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1.
JAMA ; 327(13): 1247-1259, 2022 04 05.
Article in English | MEDLINE | 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. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.


Subject(s)
COVID-19 , Critical Illness , Platelet Aggregation Inhibitors , Venous Thromboembolism , Adult , Anticoagulants/adverse effects , Anticoagulants/therapeutic use , Aspirin/adverse effects , Aspirin/therapeutic use , Bayes Theorem , COVID-19/complications , COVID-19/drug therapy , COVID-19/mortality , COVID-19/therapy , Critical Illness/mortality , Critical Illness/therapy , Female , Hemorrhage/chemically induced , Humans , Male , Middle Aged , Platelet Aggregation Inhibitors/adverse effects , Platelet Aggregation Inhibitors/therapeutic use , Purinergic P2Y Receptor Antagonists/adverse effects , Purinergic P2Y Receptor Antagonists/therapeutic use , Respiration, Artificial , Venous Thromboembolism/drug therapy , Venous Thromboembolism/etiology
3.
J Clin Microbiol ; 60(4): e0228321, 2022 04 20.
Article in English | MEDLINE | ID: covidwho-1759279

ABSTRACT

Tools to detect SARS-CoV-2 variants of concern and track the ongoing evolution of the virus are necessary to support public health efforts and the design and evaluation of novel COVID-19 therapeutics and vaccines. Although next-generation sequencing (NGS) has been adopted as the gold standard method for discriminating SARS-CoV-2 lineages, alternative methods may be required when processing samples with low viral loads or low RNA quality. To this aim, an allele-specific probe PCR (ASP-PCR) targeting lineage-specific single nucleotide polymorphisms (SNPs) was developed and used to screen 1,082 samples from two clinical trials in the United Kingdom and Brazil. Probit regression models were developed to compare ASP-PCR performance against 1,771 NGS results for the same cohorts. Individual SNPs were shown to readily identify specific variants of concern. ASP-PCR was shown to discriminate SARS-CoV-2 lineages with a higher likelihood than NGS over a wide range of viral loads. The comparative advantage for ASP-PCR over NGS was most pronounced in samples with cycle threshold (CT) values between 26 and 30 and in samples that showed evidence of degradation. Results for samples screened by ASP-PCR and NGS showed 99% concordant results. ASP-PCR is well suited to augment but not replace NGS. The method can differentiate SARS-CoV-2 lineages with high accuracy and would be best deployed to screen samples with lower viral loads or that may suffer from degradation. Future work should investigate further destabilization from primer-target base mismatch through altered oligonucleotide chemistry or chemical additives.


Subject(s)
COVID-19 , SARS-CoV-2 , Alleles , COVID-19/diagnosis , Humans , Polymerase Chain Reaction , SARS-CoV-2/genetics
4.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-329063

ABSTRACT

Background: We evaluated the use of baricitinib, a Janus kinase (JAK) 1/2 inhibitor, for the treatment of patients admitted to hospital because of COVID-19. Methods: This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple possible treatments in patients hospitalised for COVID-19. Eligible and consenting patients were randomly allocated (1:1) to either usual standard of care alone (usual care group) or usual care plus baricitinib 4 mg once daily by mouth for 10 days or until discharge if sooner (baricitinib group). The primary outcome was 28-day mortality assessed in the intention-to-treat population. A meta-analysis was conducted that included the results from the RECOVERY trial and all previous randomised controlled trials of baricitinib or other JAK inhibitor in patients hospitalised with COVID-19. Findings: Between 2 February 2021 and 29 December 2021, 8156 patients were randomly allocated to receive usual care plus baricitinib versus usual care alone. At randomisation, 95% of patients were receiving corticosteroids and 23% receiving tocilizumab (with planned use within the next 24 hours recorded for a further 9%). Overall, 513 (12%) of 4148 patients allocated to baricitinib versus 546 (14%) of 4008 patients allocated to usual care died within 28 days (age-adjusted rate ratio 0.87;95% CI 0.77-0.98;p=0.026). This 13% proportional reduction in mortality was somewhat smaller than that seen in a meta-analysis of 8 previous trials of a JAK inhibitor (involving 3732 patients and 425 deaths) in which allocation to a JAK inhibitor was associated with a 43% proportional reduction in mortality (rate ratio 0.57;95% CI 0.45-0.72). Including the results from RECOVERY into an updated meta-analysis of all 9 completed trials (involving 11,888 randomised patients and 1484 deaths) allocation to baricitinib or other JAK inhibitor was associated with a 20% proportional reduction in mortality (rate ratio 0.80;95% CI 0.71-0.89;p<0.001). In RECOVERY, there was no significant excess in death or infection due to non-COVID-19 causes and no excess of thrombosis, or other safety outcomes. Interpretation: In patients hospitalised for COVID-19, baricitinib significantly reduced the risk of death but the size of benefit was somewhat smaller than that suggested by previous trials. The total randomised evidence to date suggests that JAK inhibitors (chiefly baricitinib) reduce mortality in patients hospitalised for COVID-19 by about one-fifth.

