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Background: Extended thromboprophylaxis has not been widely implemented in acutely ill medical patients because of bleeding concerns. The MAGELLAN (Multicenter, Randomized, Parallel Group Efficacy and Safety Study for the Prevention of Venous Thromboembolism in Hospitalized Medically Ill Patients Comparing Rivaroxaban With Enoxaparin) and MARINER (Medically Ill Patient Assessment of Rivaroxaban Versus Placebo in Reducing Post-Discharge Venous Thrombo-Embolism Risk) trials evaluated whether rivaroxaban compared with enoxaparin or placebo could prevent venous thromboembolism without increased bleeding. We hypothesized that patients with major bleeding but not those with nonmajor clinically relevant bleeding would be at an increased risk of all-cause mortality (ACM). Methods: We evaluated all bleeding events in patients taking at least 1 dose of study drug and their association with ACM in 4 mutually exclusive groups: (1) no bleeding, or first event was (2) nonmajor clinically relevant bleeding, (3) major bleeding, or (4) trivial bleeding. Using a Cox proportional hazards model adjusted for differences in baseline characteristics associated with ACM, we assessed the risk of ACM after such events. Results: Compared with patients with no bleeding, the risk of ACM for patients with nonmajor clinically relevant bleeding was not increased in MARINER (hazard ratio, 0.43; P =0.235) but was increased in MAGELLAN (hazard ratio, 1.74; P =0.021). Major bleeding was associated with a higher incidence of ACM in both studies, whereas trivial bleeding was not associated with ACM in either study. Conclusions: Patients with major bleeding had an increased risk of ACM, whereas nonmajor clinically relevant bleeding was not consistently associated with an increased risk of death. These results inform the risk-benefit calculus of extended thromboprophylaxis in medically ill patients. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: MAGELLAN, NCT00571649. URL: https://www.clinicaltrials.gov ; Unique identifier: MARINER, NCT02111564.

Background Antithrombotic therapies are associated with an increased bleeding risk. Abnormal uterine bleeding data have been reported in clinical trials of patients with venous thromboembolism (VTE), but data are limited for patients with atrial fibrillation (AF). Objective Using real-world data from four US healthcare databases (October 2010 to December 2018), we compared the occurrence of severe uterine bleeding among women newly exposed to rivaroxaban, apixaban, dabigatran, and warfarin stratified by indication. Methods To reduce potential confounding, patients in comparative cohorts were matched on propensity scores. Treatment effect estimates were generated using Cox proportional hazard models for each indication, in each database, and only for pairwise comparisons that met a priori study diagnostics. If estimates were homogeneous (I2 < 40%), a meta-analysis across databases was performed and pooled hazard ratios reported. Results Data from 363,919 women newly exposed to a direct oral anticoagulant or warfarin with a prior diagnosis of AF (60.8%) or VTE (39.2%) were analyzed. Overall incidence of severe uterine bleeding was low in the populations exposed to direct oral anticoagulants, although relatively higher in the younger VTE population vs the AF population (unadjusted incidence rates: 2.8–33.7 vs 1.9–10.0 events/1000 person-years). In the propensity score-matched AF population, a suggestive, moderately increased risk of severe uterine bleeding was observed for rivaroxaban relative to warfarin [hazard ratios and 95% confidence intervals from 0.83 (0.27–2.48) to 2.84 (1.32–6.23) across databases with significant heterogeneity], apixaban [pooled hazard ratio 1.45 (0.91–2.28)], and dabigatran [2.12 (1.01–4.43)], which were sensitive to the time-at-risk period. In the propensity score-matched VTE population, a consistent increased risk of severe uterine bleeding was observed for rivaroxaban relative to warfarin [2.03 (1.19–3.27)] and apixaban [2.25 (1.45–3.41)], which were insensitive to the time-at-risk period. Conclusions For women who need antithrombotic therapy, personalized management strategies with careful evaluation of benefits and risks are required. ClinicalTrials.gov Registration NCT04394234; registered in May 2020. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-021-01060-4.

The Saint George’s Respiratory Questionnaire (SGRQ) is a frequently used tool to assess health status in pulmonary disease patients. However, its performance characteristics in sarcoidosis patients are not well characterized. Data from a clinical trial of 138 symptomatic adults with sarcoidosis were used to examine the performance characteristics of SGRQ. Data were available at both baseline and week 24. Other assessments included FVC, FEV1, ATS dyspnea score, Borg’s CR 10 dyspnea score, 6-min walk distance (6MWD), and Short Form-36 Physical Component Summary (SF-36 PCS) score. Baseline SGRQ was 46.8, indicating impaired health status. At baseline, SGRQ total score correlated significantly with % predicted FVC, FEV1, ATS dyspnea score, Borg’s CR 10 dyspnea score, 6MWD, and SF-36 PCS (r = − 0.37, − 0.32, 0.57, 0.40, − 0.55, and − 0.80, respectively, p

Background Hospitalized acutely ill medical patients are at risk for fatal and major thromboembolic events. Whether use of extended-duration primary thromboprophylaxis can prevent such events is unknown. Objectives The purpose of this study was to evaluate whether extended-duration rivaroxaban reduces the risk of venous and arterial fatal and major thromboembolic events without significantly increasing major bleeding in acutely ill medical patients after discharge. Methods MARINER (A Study of Rivaroxaban [JNJ-39039039] on the Venous Thromboembolic Risk in Post-Hospital Discharge Patients) studied acutely ill medical patients with additional risk factors for venous thromboembolism (VTE). Medically ill patients with a baseline creatinine clearance ≥50 ml/min were randomized in a double-blind fashion to rivaroxaban 10 mg or placebo daily at hospital discharge for 45 days. Exploratory efficacy analyses were performed with the intent-to-treat population including all data through day 45. Time-to-event curves were calculated using the Kaplan-Meier method. A blinded independent committee adjudicated all clinical events. Results In total, 4,909 patients were assigned to rivaroxaban and 4,913 patients to placebo. The mean age was 67.8 years, 55.5% were men, mean baseline creatinine clearance was 87.8 ml/min, and mean duration of hospitalization was 6.7 days. The pre-specified composite efficacy endpoint (symptomatic VTE, myocardial infarction, nonhemorrhagic stroke, and cardiovascular death) occurred in 1.28% and 1.77% of patients in the rivaroxaban and placebo groups, respectively (hazard ratio: 0.72; 95% confidence interval: 0.52 to 1.00; p = 0.049), whereas major bleeding occurred in 0.27% and 0.18% of patients in the rivaroxaban and placebo groups, respectively (hazard ratio: 1.44; 95% confidence interval: 0.62 to 3.37; p = 0.398). Conclusions Extended-duration rivaroxaban in hospitalized medically ill patients resulted in a 28% reduction in fatal and major thromboembolic events without a significant increase in major bleeding. (A Study of Rivaroxaban [JNJ-39039039] on the Venous Thromboembolic Risk in Post-Hospital Discharge Patients [MARINER]; NCT02111564)

An individualized approach to identify acutely ill medical patients at increased risk of venous thromboembolism (VTE) and a low risk of bleeding to optimize the benefit and risk of extended thromboprophylaxis (ET) is needed. The International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) VTE risk score has undergone extensive external validation in medically ill patients for in-hospital use and a modified model was used in the MARINER trial of ET also incorporating an elevated D-dimer. The MAGELLAN study demonstrated efficacy with rivaroxaban but had excess bleeding. This retrospective analysis investigated whether the modified IMPROVE VTE model with an elevated D-dimer could identify a high VTE risk subgroup of patients for ET from a subpopulation of the MAGELLAN study, which was previously identified as having a lower risk of bleeding. We incorporated the modified IMPROVE VTE score using a cutoff score of 4 or more or 2 and 3 with an elevated D-dimer (>2 times the upper limit of normal) to the MAGELLAN subpopulation. In total, 56% of the patients met the high-risk criteria. In the placebo group, the total VTE event rate at Day 35 was 7.94% in the high-risk group and 2.83% for patients in the lower-risk group. A reduction in VTE was observed with rivaroxaban in the high-risk group (relative risk [RR]: 0.68, 95% confidence interval [CI]: 0.51–0.91, p = 0.008) and in the lower-risk group (RR: 0.69, 95% CI: 0.40 -1.20, p = 0.187). The modified IMPROVE VTE score with an elevated D-dimer identified a nearly threefold higher VTE risk subpopulation of patients where a significant benefit exists for ET using rivaroxaban.

