Identification of alveolar and blood prognosis biomarkers in acute respiratory distress syndrome

Le syndrome de détresse respiratoire aiguë (SDRA) est la forme la plus grave d'insuffisance respiratoire hypoxémiante aiguë et touche 10 % des patients admis en unités de soins intensifs. Les infections pulmonaires représentent la majorité des facteurs de risque du SDRA. La mortalité hospitalière du SDRA est de 40 %, possiblement en raison de l'énorme hétérogénéité au sein de ce syndrome. Comme la plupart des interventions pharmacologiques testées dans le SDRA ont donné des résultats décevants, l'identification de biomarqueurs de gravité de la maladie, cibles thérapeutiques potentielles, est devenue un axe de recherche majeur. Alors que le sang a été l'échantillon biologique le plus couramment utilisé pour rechercher des biomarqueurs candidats, le liquide de lavage broncho-alvéolaire (LBA) est l'échantillon le plus proche du site de la lésion et reflète plus précisément l'environnement pulmonaire local. Dans notre travail de recherche translationnelle, nous avons concentré nos recherches sur le compartiment alvéolaire dans le contexte du SDRA induit par la pneumonie. Dans un premier temps, nous avons quantifié les NETs (neutrophils extracellular traps) alvéolaires et sanguins chez trente-cinq patients immunocompétents atteints de SDRA induit par une pneumonie et nous avons évalué leur lien avec le nombre de jours sans ventilation mécanique. Nous avons observé que les NETs étaient élevés dans le sang et le LBA, étaient associés aux taux d'interleukine-8 (IL-8) et à celui des neutrophiles ; mais n'étaient pas associés à la mortalité ou à la durée de la ventilation mécanique. Secondairement, nous avons évalué l'interrelation des biomarqueurs de SDRA septique dans les compartiments alvéolaire et sanguin et avons exploré leur association avec le pronostic du SDRA induit par une pneumonie. Pour ce faire, nous avons quantifié 22 biomarqueurs dans le LBA et le sérum, ainsi que l’expression d’ HLA‑DR par les monocytes alvéolaires chez 70 patients atteints de SDRA induit par une pneumonie. Nous avons constaté que l'IL-8 était la cytokine la plus compartimentalisée et que, après ajustement sur des facteurs confondants, des ratios de concentration LBA/sérum faibles d'IL-1Ra étaient associés à la mortalité hospitalière. Malgré le fait qu'une diminution de l'expression monocytique d’HLA-DR soit utilisée comme marqueur d’immunosuppression induite par le sepsis, nous n'avons pas observé d'association significative entre l'expression d’HLA-DR monocytaire alvéolaire et la mortalité hospitalière. Dans un troisième temps nous avons profité de la récente technique de coloration intracellulaire en cytométrie en flux pour évaluer si l'expression d’HLA-DR par les monocytes alvéolaires était associée à leurs altérations fonctionnelles. Nous avons réalisé des tests fonctionnels sur des monocytes alvéolaires et sanguins après stimulation in vitro par des lipopolysaccharides (LPS). L'activité de phagocytose et la production intracellulaire du facteur de nécrose tumorale (TNF) ont été quantifiées à l'aide d'anticorps spécifiques conjugués au fluorochrome. Dix patients atteints de SDRA lié à une pneumonie présentaient une expression d’HLA-DR significativement plus faible à la fois sur les monocytes circulants et alvéolaires. Chez les patients atteints de SDRA lié à une pneumonie, notre étude a démontré que les monocytes ont un statut désactivé et une capacité de production de cytokines inflammatoires altérée mais conservent une activité phagocytaire similaire à celle des témoins non SDRA. Cependant, le niveau d'expression d’HLA-DR sur les monocytes alvéolaires ne semble ni être marqueur de substitution de leur activité ni un biomarqueur pronostic du SDRA induit par une pneumonie. L'absence d’identification de biomarqueur spécifique du pronostic du SDRA doit nous pousser à faire un phénotypage plus approfondi et une analyse intégrative des sources de variation étiologique, physiopathologique et biologique afin de proposer une médecine de précision.Acute respiratory distress syndrome (ARDS) is the most severe form of acute hypoxemic respiratory failure and affects 10% of patients admitted to intensive care units. Pulmonary infections represent the vast majority of risk factors for ARDS and are associated with septic shock in approximately two-thirds of cases. In-hospital mortality from ARDS remains as high as 40%, possibly due to the enormous heterogeneity within this syndrome. As most of the pharmacological interventions tested in ARDS have given disappointing results, the identification of biomarkers of disease severity, potential therapeutic targets, has become a major research axis. While blood has been the most commonly used biological sample to search for candidate biomarkers, bronchoalveolar lavage (BAL) fluid is the closest sample to the site of injury and more accurately reflects the local lung environment. In our translational research work, we have focused our research on the alveolar compartment in the context of pneumonia-related ARDS. First, we quantified alveolar and blood NETs (neutrophils extracellular traps) in thirty-five immunocompetent patients with pneumonia-related ARDS and assessed their relationship with ventilator-free days. We observed that NETs were elevated in blood and BAL fluid and associated with interleukin-8 (IL-8) and neutrophil levels. However, elevated levels of NETs were not associated with mortality or with duration of mechanical ventilation. Secondly, we aimed at assessing the interrelation of ARDS/ sepsis biomarkers in the alveolar and blood compartments and explored their association with clinical outcomes. We quantified twenty‑two biomarkers in BAL fluid, in serum and evaluated HLA‑DR expression on both alveolar and circulating monocytes from seventy ARDS pneumonia-related patients. We found that IL‑8 was the most compartmentalized cytokine and, after adjusting for confounding factors, lower BAL fluid‑to‑serum concentration ratios of IL‑1Ra were associated with hospital mortality in patients with pneumonia‑related ARDS. Despite the fact that sustained decreased expression of the HLA-DR on circulating monocytes is used as a surrogate marker of immune failure during sepsis, we didn’t observe a significant association between alveolar monocytic HLA‑DR expression and hospital mortality. Thirdly, in the context of pneumonia-related ARDS, we took advantage of the recent technique of intracellular staining in flow cytometry to assess whether the expression of HLA-DR by alveolar monocytes was associated with their functional alterations. In this context, we performed functional tests on alveolar and blood monocytes after in vitro stimulation with lipopolysaccharides (LPS). Phagocytosis activity and intracellular production of tumor necrosis factor (TNF) were quantified using specific fluorochrome-conjugated antibodies. Ten patients with pneumonia-related ARDS had significantly lower HLA-DR expression on both circulating and alveolar monocytes. In patients with pneumonia-related ARDS, our study showed that monocytes have a deactivated status and an impaired inflammatory cytokine production capacity but keep similar phagocytic activity to non-ARDS controls. However, the level of HLA-DR expression on alveolar monocytes seems neither to be a surrogate marker of their activity nor a prognostic biomarker of pneumonia-related ARDS. The lack of identification of a specific prognosis biomarker of ARDS should encourage us to a deeper phenotyping and systematically address the variations in aetiology, physiology and biology in order to propose a precision medicine

