between January 2004 and August 2005, 6 study sites enrolled 110 symptomatic patients (75 men; mean age 68+/-9 years) with a single de novo >70% SFA lesion <10 cm long treated with the self-expanding nitinol Conformexx stent. The primary study endpoint was binary restenosis determined by duplex ultrasound at 12 months. Secondary 12-month endpoints were target lesion revascularization (TLR), ankle-brachial index (ABI), mean Rutherford category, >1-class change in Rutherford category, and major adverse events. Data were analyzed according to the intention-to-treat principle and according to the actual treatment received ("on treatment" analysis). Outcomes were compared to the historical balloon angioplasty (BA) arm and the Luminexx 3 stent arm of the randomized FAST study. RESULTS: Technical success was achieved in 106 (96%) patients; at 1 year, the primary endpoint of ultrasound-assessed binary restenosis was reached in 14 (23.3%) of 60 patients (95% CI 13.4% to 36%). This restenosis rate was lower versus the historical BA (38.6%, p=0.057) or Luminexx 3 stent controls (31.7%, p=0.284) from FAST. The clinically driven TLR was 7.4% (7 of 94 clinically controlled patients), which was also lower compared to 18.3% (p=0.098) and 14.9% (p=0.267) for the historical BA and Luminexx 3 stent groups, respectively. The mean Rutherford category was reduced from 2.75+/-0.79 to 0.94+/-1.38 (p<0.0001); 85.1% were improved by at least 1 Rutherford category. The ABI increased from 0.62+/-0.15 to 0.85+/-0.20 (p<0.0001). CONCLUSION: This study of patients with SFA lesions documented favorable outcomes using nitinol stents in TASC-II A or B lesions after 1 year. The study was underpowered to prove superiority of the Conformexx nitinol stent design compared to historical balloon only or Luminexx 3 stent groups.