Background Thromboprophylaxis extended after hospital discharge in medically ill patients currently is not recommended by practice guidelines because of uncertainty about the benefit for preventing major or fatal thromboembolic events, and the risk of bleeding. Methods and Results We assessed the benefit and risk of thromboprophylaxis with rivaroxaban 10 mg once daily extended for 25 to 45 days after hospitalization for preventing major thromboembolism in medically ill patients using the pooled data in 16 496 patients from 2 randomized trials, MARINER (Medically Ill Patient Assessment of Rivaroxaban Versus Placebo in Reducing Post‐Discharge Venous Thrombo‐Embolism Risk) and MAGELLAN (Multicenter, randomized, parallel‐group efficacy and safety study for the prevention of venous thromboembolism in hospitalized medically ill patients comparing rivaroxaban with enoxaparin). The data from the MARINER trial were pooled with the data from the MAGELLAN trial in patients who were free of thrombotic or bleeding events up to the last dose of enoxaparin/placebo and who continued in the outpatient phase of thromboprophylaxis. The composite outcome of major thromboembolic events (symptomatic deep vein thrombosis, nonfatal pulmonary embolism, myocardial infarction, and nonhemorrhagic stroke) and all‐cause mortality was used to assess benefit and was compared with the risk of the composite of fatal and critical site bleeding. The incidence of the composite efficacy outcome was 1.80% (148 of 8222 patients) in the rivaroxaban group, compared with 2.31% (191 of 8274 patients in the placebo group) (HR, 0.78 [95% CI, 0.63–0.97], P =0.024). Fatal or critical site bleeding events were infrequent and occurred in P =0.214). Conclusions The results suggest a benefit for reducing major thromboembolic outcomes (number needed to treat: 197), with a favorable trade‐off to fatal or critical site bleeding (number needed to harm: 2045). Registration URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT00571649 and NCT02111564.

Background: Bronchiectasis is a chronic inflammation of the bronchi with recurrent infections and hemoptysis. The MAGELLAN study compared oral rivaroxaban, 10 mg once daily (QD), for 35 ± 4 days with subcutaneous enoxaparin 40 mg QD for 10 ± 4 days followed by placebo for 25 ± 4 days to prevent venous thromboembolism in patients hospitalized with an acute medical illness. MAGELLAN included a subset of patients with bronchiectasis. In a post hoc analysis, we evaluated the incidence and severity of pulmonary bleeding in patients with bronchiectasis who were hospitalized for an acute medical illness. This analysis included MAGELLAN patients diagnosed with bronchiectasis at baseline. Patients were evaluated by treatment group for International Society on Thrombosis and Haemostasis major bleeding, non-major clinically relevant (NMCR) bleeding, and the composite of the 2 (ie, clinically relevant bleeding). Results: Medically ill patients with bronchiectasis were randomized to rivaroxaban (n = 60) or enoxaparin/placebo (n = 61). There were 2 fatal pulmonary bleeds and 1 fatal gastrointestinal bleed in the rivaroxaban arm and no fatal or major bleeding in the enoxaparin/placebo arm. The incidence of major bleeding was 5% in the rivaroxaban arm. One NMCR bleed occurred in the rivaroxaban arm and 2 NMCR bleeds occurred in the enoxaparin/placebo arm. The incidence of clinically relevant bleeding was 6.7% versus 3.3% in the rivaroxaban and enoxaparin/placebo groups, respectively (relative risk = 2.06 [95% confidence interval: 0.351-12.046]). Conclusion: In-patients hospitalized with bronchiectasis and an acute medical illness, clinically relevant bleeding, including fatal pulmonary hemorrhage, occurs more frequently with extended rivaroxaban thromboprophylaxis than with enoxaparin followed by placebo.

Background COVID-19 is associated with both venous and arterial thrombotic complications. While prophylactic anticoagulation is now widely recommended for hospitalized patients with COVID-19, the effectiveness and safety of thromboprophylaxis in outpatients with COVID-19 has not been established. Study Design PREVENT-HD is a double-blind, placebo-controlled, pragmatic, event-driven phase 3 trial to evaluate the efficacy and safety of rivaroxaban in symptomatic outpatients with laboratory-confirmed COVID-19 at risk for thrombotic events, hospitalization, and death. Several challenges posed by the pandemic have necessitated innovative approaches to clinical trial design, start-up, and conduct. Participants are randomized in a 1:1 ratio, stratified by time from COVID-19 confirmation, to either rivaroxaban 10 mg once daily or placebo for 35 days. The primary efficacy end point is a composite of symptomatic venous thromboembolism, myocardial infarction, ischemic stroke, acute limb ischemia, non-central nervous system systemic embolization, all-cause hospitalization, and all-cause mortality. The primary safety end point is fatal and critical site bleeding according to the International Society on Thrombosis and Haemostasis definition. Enrollment began in August 2020 and is expected to enroll approximately 4,000 participants to yield the required number of end point events. Conclusions PREVENT-HD is a pragmatic trial evaluating the efficacy and safety of the direct oral anticoagulant rivaroxaban in the outpatient setting to reduce major venous and arterial thrombotic events, hospitalization, and mortality associated with COVID-19.

Background Asymptomatic proximal deep vein thrombosis (DVT) is an end point frequently used to evaluate the efficacy of anticoagulant thromboprophylaxis in medical patients. Recently, the clinical relevance of asymptomatic DVT has been challenged. Methods and Results The objective of this study was to evaluate the relationship between asymptomatic proximal DVT and all‐cause mortality (ACM) using a cohort analysis of a randomized trial for the prevention of venous thromboembolism (VTE) in acutely ill medical patients. Patients who received at least 1 dose of study drug and had an adequate compression ultrasound examination of the legs on either day 10 or day 35 were categorized into 1 of 3 cohorts: no VTE, asymptomatic proximal DVT, or symptomatic DVT. Cox proportional hazards model, with adjustment for significant independent predictors of mortality, were used to compare the incidences of ACM. Of the 7036 patients, 6776 had no VTE, 236 had asymptomatic DVT, and 24 had symptomatic VTE. The incidence of ACM was 4.8% in patients without VTE. Both asymptomatic proximal DVT (mortality, 11.4%; hazard ratio [HR], 2.31; 95% CI, 1.52–3.51; P P Conclusions Asymptomatic proximal DVT is associated with higher ACM than no VTE and remains a relevant end point to evaluate the efficacy of anticoagulant thromboprophylaxis in medical patients. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00571649.

Temporal inference from laboratory testing results and triangulation with clinical outcomes extracted from unstructured electronic health record (EHR) provider notes is integral to advancing precision medicine. Here, we studied 246 SARS-CoV-2 PCR-positive (COVIDpos) patients and propensity-matched 2460 SARS-CoV-2 PCR-negative (COVIDneg) patients subjected to around 700,000 lab tests cumulatively across 194 assays. Compared to COVIDneg patients at the time of diagnostic testing, COVIDpos patients tended to have higher plasma fibrinogen levels and lower platelet counts. However, as the infection evolves, COVIDpos patients distinctively show declining fibrinogen, increasing platelet counts, and lower white blood cell counts. Augmented curation of EHRs suggests that only a minority of COVIDpos patients develop thromboembolism, and rarely, disseminated intravascular coagulopathy (DIC), with patients generally not displaying platelet reductions typical of consumptive coagulopathies. These temporal trends provide fine-grained resolution into COVID-19 associated coagulopathy (CAC) and set the stage for personalizing thromboprophylaxis.