Identification de biomarqueurs pronostiques alvéolaires et sanguins au cours du syndrome de détresse respiratoire aiguë infectieux

Acute respiratory distress syndrome (ARDS) is the most severe form of acute hypoxemic respiratory failure and affects 10% of patients admitted to intensive care units. Pulmonary infections represent the vast majority of risk factors for ARDS and are associated with septic shock in approximately two-thirds of cases. In-hospital mortality from ARDS remains as high as 40%, possibly due to the enormous heterogeneity within this syndrome. As most of the pharmacological interventions tested in ARDS have given disappointing results, the identification of biomarkers of disease severity, potential therapeutic targets, has become a major research axis. While blood has been the most commonly used biological sample to search for candidate biomarkers, bronchoalveolar lavage (BAL) fluid is the closest sample to the site of injury and more accurately reflects the local lung environment. In our translational research work, we have focused our research on the alveolar compartment in the context of pneumonia-related ARDS. First, we quantified alveolar and blood NETs (neutrophils extracellular traps) in thirty-five immunocompetent patients with pneumonia-related ARDS and assessed their relationship with ventilator-free days. We observed that NETs were elevated in blood and BAL fluid and associated with interleukin-8 (IL-8) and neutrophil levels. However, elevated levels of NETs were not associated with mortality or with duration of mechanical ventilation. Secondly, we aimed at assessing the interrelation of ARDS/ sepsis biomarkers in the alveolar and blood compartments and explored their association with clinical outcomes. We quantified twenty‑two biomarkers in BAL fluid, in serum and evaluated HLA‑DR expression on both alveolar and circulating monocytes from seventy ARDS pneumonia-related patients. We found that IL‑8 was the most compartmentalized cytokine and, after adjusting for confounding factors, lower BAL fluid‑to‑serum concentration ratios of IL‑1Ra were associated with hospital mortality in patients with pneumonia‑related ARDS. Despite the fact that sustained decreased expression of the HLA-DR on circulating monocytes is used as a surrogate marker of immune failure during sepsis, we didn’t observe a significant association between alveolar monocytic HLA‑DR expression and hospital mortality. Thirdly, in the context of pneumonia-related ARDS, we took advantage of the recent technique of intracellular staining in flow cytometry to assess whether the expression of HLA-DR by alveolar monocytes was associated with their functional alterations. In this context, we performed functional tests on alveolar and blood monocytes after in vitro stimulation with lipopolysaccharides (LPS). Phagocytosis activity and intracellular production of tumor necrosis factor (TNF) were quantified using specific fluorochrome-conjugated antibodies. Ten patients with pneumonia-related ARDS had significantly lower HLA-DR expression on both circulating and alveolar monocytes. In patients with pneumonia-related ARDS, our study showed that monocytes have a deactivated status and an impaired inflammatory cytokine production capacity but keep similar phagocytic activity to non-ARDS controls. However, the level of HLA-DR expression on alveolar monocytes seems neither to be a surrogate marker of their activity nor a prognostic biomarker of pneumonia-related ARDS. The lack of identification of a specific prognosis biomarker of ARDS should encourage us to a deeper phenotyping and systematically address the variations in aetiology, physiology and biology in order to propose a precision medicine.Le syndrome de détresse respiratoire aiguë (SDRA) est la forme la plus grave d'insuffisance respiratoire hypoxémiante aiguë