ASPIRE.

Study characteristics
Methods	Multicentre, randomised, double‐blind, placebo‐controlled trial Exclusions after randomisation: 12 (6 in placebo and 6 in aspirin group) who were enrolled after a diagnosis of the first unprovoked proximal DVT and who were included in the analysis were subsequently found to be ineligible after a review of the records. 12 (10 in placebo and 2 in aspirin) revoked consent Intention‐to‐treat approach mentioned Losses to follow‐up: 6 (4 in placebo and 2 in aspirin group) Study duration: May 2003 to August 2011 Duration of follow‐up: 12 to 48 months
Participants	Country: Argentina, Australia, Canada, India and New Zealand Participants: 822 included and analysed (treatment: 411; control: 411) at 56 sites in five countries. Our participant group of interest (DVT with or without PE) had 583 participants. Age: mean 54 ± 15.8 years in the placebo group and 55 ± 16 years in the aspirin group Sex: male 447 (54%); female 375 (46%) Inclusion criteria: men and women aged over 18 first episode of unprovoked proximal DVT or PE completion of initial treatment with unfractionated heparin or low‐molecular‐weight heparin (or effective alternative) and warfarin (recommended minimum duration 6 months, maximum 12 months) commencement of study medication recommended within 6 weeks (and as soon as possible) of cessation of the initial anticoagulant therapy Exclusion criteria: allergy, intolerance, or contraindication for aspirin clear indication for aspirin, clopidogrel, or a conventional cyclooxygenase (COX 1/2) or NSAIDs indication for long‐term anticoagulant therapy (e.g. prosthetic heart valve) life expectancy less than 6 months active bleeding or at high risk of bleeding anticipated non‐adherence to study medications inability to attend follow‐up because of geographic inaccessibility
Interventions	Antiplatelet agents: in the test group, enteric‐coated aspirin 100 mg tablets daily participants were asked to take 1 tablet daily for a minimum of 2 years Control: placebo participants were asked to take 1 tablet daily for a minimum of 2 years Co‐treatment: initial treatment with unfractionated heparin or low‐molecular‐weight heparin (or effective alternative) and warfarin (recommended minimum duration 6 months, maximum 12 months). It was recommended that a target INR of 2–3 be maintained with warfarin therapy for 6–12 months. ‘Patients who receive a shorter duration of warfarin treatment (no less than 6 weeks) remain eligible for inclusion in the ASPIRE study. Because the risk of recurrent VTE is relatively stable after the first 3–6 months and remains persistently elevated thereafter for at least several years, variation in the actual duration of warfarin prior to randomisation should not materially impact on study power’. ‘Patients initially treated with fibrinolytic therapy (e.g. tPA or streptokinase) who are also treated with heparin and warfarin are eligible for inclusion’. DVT phase: chronic (after 21 days). Study began after initial anticoagulant treatment of 6–12 months.
Outcomes	Primary Recurrence of VTE, defined as a composite of symptomatic, objectively‐confirmed DVT, nonfatal PE, or fatal PE Secondary Composite of symptomatic VTE, myocardial infarction, stroke, or cardiovascular death (all serious thrombotic vascular events) Symptomatic VTE Myocardial infarction Stroke All‐cause mortality Major bleeding (a measure of net clinical benefit) Safety Major and minor bleeding Other ‘The incidence of post‐phlebitic syndrome and an assessment of cost‐effectiveness of therapy will be incorporated in sub‐studies within the trial’. duration of hospitalisation
Notes	Aspirin and placebo were provided by Bayer Healthcare Pharmaceuticals; ‘the company played no other role in the study and was not involved in the collection or analysis of the data or in the preparation of the manuscript’. Other economic information was not available. Additional data provided by trialists (personal communication)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Sequence generation was by a web‐based randomisation system.
Allocation concealment (selection bias)	Low risk	Quote: 'After receipt of appropriate baseline data, the patient will be randomised and the completed Randomisation Form will be sent to the central coordinating centre.' Quote: 'Each patient will be provided with a trial card/file containing contact details for their centre/other centres, information to show to their usual doctors and a copy of their baseline scan report.' Comment: information from study protocol document
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Aspirin and placebo were matched, and both were provided by Bayer Healthcare Pharmaceuticals.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: 'All episodes of venous thromboembolism, myocardial infarction, and stroke and the causes of death were adjudicated by an independent outcome assessment committee whose members were unaware of the group assignments'.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: 'Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups. Aspirin: 6 no qualifying DVT, 2 revoked consent and 2 lost to follow‐up (401/411 = 97% completed); Placebo: 6 no qualifying DVT, 10 revoked consent and 4 lost to follow‐up (391/411 = 95% completed). All 822 participants were analysed by intention‐to‐treat approach'. Comment: data from appendix figure 1 of the study report.
Selective reporting (reporting bias)	Low risk	The study protocol is available and all of the study’s prespecified (primary and secondary) outcomes that are of interest in the review have been reported in the prespecified way.
Other bias	Low risk	Aspirin and placebo were provided by Bayer Healthcare Pharmaceuticals. Quote: 'the company played no other role in the study and was not involved in the collection or analysis of the data or in the preparation of the manuscript'