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Bradbury, Charlotte A. M. D. PhD, Lawler, Patrick R. M. D. M. P. H.; Stanworth, Simon J. M. D.; McVerry, Bryan J. M. D.; McQuilten, Zoe PhD, Higgins, Alisa M. PhD, Mouncey, Paul R. MSc, Al-Beidh, Farah PhD, Rowan, Kathryn M. PhD, Berry, Lindsay R. PhD, Lorenzi, Elizabeth PhD, Zarychanski, Ryan M. D. MSc, Arabi, Yaseen M. M. D.; Annane, Djillali M. D. PhD, Beane, Abi PhD, van Bentum-Puijk, Wilma MSc, Bhimani, Zahra M. P. H.; Bihari, Shailesh PhD, M Bonten, Marc J. M. D. PhD, Brunkhorst, Frank M. M. D. PhD, Buzgau, Adrian MSc, Buxton, Meredith PhD, Carrier, Marc M. D. MSc, Cheng, Allen C. Mbbs PhD, Cove, Matthew Mbbs, Detry, Michelle A. PhD, Estcourt, Lise J. MBBCh PhD, Fitzgerald, Mark PhD, Girard, Timothy D. M. D. Msci, Goligher, Ewan C. M. D. PhD, Goossens, Herman PhD, Haniffa, Rashan PhD, Hills, Thomas Mbbs PhD, Huang, David T. M. D. M. P. H.; Horvat, Christopher M. M. D.; Hunt, Beverley J. M. D. PhD, Ichihara, Nao M. D. M. P. H. PhD, Lamontagne, Francois M. D.; Leavis, Helen L. M. D. PhD, Linstrum, Kelsey M. M. S.; Litton, Edward M. D. PhD, Marshall, John C. M. D.; McAuley, Daniel F. M. D.; McGlothlin, Anna PhD, McGuinness, Shay P. M. D.; Middeldorp, Saskia M. D. PhD, Montgomery, Stephanie K. MSc, Morpeth, Susan C. M. D. PhD, Murthy, Srinivas M. D.; Neal, Matthew D. M. D.; Nichol, Alistair D. M. D. PhD, Parke, Rachael L. PhD, Parker, Jane C. B. N.; Reyes, Luis F. M. D. PhD, Saito, Hiroki M. D. M. P. H.; Santos, Marlene S. M. D. Mshs, Saunders, Christina T. PhD, Serpa-Neto, Ary PhD MSc M. D.; Seymour, Christopher W. M. D. MSc, Shankar-Hari, Manu M. D. PhD, Singh, Vanessa, Tolppa, Timo Mbbs, Turgeon, Alexis F. M. D. MSc, Turner, Anne M. M. P. H.; van de Veerdonk, Frank L. M. D. PhD, Green, Cameron MSc, Lewis, Roger J. M. D. PhD, Angus, Derek C. M. D. M. P. H.; McArthur, Colin J. M. D.; Berry, Scott PhD, G Derde, Lennie P. M. D. PhD, Webb, Steve A. M. D. PhD, Gordon, Anthony C. Mbbs M. D..
JAMA ; 327(13):1247, 2022.
Article in English | ProQuest Central | ID: covidwho-1801957

