WARFASA

Background

Multicenter, investigator-initiated, double-blind, placebo-controlled RCT (WARFASA). 402 patients with first-ever objectively confirmed unprovoked proximal DVT or PE who had completed 6–18 months of oral anticoagulant therapy with VKA. Aspirin 100 mg daily vs placebo for 2 years (with option for extension). The hypothesis was that aspirin's antithrombotic effect — through inhibition of platelet COX-1 and reduction of thromboxane A2 — could reduce VTE recurrence after cessation of anticoagulation, given that platelet activation contributes to recurrent thrombosis, particularly arterial-type events. Conducted across multiple Italian centers (WARFASA) concurrently with ASPIRE (Brighton, Lancet 2012), a parallel trial with nearly identical design in Australia/New Zealand.

Interventions and follow up

Arm A: Aspirin 100 mg orally once daily × 2 years (extension permitted)
Arm B: Placebo orally once daily × 2 year
Primary endpoint: Recurrence of symptomatic, objectively confirmed VTE
mFollow up: 24.6 month

Results

VTE recurrence (per year): 6.6% (aspirin) vs 11.2% (placebo), HR 0.58 (95% CI 0.36–0.93), P=.02
VTE recurrence during treatment period: 5.9% vs 11.0% per year, HR 0.55 (95% CI 0.33–0.92)
Major bleeding: 1 patient each arm — virtually none

Adverse events

Main adverse events: Remarkably clean safety profile — one major bleed in each arm. Minor bleeding (epistaxis, bruising) not significantly different. No excess GI events, cardiovascular events, or strokes with aspirin. Aspirin was extremely well tolerated in this population.

Conclusions

Aspirin 100 mg/day significantly reduced recurrence of unprovoked VTE by ~42% compared to placebo after cessation of anticoagulation, with no excess major bleeding, providing a safe but less potent alternative to extended anticoagulation for patients in whom anticoagulant therapy is not continued.

Key Limitations

Key Limitations: VKA-treated population (not DOAC-treated) — results apply to patients stopping anticoagulation after completing standard VKA therapy; most patients today complete initial DOAC therapy. Aspirin reduces but does not eliminate recurrence risk (HR 0.58 = 42% reduction vs HR ~0.25–0.34 with DOAC extended therapy per AMPLIFY-EXT/EINSTEIN-CHOICE); it is inferior to anticoagulation. Concurrent ASPIRE trial (Brighton, Lancet 2012, n=822) showed similar magnitude benefit (HR 0.74, CI 0.52–1.05, P=.09 — non-significant in ASPIRE alone) but pooled analysis with WARFASA demonstrates consistent ~35% relative risk reduction. Aspirin does not adequately protect patients with severe thrombophilia (antithrombin deficiency, protein C/S deficiency, homozygous FVL, APS), who require continued anticoagulation. Duration of aspirin beyond 2 years is unclear.

Clinical Context

WARFASA and ASPIRE together established aspirin as a modest alternative for extended VTE prevention in patients who cannot or do not wish to continue anticoagulation. ASH 2020 VTE guidelines suggest aspirin over no treatment if anticoagulation is stopped after unprovoked VTE, but strongly prefer extended DOAC therapy for patients tolerable of anticoagulation. Aspirin is most relevant for: patients declining anticoagulation, very high bleeding risk, low VTE recurrence risk (distal DVT, provoked PE resolving). The advent of reduced-dose DOAC extended therapy (rivaroxaban 10 mg, apixaban 2.5 mg BID) with major bleeding rates no higher than aspirin has further marginalized aspirin's role.

References

References: Becattini C et al, NEJM 2012 (WARFASA primary)