Randomized trials of therapeutic heparin for COVID-19: A meta-analysis.

BACKGROUND: Pulmonary endothelial injury and microcirculatory thromboses likely contribute to hypoxemic respiratory failure, the most common cause of death, in patients with COVID-19. Randomized controlled trials (RCTs) suggest differences in the effect of therapeutic heparin between moderately and severely ill patients with COVID-19. We did a systematic review and meta-analysis of RCTs to determine the effects of therapeutic heparin in hospitalized patients with COVID-19. METHODS: We searched PubMed, Embase, Web of Science, medRxiv, and medical conference proceedings for RCTs comparing therapeutic heparin with usual care, excluding trials that used oral anticoagulation or intermediate doses of heparin in the experimental arm. Mantel-Haenszel fixed-effect meta-analysis was used to combine odds ratios (ORs). RESULTS AND CONCLUSIONS: There were 3 RCTs that compared therapeutic heparin to lower doses of heparin in 2854 moderately ill ward patients, and 3 RCTs in 1191 severely ill patients receiving critical care. In moderately ill patients, there was a nonsignificant reduction in all-cause death (OR, 0.76; 95% CI, 0.57-1.02), but significant reductions in the composite of death or invasive mechanical ventilation (OR, 0.77; 95% CI, 0.60 0.98), and death or any thrombotic event (OR, 0.58; 95% CI, 0.45-0.77). Organ support-free days alive (OR, 1.29; 95% CI, 1.07-1.57) were significantly increased with therapeutic heparin. There was a nonsignificant increase in major bleeding. In severely ill patients, there was no evidence for benefit of therapeutic heparin, with significant treatment-by-subgroup interactions with illness severity for all-cause death (P = .034). In conclusion, therapeutic heparin is beneficial in moderately ill patients but not in severely ill patients hospitalized with COVID-19.

Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial.

OBJECTIVE: To evaluate the effects of therapeutic heparin compared with prophylactic heparin among moderately ill patients with covid-19 admitted to hospital wards. DESIGN: Randomised controlled, adaptive, open label clinical trial. SETTING: 28 hospitals in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and US. PARTICIPANTS: 465 adults admitted to hospital wards with covid-19 and increased D-dimer levels were recruited between 29 May 2020 and 12 April 2021 and were randomly assigned to therapeutic dose heparin (n=228) or prophylactic dose heparin (n=237). INTERVENTIONS: Therapeutic dose or prophylactic dose heparin (low molecular weight or unfractionated heparin), to be continued until hospital discharge, day 28, or death. MAIN OUTCOME MEASURES: The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation, or admission to an intensive care unit, assessed up to 28 days. The secondary outcomes included all cause death, the composite of all cause death or any mechanical ventilation, and venous thromboembolism. Safety outcomes included major bleeding. Outcomes were blindly adjudicated. RESULTS: The mean age of participants was 60 years; 264 (56.8%) were men and the mean body mass index was 30.3 kg/m2. At 28 days, the primary composite outcome had occurred in 37/228 patients (16.2%) assigned to therapeutic heparin and 52/237 (21.9%) assigned to prophylactic heparin (odds ratio 0.69, 95% confidence interval 0.43 to 1.10; P=0.12). Deaths occurred in four patients (1.8%) assigned to therapeutic heparin and 18 patients (7.6%) assigned to prophylactic heparin (0.22, 0.07 to 0.65; P=0.006). The composite of all cause death or any mechanical ventilation occurred in 23 patients (10.1%) assigned to therapeutic heparin and 38 (16.0%) assigned to prophylactic heparin (0.59, 0.34 to 1.02; P=0.06). Venous thromboembolism occurred in two patients (0.9%) assigned to therapeutic heparin and six (2.5%) assigned to prophylactic heparin (0.34, 0.07 to 1.71; P=0.19). Major bleeding occurred in two patients (0.9%) assigned to therapeutic heparin and four (1.7%) assigned to prophylactic heparin (0.52, 0.09 to 2.85; P=0.69). CONCLUSIONS: In moderately ill patients with covid-19 and increased D-dimer levels admitted to hospital wards, therapeutic heparin was not significantly associated with a reduction in the primary outcome but the odds of death at 28 days was decreased. The risk of major bleeding appeared low in this trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT04362085.

Viscosupplementation for knee osteoarthritis: systematic review and meta-analysis.

