Exclusion criteria and their rationale
| Exclusion criterion | Rationale |
| Presence of leg DVT or upper extremity DVT (subclavian vein or above) | Absolute indication for therapeutic anticoagulation |
| Active cancer | High risk of recurrent VTE if left untreated36 |
| History of ≥1 prior episode of unprovoked VTE (±thrombophilia)37 | High risk of recurrent VTE after stopping anticoagulation38–40 |
| Clinical instability (systolic blood pressure <100 mm Hg or arterial oxygen saturation <92% at ambient air) at the time of presentation | Risk of clinical deterioration4 14 41 |
| Active bleeding or at high risk of bleeding (eg, signs of active bleeding, ischaemic stroke during preceding <10 days,42 major gastrointestinal bleeding during preceding <3 months, intracranial or intraocular bleeding <6 months,42 major trauma or surgery during preceding <1 month,42 43 platelets <75 ×10ˆ9/L 3 44 or double anti-platelet therapy at the time of enrolment) | Contraindication to rivaroxaban |
| Severe renal failure (creatinine clearance <30 mL/min) | Contraindication to rivaroxaban |
| Severe liver insufficiency (Child-Pugh B and C) | Contraindication to rivaroxaban |
| Concomitant use of strong CYP3A4 inhibitors (ie, HIV protease inhibitors (saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, tipranavir, darunavir), systemic azole antifungals (ie, ketoconazole, itraconazole, voriconazole or posaconazole)) or strong CYP3A4 inducers (ie, rifampicin, rifabutin, rifapentin, phenytoin, phenobarbital, primidone, carbamazepine or St. John’s Wort) | Contraindication to rivaroxaban |
| Known hypersensitivity to rivaroxaban | Contraindication to rivaroxaban |
| Need for therapeutic anticoagulation for another reason (atrial fibrillation/flutter, mechanical heart valves, previous VTE, known antiphospholipid antibody syndrome with unprovoked VTE) | Randomisation to placebo unethical |
| Therapeutic anticoagulation for >72 hours for any reason at the time of screening | Could confound study outcomes |
| Hospitalised for >72 hours prior to the diagnosis of isolated SSPE (hospital-acquired VTE) | Could confound study outcomes due to influence of cotreatments |
| Known pregnancy or breast feeding | Contraindication to rivaroxaban |
| Lack of safe contraception in women of childbearing potential | Rivaroxaban is contraindicated in pregnancy |
| Refusal or inability to provide informed consent | Unethical |
| Prior enrolment in this trial | Confounds study outcomes |
DVT, deep vein thrombosis; VTE, venous thromboembolism