Patients with renal impairment are at higher risk of thrombosis and bleeding than those with normal renal function. The optimal rivaroxaban dose for thromboprophylaxis in acutely ill medical patients with renal impairment is unknown. MARINER and MAGELLAN were multicenter, randomized clinical trials of rivaroxaban in acutely ill medical patients. Efficacy and safety outcomes in patients with renal impairment in MARINER (7.5 mg once daily) were compared with those in patients with normal renal function in MARINER (10 mg once daily) and in a subpopulation of MAGELLAN that excluded patients at high risk for bleeding at baseline (10 mg once daily). Compared with enoxaparin/placebo in the MAGELLAN subpopulation, the relative risk (RR) of symptomatic venous thromboembolism (VTE) and VTE-related death with rivaroxaban 10 mg in patients with renal impairment (RR = 0.62; 95% confidence interval [CI] 0.27–1.44) was similar to that in those with normal renal function (RR = 0.78; 95% CI 0.44–1.40), while in MARINER, the 7.5 mg dose did not reduce the risk in patients with renal impairment (hazard ratio = 1.00; 95% CI 0.52–1.92). Major bleeding with rivaroxaban 10 mg once daily was higher in patients with renal impairment than in those with normal renal function in MAGELLAN (1.54% vs. 0.98%) and in the MAGELLAN subpopulation (0.94% vs. 0.61%). At a dose of 10 mg once daily, rivaroxaban is effective for thromboprophylaxis in acutely ill medical patients with impaired or normal renal function. The safety of this regimen is enhanced without loss of efficacy by excluding patients at high risk for bleeding, but not by using a reduced-dose strategy. Trial Registration ClinicalTrials.gov identifiers: NCT00571649 for the MAGELLAN trial, NCT02111564 for the MARINER trial.

Temporal inference from laboratory testing results and their triangulation with clinical outcomes as described in the associated unstructured text from the provider notes in the Electronic Health Record (EHR) is integral to advancing precision medicine. Here, we studied 181 COVIDpos and 7,775 COVIDneg patients subjected to 1.3 million laboratory tests across 194 assays during a two-month observation period centered around their SARS-CoV-2 PCR testing dates. We found that compared to COVIDneg at the time of clinical presentation and diagnostic testing, COVIDpos patients tended to have higher plasma fibrinogen levels and similarly low platelet counts, with approximately 25% of patients in both cohorts showing outright thrombocytopenia. However, these measures show opposite longitudinal trends as the infection evolves, with declining fibrinogen and increasing platelet counts to levels that are lower and higher compared to the COVIDneg cohort, respectively. Our EHR augmented curation efforts suggest a minority of patients develop thromboembolic events after the PCR testing date, including rare cases with disseminated intravascular coagulopathy (DIC), with most patients lacking the platelet reductions typically observed in consumptive coagulopathies. These temporal trends present, for the first time, fine-grained resolution of COVID-19 associated coagulopathy (CAC), via a digital framework that synthesizes longitudinal lab measurements with structured medication data and neural network-powered extraction of outcomes from the unstructured EHR. This study demonstrates how a precision medicine platform can help contextualize each patients specific coagulation profile over time, towards the goal of informing better personalization of thromboprophylaxis regimen.

Background Data from preclinical and clinical studies support the evaluation of histamine 4 receptor antagonists in the treatment of asthma. Toreforant is a selective histamine 4 receptor antagonist that could be effective in patients with eosinophilic asthma. Objective To evaluate the efficacy and safety of toreforant in patients with eosinophilic, persistent asthma that was inadequately controlled despite current treatment. Methods In this phase 2a, multicenter, randomized, double-blinded, parallel-group, placebo-controlled, proof-of-concept study, 162 eligible patients were randomized (1:1) to placebo or 30 mg of toreforant once daily through week 24 and followed for 4 weeks. The primary end point was change from baseline in pre-bronchodilator percent-predicted forced expiratory volume in 1 second at week 16. Secondary end points included change from baseline at week 16 in postbronchodilator percent-predicted forced expiratory volume in 1 second, Asthma Control Questionnaire scores, weekly averages of Daytime and Nighttime Asthma Diary Symptom Scores, and weekly average of number of puffs in a day that rescue medication was used. Results There was no significant difference between groups in pre-bronchodilator percent-predicted forced expiratory volume in 1 second at week 16 (difference in least-square means −0.19%; 95% confidence interval −3.01 to 2.64; P = .90). Similarly, there were no significant differences between groups at week 16 in changes from baseline in the secondary end points (P ≥ .30). Toreforant was generally well tolerated. No deaths or serious adverse events were reported at any time point. Conclusion Toreforant, at the dose tested, failed to provide therapeutic benefit in this population of patients with uncontrolled, eosinophilic, persistent asthma. Trial Registration ClinicalTrials.gov, NCT01823016

Background The effects of H4 R antagonists in preclinical asthma models support the study of antagonists of the H4 R in the treatment of asthma in humans. JNJ-39758979 is a potent and highly selective oral H4 R antagonist. Objective We sought to evaluate the safety and efficacy of the H4 R-antagonist JNJ-39758979 in adult patients with uncontrolled asthma. Methods One hundred and fifteen eligible patients were randomly assigned to JNJ-39758979 300 mg or placebo once daily for 12 weeks in this phase 2a, double-blind, multicenter, placebo-controlled study. Primary efficacy was assessed via week-12 change from baseline in pre-bronchodilator forced expiratory volume in 1 second (FEV1 ). Secondary efficacy assessments included patient-reported outcome (PRO) asthma assessments (Asthma Daily Diary data [AM and PM peak expiratory flow rate, number of puffs of albuterol/salbutamol, the presence of nocturnal awakenings and asthma symptom score]). Results The study did not meet the primary end-point. However, nominally significant improvements in pre-bronchodilator FEV1 were observed with JNJ-39758979 versus placebo at week 12 in pre-specified subgroups with elevated exhaled nitric oxide, sputum eosinophils or blood eosinophils at baseline. Nominally significant improvements across PRO assessments were consistently observed in the overall population, as well as in eosinophilic subgroups. Safety, such as adverse event rates, was comparable between JNJ-39758979 and placebo. No serious adverse events were reported. No clinically relevant changes in laboratory values were observed. Conclusions and clinical relevance The findings suggest potential benefit of H4 R antagonists on lung function and asthma control in eosinophilic asthma patients and warrant further evaluation of this mechanism in asthma with eosinophilic inflammation. NCT00946569.

Background The Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study profiled patients with mild, moderate, and severe asthma and nonatopic healthy control subjects. Objective We explored this data set to define type 2 inflammation based on airway mucosal IL-13–driven gene expression and how this related to clinically accessible biomarkers. Methods IL-13–driven gene expression was evaluated in several human cell lines. We then defined type 2 status in 25 healthy subjects, 28 patients with mild asthma, 29 patients with moderate asthma, and 26 patients with severe asthma based on airway mucosal expression of (1) CCL26 (the most differentially expressed gene), (2) periostin, or (3) a multigene IL-13 in vitro signature (IVS). Clinically accessible biomarkers included fraction of exhaled nitric oxide (Feno) values, blood eosinophil (bEOS) counts, serum CCL26 expression, and serum CCL17 expression. Results Expression of airway mucosal CCL26, periostin, and IL-13–IVS all facilitated segregation of subjects into type 2–high and type 2–low asthmatic groups, but in the ADEPT study population CCL26 expression was optimal. All subjects with high airway mucosal CCL26 expression and moderate-to-severe asthma had Feno values (≥35 ppb) and/or high bEOS counts (≥300 cells/mm 3 ) compared with a minority (36%) of subjects with low airway mucosal CCL26 expression. A combination of Feno values, bEOS counts, and serum CCL17 and CCL26 expression had 100% positive predictive value and 87% negative predictive value for airway mucosal CCL26–high status. Clinical variables did not differ between subjects with type 2–high and type 2–low status. Eosinophilic inflammation was associated with but not limited to airway mucosal type 2 gene expression. Conclusion A panel of clinical biomarkers accurately classified type 2 status based on airway mucosal CCL26, periostin, or IL-13–IVS gene expression. Use of Feno values, bEOS counts, and serum marker levels (eg, CCL26 and CCL17) in combination might allow patient selection for novel type 2 therapeutics.

