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 and Timothy A. Brighton for the INSPIRE Study Investigators* (International Collaboration of Aspirin Trials for Recurrent Venous Thromboembolism) Circulation. 2014;130:1062-1071; originally published online August 25, 2014; doi: 10.1161/CIRCULATIONAHA.114.008828 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539

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Vascular Medicine Aspirin for the Prevention of Recurrent Venous Thromboembolism The INSPIRE Collaboration John Simes, MD; Cecilia Becattini, MD; Giancarlo Agnelli, MD; John W. Eikelboom, MB, BS; Adrienne C. Kirby, MSc; Rebecca Mister, MSc; Paolo Prandoni, MD; Timothy A. Brighton, MB, BS; for the INSPIRE Study Investigators* (International Collaboration of Aspirin Trials for Recurrent Venous Thromboembolism) 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.    (Circulation. 2014;130:1062-1071.) Key Words: aspirin ◼ clinical trial ◼ embolism ◼ meta-analysis ◼ prevention ◼ thrombosis

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atients with unprovoked venous thromboembolism (VTE) remain at high risk of recurrence after discontinuation of vitamin K antagonist therapy, with an ≈10% risk within the first year and 5% per year thereafter.1–6 Extending treatment with vitamin K antagonists reduces the risk of recurrence while treatment continues,1–7 but is associated with an increased risk of bleeding and the inconvenience of laboratory monitoring and dose adjustment.8

Editorial see p 1031 Clinical Perspective on p 1071 Several studies have evaluated the efficacy of new oral anticoagulants for the prevention of recurrent VTE as part of initial or extended treatment.9–14 They have been shown to be effective alternatives to warfarin, but still carry a risk of bleeding and are expensive. Aspirin treatment, as a low-cost

Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz. Received January 19, 2014; accepted July 7, 2014. 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.). *A full list of investigators is contained in the Appendix. The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA. 114.008828/-/DC1. Correspondence to John Simes, MD, National Health and Medical Research Council (NHMRC) Clinical Trials Centre, Medical Foundation Building, University of Sydney, NSW 2006, Australia. E-mail [email protected] © 2014 American Heart Association, Inc. Circulation is available at http://circ.ahajournals.org

DOI: 10.1161/CIRCULATIONAHA.114.008828

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Simes et al   INSPIRE: Aspirin for Recurrent VTE   1063 and relatively safe means of preventing further events in this clinical setting, has been recently evaluated in the Aspirin for the Prevention of Recurrent Venous Thromboembolism (the Warfarin and Aspirin [WARFASA]) and the Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE).15,16 The trials showed that aspirin reduces the risk of recurrent VTE but they were not individually powered to detect moderate treatment effects for particular outcomes or subgroups. A combined patient-level analysis of WARFASA and ASPIRE was planned, and a protocol for this project was developed before unblinding of the results of either trial (ACTRN12611000684921). The purpose of the INSPIRE analysis was to more accurately estimate the effects of aspirin treatment: overall, on individual outcomes, and in prespecified subgroups of patients.

Methods Study Protocols The ASPIRE and WARFASA studies were independent, investigatorinitiated, randomized, double-blind, placebo-controlled, clinical trials designed to examine the efficacy and safety of low-dose aspirin in the extended treatment of VTE. Eligible patients were those with a first episode of unprovoked VTE, defined as proximal deep-vein thrombosis (DVT) or pulmonary embolism (PE), who had completed initial treatment with heparin and warfarin or an equivalent anticoagulant regimen. Venous thromboembolism was considered as unprovoked when it occurred in the absence of any known specific permanent or temporary clinical risk factor. The main inclusion and exclusion criteria for the 2 studies are reported in Table I in the online-only Data Supplement.

Patients in each trial received 100 mg enteric-coated aspirin or matching placebo (Bayer HealthCare, Germany) once daily and were followed up for recurrent VTE, arterial ischemic events (myocardial infarction and stroke), bleeding, and death. Both study protocols allowed for interruption of study medication (for example, for major surgery) and for anticoagulant thromboprophylaxis for situations of risk while on the study. Patients were followed up for at least 2 years in the WARFASA trial and up to 4 years in ASPIRE.

Design and Rationale Early in the recruitment phases of both studies, the management committees agreed to combine the data from the 2 trials in a prospective, combined patient-level analysis. Both trials had been planned with harmonization of their study designs, including similar eligibility criteria, study interventions, and definitions of outcomes.15,16 Although it was recognized that the ASPIRE and WARFASA trials would provide important information, neither was powered for reliable estimates of moderate treatment effects on particular outcomes or within particular subgroups. With a planned 2000 patients, INSPIRE would have 80% power to detect a 30% reduction in VTE. Owing to slow recruitment, the final sample size of the combined trials was 1225, giving 80% power to detect a 35% reduction.

Outcome Measures The primary outcome for the INSPIRE study was recurrent VTE, defined as the occurrence of newly diagnosed symptomatic VTE or fatal PE. Secondary outcomes were as follows: (1) major vascular events: the composite of recurrent VTE, myocardial infarction, stroke, or cardiovascular death; and (2) recurrent VTE, myocardial infarction, stroke, all-cause mortality, and major bleeding, a measure of the net clinical benefit. In addition, the component outcomes

1225 randomized 822 ASPIRE 403 WARFASA

609 assigned placebo

616 assigned aspirin

411 ASPIRE

411 ASPIRE

198 WARFASA

205 WARFASA

608 received placebo

616 received aspirin

411 ASPIRE

411 ASPIRE

197 WARFASA

205 WARFASA

1 did not receive study treatment 1 WARFASA

6 no qualifying DVT

6 no qualifying DVT

6 ASPIRE

6 ASPIRE

20 revoked consent

11 revoked consent

10 ASPIRE

2 ASPIRE

10 WARFASA

9 WARFASA

7 lost to follow-up

6 lost to follow-up

4 ASPIRE

2 ASPIRE

3 WARFASA)

4 WARFASA

608 included in efficacy and safety analysis

616 included in efficacy and safety analysis

411 ASPIRE

411 ASPIRE

197 WARFASA

205 WARFASA

Figure 1. Consort flow diagram.

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1064  Circulation  September 23, 2014 event (DVT, PE, or both), sex, age groups (

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

In patients with a first unprovoked venous thromboembolism (VTE) the risk of recurrent VTE remains high after anticoagulant treatment is discontinued...
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