Randomized clinical trial to evaluate a routine full anticoagulation Strategy in Patients with Coronavirus Infection (SARS-CoV2) admitted to hospital: Rationale and design of the ACTION (AntiCoagulaTlon cOroNavirus)-Coalition IV trial.

BACKGROUND: Observational studies have suggested a higher risk of thrombotic events in patients with coronavirus disease 2019 (COVID-19). Moreover, elevated D-dimer levels have been identified as an important prognostic marker in COVID-19 directly associated with disease severity and progression. Prophylactic anticoagulation for hospitalized COVID-19 patients might not be enough to prevent thrombotic events; therefore, therapeutic anticoagulation regimens deserve clinical investigation. DESIGN: ACTION is an academic-led, pragmatic, multicenter, open-label, randomized, phase IV clinical trial that aims to enroll around 600 patients at 40 sites participating in the Coalition COVID-19 Brazil initiative. Eligible patients with a confirmed diagnosis of COVID-19 with symptoms up to 14 days and elevated D-dimer levels will be randomized to a strategy of full-dose anticoagulation for 30 days with rivaroxaban 20 mg once daily (or full-dose heparin if oral administration is not feasible) vs standard of care with any approved venous thromboembolism prophylaxis regimen during hospitalization. A confirmation of COVID-19 was mandatory for study entry, based on specific tests used in clinical practice (RT-PCR, antigen test, IgM test) collected before randomization, regardless of in the outpatient setting or not. Randomization will be stratified by clinical stability at presentation. The primary outcome is a hierarchical analysis of mortality, length of hospital stay, or duration of oxygen therapy at the end of 30 days. Secondary outcomes include the World Health Organization's 8-point ordinal scale at 30 days and the following efficacy outcomes: incidence of venous thromboembolism , acute myocardial infarction, stroke, systemic embolism, major adverse limb events, duration of oxygen therapy, disease progression, and biomarkers. The primary safety outcomes are major or clinically relevant non-major bleeding according to the International Society on Thrombosis and Haemostasis criteria. SUMMARY: The ACTION trial will evaluate whether in-hospital therapeutic anticoagulation with rivaroxaban for stable patients, or enoxaparin for unstable patients, followed by rivaroxaban through 30 days compared with standard prophylactic anticoagulation improves clinical outcomes in hospitalized patients with COVID-19 and elevated D-dimer levels.

Combined Use of Tocilizumab and Mesenchymal Stromal Cells in the Treatment of Severe Covid-19: Case Report.

The coronavirus pandemic is one of the most significant public health events in recent history. Currently, no specific treatment is available. Some drugs and cell-based therapy have been tested as alternatives to decrease the disease's symptoms, length of hospital stay, and mortality. We reported the case of a patient with a severe manifestation of COVID-19 in critical condition who did not respond to the standard procedures used, including six liters of O2 supplementation under a nasal catheter and treatment with dexamethasone and enoxaparin in prophylactic dose. The patient was treated with tocilizumab and an advanced therapy product based on umbilical cord-derived mesenchymal stromal cells (UC-MSC). The combination of tocilizumab and UC-MSC proved to be safe, with no adverse effects, and the results of this case report prove to be a promising alternative in the treatment of patients with severe acute respiratory syndrome due to SARS-CoV-2.

Clinical Variants, Characteristics, and Outcomes Among COVID-19 Patients: A Case Series Analysis at a Tertiary Care Hospital in Karachi, Pakistan.

