Effect of Antiplatelet Therapy on Survival and Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial.

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.

Development and validation of a tool to appraise guidelines on SARS-CoV-2 infection control strategies in healthcare workers.

BACKGROUND: Clinical guidelines on infection control strategies in healthcare workers (HCWs) play an important role in protecting them during the severe acute respiratory syndrome coronavirus 2 pandemic. Poorly constructed guidelines that are incomprehensive and/or ambiguous may compromise HCWs' safety. OBJECTIVE: The objective of this study was to develop and validate a tool to appraise guidelines on infection control strategies in HCWs based on the guidelines published early in the coronavirus disease 2019 pandemic. DESIGN, SETTING, AND OUTCOMES: A three-stage, web-based, Delphi consensus-building process among a panel of diverse HCWs and healthcare managers was performed. The tool was validated by appraising 40 international, specialty-specific, and procedure-specific guidelines along with national guidelines from countries with a wide range of gross national income. RESULTS: Overall consensus (≥75%) was reached at the end of three rounds for all six domains included in the tool. The Delphi panel recommended an ideal infection control guideline should encompass six domains: general characteristics (domain 1), engineering recommendations (domain 2), personal protective equipment (PPE) use (domain 3), and administrative aspects (domain 4-6) of infection control. The appraisal tool performed well across the six domains, and the inter-rater agreement was excellent for the 40 guidelines. All included guidelines performed relatively better in domains 1-3 than in domains 4-6, and this was more evident in guidelines originating from lower income countries. CONCLUSION: The guideline appraisal tool was robust and easy to use. Engineering recommendations aspects of infection control, administrative measures that promote optimal PPE use, and HCW wellbeing were generally lacking in assessed guidelines. This tool may enable health systems to adopt high-quality HCW infection control guidelines during the severe acute respiratory syndrome coronavirus 2 pandemic and may also provide a framework for future guideline development.

Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19.

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.).

Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19.

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.).

Personal protective equipment preparedness in intensive care units during the coronavirus disease 2019 pandemic: An Asia-Pacific follow-up survey.

BACKGROUND: Personal-protective equipment (PPE)-preparedness, defined as adherence to guidelines, healthcare worker (HCW) training, procuring PPE stocks and responding appropriately to suspected cases, is crucial to prevent HCW-infections. OBJECTIVES: To perform a follow-up survey to assess changes in PPE-preparedness across six Asia-Pacific countries during the COVID-19 pandemic. METHODS: A prospective follow-up cross-sectional, web-based survey was conducted between 10/08/2020 to 01/09/ 2020, five months after the initial Phase 1 survey. The survey was sent to the same 231 intensivists across the six Asia-Pacific countries (Australia, Hong Kong, India, New Zealand, Philippines, and Singapore) that participated in Phase 1. The main outcome measure was to identify any changes in PPE-preparedness between Phases 1 and 2. FINDINGS: Phase 2 had responses from 132 ICUs (57%). Compared to Phase 1 respondents reported increased use of PPE-based practices such as powered air-purifying respirator (40.2% vs. 6.1%), N95-masks at all times (86.4% vs. 53.7%) and double-gloving (87.9% vs. 42.9%). The reported awareness of PPE stocks (85.6% vs. 51.9%), mandatory showering policies following PPE-breach (31.1% vs. 6.9%) and safety perception amongst HCWs (60.6% vs. 28.4%) improved significantly during Phase 2. Despite reported statistically similar adoption rate of the buddy system in both phases (42.4% vs. 37.2%), there was a reported reduction in donning/doffing training in Phase 2 (44.3% vs. 60.2%). There were no reported differences HCW training in other areas, such as tracheal intubation, intra-hospital transport and safe waste disposal, between the 2 phases. CONCLUSIONS: Overall reported PPE-preparedness improved between the two survey periods, particularly in PPE use, PPE inventory and HCW perceptions of safety. However, the uptake of HCW training and implementation of low-cost safety measures continued to be low and the awareness of PPE breach management policies were suboptimal. Therefore, the key areas for improvement should focus on regular HCW training, implementing low-cost buddy-system and increasing awareness of PPE-breach management protocols.

Potential for bacteriophage therapy for Staphylococcus aureus pneumonia with influenza A coinfection.

The ability of influenza A virus to evolve, coupled with increasing antimicrobial resistance, could trigger an influenza pandemic with great morbidity and mortality. Much of the 1918 influenza pandemic mortality was likely due to bacterial coinfection, including Staphylococcus aureus pneumonia. S. aureus resists many antibiotics. The lack of new antibiotics suggests alternative antimicrobials, such as bacteriophages, are needed. Potential delivery routes for bacteriophage therapy (BT) include inhalation and intravenous injection. BT has recently been used successfully in compassionate access pulmonary infection cases. Phage lysins, enzymes that hydrolyze bacterial cell walls and which are bactericidal, are efficacious in animal pneumonia models. Clinical trials will be needed to determine whether BT can ameliorate disease in influenza and S. aureus coinfection.

Personal protective equipment preparedness in Asia-Pacific intensive care units during the coronavirus disease 2019 pandemic: A multinational survey.

BACKGROUND: There has been a surge in coronavirus disease 2019 admissions to intensive care units (ICUs) in Asia-Pacific countries. Because ICU healthcare workers are exposed to aerosol-generating procedures, ensuring optimal personal protective equipment (PPE) preparedness is important. OBJECTIVE: The aim of the study was to evaluate PPE preparedness across ICUs in six Asia-Pacific countries during the initial phase of the coronavirus disease 2019 pandemic, which is defined by the World Health Organization as guideline adherence, training healthcare workers, procuring stocks, and responding appropriately to suspected cases. METHODS: A cross-sectional Web-based survey was circulated to 633 level II/III ICUs of Australia, New Zealand (NZ), Singapore, Hong Kong (HK), India, and the Philippines. FINDINGS: Two hundred sixty-three intensivists responded, representing 231 individual ICUs eligible for analysis. Response rates were 68-100% in all countries except India, where it was 24%. Ninety-seven percent of ICUs either conformed to or exceeded World Health Organization recommendations for PPE practice. Fifty-nine percent ICUs used airborne precautions irrespective of aerosol generation procedures. There were variations in negative-pressure room use (highest in HK/Singapore), training (best in NZ), and PPE stock awareness (best in HK/Singapore/NZ). High-flow nasal oxygenation and noninvasive ventilation were not options in most HK (66.7% and 83.3%, respectively) and Singapore ICUs (50% and 80%, respectively), but were considered in other countries to a greater extent. Thirty-eight percent ICUs reported not having specialised airway teams. Showering and "buddy systems" were underused. Clinical waste disposal training was suboptimal (38%). CONCLUSIONS: Many ICUs in the Asia-Pacific reported suboptimal PPE preparedness in several domains, particularly related to PPE training, practice, and stock awareness, which requires remediation. Adoption of low-cost approaches such as buddy systems should be encouraged. The complete avoidance of high-flow nasal oxygenation reported by several intensivists needs reconsideration. Consideration must be given to standardise PPE guidelines to minimise practice variations. Urgent research to evaluate PPE preparedness and severe acute respiratory syndrome coronavirus 2 transmission is required.