Acutely ill medical patients are at risk of venous thromboembolism (VTE) and VTE-related mortality during hospitalization and posthospital discharge, but widespread adoption of extended thromboprophylaxis has not occurred. We analyzed a subpopulation within the MAGELLAN study of extended thromboprophylaxis with rivaroxaban to reevaluate the benefit risk profile. We identified 5 risk factors for major and fatal bleeding after a clinical analysis of the MAGELLAN study and analyzed efficacy and safety with these patients excluded (n = 1551). Risk factors included: active cancer, dual antiplatelet therapy at baseline, bronchiectasis/pulmonary cavitation, gastroduodenal ulcer, or bleeding within 3 months before randomization. We evaluated efficacy, safety, and benefit risk using clinically comparable endpoints in the subpopulation. At day 10, rivaroxaban was noninferior to enoxaparin (relative risk [RR] = 0.82, 95% confidence interval [CI] = 0.58-1.15) and at day 35 rivaroxaban was significantly better than enoxaparin/placebo (RR = 0.68, 95% CI = 0.53-0.88) in reducing VTE and VTE-related death. Major bleeding was reduced at day 10 (RR = 2.18, 95% CI = 1.07-4.44 vs 1.19, 95% CI = 0.54-2.65) and at day 35 (2.87, 95% CI = 1.60-5.15 vs 1.48, 95% CI = 0.77-2.84) for MAGELLAN versus this subpopulation, respectively. The benefit risk profile was favorable in this subpopulation treated for 35 days, with the number needed to treat ranging from 55 to 481 and number needed to harm from 455 to 1067 for all pairwise evaluations. Five exclusionary criteria defined a subpopulation of acutely ill medical patients with a positive benefit risk profile for in-hospital and extended thromboprophylaxis with rivaroxaban.

Background The innate immune system senses viral infection through pattern recognition receptors (PRRs), leading to type I interferon production. The role of type I interferon and PPRs in rhinovirus-induced asthma exacerbations in vivo are uncertain. Objectives We sought to compare bronchial mucosal type I interferon and PRR expression at baseline and after rhinovirus infection in atopic asthmatic patients and control subjects. Methods Immunohistochemistry was used to detect expression of IFN-α, IFN-β, and the PRRs: Toll-like receptor 3, melanoma differentiation–associated gene 5, and retinoic acid–inducible protein I in bronchial biopsy specimens from 10 atopic asthmatic patients and 15 nonasthmatic nonatopic control subjects at baseline and on day 4 and 6 weeks after rhinovirus infection. Results We observed IFN-α/β deficiency in the bronchial epithelium at 3 time points in asthmatic patients in vivo. Lower epithelial IFN-α/β expression was related to greater viral load, worse airway symptoms, airway hyperresponsiveness, and reductions in lung function during rhinovirus infection. We found lower frequencies of bronchial subepithelial monocytes/macrophages expressing IFN-α/β in asthmatic patients during infection. Interferon deficiency at baseline was not accompanied by deficient PRR expression in asthmatic patients. Both epithelial and subepithelial PRR expression were induced during rhinovirus infection. Rhinovirus infection–increased numbers of subepithelial interferon/PRR-expressing inflammatory cells were related to greater viral load, airway hyperresponsiveness, and reductions in lung function. Conclusions Bronchial epithelial IFN-α/β expression and numbers of subepithelial IFN-α/β–expressing monocytes/macrophages during infection were both deficient in asthmatic patients. Lower epithelial IFN-α/β expression was associated with adverse clinical outcomes after rhinovirus infection in vivo. Increases in numbers of subepithelial cells expressing interferon/PRRs during infection were also related to greater viral load/illness severity.

Data from preclinical and clinical studies support the evaluation of histamine 4 receptor antagonists in the treatment of asthma. Toreforant is a selective histamine 4 receptor antagonist that could be effective in patients with eosinophilic asthma.To evaluate the efficacy and safety of toreforant in patients with eosinophilic, persistent asthma that was inadequately controlled despite current treatment.In this phase 2a, multicenter, randomized, double-blinded, parallel-group, placebo-controlled, proof-of-concept study, 162 eligible patients were randomized (1:1) to placebo or 30 mg of toreforant once daily through week 24 and followed for 4 weeks. The primary end point was change from baseline in pre-bronchodilator percent-predicted forced expiratory volume in 1 second at week 16. Secondary end points included change from baseline at week 16 in postbronchodilator percent-predicted forced expiratory volume in 1 second, Asthma Control Questionnaire scores, weekly averages of Daytime and Nighttime Asthma Diary Symptom Scores, and weekly average of number of puffs in a day that rescue medication was used.There was no significant difference between groups in pre-bronchodilator percent-predicted forced expiratory volume in 1 second at week 16 (difference in least-square means -0.19%; 95% confidence interval -3.01 to 2.64; P = .90). Similarly, there were no significant differences between groups at week 16 in changes from baseline in the secondary end points (P ≥ .30). Toreforant was generally well tolerated. No deaths or serious adverse events were reported at any time point.Toreforant, at the dose tested, failed to provide therapeutic benefit in this population of patients with uncontrolled, eosinophilic, persistent asthma.ClinicalTrials.gov, NCT01823016.

There is an association with acute viral infection of the respiratory tract and exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Although these exacerbations are associated with several types of viruses, human rhinoviruses (HRVs) are associated with the vast majority of disease exacerbations. Due to the lack of an animal species that is naturally permissive for HRVs to use as a facile model system, and the limitations associated with animal models of asthma and COPD, studies of controlled experimental infection of humans with HRVs have been used and conducted safely for decades. This review discusses how these experimental infection studies with HRVs have provided a means of understanding the pathophysiology underlying virus-induced exacerbations of asthma and COPD with the goal of developing agents for their prevention and treatment.

Background Human rhinoviruses (HRVs) commonly precipitate asthma exacerbations. Toll-like receptor 3, an innate pattern recognition receptor, is triggered by HRV, driving inflammation that can worsen asthma. Objective We sought to evaluate an inhibitory mAb to Toll-like receptor 3, CNTO3157, on experimental HRV-16 inoculation in healthy subjects and asthmatic patients. Methods In this double-blind, multicenter, randomized, parallel-group study in North America and Europe, healthy subjects and patients with mild-to-moderate stable asthma received single or multiple doses of CNTO3157 or placebo, respectively, and were then inoculated with HRV-16 within 72 hours. All subjects were monitored for respiratory symptoms, lung function, and nasal viral load. The primary end point was maximal decrease in FEV 1 during 10 days after inoculation. Results In asthmatic patients (n = 63) CNTO3157 provided no protection against FEV 1 decrease (least squares mean: CNTO3157 [n = 30] = −7.08% [SE, 8.15%]; placebo [n = 25] = −5.98% [SE, 8.56%]) or symptoms after inoculation. In healthy subjects (n = 12) CNTO3157 versus placebo significantly attenuated upper ( P = .03) and lower ( P = .02) airway symptom scores, with area-under-the-curve increases of 9.1 (15.1) versus 34.9 (17.6) and 13.0 (18.4) versus 50.4 (25.9) for the CNTO3157 (n = 8) and placebo (n = 4) groups, respectively, after inoculation. All of the severe and 4 of the nonserious asthma exacerbations occurred while receiving CNTO3157. Conclusion In summary, CNTO3157 was ineffective in attenuating the effect of HRV-16 challenge on lung function, asthma control, and symptoms in asthmatic patients but suppressed cold symptoms in healthy subjects. Other approaches, including blockade of multiple pathways or antiviral agents, need to be sought for this high unmet medical need.

Summary The molecular basis of sarcoidosis phenotype heterogeneity and its relationship to effective treatment of sarcoidosis have not been elucidated. Peripheral samples from sarcoidosis subjects who participated in a Phase II study of golimumab [anti-tumour necrosis factor (TNF)-α] and ustekinumab [anti-interleukin (IL)−12p40] were used to measure the whole blood transcriptome and levels of serum proteins. Differential gene and protein expression analyses were used to explore the molecular differences between sarcoidosis phenotypes as defined by extent of organ involvement. The same data were also used in conjunction with an enrichment algorithm to identify gene expression changes associated with treatment with study drugs compared to placebo. Our analyses revealed marked heterogeneity among the three sarcoidosis phenotypes included in the study cohort, including striking differences in enrichment of the interferon pathway. Conversely, enrichments of multiple pathways, including T cell receptor signalling, were similar among phenotypes. We also identify differences between treatment with golimumab and ustekinumab that may explain the differences in trends for clinical efficacy observed in the trial. We find that molecular heterogeneity is associated with sarcoidosis in a manner that may be related to the extent of organ involvement. These findings may help to explain the difficulty in identifying clinically efficacious sarcoidosis treatments and suggest hypotheses for improved therapeutic strategies.