Introduction Coronavirus disease 2019 (COVID-19) has become a global threat to public health. The current study investigates alterations in the biological estimates concerning the severity, recovery, mortality, and assessment of treatment-based outcomes. Methods A case series of 165 COVID-19 patients admitted to OMI Institute (a tertiary care hospital) was conducted between May and August 2020. The data regarding demographic characteristics, comorbid conditions, radiographic abnormalities, biological estimations, symptoms, treatment, disease progression, complications, and outcomes were recorded using a structured questionnaire. Laboratory estimations included complete blood count (CBC), renal and electrolyte profile, liver function tests (LFTs), hematological indices, and inflammatory markers. Chest X-ray, electrocardiogram (ECG), and a high-resolution computed tomography (HRCT) scan were also performed, and data were extracted from the medical records. Analysis was done using the Statistical Package for the Social Sciences (SPSS) version 22.0. Results Out of the 165 COVID-19 patients, 79.4% recovered and were successfully discharged, while 20.6% of inpatient died. The patients' mean age was 56.03 ± 15.96 years, with a male majority (55.1%). The most common comorbid conditions were diabetes and hypertension; fever and dry cough were among the most frequently reported symptoms. The chest imaging findings among the severe/critical COVID-19 patients showed extensive bilateral patchy opacities. The median laboratory investigations, including neutrophil-to-lymphocyte ratio (NLR) (14.83), C-reactive protein (CRP) (7.4 mg/dl), lactate dehydrogenase (LDH) (786 IU/L), ferritin (1401.15 mcg/ml), and mean oxygen saturation (88.25%), were significantly altered among cases with increased disease severity and those who expired (p<0.05). The proportion of acute respiratory distress syndrome (ARDS) and sepsis development was significantly high among severe/critical COVID-19 patients (p<0.05). Treatment with tocilizumab, remdesivir, doxycycline, ivermectin, enoxaparin sodium, and steroids was deemed to be potentially effective treatment options in terms of reducing COVID-19 severity and chances of recovery. Furthermore, age (OR 1.05; p=0.047), presence of comorbidity (OR 8.471; p=0.004), high NLR, LDH (final outcome) (OR 1.361 and 1.018; p<0.05), and CRP levels (midpoint) (OR 1.631; p=0.05) were identified as the strong predictors of death among COVID-19 patients. Conclusion The study identified several alterations in the clinical profile of the COVID-19 patients concerning severity during the hospital stay, affecting prognosis. Clinically, tocilizumab, remdesivir, doxycycline, ivermectin, enoxaparin sodium, and steroids were identified as potential therapeutic options for COVID-19 due to their ability to alter disease-associated severity and recovery rate.

Optimal Dosing of Prophylactic Enoxaparin after Surgical Procedures: Results of the Double-Blind, Randomized, Controlled FIxed or Variable Enoxaparin (FIVE) Trial.

BACKGROUND: The accepted "one-size-fits-all" dose strategy for prophylactic enoxaparin may not optimize the medication's risks and benefits after surgical procedures. The authors hypothesized that weight-based administration might improve the pharmacokinetics of prophylactic enoxaparin when compared to fixed-dose administration. METHODS: The FIxed or Variable Enoxaparin (FIVE) trial was a randomized, double-blind trial that compared the pharmacokinetic and clinical outcomes of patients assigned randomly to postoperative venous thromboembolism prophylaxis using enoxaparin 40 mg twice daily or enoxaparin 0.5 mg/kg twice daily. Patients were randomized after surgery and received the first enoxaparin dose at 8 hours after surgery. Primary hypotheses were (1) weight-based administration is noninferior to a fixed dose for avoiding underanticoagulation (anti-factor Xa <0.2 IU/ml) and (2) weight-based administration is superior to fixed-dose administration for avoiding overanticoagulation (anti-factor Xa >0.4 IU/ml). Secondary endpoints were 90-day venous thromboembolism and bleeding. RESULTS: In total, 295 patients were randomized, with 151 assigned to fixed-dose and 144 to weight-based administration of enoxaparin. For avoidance of under anticoagulation, weight-based administration had a greater effectiveness (79.9 percent versus 76.6 percent); the 3.3 percent (95 percent CI, -7.5 to 12.5 percent) greater effectiveness achieved statistically significant noninferiority relative to the a priori specified -12 percent noninferiority margin (p = 0.004). For avoidance of overanticoagulation, weight-based enoxaparin administration was superior to fixed-dose administration (90.6 percent versus 82.2 percent); the 8.4 percent (95 percent CI, 0.1 to 16.6 percent) greater effectiveness showed significant safety superiority (p = 0.046). Ninety-day venous thromboembolism and major bleeding were not different between fixed-dose and weight-based cohorts (0.66 percent versus 0.69 percent, p = 0.98; 3.3 percent versus 4.2 percent, p = 0.72, respectively). CONCLUSION: Weight-based administration showed superior pharmacokinetics for avoidance of underanticoagulation and overanticoagulation in postoperative patients receiving prophylactic enoxaparin. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, I.

