The goal of this clinical trial is to find out the clinical and cost effectiveness of Thromboprophylaxis in participants who have been placed in a plaster cast or splint after injury.

The main questions it aims to answer are:

• whether giving tablets to people at high risks of clots after a leg injury is as good as injections (standard care)
• whether giving any medication after a leg injury is better than standard care (advice only) for people at low risk of clots.

Participants will be assessed to be high risk (TiLLI High) or low risk (TiLLI Low). People who are at high risk of clots will have either tablets or injections to reduce their risk. People at low risk will receive tablets, injections or no medication.

Drug treatments will be provided for the duration of immobilisation or up to 42 days (whichever is earlier), in accordance with current NICE guidelines. The participants will be followed up for 90 days following randomisation.

People have an increased risk of blood clots when they have a leg injury treated with a plaster cast or a splint, which happens to over 70,000 people every year in the UK. Blood clots can cause long term problems in the legs and can also move to the lungs, causing serious illness and occasionally death. Medicines are available to reduce the risk of blood clots, but they can also increase the risk of bleeding. In people at high risk of clots, most hospitals use the recommended daily injections which can be uncomfortable and sometimes difficult to give. Tablets are available that reduce the risk of blood clots in other groups, but it is not known if tablets work as well as the injections for people with a leg injury. It is also not known whether people at low risk of blood clots may benefit from any medication. As such, a national research body has identified the need for further study on this topic.

The TiLLI study has two aims - to determine whether giving tablets to people at high risk of clots after a leg injury is as good as injections, and whether giving any medication is better than standard care (advice only) for people at low risk of clots.

The TiLLI study consists of two linked trials: TiLLI-High and TiLLI-Low. People who have been placed in a plaster cast or splint after a leg injury will be invited to participate. Those who agree and are at high risk of clots will enter TiLLI-High and be randomised to receive either tablets or injections to reduce their risk of blood clots; those at low risk will enter TiLLI-Low and will be randomised to receive tablets, injections, or no medication. Patients and doctors will know what medication they are taking. All patients will be provided with written guidance on the signs and symptoms of blood clots and advice on managing their medication.

Information will be collected from study participants up to 90 days after joining the study to find out whether anyone suffers blood clots or complications from the medication. This data will be collected by reviewing medical records and contacting participants as needed. To encourage people from different backgrounds to take part, the study will run from lots of different hospitals across the UK. Study materials will be translated into different languages for those who do not speak English. The investigators will collect as much information as possible from people without extra hospital visits. An independent panel will look at the data as the study progresses to decide whether it is safe to continue.

The study will cost approximately £300 per patient, which is excellent value for money. If these trials show that tablets are as effective as injections, approximately 20,000 patients will be able to avoid injections and >£1.5 million will be released back to NHS resources, every year. When the study is finished, the investigators will share the findings with staff in the NHS, patient charities and national guideline bodies. They will also publish the findings in the medical press and work with international research groups to answer further research questions on this topic.

Inclusion Criteria:

• Age >/= 16 years
• Placed in temporary lower limb immobilisation (rigid cast or brace) as a result an injury that occurred within the last 7 calendar days

Exclusion Criteria:

• Hospital admission is required direct from the emergency department, minor injuries unit, or fracture clinic setting with an expected length of stay >2 calendar days.
• Absolute contraindication or known hypersensitivity to anticoagulants, including history of end stage renal failure (eGFR <20ml/min/1.73m2), hepatic failure or use of concomitant systemic treatment with azole-antimycotics (such as ketoconazole, itraconazole, voriconazole and posaconazole), HIV protease inhibitors (e.g. ritonavir) or active substances strongly inhibiting elimination pathways such as CYP3A4 or P-gp (such as clarithromycin, erythromycin or dronaderone) or a history of heparin induced thrombocytopenia.
• Pregnancy, actively seeking conception, or active breastfeeding.
• Preceding use of anticoagulant treatment for >3 calendar days at prophylactic or therapeutic dose.
• Prior enrolment in the TiLLI study.
• Non-rigid immobilisation (crepe bandage, tubigrip support, strapping).
• Time since prescription of rigid immobilisation >3 calendar days
• Co-enrolment onto a CTIMP where an anticoagulant is administered
• People lacking the capacity to consent
• Inability or refusal to use acceptable contraception up until after the last administration of IMP. Only applicable for women of childbearing potential who have been randomised to receive apixaban or rivaroxaban

Open-label study. Trial Statistician and Health Economist to be blinded for analysis