Treatment of the Antiphospholipid Syndrome

Treatment of the Antiphospholipid Syndrome Antiphospholipid syndrome  autoimmune thrombophilic disorder   antiphospholipid antibodies at least one clinical manifestation    venous thrombosis arterial thrombosis recurrent fetal loss  occurs in isolation as 1° disease or in association w/ CTDx  SLE Classification criteria (Sapporo, 1999)  clinical criteria   vascular thrombosis pregnancy morbidity anticardiolipin Ab (IgG or IgM) of moderate or high titer lupus anticoagulant   laboratory criteria   Prolonged phospholipid-dependent coagulation aPTT, kaolin clotting time, dilute Russell’s viper venom  Spectrum of disease  Heterogenous clinical picture    Ab positive (AC Ab or LA), asymptomatic women w/ history or pregnancy loss demonstrated thrombosis  increasing risk arterial or venous  catastrophic APLAS  Allows for stratification of risk and therapeutic options Therapeutic challenges  Role for prophylaxis in asymptomatic patients and non-gravid women w/ AP pregnancy complications  Guidelines for effective anti-coagulation in patients w/ a history of thrombosis Rate of non gravid vascular thrombosis (Arthritis and Rheumatism 2001, 44:1466)      retrospective study patients diagnosed w/ 1° or 2° APLAS solely on the basis of pregnancy loss no previous history of non gravid thrombosis use of aspirin obtained from charts follow up time defined as first thrombotic event or last MD visit Clinical characteristics Charac teristi cs Age at initial pregnancy event 1° APS 2° APS Duration of Tx (months)  ASA treated (N = 31) 29 ± 4.9 21 10 49 ± 37 Not treated (N = 34) 28.9 ± 6.2 17 15 NA  29 patients low dose ASA (81mg/d) 2 patients standard dose ASA (325 mg/d) High incidence of non-pregnancy related thrombosis in APS patients presenting w/ pregnancy loss Charac teristi cs No of further events % w/ further events ASA treated (N = 31) 3 10 Not treated (N = 34) 20 59  ASA prophylaxis beneficial in this APS subgroup Treatment   antiphospholipid antibodies positive asymptomatic   do not require anticoagulation may consider ASA   Extrapolated from single study in women w/ a history of recurrent fetal loss ASA found to lower the risk of thrombosis Treatment    clinically active disease requires life long anticoagulation risk of recurrence between 20% and 70% early retrospective studies suggested that INR > 3.0 greater protection A comparison of two intensities of warfarin for the prevention of recurrent thombosis in patients with antiphospholipid antibody syndrome (NEJM 2003, 349:1133) Study design    RCT double blind selected patients randomized   moderate intensity warfarin group (INR 2.0 -3.0) high intensity warfarin group (INR 3.1 - 4.0) Selection criteria Objective confirmation of arterial and/or venous thromboembolism Positive antiphospholipid Ab testing x 2 with samples drawn > 3 months apart    Positive lupus anticoagulant Positive IgG anticardiolipin Ab (moderate to high titer) Both LCA and ACA positive Exclusion criteria  bleeding risk (19 %)   thrombocytopenia (< 50) Hx of intracranial hemorrhage or GI bleed or CVA within 3 months     pregnancy or planned pregnancy (21 %) contraindication to coumadin inability to comply with followup history of recurrent thrombosis while receiving coumadin targeted to an INR 2.0 or greater (14 %) Base line characteristics Charac teristi cs No of patients Age (mean) Female Venous thrombosis Thrombosis w/in 6 months of study INR 3.1 - 4.0 56 43 27 (48 %) 42 (75 %) 16 (29) INR 2.0 - 3.0 58 41 41 (71 %) 45 (78 %) 21 (36) Outcome measures  1° study outcome  recurrent arterial and/or venous thrombosis      CVA/TIA AMI peripheral arterial occlusion cerebral vein thrombosis DVT/PE  1° safety outcome was bleeding Time to first recurrent thrombosis    3.4% recurrence in low intensity group 10.7 % recurrence in high intensity group 7 % recurrence in total study population Recurrence events in moderate intensity group Previous event New event AMI and DVT AMI DVT DVT INR 1.6 2.8 Recurrence events in high intensity group Previous event Peripheral arterial thrombus DVT PE DVT CVA AMI  New event DVT INR 3.1 DVT CVA DVT AMI 3.9 1.0 0.9 1.9 60 % of patients subtherapeutic for limits defined for high and moderate intensity groups Percentage of time Below Within Above target target target Moderate intensity High intensity  19 % 43 % 71 % 40 % 11 % 17 %  Higher proportion of patients in high intensity group in subtherapeutic range Within subtherapeutic populatin 86% at INR 2.0 - 3.0 Conclusions  Absolute risk of thrombosis low in moderate intensity group Moderate intensity coumadin was as effective as high intensity therapy for selected population 