Drug-coated balloons to improve femoropopliteal artery patency: rationale and design of the LEVANT 2 trial

Background Atherosclerotic peripheral artery disease (PAD) is common and results in limitations in quality of life and potential progression to limb loss. Options for therapy include medical therapy, supervised exercise, surgical revascularization, and, more recently, endovascular therapies to restore arterial perfusion to the limb. Endovascular revascularization has evolved over the past 2 decades, from percutaneous transluminal angioplasty (PTA) to self-expanding stents, atherectomy, laser angioplasty, and drug-eluting stents. Despite impressive technologic advances, PTA remains the standard of care at many institutions and is the recommended primary treatment modality for femoral-popliteal PAD according to current American College of Cardiology Foundation/American Heart Association guidelines. However, restenosis after PTA is common. Therefore, a significant clinical need remains for a device that is able to achieve more durable patency than PTA but does not require a permanent implant. Drug-coated balloons (DCBs) have the potential to address this need. Several randomized controlled clinical trials of PTA balloons coated with different formulations of paclitaxel have been conducted in Europe (N Engl J Med 2008;358:689-699) (Circulation 2008;118:1358-1365) (Circ Cardiovasc Interv 2012;5:831-840) (JACC Cardiovas Interv 2014;7:10-19) and demonstrated more durable efficacy than PTA with comparable safety. These studies were limited by small sample sizes and powered solely for an angiographic primary end point. The pivotal LEVANT 2 trial was designed in collaboration with the US Food and Drug Administration to demonstrate safety and efficacy in a large population and to obtain US Food and Drug Administration approval. Methods A prospective, multicenter, single-blind trial comparing the Lutonix DCB (Bard Lutonix; New Hope, MN) versus PTA for treatment of femoropopliteal PAD (LEVANT 2) is the first US-based 2:1 randomized controlled trial of 476 patients with femoral-popliteal PAD designed to demonstrate superior efficacy and noninferior safety of a novel paclitaxel DCB compared with PTA. The primary efficacy end point is primary patency at 12 months. The primary safety end point is composite freedom at 12 months from perioperative death, index limb amputation, reintervention, and limb-related mortality. A series of important secondary end points include physical functioning, quality of life, revascularizations, and alternative measures of patency. To minimize bias potential for confounding variables, LEVANT 2 (1) excluded patients stented after predilation before randomization, (2) incorporated very stringent criteria for bailout stenting, (3) did not count bailout stenting as a target lesion revascularization or failure of any end point, (4) required a blinded clinician to perform clinical evaluations at follow-up, and (5) required clinical assessment before review of duplex ultrasound results. Conclusions LEVANT 2 represents the first US-inclusive multicenter, randomized controlled trial to assess the safety and efficacy of a novel DCB compared with PTA as primary therapy for symptomatic PAD on the background of standard medical therapy

Persistent Organic Pollutant in the Venetian coastal environment

The Venetian coastal area is characterized by a strong anthropogenic impact and its quality is very important because of local economical activities, such as tourism or fishing. In the context of the Water Framework Directive (WFD, 2000/60/EC), the aim of the project Q-ALiVe (Qualità dell’Ambiente Litoraneo Veneto) is to check the environmental quality of the Venetian coastal area and whether rivers contamination could influence it. We studied an area going from the mouth of the Adige river to the Malamocco inlet of the Venice lagoon (including the mouth of the Brenta river and the Chioggia lagoon inlet), to distance from the coast of up to about a kilometer. In this work we presented the data relative to Persistent Organic Pollutants (POPs) as PCBs, PBDEs and PAHs, in samples of seawater. Samples were collected during four different sampling campaigns, in different seasons (June 2011, August 2011, September 2011, November 2011); in each sampling campaign we collected 10 samples of surface water. Analytical samples procedures for POPs include liquid-liquid continuous extraction, followed by an automated purification step, with neutral silica columns. Analysis were made by HRGC-HRMS (PCBs) or HRGC-LRMS (PAHs and PBDEs). Quantification was made by isotope dilution. Results suggest a negligible influence of rivers contamination to the quality of the sea facing the city of Chioggia and the Venice lagoon. Funds for this work were provided, in the framework of Q-ALiVe Project, by the Regione del Veneto - L.R. 15/07

Influence of Site and Operator Characteristics on Carotid Artery Stent Outcomes Analysis of the CAPTURE 2 (Carotid ACCULINK/ACCUNET Post Approval Trial to Uncover Rare Events) Clinical Study