et touche 10 % des patients admis en unités de soins intensifs. Les infections pulmonaires représentent la majorité des facteurs de risque du SDRA. La mortalité hospitalière du SDRA est de 40 %, possiblement en raison de l'énorme hétérogénéité au sein de ce syndrome. Comme la plupart des interventions pharmacologiques testées dans le SDRA ont donné des résultats décevants, l'identification de biomarqueurs de gravité de la maladie, cibles thérapeutiques potentielles, est devenue un axe de recherche majeur. Alors que le sang a été l'échantillon biologique le plus couramment utilisé pour rechercher des biomarqueurs candidats, le liquide de lavage broncho-alvéolaire (LBA) est l'échantillon le plus proche du site de la lésion et reflète plus précisément l'environnement pulmonaire local. Dans notre travail de recherche translationnelle, nous avons concentré nos recherches sur le compartiment alvéolaire dans le contexte du SDRA induit par la pneumonie. Dans un premier temps, nous avons quantifié les NETs (neutrophils extracellular traps) alvéolaires et sanguins chez trente-cinq patients immunocompétents atteints de SDRA induit par une pneumonie et nous avons évalué leur lien avec le nombre de jours sans ventilation mécanique. Nous avons observé que les NETs étaient élevés dans le sang et le LBA, étaient associés aux taux d'interleukine-8 (IL-8) et à celui des neutrophiles ; mais n'étaient pas associés à la mortalité ou à la durée de la ventilation mécanique. Secondairement, nous avons évalué l'interrelation des biomarqueurs de SDRA septique dans les compartiments alvéolaire et sanguin et avons exploré leur association avec le pronostic du SDRA induit par une pneumonie. Pour ce faire, nous avons quantifié 22 biomarqueurs dans le LBA et le sérum, ainsi que l’expression d’ HLA‑DR par les monocytes alvéolaires chez 70 patients atteints de SDRA induit par une pneumonie. Nous avons constaté que l'IL-8 était la cytokine la plus compartimentalisée et que, après ajustement sur des facteurs confondants, des ratios de concentration LBA/sérum faibles d'IL-1Ra étaient associés à la mortalité hospitalière. Malgré le fait qu'une diminution de l'expression monocytique d’HLA-DR soit utilisée comme marqueur d’immunosuppression induite par le sepsis, nous n'avons pas observé d'association significative entre l'expression d’HLA-DR monocytaire alvéolaire et la mortalité hospitalière. Dans un troisième temps nous avons profité de la récente technique de coloration intracellulaire en cytométrie en flux pour évaluer si l'expression d’HLA-DR par les monocytes alvéolaires était associée à leurs altérations fonctionnelles. Nous avons réalisé des tests fonctionnels sur des monocytes alvéolaires et sanguins après stimulation in vitro par des lipopolysaccharides (LPS). L'activité de phagocytose et la production intracellulaire du facteur de nécrose tumorale (TNF) ont été quantifiées à l'aide d'anticorps spécifiques conjugués au fluorochrome. Dix patients atteints de SDRA lié à une pneumonie présentaient une expression d’HLA-DR significativement plus faible à la fois sur les monocytes circulants et alvéolaires. Chez les patients atteints de SDRA lié à une pneumonie, notre étude a démontré que les monocytes ont un statut désactivé et une capacité de production de cytokines inflammatoires altérée mais conservent une activité phagocytaire similaire à celle des témoins non SDRA. Cependant, le niveau d'expression d’HLA-DR sur les monocytes alvéolaires ne semble ni être marqueur de substitution de leur activité ni un biomarqueur pronostic du SDRA induit par une pneumonie. L'absence d’identification de biomarqueur spécifique du pronostic du SDRA doit nous pousser à faire un phénotypage plus approfondi et une analyse intégrative des sources de variation étiologique, physiopathologique et biologique afin de proposer une médecine de précision