Background: Venous thromboembolism (VTE) is common after hospitalization in acutely ill medical patients, yet extended thromboprophylaxis has not been widely implemented due to concerns about bleeding. The MARINER study (NCT02111564) compared thromboprophylaxis with rivaroxaban (10mg daily or 7.5mg daily in subjects with creatinine clearance 30- Methods: We evaluated all bleeding events in subjects taking at least one dose of study drug from randomization until 2 days after the last dose (safety population) and their association with ACM through the Day 75 visit in 3 mutually exclusive groups: (1) subjects with no MB or NMCRB; (2) subjects whose first event was NMCRB; and (3) subjects whose first event was MB. Subjects only developing minimal or trivial bleeding were grouped with those who had no bleeding. Using a Cox proportional hazards model that included the bleeding group variable and baseline covariates that were significantly associated with ACM at p Results: The incidence of ACM among subjects who had a NMCRB was not increased over that in subjects without bleeding (2/136, 1.5% vs 218/11800, 1.8%, HR 0.41 95%CI 0.10, 1.67, p=0.213), while those experiencing MB had a higher incidence of death (4/26, 15.4% vs 218/11800, 1.8%, HR 3.43 95%CI 1.23, 9.54, p=0.018). Results of landmark analyses from the first bleeding event or end of treatment + 2 days to ACM for the three groups are displayed (Figure). Limitations: This analysis was post hoc and the MARINER trial excluded subjects at a high risk of bleeding. Conclusion: Although few subjects had MB events, those who did had an increased risk of ACM, while those who had NMCRB events did not. This suggests that the modest increase in NMCRB in trials of extended thromboprophylaxis may be an acceptable tradeoff to prevent VTE. Disclosures Spyropoulos: Janssen R&D, LLC: Consultancy; ATLAS (Colorado Prevention Center): Consultancy; Bayer Healthcare: Consultancy; Portola: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; Daiichi Sankyo: Consultancy. Ageno:Bayer: Membership on an entity's Board of Directors or advisory committees, Other: research support,travel support ; BMS Pfizer: Other: travel support; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Other: conference and travel support; Portola: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Aspen: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Other: travel support. Albers:Janssen R&D, LLC: Consultancy; Bayer Healthcare: Consultancy. Elliott:Bayer Healthcare: Consultancy; University of Cincinnati: Honoraria; Spectrum Health: Honoraria; Janssen R&D, LLC: Consultancy. Halperin:Ortho-McNeil-Janssen: Consultancy; Johnson & Johnson: Consultancy; ATLAS (Colorado Prevention Center): Consultancy; NIH: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Boehringer Ingelheim: Consultancy. Hiatt:Bayer Healthcare: Consultancy; NIH: Research Funding; Janssen R&D, LLD: Consultancy. Maynard:Janssen R&D, LLC: Consultancy. Steg:Novartis: Consultancy; Regeneron: Consultancy; Lilly: Consultancy; Pfizer: Consultancy; Boehringer Ingelheim: Consultancy; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Amarin: Consultancy; Servier: Consultancy, Research Funding; Merck: Research Funding, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Bayer Healthcare: Consultancy, Research Funding; Janssen R&D, LLC: Consultancy, Research Funding; AstraZeneca: Consultancy. Weitz:Novartis: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Daiichi-Sankyo: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Bayer Healthcare: Consultancy, Honoraria; Janssen R&D, LLC: Consultancy; Pfizer: Consultancy, Honoraria; Portola: Consultancy, Honoraria. Spiro:Bayer U.S. LLC: Employment, Equity Ownership. Lu:Janssen R&D, LLC: Employment, Equity Ownership. Sugarmann:Janssen Research and Development LLC: Employment, Equity Ownership. Lipardi:Janssen Research and Develompent: Employment, Equity Ownership. Raskob:Boehringer Ingelheim: Consultancy; Eli Lilly: Consultancy; Pfizer: Consultancy, Honoraria; Tetherex: Consultancy; Daiichi Sankyo: Consultancy, Honoraria; Anthos: Consultancy; BMS: Consultancy, Honoraria; Janssen R&D, LLC: Consultancy, Honoraria; Portola: Consultancy; Novartis: Consultancy; Bayer Healthcare: Consultancy, Honoraria. Barnathan:Janssen Research and Development LLC: Employment, Equity Ownership. OffLabel Disclosure: Rivaroxaban is a Factor Xa inhibitor. The study evaluated the efficacy and safety of rivaroxaban post-hospitalization in subjects with an acute medical illness as thromboprophylaxis for venous thromboembolism.

Background: Acutely ill medical patients with a history of cancer are at risk of venous thromboembolic events (VTE) in hospital and after discharge. Rivaroxaban was evaluated for VTE prevention in acutely ill medical patients in two randomized clinical trials of extended thromboprophylaxis with rivaroxaban. MAGELLAN (NCT00571649) included patients with active cancer undergoing treatment as well as those with only a history of cancer while the MARINER study (NCT02111564) only included patients with a history of cancer but not active cancer. In MAGELLAN treatment began in hospital (rivaroxaban 10mg QD for 35±4 days vs enoxaparin for 10±4 days followed by placebo), whereas in MARINER, treatment began at discharge (rivaroxaban 10mg QD or 7.5mg QD for those with baseline creatinine clearance 30- Methods: MAGELLAN and MARINER patients with a history of cancer or cancer in remission but without active cancer undergoing treatment were identified and compared to the subgroup of patients with no history of cancer. Relevant baseline demographics and cancer characteristics were summarized. The primary efficacy outcome was the composite of asymptomatic proximal deep vein thrombosis (DVT), symptomatic VTE and VTE-related death at Day 35 in the modified intention to treat population in MAGELLAN and the composite of symptomatic VTE and VTE-related death up to Day 45 in the intention to treat population in MARINER. The key safety outcome analyzed for both studies was the incidence of clinically relevant bleeding (the composite of ISTH major or non-major clinically relevant bleeding) on treatment + 2 days in randomized subjects who took at least one dose of study drug. Results: In MAGELLAN in the subgroup with a history of cancer, the most frequent reason for hospitalization was an acute infectious disease (61%). In the history of cancer subgroup, the primary efficacy outcome occurred in 8/203 (3.9%) patients on rivaroxaban and in 16/192 (8.3%) patients on enoxaparin/placebo (RR=0.45; 95%CI 0.19, 1.03) whereas in the subgroup with no cancer, it occurred in 95/2467 (3.85%) in patients on rivaroxaban and in 133/2562 (5.19%) in those on enoxaparin/placebo (RR=0.74; 95%CI 0.57, 0.96). Clinically relevant bleeding was increased with rivaroxaban to a similar degree in both subgroups in MAGELLAN. There was no fatal bleeding in patients with history of cancer (Table). In MARINER in the subgroup with a history of cancer, the most frequent reason for hospitalization was heart failure (36%). In the history of cancer subgroup, the primary efficacy outcome occurred in 5/488 (1.02%) in patients in the rivaroxaban group and in 7/533 (1.31%) in patients in the placebo group (HR=0.76; 95%CI 0.24, 2.40) while in those without cancer, it occurred in 45/5519 (0.82%) patients in the rivaroxaban group and in 59/5479 (1.08%) in the placebo group (HR=0.76; 95%CI 0.51,1.11). Clinically relevant bleeding was increased with rivaroxaban to a similar degree in both subgroups in MARINER. There was no fatal bleeding in patients with history of cancer (Table). In both studies, major bleeding was similar in both treatment groups in the subgroup with a history of cancer. Conclusion: VTE was generally more frequent in patients with a history of cancer than those without it. In MAGELLAN, rivaroxaban appears more effective compared with enoxaparin/placebo in reducing the primary composite efficacy outcome in the subgroup with a history of cancer than those without cancer, whereas in MARINER, the reduction in symptomatic VTE and VTE-related death with rivaroxaban was similar in both subgroups. Although clinically relevant bleeding was increased in both studies, major bleeding was similar in those with a history of cancer in both studies and no fatal bleeding events were observed in the history of cancer subgroup in either study. Altogether, these data suggest a generally favorable benefit risk profile for extended thromboprophylaxis with rivaroxaban in acutely ill medical patients with a history of cancer. Disclosures Spyropoulos: Janssen R&D, LLC: Consultancy; ATLAS (Colorado Prevention Center): Consultancy; Bayer Healthcare: Consultancy; Portola: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; Daiichi Sankyo: Consultancy. Lipardi:Janssen Research and Develompent: Employment, Equity Ownership. Cohen:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ACI Clinical: Consultancy; Boehringer-Ingelheim: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CSL Behring: Consultancy; Takeda: Consultancy; GLG: Consultancy; Leo Pharma: Consultancy; Boston Scientific: Consultancy; TRN: Consultancy; UK Government Health Select Committee: Other: advised the UK Government Health Select Committee, the all-party working group on thrombosis, the Department of Health, and the NHS, on the prevention of VTE; Navigant: Consultancy; GlaxoSmithKline: Consultancy, Speakers Bureau; McKinsey: Consultancy; Medscape: Consultancy, Speakers Bureau; Temasek Capital: Consultancy; Lifeblood: Other: advisor to Lifeblood: the thrombosis charity and is the founder of the European educational charity the Coalition to Prevent Venous Thromboembolism; Guidepoint Global: Consultancy; ONO: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Aspen: Consultancy, Speakers Bureau. Vučković:Janssen Research & Development, LLC: Consultancy. Xu:Janssen R&D, LLC: Employment, Equity Ownership. Lu:Janssen R&D, LLC: Employment, Equity Ownership. Spiro:Bayer U.S. LLC: Employment, Equity Ownership. Barnathan:Janssen Research and Development LLC: Employment, Equity Ownership. Raskob:Tetherex: Consultancy; Portola: Consultancy; Bayer Healthcare: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy; Daiichi Sankyo: Consultancy, Honoraria; Anthos: Consultancy; Eli Lilly: Consultancy; Novartis: Consultancy; Janssen R&D, LLC: Consultancy, Honoraria; BMS: Consultancy, Honoraria. OffLabel Disclosure: Rivaroxaban is a Factor Xa inhibitor. It is currently under review by FDA for approval as thromboprophylaxis in acutely ill medical patients at risk for venous thromboembolism.

