Enoxaparin for primary thromoprophylaxis in ambulatory patients with coronavirus: the multicenter randomized controlled ovid trial

Background. Coronavirus disease (COVID-19) has emerged as a pandemic and a public health crisis of global proportions. One of the most frequently described poor prognostic features in patients with COVID-19 is the development of pneumonia and coagulopathy, reflected by an increase in D-dimers. Studies from Europe and Northern America suggested that not only venous thromboembolism represents the predominant vascular complications in COVID-19 patients, but also that its incidence might be higher than previously observed in other groups of patients admitted to hospital for acute conditions. Venous thromboembolism (VTE), encompassing deep vein thrombosis, lung thrombosis, and pulmonary embolism, can be the first clinical manifestation of COVID-19 caused by local and systemic inflammation, reduced mobility, hypoxia, endothelial dysfunction.In particular, the cumulative incidence of VTE in COVID-19 patients is approximately 20-30% (up to 70% in ICU patients undergoing VTE screening). Half of the VTE events, mostly PE, however, were diagnosed at hospital admission, suggesting that these events developed during the home quarantine.Recent guidance stated that prophylactic-dose LMWH, such as enoxaparin, should be considered in all patients who require hospital admission for COVID-19 in the absence of any contraindications. One of the better known non-anticoagulant properties of heparins, their anti-inflammatory function, include binding to inflammatory cytokines, inhibition of neutrophil chemotaxis and leukocyte migration, neutralization of the positively charged peptide complement factor C5a, and sequestering acute phase proteins: this may provide a benefit in COVID infection where pro-inflammatory cytokines are markedly raised and acute respiratory distress syndrome represents a feared and life-threatening complication.It remains unclear whether COVID-19 patients not admitted to the hospital due to non-severe clinical conditions should receive thromboprophylaxis and whether this provides a clinical benefit weighed against the risk of anticoagulant-associated bleeding. The evidence is scarce also for non-COVID-19 patients. The most recent American Society of Hematology (ASH) guidelines state that In medical outpatients with minor provoking risk factors for VTE (eg, immobility, minor injury, illness, infection), the ASH guideline panel suggests not using VTE prophylaxis (conditional recommendation, very low certainty in the evidence of effect).Research Question.We hypothesize that thromboprophylaxis with standard-dose low-molecular-weight heparin in symptomatic outpatients with COVID-19 may reduce hospitalizations and all-cause death by reducing the risk of developing coagulopathy and preventing thromboembolic events.Specific objectives.The purpose of this study is to show the superiority of ambulatory thromboprophylaxis with enoxaparin versus no treatment to prevent any hospitalization and all-cause death within 30 days of randomization in patients aged 50 or older with COVID-19. Key secondary objectives for this study are to determine if enoxaparin administration versus no treatment reduces specific cardiovascular and thromboembolic complications, namely venous thromboembolism, myocardial infarction or stroke, within 14 days, 30 days and 90 days of randomization and if this intervention is associated with a net clinical benefit, accounting for major bleeding events. Methods.The study will be conducted as an investigator-initiated, multicentre, randomized open-label controlled trial. In the study, a total of 1,000 adult patients aged 50 or older with COVID-19 and candidates to ambulatory treatment will be randomized to receive enoxaparin 40 mg sc once daily or no treatment for a total of 14 days. The primary outcome, a composite of any hospitalization or all-cause death, will be assessed within 30 days of enrolment. We implemented logistical solutions to integrate the process of SARS-CoV2 testing, pre-screening, screening (hot-line and flyers), in-hospital recruitment, enrolment, and randomization/allocation at five University hospitals and 2 large cantonal hospitals in Switzerland. A nationwide OVID Hot-Line telephone number will be made available in 3 languages (German, French, Italian) for interested patients or test centers to contact the Hot-Line. Standard procedures concerning privacy, discussion with patients on details of the study, collection of informed consent, and instruction on how to administer the study medication will be maintained in conformity with GCP recommendations. This will also include outcome measurements to be conducted by telephone with a standardized questionnaire.Having adopted a 'hard' primary outcome, hospitalization or death, and having extended the follow-up period up to 90 days, we aim to achieve two objectives: (1) obtaining uncontestable estimates of major clinical relevance, (ii) minimizing the potential reporting bias typical of open-label studies.Expected results and impact.As the vast majority of COVID-19 have been and are being treated in the outpatient setting, the results of the present study will have a major impact on the way this condition is treated and will be applicable to billion people, notably the most fragile part of the general population, worldwide. Beyond COVID-19, this study will investigate for the first time the concept of ambulatory thromboprophylaxis and represent the first large study on this topic.