A Case of Moderately Severe COVID-19 in a Healthcare Worker in Russia: Virus Isolation and Full Genome Sequencing.

The coronavirus disease 2019 (COVID-19) pandemic is probably the most studied one in history from both clinical and molecular-epidemiological perspectives. Nonetheless, data on the correlation between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral genotypes and COVID-19 symptoms caused by them are still scarce. In this report, we present a moderately severe COVID-19 case in a healthcare worker in Moscow, Russia, supplemented with the data on its causative agent's phenotype regarding in vitro and full-genome characterization. The 44-year-old male healthcare worker who had frequent professional contacts with COVID-19 patients was hospitalized with a viral pneumonia diagnosis and soon started to exhibit fever, dry paroxysmal cough, loss of smell, and typical ground-glass opacities found in both lungs on chest CT scans. The COVID-19 diagnosis was verified by real-time quantitative polymerase chain reaction (qRT-PCR), immunochromatography, and immunochemiluminescent assays. The patient was treated with hydroxychloroquine, azithromycin, paracetamol, and enoxaparin, leading to his recovery after two weeks from the disease onset. The virus was successfully isolated from the nasopharyngeal swab sample taken on the fifth day of the disease onset using the Vero E6 cell line and exhibited a pronounced cytopathic effect (CPE) with a viral titer reaching 106 TCID50/ml in the cell culture medium. The full genome sequence of the viral isolate was obtained and 8 nucleotide and 5 amino acid mutations compared to the Wuhan-Hu-1 reference genome were identified. Viral isolate belonged to GR / 20B / B.1.1 genetic lineage (GISAID, Nextstrain, Pangolin nomenclatures, respectively) - the most prevalent genotype found in Russia to date.

Aggressive Thromboprophylaxis Improves Clinical Process and Decreases the Need of Intensive Care Unit in Covid-19.

BACKGROUND AND OBJECTIVES: COVID-19 might cause thrombosis in the arterial and venous system either directly or via indirect means such as cytokine storm or hypoxia. Enoxaparin might contribute to clinical recovery in COVID-19 patients, both by reducing the risk of thrombosis with anticoagulant effect and avoiding the cytokine storm with its anti-inflammatory effect. In this study, the clinical results of prophylactic enoxaparin usage in COVID-19 patients in our hospital were investigated. METHODS: We retrospectively analyzed the patients who had hospitalized in our hospital with the diagnosis of COVID-19 between March 12 and April 17, 2020. Patients were divided into two groups according to their clinical status. Patients who were discharged to their home were in Group-I and were transferred to intensive care unit (ICU) were in Group-II. Patients' demographics and laboratory examinations were compared between the groups. Then the effect of LMWH treatment in the rate of ICU transfer was evaluated. RESULTS: There were 1216 hospitalized patients with COVID-19 in the study period. Increased age, levels of D-Dimer and fibrinogen and decreased hemoglobin, platelet, lymphocyte values were found to be statistically significantly risk factor for the need of ICU. Transfer rates of ICU were two times more in the patients who did not used enoxaparin and readmission after the discharge was higher in the patients who did not received enoxaparin in the hospital. CONCLUSION: Enoxaparin treatment in COVID-19 might be effective not only anticoagulant effect but also anti-inflammatory effect that decreased the risk cytokine storm. In the patients with COVID-19 disease, starting enoxaparin treatment in the earlier stage will decrease the risk of microthrombosis in vital organs and might improve the clinical outcomes.

Higher heparin dosages reduce thromboembolic complications in patients with COVID-19 pneumonia.

