| Study characteristics |
| Methods |
Study design: multicentre, open‐label with blinded outcomes adjudication, investigator‐sponsored, 2‐armed, phase IV, parallel‐assignment RCT Type of publication: abstract of event Setting and dates: hospital, 21 June 2020‐28 February 2021 Country: Brazil Language: English Number of centres: 8 |
| Participants |
3331 participants were assessed for eligibility, 615 participants randomised, 614 analysed (experimental (therapeutic anticoagulation) = 310, comparator (prophylactic anticoagulation) = 304, 1 participant withdrew consent), ≥ 18 years Mean age (years) ± SD: 56.7 ± 14.1 (experimental), 56.5 ± 14.5 (comparator) Gender (male/female): 192/119 (experimental), 176/128 (comparator) Severity of condition: need for oxygen in 76% (catheter or mask 60%, high‐flow nasal cannula 8%, tracheal intubation 7%); unstable clinical condition 23 (7.4%) experimental, 16 (5.3%) comparator, stable clinical condition 288 (92.6%) experimental, 288 (94.7%) comparator; disease state at baseline (experimental/comparator): mild 30 (9.6%) / 39 (12.8%), moderate 257 (82.6%) / 249 (81.9%), severe 24 (7.7%) / 16 (5.3%) Comorbidities (experimental/comparator): chronic lung disease 7 (2.3%) / 12 (3.9%), diabetes 83 (26.7%) / 67 (22.0%), current smoker/former smoker 56 (18.0%)/63 (20.7%), hypertension 151 (48.6%)/151 (49.7%), heart failure 8 (2.6%)/5 (1.6%), coronary disease 12 (3.9%)/16 (5.3%) BMI (kg/m²), mean ± SD: 30.3 ± 6.0 (experimental), 30.3 ± 6.1 (comparator) Anticoagulation before randomisation (experimental/comparator): 285 (91.7%) / 275 (90.5%) Baseline medication (experimental/comparator): antiplatelet 22 (7.1%) / 26 (8.6%), vasopressor 16 (5.1%) / 8 (2.6%), systemic corticosteroids 257 (82.6%)/253 (83.2%) D‐dimer ≥ 3 x ULN (experimental/comparator): 84 (27.0%) / 83 (27.3%)
Inclusion
Patients with confirmed diagnosis of COVID‐19 admitted to hospital Onset of symptoms leading to hospitalisation < 14 days Patients ≥ 18 years D‐dimer ≥ 3 x the ULN Agreement to participate by providing the informed consent form
Exclusion
Patients with indication for full anticoagulation during inclusion (for example, diagnosis of VTE, atrial fibrillation, mechanical valve prosthesis) Platelets < 50,000/m³ Need for ASA therapy > 100 mg Need for P2Y12 inhibitor therapy (clopidogrel, ticagrelor or prasugrel) Chronic use of non‐hormonal anti‐inflammatory drugs Sustained uncontrolled systolic BP of ≥ 180 mmHg or diastolic BP of ≥ 100 mmHg INR > 1.5 Patients contraindicated to full anticoagulation (active bleeding, liver failure, blood dyscrasia or prohibitive haemorrhage risk as evaluated by the investigator) Criteria for DIC A history of haemorrhagic stroke or any intracranial bleeding at any time in the past or current intracranial neoplasm (benign or malignant), cerebral metastases, arteriovenous (AV) malformation, or aneurysm; Active cancer (excluding non‐melanoma skin cancer) defined as cancer not in remission or requiring active chemotherapy or adjunctive therapies such as immunotherapy or radiotherapy Hypersensitivity to rivaroxaban Use of strong inhibitors of cytochrome P450 (CYP) 3A4 and/or P‐glycoprotein (P‐gp) (e.g. protease inhibitors, ketoconazole, Itraconazole) and/or use of P‐gp and strong CYP3A4 inducers (such as but not limited to rifampin/rifampicin, rifabutin, rifapentine, phenytoin, phenobarbital, carbamazepine, or St. John's Wort) Known HIV infection CrCl < 30 mL/min according to the Cockcroft‐Gault Formula Pregnancy or breastfeeding
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| Interventions |
Experimental: routine full anticoagulation strategy. Stable patients received rivaroxaban 20 mg daily. Unstable patients received enoxaparin 1 mg/kg twice daily. Followed by rivaroxaban for 30 days, irrespective of the duration of hospitalisation Comparator: usual standard care and currently have no indication of full anticoagulation. Control group with enoxaparin 40 mg/d |
| Outcomes |
Primary (specified)
Hierarchical composite endpoint composed of mortality, number of days alive, number of days in the hospital and number of days with oxygen therapy at the end of 30 days (time frame: in 30 days) The primary objective will be analysed using the win ratio approach comparing every participant of treatment group to every participant of control group to determine a winner.
Primary (collected)
Hierarchical analysis of mortality, duration of hospitalisation, and duration of oxygen use through 30 days Major or clinically relevant non‐major bleeding according to ISTH criteria
Secondary (specified)
Incidence of VTE (time frame: 30 days) Incidence of acute myocardial infarction (time frame: 30 days) Incidence of stroke (time frame: 30 days) Number of days using oxygen therapy (time frame: 30 days) Peak of troponin (time frame: 30 days) Peak of D‐dimer (time frame: 30 days) Incidence of major bleeding and clinically relevant non‐major bleeding by the ISTH criteria (time frame: 30 days). It will be considered the main safety endpoint
Secondary (collected)
Time points reported: at 30 days after the start of the intervention |
| Notes |
Protocol available (NCT04394377) Sponsor/funding: quote "Unrestricted research grant from Bayer S.A., which was not involved in design, conduct or interpretation of the study" COIs: all listed study authors declared some financial support from the industry |
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| Item |
Authors' judgement |
Support for judgement |
| Random sequence generation (selection bias) |
Yes |
Quote "Concealed randomisation will be performed using a central, automated, electronic web‐based system." |
| Allocation concealment (selection bias) |
Yes |
Quote "Concealed randomisation will be performed using a central, automated, electronic web‐based system." |
| Blinding of participants and personnel (performance bias) |
No |
Quote "The study is open‐label with blinded outcomes adjudication" |
| Blinding of outcome assessment (detection bias) |
Yes |
Quote "The study is open‐label with blinded outcomes adjudication" |
| Incomplete outcome data (attrition bias) |
Yes |
There was one loss in the experimental group (1/311, 0.3%): one participant withdrew consent and declined to contribute data. |
| Selective reporting (reporting bias) |
Yes |
All prespecified outcomes were reported. |
| Other bias |
Yes |
We do not suspect any other bias related to this study. |