5.
Crit Care Med ; 50(6): e548-e556, 2022 06 01.
Article in English | MEDLINE | ID: covidwho-1691782

ABSTRACT

OBJECTIVES: To determine whether patients admitted to an ICU during times of unprecedented ICU capacity strain, during the COVID-19 pandemic in the United Kingdom, experienced a higher risk of death. DESIGN: Multicenter, observational cohort study using routine clinical audit data. SETTING: Adult general ICUs participating the Intensive Care National Audit & Research Centre Case Mix Programme in England, Wales, and Northern Ireland. PATIENTS: One-hundred thirty-thousand six-hundred eighty-nine patients admitted to 210 adult general ICUs in 207 hospitals. INTERVENTIONS: Multilevel, mixed effects, logistic regression models were used to examine the relationship between levels of ICU capacity strain on the day of admission (typical low, typical, typical high, pandemic high, and pandemic extreme) and risk-adjusted hospital mortality. MEASUREMENTS AND MAIN RESULTS: In adjusted analyses, compared with patients admitted during periods of typical ICU capacity strain, we found that COVID-19 patients admitted during periods of pandemic high or pandemic extreme ICU capacity strain during the first wave had no difference in hospital mortality, whereas those admitted during the pandemic high or pandemic extreme ICU capacity strain in the second wave had a 17% (odds ratio [OR], 1.17; 95% CI, 1.05-1.30) and 15% (OR, 1.15; 95% CI, 1.00-1.31) higher odds of hospital mortality, respectively. For non-COVID-19 patients, there was little difference in trend between waves, with those admitted during periods of pandemic high and pandemic extreme ICU capacity strain having 16% (OR, 1.16; 95% CI, 1.08-1.25) and 30% (OR, 1.30; 95% CI, 1.14-1.48) higher overall odds of acute hospital mortality, respectively. CONCLUSIONS: For patients admitted to ICU during the pandemic, unprecedented levels of ICU capacity strain were significantly associated with higher acute hospital mortality, after accounting for differences in baseline characteristics. Further study into possible differences in the provision of care and outcome for COVID-19 and non-COVID-19 patients is needed.


Subject(s)
COVID-19 , Adult , COVID-19/epidemiology , Critical Care , Hospital Mortality , Humans , Intensive Care Units , Pandemics , Retrospective Studies
6.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-310422

ABSTRACT

Objectives: To develop and validate a prediction model for 28-day in-hospital mortality among adult patients critically ill with COVID-19 in the UK. Design Observational cohort study. Setting 287 adult critical care units in England, Wales and Northern Ireland, of which 260 admitted at least one eligible patient. Participants 10,933 patients with confirmed COVID-19 of whom 10,401 were eligible (excluding 532 patients with a duration of critical care less than 24 hours and 1 patient with unknown 28-day outcome): 8,666 development (March-April 2020) and 1,735 temporal validation (May-August 2020). Main outcome measures 28-day in-hospital mortality from start of critical care. Results Two models were developed using 14 patient level predictors selected from 30 candidate predictors, with and without adjustment for calendar time. In the temporal validation data, the model discrimination was maintained (c index 0.78) but calibration was poor, particularly for the model not adjusted for calendar time (ratio of observed to predicted mortality 0.74 versus 0.88 for the model adjusted for calendar time). Conclusions We developed and validated a prediction model for 28-day in-hospital mortality for patients critically ill with COVID-19. Although absolute predictions were inaccurate due to changing outcomes, the models will support risk-adjustment in analyses and monitoring changes in risk-adjusted outcome over time.

