Heart and Vascular

Carpenter, J. P., J. S. Lane, 3rd, J. Trani, S. Hussain, C. Healey, C. J. Buckley, H. Hashemi and R. Cuff (2018). “Refinement of anatomic indications for the Nellix System for endovascular aneurysm sealing based on 2-year outcomes from the EVAS FORWARD IDE trial.” J Vasc Surg. Mar 30. [Epub ahead of print].

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BACKGROUND: The Nellix System (Endologix, Inc, Irvine, Calif) for endovascular aneurysm sealing (EVAS) is a novel approach to abdominal aortic aneurysm treatment and conceptually different from endovascular aneurysm repair, whereby polymer is employed to fill and actively manage the abdominal aortic aneurysm sac. One-year safety and effectiveness results of the Nellix pivotal trial demonstrated encouraging outcomes with very low morbidity and mortality and high procedural and treatment success. Two-year imaging revealed a signal of migration, leading to a field safety notification issued by the manufacturer on October 21, 2016, and a dedicated root cause analysis, resulting in refinements to the instructions for use (IFU). We report the 2-year results of the investigational device exemption pivotal trial stratified according to the new and original criteria for selection of patients. METHODS: Comprehensive engineering evaluations, statistical analyses, and clinical assessments were conducted looking at patients enrolled in the pivotal trial (N = 150), roll-in cohort (N = 29), and continued access program (N = 154). All patients in all cohorts were treated on-IFU at the time of enrollment. Logistic regression models supported the mechanism that migration with Nellix is associated with a small aortic flow lumen relative to a large aneurysm thrombus burden and large aortic neck diameters. Based on these findings, refinements to the IFU criteria were applied, excluding patients with a thrombus index (maximum aneurysm sac/maximum flow lumen diameter) >1.4, aortic neck diameter >28 mm, and aortic neck conicity (>10% diameter change along the infrarenal neck) and requiring a 10-mm distal seal zone in the iliac artery. RESULTS: Freedom from all-cause mortality at 2 years was 94%. Patient outcomes were then stratified on the refined morphologic criteria and analyzed retrospectively. Two-year freedom from composite endoleak was high among both cohorts (95% on-IFU vs 92% off-IFU). Freedom from migration was 97.7% on-IFU vs 93.2% off-IFU (P = .0125). Freedom from aneurysm enlargement was 98.1% on-IFU vs 93.5% off-IFU (P value is not available because of failure of log-rank test assumptions). Composite freedom from migration, type IA endoleak, or aneurysm expansion was 95.9% among the on-IFU cohort vs 85.1% in the off-IFU cohort (P = .0017). CONCLUSIONS: Consistent with the introduction of a novel therapy, the presentation of failure modes of EVAS over time was inevitable. Using detailed imaging as well as engineering and statistical analysis, we were able to understand risk factors for adverse events specific to EVAS and defined those patients best suited for Nellix. With this EVAS-specific approach to defining IFU, on-IFU patients were identified as those with large aneurysms with little thrombus that would be prone to type II endoleaks and sac expansion with traditional devices. When treated with Nellix, these patients were predicted to experience exceptional results, especially with regard to a low composite endoleak rate and low all-cause mortality.

Main, M. L., S. B. Feinstein, L. M. Feinstein, P. A. Grayburn and S. R. Wilson (2016). “Transient Ischemic Attack Caused by Contrast Echocardiography in a Patient with Platypnea-Orthodeoxia.” Echocardiography 33(1): 165-166.

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We read with interest the recent report by Loncar et al. The authors report a case of transient right hemiparesis temporally associated with the intravenous injection of agitated saline microbubbles. The study reportedly revealed “massive passage” of the agitated saline into the left heart in the setting of a large atrial septal aneurysm and two separate atrial septal defects. As the authors note, agitated saline studies have been associated with transient ischemic attacks (TIA), although this is the first report in a patient with platypnea-orthodeoxia. Although the authors reach a broad conclusion regarding risk associated with “contrast echocardiography” in general, they fail to distinguish the known differences between ultrasound contrast agents (UCAs) comprised of agitated saline microbubbles, used in their study, and UCAs that are commercially prepared and FDA-approved. Agitated saline studies utilize significant quantities (~10 mL) of large, unstable, air-filled microbubbles that have no shell and typically are injected with concomitant provocative maneuvers such as Valsalva or cough, aimed at actively potentiating atrial septal passage. In contrast, commercially prepared UCAs consist of very small microspheres (3–4 µm mean diameter) with a narrow size distribution and an encapsulating, biocompatible shell. Commercial UCAs have been approved by regulatory agencies worldwide and act as true intravascular flow tracers. The authors note that commercially available UCAs are contraindicated in patients with right to left shunts, based on theoretical concern for similar neurologic events following administration of these agents. However, the FDA has been asked to rescind the contraindication because it is not based on sound scientific data. In fact, there have been no published reports of ischemic neurologic events attributed to injection of commercial UCAs despite use in millions of patients worldwide, and empiric and experimental observations directly refute the contention that there is any neurologic risk with commercial UCAs. In a recent single-center study of 39 020 patients who were administered commercial UCAs, no TIAs or strokes were found in a subset of 418 patients with known PFOs. Additionally, large registries have reported no neurologic safety signals, despite the fact that based on population statistics, up to ~25% of these patients likely had PFOs. Further, as we have previously noted, FDA guidance regarding UCAs in patients with PFOs is contradicted by FDA’s own labeling for macroaggregated albumin (MAA), which is routinely used in ventilation–perfusion scans of the lungs. MAA has a particle size of 10–90 µm and is potentially capable of occluding arterioles, yet carries only a “warning” for use in patients with PFOs. Recent data indicate that judicious use of commercial UCAs in critically ill patients with baseline technically difficult echocardiograms is associated with lower mortality,[6] perhaps due to earlier and more accurate diagnosis. Withholding UCAs based on discredited theoretical risks is not evidence-based medicine or patient-centered care. The authors should use more specificity when describing “contrast echocardiography” to avoid confusion between agitated saline studies and commercially prepared UCAs that have decidedly different physio-chemical attributes and safety profiles.