ABSTRACT

Importance The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncertain. Objective To determine whether antiplatelet therapy improves outcomes for critically ill adults with COVID-19. Design, Setting, and Participants In an ongoing adaptive platform trial (REMAP-CAP) testing multiple interventions within multiple therapeutic domains, 1557 critically ill adult patients with COVID-19 were enrolled between October 30, 2020, and June 23, 2021, from 105 sites in 8 countries and followed up for 90 days (final follow-up date: July 26, 2021). Interventions Patients were randomized to receive either open-label aspirin (n = 565), a P2Y12 inhibitor (n = 455), or no antiplatelet therapy (control;n = 529). Interventions were continued in the hospital for a maximum of 14 days and were in addition to anticoagulation thromboprophylaxis. Main Outcomes and Measures The primary end point was organ support–free days (days alive and free of intensive care unit–based respiratory or cardiovascular organ support) within 21 days, ranging from −1 for any death in hospital (censored at 90 days) to 22 for survivors with no organ support. There were 13 secondary outcomes, including survival to discharge and major bleeding to 14 days. The primary analysis was a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented improved survival, more organ support–free days, or both. Efficacy was defined as greater than 99% posterior probability of an OR greater than 1. Futility was defined as greater than 95% posterior probability of an OR less than 1.2 vs control. Intervention equivalence was defined as greater than 90% probability that the OR (compared with each other) was between 1/1.2 and 1.2 for 2 noncontrol interventions. Results The aspirin and P2Y12 inhibitor groups met the predefined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the prespecified criterion for futility was met for the pooled antiplatelet group compared with control. Among the 1557 critically ill patients randomized, 8 patients withdrew consent and 1549 completed the trial (median age, 57 years;521 [33.6%] female). The median for organ support–free days was 7 (IQR, −1 to 16) in both the antiplatelet and control groups (median-adjusted OR, 1.02 [95% credible interval {CrI}, 0.86-1.23];95.7% posterior probability of futility). The proportions of patients surviving to hospital discharge were 71.5% (723/1011) and 67.9% (354/521) in the antiplatelet and control groups, respectively (median-adjusted OR, 1.27 [95% CrI, 0.99-1.62];adjusted absolute difference, 5% [95% CrI, −0.2% to 9.5%];97% posterior probability of efficacy). Among survivors, the median for organ support–free days was 14 in both groups. Major bleeding occurred in 2.1% and 0.4% of patients in the antiplatelet and control groups (adjusted OR, 2.97 [95% CrI, 1.23-8.28];adjusted absolute risk increase, 0.8% [95% CrI, 0.1%-2.7%];99.4% probability of harm). Conclusions and Relevance Among critically ill patients with COVID-19, treatment with an antiplatelet agent, compared with no antiplatelet agent, had a low likelihood of providing improvement in the number of organ support–free days within 21 days.

2.
Lancet Respir Med ; 10(1): 107-120, 2022 01.
Article in English | MEDLINE | ID: covidwho-1591647

ABSTRACT

Acute respiratory distress syndrome (ARDS) is a heterogeneous clinical syndrome. Understanding of the complex pathways involved in lung injury pathogenesis, resolution, and repair has grown considerably in recent decades. Nevertheless, to date, only therapies targeting ventilation-induced lung injury have consistently proven beneficial, and despite these gains, ARDS morbidity and mortality remain high. Many candidate therapies with promise in preclinical studies have been ineffective in human trials, probably at least in part due to clinical and biological heterogeneity that modifies treatment responsiveness in human ARDS. A precision medicine approach to ARDS seeks to better account for this heterogeneity by matching therapies to subgroups of patients that are anticipated to be most likely to benefit, which initially might be identified in part by assessing for heterogeneity of treatment effect in clinical trials. In October 2019, the US National Heart, Lung, and Blood Institute convened a workshop of multidisciplinary experts to explore research opportunities and challenges for accelerating precision medicine in ARDS. Topics of discussion included the rationale and challenges for a precision medicine approach in ARDS, the roles of preclinical ARDS models in precision medicine, essential features of cohort studies to advance precision medicine, and novel approaches to clinical trials to support development and validation of a precision medicine strategy. In this Position Paper, we summarise workshop discussions, recommendations, and unresolved questions for advancing precision medicine in ARDS. Although the workshop took place before the COVID-19 pandemic began, the pandemic has highlighted the urgent need for precision therapies for ARDS as the global scientific community grapples with many of the key concepts, innovations, and challenges discussed at this workshop.


Subject(s)
Precision Medicine , Respiratory Distress Syndrome , COVID-19 , Humans , Respiratory Distress Syndrome/therapy
3.
N Engl J Med ; 385(9): 790-802, 2021 Aug 26.
Article in English | MEDLINE | ID: covidwho-1343498

ABSTRACT

BACKGROUND: Thrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19. METHODS: In this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care-level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level. RESULTS: The trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support-free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis. CONCLUSIONS: In noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589, NCT04505774, NCT04359277, and NCT02735707.).