Coronavirus disease 2019 (COVID-19) is a new viral disease complicating with acute thrombophylic conditions, probably also via an inflammatory burden. Anticoagulants are efficacious, but their optimal preventive doses are unknown. The present study was aimed to compare different enoxaparin doses/kg of body weight in the prevention of clot complications in COVID-19 pneumonia. Retrospective data from a cohort of adult patients hospitalized for COVID-19 pneumonia, never underwent to oropharyngeal intubation before admission, were collected in an Internal Medicine environments equipped for non-invasive ventilation. Unfavorable outcomes were considered as: deep venous thrombosis, myocardial infarction, stroke, pulmonary embolism, cardiovascular death. Fourteen clinical thromboembolic events among 42 hospitalized patients were observed. Patients were divided into two group on the basis of median heparin dose (0.5 mg-or 50 IU-for kg). The decision about heparin dosing was patient by patient. Higher enoxaparin therapy (mean 0.62±0.16 mg/kg) showed a better thromboprophylactic action (HR=0.2, p=0.04) with respect to lower doses (mean 0.42±0.06 mg/kg), independently from the clinical presentation of the disease. Therefore, COVID-19 pneumonia might request higher enoxaparin doses to reduce thromboembolic events in hospitalized patients, even if outside intensive care units.

Enoxaparin is associated with lower rates of mortality than unfractionated Heparin in hospitalized COVID-19 patients.

BACKGROUND: Coagulopathies are a major class among COVID-19 associated complications. Although anticoagulants such as unfractionated Heparin and Enoxaparin are both being used for therapeutic mitigation of COVID associated coagulopathy (CAC), differences in their clinical outcomes remain to be investigated. METHODS: We analyzed records of 1,113 patients in the Mayo Clinic Electronic Health Record (EHR) database who were admitted to the hospital for COVID-19 between April 4, 2020 and August 31, 2020, including 19 different Mayo Clinic sites in Arizona, Florida, Minnesota, and Wisconsin. Among this patient population, we compared cohorts of patients who received different types of anticoagulants, including 441 patients who received unfractionated Heparin and 166 patients who received Enoxaparin. Clinical outcomes at 28 days were compared, and propensity score matching was used to control for potential confounding variables including: demographics, comorbidities, ICU status, chronic kidney disease stage, and oxygenation status. Patients with a history of acute kidney injury and patients who received multiple types of anticoagulants were excluded from the study. FINDINGS: We find that COVID-19 patients administered unfractionated Heparin but not Enoxaparin have higher rates of 28-day mortality (risk ratio: 4.3; 95% Confidence Interval [C.I.].: [1.8, 10.2]; p-value: 8.5e-4, Benjamini Hochberg [BH] adjusted p-value: 2.1e-3), after controlling for potential confounding factors. INTERPRETATION: This study emphasizes the need for mechanistically investigating differential modulation of the COVID-associated coagulation cascades by Enoxaparin versus unfractionated Heparin. FUNDING: This work was supported by Nference, inc.

Antithrombotic and Anti-Inflammatory Effects of Fondaparinux and Enoxaparin in Hospitalized COVID-19 Patients: The FONDENOXAVID Study.

BACKGROUND: Since the outbreak of novel coronavirus SARS-CoV2 around the world, great attention has been paid to the effects of such antithrombotic drugs as heparinoids, because they have antiviral action in vitro and antithrombotic actions in vivo. We conducted a retrospective analysis in inpatients with confirmed COVID-19 on the anti-inflammatory and antithrombotic effects of enoxaparin and fondaparinux at prophylactic doses. METHODS: This retrospective cohort study used patients with confirmed COVID-19 during the first months of the Italian outbreak from February 18 to April 30, 2020. Our aim was to compare clinical characteristics, prophylactic treatment, markers of inflammation, and thrombotic outcomes in inpatients positive for SARS-CoV2 during hospitalization associated with thromboprophylaxis with enoxaparin (40 mg or 60 mg once daily) or fondaparinux (2.5 mg once daily). Statistical analysis was conducted with using MatLab R2016B and ad hoc functions. RESULTS: There were no significatant differences in clinical characteristics between patients that used enoxaparin or fondaparinux as thromboprophylaxis for SARS-CoV2. No differences were found in D-dimer and fibrinogen levels either, which were used as markers of inflammation during the infection at testing on admission and after 3 weeks.Significant differences in CRP, IL6, and LDH were found in patients after 21 days' treatment. DISCUSSION: Increased levels of fibrinogen and D-dimer in patients with confirmed COVID-19 have been reported in several studies. Our results showed that anti-inflammatory effects of fondaparinux and enoxaparin after 3 weeks of prophylactic treatment were similar when levels of fibrinogen and D-dimer were considered. Furthermore, levels of CRP showed a decrease in patients treated with enoxaparin and fondaparinux, although the decrease in the fondaparinux group seems to be more relevant.