Enterocytozoon bieneusi Microsporidiosis in Stem Cell Transplant Recipients Treated with Fumagillin

International audienceEnterocytozoon bieneusi microsporidiosis is an emerging disease in immunocompromised patients. We report 2 cases of this disease in allogeneic hematopoietic stem cell transplant patients successfully treated with fumagillin. Thrombocytopenia occurred but without major adverse events. Modifications of immunosuppression could be avoided when E. bieneusi is rapidly identified and fumagillin therapy is started promptly

Severe Ketoalkalosis as Initial Presentation of Imported Human Rabies in France

International audienceWe report a patient with an unusual initial metabolic presentation of imported human rabies who became symptomatic within 2 weeks of returning from Mali to France. This is the single case of imported human rabies identified in France within the past 11 years and the first report of viral RNA in bronchial secretions. CASE REPORT A 57-year-old male without past medical history presented to an emergency room in March 2014 because of fever and generalized pain. He had been a resident of France for the previous 15 years and had returned 2 weeks earlier following a 6-month stay in Mali. Approximately 1 month before his return to France, he underwent a right foot injury from a tree branch which eventually healed with local care. On admission, he was conscious and cooperative but appeared anxious; he had fever (38.2°C) and abundant sweating and complained of generalized pain, mostly in the lower limbs. A clean, noninflammatory wound scar was noted on the right foot. He had marked tachypnea (rate, 40 inspirations/minute) and periodic deeper inspirations. Chest examination results were unremark-able. Arterial blood gas measurements while the patient was breathing room air were as follows: pH 7.79; partial pressure of carbon dioxide (PaCO 2), 11 mm Hg; PaO 2 , 136 mm Hg; bicar-bonates, 16 mmol/liter; and lactate, 3.7 mmol/liter. The capillary blood glucose was measured at 12 mmol/liter, and a urine dipstick revealed glycosuria (3) and ketonuria (3). Serum creatinine was at 94 mol/liter and sodium at 136 mmol/liter. Thick and thin blood smears were negative for malaria. Chest X-ray results were normal. The patient was transferred to our intensive care unit (ICU) with a presumptive diagnosis of uncontrolled diabetes and unexplained severe respiratory alkalosis. He received intravenous fluids, continuous insulin infusion, and tetanus prevention with vaccination and serotherapy. Hyperventilation, ketonuria, and metabolic abnormalities resolved within 2 days, with normaliza-tion of pH and PaCO 2. Glycated hemoglobin was 6.5%, and the patient required no further insulin administration during his ICU stay. Two days after ICU admission, he developed bouts of hyper-activity, disorientation, and delirium with thoughts of impending death associated with persecution ideas, alternating with periods of drowsiness and returns to normal behavior when he seemed aware of his disorder and criticized it. Hypersalivation was remarkable , and the patient occasionally spat on ICU personnel. Motor weakness, deep tendon reflexes, and limb sensory perceptions were normal. The results of a computed tomography scan and magnetic resonance imaging (MRI) of the brain were unre-markable. Electroencephalogram results showed no epileptic activity. The cerebrospinal fluid (CSF) test result was normal, with a negative PCR test for herpes simplex virus 1 (HSV-1) and HSV-2. Serological tests for human immunodeficiency virus type 1 (HIV-1) and HIV-2 and HIV-1 p24 antigen were negative. Thyroid stimulating hormone and ammonia levels were in the normal range. Syphilis serologic tests, including Venereal Disease Research Laboratory (VDRL) and Treponema Pallidum Hem Agglutination (TPHA) tests, were negative. On day 8 of ICU admission, the patient developed a rapidly extensive flaccid and areflectic tetraparesis without involvement of cranial nerves. His condition deteriorated, with altered consciousness and hypercapnic acidosis, and the patient required mechanical ventilation on day 9. Results of a repeated CSF analysis were normal. Results of a second cerebral and cervical MRI test were normal. Electroneuromyography showed an acute motor ax-onal neuropathy of both upper and lower limbs without sensory impairment. The results of a search for antineuron antibodies were negative, and the urinary porphobilinogen level was normal. The patient received methylprednisolone (1 g/day from day 8 to day 10) and intravenous immunoglobulin (2 g/kg of body weight from day 8 to day 12) for suspected paraneoplastic limbic enceph-alitis or Guillain-Barré syndrome. A search for rabies was performed on a skin biopsy specimen and salivary swabs obtained on day 13. A profound coma with periodic inspiratory spasms persisted , and the patient died on day 19 after ICU admission