Carpenter, J. P., R. Cuff, C. Buckley, C. Healey, S. Hussain, M. M. Reijnen, J. Trani and D. Bockler (2016). “Results of the Nellix system investigational device exemption pivotal trial for endovascular aneurysm sealing.” J Vasc Surg 63(1): 23-31.e21.

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OBJECTIVE: The Nellix EndoVascular Aneurysm Sealing system (Endologix, Inc, Irvine, Calif) is a novel approach to abdominal aortic aneurysm (AAA) endovascular repair whereby biocompatible polymer is employed to exclude and to seal the AAA sac. We report 30-day results of the U.S. pivotal trial. METHODS: Consecutive, eligible, consenting patients were enrolled at 29 sites in the United States and Europe.  Inclusion criteria required an asymptomatic infrarenal AAA, with aortic neck length >/=10 mm and angle to the sac </=60 degrees, aortic neck diameter of 18 to 32 mm, aneurysm blood lumen diameter </=6 cm, common iliac artery lumen diameter of 9 to 35 mm, access artery diameter >/=6 mm, and serum creatinine level </=2 mg/dL. Follow-up at 30 days included clinical assessment and computed tomography angiography evaluation of endoleaks and device integrity as assessed by a core laboratory. The primary safety end point is the incidence of independently adjudicated 30-day major adverse events (MAEs), with success defined as superiority with reference to the Society for Vascular Surgery open repair control group (56%). RESULTS: Between January and November 2014, 150 trial patients having a mean AAA diameter of 5.8 cm were enrolled and treated with the Nellix system with 100% procedural success. One early death (0.7%) occurred secondary to multisystem organ failure. All 149 surviving patients completed 30-day follow-up. There were no aneurysm ruptures, conversions, limb thromboses, stent fractures, or stent kinking. Five early MAEs occurred in four patients (2.7%) and included one death, bowel ischemia (1), renal failure (2), and respiratory failure (1). One (0.7%) secondary intervention to treat inadvertent coverage of a renal artery was performed. The core laboratory identified nine (6%) endoleaks (one type I, eight type II) on 30-day computed tomography angiography. Freedom from MAE was 97.3% (95% confidence interval, 93.3%-99.0%). CONCLUSIONS: In selected patients, perioperative outcomes with the Nellix system for endovascular aneurysm sealing are encouraging, with very low 30-day morbidity and mortality and high procedural success. The primary safety end point has been achieved. Longer term follow-up is in progress.

Thijs, V. N., J. Brachmann, C. A. Morillo, R. S. Passman, T. Sanna, R. A. Bernstein, H. C. Diener, V. Di Lazzaro, M. M. Rymer, L. Hogge, T. B. Rogers, P. D. Ziegler and M. D. Assar (2015). “Predictors for atrial fibrillation detection after cryptogenic stroke: Results from CRYSTAL AF.” Neurology.

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OBJECTIVE: We assessed predictors of atrial fibrillation (AF) in cryptogenic stroke (CS) or transient ischemic attack (TIA) patients who received an insertable cardiac monitor (ICM). METHODS: We studied patients with CS/TIA who were randomized to ICM within the CRYSTAL AF study. We assessed whether age, sex, race, body mass index, type and severity of index ischemic event, CHADS2 score, PR interval, and presence of diabetes, hypertension, congestive heart failure, or patent foramen ovale and premature atrial contractions predicted AF development within the initial 12 and 36 months of follow-up using Cox proportional hazards models. RESULTS: Among 221 patients randomized to ICM (age 61.6 +/- 11.4 years, 64% male), AF episodes were detected in 29 patients within 12 months and 42 patients at 36 months. Significant univariate predictors of AF at 12 months included age (hazard ratio [HR] per decade 2.0 [95% confidence interval 1.4-2.8], p = 0.002), CHADS2 score (HR 1.9 per one point [1.3-2.8], p = 0.008), PR interval (HR 1.3 per 10 milliseconds [1.2-1.4], p < 0.0001), premature atrial contractions (HR 3.9 for >123 vs 0 [1.3-12.0], p = 0.009 across quartiles), and diabetes (HR 2.3 [1.0-5.2], p < 0.05). In multivariate analysis, age (HR per decade 1.9 [1.3-2.8], p = 0.0009) and PR interval (HR 1.3 [1.2-1.4], p < 0.0001) remained significant and together yielded an area under the receiver operating characteristic curve of 0.78 (0.70-0.85). The same predictors were found at 36 months. CONCLUSION: Increasing age and a prolonged PR interval at enrollment were independently associated with an increased AF incidence in CS patients. However, they offered only moderate predictive ability in determining which CS patients had AF detected by the ICM.