Healthcare disparities among anticoagulation therapies for severe COVID-19 patients in the multi-site VIRUS registry.

Here we analyze hospitalized andintensive care unit coronavirus disease 2019 (COVID-19) patient outcomes from the international VIRUS registry (https://clinicaltrials.gov/ct2/show/NCT04323787). We find that COVID-19 patients administered unfractionated heparin but not enoxaparin have a higher mortality-rate (390 of 1012 = 39%) compared to patients administered enoxaparin but not unfractionated heparin (270 of 1939 = 14%), presenting a risk ratio of 2.79 (95% confidence interval [CI]: [2.42, 3.16]; p = 4.45e-52). This difference persists even after balancing on a number of covariates including demographics, comorbidities, admission diagnoses, and method of oxygenation, with an increased mortality rate on discharge from the hospital of 37% (268 of 733) for unfractionated heparin versus 22% (154 of 711) for enoxaparin, presenting a risk ratio of 1.69 (95% CI: [1.42, 2.00]; p = 1.5e-8). In these balanced cohorts, a number of complications occurred at an elevated rate for patients administered unfractionated heparin compared to patients administered enoxaparin, including acute kidney injury, acute cardiac injury, septic shock, and anemia. Furthermore, a higher percentage of Black/African American COVID patients (414 of 1294 [32%]) were noted to receive unfractionated heparin compared to White/Caucasian COVID patients (671 of 2644 [25%]), risk ratio 1.26 (95% CI: [1.14, 1.40]; p = 7.5e-5). After balancing upon available clinical covariates, this difference in anticoagulant use remained statistically significant (311 of 1047 [30%] for Black/African American vs. 263 of 1047 [25%] for White/Caucasian, p = .02, risk ratio 1.18; 95% CI: [1.03, 1.36]). While retrospective studies cannot suggest any causality, these findings motivate the need for follow-up prospective research into the observed racial disparity in anticoagulant use and outcomes for severe COVID-19 patients.

Early initiation of prophylactic anticoagulation for prevention of coronavirus disease 2019 mortality in patients admitted to hospital in the United States: cohort study.

OBJECTIVE: To evaluate whether early initiation of prophylactic anticoagulation compared with no anticoagulation was associated with decreased risk of death among patients admitted to hospital with coronavirus disease 2019 (covid-19) in the United States. DESIGN: Observational cohort study. SETTING: Nationwide cohort of patients receiving care in the Department of Veterans Affairs, a large integrated national healthcare system. PARTICIPANTS: All 4297 patients admitted to hospital from 1 March to 31 July 2020 with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and without a history of anticoagulation. MAIN OUTCOME MEASURES: The main outcome was 30 day mortality. Secondary outcomes were inpatient mortality, initiating therapeutic anticoagulation (a proxy for clinical deterioration, including thromboembolic events), and bleeding that required transfusion. RESULTS: Of 4297 patients admitted to hospital with covid-19, 3627 (84.4%) received prophylactic anticoagulation within 24 hours of admission. More than 99% (n=3600) of treated patients received subcutaneous heparin or enoxaparin. 622 deaths occurred within 30 days of hospital admission, 513 among those who received prophylactic anticoagulation. Most deaths (510/622, 82%) occurred during hospital stay. Using inverse probability of treatment weighted analyses, the cumulative incidence of mortality at 30 days was 14.3% (95% confidence interval 13.1% to 15.5%) among those who received prophylactic anticoagulation and 18.7% (15.1% to 22.9%) among those who did not. Compared with patients who did not receive prophylactic anticoagulation, those who did had a 27% decreased risk for 30 day mortality (hazard ratio 0.73, 95% confidence interval 0.66 to 0.81). Similar associations were found for inpatient mortality and initiation of therapeutic anticoagulation. Receipt of prophylactic anticoagulation was not associated with increased risk of bleeding that required transfusion (hazard ratio 0.87, 0.71 to 1.05). Quantitative bias analysis showed that results were robust to unmeasured confounding (e-value lower 95% confidence interval 1.77 for 30 day mortality). Results persisted in several sensitivity analyses. CONCLUSIONS: Early initiation of prophylactic anticoagulation compared with no anticoagulation among patients admitted to hospital with covid-19 was associated with a decreased risk of 30 day mortality and no increased risk of serious bleeding events. These findings provide strong real world evidence to support guidelines recommending the use of prophylactic anticoagulation as initial treatment for patients with covid-19 on hospital admission.