Effects of Standard-Dose Prophylactic, High-Dose Prophylactic, and Therapeutic Anticoagulation in Patients With Hypoxemic COVID-19 Pneumonia The ANTICOVID Randomized Clinical Trial

International audienceImportance Given the high risk of thrombosis and anticoagulation-related bleeding in patients with hypoxemic COVID-19 pneumonia, identifying the lowest effective dose of anticoagulation therapy for these patients is imperative. OBJECTIVES To determine whether therapeutic anticoagulation (TA) or high-dose prophylactic anticoagulation (HD-PA) decreases mortality and/or disease duration compared with standard-dose prophylactic anticoagulation (SD-PA), and whether TA outperforms HD-PA; and to compare the net clinical outcomes among the 3 strategies. DESIGN, SETTINGS, AND PARTICIPANTS The ANTICOVID randomized clinical open-label trial included patients with hypoxemic COVID-19 pneumonia requiring supplemental oxygen and having no initial thrombosis on chest computer tomography with pulmonary angiogram at 23 health centers in France from April 14 to December 13, 2021. Of 339 patients randomized, 334 were included in the primary analysis-114 patients in the SD-PA group, 110 in the HD-PA, and 110 in the TA. At randomization, 90% of the patients were in the intensive care unit. Data analyses were performed from April 13, 2022, to January 3, 2023. INTERVENTIONS Patients were randomly assigned (1:1:1) to receive either SD-PA, HD-PA, or TA with low-molecular-weight or unfractionated heparin for 14 days. MAIN OUTCOMES AND MEASURES A hierarchical criterion of all-cause mortality followed by time to clinical improvement at day 28. Main secondary outcome was net clinical outcome at day 28 (composite of thrombosis, major bleeding, and all-cause death). RESULTS Among the study population of 334 individuals (mean [SD] age, 58.3 [13.0] years; 226 [67.7%] men and 108 [32.3%] women), use of HD-PA and SD-PA had similar probabilities of favorable outcome (47.3% [95%CI, 39.9% to 54.8%] vs 52.7%[95%CI, 45.2%to 60.1%]; P = .48), as did TA compared with SD-PA (50.9% [95%CI, 43.4%to 58.3%] vs 49.1% [95%CI, 41.7%to 56.6%]; P = .82) and TA compared with HD-PA (53.5%[95%CI 45.8% to 60.9%] vs 46.5% [95%CI, 39.1% to 54.2%]; P = .37). Net clinical outcome was met in 29.8% of patients receiving SD-PA (20.2%thrombosis, 2.6%bleeding, 14.0% death), 16.4% receiving HD-PA (5.5%thrombosis, 3.6%bleeding, 11.8%death), and 20.0% receiving TA (5.5% thrombosis, 3.6% bleeding, 12.7%death). Moreover, HD-PA and TA use significantly reduced thrombosis compared with SD-PA (absolute difference, -14.7 [95%CI -6.2 to -23.2] and -14.7 [95%CI -6.2 to -23.2], respectively). Use of HD-PA significantly reduced net clinical outcome compared with SD-PA (absolute difference, -13.5; 95%CI -2.6 to -24.3). CONCLUSIONS AND RELEVANCE This randomized clinical trial found that compared with SD-PA, neither HD-PAnor TAuse improved the primary hierarchical outcome of all-cause mortality or time to clinical improvement in patients with hypoxemicCOVID-19 pneumonia; however, HD-PA resulted in significantly better net clinical outcome by decreasing the risk of de novo thrombosis