7.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-309606

ABSTRACT

Rationale: Examining trends in patient characteristics, processes of care and outcomes, across an epidemic, provides important opportunities for learning. Objectives: To report and explore changes in admission rates, patient characteristics, processes of care and outcomes for all patients with COVID-19 admitted to intensive care units (ICUs) in England, Wales and Northern Ireland. Methods: Population cohort of 10,287 patients with COVID-19 in the Case Mix Programme national clinical audit from 1 February to 2 July, 2020. Analyses were stratified by time period (pre-peak, peak, post-peak) and geographical region. Multivariable logistic regression was used to estimate differences in 28-day mortality, adjusting for patient characteristics over time. Main results: Admissions to ICU peaked simultaneously across regions on 1 April, with ongoing admissions peaking ten days later. Compared with pre- and post-peak periods, patients admitted during the peak were slightly younger but had greater respiratory and renal dysfunction. Use of invasive ventilation and renal replacement reduced over time. Twenty-eight-day mortality reduced from 43.5% (95% CI 41.6% to 45.5%) pre-peak to 34.3% (95% CI 32.3% to 36.2%) post-peak;a difference of −8.8% (95% CI: −5.2%, −12.3%) after adjusting for patient characteristics. London experienced the highest admission rate and had higher mortality during the peak period but a greater reduction in post-peak mortality. Conclusion: This study highlights changes in patient characteristics, processes of care and outcomes, during the UK COVID-19 epidemic. After adjusting for the changes in patient characteristics and first 24-hour physiology, there was substantial improvement in 28-day mortality over the course of the epidemic.

8.
Resuscitation ; 173: 4-11, 2022 04.
Article in English | MEDLINE | ID: covidwho-1676901

ABSTRACT

AIMS: To compare in-hospital cardiac arrest (IHCA) rates and patient outcomes during the first COVID-19 wave in the United Kingdom (UK) in 2020 with the same period in previous years. METHODS: A retrospective, multicentre cohort study of 154 UK hospitals that participate in the National Cardiac Arrest Audit and have intensive care units participating in the Case Mix Programme national audit of intensive care. Hospital burden of COVID-19 was defined by the number of patients with confirmed SARS-CoV2 infection admitted to critical care per 10,000 hospital admissions. RESULTS: 16,474 patients with IHCA where a resuscitation team attended were included. Patients admitted to hospital during 2020 were younger, more often male, and of non-white ethnicity compared with 2016-2019. A decreasing trend in IHCA rates between 2016 and 2019 was reversed in 2020. Hospitals with higher burden of COVID-19 had the greatest difference in IHCA rates (21.8 per 10,000 admissions in April 2020 vs 14.9 per 10,000 in April 2019). The proportions of patients achieving ROSC ≥ 20 min and surviving to hospital discharge were lower in 2020 compared with 2016-19 (46.2% vs 51.2%; and 21.9% vs 22.9%, respectively). Among patients with IHCA, higher hospital burden of COVID-19 was associated with reduced survival to hospital discharge (OR = 0.95; 95% CI 0.93 to 0.98; p < 0.001). CONCLUSIONS: In comparison with 2016-2019, the first COVID-19 wave in 2020 was associated with a higher rate of IHCA and decreased survival among patients attended by resuscitation teams. These changes were greatest in hospitals with the highest COVID-19 burden.


Subject(s)
COVID-19 , Cardiopulmonary Resuscitation , Heart Arrest , COVID-19/epidemiology , Cohort Studies , Heart Arrest/epidemiology , Heart Arrest/therapy , Hospitals , Humans , Male , Pandemics , RNA, Viral , Retrospective Studies , SARS-CoV-2 , United Kingdom/epidemiology
9.
Lancet Infect Dis ; 21(11): 1518-1528, 2021 11.
Article in English | MEDLINE | ID: covidwho-1636381

