WARFASA

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Becattini C, et al. "Aspirin for preventing the recurrence of venous thromboembolism". The New England Journal of Medicine. 2012. 366(21):1959-1967.
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Clinical Question

In patients with unprovoked VTE who have completed anticoagulation, does aspirin reduce the risk of recurrent VTE?

Bottom Line

Aspirin reduces the risk of recurrent VTE among patients who have completed 6-18 months of anticoagulation. Although results differed from ASPIRE, that trial had significant limitations.

Major Points

After 3-6 months of oral anticoagulation for a first unprovoked episode of VTE, the 1-year risk of recurrence is approximately 11%.[1] This trial studied low-dose aspirin as secondary VTE prophylaxis among patients that had completed anticoagulation.

The Warfarin and Aspirin (WARFASA) trial enrolled 405 patients with a first unprovoked episode of VTE who had completed 6-18 months of warfarin or similar oral anticoagulant therapy. Patients were randomized to aspirin 100 mg daily or matching placebo and followed for events. The primary outcome was recurrent VTE objectively confirmed by ultrasound, CT, or V/Q imaging, and the main secondary outcomes were CV events and major bleeding. At a mean follow-up of 2 years, aspirin was associated with fewer VTE recurrences (6.6% vs. 11.2% per year, NNT 22) without a statistically significant difference in CV events (P=0.06) or major bleeding.

The related ASPIRE trial (2012) studied similar patients under the same protocol as WARFASA, but only showed a nonsignificant trend towards fewer VTE recurrences with aspirin. As a result, ASPIRE was technically a negative study. The discordance between the results of WARFASA and ASPIRE may be explained by 1) the fact that ASPIRE's enrollment fell short of the sample size dictated by its prespecified power calculation, 2) differences in inclusion criteria between trials, and 3) that only about two-thirds of ASPIRE patients received ≥6 months of anticoagulation prior to the initiation of aspirin (whereas all patients in WARFASA received ≥6 months of anticoagulation). Despite these limitations, ASPIRE's patients are likely more representative of a real-world cohort of VTE patients, who typically receive only 3-6 months of anticoagulation for a first unprovoked event. Regardless, a prospectively planned,[2] pooled analysis of data from WARFASA and ASPIRE demonstrated a 32% reduction in VTE recurrence (HR 0.68; P=0.007) and a 34% reduction in the composite endpoint of VTE recurrence or CV events (HR 0.66; P=0.002).[3]

Guidelines

CHEST Antithrombotic Therapy for VTE Disease (2016, adapted): [4]

  • 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):[5]

  • 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

  • Multicenter, double-blind, randomized, placebo-controlled trial
  • N=403 patients with one episode of unprovoked VTE who have finished anticoagulation therapy
    • Aspirin (n=205)
    • Placebo (n=198)
  • Setting: 25 centers in Europe
  • Enrollment: 2004-2010
  • Median follow-up: 2 years
  • Analysis: Modified intention-to-treat
  • Primary outcome: Recurrent VTE

Population

Inclusion Criteria

  • Age ≥18 years
  • Completed therapy with 6-18 months of vitamin K antagonist for first, symptomatic, unprovoked, objectively confirmed proximal DVT, PE, or both

Exclusion Criteria

  • Cancer or major thrombophilia
  • Indication for long-term anticoagulation
  • Atherosclerotic disease requiring antiplatelet therapy
  • Active bleeding
  • High-risk for future bleeding or bleeding episode while on AC
  • Allergy or intolerance to ASA
  • Life expectancy <6 months
  • High risk of medication noncompliance
  • Pregnancy or breast feeding
  • Participation in a trial in prior 30 days
  • HRT-related VTE

Baseline Characteristics

  • Age: 62 years
  • Male: 64%
  • BMI: 27.3 kg/m2
  • White: 99%
  • DVT: 62.7%
  • PE: 37.3%
  • Duration of VKA treatment
    • 6 mos: 34.3%
    • 12 mos: 55.4%
    • 18 mos: 10.2%

Interventions

  • Randomly assigned to aspirin 100mg or placebo daily for two years.
  • Treatment initiated within two weeks of completing oral anticoagulation therapy.

Outcomes

Comparisons are aspirin vs. placebo.

Primary Outcome

Recurrent VTE
6.6% vs. 11.2% per year (HR 0.58; 95% CI 0.36-0.93; P=0.02; NNT=22)
PE: 11 vs. 14 events (HR 0.70; 95% CI 0.32-1.54; P=0.37)
PE mortality: 1 event each
DVT: 16 vs. 28 events (HR 0.51; 95% CI 0.27-0.94; P=0.03)

Secondary Outcomes

Bleeding
Major or clinically relevant non-major: 4 events each
Major: 1 event each
Clinically relevant non-major: 3 events each
Death
6 vs. 5 events (HR 1.04; 95% CI 0.32-3.42; P=0.95)
Composite recurrent VTE or death
33 vs. 47 events (HR 0.62; 95% CI 0.40-0.97; P=0.04)
Arterial event
(Defined as MI, UA, CVA, TIA, or acute limb ischemia)
8 vs. 5 events (HR 1.43; 95% CI 0.47-4.37; P=0.53)
Composite recurrent VTE or arterial event
36 vs. 48 events (HR 0.67; 95% CI 0.43-1.03; P=0.06)

Criticisms

  • Slow recruitment
  • Not powered to detect changes in ischemic heart disease and CVA
  • Use of a risk-stratification model could be useful in patient selection[6]
  • The ultrasound criteria used for DVT diagnosis had previously been given a weak recommendation and may have biased the results[6]

Funding

  • University of Perugia support
  • Bayer HealthCare
  • Aventis Fellowship for Clinical Research from the International Society of Thrombosis and Haemostasis
  • Authors with financial conflicts of interest

Further Reading

  1. Prandoni P, et al. "The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients." Haematologica 2007. 92(2):199-205.
  2. Becker RC. "Aspirin and the Prevention of Venous Thromboembolism". N Engl J Med. 2012. 366:2028-2030
  3. Warkentin TE. "Aspirin for Dual Prevention of Venous and Arterial Thrombosis." N Engl J Med. 2012. 367:2039-2041
  4. C, et al. "Antithrombotic therapy for VTE Disease: Chest Guideline and Expert Panel Report." Chest. 2016;149(2):315-352.
  5. 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.
  6. 6.0 6.1 NEJM letters to the editor