A randomized clinical trial of high‐intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS)
Open accessAbstract
Background The optimal intensity of oral anticoagulation for the prevention of recurrent thrombosis in patients with antiphospholipid antibody syndrome is uncertain. Retrospective studies show that only high-intensity oral anticoagulation [target international normalized ratio (INR) >3.0] is effective but a recent randomized clinical trial comparing high (INR range 3.0-4.0) vs. moderate (INR 2.0-3.0) intensities of anticoagulation failed to confirm this assumption.Methods We conducted a randomized trial in which 109 patients with antiphospholipid syndrome (APS) and previous thrombosis were given either high-intensity warfarin (INR range 3.0-4.5, 54 patients) or standard antithrombotic therapy (warfarin, INR range 2.0-3.0 in 52 patients or aspirin alone, 100 mg day(-1) in three patients) to determine whether intensive anticoagulation is superior to standard treatment in preventing symptomatic thromboembolism without increasing the bleeding risk.Results The 109 patients enrolled in the trial were followed up for a median time of 3.6 years. Mean INR during follow-up was 3.2 (SD 0.6) in the high-intensity warfarin group and 2.5 (SD 0.3) (P < 0.0001) in the conventional treatment patients given warfarin. Recurrent thrombosis was observed in six of 54 patients (11.1%) assigned to receive high-intensity warfarin and in three of 55 patients (5.5%) assigned to receive conventional treatment [hazard ratio for the high intensity group, 1.97; 95% confidence interval (CI) 0.49-7.89]. Major and minor bleeding occurred in 15 patients (two major) (27.8%) assigned to receive high-intensity warfarin and eight (three major) (14.6%) assigned to receive conventional treatment (hazard ratio 2.18; 95% CI 0.92-5.15).Conclusions High-intensity warfarin was not superior to standard treatment in preventing recurrent thrombosis in patients with APS and was associated with an increased rate of minor hemorrhagic complications.
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In patients with antiphospholipid syndrome and first venous thrombosis, there is no additional benefit of a vitamin K antagonist target INR of 3-4 versus 2-3, based on an RCT and pooled data from five studies that included a majority with venous events.
“Data from an RCT21 reporting exclusively on patients with venous events and pooled data from five studies that included a majority with venous events21–25 showed no additional benefit of a target INR of 3–4 vs INR of 2–3.”
From EULAR recommendations for the management of antiphospholipid syndrome in adults (2019) · cites this paper as [22]
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Experimental — accuracy not yet measuredPooled data from two retrospective studies and two RCTs showed no statistically significant difference in thrombosis recurrences between vitamin K antagonist target INR 3-4 and INR 2-3 (relative risk 0.46 (0.06-3.52)).
“Pooled data from two retrospective studies and two RCTs21–24 showed that there was no statistically significant difference in thrombosis recurrences between treatment with VKA with a target INR of 3–4 and treatment with INR of 2–3 (relative risk (RR) 0.46 (0.06–3.52)).”
From EULAR recommendations for the management of antiphospholipid syndrome in adults (2019) · cites this paper as [22]
The Study design and Results sections (page not specified) establish that WAPS is one of the randomized trials comparing high- and conventional-intensity treatment and found no statistically significant difference in recurrent thrombosis. But its pooled analysis includes only WAPS and the Crowther trial; it does not report a pooled analysis of two retrospective studies and two RCTs or the stated RR of 0.46 (0.06–3.52). (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe 10-year cumulative TE incidence of 24.3% compares well to the thrombotic risk observed in the WAPS study and the Euro-Phospholipid Project registry, but was lower than the value in the Piedmont cohort study and higher than that in the study by Pengo et al.
“The 10-year cumulative TE incidence of 24.3% compares well to the thrombotic risk observed in the WAPS study [31] and the very large Euro-Phospholipid Project registry [6], but was lower than the value in the recently published Piedmont cohort study [32] and higher than that in the recently published study by Pengo et al. [30].”
From Cardiovascular risk factors are major determinants of thrombotic risk in patients with the lupus anticoagulant (2017) · cites this paper as [31]
According to the literature, most relapses in antiphospholipid syndrome occur early during follow-up and at the same site as the previous event.
“According to the literature, most of these relapses were observed early during the study, at the same site as the previous event [2].”
From Antithrombotic effects of hydroxychloroquine in primary antiphospholipid syndrome patients (2013) · cites this paper as [2]
The Addendum (Table 2; page unavailable) reports recurrent thrombosis by event type and treatment group, but not when events occurred or whether they were at the site of a previous event. Searches for early recurrences and the site of previous events found no passage establishing either part of the claim. (LLM, conf=0.76)
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“3% compares well to the thrombotic risk observed in the WAPS study [31] and the very large Euro-Phospholipid Project registry [6], but was lower than the value in the recently published Piedmont cohort study [32] and higher than that in the recently published study by Pengo et al.”
Result
- Authors
- FINAZZI, G., MARCHIOLI, R., BRANCACCIO, V., SCHINCO, P., WISLOFF, F., MUSIAL, J., BAUDO, F., BERRETTINI, M., Testa, S., D'ANGELO, A., TOGNONI, G., & BARBUI, T.
- Affiliations
- Mario Negri Sud Foundation (IT)
- Ospedale Antonio Cardarelli (IT)
- Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT)
- University of Perugia (IT)
- Istituti Ospitalieri di Cremona (IT)
- Corresponding author
- MARCHIOLI, R.
- Venue
- Journal of Thrombosis and Haemostasis
- Publisher
- Elsevier BV
- Published
- 2005-05
- Volume
- 3
- Issue
- 5
- Pages
- 848-853
- ISSN
- 1538-7836 (ISSN-L)
- OpenAlex
- W2027467473
- Cited by
- 585
- References
- 15
- Citations by year
- 2026: 5 · 2025: 17 · 2024: 23 · 2023: 18 · 2022: 23 · 2021: 25 · 2020: 32 · 2019: 27 · 2018: 35 · 2017: 25 · 2016: 30 · 2015: 30 · 2014: 31 · 2013: 28 · 2012: 36
- FWCI
- 21.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Thrombosis and Haemostasis (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Health Sciences › Medicine › Internal Medicine › Venous Thromboembolism Diagnosis and Management
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Keywords
- antiphospholipid syndrome, oral anticoagulation, recurrent thrombosis, thromboprophylaxis, aspirin, bleeding risk, international normalized ratio, antithrombotic therapy, venous thrombosis, arterial thrombosis, stroke prevention, pregnancy complications, antiphospholipid antibodies
- MeSH terms
- Administration, Oral, Adult, Algorithms, Anticoagulants, Aspirin, Clinical Trials as Topic, Female, Fibrinolytic Agents, Humans, Male, Middle Aged, Recurrence, Risk, Statistics as Topic, Thromboembolism, Thrombosis, Time Factors, Warfarin, Odds Ratio, Antiphospholipid Syndrome, Treatment Outcome, Antibodies, Anticardiolipin, International Normalized Ratio
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