Non-Warfarin Oral Anticoagulants in Anti-Phospholipid Syndrome

Introduction: Anti-Phospholipid Syndrome (APS) is a serious and deadly disorder leading to a significant risk of thrombi, requiring lifelong therapeutic anticoagulation. Traditionally, the vitamin K antagonist (VKA) warfarin has been considered standard of care in this patient population. However, the VKAs require frequent laboratory monitoring, have a narrow therapeutic window, numerous drug interactions and dietary restrictions.  Due to these factors, many patients suffer recurrent thrombi and/or major bleeding, warranting therapy modification or switching to parenteral anticoagulants. The non-warfarin oral anticoagulants (NOACs), specifically the direct Xa inhibitors apixaban and rivaroxaban, have been approved for the treatment of venous thromboembolism and represent attractive options for these patients.   

Methods: We designed a retrospective analysis of all patients at the University of Virginia with APS that were treated with either apixaban or rivaroxaban since September 2011. All patients were required to have a definitive diagnosis of APS [defined by the Sydney criteria as an arterial or venous thrombosis and IgM and/or IgG anti-cardiolipin antibody >40GLP, IgG and/or IgM beta-2 glycoprotein >99^th percentile, and/or positive lupus anticoagulant (e.g. prolonged silica clot time or dilute Russell viper venom time)].  Patients were reviewed for recurrent thrombi, severe bleeding or other complications that led to changes in their management.  

Results: Sixty-six patients were identified with suspected APS, with 18 being treated with a NOAC.  Of these, 10 had definitive APS per the Sydney criteria and were analyzed.  6/10 (60%) were treated with apixaban and 4/10 (40%) were treated with rivaroxaban. No patients developed severe bleeding or thrombotic complications and none required changes of their therapy.  30% started a NOAC as the first line outpatient regimen with the remaining 70% being previously treated with other anticoagulants. 7/10 (70%) were treated with warfarin and 3 patients were treated with fondaparinux before changing to a NOAC. Reasons for stopping warfarin were difficulty managing INRs (33%) or thrombi while on warfarin (66%). Of those previously on fondaparinux, reasons for changing therapy were transient ischemic attack (33%), difficulty with injections (33%) and cost (33%). Of these 10 patients, safe and effective anticoagulation with a NOAC was noted for up to 36 months without adverse effects.

Conclusion: Apixaban and rivaroxaban showed to be a safe and effective first line outpatient regimen for patients with APS or patients with APS who develop recurrent thrombi on warfarin or parenteral anticoagulation. Further prospective studies are needed before their use should be considered standard of care.

Table 1. Patients with Anti-Phospholipid Syndrome Treated with Non-Warfarin Oral Anticoagulant

Patient	First Positive Test	Second Positive Test	Serum Testing Performed off Warfarin	Anticoagulant	Length of Treatment (in months)	Bleeding Complications	Thrombotic Complications	Prior Anticoagulant Use	Reason Therapy was Changed
1	Cardiolipin IgG 52, β2 IgG >112	Cardiolipin IgG 76, β2 IgG >112; RVVT prolonged	No	Apixaban	8	None	None	Yes (warfarin)	Difficult to control INR
2	Cardiolipin IgG >15; RVVT prolonged	Cardiolipin IgG >15; RVVT prolonged	Yes	Apixaban	6	None	None	Yes (warfarin)	Difficult to control INR
3	Cardiolipin & β2 >112	Cardiolipin & β2 >112	Yes	Apixaban	2	None	None	Yes (warfarin)	Stroke while on warfarin
4	Cardiolipin IgM 66, β2 IgM 68	Cardiolipin IgM 98, β2 IgM 87	Yes	Apixaban	8	None	None	No	N/A
5	β2 IgG 122; + LA	Cardiolipin & β2 >112	No	Apixaban	7	None	None	Yes (warfarin)	Multiple strokes while on warfarin
6	β2 IgM 29; + LA	Cardiolipin IgM 50, β2 IgM 74 RVVT prolonged	Yes	Apixaban	4	None	None	Yes (Fondaparinux)	Difficulty with injections
7	Cardiolipin IgG 73	Cardiolipin IgG & β2 IgG>112; RVVT prolonged	Yes	Rivaroxaban	36	None	None	Yes (warfarin & fondaparinux)	Thrombi on warfarin & fondaparinux
8	Cardiolipin IgG>112; RVVT  prolonged	Cardiolipin IgG>112	Yes*	Rivaroxaban	2	None	None	Yes (warfarin)	Difficult to control INR
9	Cardiolipin IgM & β2 IgM>112	Cardiolipin IgM & β2 IgM>112	Yes*	Rivaroxaban	15	None	None	No	N/A
10	β2 IgG>100 RVVT prolonged	β2 IgG>100; RVVT prolonged	No	Rivaroxaban	31	None	None	Yes (warfarin & fondaparinux)	Thrombi on warfarin & fondaparinux

*Second serum testing drawn while on rivaroxaban