Background: Asymptomatic proximal deep-vein thrombosis (ASxDVT) is an efficacy endpoint that has been used for several decades in clinical trials evaluating thromboprophylaxis with anticoagulants. Previous studies have suggested the finding of ASxDVT on routine ultrasonography is associated with increased subsequent all-cause mortality (ACM). We evaluated the relationship between ASxDVT and subsequent ACM using the data from the MAGELLAN study (NCT00571649), a randomized clinical trial that evaluated rivaroxaban compared with enoxaparin followed by placebo for the prevention of venous thromboembolism (VTE) in acutely ill medical patients in which routine compression ultrasonography was performed at Day 10 and at Day 35. Patients were followed up through 90 days. Methods: A post hoc analysis was performed using patients who received at least one dose of study drug and had an adequate ultrasound result at Day 10 or Day 35 (modified intent-to-treat population, mITT). Patients were categorized into one of three mutually exclusive groups: (1) those without VTE; (2) those with symptomatic VTE (SxVTE); and (3) those with an ASxDVT. If patients had an ASxDVT followed by an SxVTE event, they were categorized into the ASxDVT group. Baseline covariates (age, sex, race, BMI, diabetes, creatinine clearance, heart failure, acute ischemic stroke, acute infectious disease, inflammatory disease, acute respiratory insufficiency, history of VTE, history of cancer, history of anemia and assigned treatment group) were tested for association with ACM (p Results: In total, 7036 patients were included in the combined mITT Day 10 /mITT Day 35 analysis set. Of these, 6776 (96.3%) were included in the no VTE group, 236 (3.3%) in the ASxDVT group and 24 (0.34%) in the SxVTE group. Compared with no VTE (incidence of ACM=4.8%), both ASxDVT (11.4%, HR 2.31, 95%CI 1.52-3.51, p Limitations: The analysis was post hoc and the groups were defined post-randomization. Adjustment was done for baseline variables that were significantly associated with ACM but may not fully compensate for potential post-randomization differences. Conclusion: These results suggest that the finding of an asymptomatic proximal DVT on routine compression ultrasonography is associated with a significantly higher ACM in acutely ill medical patients. A similar relationship was found for SxVTE and ACM, which supports the validity of ASxDVT as an indicator of clinically important disease and an appropriate endpoint for thromboprophylaxis trials in the medically ill. Disclosures Raskob: Janssen R&D, LLC: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy; Boehringer Ingelheim: Consultancy; Eli Lilly: Consultancy; Anthos: Consultancy; Tetherex: Consultancy; Portola: Consultancy; BMS: Consultancy, Honoraria; Bayer Healthcare: Consultancy, Honoraria. Spyropoulos:Daiichi Sankyo: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; Portola: Consultancy; Bayer Healthcare: Consultancy; ATLAS (Colorado Prevention Center): Consultancy; Janssen R&D, LLC: Consultancy. Cohen:Lifeblood: Other: advisor to Lifeblood: the thrombosis charity and is the founder of the European educational charity the Coalition to Prevent Venous Thromboembolism; AbbVie: Consultancy; Aspen: Consultancy, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy; Guidepoint Global: Consultancy; Boston Scientific: Consultancy; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ONO: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medscape: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boehringer-Ingelheim: Consultancy, Speakers Bureau; McKinsey: Consultancy; Johnson and Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Consultancy; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; GLG: Consultancy; Leo Pharma: Consultancy; Navigant: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Temasek Capital: Consultancy; TRN: Consultancy; UK Government Health Select Committee: Other: advised the UK Government Health Select Committee, the all-party working group on thrombosis, the Department of Health, and the NHS, on the prevention of VTE; ACI Clinical: Consultancy. Weitz:Novartis: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Daiichi-Sankyo: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Bayer Healthcare: Consultancy, Honoraria; Janssen R&D, LLC: Consultancy; Pfizer: Consultancy, Honoraria; Portola: Consultancy, Honoraria. Ageno:Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Aspen: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Other: conference and travel support; Portola: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: research support,travel support ; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Other: travel support; BMS Pfizer: Other: travel support. De Sanctis:Bayer US LLC: Employment, Equity Ownership. Lu:Janssen R&D, LLC: Employment, Equity Ownership. Xu:Janssen R&D, LLC: Employment, Equity Ownership. Albanese:Janssen Research and Development LLC: Employment, Equity Ownership. Sugarmann:Janssen Research and Development LLC: Employment, Equity Ownership. Lipardi:Janssen Research and Develompent: Employment, Equity Ownership. Spiro:Bayer U.S. LLC: Employment, Equity Ownership. Barnathan:Janssen Research and Development LLC: Employment, Equity Ownership. OffLabel Disclosure: Rivaroxaban is a factor Xa inhibitor and is currently under review by the FDA for thromboprophylaxis in patients with acute medical illness

Summary Rationale There was an increased number of malignancies in infliximab-treated (5.7%) over placebo-treated (1.3%) patients in a 44-week, phase 2 clinical study of 234 patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). Objectives To collect malignancy and mortality data from completed clinical studies of infliximab in COPD treatment. Methods The multicenter, observational Remicade Safety Under Long-Term Study in COPD (RESULTS COPD) collected malignancy and mortality data every six months for five years from patients who received ≥1 study-agent dose in a phase 2 study. Co-primary endpoints were the number of patients with malignancy and the number of deaths. Secondary endpoints included the number of patients with a malignancy according to malignancy type. Results There was a gap period between the end of the phase 2 study and the initiation of RESULTS COPD, during which six malignancies and 14 deaths were reported spontaneously for the 107 (45.7%) of 234 patients with long-term safety information. Twenty-eight patients (overall 12.0%; placebo 10.4%, infliximab 12.7%) reported malignancies, including 12 patients during RESULTS COPD. Twenty-six patients (overall 11.1%; placebo 9.1%, infliximab 12.1%) died, including nine during RESULTS COPD. Lung cancer was the most common malignancy type (placebo n = 2; infliximab n = 10). Conclusions The greater proportion of malignancies observed with infliximab versus placebo in a phase 2 study diminished over the long-term follow-up. Due to the observational nature, limited patient participation, potential reporting bias from the interim spontaneous reporting period, and unblinding of all patients, more definitive conclusions cannot be drawn. Trial Registration Number: NCT00056264.

