Review Article

Treatment of Thrombotic Antiphospholipid Syndrome: The Rationale of Current Management—An Insight into Future Approaches

Table 1

Details of clinical studies investigating efficacy of antiplatelet and anticoagulant regimens in thrombotic APS.

Author, year [Ref]Type of study patientsSapporo criteriaThrombotic events 
A/V
TreatmentsObservation timeRecurrence rateMain findings

Rosove and Brewer, 1992 [33]RC70No31/39None 
LDASA 
Warfarin INR <2.0 
Warfarin INR 2.0–2.9 
Warfarin INR >3.0
161.2 pt.-years 
37.8 pt.-years 
11.3 pt.-years 
40.9 pt.-years 
110.2 pt.-years
0.19/pt.-year 
0.32/pt.-year 
0.57/pt.-year 
0.07/pt.-year 
0
Intermediate-high intensity warfarin conferred better antithrombotic protection than low-intermediate warfarin and LDASA

Derksen et al., 1993 [35]RC19Yes0/19None 
Warfarin INR 2.5–4.0
8–248 monthsNAAnticoagulation was effective in preventing thrombosis compared to placebo

Khamashta et al., 1995 [34]RC147Yes67/80None 
LDASA 
Warfarin INR <3.0 (+LDASA) 
Warfarin INR >3.0 (+LDASA)
280.6 pt.-years 
240.3 pt.-years 
141.3 pt.-years 
197.3 pt.-years
0.29/pt.-year 
0.18/pt.-year 
0.23/pt.-year 
0.015/pt.-year
Warfarin INR >3.0 ± LDASA was significantly more effective than warfarin INR <3.0 ± LDASA in preventing thrombotic recurrences

Krnic-Barrie et al., 1997 [15]RC61No38/23None 
LDASA 
Warfarin  
Warfarin + LDASA
124.9 pt.-years 
36.6 pt.-years 
63.0 pt.-years 
30.6 pt.-years
A: 0.192/V: 0.11/pt.-year 
A: 0.082/V: 0.027/pt.-year 
A: 0.048/V: 0/pt.-year 
A: 0/V: 0/pt.-year
Warfarin treatment, with or without LDASA, was more effective than placebo and LDASA alone in preventing recurrence

Munoz-Rodríguez et al., 1999 [40]RC47Yes19/28None 
LDASA  
Warfarin INR 2.5–3.5
4–50 months91% 
41% 
19%
Warfarin was more effective than placebo and LDASA in preventing thrombotic recurrences

Ruiz-Irastorza et al., 2002 [14]RC66Yes51/32Warfarin INR 3.0–4.066 pt.-years0.09/pt.-yearDespite high-intensity warfarin, the risk of thrombotic recurrences was high

Wittkowsky et al., 2006 [39]RC36Yes14/16Warfarin INR 2.0–3.0 
Warfarin INR >3.0
62.5 pt.-years0.096/pt.-year67% of the recurrences occurred at INR <3.0

Girón-González et al., 2004 [41]PC158Yes70/106Warfarin INR 2.5–3.5624 pt.-years0.005/pt.-yearThrombotic recurrence was associated with INR below target

Ames et al., 2005 [27]PC67Yes17/50Warfarin INR <2.0 
Warfarin INR 2.0–3.0 
Warfarin INR 3.1–4.0 
Warfarin INR >4.0
9 weeks 
122 weeks 
9 weeks 
5 weeks
0 
0.04/pt.-year 
0.1/pt.-year 
0
Recurrence rates were higher in patients receiving high-intensity than low-intensity anticoagulation

Ginsberg et al., 1995 [30]PC subgroup analysis16No0/16None 
Warfarin INR 2.0–3.0
8.7 months 
3 months
18% 
0
No recurrence was observed with warfarin INR 2.0–3.0

Prandoni et al., 1996 [29]RC subgroup analysis15Yes0/15None 
Warfarin INR 2.0–3.0
1–10 years0.038/pt.-year 
0
No recurrence was observed with warfarin INR 2.0–3.0

Rance et al., 1997 [31]RC subgroup analysis27No0/27None 
Warfarin INR 2.0–3.0
1–4 yearsNA 
0
No recurrence was observed with warfarin INR 2.0–3.0

Schulman et al., 1998 [32]RCT subgroup analysis68No0/68None 
Warfarin INR 2.0–2.8
4 years0.01/pt.-year 
0
No recurrence was observed with warfarin INR 2.0–2.8

Levine et al., 2004 [42]RCT subgroup analysis720No720/0ASA  
Warfarin INR 1.4–2.8
2 years22.18% 
26.15%
ASA and low-intensity anticoagulation were equally effective for secondary stroke prevention

Crowther et al., 2003 [19]RCT114Yes27/87Warfarin INR 2.0–3.0 
Warfarin INR 3.1–4.0
2.7 years0.013/pt.-year 
0.032/pt.-year
Warfarin at INR 2.0–3.0 was as effective as warfarin at INR 3.1–4.0 in secondary prevention of thrombosis

Finazzi et al., 2005 [20]RCT109Yes44/75Warfarin INR 2.0–3.0 
Warfarin INR 3.0–4.5
3.3 years 
3.5 years
0.016/pt.-year 
0.031/pt.-year
Warfarin at INR 2.0–3.0 was as effective as warfarin at INR 3.1–4.5 in secondary prevention of thrombosis

Tan et al., 2009 [16]RC59Yes29/30Warfarin INR 2.0–3.0 
Warfarin INR 3.1–4.0
8.8 years23.7%Warfarin at INR 2.0–3.0 is as effective as warfarin at INR >3 in preventing venous rethromboses and less effective in preventing arterial rethromboses

Cervera et al., 2009 [2]PC1000YesLDASA 
Warfarin
5 years14% 
21.4%
Antiaggregation and anticoagulation are associated with a significant recurrence rate

Pengo et al., 2010 [18]RC160Yes76/69No treatment 
Warfarin (median INR 2.3)
10 years44.2%Oral anticoagulation was the only predictor of thromboembolic events

Okuma et al., 2010 [43]RCT20No0/20LDASA 
Warfarin INR 2.0–3.0 + LDASA
3.9 yearsNAWarfarin + LDASA was more effective that LDASA alone in secondary prevention of stroke

Fujieda et al., 2012 [44]RC82Yes82/0Warfarin 
Antiplatelet 
Warfarin + antiplatelet 
Dual antiplatelet
8.5 years
3.4/100/pt.-year 

0
Dual antiplatelet regimen was beneficial in preventing recurrences in refractory APS

A: arterial; V: venous; PC: prospective cohort; RC: retrospective cohort; RCT: randomized controlled trial; LDASA: low-dose aspirin.