Subject(s)
Anticoagulants/administration & dosage , COVID-19/drug therapy , Heparin/administration & dosage , Thrombosis/prevention & control , Adult , Aged , Anticoagulants/adverse effects , Anticoagulants/therapeutic use , COVID-19/mortality , Female , Hemorrhage/chemically induced , Heparin/adverse effects , Heparin/therapeutic use , Heparin, Low-Molecular-Weight/therapeutic use , Hospital Mortality , Humans , Male , Middle Aged , Survival Analysis
4.
N Engl J Med ; 385(9): 777-789, 2021 Aug 26.
Article in English | MEDLINE | ID: covidwho-1343497

ABSTRACT

BACKGROUND: Thrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19. METHODS: In an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. RESULTS: The trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support-free days was 1 (interquartile range, -1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, -1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio <1.2], 99.9%). The percentage of patients who survived to hospital discharge was similar in the two groups (62.7% and 64.5%, respectively; adjusted odds ratio, 0.84; 95% credible interval, 0.64 to 1.11). Major bleeding occurred in 3.8% of the patients assigned to therapeutic-dose anticoagulation and in 2.3% of those assigned to usual-care pharmacologic thromboprophylaxis. CONCLUSIONS: In critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin did not result in a greater probability of survival to hospital discharge or a greater number of days free of cardiovascular or respiratory organ support than did usual-care pharmacologic thromboprophylaxis. (REMAP-CAP, ACTIV-4a, and ATTACC ClinicalTrials.gov numbers, NCT02735707, NCT04505774, NCT04359277, and NCT04372589.).


Subject(s)
Anticoagulants/administration & dosage , COVID-19/drug therapy , Heparin/administration & dosage , Thrombosis/prevention & control , Aged , Anticoagulants/adverse effects , Anticoagulants/therapeutic use , COVID-19/mortality , Critical Illness , Female , Hemorrhage/chemically induced , Heparin/adverse effects , Heparin/therapeutic use , Hospital Mortality , Humans , Logistic Models , Male , Middle Aged , Odds Ratio , Respiration, Artificial , Treatment Failure
5.
Ann Am Thorac Soc ; 17(7): 879-891, 2020 07.
Article in English | MEDLINE | ID: covidwho-679536

ABSTRACT

There is broad interest in improved methods to generate robust evidence regarding best practice, especially in settings where patient conditions are heterogenous and require multiple concomitant therapies. Here, we present the rationale and design of a large, international trial that combines features of adaptive platform trials with pragmatic point-of-care trials to determine best treatment strategies for patients admitted to an intensive care unit with severe community-acquired pneumonia. The trial uses a novel design, entitled "a randomized embedded multifactorial adaptive platform." The design has five key features: 1) randomization, allowing robust causal inference; 2) embedding of study procedures into routine care processes, facilitating enrollment, trial efficiency, and generalizability; 3) a multifactorial statistical model comparing multiple interventions across multiple patient subgroups; 4) response-adaptive randomization with preferential assignment to those interventions that appear most favorable; and 5) a platform structured to permit continuous, potentially perpetual enrollment beyond the evaluation of the initial treatments. The trial randomizes patients to multiple interventions within four treatment domains: antibiotics, antiviral therapy for influenza, host immunomodulation with extended macrolide therapy, and alternative corticosteroid regimens, representing 240 treatment regimens. The trial generates estimates of superiority, inferiority, and equivalence between regimens on the primary outcome of 90-day mortality, stratified by presence or absence of concomitant shock and proven or suspected influenza infection. The trial will also compare ventilatory and oxygenation strategies, and has capacity to address additional questions rapidly during pandemic respiratory infections. As of January 2020, REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) was approved and enrolling patients in 52 intensive care units in 13 countries on 3 continents. In February, it transitioned into pandemic mode with several design adaptations for coronavirus disease 2019. Lessons learned from the design and conduct of this trial should aid in dissemination of similar platform initiatives in other disease areas.Clinical trial registered with www.clinicaltrials.gov (NCT02735707).


Subject(s)
Community-Acquired Infections/therapy , Coronavirus Infections/therapy , Influenza, Human/therapy , Pneumonia, Viral/therapy , Pneumonia/therapy , Anti-Bacterial Agents/therapeutic use , Antiviral Agents/therapeutic use , Betacoronavirus , COVID-19 , Evidence-Based Medicine , Humans , Pandemics , Point-of-Care Systems , SARS-CoV-2
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