BACKGROUND: Asthma is a biologically heterogeneous disease and development of novel therapeutics requires understanding of pathophysiologic phenotypes. There is uncertainty regarding the stability of clinical characteristics and biomarkers in asthma over time. This report presents the longitudinal stability over 12 months of clinical characteristics and clinically accessible biomarkers from ADEPT.METHODS: Mild, moderate, and severe asthma subjects were assessed at 5 visits over 12 months. Assessments included patient questionnaires, spirometry, bronchodilator reversibility, fractional exhaled nitric oxide (FENO), and biomarkers measured in induced sputum.RESULTS: Mild (n = 52), moderate (n = 55), and severe (n = 51) asthma cohorts were enrolled from North America and Western Europe. For all clinical characteristics and biomarkers, group mean data showed no significant change from visit to visit. However, individual data showed considerable variability. FEV1/FVC ratio showed excellent reproducibility while pre-bronchodilator FEV1 and FVC were only moderately reproducible. Of note bronchodilator FEV1 reversibility showed low reproducibility, with the nonreversible phenotype much more reproducible than the reversible phenotype. The 7-item asthma control questionnaire (ACQ7) demonstrated moderate reproducibility for the combined asthma cohorts, but the uncontrolled asthma phenotype (ACQ7 > 1.5) was inconstant in mild and moderate asthma but stable in severe asthma. FENO demonstrated good reproducibility, with the FENO-low phenotype (FENO CONCLUSIONS: The ADEPT cohort showed group stability, individual stability in some parameters e.g. low FEV1/FVC ratio, and low FENO, but marked individual variability in other clinical characteristics and biomarkers e.g. type-2 biomarkers over 12 months. This variability is possibly related to seasonal variations in climate and allergen exposure, medication changes and acute exacerbations. The implications for patient selection strategies based on clinical biomarkers may be considerable.

Background: Hospitalized medically ill patients are at risk for venous thromboembolism (VTE) for at least 45 days after discharge. This observation prompted the MAGELLAN and MARINER trials, which evaluated the efficacy and safety of rivaroxaban for extended thromboprophylaxis. In MAGELLAN, rivaroxaban (10 mg once daily) started in hospital and continued for 35 days was compared with a 10±4 day course of enoxaparin (40 mg once daily) followed by placebo. In MARINER, a 45-day course of rivaroxaban (10 mg once daily for those with creatinine clearance [CrCl] ≥50ml/min and 7.5 mg once daily for those with CrCl 30- Methods: We evaluated key efficacy and safety outcomes in patients with moderate renal insufficiency and those with normal renal function from days 1 to 35 in the MAGELLAN study and in a MARINER-like subpopulation of MAGELLAN using the criteria defined a priori for patient exclusion used in the MARINER study. These criteria were: 1) active gastroduodenal ulcer within 3 months of randomization or currently symptomatic, 2) any bleeding within 3 months prior to randomization or during index hospitalization prior to randomization, 3) active cancer at randomization, 4) medical history of severe bronchiectasis or pulmonary cavitation, or 5) dual antiplatelet therapy at baseline. These criteria excluded approximately 20% of subjects in MAGELLAN at high risk of bleeding. Results: The rates of VTE and VTE related death in both the rivaroxaban and enoxaparin/placebo groups were approximately twofold higher in subjects with renal impairment than in those with normal renal function, but the relative risk reduction with rivaroxaban treatment (10mg) compared with enoxaparin/placebo was similar in both renal function subgroups. Rates of major and clinically relevant bleeding in the rivaroxaban group were approximately 50% higher in patients with renal impairment compared with those with normal renal function. In the MARINER like subpopulation, the relative risk reductions for efficacy outcomes were maintained in both renal subgroups, whereas the increase in major bleeding with rivaroxaban was reduced by approximately 50%. Conclusions: Medically-ill patients with renal impairment given extended thromboprophylaxis are at increased risk for both VTE and major bleeding. Use of the MARINER criteria to exclude patients at increased risk of bleeding appears to reduce the major bleeding risk without compromising the efficacy of 10mg daily of rivaroxaban. Figure Figure. Disclosures Weitz: Novartis: Honoraria; Servier: Honoraria; Janssen: Honoraria; Ionis: Consultancy, Honoraria; Daiichi-Sankyo: Honoraria; Bristol-Myers Squibb: Honoraria; Boehringer Ingelheim: Honoraria, Research Funding; Bayer: Honoraria. Raskob:Janssen: Consultancy; Bayer: Consultancy; BMS: Consultancy; Daiichi Sankyo: Consultancy; Boehringer Ingelheim: Consultancy; Eli Lilly: Consultancy; Pfizer: Consultancy, Honoraria; Novartis: Consultancy. Spyropoulos:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Colorado Prevention Center - ATLAS: Consultancy; Portola: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cohen:Aspen: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Boehringer Ingelheim: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy, Speakers Bureau; GSK: Consultancy, Speakers Bureau; Janssen: Speakers Bureau; Medscape: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Portola: Consultancy, Speakers Bureau; AbbVie: Consultancy; ACI Clinical: Consultancy; Boston Scientific: Consultancy; CLS Behring: Consultancy; GLG: Consultancy; Guidepoint Global: Consultancy; Leo Pharma: Consultancy; McKinsey: Consultancy; Sanofi: Consultancy; Navigant: Consultancy; ONO: Consultancy; Takeda: Consultancy; Temasek Capital: Consultancy; TRN: Consultancy. Spiro:Bayer: Employment, Equity Ownership. De Sanctis:Bayer: Employment, Equity Ownership. Xu:Janssen Research and Development LLC: Employment, Equity Ownership. Suh:Janssen Research and Development LLC: Employment, Equity Ownership. Lu:Janssen Research and Development LLC: Employment. Lipardi:Janssen Research and Development LLC: Employment, Equity Ownership. Barnathan:Janssen Research and Development LLC: Employment, Equity Ownership.

Objectives The FINESSE-ANGIO (Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events–Angiographic) study evaluated acute treatment effects on infarct-related artery (IRA) patency and angiographic correlates of coronary microcirculatory function. Background The FINESSE trial evaluated the effects on clinical outcomes of primary percutaneous coronary intervention (PCI) facilitated with pre–catheterization laboratory administration of abciximab with half-dose reteplase (combination-facilitated group), abciximab alone (abciximab-facilitated group), or with abciximab administered immediately before the procedure (primary PCI). Methods The FINESSE-ANGIO substudy compared the effects of the 3 treatment strategies on patency (TIMI [Thrombolysis In Myocardial Infarction] flow grade 2/3) of the IRA at basal coronary angiography. The secondary efficacy end points were corrected TIMI frame count, percentage of patients achieving TIMI flow grade 3, and the percentage achieving myocardial blush grade 2/3 of the IRA at post-PCI angiography. All angiographies were evaluated at a central core laboratory. Results Of the 2,452 FINESSE patients, 637 were included in the FINESSE-ANGIO substudy. Patients in the combination-facilitated group exhibited significantly higher rates of baseline IRA patency compared with the abciximab-facilitated and the primary PCI groups (76.1% vs. 43.7% and 32.7%, respectively; p Conclusions Pre–catheterization laboratory administration of abciximab alone and especially in combination with half-dose reteplase resulted in higher rates of IRA patency at baseline coronary angiography compared with no pre-treatment. However, post-procedural angiographic and microcirculatory variables were unaffected by facilitation therapy.

Objectives The aim of this study was to assess the risk-benefit of enoxaparin (Sanofi-Aventis, Paris, France) in primary percutaneous coronary intervention (PCI). Background Randomized studies have demonstrated the superiority of enoxaparin over unfractionated heparin (UFH) in acute ST-segment elevation myocardial infarction (STEMI) treated with fibrinolytics. Methods In the FINESSE (Facilitated INtervention with Enhanced Reperfusion Speed to Stop Events) trial—a double-blind, placebo-controlled study—2,452 patients with STEMI were randomized to primary PCI or facilitated PCI with abciximab alone or with half-dose reteplase. In this prospective FINESSE substudy, centers pre-specified use of either enoxaparin (0.5 mg/kg intravenous [IV], 0.3 mg/kg subcutaneous [SC]) or UFH (40 U/kg IV, 3,000 U maximum) with PCI. A logistic-regression model and a propensity multivariate model, both adjusted for baseline variables, were used to evaluate primary safety and secondary efficacy end points for enoxaparin versus UFH. Results Enoxaparin was administered to 759 patients and UFH to 1,693 patients. Nonintracranial Thrombolysis In Myocardial Infarction (TIMI) major/minor bleeding was not significantly different, but lower nonintracranial TIMI major bleeding was found with enoxaparin (2.6% vs. UFH 4.4%, logistic-regression adjusted odds ratio [OR]: 0.55; 95% confidence interval [CI]: 0.31 to 0.99, p = 0.045), whereas intracranial hemorrhage was similar (0.27% vs. 0.24%, adjusted OR: 1.03; 95% CI: 0.11 to 9.68, p = 0.980). Lower death, myocardial infarction, urgent revascularization, or refractory ischemia through 30 days was also associated with enoxaparin (5.3%) versus UFH (8.0%, adjusted OR: 0.47, 95% CI: 0.31 to 0.72, p = 0.0005) as was all-cause mortality through 90 days (3.8% vs. 5.6%, respectively, adjusted OR: 0.59, 95% CI: 0.35 to 0.99, p = 0.046). End points evaluating the net clinical benefit also significantly favored enoxaparin over UFH. Conclusions Enoxaparin seems to be associated with a lower risk of cardiovascular outcomes compared with UFH in patients with STEMI undergoing primary PCI. Confirmation of these findings in a randomized study is warranted. (A Study of Abciximab and Reteplase When Administered Prior to Catheterization After a Myocardial Infarction [Finesse]; NCT00046228)

