ASPIRE

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Brighton TA, et al. "Low-Dose Aspirin for Preventing Recurrent Venous Thromboembolism". The New England Journal of Medicine. 2012. 367(21):1979-1987.
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Clinical Question

Among patients with an unprovoked VTE who have completed anticoagulation therapy, does aspirin reduce recurrent VTE?

Bottom Line

Among patients with an unprovoked VTE who have completed anticoagulation therapy, aspirin was associated with fewer major vascular events and a nonsignificant trend towards fewer recurrent VTE; a combined analysis with WARFASA showed a reduction in recurrent VTE with aspirin.

Major Points

The risk of recurrent VTE following completion of treatment for an unprovoked event is approximately 10% within the first year following the discontinuation of anticoagulation. Several studies, including WARFASA (2012), AMPLIFY-EXT (2013), and ASPIRE have studied the benefits of continuation of aspirin or lower-dose anticoagulant in this setting.

Published in 2012, the Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE) trial randomized 822 patients with a first unprovoked episode of VTE who had completed anticoagulation therapy to aspirin 100mg daily or placebo. About three-quarters (73%) of patients had completed ≥6 months of anticoagulation by the time of randomization. At a mean follow-up of 3.1 years, aspirin was associated with a nonsignificant trend towards fewer recurrent VTE events (4.8% vs. 6.5%; P=0.09) and fewer CV events (5.2% vs. 8.0%); there was a trend towards more bleeding in the aspirin group, but this did not reach statistical significance (1.1% vs. 0.6%; P=0.22). The trial's secondary outcome, a composite recurrent VTE, MI, CVA, or CV death, occurred less frequently with aspirin compared to placebo (5.2% vs. 8%).

Limitations of ASPIRE included its slow enrollment and failure to reach the 3,000 patients required in the trial's power calculation. Nevertheless, a pooled analysis of data from ASPIRE and WARFASA demonstrated a 32% relative reduction in VTE recurrence.[1] Why WARFASA achieved statistical significance for its primary outcome and ASPIRE did not probably stem from the smaller patient population in ASPIRE and the fact that all patients in WARFASA received ≥6 months of therapeutic anticoagulation prior to enrollment (compared to 73% in ASPIRE). Together, ASPIRE and WARFASA make a strong case for at least low-dose aspirin as secondary prevention of VTE following standard anticoagulation.

Guidelines

CHEST Antithrombotic Therapy for VTE Disease (2016, adapted): [2]

  • In patients with DVT of the leg or PE and no cancer, as long-term (first 3 months) anticoagulant therapy, dabigatran, rivaroxaban, apixaban, or edoxaban are recommended over vitamin K antagonist (VKA) therapy (all Grade 2B)
  • In patients with DVT of the leg or PE and cancer (“cancer-associated thrombosis”), as long-term (first 3 months) anticoagulant therapy, LMWH is recommended over other agents (Grade 2C)
  • In patients with DVT of the leg or PE who receive extended therapy, recommend no need to change the choice of anticoagulant after the first 3 months (Grade 2C)
  • In patients who have recurrent VTE on VKA therapy (in the therapeutic range) or on dabigatran, rivaroxaban, apixaban, or edoxaban (and are believed to be compliant), recommend switching to treatment with LMWH at least temporarily (Grade 2C).
  • In patients with an unprovoked DVT of the leg (isolated distal or proximal) or PE, we recommend treatment with anticoagulation for at least 3 months over treatment of a shorter duration (Grade 1B), and we recommend treatment with anticoagulation for 3 months over treatment of a longer, time-limited period (eg, 6, 12, or 24 months) (Grade 1B).
  • In patients with a first VTE that is an unprovoked proximal DVT of the leg or PE and who have a (i) low or moderate bleeding risk (see text), we suggest extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 2B), and a (ii) high bleeding risk (see text), we recommend 3 months of anticoagulant therapy over extended therapy (no scheduled stop date) (Grade 1B).
  • In patients with a second unprovoked VTE and who have a (i) low bleeding risk (see text), we recommend extended anticoagulant therapy (no scheduled stop date) over 3 months (Grade 1B); (ii) moderate bleeding risk (see text), we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B); or (iii) high bleeding risk (see text), we suggest 3 months of anticoagulant therapy over extended therapy (no scheduled stop date) (Grade 2B).
  • In patients with DVT of the leg or PE and active cancer (“cancer-associated thrombosis”) and who (i) do not have a high bleeding risk, we recommend extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 1B), and (ii) have a high bleeding risk, we suggest extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 2B).
  • In patients with an unprovoked proximal DVT or PE who are stopping anticoagulant therapy and do not have a contraindication to aspirin, we suggest aspirin over no aspirin to prevent recurrent VTE (Grade 2B).

ESC Guidelines on the diagnosis and management of acute pulmonary embolism (2014, adapted):[3]

  • For patients with PE secondary to a transient (reversible) risk factor, oral anticoagulation is recommended for 3 months (class I, level B).
  • For patients with unprovoked PE, oral anticoagulation is recommended for at least 3 months (class I, level A).
  • Extended oral anticoagulation should be considered for patients with a first episode of unprovoked PE and low bleeding risk (class IIa, level B).
  • Anticoagulation treatment of indefinite duration is recommended for patients with a second episode of unprovoked PE (class I, level B).
  • Alternatives to a VKA for patients who need extended anticoagulation (class IIa, level B):
    • Rivaroxaban 20 mg daily
    • Dabigatran 150 mg BID (or 110 mg BID for patients ≥80 years of age or taking concomitant verapimil)
    • Apixaban 2.5 mg BID
  • In patients who receive extended anticoagulation, the risk-benefit ratio of continuing such treatment should be reassessed at regular intervals (class I, level C).
  • In patients who refuse to take or are unable to tolerate any form of oral anticoagulants, aspirin may be considered for extended secondary VTE prophylaxis (class IIb, level B).
  • For patients with PE and cancer, LMWH should be considered for the first 3-6 months (class IIa, level B).
  • For patients with PE and cancer, extended anticoagulation should be considered for an indefinite period or until the cancer is cured (class IIa, level C).