ABSTRACT

BACKGROUND: A more transmissible variant of SARS-CoV-2, the variant of concern 202012/01 or lineage B.1.1.7, has emerged in the UK. We aimed to estimate the risk of critical care admission, mortality in patients who are critically ill, and overall mortality associated with lineage B.1.1.7 compared with non-B.1.1.7. We also compared clinical outcomes between these two groups. METHODS: For this observational cohort study, we linked large primary care (QResearch), national critical care (Intensive Care National Audit & Research Centre Case Mix Programme), and national COVID-19 testing (Public Health England) databases. We used SARS-CoV-2 positive samples with S-gene molecular diagnostic assay failure (SGTF) as a proxy for the presence of lineage B.1.1.7. We extracted two cohorts from the data: the primary care cohort, comprising patients in primary care with a positive community COVID-19 test reported between Nov 1, 2020, and Jan 26, 2021, and known SGTF status; and the critical care cohort, comprising patients admitted for critical care with a positive community COVID-19 test reported between Nov 1, 2020, and Jan 27, 2021, and known SGTF status. We explored the associations between SARS-CoV-2 infection with and without lineage B.1.1.7 and admission to a critical care unit (CCU), 28-day mortality, and 28-day mortality following CCU admission. We used Royston-Parmar models adjusted for age, sex, geographical region, other sociodemographic factors (deprivation index, ethnicity, household housing category, and smoking status for the primary care cohort; and ethnicity, body-mass index, deprivation index, and dependency before admission to acute hospital for the CCU cohort), and comorbidities (asthma, chronic obstructive pulmonary disease, type 1 and 2 diabetes, and hypertension for the primary care cohort; and cardiovascular disease, respiratory disease, metastatic disease, and immunocompromised conditions for the CCU cohort). We reported information on types and duration of organ support for the B.1.1.7 and non-B.1.1.7 groups. FINDINGS: The primary care cohort included 198 420 patients with SARS-CoV-2 infection. Of these, 117 926 (59·4%) had lineage B.1.1.7, 836 (0·4%) were admitted to CCU, and 899 (0·4%) died within 28 days. The critical care cohort included 4272 patients admitted to CCU. Of these, 2685 (62·8%) had lineage B.1.1.7 and 662 (15·5%) died at the end of critical care. In the primary care cohort, we estimated adjusted hazard ratios (HRs) of 2·15 (95% CI 1·75-2·65) for CCU admission and 1·65 (1·36-2·01) for 28-day mortality for patients with lineage B.1.1.7 compared with the non-B.1.1.7 group. The adjusted HR for mortality in critical care, estimated with the critical care cohort, was 0·91 (0·76-1·09) for patients with lineage B.1.1.7 compared with those with non-B.1.1.7 infection. INTERPRETATION: Patients with lineage B.1.1.7 were at increased risk of CCU admission and 28-day mortality compared with patients with non-B.1.1.7 SARS-CoV-2. For patients receiving critical care, mortality appeared to be independent of virus strain. Our findings emphasise the importance of measures to control exposure to and infection with COVID-19. FUNDING: Wellcome Trust, National Institute for Health Research Oxford Biomedical Research Centre, and the Medical Sciences Division of the University of Oxford.


Subject(s)
COVID-19/mortality , Critical Care/statistics & numerical data , Intensive Care Units/statistics & numerical data , SARS-CoV-2/isolation & purification , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/diagnosis , COVID-19/therapy , COVID-19/virology , COVID-19 Nucleic Acid Testing/statistics & numerical data , England/epidemiology , Female , Hospital Mortality , Humans , Male , Middle Aged , Risk Assessment/statistics & numerical data , Risk Factors , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Severity of Illness Index , Young Adult
10.
2021.
Preprint in English | Other preprints | ID: ppcovidwho-295804

ABSTRACT

ABSTRACT Background Treatment of COVID-19 patients with convalescent plasma containing neutralising antibody to SARS-CoV-2 is under investigation as a means of reducing viral loads, ameliorating disease outcomes, and reducing mortality. However, its efficacy might be reduced in those infected with the emerging B.1.1.7 SARS-CoV-2 variant. Here, we report the diverse virological characteristics of UK patients enrolled in the Immunoglobulin Domain of the REMAP-CAP randomised controlled trial. Methods SARS-CoV-2 viral RNA was detected and quantified by real-time PCR in nasopharyngeal swabs obtained from study subjects within 48 hours of admission to intensive care unit. Antibody status was determined by spike-protein ELISA. B.1.1.7 strain was differentiated from other SARS-CoV-2 strains by two novel typing methods detecting the B.1.1.7-associated D1118H mutation with allele-specific probes and by restriction site polymorphism (SfcI). Findings Of 1260 subjects, 90% were PCR-positive with viral loads in nasopharyngeal swabs ranging from 72 international units [IUs]/ml to 1.7×10 11 IU/ml. Median viral loads were 45-fold higher in those who were seronegative for IgG antibodies (n=314;28%) compared to seropositives (n=804;72%), reflecting in part the latter group’s possible later disease stage on enrolment. Frequencies of B.1.1.7 infection increased from early November (<1%) to December 2020 (>60%). Anti-SARS-CoV-2 seronegative individuals infected with wild-type SARS-CoV-2 had significantly higher viral loads than seropositives (medians of 1.2×10 6 and 3.4 ×10 4 IU/ml respectively;p=2×10 −9 ). However, viral load distributions were elevated in both seropositive and seronegative subjects infected with B.1.1.7 (13.4×10 6 and 7.6×10 6 IU/ml;p=0.18). Interpretation High viral loads in seropositive B.1.1.7-infected subjects are consistent with increased replication capacity and/or less effective clearance by innate or adaptive immune response of B.1.1.7 strain than wild-type. As viral genotype was associated with diverse virological and immunological phenotypes, metrics of viral load, antibody status and infecting strain should be used to define subgroups for analysis of treatment efficacy.