ObjectivesThe aim of this study was to analyze the CAPTURE 2 (Carotid ACCULINK/ACCUNET Post Approval Trial to Uncover Rare Events) study for physician- or site-related variables associated with differential outcomes for carotid artery stenting (CAS).BackgroundThe CAPTURE 2 trial is an ongoing, prospective, nonrandomized, independently adjudicated, multicenter clinical study enrolling high-surgical-risk patients undergoing CAS.MethodsIn this assessment of the CAPTURE 2 study, the American Heart Association carotid endarterectomy guideline limits were used to define acceptable site and physician CAS outcomes; therefore, the resulting population of nonoctogenarian, asymptomatic subjects in this analysis is confined to 3,388 (of the total 5,297) subjects treated at 180 U.S. hospitals by 459 operators between March 2006 and January 2009.ResultsThe rates of death, stroke, and myocardial infarction and death and stroke (DS) at 30 days were 3.5% and 3.3%, respectively, for the full CAPTURE 2 study cohort and 2.9% and 2.7%, respectively, for the asymptomatic, nonoctogenarian subgroup. In this subgroup, two-thirds of sites (118 of 180, 66%) had no DS events. Within the remaining sites, an inverse relationship between event rates and hospital patient volume as well as between event rates and individual operator volume was observed. The DS rates trended lower for interventional cardiologists compared with other specialties.ConclusionsOutcomes from the largest prospectively gathered, independently adjudicated, multicenter CAS study indicate that CAS can be safely performed in a variety of hospital settings by physicians with various specialties. The most important determinant of perioperative CAS outcomes was both site and operator CAS volume. A threshold of 72 cases was found to be necessary for consistently achieving a DS rate below 3% in this later-phase single arm study; background era and non-study operator experience will affect this determination.(Second Phase of “Carotid RX ACCULINK/RX ACCUNET Post-Approval Trial to Uncover Unanticipated or Rare Events”; NCT00302237

The Incidence and Health Economic Burden of Ischemic Amputation in Minnesota, 2005-2008

Critical limb ischemia (CLI) is the most severe manifestation of peripheral artery disease (PAD), is associated with high rates of myocardial infarction, stroke, and amputation, and has a high health economic cost. The objective of this study was to estimate the incidence of lower limb amputation, the most serious consequence of CLI, and to create a surveillance methodology for the incidence of ischemic amputation in Minnesota

Mechanisms of tissue uptake and retention of paclitaxel-coated balloons: impact on neointimal proliferation and healing

Background: The efficacy of paclitaxel-coated balloons (PCB) for restenosis prevention has been demonstrated in humans. However, the mechanism of action for sustained drug retention and biological efficacy following single-time drug delivery is still unknown. Methods and results The pharmacokinetic profile and differences in drug concentration (vessel surface vs arterial wall) of two different paclitaxel coating formulations (3 µg/mm2) displaying opposite solubility characteristics (CC=crystalline vs AC=amorphous) were tested in vivo and compared with paclitaxel-eluting stents (PES). Also, the biological effect of both PCB formulations on vascular healing was tested in the porcine coronary injury model. One hour following balloon inflation, both formulations achieved similar arterial paclitaxel levels (CC=310 vs AC=245 ng/mg; p=NS). At 24 h, the CC maintained similar tissue concentrations, whereas the AC tissue levels declined by 99% (p<0.01). At this time point, arterial levels were 20-fold (CC) and 5-fold (AC) times higher compared to the PES group (p<0.05). At 28 days, arterial levels retained were 9.2% (CC) and 0.04% (AC, p<0.01) of the baseline levels. Paclitaxel concentration on the vessel surface was higher in the CC at 1 (CC=36.7% vs AC=13.1%, p<0.05) and 7 days (CC=38.4% vs AC=11%, p<0.05). In addition, the CC induced higher levels of neointimal inhibition, fibrin deposition and delayed healing compared with the AC group. Conclusions: The presence of paclitaxel deposits on the vessel surface driving diffusion into the arterial tissue in a time-dependent fashion supports the mechanism of action of PCB. This specific pharmacokinetic behaviour influences the patterns of neointimal formation and healing

Tibiopedal arterial minimally invasive retrograde revascularization (TAMI) in patients with peripheral arterial disease and critical limb ischemia. On behalf of the Peripheral Registry of Endovascular Clinical Outcomes (PRIME)

Objectives and backgroundComplex peripheral arterial disease (PAD) and critical limb ischemia (CLI) are associated with high morbidity and mortality. Endovascular techniques have become prevalent in treatment of advanced PAD and CLI, and use of techniques such as tibiopedal minimally invasive revascularization (TAMI), have been proven safe in small, singleâ center series. However, its use has not been systematically compared to traditional approaches.Methods and resultsThis is a retrospective, multicenter analysis which enrolled 744 patients with advanced PAD and CLI who underwent 1,195 endovascular interventions between January 2013 and April 2018. Data was analyzed based on access used for revascularization: 840 performed via femoral access, 254 via dual access, and 101 via TAMI. The dual access group had the highest median Rutherford Class and lowest number of patent tibial vessels. Median fluoroscopy time, procedure time, hospital stay, and contrast volume were significantly lower in the TAMI access group when compared to both femoral/dual access groups. There was also a significant difference between all groups regarding location of target lesions: Femoropopliteal lesions were most commonly treated via femoral access; infrapopliteal lesions, via TAMI, and multilevel lesions via dual access.ConclusionsStandâ alone TAMI or tibial access as an integral part of a dual access treatment strategy, is safe and efficacious in the treatment of patients with advanced PAD and CLI who have infrapopliteal lesions. Larger prospective and randomized studies may be useful to further validate this approach.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154326/1/ccd28639.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154326/2/ccd28639_am.pd

