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.

The Impact of a Clinical Decision Support System for Addressing Physical Activity and Healthy Eating During Smoking Cessation Treatment: Hybrid Type I Randomized Controlled Trial.

BACKGROUND: People who smoke have other risk factors for chronic diseases, such as low levels of physical activity and poor diet. Clinical decision support systems (CDSSs) might help health care practitioners integrate interventions for diet and physical activity into their smoking cessation programming but could worsen quit rates. OBJECTIVE: The aims of this study are to assess the effects of the addition of a CDSS for physical activity and diet on smoking cessation outcomes and to assess the implementation of the study. METHODS: We conducted a pragmatic hybrid type I effectiveness-implementation trial with 232 team-based primary care practices in Ontario, Canada, from November 2019 to May 2021. We used a 2-arm randomized controlled trial comparing a CDSS addressing physical activity and diet to treatment as usual and used the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework to measure implementation outcomes. The primary outcome was self-reported 7-day tobacco abstinence at 6 months. RESULTS: We enrolled 5331 participants in the study. Of these, 2732 (51.2%) were randomized to the intervention group and 2599 (48.8%) to the control group. At the 6-month follow-up, 29.7% (634/2137) of respondents in the intervention arm and 27.3% (552/2020) in the control arm reported abstinence from tobacco. After multiple imputation, the absolute group difference was 2.1% (95% CI -0.5 to 4.6; F1,1000.42=2.43; P=.12). Mean exercise minutes changed from 32 (SD 44.7) to 110 (SD 196.1) in the intervention arm and from 32 (SD 45.1) to 113 (SD 195.1) in the control arm (group effect: B=-3.7 minutes; 95% CI -17.8 to 10.4; P=.61). Servings of fruit and vegetables changed from 2.64 servings to 2.42 servings in the intervention group and from 2.52 servings to 2.45 servings in the control group (incidence rate ratio for intervention group=0.98; 95% CI 0.93-1.02; P=.35). CONCLUSIONS: A CDSS for physical activity and diet may be added to a smoking cessation program without affecting the outcomes. Further research is needed to improve the impact of integrated health promotion interventions in primary care smoking cessation programs. TRIAL REGISTRATION: ClinicalTrials.gov NCT04223336 https://www.clinicaltrials.gov/ct2/show/NCT04223336. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/19157.

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.

Genetics Adviser: a protocol for a mixed-methods randomised controlled trial evaluating a digital platform for genetics service delivery.

INTRODUCTION: The high demand for genetic tests and limited supply of genetics professionals has created a need for alternative service delivery models. Digital tools are increasingly being used to support multiple points in the genetic testing journey; however, none are transferable across multiple clinical specialties and settings nor do they encompass the entire trajectory of the journey. We aim to evaluate the effectiveness of the Genetics Adviser, an interactive, patient-facing, online digital health tool that delivers pre-test counselling, provides support during the waiting period for results, and returns results with post-test counselling, encompassing the entire patient genetic testing journey. METHODS AND ANALYSIS: We will compare the Genetics Adviser paired with a brief genetic counselling session to genetic counselling alone in a randomised controlled trial. One hundred and forty patients who previously received uninformative genetic test results for their personal and family history of cancer will be recruited from familial cancer clinics in Toronto and offered all clinically significant results from genomic sequencing. Participants randomised into the intervention arm will use the Genetics Adviser to learn about genomic sequencing, receive pre-test counselling, support during the waiting period and results, supplemented with brief counselling from a genetic counsellor. Participants in the control arm will receive standard pre-test and post-test counselling for genomic sequencing from a genetic counsellor. Our primary outcome is decisional conflict following pre-test counselling from the Genetics Adviser+genetic counsellor or counsellor alone. Secondary outcomes include: knowledge, satisfaction with decision-making, anxiety, quality of life, psychological impact of results, empowerment, acceptability and economic impact for patients and the health system. A subset of patients will be interviewed to assess user experience. ETHICS AND DISSEMINATION: This study has been approved by Clinical Trials Ontario Streamlined Research Ethics Review System (REB#20-035). Results will be shared through stakeholder workshops, national and international conferences and peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04725565.

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.

Effect of Continuous Electrocardiogram Monitoring on Detection of Undiagnosed Atrial Fibrillation After Hospitalization for Cardiac Surgery: A Randomized Clinical Trial.

