INSPIRE

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Simes J, et al. "Aspirin for the prevention of recurrent venous thromboembolism: the INSPIRE collaboration". Circulation. 2014. 130(13):1062-1071.
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Clinical Question

In patients with previous unprovoked venous thromboembolism (VTE) and no longer taking anticoagulation treatment, does taking aspirin as compared to placebo decrease the risk of VTE recurrence, major vascular events (MI, stroke, cardiovascular disease death), and bleeding overall and within predefined subgroups?

Bottom Line

Aspirin after anticoagulation treatment reduces the overall risk of VTE 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.

Major Points

There is a high risk of recurrent venous VTE in patients that have experienced a previous unprovoked VTE and have since discontinued anticoagulation therapy. Long-term treatment with anticoagulants, such as vitamin K antagonists, has increased bleeding risk and is inconvenient in terms of monitoring and dose adjustments. Treatment with aspirin is a low cost and relatively safe alternative. The Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE) and the Aspirin for the Prevention of Recurrent Venous Thromboembolism (the Warfarin and Aspirin [WARFASA]) trials found that aspirin does reduce the risk of recurrent VTE, but were not individually powered to detect moderate treatment effects for particular outcomes or subgroups. The INSPIRE analysis more accurately estimates the aspirin effects overall, on individual outcomes, and in prespecified subgroups. Aspirin therapy showed a 32% relative reduction in VTE compared to placebo.

Guidelines

2012 ACCP Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines; discusses aspirin and new therapies for DVT/VTE prevention; no current guidelines for aspirin and secondary prevention.

Design

  • Prospective patient-level meta-analysis of two independent, investigator-initiated, randomized, double-blind, placebo-controlled clinical trials
  • Studies dated 2012 and published in English
  • Patients included:
    • TOTAL (n=1224)
      • Aspirin (n=616)
      • Placebo (n=608)
    • WARFASA (n=402)
      • Aspirin (n=205)
      • Placebo (n=197)
    • ASPIRE (n=822)
      • Aspirin (n=411)
      • Placebo (n=411)
  • Mean follow-up: 30.4 months
  • Analysis: Intention-to-treat
  • Tests for heterogeneity of treatment effect between trials on each outcome were done before the combined analyses

Population

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.

Inclusion Criteria

Included:

  • ASPIRE:
    • Age >18
    • First unprovoked deep-vein thrombosis or pulmonary embolism (no transient risk factor)
    • Initial unfractionated heparin/or low-molecular weight heparin and warfarin
    • Recommended 6-24 months treatment
  • WARFASA:
    • No age restriction
    • First idiopathic deep-vein thrombosis or pulmonary embolism (no known risk factor)
    • Initial unfractionated heparin or low-molecular weight heparin and warfarin
    • Recommended 6-12 months treatment

Exclusion Criteria

Excluded:

  • ASPIRE:
    • Indication or contraindication for aspirin
    • Indication for continued antiplatelet or oral anticoagulation
    • Increased bleeding risk
    • COX 1 or COX 2 inhibitor
    • Life expectancy <12 months
    • Expected nonadherence
    • Anticipated difficult follow-up
  • WARFASA:
    • Indication or contraindication for aspirin
    • Indication for continued antiplatelet or oral anticoagulation
    • Known thrombophilia excluded (including lupus anticoagulants, anticardiolipin antibodies, homozygous or combined Factor V Leiden mutation and prothrombin gene mutation, antithrombin deficiency, cancer)
    • History of cancer
    • Increased bleeding risk
    • COX 1 or COX 2 inhibitor
    • Life expectancy <6 months
    • Expected nonadherence
    • Anticipated difficult follow-up

Baseline Characteristics

INSPIRE Demographics:

  • Number: Placebo n=608, Aspirin n=616
  • Age (mean, years): Placebo 57, Aspirin 57
  • BMI (mean): Placebo 28, Aspirin 29
  • Qualifying event
    • DVT only: Placebo n=362, Aspirin n=358
    • PE only: Placebo n=137, Aspirin n=149
    • DVT and PE: Placebo n=105, Aspirin n=105
  • Duration of anticoagulation
    • <6 months: Placebo n=110, Aspirin n=142
    • 6-9 months: Placebo n=291, Aspirin n=272
    • 9-12 months: Placebo n=103, Aspirin n=121
    • >12 months: Placebo n=104, Aspirin n=81
  • Initial therapy
    • Low-molecular-weight heparin: Placebo n=522, Aspirin n=515
    • Unfractionated heparin: Placebo n=52, Aspirin n=60
    • Other: Placebo n=34, Aspirin n=41
  • Subsequent therapy
    • Low-molecular-weight heparin: Placebo n=4, Aspirin n=5
    • Unfractionated heparin: Placebo n=538, Aspirin n=548
    • Other: Placebo n=66, Aspirin n=63
  • Current Smoker
    • Placebo n=69, Aspirin n=69
  • Active Malignancy at Baseline
    • Placebo n=7, Aspirin n=11

Interventions

The study is a meta-analysis of two studies that evaluated aspirin therapy (100 mg enteric-coated aspirin given once daily) compared to matching placebo for secondary prevention of VTE.

Outcomes

Primary outcome: recurrent VTE, defined as fatal pulmonary embolism (PE) or newly diagnosed symptomatic VTE

Primary Outcomes

  • Recurrent VTE:
    • Placebo: 112 of 608 patients (18.4%)
    • Aspirin: 81 of 616 (13.1%)
    • 32% relative reduction in VTE (HR, 0.68; 95% CI, 0.51-0.90; p=0.008)
    • NNT= 42

Secondary Outcomes

  • Aspirin reduced the risk of major vascular events (symptomatic VTE, myocardial infarction, stroke, or cardiovascular death) by 34%, corresponding to 34 needed to treat per year to prevent an event
  • Clinically relevant bleeding: 12 patients in the placebo group (7 were major); 18 patients in the aspirin group (9 were major)
  • Net clinical benefit (symptomatic VTE, myocardial infarction, stroke, all-cause mortality and major bleeding) improved with aspirin by 33%, NNT=31

Subgroup Analysis

Prespecified subgroups were evaluated in terms of either the effect on VTE or on major vascular events. No significant interactions (p>0.1) exist.

Adverse Events

None recorded in the meta-analysis

Criticisms

  • The study addressed a clear clinical question
  • The study used proper inclusion criteria
  • Thorough details about the trials were provided

The study duration of 4 years was adequate to get desired results

  • The author used proper methods for pooling the data for the meta-analysis
  • The conclusion of the study was supported by the data

Funding

The ASPIRE study was funded by grants from the National Health and Medical Research Council (Project grants 301911 [2003] and 570967 [2008]), New Zealand Health Research Council (HRC; 05/080R [2005]), New South Wales Health, and Australian Society of Thrombosis and Haemostasis. The WARFASA study was funded by the University of Perugia and a grant-in-aid from Bayer HealthCare. The study drug (aspirin and placebo) for both studies was provided by Bayer HealthCare.

Further Reading