Cyclosporine A plus low-dose steroid treatment in COVID-19 improves clinical outcomes in patients with moderate to severe disease: A pilot study.

BACKGROUND: COVID-19 pandemic causes high global morbidity and mortality and better medical treatments to reduce mortality are needed. OBJECTIVE: To determine the added benefit of cyclosporine A (CsA), to low-dose steroid treatment, in patients with COVID-19. METHODS: Open-label, non randomized pilot study of patients with confirmed infection of SARS-CoV-2 hospitalized from April to May 2020 at a single centre in Puebla, Mexico. Patients were assigned to receive either steroids or CsA plus steroids. Pneumonia severity was assessed by clinical, laboratory, and lung tomography. The death rate was evaluated at 28 days. RESULTS: A total of 209 adult patients were studied, 105 received CsA plus steroids (age 55.3 ± 13.3; 69% men), and 104 steroids alone (age 54.06 ± 13.8; 61% men). All patients received clarithromycin, enoxaparin and methylprednisolone or prednisone up to 10 days. Patient's death was associated with hypertension (RR = 3.5) and diabetes (RR = 2.3). Mortality was 22 and 35% for CsA and control groups (P = 0.02), respectively, for all patients, and 24 and 48.5% for patients with moderate to severe disease (P = 0.001). Higher cumulative clinical improvement was seen for the CsA group (Nelson Aalen curve, P = 0.001, log-rank test) in moderate to severe patients. The Cox proportional hazard analysis showed the highest HR improvement value of 2.15 (1.39-3.34, 95%CI, P = 0.0005) for CsA treatment in moderate to severe patients, and HR = 1.95 (1.35-2.83, 95%CI, P = 0.0003) for all patients. CONCLUSION: CsA used as an adjuvant to steroid treatment for COVID-19 patients showed to improve outcomes and reduce mortality, mainly in those with moderate to severe disease. Further investigation through controlled clinical trials is warranted.

COVID-19-associated coagulopathy: thromboembolism prophylaxis and poor prognosis in ICU.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with coagulation abnormalities which are indicators of higher mortality especially in severe cases. METHODS: We studied patients with proven COVID-19 disease in the intensive care unit of Jinyintan Hospital, Wuhan, China from 30 to 2019 to 31 March 2020. RESULTS: Of 180 patients, 89 (49.44 %) had died, 85 (47.22 %) had been discharged alive, and 6 (3.33 %) were still hospitalised by the end of data collection. A D-dimer concentration of > 0.5 mg/L on admission was significantly associated with 30 day mortality, and a D-dimer concentration of > 5 mg/L was found in a much higher proportion of non-survivors than survivors. Sepsis-induced coagulopathy (SIC) and disseminated intravascular coagulation (DIC) scoring systems were dichotomised as < 4 or ≥ 4 and < 5 or ≥ 5, respectively, and the mortality rate was significantly different between the two stratifications in both scoring systems. Enoxaparin was administered to 68 (37.78 %) patients for thromboembolic prophylaxis, and stratification by the D-dimer concentration and DIC score confirmed lower mortality in patients who received enoxaparin when the D-dimer concentration was > 2 than < 2 mg/L or DIC score was ≥ 5 than < 5. A low platelet count and low serum calcium concentration were also related to mortality. CONCLUSIONS: A D-dimer concentration of > 0.5 mg/L on admission is a risk factor for severe disease. A SIC score of > 4 and DIC score of > 5 may be used to predict mortality. Thromboembolic prophylaxis can reduce mortality only in patients with a D-dimer concentration of > 2 mg/L or DIC score of ≥ 5.

