Pulmonary complications and mortality among COVID-19 patients undergoing a surgery: a multicenter cohort study (preprint)

Background Managing COVID-19-positive patients requiring surgery is complex due to perceived heightened perioperative risks. However, Canadian data in this context remains scarce. To address this gap, we conducted a multicenter cohort study in the province of Québec, the Canadian province most affected during the initial waves of the pandemic, to comprehensively assess the impact of COVID-19 symptoms, and recovery time, on postoperative outcomes in surgical patients. Methods We included adult surgical patients with either active COVID-19 at time of surgery or those who had recovered from the disease, from March 13, 2020, to April 30, 2021. We evaluated the association between symptoms or recovery time and postoperative pulmonary complications and hospital mortality using multivariable logistic regression and Cox models. Results We included 105 patients with an active infection (47 were symptomatic and 58 were asymptomatic) and 206 who had healed from COVID-19 in seven hospitals. Among patients with an active infection, those who were symptomatic had a higher risk of pulmonary complications (odds ratio = 3.19; 95% CI, from 1.12 to 9.68; p = 0.03) and hospital mortality (hazard ratio = 3.67; 95% CI, from 1.19 to 11.32; p = 0.02). We did not observe any significant effect of the duration of recovery prior to surgery on patients who had healed from their infection. Their postoperative outcomes were also similar to those observed in asymptomatic patients. Interpretation Symptomatic status should be considered in the decision to proceed with surgery in COVID-19-positive patients. Our results may help optimize surgical care in this patient population. Trial registration: ClinicalTrials.gov Identifier: NCT04458337, Registration Date: July 7, 2020.

REAL-WORLD EFFECTIVENESS OF NIRMATRELVIR/RITONAVIR ON COVID-19-ASSOCIATED HOSPITALIZATION PREVENTION: A POPULATION-BASED COHORT STUDY IN THE PROVINCE OF QUEBEC, CANADA (preprint)

ABSTRACT Introduction The nirmatrelvir/ritonavir (PAXLOVIDTM) is an antiviral blocking the replication of SARS-CoV-2. Early treatment with this antiviral has showed to reduce COVID-19 hospitalization and death in unvaccinated outpatients with mild-to-moderate COVID-19 and high risk of progression to severe disease with variants before Omicron. However, the current epidemiological context and the level of immunity in the population (vaccination and/or natural infection) have evolved considerably since the disclosure of these results. Thus, real-world evidence studies in vaccinated outpatients with lineage and sublineage of the variant are needed. Objective To assess whether nirmatrelvir/ritonavir treatment reduces the risk of COVID-19-associated hospitalization among Quebec outpatients with mild-to-moderate COVID-19 at high risk of progression to severe disease in a real-world context, regardless of vaccination status and circulating variants, in the province of Quebec. Methods This was a retrospective cohort study of SARS-CoV-2-infected outpatients who received nirmatrelvir/ritonavir between March 15 and August 15, 2022, using data from the Quebec provincial clinico-administrative databases. Outpatients treated with nirmatrelvir/ritonavir were compared to unexposed ones. The treatment group was matched with controls using propensity-score matching in a ratio of 1:1. The outcome was COVID-19-associated hospitalization occurring within 30 days following the index date. Poisson regression with robust error variance was used to estimate the relative risk of hospitalization among the treatment group compared to the control group. Results A total of 16,601 and 242,341 outpatients were eligible to be included in the treatment (nirmatrelvir/ritonavir) and control groups respectively. Among treated outpatients, 8,402 were matched to controls. Regardless of vaccination status, nirmatrelvir/ritonavir-treated outpatient status was associated with a 69% reduced relative risk of COVID-19-associated hospitalization (RR: 0.31 [95% CI: 0.28; 0.36]). The effect was more pronounced in outpatients without a complete primary vaccination course (RR: 0.04 [95% CI: 0.03; 0.06]), while treatment with nirmatrelvir/ritonavir was not associated with benefit when outpatients with a complete primary vaccination course were considered (RR: 0.93 [95% CI: 0.78; 1.08]) Subgroups analysis among outpatients with a primary vaccination course showed that nirmatrelvir/ritonavir treatment was associated with a significant decrease in relative risk of hospitalization in severely immunocompromised outpatients (RR: 0.66 [95% CI: 0.50; 0.89]) and in outpatients aged 70 years and older (RR: 0.50 [95% CI: 0.34; 0.74]) when the last dose of the vaccine was received more than six months before. Conclusions Among SARS-CoV-2 infected outpatients at high risk for severe COVID-19 during Omicron BA.2 and BA.4/5 surges, treatment with nirmatrelvir/ritonavir was associated with a significant reduced relative risk of COVID-19-associated hospitalization. This effect was observed in outpatients with incomplete primary vaccination course and in outpatients who were severely immunocompromised. Except for severely immunocompromised outpatients, no evidence of benefit was found in any category of outpatient with a complete primary vaccination course whose last dose of COVID-19 vaccine was received within six months.

