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ASTRO-APS

Apixaban compared with warfarin to prevent thrombosis in thrombotic antiphospholipid syndrome: a randomized trial

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Year of Publication: 2022

Authors: Scott C. Woller, Scott M. Stevens, David Kaplan, ..., C. Greg Elliott

Journal: Blood Advances

Citation: Woller SC, Stevens SM, Kaplan D, et al. Blood Adv. 2022 Mar 22;6(6):1661–1670.

Link: https://doi.org/10.1182/bloodadvances.2021005808

PDF: https://ashpublications.org/bloodadvance...v2021005808.pdf

Clinical Question

Is apixaban a safe and effective alternative to warfarin for preventing recurrent thrombosis in patients with thrombotic antiphospholipid syndrome (TAPS)?

Bottom Line

In this small pilot RCT, apixaban was associated with a higher rate of ischemic stroke compared to warfarin among patients with TAPS, leading to early study termination and reinforcing concerns that DOACs may not be suitable alternatives to warfarin in this population.

        Major Points
        Multicenter PROBE-design trial comparing apixaban and warfarin in 48 patients with thrombotic APS (TAPS).
Trial was terminated early after 6 strokes occurred in apixaban group vs 0 in warfarin group.
Two protocol changes: (1) apixaban dose increased from 2.5 mg to 5 mg BID, (2) exclusion of patients with history of arterial thrombosis.
No major or clinically relevant non-major bleeds occurred in apixaban group; 1 major bleed in warfarin group.
Patients on apixaban reported significantly higher satisfaction with anticoagulation therapy across all time points.

      

Design

Study Type: Randomized, open-label, blinded-endpoint (PROBE)

Randomization: 1

Blinding: Blinded outcome adjudication

Enrollment Period: February 2015 – March 2019

Follow-up Duration: 12 months

Centers: 2

Countries: United States

Sample Size: 48

Analysis: Intention-to-treat, as-treated, and person-time analyses

Inclusion Criteria

Adults with thrombotic antiphospholipid syndrome (TAPS)
Receiving therapeutic anticoagulation for ≥6 months
Classified as definite, likely, or historical APS per Sapporo criteria

Exclusion Criteria

Anticoagulation for another indication
Dual antiplatelet therapy or aspirin >165 mg/day
Pregnancy or intent to become pregnant
Life expectancy <1 year
Baseline hemoglobin <8 g/dL, platelets <50,000/µL, creatinine >2.5 mg/dL, total bilirubin >1.5x ULN
Thrombosis while on therapeutic warfarin (INR ≥2.0)

Baseline Characteristics

Characteristic	Control	Active
Mean Age	48.5 (14.36)	46 (11.53)
Female %	84%	82.6%
BMI	32.3 (5.96)	31.2 (8.06)
Triple Positivity	28%	30.4%
Stroke History	28%	21.7%
DVT	68%	73.9%
PE	28%	47.8%
Hypertension	16%	13%
Diabetes	16%	17.4%
Hyperlipidemia	16%	17.4%
Smoker	24%	17.4%

Arms

Field	Apixaban	Control
Intervention	Apixaban 2.5 mg BID initially; increased to 5 mg BID mid-trial per DSMB recommendation	Warfarin with target INR 2–3, managed per clinical routine
Duration	12 months	12 months

Outcomes

Outcome	Type	Control	Intervention	P-value
Composite of clinically overt thrombosis and vascular death	Primary	0 events	6 ischemic strokes
Major bleeding	Secondary	1 event (vaginal hemorrhage)	0 events
Patient satisfaction (ACTS)	Secondary	Lower scores at all time points	Higher scores at all time points	<0.01
Ischemic Stroke	Adverse	0	6
Major Bleed	Adverse	1	0

Subgroup Analysis

After excluding patients with prior arterial thrombosis, 2 strokes still occurred in apixaban arm (n=17) vs 0 in warfarin (n=16); trend persisted across both apixaban doses (2.5 mg and 5 mg).

Criticisms

Early termination due to safety concerns and funding loss
Small sample size (n=48) limited statistical power
Multiple protocol changes (dose escalation, exclusion of arterial thrombosis)
Open-label design may introduce bias despite blinded adjudication
Results not generalizable due to heterogeneous cohort and limited site participation

Funding

Investigator-initiated funding from Bristol-Myers-Squibb/Pfizer paid to Intermountain Healthcare

Based on: ASTRO-APS (Blood Advances, 2022)