Editor's Choice - Real World Study of Mortality After the Use of Paclitaxel Coated Devices in Peripheral Vascular Intervention.

OBJECTIVE: This observational cohort study examined outcomes after peripheral vascular intervention (PVI) with paclitaxel coated devices (PCD) and non-PCD, and evaluated heterogeneity of treatment effect in populations of interest. METHODS: The study included patients undergoing percutaneous transluminal angioplasty and or stent placement between 1 October 2015 and 31 December 2018 in the Vascular Quality Initiative Registry linked to Medicare claims. It determined differences in patient mortality and ipsilateral major amputation after PVI with PCD and non-PCD using Kaplan-Meier analyses and Cox regressions with inverse probability weighting in three cohorts: (A) patients treated for femoropopliteal or infrapopliteal occlusive disease with or without any other concurrent treatment (n = 11 452); (B) those treated for isolated superficial femoral or popliteal artery disease (n = 5 519); and (C) patients with inclusion criteria designed to approximate RCT populations (n = 2 278). RESULTS: The mean age of patients was 72.3 (SD = 10.9) years, and 40.6% were female. In cohort A, patients receiving PCD had a lower mortality rate (HR 0.88, 95% CI 0.79 - 0.98) than those receiving non-PCD. There was no significant difference in mortality between groups in cohort B (HR 0.91, 95% CI 0.80 - 1.04) and cohort C (HR 1.10, 95% CI 0.84 - 1.43). Patients receiving PCD did not have a significantly elevated risk of major amputation compared with those receiving non-PCD (cohort A: HR 0.84, 95% CI 0.70 - 1.00; cohort B: HR 0.84, 95% CI 0.67 - 1.06; and cohort C: HR 1.05, 95% CI 0.51 - 2.14). CONCLUSION: No increased patient mortality or major amputation was found at three years after PVI with PCD vs. non-PCD in this large, linked registry claims study, after accounting for heterogeneity of treatment effect by population. The analysis and results from three cohorts intended to mirror the cohorts of previous studies provide robust and niche real world evidence on PCD safety and help to understand and reconcile previously discrepant findings.

Navigating the Regulatory Pathway for Medical Devices-a Conversation with the FDA, Clinicians, Researchers, and Industry Experts.

Successful translation of new and innovative medical products from concept to clinical use is a complex endeavor that requires understanding and overcoming a variety of challenges. In particular, regulatory pathways and processes are often unfamiliar to academic researchers and start-ups, and even larger companies. Growing evidence suggests that the successful translation of ideas to products requires collaboration and cooperation between clinicians, researchers, industry, and regulators. A multi-stakeholder group developed this review to enhance regulatory knowledge and thereby improve translational success for medical devices. Communication between and among stakeholders is identified as a critical factor. Current regulatory programs and processes to facilitate communication and translation of innovative devices are described and discussed. Case studies are used to highlight the importance of flexibility when considering evidence requirements. We provide a review of emerging strategies, opportunities, and best practices to increase the regulatory knowledge base and facilitate medical device translation by all stakeholders. Clinicians, regulators, industry, and researchers require regulatory knowledge and collaboration for successful translation of innovative medical devices.

Decision analysis of retrievable inferior vena cava filters in patients without pulmonary embolism.

BACKGROUND: Retrievable filters are increasingly implanted for prophylaxis in patients without pulmonary embolism (PE) but who may be at transient risk. These devices are often not removed after the risk of PE has diminished. This study employs decision analysis to weigh the risks and benefits of retrievable filter use as a function of the filter's time in situ. METHODS: Medical literature on patients with inferior vena cava (IVC) filters and a transient risk of PE were reviewed. Weights reflecting relative severity were assigned to each adverse event. The risk score was defined as weight × occurrence rate and combines the frequency and severity for each type of adverse event. The value function in the decision model combines the following risks: (1) risk in situ; (2) risk of removal, and (3) relative risk without filters. A decreasing net risk score represents a net expected benefit, and an increasing net risk score indicates the expected harm outweighs the expected benefit. RESULTS: The net risk score reaches its minimum between day 29 and 54 postimplantation. This is consistent with an increasing net risk associated with continued use of retrievable IVC filters in patients with transient, reversible risk of PE. The results were insensitive to reasonable variations in the assessed weights and adverse event occurrence rates. CONCLUSIONS: For patients with retrievable IVC filters in whom the transient risk of PE has passed, quantitative decision analysis suggests the benefit/risk profile begins to favor filter removal between 29 and 54 days after implantation.

Stretch increases alveolar epithelial permeability to uncharged micromolecules.

We measured stretch-induced changes in transepithelial permeability in vitro to uncharged tracers 1.5-5.5 A in radius to identify a critical stretch threshold associated with failure of the alveolar epithelial transport barrier. Cultured alveolar epithelial cells were subjected to a uniform cyclic (0.25 Hz) biaxial 12, 25, or 37% change in surface area (DeltaSA) for 1 h. Additional cells served as unstretched controls. Only 37% DeltaSA (100% total lung capacity) produced a significant increase in transepithelial tracer permeability, with the largest increases for bigger tracers. Using the permeability data, we modeled the epithelial permeability in each group as a population of small pores punctuated by occasional large pores. After 37% DeltaSA, increases in paracellular transport were correlated with increases in the radii of both pore populations. Inhibition of protein kinase C and tyrosine kinase activity during stretch did not affect the permeability of stretched cells. In contrast, chelating intracellular calcium and/or stabilizing F-actin during 37% DeltaSA stretch reduced but did not eliminate the stretch-induced increase in paracellular permeability. These results provide the first in vitro evidence that large magnitudes of stretch increase paracellular transport of micromolecules across the alveolar epithelium, partially mediated by intracellular signaling pathways. Our monolayer data are supported by whole lung permeability results, which also show an increase in alveolar permeability at high inflation volumes (20 ml/kg) at the same rate for both healthy and septic lungs.

Measurement of stretch-induced loss of alveolar epithelial barrier integrity with a novel in vitro method.

Mechanical ventilation with high tidal volumes has been shown to contribute to the formation or worsening of interstitial and alveolar edema. Previously we showed that application of large biaxial deformations in vitro perturbs the concentration and distribution of functional tight junction proteins in alveolar epithelial cells. Using a novel method, we determined that applied epithelial strain increases paracellular permeability in a dose- and rate-dependent manner. Primary rat alveolar epithelial cells were subjected to 12%, 25%, or 37% change in surface area (Delta SA) cyclic equibiaxial stretch for 1 h. Cells were also stretched noncyclically at 25% Delta SA for 1 h. During the experimental period, a fluorescently tagged ouabain derivative was added to the apical fluid. Evidence of binding indicated functional failure of the paracellular transport barrier. The percentage of field area stained was quantified from microscopic images. There was no significant evidence of basolateral fluorescent staining at 12% Delta SA or at 25% Delta SA applied cyclically or statically. However, cyclic stretch at 37% Delta SA resulted in significantly more staining than in unstretched cells (P < 0.0001) or those stretched at either 12% (P < 0.0001) or 25% cyclic (P < 0.0005) or static (P < 0.05) Delta SA. These results suggest that large cyclic tidal volumes may increase paracellular permeability, potentially resulting in alveolar flooding.