WARFASA.

Study characteristics
Methods	Multicentre, randomised, double‐blind, placebo‐controlled trial Exclusions after randomisation: one participant in the placebo group did not receive the treatment and was excluded after randomisation Intention‐to‐treat approach: "modified intention‐to‐treat principle, with all patients who received at least one dose of the assigned study drug after randomisation included in the analysis." Losses to follow‐up: four participants in the placebo group (2%); three participants in the antiplatelet group (1.4%) were lost to follow‐up. Other treatment dropout: in the control group, 9 withdrew consent, 8 had new indication for aspirin, 2 had new indication other than VTE for VKAs and 6 had adverse events. In the antiplatelet group, 10 withdrew consent, 13 had new indication for aspirin, 3 had new indication other than VTE for VKAs and 7 had adverse events. Study duration: May 2004 to August 2010 Duration of follow‐up: median period of the study duration was 24.8 months for the aspirin group and 24.2 months for the placebo group
Participants	Country: authors have affiliations from Italy and Austria. According to protocol information, participants were scheduled to be recruited from 25 European centres in Austria, Denmark, France, Great Britain, Italy, and the Netherlands according protocol information, but nothing was described in the study report. Participants: 403 participants included and randomised but only 402 were analysed in this study. 205 participants received aspirin, 197 received placebo, and one participant, who was assigned to the placebo group, did not receive the study drug (excluded after randomisation). In our review, we could utilise data from 122 participants who received antiplatelet agents and 130 participants who received the placebo because they were described as participants with DVT with or without PE and only for the outcome recurrent VTE ‐ early and intermediate. Data for the other outcomes were not stratified by types of participant and included data from participants with PE only (beyond the scope of this review). Age: mean ± standard deviation was 61.9 ± 15.3 years in the aspirin group and 62.1 ± 15.1 years in the placebo group Sex: male 135/205 (65.8%) in the aspirin group and male 122/197 (61.9%) in the placebo group. Total of 257 (64%) male and 145 (36%) female Inclusion criteria: participants ‘older than 18 years of age were eligible for the study if they had been treated for 6–18 months with VKAs (with a target INR of 2.0–3.0) for first‐ever, objectively confirmed, symptomatic, unprovoked proximal deep venous thrombosis, PE, or both’. Exclusion criteria: known cancer known major thrombophilia (antiphospholipid antibodies or lupus anticoagulant or homozygous factor V Leiden or prothrombin G21210A or double heterozygosity for factor V Leiden and prothrombin G21210A or deficiency of antithrombin, protein C or S) an indication for long‐term anticoagulant therapy other than VTE (as atrial fibrillation or prosthetic heart valve) previous symptomatic complications of atherosclerosis requiring treatment with aspirin or other antiplatelet agents active bleeding or high risk for bleeding or a bleeding episode which occurred during the 6–18 months of anticoagulation known allergy or intolerance to aspirin life expectancy shorter than 6 months anticipated non‐adherence to study medications pregnancy or breast‐feeding participation in another experimental pharmacotherapeutic program within 30 days before randomisation women with VTE associated with the use of oestro‐progestin therapy DVT phase: chronic (after 21 days) study began after 6 months of anticoagulation
Interventions	Antiplatelet agent: aspirin, 100 mg once daily Control: placebo, once daily Co‐treatment: previous treatment with VKAs for 6–18 months (target INR of 2.0 to 3.0) Appendix information: ‘Other anticoagulants and fibrinolytic agents were not allowed during the study period. The administration of NSAID was allowed with caution if considered necessary’. no information about compression stockings or other concomitant treatment