Effects of Standard-Dose Prophylactic, High-Dose Prophylactic, and Therapeutic Anticoagulation in Patients With Hypoxemic COVID-19 Pneumonia The ANTICOVID Randomized Clinical Trial

International audienceIMPORTANCE Given the high risk of thrombosis and anticoagulation-related bleeding in patients with hypoxemic COVID-19 pneumonia, identifying the lowest effective dose of anticoagulation therapy for these patients is imperative. OBJECTIVES To determine whether therapeutic anticoagulation (TA) or high-dose prophylactic anticoagulation (HD-PA) decreases mortality and/or disease duration compared with standard-dose prophylactic anticoagulation (SD-PA), and whether TA outperforms HD-PA; and to compare the net clinical outcomes among the 3 strategies. DESIGN, SETTINGS, AND PARTICIPANTS The ANTICOVID randomized clinical open-label trial included patients with hypoxemic COVID-19 pneumonia requiring supplemental oxygen and having no initial thrombosis on chest computer tomography with pulmonary angiogram at 23 health centers in France from April 14 to December 13, 2021. Of 339 patients randomized, 334 were included in the primary analysis-114 patients in the SD-PA group, 110 in the HD-PA, and 110 in the TA. At randomization, 90% of the patients were in the intensive care unit. Data analyses were performed from April 13, 2022, to January 3, 2023. INTERVENTIONS Patients were randomly assigned (1:1:1) to receive either SD-PA, HD-PA, or TA with low-molecular-weight or unfractionated heparin for 14 days. MAIN OUTCOMES AND MEASURES A hierarchical criterion of all-cause mortality followed by time to clinical improvement at day 28. Main secondary outcome was net clinical outcome at day 28 (composite of thrombosis, major bleeding, and all-cause death). RESULTS Among the study population of 334 individuals (mean [SD] age, 58.3 [13.0] years; 226 [67.7%] men and 108 [32.3%] women), use of HD-PA and SD-PA had similar probabilities of favorable outcome (47.3% [95%CI, 39.9% to 54.8%] vs 52.7%[95%CI, 45.2%to 60.1%]; P = .48), as did TA compared with SD-PA (50.9% [95%CI, 43.4%to 58.3%] vs 49.1% [95%CI, 41.7%to 56.6%]; P = .82) and TA compared with HD-PA (53.5%[95%CI 45.8% to 60.9%] vs 46.5% [95%CI, 39.1% to 54.2%]; P = .37). Net clinical outcome was met in 29.8% of patients receiving SD-PA (20.2%thrombosis, 2.6%bleeding, 14.0% death), 16.4% receiving HD-PA (5.5%thrombosis, 3.6%bleeding, 11.8%death), and 20.0% receiving TA (5.5% thrombosis, 3.6% bleeding, 12.7%death). Moreover, HD-PA and TA use significantly reduced thrombosis compared with SD-PA (absolute difference, -14.7 [95%CI -6.2 to -23.2] and -14.7 [95%CI -6.2 to -23.2], respectively). Use of HD-PA significantly reduced net clinical outcome compared with SD-PA (absolute difference, -13.5; 95%CI -2.6 to -24.3). CONCLUSIONS AND RELEVANCE This randomized clinical trial found that compared with SD-PA, neither HD-PAnor TAuse improved the primary hierarchical outcome of all-cause mortality or time to clinical improvement in patients with hypoxemicCOVID-19 pneumonia; however, HD-PA resulted in significantly better net clinical outcome by decreasing the risk of de novo thrombosis