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Early discharge and home treatment of patients with low-risk pulmonary embolism with the oral factor Xa inhibitor rivaroxaban: an international multicentre single-arm clinical trial.

口服 Xa 因子抑制剂利伐沙班对低危肺栓塞患者的早期出院和家庭治疗: 一项国际多中心单臂临床试验。

  • 影响因子:8.07
  • DOI:10.1093/eurheartj/ehz367
  • 作者列表:"Barco S","Schmidtmann I","Ageno W","Bauersachs RM","Becattini C","Bernardi E","Beyer-Westendorf J","Bonacchini L","Brachmann J","Christ M","Czihal M","Duerschmied D","Empen K","Espinola-Klein C","Ficker JH","Fonseca C","Genth-Zotz S","Jiménez D","Harjola VP","Held M","Iogna Prat L","Lange TJ","Manolis A","Meyer A","Mustonen P","Rauch-Kroehnert U","Ruiz-Artacho P","Schellong S","Schwaiblmair M","Stahrenberg R","Westerweel PE","Wild PS","Konstantinides SV","Lankeit M","HoT-PE Investigators .
  • 发表时间:2020-01-21

AIMS:To investigate the efficacy and safety of early transition from hospital to ambulatory treatment in low-risk acute PE, using the oral factor Xa inhibitor rivaroxaban. METHODS AND RESULTS:We conducted a prospective multicentre single-arm investigator initiated and academically sponsored management trial in patients with acute low-risk PE (EudraCT Identifier 2013-001657-28). Eligibility criteria included absence of (i) haemodynamic instability, (ii) right ventricular dysfunction or intracardiac thrombi, and (iii) serious comorbidities. Up to two nights of hospital stay were permitted. Rivaroxaban was given at the approved dose for PE for ≥3 months. The primary outcome was symptomatic recurrent venous thromboembolism (VTE) or PE-related death within 3 months of enrolment. An interim analysis was planned after the first 525 patients, with prespecified early termination of the study if the null hypothesis could be rejected at the level of α = 0.004 (<6 primary outcome events). From May 2014 through June 2018, consecutive patients were enrolled in seven countries. Of the 525 patients included in the interim analysis, three (0.6%; one-sided upper 99.6% confidence interval 2.1%) suffered symptomatic non-fatal VTE recurrence, a number sufficiently low to fulfil the condition for early termination of the trial. Major bleeding occurred in 6 (1.2%) of the 519 patients comprising the safety population. There were two cancer-related deaths (0.4%). Conclusion: Early discharge and home treatment with rivaroxaban is effective and safe in carefully selected patients with acute low-risk PE. The results of the present trial support the selection of appropriate patients for ambulatory treatment of PE.


目的: 探讨口服 Xa 因子抑制剂利伐沙班治疗低危急性肺栓塞的疗效和安全性。 方法和结果: 我们在急性低风险 PE 患者中进行了一项前瞻性多中心单臂研究者发起和学术赞助的管理试验 (EudraCT 标识符 2013-001657-28)。合格标准包括无 (i) 血流动力学不稳定,(ii) 右心室功能障碍或心内血栓,和 (iii) 严重合并症。最多允许住院两晚。利伐沙班按批准剂量给予 PE ≥ 3 个月。主要结局是入组后 3 个月内有症状的复发性静脉血栓栓塞 (VTE) 或 PE 相关死亡。在最初的 525 名患者之后计划进行中期分析,如果零假设可以在 α = 0.004 (<6 个主要结局事件) 水平被拒绝,则预先设定提前终止研究。从 2014年5月到 2018年6月,在 7 个国家连续入组患者。在纳入中期分析的 525 例患者中,3 例 (0.6%; 单侧上 99.6% 置信区间 2.1%) 出现症状性非致死性 VTE 复发,一个足够低的数字,足以满足提前终止审判的条件。安全人群 1.2% 例患者中有 6 例 (519) 发生大出血。有两例癌症相关死亡 (0.4%)。 结论: 利伐沙班早期出院和家庭治疗对精心选择的急性低危 PE 患者是有效和安全的。本试验结果支持选择合适的 PE 门诊治疗患者。



作者列表:["De Cunto G","Brancaleone V","Riemma MA","Cerqua I","Vellecco V","Spaziano G","Cavarra E","Bartalesi B","D'Agostino B","Lungarella G","Cirino G","Lucattelli M","Roviezzo F"]