Aggregometry and thromboelastography to identify the timing to trach a COVID-19 patient receiving both antiplatelet therapy and enoxaparin.

In COVID-19 patients receiving enoxaparin and antiplatelets therapy, aggregometry and thromboelastography might be considered an adjunctive tool to identify the time to perform procedures at risk of bleeding, such as tracheostomy.

Increasing dosages of low-molecular-weight heparin in hospitalized patients with Covid-19.

We conducted an observational cohort study in adult patients consecutively admitted for the respiratory illness Covid-19 to our hub hospital from March 9 to April 7, 2020. The high observed rate of venous thromboembolism prompted us to increase the prophylactic doses of enoxaparin from 40 mg daily up to 1 mg/kg twice daily in patients admitted to intensive care units (ICU), 0.7 mg/kg twice daily in high-intensity of care wards and 1 mg/kg daily in low-intensity of care wards. Patients on high enoxaparin doses were compared to those who received prophylaxis with the standard dosage. Efficacy endpoints were mortality, clinical deterioration, and the occurrence of venous thromboembolism, safety endpoint was the occurrence of major bleeding. Of 278 patients with Covid-19, 127 received prophylaxis with high enoxaparin doses and 151 with standard dosage. At 21 days, the incidence rate of death and clinical deterioration were lower in patients on higher doses than in those on the standard dosage (hazard ratio 0.39, 95% confidence interval 0.23-0.62), and the incidence of venous thromboembolism was also lower (hazard ratio 0.52, 95% confidence interval 0.26-1.05). Major bleeding occurred in four of 127 patients (3.1%) on the high enoxaparin dosage. In conclusion, in the cohort of patients with Covid-19 treated with high enoxaparin dosages we observed a 60% reduction of mortality and clinical deterioration and a 50% reduction of venous thromboembolism compared to standard dosage prophylaxis. However, 3% of patients on high enoxaparin dosages had non-fatal major bleeding.

Thromboprofilaxys With Fondaparinux vs. Enoxaparin in Hospitalized COVID-19 Patients: A Multicenter Italian Observational Study.

Importance: The use of anticoagulant therapy with heparins decreased mortality in hospitalized patients with severe coronavirus disease 2019 (COVID-19). Even if enoxaparin and fondaparinux have the same clinical indication for venous thromboembolism (VTE) prevention; to date, there are no data about the use of fondaparinux in terms of safety, effectiveness, and impact on clinical prognosis among COVID-19 patients. Objective: To evaluate the safety, effectiveness, and clinical impact of VTE prophylaxis with fondaparinux and enoxaparin among COVID-19 patients hospitalized in internal medicine units. Design, Setting, and Participants: This was a retrospective multicenter observation study, including consecutive symptomatic patients with laboratory-proven COVID-19 admitted to internal medicine units of five Italian hospitals from 15th February to 15th March 2020. Main Outcomes and Measures: The primary safety outcome was the composite of major bleeding and clinically relevant non-major bleeding; the primary effectiveness outcome was the composite of all events classified as pulmonary embolism and deep venous thrombosis. The secondary effectiveness outcome included acute respiratory distress syndrome and all-cause death. Results: Among 120 COVID-19 patients enrolled in the study, 74 were taking enoxaparin (4,000 or 6,000 units/day) and 46 fondaparinux (2.5 units/day). No statistically significant difference in demographic and laboratory and clinical characteristics between the two groups has been shown. During a median follow-up of 32 (interquartile range: 14-51) days, the cumulative incidence rates of VTE and bleeding events on pharmacological thromboprophylaxis with heparins were 19% and 8%, respectively. The incidence of both VTE (6.5 vs. 13.5%; P = 0.36) and bleeding events (6.5 vs. 4.1%; P = 0.68) did not show a significant difference between COVID-19 patients on fondaparinux compared with those on enoxaparin therapy. The regression model for the risk of outcome events according to different VTE prophylaxis drugs did not show significant differences. Conclusions and Relevance: Although these results need confirmation by prospective studies including a larger population, our study provides preliminary evidence of a safe and efficacy use of fondaparinux for VTE prophylaxis in hospitalized COVID-19 patients.