OBJECTIVE: To evaluate the effectiveness and safety of viscosupplementation for pain and function in patients with knee osteoarthritis. DESIGN: Systematic review and meta-analysis of randomised trials. DATA SOURCES: Searches were conducted of Medline, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases from inception to 11 September 2021. Unpublished trials were identified from the grey literature and trial registries. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Randomised trials comparing viscosupplementation with placebo or no intervention for knee osteoarthritis treatment. MAIN OUTCOME MEASURES: The prespecified primary outcome was pain intensity. Secondary outcomes were function and serious adverse events. Pain and function were analysed as standardised mean differences (SMDs). The prespecified minimal clinically important between group difference was -0.37 SMD. Serious adverse events were analysed as relative risks. METHODS: Two reviewers independently extracted relevant data and assessed the risk of bias of trials using the Cochrane risk of bias tool. The predefined main analysis was based only on large, placebo controlled trials with ≥100 participants per group. Summary results were obtained through a random effects meta-analysis model. Cumulative meta-analysis and trial sequential analysis under a random effects model were also performed. RESULTS: 169 trials provided data on 21 163 randomised participants. Evidence of small study effects and publication biases was observed for pain and function (Egger's tests with P<0.001 and asymmetric funnel plots). Twenty four large, placebo controlled trials (8997 randomised participants) included in the main analysis of pain indicated that viscosupplementation was associated with a small reduction in pain intensity compared with placebo (SMD -0.08, 95% confidence interval -0.15 to -0.02), with the lower bound of the 95% confidence interval excluding the minimal clinically important between group difference. This effect corresponds to a difference in pain scores of -2.0 mm (95% confidence interval -3.8 to -0.5 mm) on a 100 mm visual analogue scale. Trial sequential analysis for pain indicated that since 2009 there has been conclusive evidence of clinical equivalence between viscosupplementation and placebo. Similar conclusions were obtained for function. Based on 15 large, placebo controlled trials on 6462 randomised participants, viscosupplementation was associated with a statistically significant higher risk of serious adverse events than placebo (relative risk 1.49, 95% confidence interval 1.12 to 1.98). CONCLUSION: Strong conclusive evidence indicates that viscosupplementation leads to a small reduction in knee osteoarthritis pain compared with placebo, but the difference is less than the minimal clinically important between group difference. Strong conclusive evidence indicates that viscosupplementation is also associated with an increased risk of serious adverse events compared with placebo. The findings do not support broad use of viscosupplementation for the treatment of knee osteoarthritis. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021236894.

Prone positioning of patients with moderate hypoxaemia due to covid-19: multicentre pragmatic randomised trial (COVID-PRONE).

OBJECTIVES: To assess the effectiveness of prone positioning to reduce the risk of death or respiratory failure in non-critically ill patients admitted to hospital with covid-19. DESIGN: Multicentre pragmatic randomised clinical trial. SETTING: 15 hospitals in Canada and the United States from May 2020 until May 2021. PARTICIPANTS: Eligible patients had a laboratory confirmed or a clinically highly suspected diagnosis of covid-19, needed supplemental oxygen (up to 50% fraction of inspired oxygen), and were able to independently lie prone with verbal instruction. Of the 570 patients who were assessed for eligibility, 257 were randomised and 248 were included in the analysis. INTERVENTION: Patients were randomised 1:1 to prone positioning (that is, instructing a patient to lie on their stomach while they are in bed) or standard of care (that is, no instruction to adopt prone position). MAIN OUTCOME MEASURES: The primary outcome was a composite of in-hospital death, mechanical ventilation, or worsening respiratory failure defined as needing at least 60% fraction of inspired oxygen for at least 24 hours. Secondary outcomes included the change in the ratio of oxygen saturation to fraction of inspired oxygen. RESULTS: The trial was stopped early on the basis of futility for the pre-specified primary outcome. The median time from hospital admission until randomisation was 1 day, the median age of patients was 56 (interquartile range 45-65) years, 89 (36%) patients were female, and 222 (90%) were receiving oxygen via nasal prongs at the time of randomisation. The median time spent prone in the first 72 hours was 6 (1.5-12.8) hours in total for the prone arm compared with 0 (0-2) hours in the control arm. The risk of the primary outcome was similar between the prone group (18 (14%) events) and the standard care group (17 (14%) events) (odds ratio 0.92, 95% confidence interval 0.44 to 1.92). The change in the ratio of oxygen saturation to fraction of inspired oxygen after 72 hours was similar for patients randomised to prone positioning and standard of care. CONCLUSION: Among non-critically ill patients with hypoxaemia who were admitted to hospital with covid-19, a multifaceted intervention to increase prone positioning did not improve outcomes. However, wide confidence intervals preclude definitively ruling out benefit or harm. Adherence to prone positioning was poor, despite multiple efforts to increase it. Subsequent trials of prone positioning should aim to develop strategies to improve adherence to awake prone positioning. STUDY REGISTRATION: ClinicalTrials.gov NCT04383613.