Therapeutic Anticoagulation in Non-Critically Ill Patients with Covid-19 (preprint)

BackgroundThrombo-inflammation may contribute to morbidity and mortality in Covid-19. We hypothesized that therapeutic-dose anticoagulation may improve outcomes in non-critically ill patients hospitalized for Covid-19. MethodsIn an open-label adaptive multiplatform randomized controlled trial, non-critically ill patients hospitalized for Covid-19, defined by the absence of critical care-level organ support at enrollment, were randomized to a pragmatic strategy of therapeutic-dose anticoagulation with heparin or usual care pharmacological thromboprophylaxis. The primary outcome combined survival to hospital discharge and days free of organ support through 21 days, which was evaluated with Bayesian statistical models according to baseline D-dimer. ResultsThe trial was stopped when prespecified criteria for superiority were met for therapeutic-dose anticoagulation in groups defined by high ([≥]2-fold elevated) and low (<2-fold elevated) D-dimer. Among 2219 participants in the final analysis, the probability that therapeutic anticoagulation increased organ support-free days compared to thromboprophylaxis was 99.0% (adjusted odds ratio 1.29, 95% credible interval 1.04 to 1.61). The adjusted absolute increase in survival to hospital discharge without organ support with therapeutic-dose anticoagulation was 4.6% (95% credible interval 0.7 to 8.1). In the primary adaptive stopping groups, the final probabilities of superiority for therapeutic anticoagulation were 97.3% in the high D-dimer group and 92.9% in the low D-dimer group. Major bleeding occurred in 1.9% and 0.9% of participants randomized to therapeutic anticoagulation and thromboprophylaxis, respectively. ConclusionsIn non-critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increases the probability of survival to hospital discharge with reduced use of organ support. Trial registration numbers: NCT02735707, NCT04505774, NCT04359277, NCT04372589

Therapeutic Anticoagulation in Critically Ill Patients with Covid-19-Preliminary Report (preprint)

Background Thrombosis may contribute to morbidity and mortality in Covid-19. We hypothesized that therapeutic anticoagulation would improve outcomes in critically ill patients with Covid-19. Methods We conducted an open-label, adaptive, multiplatform, randomized, clinical trial. Patients with severe Covid-19, defined as the requirement for organ support with high flow nasal cannula, non-invasive ventilation, invasive ventilation, vasopressors, or inotropes, were randomized to receive therapeutic anticoagulation with heparin or pharmacological thromboprophylaxis as per local usual care. The primary outcome was an ordinal scale combining in-hospital mortality (assigned -1) and days free of organ support to day 21. Results Therapeutic anticoagulation met the pre-defined criteria for futility in patients with severe Covid-19. The primary outcome was available for 1,074 participants (529 randomized to therapeutic anticoagulation and 545 randomized to usual care pharmacological thromboprophylaxis). Median organ support-free days were 3 days (interquartile range -1, 16) in patients assigned to therapeutic anticoagulation and 5 days (interquartile range -1, 16) in patients assigned to usual care pharmacological thromboprophylaxis (adjusted odds ratio 0.87, 95% credible interval (CrI) 0.70-1.08, posterior probability of futility [odds ratio<1.2] 99.8%). Hospital survival was comparable between groups (64.3% vs. 65.3%, adjusted odds ratio 0.88, 95% CrI 0.67-1.16). Major bleeding occurred in 3.1% of patients assigned to therapeutic anticoagulation and 2.4% of patients assigned to usual care pharmacological thromboprophylaxis. Conclusions In patients with severe Covid-19, therapeutic anticoagulation did not improve hospital survival or days free of organ support compared to usual care pharmacological thromboprophylaxis.

