TRAPS 2 Years Outcomes
(2021)Objective
Rivaroxaban versus warfarin for high-risk antiphospholipid syndrome patients.
Study Summary
Intervention
Rivaroxaban (20 mg daily) or warfarin (INR 2.0–3.0). Trial was stopped early due to excess arterial thromboses in the rivaroxaban arm. Post-trial, most patients were switched to warfarin and followed for 2 years.
Inclusion Criteria
Patients with high-risk, triple-positive antiphospholipid syndrome randomized in the original TRAPS trial and available for extended follow-up after study closure.
Study Design
Arms: DOAC (Rivaroxaban/Dabigatran) vs. Warfarin
Patients per Arm: DOAC: 6, Warfarin: 109 (from 115 available patients)
Outcome
Bottom Line
After the premature closure of the TRAPS trial, a 2-year follow-up revealed significantly more composite outcome events, specifically thromboembolic events, in high-risk, triple-positive antiphospholipid syndrome patients who remained on DOACs compared to those who switched to warfarin, further supporting the use of warfarin in this high-risk population.
Major Points
- The original TRAPS trial was prematurely stopped on January 28, 2018, due to an excess of arterial events in the rivaroxaban group — this follow-up extends the safety signal to 2 additional years.
- Of 120 randomized patients, 115 were available for this 2-year follow-up study (January 28, 2018, to January 28, 2020); 5 patients lost to follow-up.
- Extreme group asymmetry: only 6 patients remained on DOACs (5 rivaroxaban, 1 dabigatran) vs 109 on warfarin — reflecting that most physicians heeded the original TRAPS warning.
- Composite outcome events occurred in 2 of 6 (33.3%) patients on DOACs and 6 of 109 (5.5%) patients on warfarin (HR 6.9, 95% CI 1.4–34.5, P=0.018).
- Thromboembolic events specifically were significantly more frequent in DOAC patients (HR 13.3, 95% CI 2.2–79.9, P=0.005) — both events were thromboembolic (1 DVT, 1 ischemic stroke).
- One DOAC patient experienced proximal DVT (on dabigatran) and another an ischemic stroke (on rivaroxaban) — both major DOACs failed in triple-positive APS.
- Warfarin group events were heterogeneous: 3 thromboembolic (2 arterial, 1 venous), 2 major bleeding (metrorrhagia), 1 CV death post-surgery — not purely thrombotic failures.
- Despite the trial's early termination, the persistent signal over 2 years of real-world follow-up reinforced the original TRAPS conclusion — DOACs are unsafe in triple-positive APS.
- Reinforced ISTH 2020 guidance and EULAR/ACR recommendations against DOAC use in triple-positive APS, making this follow-up clinically impactful despite its observational design.
- Together with TRAPS, RAPS, and subsequent meta-analyses, this study cemented the paradigm that warfarin remains the only acceptable anticoagulant for high-risk triple-positive APS — DOACs are contraindicated.
Study Design
- Study Type
- Prospective, observational follow-up study after a prematurely stopped randomized, open-label, noninferiority trial
- Randomization
- No
- Blinding
- Open-label (no blinding in the follow-up study)
- Sample Size
- 115
- Follow-up
- 2 years
- Centers
- 14
- Countries
- Italy
Primary Outcome
Definition: Composite of objectively proven venous or arterial thrombosis, major bleeding, and vascular death.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 6 of 109 (5.5%) patients | 2 of 6 (33.3%) patients | 6.9 (1.4-34.5) | 0.018 |
Limitations & Criticisms
- Extreme group imbalance (6 DOAC vs 109 warfarin) makes statistical comparisons unreliable — wide confidence intervals reflect extreme uncertainty (HR 6.9, CI 1.4–34.5).
- Observational follow-up of a prematurely stopped trial — not a randomized comparison; the decision to remain on DOACs was patient/physician-driven, introducing severe selection bias.
- Only 2 events in 6 DOAC patients drive the entire signal — a single event more or fewer would dramatically change the hazard ratio and significance.
- Detailed clinical characteristics for the 6 DOAC-continuing patients vs 109 warfarin patients are not provided, preventing assessment of confounding (e.g., were DOAC patients non-adherent to prior warfarin?).
- No standardized monitoring protocol during follow-up — INR control quality (TTR) in the warfarin group was not reported, preventing assessment of anticoagulation adequacy.
- Single-country study (Italy only) — results may not generalize across different healthcare systems, APS management protocols, and ethnic populations.
- No assessment of medication adherence or compliance during the 2-year follow-up period for either group.
- The composite endpoint includes bleeding and CV death alongside thrombosis — warfarin group's 2 bleeding events and 1 CV death are not thrombotic failures, complicating direct comparison.
- Cannot distinguish whether the 6 patients who stayed on DOACs had unique clinical or behavioral characteristics (risk tolerance, physician preference, access issues) that independently predicted worse outcomes.
Citation
J Thromb Haemost. 2021;19:531-535. doi:10.1111/jth.15158