11.
J Infect Dis ; 224(4): 595-605, 2021 08 16.
Article in English | MEDLINE | ID: covidwho-1367024

ABSTRACT

BACKGROUND: Convalescent plasma containing neutralizing antibody to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is under investigation for coronavirus disease 2019 (COVID-19) treatment. We report diverse virological characteristics of UK intensive care patients enrolled in the Immunoglobulin Domain of the REMAP-CAP randomized controlled trial that potentially influence treatment outcomes. METHODS: SARS-CoV-2 RNA in nasopharyngeal swabs collected pretreatment was quantified by PCR. Antibody status was determined by spike-protein ELISA. B.1.1.7 was differentiated from other SARS-CoV-2 strains using allele-specific probes or restriction site polymorphism (SfcI) targeting D1118H. RESULTS: Of 1274 subjects, 90% were PCR positive with viral loads 118-1.7 × 1011IU/mL. Median viral loads were 40-fold higher in those IgG seronegative (n = 354; 28%) compared to seropositives (n = 939; 72%). Frequencies of B.1.1.7 increased from <1% in November 2020 to 82% of subjects in January 2021. Seronegative individuals with wild-type SARS-CoV-2 had significantly higher viral loads than seropositives (medians 5.8 × 106 and 2.0 × 105 IU/mL, respectively; P = 2 × 10-15). CONCLUSIONS: High viral loads in seropositive B.1.1.7-infected subjects and resistance to seroconversion indicate less effective clearance by innate and adaptive immune responses. SARS-CoV-2 strain, viral loads, and antibody status define subgroups for analysis of treatment efficacy.


Subject(s)
Antibodies, Viral/immunology , COVID-19/immunology , COVID-19/therapy , SARS-CoV-2/immunology , Viral Load/immunology , Aged , Antibodies, Neutralizing/immunology , COVID-19/virology , Critical Illness , Female , Humans , Immunization, Passive , Immunoglobulin G/immunology , Male , Middle Aged , RNA, Viral/immunology , Serologic Tests/methods , Spike Glycoprotein, Coronavirus/immunology , United Kingdom
13.
Journal of the Intensive Care Society ; : 17511437211022129, 2021.
Article in English | Sage | ID: covidwho-1257918

ABSTRACT

The National ECMO Service for patients in acute severe respiratory failure in England responded to the challenge of the coronavirus pandemic by implementing a central electronic referral system within days. Prior to this, each ECMO centre managed independently around 20 ECMO referrals per month. Early during the pandemic, we recognised the need for a referral system to co-ordinate the anticipated increased number of referrals. We implemented rapidly a referral system with universal access across England. This allowed the five National ECMO centres to manage over 1000 referrals in the first seven weeks of the pandemic. Key benefits of the new system included facilitated communication and collaboration between centres;data on demand;and capacity shared in real-time. We believe this was instrumental in allowing us to continue to provide for the whole country, respond at scale, and facilitate our collaborative work as a multidisciplinary team.