Convalescent plasma for adults with acute COVID-19 respiratory illness (CONCOR-1): Study protocol for an international, multicenter, randomized, open-label trial (preprint)

Background: Convalescent plasma has been used for numerous viral diseases including influenza, severe acute respiratory syndrome, Middle East respiratory syndrome and Ebola virus; however, evidence to support its use is weak. SARS-CoV-2 is a novel coronavirus responsible for the 2019 global pandemic of COVID-19 community acquired pneumonia. We have undertaken a randomized controlled trial to assess the efficacy and safety of COVID-19 convalescent plasma (CCP) in patients with SARS-CoV-2 infection.Methods: CONCOR-1 is an open-label, multicenter, randomized trial. Inclusion criteria include: patients >16 years; admitted to hospital with COVID-19 infection; receiving supplemental oxygen for respiratory complications of COVID-19; and, availability of blood group compatible CCP. Exclusion criteria are: onset of respiratory symptoms more than 12 days prior to randomization; intubated or planned for intubation; and previous severe reactions to plasma. Consenting patients will be randomized 2:1 to receive either approximately 500 mL of CCP or standard of care. CCP will be collected from donors who have recovered from COVID-19 and who have detectable anti-SARS-CoV-2 antibodies quantified serologically. The primary outcome is intubation or death at Day 30. Secondary outcomes include ventilator free days, length of stay in intensive care or hospital, transfusion reactions, serious adverse events, and reduction in SARS-CoV-2 viral load.  Exploratory analyses include patients who received CCP containing high titre antibodies. A sample size of 1200 patients gives 80% power to detect a 25% relative risk reduction assuming a 30% baseline risk of intubation or death at 30 days (two-sided test; α =0.05). An interim analysis and sample size re-estimation will be done by an unblinded independent biostatistician after primary outcome data are available for 50% of the target recruitment (n= 600). Discussion: This trial will determine whether CCP will reduce intubation or death non-intubated adults with COVID-19. The trial will also provide information on the role of and thresholds for SARS-CoV-2 antibody titers and neutralization assays for donor qualification.Trial registration: Clinicaltrials.gov NCT04348656; registered 16 April 2020; https://clinicaltrials.gov/ct2/show/NCT04348656?term=NCT04348656&draw=2&rank=1

Post-exposure Prophylaxis or Preemptive Therapy for SARS-Coronavirus-2: Study Protocol for a Pragmatic Randomized Controlled Trial (preprint)

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 causing the coronavirus disease 2019 (COVID-19) pandemic. Currently, there are a lack of evidence-based therapies to prevent COVID-19 following exposure, or to prevent worsening of symptoms following confirmed infection. We describe the design of a clinical trial of hydroxychloroquine for post-exposure prophylaxis and pre-emptive therapy for COVID-19. Methods: We will conduct two nested multicenter international double-blind randomized placebo-controlled clinical trials of hydroxychloroquine for: 1) post-exposure prophylaxis (PEP) of asymptomatic household contacts or healthcare workers exposed to COVID-19 within the past four days, and 2) pre-emptive therapy (PET) for symptomatic outpatients with COVID-19 with a total symptom duration of less than 4 days. We will recruit 1500 patients for each the PEP and PET trials. Participants will be randomized 1:1 to receive 5 days of hydroxychloroquine or placebo. The primary PEP trial outcome will be the incidence of symptomatic COVID-19 disease. The primary PET trial outcome will be an ordinal scale of disease severity (not hospitalized; hospitalized without intensive care, hospitalization with intensive care, or death). Participant screening, informed consent, and follow up will be exclusively internet-based with appropriate regulatory and research ethics board approvals in Canada and the United States. Discussion: These complementary randomized control trials are innovatively designed and adequately powered to rapidly answer urgent questions regarding the effectiveness of hydroxychloroquine to reduce transmission and disease severity of COVID-19 during a pandemic. In-person participant follow-up will not be conducted in order to facilitate social distancing strategies and reduce risks of exposure to study personnel. Innovative trial approaches are needed to urgently assess therapeutic options to mitigate the global impact of this pandemic. Trials Registration: clinicaltrials.gov (NCT04308668); 16 March 2020.