Cash transfer during the COVID-19 pandemic: a multicentre, randomised controlled trial.

OBJECTIVE: To evaluate the effect of a one-time cash transfer of $C1000 in people who are unable to physically distance due to insufficient income. DESIGN: Open-label, multi-centre, randomised superiority trial. SETTING: Seven primary care sites in Ontario, Canada; six urban sites associated with St. Michael's Hospital in Toronto and one in Manitoulin Island. PARTICIPANTS: 392 individuals who reported trouble affording basic necessities due to disruptions related to COVID-19. INTERVENTION: After random allocation, participants either received the cash transfer of $C1000 (n=196) or physical distancing guidelines alone (n=196). MAIN OUTCOME MEASURES: The primary outcome was the maximum number of symptoms consistent with COVID-19 over 14 days. Secondary outcomes were meeting clinical criteria for COVID-19, SARS-CoV-2 presence, number of close contacts, general health and ability to afford basic necessities. RESULTS: The primary outcome of number of symptoms reported by participants did not differ between groups after 2 weeks (cash transfer, mean 1.6 vs 1.9, ratio of means 0.83; 95% CI 0.56 to 1.24). There were no statistically significant effects on secondary outcomes of the meeting COVID-19 clinical criteria (7.9% vs 12.8%; risk difference -0.05; 95% CI -0.11 to 0.01), SARS-CoV-2 presence (0.5% vs 0.6%; risk difference 0.00 95% CI -0.02 to 0.02), mean number of close contacts (3.5 vs 3.7; rate ratio 1.10; 95% CI 0.83 to 1.46), general health very good or excellent (60% vs 63%; risk difference -0.03 95% CI -0.14 to 0.08) and ability to make ends meet (52% vs 51%; risk difference 0.01 95% CI -0.10 to 0.12). CONCLUSIONS: A single cash transfer did not reduce the COVID-19 symptoms or improve the ability to afford necessities. Further studies are needed to determine whether some groups may benefit from financial supports and to determine if a higher level of support is beneficial. TRIAL REGISTRATION NUMBER: NCT04359264.

Cash transfer during the COVID-19 pandemic: a multicentre, randomised controlled trial

Objective To evaluate the effect of a one-time cash transfer of $C1000 in people who are unable to physically distance due to insufficient income. Design Open-label, multi-centre, randomised superiority trial. Setting Seven primary care sites in Ontario, Canada;six urban sites associated with St. Michael’s Hospital in Toronto and one in Manitoulin Island. Participants 392 individuals who reported trouble affording basic necessities due to disruptions related to COVID-19. Intervention After random allocation, participants either received the cash transfer of $C1000 (n=196) or physical distancing guidelines alone (n=196). Main outcome measures The primary outcome was the maximum number of symptoms consistent with COVID-19 over 14 days. Secondary outcomes were meeting clinical criteria for COVID-19, SARS-CoV-2 presence, number of close contacts, general health and ability to afford basic necessities. Results The primary outcome of number of symptoms reported by participants did not differ between groups after 2 weeks (cash transfer, mean 1.6 vs 1.9, ratio of means 0.83;95% CI 0.56 to 1.24). There were no statistically significant effects on secondary outcomes of the meeting COVID-19 clinical criteria (7.9% vs 12.8%;risk difference −0.05;95% CI −0.11 to 0.01), SARS-CoV-2 presence (0.5% vs 0.6%;risk difference 0.00 95% CI −0.02 to 0.02), mean number of close contacts (3.5 vs 3.7;rate ratio 1.10;95% CI 0.83 to 1.46), general health very good or excellent (60% vs 63%;risk difference −0.03 95% CI −0.14 to 0.08) and ability to make ends meet (52% vs 51%;risk difference 0.01 95% CI −0.10 to 0.12). Conclusions A single cash transfer did not reduce the COVID-19 symptoms or improve the ability to afford necessities. Further studies are needed to determine whether some groups may benefit from financial supports and to determine if a higher level of support is beneficial. Trial registration number NCT04359264.