15.
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
16.
N Engl J Med ; 384(16): 1491-1502, 2021 04 22.
Article in English | MEDLINE | ID: covidwho-1101727

ABSTRACT

BACKGROUND: The efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS: We evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours after starting organ support in the intensive care unit (ICU), were randomly assigned to receive tocilizumab (8 mg per kilogram of body weight), sarilumab (400 mg), or standard care (control). The primary outcome was respiratory and cardiovascular organ support-free days, on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with predefined criteria for superiority, efficacy, equivalence, or futility. An odds ratio greater than 1 represented improved survival, more organ support-free days, or both. RESULTS: Both tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support-free days was 10 (interquartile range, -1 to 16) in the tocilizumab group, 11 (interquartile range, 0 to 16) in the sarilumab group, and 0 (interquartile range, -1 to 15) in the control group. The median adjusted cumulative odds ratios were 1.64 (95% credible interval, 1.25 to 2.14) for tocilizumab and 1.76 (95% credible interval, 1.17 to 2.91) for sarilumab as compared with control, yielding posterior probabilities of superiority to control of more than 99.9% and of 99.5%, respectively. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08) and a posterior probability of superiority of more than 99.9%. All secondary analyses supported efficacy of these interleukin-6 receptor antagonists. CONCLUSIONS: In critically ill patients with Covid-19 receiving organ support in ICUs, treatment with the interleukin-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.).


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/drug therapy , Receptors, Interleukin-6/antagonists & inhibitors , Adult , Aged , Antibodies, Monoclonal, Humanized/adverse effects , COVID-19/complications , COVID-19/mortality , COVID-19/therapy , Critical Illness , Female , Hospital Mortality , Humans , Intensive Care Units , Male , Middle Aged , Odds Ratio , Respiration, Artificial
17.
N Engl J Med ; 384(8): 693-704, 2021 Feb 25.
Article in English | MEDLINE | ID: covidwho-1101722

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. METHODS: In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the final results of this assessment. RESULTS: A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.92 to 1.55). CONCLUSIONS: In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936; ISRCTN number, 50189673.).


Subject(s)
COVID-19/drug therapy , Dexamethasone/therapeutic use , Glucocorticoids/therapeutic use , Oxygen Inhalation Therapy , Respiration, Artificial , Administration, Oral , Aged , Aged, 80 and over , Anti-Infective Agents/therapeutic use , COVID-19/mortality , COVID-19/therapy , Dexamethasone/administration & dosage , Dexamethasone/adverse effects , Drug Therapy, Combination , Female , Glucocorticoids/administration & dosage , Glucocorticoids/adverse effects , Hospitalization , Humans , Injections, Intravenous , Kaplan-Meier Estimate , Length of Stay , Male , Odds Ratio , United Kingdom
18.
Intensive Care Med ; 47(3): 282-291, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1092644

ABSTRACT

Coronavirus disease 19 (COVID-19) has posed unprecedented healthcare system challenges, some of which will lead to transformative change. It is obvious to healthcare workers and policymakers alike that an effective critical care surge response must be nested within the overall care delivery model. The COVID-19 pandemic has highlighted key elements of emergency preparedness. These include having national or regional strategic reserves of personal protective equipment, intensive care unit (ICU) devices, consumables and pharmaceuticals, as well as effective supply chains and efficient utilization protocols. ICUs must also be prepared to accommodate surges of patients and ICU staffing models should allow for fluctuations in demand. Pre-existing ICU triage and end-of-life care principles should be established, implemented and updated. Daily workflow processes should be restructured to include remote connection with multidisciplinary healthcare workers and frequent communication with relatives. The pandemic has also demonstrated the benefits of digital transformation and the value of remote monitoring technologies, such as wireless monitoring. Finally, the pandemic has highlighted the value of pre-existing epidemiological registries and agile randomized controlled platform trials in generating fast, reliable data. The COVID-19 pandemic is a reminder that besides our duty to care, we are committed to improve. By meeting these challenges today, we will be able to provide better care to future patients.


Subject(s)
COVID-19 , Critical Care/trends , Pandemics , Critical Care/organization & administration , Disaster Planning , Humans , Intensive Care Units/organization & administration , Monitoring, Physiologic/instrumentation , Monitoring, Physiologic/methods , Personal Protective Equipment , Surge Capacity , Telemedicine , Workflow
19.
Crit Care Med ; 49(1): 102-111, 2021 01 01.
Article in English | MEDLINE | ID: covidwho-1024138