METHODS:BACKGROUND AND PURPOSE:A critical role for sphingosine kinase/sphingosine-1-phosphate (S1P) pathway in the control of airway function has been demonstrated in respiratory diseases. Here, we address S1P contribution in a mouse model of mild chronic obstructive pulmonary disease (COPD). EXPERIMENTAL APPROACH:C57BL/6J mice have been exposed to room air or cigarette smoke up to 11 months and killed at different time points. Functional and molecular studies have been performed. KEY RESULTS:Cigarette smoke caused emphysematous changes throughout the lung parenchyma coupled to a progressive collagen deposition in both peribronchiolar and peribronchial areas. The high and low airways showed an increased reactivity to cholinergic stimulation and α-smooth muscle actin overexpression. Similarly, an increase in airway reactivity and lung resistances following S1P challenge occurred in smoking mice. A high expression of S1P, Sph-K2 , and S1P receptors (S1P2 and S1P3 ) has been detected in the lung of smoking mice. Sphingosine kinases inhibition reversed the increased cholinergic response in airways of smoking mice. CONCLUSIONS AND IMPLICATIONS:S1P signalling up-regulation follows the disease progression in smoking mice and is involved in the development of airway hyperresponsiveness. Our study defines a therapeutic potential for S1P inhibitors in management of airways hyperresponsiveness associated to emphysema in smokers with both asthma and COPD.

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作者列表:["Bernstein DM","Toth B","Rogers RA","Kling DE","Kunzendorf P","Phillips JI","Ernst H"]

METHODS::The interim results from this 90-day multi-dose, inhalation toxicology study with life-time post-exposure observation has shown an important fundamental difference in persistence and pathological response in the lung between brake dust derived from brake-pads manufactured with chrysotile, TiO2 or chrysotile alone in comparison to the amphiboles, crocidolite and amosite asbestos. In the brake dust exposure groups no significant pathological response was observed at any time. Slight macrophage accumulation of particles was noted. Wagner-scores, were from 1 to 2 (1 = air-control group) and were similar to the TiO2 group. Chrysotile being biodegradable, shows a weakening of its matrix and breaking into short fibers & particles that can be cleared by alveolar macrophages and continued dissolution. In the chrysotile exposure groups, particle laden macrophage accumulation was noted leading to a slight interstitial inflammatory response (Wagner-score 1-3). There was no peribronchiolar inflammation and occasional very slight interstitial fibrosis. The histopathology and the confocal analyses clearly differentiate the pathological response from amphibole asbestos, crocidolite and amosite, compared to that from the brake dust and chrysotile. Both crocidolite and amosite induced persistent inflammation, microgranulomas, and fibrosis (Wagner-scores 4), which persisted through the post exposure period. The confocal microscopy of the lung and snap-frozen chestwalls quantified the extensive inflammatory response and collagen development in the lung and on the visceral and parietal surfaces. The interim results reported here, provide a clear basis for differentiating the effects from brake dust exposure from those following amphibole asbestos exposure. The subsequent results through life-time post-exposure will follow.

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作者列表:["Zaragosi LE","Deprez M","Barbry P"]

METHODS::The respiratory tract is lined by a pseudo-stratified epithelium from the nose to terminal bronchioles. This first line of defense of the lung against external stress includes five main cell types: basal, suprabasal, club, goblet and multiciliated cells, as well as rare cells such as ionocytes, neuroendocrine and tuft/brush cells. At homeostasis, this epithelium self-renews at low rate but is able of fast regeneration upon damage. Airway epithelial cell lineages during regeneration have been investigated in the mouse by genetic labeling, mainly after injuring the epithelium with noxious agents. From these approaches, basal cells have been identified as progenitors of club, goblet and multiciliated cells, but also of ionocytes and neuroendocrine cells. Single-cell RNA sequencing, coupled to lineage inference algorithms, has independently allowed the establishment of comprehensive pictures of cell lineage relationships in both mouse and human. In line with genetic tracing experiments in mouse trachea, studies using single-cell RNA sequencing (RNAseq) have shown that basal cells first differentiate into club cells, which in turn mature into goblet cells or differentiate into multiciliated cells. In the human airway epithelium, single-cell RNAseq has identified novel intermediate populations such as deuterosomal cells, 'hybrid' mucous-multiciliated cells and progenitors of rare cells. Novel differentiation dynamics, such as a transition from goblet to multiciliated cells have also been discovered. The future of cell lineage relationships in the respiratory tract now resides in the combination of genetic labeling approaches with single-cell RNAseq to establish, in a definitive manner, the hallmarks of cellular lineages in normal and pathological situations.

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