ObjectivesWe hypothesized that patients most likely to benefit would be those at high risk with a shorter duration of acute ischemia and who required transfer for percutaneous coronary intervention (PCI).BackgroundThe FINESSE (Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events) study failed to demonstrate an improvement in the 90-day composite clinical end point of early treatment with abciximab plus half-dose reteplase (combination-facilitated PCI) or abciximab alone.MethodsWe performed a retrospective analysis of 2,452 patients in this double-blind, placebo-controlled study. Patients were stratified by Thrombolysis In Myocardial Infarction (TIMI) risk score for ST-segment elevation myocardial infarction (STEMI), presentation to a spoke (no PCI available) or hub site, and symptom-to-randomization time. Outcomes included the primary composite end point of death, ventricular fibrillation after 48 h, cardiogenic shock, and congestive heart failure through day 90 as well as 1-year mortality.ResultsMortality for all patients at 1 year was directly related to TIMI risk score (23 of 1,223 = 1.9% in patients with score

Background: The best method to interpret the chest roentgenogram and its sensitivity to detect effect of treatment for sarcoidosis remains unclear. In a double-blind, randomized trial of infliximab for chronic pulmonary sarcoidosis, changes in serial chest roentgenograms were examined by radiologists, blinded to order or treatment. Methods: Chest roentgenograms were obtained at 0, 6, and 24 weeks of therapy with either placebo, 3 mg/kg infliximab, or 5 mg/kg infliximab. Films were reviewed in random order by two independent radiologists, unaware of treatment. The films were compared using two methods: the prespecified objective assessment, a scoring system previously proposed by Muers; and the post hoc assessment, a 5-point Likert scale global assessment between two films. Results: Of 138 patients enrolled in the study, chest roentgenograms for all studies were available on 130 patients. There was only fair agreement between the two radiologists in the original stage of the chest roentgenogram (weighted 0.43; 95% confidence interval [CI], 0.32 to 0.54). For the Likert scale of global assessment of change, there was good agreement between the two readers (weighted 0.61; 95% CI, 0.51 to 0.71). There was good correlation between the two readers for the various components of the Muers score, especially the reticulonodular (R) score (R 0.578; p < 0.05). The initial R score was positively correlated with improvement in FVC with infliximab therapy (R 0.239; p < 0.05). Conclusion: Global assessment and the Muers scoring system were associated with good agreement between two expert readers. Improvement in both scores correlated with improvement in FVC. Trial registration: ClinicalTrials.gov Identifier: NCT00073437 (CHEST 2009; 136:526–535)

Rationale The treatment effect of golimumab, a human monoclonal antibody against tumor necrosis factor (TNF)-alpha, in severe persistent asthma is unknown. Objectives To assess the safety and efficacy of golimumab in a large population of patients with uncontrolled, severe persistent asthma. Methods From 2004 to 2006, 309 patients with severe and uncontrolled asthma, despite high-dose inhaled corticosteroids and long-acting beta(2) agonists, were randomized 1:1:1:1 to monthly subcutaneous injections of placebo or golimumab (50, 100, or 200 mg) through Week 52. Coprimary endpoints were the change from baseline through Week 24 in prebronchodilator percent-predicted FEV(1) and the number of severe asthma exacerbations through Week 24. Measurements and main results No significant differences were observed for the change in percent-predicted FEV1 (least squares mean: placebo, 2.44 [95% confidence interval (CI) -0.574 to 5.461]; combined 100-mg and 200-mg, 2.91 [0.696-5.116]) or severe exacerbations (mean +/- SD: placebo, 0.5 +/- 1.07 vs. combined 100-mg and 200-mg 0.5 +/- 0.97) through week 24. Through Week 24, 2.6% of patients treated with placebo vs. 19.5% of those treated with golimumab discontinued the study agent, and 1.3% and 7.8% discontinued study participation, respectively. An unfavorable risk-benefit profile led to early discontinuation of study-agent administration after the Week-24 database lock. Through Week 76, 20.5% of patients treated with placebo and 30.3% of patients treated with golimumab experienced serious adverse events, with serious infections occurring more frequently in golimumab-treated patients. One death and all eight malignancies occurred in the active groups. Conclusions Overall, treatment with golimumab did not demonstrate a favorable risk-benefit profile in this study population of patients with severe persistent asthma. Clinical trial registered with www.clinicaltrials.gov (NCT00207740).

Background— Vitronectin is a multifunctional protein with a multiple binding domain that interacts with a variety of plasma and cell proteins. Vitronectin binds multiple ligands, including the soluble vitronectin receptor. Abciximab binds equally well to soluble vitronectin receptor and glycoprotein IIb/IIIa, because both share the β 3 subunit. We tested whether vitronectin concentrations correlate with adverse outcomes in acute coronary syndrome patients. Methods and Results— Baseline serum samples (n=233) from a randomized, placebo-controlled trial of abciximab plus stenting (Evaluation of Platelet IIb/IIIa Inhibitor for Stenting EPISTENT) were retrospectively analyzed. We stratified vitronectin concentrations into the 3 lower quartiles (n=178; P =0.01) and 6 months (20.0% versus 6.2%; P =0.006). When baseline variables not predictive of major adverse cardiovascular event (eg, troponin positive, history of congestive heart failure, diabetes, history of hypertension, smoking status) were excluded from the multivariate model, only baseline vitronectin ≥49.7 μg/mL (at 30 days: OR, 3.23; 95% CI, 1.23, 8.49; at 6 months: OR, 3.36; 95% CI, 1.33, 8.52) and history of myocardial infarction (at 30 days: OR, 5.02; 95% CI, 1.41, 17.9; at 6 months: OR, 3.99; 95% CI, 1.28, 12.43) remained. No interaction occurred between abciximab and vitronectin. Conclusions— Our findings indicate that vitronectin may be an independent predictor of adverse cardiovascular outcomes following acute stenting.

Background and Purpose— Approximately 10% to 20% of patients with a new stroke have symptoms present on awakening (wake-up stroke), but these persons are not treated with interventions to restore perfusion because the time of onset is not known. We elected to test the safety and possible efficacy of abciximab in treatment of enrolled subjects with wake-up stroke. Methods— Abciximab in Emergency Stroke Treatment Trial-II (AbESTT-II) tested the usefulness of abciximab in improving outcomes after acute ischemic stroke and it prospectively tested an intervention in subjects that awakened with their stroke. We compared the outcomes among the subjects in the wake-up group with the other subjects in the trial. Results— Of the 801 subjects randomized in the trial, 43 (22 abciximab and 21 placebo) had wake-up strokes. Those with wake-up strokes had similar baseline characteristics as the other subjects except for a higher rate of a new stroke found on CT. Recruitment of patients into the wake-up group was halted early because of the rate of bleeding with abciximab exceeded the prespecified safety margins (3 of 22 [13.6%]) within 5 days or at discharge versus 15 of 375 (4.0%) for the nonwake-up group ( P =0.07). Favorable outcomes at 3 months, as defined by scores on the modified Rankin Scale, among the wake-up group (4 of 43 [9.3%]) were worse than the nonwake-up group (221 of 758 [29.2%]; P =0.005). Conclusions— Although the baseline characteristics of the wake-up group of subjects were similar to those of persons enrolled in the nonwake-up group, their outcomes were much poorer. Patients with wake-up stroke may not tolerate reperfusion therapies even when started within a short time of awakening.