The ARCHIMEDES study (Anti-inflammatory and anti-thRombotic therapy with colCHicine and low dose rIvaroxaban for Major adverse cardiovascular Events reDuction in ischEmic Stroke) will be a randomized, double-blind, 2x2 factorial clinical trial, which will include at least 3000 and up to a maximum of 4500 patients with ischemic stroke without indication of oral anticoagulation.

In patients with ischemic stroke, within 14 days of symptom onset, to establish the efficacy and safety of two strategies in parallel: low-dose rivaroxaban and low-dose colchicine, compared with placebo.

Inclusion Criteria:

• Patients with acute ischemic stroke aged ≥18 years old who, regardless of etiology and mechanism, do not have a definitive indication for anticoagulation, and whose symptoms onset has been within the last 14 days;
• Receiving standard therapy for acute management of ischemic stroke;
• For patients treated with fibrinolytics, a minimum period of 24 hours after the infusion of the lytic drug is required for randomization into the study.

Exclusion Criteria:

• Modified Rankin score of 4 or more at randomization;
• Refusal to provide consent;
• Severe renal failure, with glomerular filtration rate (by CKD-EPI) estimated at <15 mL/min/1.73 m2;
• Severe liver failure (child C);
• Indication for full-dose anticoagulation (for example, venous thromboembolism or atrial fibrillation);
• Previous hemorrhagic stroke or history of intracranial hemorrhage;
• Systemic treatment with a potent CYP 3A4 inhibitor (such as azole antifungals and protease inhibitors), or with a potent 3A4 inducer (such as rifampicin, phenytoin, phenobarbital, or carbamazepine);
• History of inflammatory bowel disease or chronic diarrhea;
• Prolonged treatment (> 1 month) with immunosuppressants or systemic corticosteroids;
• History of recurrent pneumonia (3 or more hospitalizations in the last 12 months);
• Pregnancy or breastfeeding;
• Any other comorbidity other than stroke and CV disease (e.g., metastatic cancer) that, in the investigator's opinion, has a significant impact on the 12-month survival.

Matching placebos will be produced for rivaroxaban and colchicine.