TRAPS
(2018)Objective
To assess whether rivaroxaban is a safe and effective alternative to warfarin for preventing thromboembolic events in high-risk patients with antiphospholipid syndrome (APS).
Study Summary
• Rivaroxaban was associated with a higher rate of thromboembolic events, especially arterial thromboses, compared to warfarin in high-risk triple-positive APS patients, leading to early termination of the trial.
Intervention
Randomized, open-label trial comparing rivaroxaban (20 mg daily) to warfarin (INR 2.0–3.0) in patients with high-risk APS (triple positivity for lupus anticoagulant, anticardiolipin, and anti-β2-glycoprotein I antibodies).
Inclusion Criteria
Adults aged ≥18 with high-risk triple-positive APS, with or without prior thrombotic events, eligible for oral anticoagulation.
Study Design
Arms: Rivaroxaban vs. Warfarin
Patients per Arm: Rivaroxaban: 59, Warfarin: 61
Outcome
• Thromboembolic events: 12% in rivaroxaban vs. 0% in warfarin group (P = 0.003); all events in rivaroxaban group were arterial (including strokes and myocardial infarctions); • Major bleeding: 4 events (6.8%) in rivaroxaban vs. 2 events (3.3%) in warfarin; • Trial stopped early due to safety concerns and excess thrombotic events in the rivaroxaban group.
Bottom Line
The TRAPS trial was prematurely terminated due to an excess of events (primarily arterial thromboembolic events) in the rivaroxaban arm, demonstrating that rivaroxaban was not noninferior to warfarin and was associated with increased risk in high-risk, triple-positive antiphospholipid syndrome patients.
Major Points
- TRAPS is the definitive trial showing that DOACs are DANGEROUS in high-risk (triple-positive) antiphospholipid syndrome — rivaroxaban was associated with a 6.7-fold increase in thromboembolic events vs warfarin.
- Trial was stopped prematurely by DSMB after 120 of planned 536 patients enrolled, due to an excess of ARTERIAL events in the rivaroxaban arm: 4 ischemic strokes + 3 MIs vs ZERO events with warfarin.
- Triple-positive APS (positive for lupus anticoagulant + anticardiolipin + anti-β2-glycoprotein I) is the HIGHEST-RISK antibody profile — these patients have the most prothrombotic phenotype and require the most reliable anticoagulation.
- Primary composite (thromboembolic events + major bleeding + vascular death): 19% rivaroxaban vs 3% warfarin (HR 6.7, 95% CI 1.5-30.5, p=0.01). The ITT analysis was even more dramatic: 22% vs 3% (HR 7.4, p=0.008).
- Mechanism hypothesis: rivaroxaban inhibits Factor Xa but APS-related thrombosis may involve multiple coagulation pathway activation (tissue factor, complement, thrombin) that warfarin's broader inhibition (Factors II, VII, IX, X) better suppresses.
- Confirmed by similar signals in other APS-DOAC trials: RAPS (rivaroxaban, increased thrombin generation markers) and a subsequent meta-analysis showing DOACs are inferior to warfarin for APS arterial events specifically.
- Dramatically changed clinical practice: all major guidelines now RECOMMEND AGAINST DOACs in triple-positive APS. Warfarin remains standard of care, with target INR 2.0-3.0 (some experts advocate 3.0-4.0 for arterial events).
- Events were predominantly ARTERIAL (stroke and MI) rather than venous — suggesting APS arterial thrombosis has a different coagulation mechanism than venous thrombosis, which may respond to Factor Xa inhibition.
- No deaths in either arm — suggesting events were survivable, but the morbidity burden (4 ischemic strokes) was substantial and potentially disabling.
- Important caveat: results apply to TRIPLE-POSITIVE APS only. Single- or double-positive APS patients may tolerate DOACs, but this remains unproven. Many experts still prefer warfarin for any APS with arterial events.
Study Design
- Study Type
- Prospective randomized phase 3 open-label non-inferiority study with blinded end point adjudication
- Randomization
- Yes
- Blinding
- Blinded end point adjudication (patients and local investigators were not masked to treatment)
- Sample Size
- 120
- Follow-up
- Mean follow-up was 569 days ('as treated') and 611 days (ITT)
- Centers
- 14
- Countries
- Italy
Primary Outcome
Definition: Cumulative incidence of thromboembolic events (arterial or venous), major bleeding, and vascular death.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 2 (3%) events ('as treated') | 11 (19%) events ('as treated') | 6.7 (1.5-30.5) | 0.01 |
Limitations & Criticisms
- Premature termination (120 of 536 planned) — drastically underpowered for noninferiority testing. The dramatic event imbalance (19% vs 3%) may partly reflect small-sample variability.
- Very small number of total events (11 rivaroxaban, 2 warfarin in 'as-treated') — wide confidence intervals (HR 6.7, CI 1.5-30.5) indicate substantial uncertainty in the true effect size.
- Open-label design — patients and investigators knew treatment assignment. This could influence INR monitoring vigilance, aspirin prescribing, and even event reporting, though endpoint adjudication was blinded.
- Single-country trial (Italy) — Italian APS management patterns, warfarin monitoring quality, and patient demographics may differ from other settings.
- Only tested rivaroxaban — cannot extrapolate to apixaban, edoxaban, or dabigatran. Different DOACs have different mechanisms, and some may perform better in APS. However, RAPS and ASTRO-APS showed similar signals.
- Noninferiority margin derived from observational data rather than a prior RCT — methodologically weaker foundation for the statistical design.
- Aspirin use was not standardized — variable antiplatelet co-therapy confounds interpretation of anticoagulant-specific effects.
- Results apply ONLY to triple-positive APS — the highest-risk subgroup (~30% of all APS patients). Single- and double-positive patients were excluded, leaving a major evidence gap.
- No mechanistic substudy — did not measure thrombin generation, anti-Xa levels, or complement activation to explain WHY rivaroxaban failed. This limits understanding of the optimal anticoagulation target in APS.
Citation
Blood. 2018;132(13):1365-1371