Aspirin for the prevention of recurrent venous thromboembolism: the INSPIRE collaboration

John Simes; Cecilia Becattini; Giancarlo Agnelli; John W Eikelboom; Adrienne C Kirby; Rebecca Mister; Paolo Prandoni; Timothy A Brighton; INSPIRE Study Investigators (International Collaboration of Aspirin Trials for Recurrent Venous Thromboembolism)

doi:10.1161/CIRCULATIONAHA.114.008828

Aspirin for the prevention of recurrent venous thromboembolism: the INSPIRE collaboration

Circulation. 2014 Sep 23;130(13):1062-71. doi: 10.1161/CIRCULATIONAHA.114.008828. Epub 2014 Aug 25.

Authors

John Simes¹, Cecilia Becattini², Giancarlo Agnelli², John W Eikelboom², Adrienne C Kirby², Rebecca Mister², Paolo Prandoni², Timothy A Brighton²; INSPIRE Study Investigators (International Collaboration of Aspirin Trials for Recurrent Venous Thromboembolism)

Collaborators

INSPIRE Study Investigators (International Collaboration of Aspirin Trials for Recurrent Venous Thromboembolism):
John Eikelboom, Tim Brighton, Giancarlo Agnelli, Cecilia Becattini, Wendy Hague, Rebecca Mister, Adrienne Kirby, Paolo Prandoni, Paul Ockelford, Alex Gallus, Denis Xavier, Rafael Diaz, John Simes, Adrienne Kirby, Kristy Mann, Rebecca Mister, Wendy Hague, Rhana Pike, John Simes, Tim Brighton, John Eikelboom, John Simes, Wendy Hague, Rebecca Mister, Adrienne Kirby, Alex Gallus, Paul Ockelford, Ross Baker, Harry Gibbs, Paul Coughlin, Denis Xavier, Rafael Diaz, Giancarlo Agnelli, Cecilia Becattini, Paolo Prandoni, Cecilia Becattini, Giancarlo Agnelli, Paolo Prandoni, Walter Ageno, Claudio Cimminiello, Sabine Eichinger

Affiliations

¹ From the National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (J.S., A.C.K., R.M.); the Division of Internal and Cardiovascular Medicine and Stroke Unit, Department of Internal Medicine, University of Perugia, Perugia, Italy (C.B., G.A.); the Population Health Research Institute, McMaster University, Hamilton, ON, Canada (J.W.E.); the Department of Cardiothoracic and Vascular Sciences, University of Padua, Padua (P.P.); and the Department of Haematology, South Eastern Area Laboratory Services (SEALS), Prince of Wales Hospital, Sydney, Australia (T.A.B.). john@ctc.usyd.edu.au.
² From the National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (J.S., A.C.K., R.M.); the Division of Internal and Cardiovascular Medicine and Stroke Unit, Department of Internal Medicine, University of Perugia, Perugia, Italy (C.B., G.A.); the Population Health Research Institute, McMaster University, Hamilton, ON, Canada (J.W.E.); the Department of Cardiothoracic and Vascular Sciences, University of Padua, Padua (P.P.); and the Department of Haematology, South Eastern Area Laboratory Services (SEALS), Prince of Wales Hospital, Sydney, Australia (T.A.B.).

PMID: 25156992
DOI: 10.1161/CIRCULATIONAHA.114.008828

Abstract

Background: In patients with a first unprovoked venous thromboembolism (VTE) the risk of recurrent VTE remains high after anticoagulant treatment is discontinued. The Aspirin for the Prevention of Recurrent Venous Thromboembolism (the Warfarin and Aspirin [WARFASA]) and the Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE) trials showed that aspirin reduces this risk, but they were not individually powered to detect treatment effects for particular outcomes or subgroups.

Methods and results: An individual patient data analysis of these trials was planned, before their results were known, to assess the effect of aspirin versus placebo on recurrent VTE, major vascular events (recurrent VTE, myocardial infarction, stroke, and cardiovascular disease death) and bleeding, overall and within predefined subgroups. The primary analysis, for VTE, was by intention to treat using time-to-event data. Of 1224 patients, 193 had recurrent VTE over 30.4 months' median follow-up. Aspirin reduced recurrent VTE (7.5%/yr versus 5.1%/yr; hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.51-0.90; P=0.008), including both deep-vein thrombosis (HR, 0.66; 95% CI, 0.47-0.92; P=0.01) and pulmonary embolism (HR, 0.66; 95% CI, 0.41-1.06; P=0.08). Aspirin reduced major vascular events (8.7%/yr versus 5.7%/yr; HR, 0.66; 95% CI, 0.50-0.86; P=0.002). The major bleeding rate was low (0.4%/yr for placebo and 0.5%/yr for aspirin). After adjustment for treatment adherence, recurrent VTE was reduced by 42% (HR, 0.58; 95% CI, 0.40-0.85; P=0.005). Prespecified subgroup analyses indicate similar relative, but larger absolute, risk reductions in men and older patients.

Conclusions: Aspirin after anticoagulant treatment reduces the overall risk of recurrence by more than a third in a broad cross-section of patients with a first unprovoked VTE, without significantly increasing the risk of bleeding.

Clinical trial registration url: www.anzctr.org.au. Unique identifier: ACTRN12611000684921.

Keywords: aspirin; clinical trial; embolism; meta-analysis; prevention; thrombosis.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Age Factors
Aged
Anticoagulants / therapeutic use*
Aspirin / therapeutic use*
Double-Blind Method
Female
Follow-Up Studies
Hemorrhage / epidemiology
Humans
Male
Middle Aged
Platelet Aggregation Inhibitors / therapeutic use*
Recurrence
Risk Factors
Sex Factors
Treatment Outcome
Venous Thromboembolism / prevention & control*
Warfarin / therapeutic use*

Substances

Anticoagulants
Platelet Aggregation Inhibitors
Warfarin
Aspirin