Prognostic factors and predictors of outcome in patients with COVID-19 and related pneumonia: a retrospective cohort study.

The aim of the present study was to simultaneously assess several potential predictors of outcome (co-morbidity, previous and in-hospital treatment, radiologic Brixia score) in patients with COVID-19. This retrospective cohort study included 258 consecutive patients with confirmed COVID-19 admitted to a medical ward at Montichiari Hospital, Brescia, Italy from February 28th to April 30rd, 2020. Patients had SARS-CoV-2 related pneumonia with respiratory failure, and were treated with hydroxychloroquine and lopinavir plus ritonavir. In some patients, additional treatment with tocilizumab, dexamethasone and enoxaparin was adopted. Outcomes (death or recovery) were assessed at the end of the discharge period or at the end of the follow-up (August 2020). During hospitalization, 59 patients died, while 6 died after discharge. The following variables were demonstrated to be associated with a worse prognosis: Radiologic Brixia score higher than 8, presence at baseline of hypertension, diabetes, chronic obstructive pulmonary disease, heart disease, cancer, previous treatment with ACE-inhibitors or anti-platelet drugs. Anticoagulant treatment during hospital admission with enoxaparin at a dose higher than 4000 U once daily was associated with a better prognosis. In conclusion, our study demonstrates that some co-morbidities and cardiovascular risk factors may affect prognosis. The radiologic Brixia score may be a useful tool to stratify the risk of death at baseline. Anticoagulant treatment with enoxaparin might be associated to a clinical benefit in terms of survival in patients with COVID-19.

Thromboprophylaxis with enoxaparin is associated with a lower death rate in patients hospitalized with SARS-CoV-2 infection. A cohort study.

BACKGROUND: Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) infection is associated with hypercoagulability caused by direct invasion of endothelial cells and\or proinflammatory cytokine release. Thromboprophylaxis with enoxaparin is recommended by current guidelines, but evidence is still weak. The aim of this study was to assess the impact of thromboprophylaxis with enoxaparin on hospital mortality in patients admitted for Coronavirus disease 2019 (COVID-19). The effects of enoxaparin on intensive care admission and hospital length-of-stay were evaluated as secondary outcomes. METHODS: Observational cohort study, with data collected from patients admitted to Poliambulanza Foundation with positive real time reverse transcription polymerase chain reaction (RT-PCR) for SARS-CoV-2 from 20th February to 10th May 2020. Multivariate logistic regression with overlap weight propensity score was used to model hospital mortality and intensive care admission, hospital length-of-stay was analyzed with a multivariate Poisson regression. Seven hundred and ninety nine (57%) patients who received enoxaparin at least once during the hospitalization were included in the enoxaparin cohort, 604 (43%) patients who did not were included in the control cohort. FINDINGS: At the adjusted analysis enoxaparin was associated with lower in-hospital mortality (Odds Ratio 0·53, 95% C.I. 0·40-0·70) compared with no enoxaparin treatment. Hospital length-of-stay was longer for patients treated with enoxaparin (Incidence Rate Ratios 1·45, 95% C.I. 1·36-1·54). Enoxaparin treatment was associated with reduced risk of intensive care admission at the adjusted analysis (Odds Ratio 0·48, 95% C.I. 0·32-0·69). INTERPRETATION: This study shows that treatment with enoxaparin during hospital stay is associated with a lower death rate and, while results from randomized clinical trials are still pending, this study supports the use of thromboprophylaxis with enoxaparin in all patients admitted for COVID-19. Moreover, when enoxaparin is used on the wards, it reduces the risk of Intensive Care Unit admission.