Design

  • Prospective, randomized, double-blind, placebo-controlled trial
  • N=822 patients with one episode of unprovoked VTE who have finished anticoagulation therapy
    • Aspirin (n=411)
    • Placebo (n=411)
  • Setting: 56 centers in 5 countries
  • Enrollment: 2003-2011
  • Median follow-up: 3.1 years
  • Analysis: Intention-to-treat
  • Primary outcome: Recurrent VTE

Population

Inclusion Criteria

  • Age ≥18 years
  • Single episode of unprovoked thrombus:
    • DVT of at least the popliteal vein
    • PE
  • Completion of AC therapy for 1.5-24 months, with INR for warfarin of 2-3 for 6-12 months

Exclusion Criteria

  • VTE risk factors in prior 2 months:
    • Confinement to bed for >1 week
    • Major surgery
    • Trauma requiring casting
    • Pregnancy
    • OCP or HRT
  • >2 years since VTE
  • Contraindication to aspirin, antiplatlet medications, or NSAIDs
  • Need to continue anticoagulation therapy
  • Medical issues limiting life expectancy or participation

Baseline Characteristics

From the aspirin group.

  • Demographics: Age 55 years, male 55%
  • Baseline health data: BMI <30 61%
  • Enrollment event: DVT 57%, PE 27%, both 14%
  • Length of anticoagulation treatment:
    • <3 months: 1%
    • 3-6 months: 28%
    • 6 to 12 months: 63%
    • ≥12 months: 8%
  • Time from completing anticoagulation therapy until randomization:
    • ≤1 day: 37%
    • 1-7 days: 17%
    • 7-30 days: 21%
    • >30 days: 25%
  • Anticoagulation: LMWH 1%, warfarin 83%, other (vitamin K antagonists, direct thrombin inhibitors, or factor Xa inhibitors) 15%

Interventions

  • Random assignment with stratification to center and length of anticoagulation to aspirin 100mg enteric coated caplets daily or placebo
  • Patients were asked to take the therapy for at least two years though it was capped at four years
    • Of note, the median length on the study medication was 27.2 months

Outcomes

Comparisons are aspirin vs. placebo. Rates are percent per year unless otherwise specified.

Primary Outcome

Recurrent VTE
14% vs. 18% (HR 0.74, 95% CI 0.52-1.05; P=0.09)
DVT: 3.3% vs. 3.8% (HR 0.86; 95% CI 0.56-1.33; P=0.50)
PE: 1.5% vs. 2.7% (HR 0.57; 95% CI 0.32-1.02; P=0.06)
VTE in 1st year: 4.9% vs. 10.6%

Secondary Outcomes

Composite recurrent VTE, MI, CVA, or CV death
5.2% vs. 8.0% (HR 0.66; 95% CI 0.48-0.92; P=0.01)
MI: 2 vs. 6 events (P=NS)
CVA: 4 vs. 5 events (P=NS)
CV mortality: 4 vs 8 events (P=NS)
Mortality
16 vs. 18 events (P=NS)
PE mortality: 1 vs. 1 event (P=NS)
CV mortality: 2 vs. 2 events (P=NS)
Other CV mortality including unknown: 1 vs. 5 events (P=NS)
Cancer mortality: 6 vs. 4 events (P=NS)
Bleeding mortality: 0 vs. 2 events (P=NS)
Other non-CV mortality: 6 vs. 4 events (P=NS)

Subgroup Analysis

There was no difference in the primary outcome for gender, length of AC treatment, age BMI, or VTE type.[4]

Adverse Events

Any bleeding
1.1% vs. 0.6% (HR 1.73; 95% CI 0.72-4.11; P=0.22)
Major: 8 vs. 6 events (P=NS)
Other clinically relevant: 6 vs. 2 events (P=NS)
Hospitalizations
25% vs. 28% (P not specified)
Discontinuation of therapy
11.9% vs. 15.1% (HR 0.79; 95% CI 0.62-1.01; P=0.06)

Criticisms

  • Slow enrollment, didn't reach prespecified 3,000 patients required for their power calculation.
  • High discontinuation rate
  • Effects of aspirin may be sex-dependent[5]

Funding

Industry (Bayer) and public funding.

Further Reading

  1. Warkentin TE. "Aspirin for Dual Prevention of Venous and Arterial Thrombosis." The New England Journal of Medicine. 2012;367:2039-2041
  2. C, et al. "Antithrombotic therapy for VTE Disease: Chest Guideline and Expert Panel Report." Chest. 2016;149(2):315-352.
  3. Konstantinides SV, et al. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014 Nov 14;35(43):3033-69.
  4. Supplementary appendix
  5. Multiple authors. "Correspondence: Aspirin for Preventing Venous Thromboembolism." The New England Journal of Medicine. 2013;368:772-773.