Importance: Postoperative atrial fibrillation (POAF) occurring after cardiac surgery is associated with adverse outcomes. Whether POAF persists beyond discharge is not well defined. Objective: To determine whether continuous cardiac rhythm monitoring enhances detection of POAF among cardiac surgical patients during the first 30 days after hospital discharge compared with usual care. Design, Setting, and Participants: This study is an investigator-initiated, open-label, multicenter, randomized clinical trial conducted at 10 Canadian centers. Enrollment spanned from March 2017 to March 2020, with follow-up through September 11, 2020. As a result of the COVID-19 pandemic, enrollment stopped on July 17, 2020, at which point 85% of the proposed sample size was enrolled. Cardiac surgical patients with CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes, prior stroke or transient ischemic attack, vascular disease, age 65-74 years, female sex) score greater than or equal to 4 or greater than or equal to 2 with risk factors for POAF, no history of preoperative AF, and POAF lasting less than 24 hours during hospitalization were enrolled. Interventions: The intervention group underwent continuous cardiac rhythm monitoring with wearable, patch-based monitors for 30 days after randomization. Monitoring was not mandated in the usual care group within 30 days after randomization. Main Outcomes and Measures: The primary outcome was cumulative AF and/or atrial flutter lasting 6 minutes or longer detected by continuous cardiac rhythm monitoring or by a 12-lead electrocardiogram within 30 days of randomization. Prespecified secondary outcomes included cumulative AF lasting 6 hours or longer and 24 hours or longer within 30 days of randomization, death, myocardial infarction, ischemic stroke, non-central nervous system thromboembolism, major bleeding, and oral anticoagulation prescription. Results: Of the 336 patients randomized (163 patients in the intervention group and 173 patients in the usual care group; mean [SD] age, 67.4 [8.1] years; 73 women [21.7%]; median [interquartile range] CHA2DS2-VASc score, 4.0 [3.0-4.0] points), 307 (91.4%) completed the trial. In the intent-to-treat analysis, the primary end point occurred in 32 patients (19.6%) in the intervention group vs 3 patients (1.7%) in the usual care group (absolute difference, 17.9%; 95% CI, 11.5%-24.3%; P < .001). AF lasting 6 hours or longer was detected in 14 patients (8.6%) in the intervention group vs 0 patients in the usual care group (absolute difference, 8.6%; 95% CI, 4.3%-12.9%; P < .001). Conclusions and Relevance: In post-cardiac surgical patients at high risk of stroke, no preoperative AF history, and AF lasting less than 24 hours during hospitalization, continuous monitoring revealed a significant increase in the rate of POAF after discharge that would otherwise not be detected by usual care. Studies are needed to examine whether these patients will benefit from oral anticoagulation therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT02793895.

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.

Efficacy of dexamethasone treatment for patients with the acute respiratory distress syndrome caused by COVID-19: study protocol for a randomized controlled superiority trial.

BACKGROUND: There are no specific generally accepted therapies for the coronavirus disease 2019 (COVID-19). The full spectrum of COVID-19 ranges from asymptomatic disease to mild respiratory tract illness to severe pneumonia, acute respiratory distress syndrome (ARDS), multisystem organ failure, and death. The efficacy of corticosteroids in viral ARDS remains unknown. We postulated that adjunctive treatment of established ARDS caused by COVID-19 with intravenous dexamethasone might change the pulmonary and systemic inflammatory response and thereby reduce morbidity, leading to a decrease in duration of mechanical ventilation and in mortality. METHODS/DESIGN: This is a multicenter, randomized, controlled, parallel, open-label, superiority trial testing dexamethasone in 200 mechanically ventilated adult patients with established moderate-to-severe ARDS caused by confirmed SARS-CoV-2 infection. Established ARDS is defined as maintaining a PaO2/FiO2 ≤ 200 mmHg on PEEP ≥ 10 cmH2O and FiO2 ≥ 0.5 after 12 ± 3 h of routine intensive care. Eligible patients will be randomly assigned to receive either dexamethasone plus standard intensive care or standard intensive care alone. Patients in the dexamethasone group will receive an intravenous dose of 20 mg once daily from day 1 to day 5, followed by 10 mg once daily from day 6 to day 10. The primary outcome is 60-day mortality. The secondary outcome is the number of ventilator-free days, defined as days alive and free from mechanical ventilation at day 28 after randomization. All analyses will be done according to the intention-to-treat principle. DISCUSSION: This study will assess the role of dexamethasone in patients with established moderate-to-severe ARDS caused by SARS-CoV-2. TRIAL REGISTRATION: ClinicalTrials.gov NCT04325061 . Registered on 25 March 2020 as DEXA-COVID19.

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.