ABSTRACT

OBJECTIVES: To identify characteristics that predict 30-day mortality among patients critically ill with coronavirus disease 2019 in England, Wales, and Northern Ireland. DESIGN: Observational cohort study. SETTING: A total of 258 adult critical care units. PATIENTS: A total of 10,362 patients with confirmed coronavirus disease 2019 with a start of critical care between March 1, 2020, and June 22, 2020, of whom 9,990 were eligible (excluding patients with a duration of critical care less than 24 hr or missing core variables). MEASUREMENTS AND MAIN RESULTS: The main outcome measure was time to death within 30 days of the start of critical care. Of 9,990 eligible patients (median age 60 yr, 70% male), 3,933 died within 30 days of the start of critical care. As of July 22, 2020, 189 patients were still receiving critical care and a further 446 were still in acute hospital. Data were missing for between 0.1% and 7.2% of patients across prognostic factors. We imputed missing data ten-fold, using fully conditional specification and continuous variables were modeled using restricted cubic splines. Associations between the candidate prognostic factors and time to death within 30 days of the start of critical care were determined after adjustment for multiple variables with Cox proportional hazards modeling. Significant associations were identified for age, ethnicity, deprivation, body mass index, prior dependency, immunocompromise, lowest systolic blood pressure, highest heart rate, highest respiratory rate, Pao2/Fio2 ratio (and interaction with mechanical ventilation), highest blood lactate concentration, highest serum urea, and lowest platelet count over the first 24 hours of critical care. Nonsignificant associations were found for sex, sedation, highest temperature, and lowest hemoglobin concentration. CONCLUSIONS: We identified patient characteristics that predict an increased likelihood of death within 30 days of the start of critical care for patients with coronavirus disease 2019. These findings may support development of a prediction model for benchmarking critical care providers.


Subject(s)
COVID-19/mortality , Critical Illness/mortality , Severity of Illness Index , Adult , COVID-19/therapy , Cohort Studies , Critical Illness/therapy , England , Female , Hospital Mortality , Humans , Male , Middle Aged , Northern Ireland , Prognosis , Respiration, Artificial/mortality , Wales
20.
N Engl J Med ; 383(21): 2030-2040, 2020 Nov 19.
Article in English | MEDLINE | ID: covidwho-990092

ABSTRACT

BACKGROUND: Hydroxychloroquine and chloroquine have been proposed as treatments for coronavirus disease 2019 (Covid-19) on the basis of in vitro activity and data from uncontrolled studies and small, randomized trials. METHODS: In this randomized, controlled, open-label platform trial comparing a range of possible treatments with usual care in patients hospitalized with Covid-19, we randomly assigned 1561 patients to receive hydroxychloroquine and 3155 to receive usual care. The primary outcome was 28-day mortality. RESULTS: The enrollment of patients in the hydroxychloroquine group was closed on June 5, 2020, after an interim analysis determined that there was a lack of efficacy. Death within 28 days occurred in 421 patients (27.0%) in the hydroxychloroquine group and in 790 (25.0%) in the usual-care group (rate ratio, 1.09; 95% confidence interval [CI], 0.97 to 1.23; P = 0.15). Consistent results were seen in all prespecified subgroups of patients. The results suggest that patients in the hydroxychloroquine group were less likely to be discharged from the hospital alive within 28 days than those in the usual-care group (59.6% vs. 62.9%; rate ratio, 0.90; 95% CI, 0.83 to 0.98). Among the patients who were not undergoing mechanical ventilation at baseline, those in the hydroxychloroquine group had a higher frequency of invasive mechanical ventilation or death (30.7% vs. 26.9%; risk ratio, 1.14; 95% CI, 1.03 to 1.27). There was a small numerical excess of cardiac deaths (0.4 percentage points) but no difference in the incidence of new major cardiac arrhythmia among the patients who received hydroxychloroquine. CONCLUSIONS: Among patients hospitalized with Covid-19, those who received hydroxychloroquine did not have a lower incidence of death at 28 days than those who received usual care. (Funded by UK Research and Innovation and National Institute for Health Research and others; RECOVERY ISRCTN number, ISRCTN50189673; ClinicalTrials.gov number, NCT04381936.).


Subject(s)
Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , Hydroxychloroquine/therapeutic use , Pneumonia, Viral/drug therapy , Aged , Aged, 80 and over , Antiviral Agents/adverse effects , Betacoronavirus , COVID-19 , Coronavirus Infections/mortality , Female , Hospitalization , Humans , Hydroxychloroquine/adverse effects , Male , Middle Aged , Pandemics , Pneumonia, Viral/mortality , Respiration, Artificial , SARS-CoV-2 , Treatment Failure
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