Outcomes	Primary Symptomatic, objectively‐confirmed recurrence of VTE, defined as the composite of deep venous thrombosis or nonfatal or fatal PE Secondary Nonfatal myocardial infarction Unstable angina Stroke Transient ischaemic attack Acute ischaemia of the lower limbs Death from any cause Safety Principal was major bleeding An overt bleeding event was defined as major if it was fatal, occurred in a critical location (intracranial, intraspinal, intraocular, retroperitoneal, intraarticular, pericardial, or intramuscular (leading to a compartment syndrome)), or was associated with a decrease in the haemoglobin level of at least 2.0 g per dL or required a transfusion of two or more units of whole blood or red cells. Clinically relevant, non‐major bleeding, defined as any overt bleeding that required a medical intervention and did not meet any of the criteria for major bleeding, was a secondary safety outcome. Adverse events (gastric pain, cutaneous reaction and renal failure) and additional necessity of antiplatelets and anticoagulant therapy were reported
Notes	Supported by the University of Perugia, a grant‐in‐aid from Bayer Healthcare, and an Aventis Fellowship for Clinical Research from the International Society of Thrombosis and Haemostasis (to Dr Becattini). Dr Agnelli reports receiving consulting fees from Bayer Healthcare, Boehringer Ingelheim, and Daiichi Sankyo and lecture fees from Bayer Healthcare, Bristol‐Myers Squibb, and Sanofi‐Aventis; Dr Eichinger, board memberships from Bayer and Boehringer Ingelheim and lecture fees from Bayer, Boehringer Ingelheim, Pfizer, and Sanofi‐Aventis; and Dr Ageno, board memberships from Bristol‐Myers Squibb, Pfizer, and Bayer Schering Pharma and lecture fees from GlaxoSmithKline, Sanofi‐Aventis, Bayer Schering Pharma, Bristol‐Myers Squibb, Pfizer, and Boehringer Ingelheim. Authors reported that aspirin and placebo tablets were supplied by Bayer Healthcare and Bayer played no role in the design of the study, in data collection or analysis or in manuscript preparation. No other economic information was reported. Although we tried to contact the authors, they did not respond. We were therefore not able to obtain stratified data from the participants with DVT and those with PE alone, preventing the inclusion of the data in this review. Because of this, we only could extract the data for recurrent VTE which was stratified by types of participant from the original paper. Additional data not provided by trialists (no response to personal communication)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: ‘The randomisation sequence will be computer generated. Patients will be randomised according to the consecutive box number assigned to the study centre. Randomisation will be 1/1 (aspirin/placebo)’. Comment: information from protocol document
Allocation concealment (selection bias)	Low risk	Quote: ‘Patients will be randomised according to the consecutive box number assigned to the study centre. Randomisation will be 1/1 (aspirin/placebo)’. Comment: information from protocol document Comment: treatment regimens (antiplatelets and placebo) were similar, tablets once daily
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: ‘double‐blind, placebo‐controlled trial’ Comment: information from protocol document Comment: treatment regimens (antiplatelets and placebo) were similar, tablets once daily
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: ‘All suspected study outcome events were assessed by a central, independent adjudication committee whose members were unaware of the group assignments and who reviewed the imaging results.’
Incomplete outcome data (attrition bias) All outcomes	Low risk	Losses and exclusions were detailed and utilised as intention‐to‐treat. Adverse events were mentioned and analysed.
Selective reporting (reporting bias)	High risk	Protocol is available Quote: ‘The study was performed in accordance with the protocol and with the provisions of the Declaration of Helsinki and local regulations’. Comment: in the 'historical versions' in ClinicalTrials.gov, the protocol was modified in its primarily and secondary outcomes near publication of the study, putting it in high risk of selective publication.
Other bias	Low risk	Financial support is mentioned and apparently did not interfere with the results. Authors reported that aspirin and placebo tablets were supplied by Bayer Healthcare and Bayer played no role in the design of the study, in data collection or analysis, or in manuscript preparation. There is no other identified reason for bias.

ASA: acetylsalicylic acid
CDS: colour Doppler ultrasound
DVT: deep vein thrombosis
GECS: graduated elastic compression stockings
INR: international normalised ratio
PE: pulmonary embolism
PTS: post‐thrombotic syndrome
tPA: tissue plasminogen activator
VKA: vitamin‐K antagonist
VTE: venous thromboembolism