- 1 Clinical Question
- 2 Bottom Line
- 3 Major Points
- 4 Guidelines
- 5 Design
- 6 Population
- 7 Interventions
- 8 Outcomes
- 9 Criticisms
- 10 Funding
- 11 Further Reading
In high-risk patients with antiphospholipid syndrome, is rivaroxaban non-inferior to warfarin for the prevention of thromboembolic events, major bleeding, and vascular death?
Use of rivaroxaban in high-risk patients with antiphospholipid syndrome is associated with an increased risk of thromboembolic events and major bleeding as compared to warfarin.
Rivaroxaban has been found to be noninferior to warfarin in the treatment of nonvalvular atrial fibrillation (ROCKET AF) and noninferior to warfarin in the prevention of recurrent VTE or bleeding in patients with acute PE (EINSTEIN-PE), but the evidence regarding the safety and efficacy of its use in patients with antiphospholipid syndrome (APLS) had not been rigorously studied. The 2016 RAPS study evaluated rivaroxaban among 116 adults with low-risk APLS and studied a surrogate endpoint of endogenous thrombin potential. There were too few events to determine clinical efficacy of rivaroxaban among this population. Demonstrating equivalence or superiority of rivaroxaban in higher-risk adults would provide clinical evidence for the use of a factor Xa inhibitor in APLS.
Published in 2018, the Trial on Rivaroxaban in AntiPhospholipid Syndrome (TRAPS) randomized 120 adults with APLS with high-risk disease to rivaroxaban or warfarin. High-risk disease was defined as triple-positive laboratory assessment (lupus anticoagulant, cardiolipin antibodies, and beta-2 glycoprotein antibodies) plus prior clinical activity. The primary outcome was thrombosis, major bleeding, or vascular mortality, which were noted to occurred more frequently in the rivaroxaban group during an interim analysis (22% vs. 3%; HR 7.4; 95% CI 1.7-32.9; P=0.008). The trial was stopped early.
TRAPS provides strong evidence against the routine use of factor Xa inhibitors in high-risk APLS. Whether it provides a clinical benefit among patients with lower risk APLS is unknown.
As of September 2018, no guidelines have been published that reflect the results of this trial.
- Randomized, open-label, parallel assignment, multicenter, non-inferiority study with blinded end-point adjudication
- Rivaroxaban (20 mg or 15 mg once daily) (n=59)
- Warfarin (INR target 2.5) (n=61)
- Setting: 14 centers in Italy
- Enrollment: 2014-2018
- Mean follow-up: 569 days in the as-treated cohort; 611 days in the intention-to-treat
- Analysis: As-treated and intention-to-treat
- Primary outcome: Thromboembolic events, major bleeding, or death
- Assays demonstrating lupus anticoagulant and same isotype antibodies for cardiolipin and β2-glycoprotein
- History of objectively proven arterial, venous, and/or biopsy-proven micro-thrombosis
- Age 18-75 years
- Contraindication to rivaroxaban
- CrCl <30 mL/min
- Pregnancy or breastfeeding
- Use of anticoagulants other than warfarin or medications with significant interaction
- High risk for bleeding (recent or planned surgery, GI bleed, CNS bleed, hemorrhagic disease, high-risk intracranial condition, SBP ≥180 mmHg)
- Liver cirrhosis or ALT greater than 3 times the upper limit of normal
- Demographics: Female 64%, age 46 years
- BMI: 28 kg/m2
- CrCl: 113.1 mL/min
- Autoimmune disease: 41%
- Previous thrombotic events: Arterial 21%, venous events 64%, venous and arterial events 15%, pregnancy morbidity 23%
- PMH: Smoking 50%, HTN 31%, DM 3%, HLD 23%, other hypercoagulable condition 15%
- Medications: Hydroxychloroquine 32%, corticosteroids 21%, ASA 18%, statin 14%
- Randomized to a group:
- Rivaroxaban - 20 mg daily for CrCl >50 mL/min; 15 mg daily for CrCl 30-50 mL/min
- Warfarin - INR goal 2.5
- Patients randomized to rivaroxaban who were already taking warfarin started treatment when the INR was below 3
- Patients randomized to warfarin had INR checked at least every 4 weeks
- All patients had regularly scheduled visits at months 1 and 3 after randomization and every 6 months thereafter
Comparisons are rivaroxaban therapy vs. warfarin therapy.
- Thromboembolic events, major bleeding, or death
- Intention-to-treat: 22% vs. 3% (HR 7.4; 95% CI 1.7-32.9; P=0.008)
- As-treated: 19% vs. 3% (HR 6.7; 95% CI 1.5-30.5; P=0.01)
- Ischemic stroke
- Intention-to-treat: 7% vs. 0%
- As-treated: 7% vs. 0%
- Myocardial infarction
- Intention-to-treat: 5% vs. 0%
- As-treated: 5% vs. 0%
- Venous thromboembolism
- Intention-to-treat: 0% vs. 0%
- As-treated: 0% vs. 0%
- Major bleeding
- Intention-to-treat: 7% vs. 3% (HR 2.3; 95% CI 0.4-12.5; P=0.3)
- As-treated: 7% vs. 3% (HR 2.5; 95% CI 0.5-13.6; P=0.3)
- Intention-to-treat: 0% vs. 0%
- As-treated: 2% vs. 0%
No subgroup analyses were performed.
No adverse events other than the outcomes listed above were reported.
- Not blinded
- Stopped prematurely
- Unclear if INR was targeted using chromogenic factor X. Traditional INR assays may be unreliable in APLS.
The study was funded by Bayer, the co-developer of rivaroxaban. No conflicts of interest were disclosed by the study authors.