Coagulopathy of hospitalised COVID-19: A Pragmatic Randomised Controlled Trial of Therapeutic Anticoagulation versus Standard Care as a Rapid Response to the COVID-19 Pandemic (RAPID COVID COAG - RAPID Trial): A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: To determine the effect of therapeutic anticoagulation, with low molecular weight heparin (LMWH) or unfractionated heparin (UFH, high dose nomogram), compared to standard care in hospitalized patients admitted for COVID-19 with an elevated D-dimer on the composite outcome of intensive care unit (ICU) admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death up to 28 days. TRIAL DESIGN: Open-label, parallel, 1:1, phase 3, 2-arm randomized controlled trial PARTICIPANTS: The study population includes hospitalized adults admitted for COVID-19 prior to the development of critical illness. Excluded individuals are those where the bleeding risk or risk of transfusion would generally be considered unacceptable, those already therapeutically anticoagulated and those who have already have any component of the primary composite outcome. Participants are recruited from hospital sites in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and the United States of America. The inclusion criteria are: 1) Laboratory confirmed COVID-19 (diagnosis of SARS-CoV-2 via reverse transcriptase polymerase chain reaction as per the World Health Organization protocol or by nucleic acid based isothermal amplification) prior to hospital admission OR within first 5 days (i.e. 120 hours) after hospital admission; 2) Admitted to hospital for COVID-19; 3) One D-dimer value above the upper limit of normal (ULN) (within 5 days (i.e. 120 hours) of hospital admission) AND EITHER: a. D-Dimer ≥2 times ULN OR b. D-Dimer above ULN and Oxygen saturation ≤ 93% on room air; 4) > 18 years of age; 5) Informed consent from the patient (or legally authorized substitute decision maker). The exclusion criteria are: 1) pregnancy; 2) hemoglobin <80 g/L in the last 72 hours; 3) platelet count <50 x 109/L in the last 72 hours; 4) known fibrinogen <1.5 g/L (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); 5) known INR >1.8 (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); 6) patient already prescribed intermediate dosing of LMWH that cannot be changed (determination of what constitutes an intermediate dose is to be at the discretion of the treating clinician taking the local institutional thromboprophylaxis protocol for high risk patients into consideration); 7) patient already prescribed therapeutic anticoagulation at the time of screening [low or high dose nomogram UFH, LMWH, warfarin, direct oral anticoagulant (any dose of dabigatran, apixaban, rivaroxaban, edoxaban)]; 8) patient prescribed dual antiplatelet therapy, when one of the agents cannot be stopped safely; 9) known bleeding within the last 30 days requiring emergency room presentation or hospitalization; 10) known history of a bleeding disorder of an inherited or active acquired bleeding disorder; 11) known history of heparin-induced thrombocytopenia; 12) known allergy to UFH or LMWH; 13) admitted to the intensive care unit at the time of screening; 14) treated with non-invasive positive pressure ventilation or invasive mechanical ventilation at the time of screening; 15) Imminent death according to the judgement of the most responsible physician; 16) enrollment in another clinical trial of antithrombotic therapy involving hospitalized patients. INTERVENTION AND COMPARATOR: Intervention: Therapeutic dose of LMWH (dalteparin, enoxaparin, tinzaparin) or high dose nomogram of UFH. The choice of LMWH versus UFH will be at the clinician's discretion and dependent on local institutional supply. Comparator: Standard care [thromboprophylactic doses of LMWH (dalteparin, enoxaparin, tinzaparin, fondaparinux)] or UFH. Administration of LMWH, UFH or fondaparinux at thromboprophylactic doses for acutely ill hospitalized medical patients, in the absence of contraindication, is generally considered standard care. MAIN OUTCOMES: The primary composite outcome of ICU admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death at 28 days. Secondary outcomes include (evaluated up to day 28): 1. All-cause death 2. Composite of ICU admission or all-cause death 3. Composite of mechanical ventilation or all-cause death 4. Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation; 5. Red blood cell transfusion (>1 unit); 6. Transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipitate and/or fibrinogen concentrate; 7. Renal replacement therapy; 8. Hospital-free days alive; 9. ICU-free days alive; 10. Ventilator-free days alive; 11. Organ support-free days alive; 12. Venous thromboembolism (defined as symptomatic or incidental, suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate); 13. Arterial thromboembolism (defined as suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate); 14. Heparin induced thrombocytopenia; 15. Trajectories of COVID-19 disease-related coagulation and inflammatory biomarkers. RANDOMISATION: Randomisation will be stratified by site and age (>65 versus ≤65 years) using a 1:1 computer-generated random allocation sequence with variable block sizes. Randomization will occur within the first 5 days (i.e. 120 hours) of participant hospital admission. However, it is recommended that randomization occurs as early as possible after hospital admission. Central randomization using an interactive web response system will ensure allocation concealment. BLINDING (MASKING): No blinding involved. This is an open-label trial. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): 462 patients (231 per group) are needed to detect a 15% risk difference, from 50% in the control group to 35% in the experimental group, with power of 90% at a two-sided alpha of 0.05. TRIAL STATUS: Protocol Version Number 1.4. Recruitment began on May 11th, 2020. Recruitment is expected to be completed March 2022. Recruitment is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04362085 Date of Trial Registration: April 24, 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Effets du climat et des interventions de santé publique sur la pandémie de COVID-19 : une étude de cohorte prospective.