Three-year sustained clinical efficacy of drug-coated balloon angioplasty in a real-world femoropopliteal cohort

Purpose:To report the 36-month outcomes from the prospective, multicenter, single-arm IN.PACT Global Study (ClinicalTrials.govidentifier NCT01609296) evaluating the performance of the IN.PACT Admiral drug-coated balloon (DCB) in real-world patients with femoropopliteal occlusive disease.Materials and Methods:The IN.PACT Global Study was conducted at 64 international sites and enrolled 1535 patients with complex lesions, which included bilateral disease, multiple lesions, de novo in-stent restenosis, long lesions, and chronic total occlusions. The predefined full clinical cohort included 1406 patients (mean age 68.6 years; 67.8% men) with claudication or rest pain treated with the study DCB. Mean lesion length was 12.09 +/- 9.54 cm; 18.0% had in-stent restenosis, 35.5% were totally occluded, and 68.7% were calcified. Freedom from clinically-driven target lesion revascularization (CD-TLR) was evaluated through 36 months. The safety composite endpoint was freedom from device- and procedure-related death through 30 days and freedom from major target limb amputation and clinically-driven target vessel revascularization within 36 months. All safety and revascularization events were reviewed by an independent clinical events committee.Results:The Kaplan-Meier estimate of freedom from CD-TLR through 36 months was 76.9%. The composite safety endpoint was achieved in 75.6% of patients. The 36-month all-cause mortality rate was 11.6%, and the major target limb amputation rate was 1.0%. The Kaplan-Meier estimate of freedom from CD-TLR through 36 months was significantly lower in patients with chronic limb-threatening ischemia (CLTI) compared with claudicants (67.6% vs 78.0%; p=0.003). Lesions affecting both the superficial femoral artery (SFA) and popliteal artery had lower Kaplan-Meier freedom from CD-TLR through 36 months (69.2%) than either isolated SFA (79.7%) or popliteal artery lesions (76.5%; log- rank p<0.001). Predictors of CD-TLR through 36 months included increased lesion length, reference vessel diameter <= 4.5 mm, in-stent restenosis, bilateral disease, CLTI, and hyperlipidemia.Conclusion:DCB angioplasty with the IN.PACT Admiral DCB for femoropopliteal disease in a diverse and complex real-world population is associated with sustained clinical efficacy and low rates of reinterventions at 3 years after the initial procedure

The FReedom from Ischemic Events - New Dimensions for Survival (FRIENDS) registry: design of a prospective cohort study of patients with advanced peripheral artery disease

Background: Advanced lower extremity peripheral artery disease (PAD), whether presenting as acute limb ischemia (ALI) or chronic critical limb ischemia (CLI), is associated with high rates of cardiovascular ischemic events, amputation, and death. Past research has focused on strategies of revascularization, but few data are available that prospectively evaluate the impact of key process of care factors (spanning pre-admission, acute hospitalization, and post-discharge) that might contribute to improving short and long-term health outcomes. Methods/Design The FRIENDS registry is designed to prospectively evaluate a range of patient and health system care delivery factors that might serve as future targets for efforts to improve limb and systemic outcomes for patients with ALI or CLI. This hypothesis-driven registry was designed to evaluate the contributions of: (i) pre-hospital limb ischemia symptom duration, (ii) use of leg revascularization strategies, and (iii) use of risk-reduction pharmacotherapies, as pre-specified factors that may affect amputation-free survival. Sequential patients would be included at an index “vascular specialist-defined” ALI or CLI episode, and patients excluded only for non-vascular etiologies of limb threat. Data including baseline demographics, functional status, co-morbidities, pre-hospital time segments, and use of medical therapies; hospital-based use of revascularization strategies, time segments, and pharmacotherapies; and rates of systemic ischemic events (e.g., myocardial infarction, stroke, hospitalization, and death) and limb ischemic events (e.g., hospitalization for revascularization or amputation) will be recorded during a minimum of one year follow-up. Discussion The FRIENDS registry is designed to evaluate the potential impact of key factors that may contribute to adverse outcomes for patients with ALI or CLI. Definition of new “health system-based” therapeutic targets could then become the focus of future interventional clinical trials for individuals with advanced PAD