Safety of paclitaxel-coated balloon angioplasty for femoropopliteal peripheral artery disease

OBJECTIVES: The aim of this study was to assess safety outcomes of femoropopliteal drug-coated balloon (DCB) angioplasty using patient-level data from the Lutonix clinical program. BACKGROUND: A recent systematic review and meta-analysis of heterogenous trials and summary-level data identified increased long-term mortality in patients treated with paclitaxel-coated balloons and stents. METHODS: We evaluated DCB angioplasty (n = 1,093) and uncoated balloon angioplasty (percutaneous transluminal angioplasty [PTA]) (n = 250) outcomes in LEVANT 1 (The Lutonix Paclitaxel-Coated Balloon for the Prevention of Femoropopliteal Restenosis), LEVANT 2 (Moxy Drug Coated Balloon vs. Standard Balloon Angioplasty for the Treatment of Femoropopliteal Arteries), and the LEVANT Japan Clinical Trial. Hazard ratios (HRs) were calculated with Cox proportional hazards modeling. RESULTS: There were no significant differences in mortality rates between DCB angioplasty and PTA. The 5-year HR was 1.01 (95% confidence interval [CI]: 0.68 to 1.52) in the aggregated LEVANT trials. The 2-year HR after DCB angioplasty was 0.99 (95% CI: 0.25 to 3.95) in LEVANT 1, 1.40 (95% CI: 0.62 to 3.14) in LEVANT 2, and 0.32 (95% CI: 0.05 to 1.92) in the LEVANT Japan Clinical Trial. The 5-year HR was 1.60 (95% CI: 0.94 to 2.72) in LEVANT 2. Adverse events and causes of death were balanced, without clustering between DCB angioplasty and PTA. Patients who underwent paclitaxel or nonpaclitaxel reinterventions had higher survival rates than those who did not undergo reinterventions. Baseline covariates predicting mortality included, among others, age (HR: 1.03 per year; p \u3c 0.0001), prior treatment of target lesion (HR: 1.67; p = 0.022), arrhythmia (HR: 1.65; p = 0.031), and diabetes (HR: 1.18; p = 0.047), without differences between the 2 arms. No dose-response relationship was identified when adjusted for key predictors of mortality. CONCLUSIONS: Analyses of patient-level data identified no mortality differences between DCB angioplasty and PTA. Furthermore, the lack of dose-response relationships or clustering of causes of death argues against a causal relationship between paclitaxel and mortality. (LEVANT 1, The Lutonix Paclitaxel-Coated Balloon for the Prevention of Femoropopliteal Restenosis [LEVANT 1], NCT00930813; Moxy Drug Coated Balloon vs. Standard Balloon Angioplasty for the Treatment of Femoropopliteal Arteries [LEVANT 2], NCT01412541; LEVANT 2 Continued Access Registry, NCT01628159; LEVANT Japan Clinical Trial, NCT01816412)

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

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