CONTEXTE: On ignore si les variations climatiques saisonnières, la fermeture des établissements scolaires ou d'autres interventions de santé publique entraîneront un ralentissement de la pandémie actuelle de maladie à coronavirus 2019 (COVID-19). Nous avons voulu déterminer si de façon globale la progression de l'épidémie est associée au climat ou aux interventions de santé publique visant à réduire la transmission du coronavirus du syndrome respiratoire aigu sévère 2 (SRAS-CoV-2). MÉTHODES: Nous avons procédé à une étude de cohorte prospective des 144 régions géopolitiques de la planète (375 609 cas) présentant au moins 10 cas de COVID-19, avec transmission locale, en date du 20 mars 2020, à l'exclusion de la Chine, de la Corée du Sud, de l'Iran et de l'Italie. Par analyse de régression à effets aléatoires pondérée, nous avons évalué le lien entre la progression de l'épidémie (exprimée sous forme de rapports de taux d'incidence [RTI] comparant les nombres cumulatifs de cas de COVID-19 du 27 mars 2020 à ceux du 20 mars 2020) avec les facteurs de latitude, température, humidité, fermeture des établissements scolaires, interdiction des grands rassemblements et mesures d'éloignement social qui étaient en place les 7 et 13 mars 2020 (période de 14 jours antérieure à l'évaluation). RÉSULTATS: Les analyses univariées ont révélé aucuns lien entre la progression de l'épidémie et les facteurs de latitude et de température, mais des liens négatifs faibles avec l'humidité relative (RTI par 10 %, 0,91, intervalle de confiance [IC] de 95 % 0,85­0,96) et l'humidité absolue (RTI par 5 g/m3 0,92, IC à 95 % 0,85­0,99). Des liens étroits ont été observés avec l'interdiction des grands rassemblements (RTI 0,65, IC à 95 % 0,53­0,79), la fermeture des établissements scolaires (RTI 0,63, IC à 95 % 0,52­0,78) et les mesures d'éloignement social (RTI 0,62, IC à 95 % 0,45­0,85). Dans un modèle multivarié, on a noté un lien étroit avec le nombre de mesures déployées par la santé publique (p pour tendance = 0,001), tandis que le lien avec l'humidité absolue s'atténuait. INTERPRÉTATION: La progression de l'épidémie de COVID-19 ne s'est pas révélée en lien avec la latitude ni avec la température, mais faiblement en lien avec l'humidité relative ou absolue. À l'inverse, les interventions de santé publique ont été étroitement associées à un ralentissement de la progression de l'épidémie.

Impact of climate and public health interventions on the COVID-19 pandemic: a prospective cohort study.

BACKGROUND: It is unclear whether seasonal changes, school closures or other public health interventions will result in a slowdown of the current coronavirus disease 2019 (COVID-19) pandemic. We aimed to determine whether epidemic growth is globally associated with climate or public health interventions intended to reduce transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We performed a prospective cohort study of all 144 geopolitical areas worldwide (375 609 cases) with at least 10 COVID-19 cases and local transmission by Mar. 20, 2020, excluding China, South Korea, Iran and Italy. Using weighted random-effects regression, we determined the association between epidemic growth (expressed as ratios of rate ratios [RRR] comparing cumulative counts of COVID-19 cases on Mar. 27, 2020, with cumulative counts on Mar. 20, 2020) and latitude, temperature, humidity, school closures, restrictions of mass gatherings, and measures of social distancing during an exposure period 14 days previously (Mar. 7 to 13, 2020). RESULTS: In univariate analyses, there were no associations of epidemic growth with latitude and temperature, but weak negative associations with relative humidity (RRR per 10% 0.91, 95% confidence interval [CI] 0.85-0.96) and absolute humidity (RRR per 5 g/m3 0.92, 95% CI 0.85-0.99). Strong associations were found for restrictions of mass gatherings (RRR 0.65, 95% CI 0.53-0.79), school closures (RRR 0.63, 95% CI 0.52-0.78) and measures of social distancing (RRR 0.62, 95% CI 0.45-0.85). In a multivariable model, there was a strong association with the number of implemented public health interventions (p for trend = 0.001), whereas the association with absolute humidity was no longer significant. INTERPRETATION: Epidemic growth of COVID-19 was not associated with latitude and temperature, but may be associated weakly with relative or absolute humidity. Conversely, public health interventions were strongly associated with reduced epidemic growth.