This review aimed to find out which type of treatment works best for preventing future stroke and other blood clotting (thrombotic) events, in people with antiphospholipid syndrome (APS).
APS is a disease where the immune system produces antibodies directed against the proteins attached to their own cells. The presence of such antibodies may increase the risk of developing blood clots (thrombosis) in the blood vessels, or causing pregnancy-related complications (such as recurrent miscarriage, death of a baby in womb, premature birth, poor growth of the baby, or serious illness in a pregnant women). Blood clots in the arteries can cause strokes, resulting in brain damage or reversible nerve symptoms. Blood clots in veins are associated with pain and limb swelling, and if they move they can block blood flow to the lungs. Two types of drugs are commonly used to prevent blood clots in people with APS: anticoagulants and antiplatelets. Anticoagulants prevent blood clot formation by interfering with the activity of proteins involved in blood clotting (clotting factors); while antiplatelets, usually aspirin, prevent platelets from sticking together and impair clot formation. Treatment with some anticoagulants (such as warfarin) requires regular blood tests to ensure their adequate action, and a balanced diet in terms of vitamin K intake, mainly in green leafy vegetables.
The evidence is current to February 2017. We looked for studies that randomly allocated people with APS to different treatments, including anticoagulants, antiplatelets, or both. We identified five studies involving 419 participants. The average age of the participants was between 41 and 50 years, and the studies included people with previous stroke or previous blood clots in large veins or arteries. Studies took place in eight different countries and had a variety of funding sources. One trial compared a novel anticoagulant (rivaroxaban) with the standard anticoagulant (warfarin). Two studies compared a high dose versus standard dose of warfarin , and two studies compared combinations of antiplatelets, anticoagulants, or both. Interventions lasted from 180 days to an average of 3.9 years (SD 2.0).
In one study with an anticoagulant (rivaroxaban), participants had no episodes of blood clotting, and there was no difference in the risk of bleeding (moderate-quality evidence). In the two studies comparing higher and lower doses of anticoagulant (warfarin), similar proportions of participants had blood clotting and major bleeding problems (low-quality evidence), but the higher dose warfarin group had a greater risk of minor bleeding problems and any bleeding problems (low-quality evidence). The two studies comparing combinations of antiplatelets and anticoagulants were both small, not well reported, and their results were inconclusive (very low-quality evidence).
Quality of the evidence
One study was well designed, and we judged it to be at low risk of bias; we judged a second study to be at low risk of bias for the main results. We considered all other studies to be at unclear or high risk of bias because of concerns about their methods or reporting of results. All the results were imprecise and did not clearly indicate benefit or harm.
We did not find enough evidence in our review to judge the benefit or harm of using anticoagulant (rivaroxaban) versus anticoagulant (warfarin) for preventing blood clots or stroke in people with APS. Treatment with high doses of the anticoagulant warfarin was associated with a higher risk of minor and any bleeding than treatment with standard doses, but we found no difference in terms of benefit. There was not enough evidence to show benefit or harm of any combination of anticoagulants and/or antiplatelets. Five ongoing studies will likely provide additional evidence in the near future.
There is not enough evidence for or against NOACs or for high-intensity VKA compared to the standard VKA therapy in the secondary prevention of thrombosis in people with APS. There is some evidence of harm for high-intensity VKA regarding minor and any bleeding. The evidence was also not sufficient to show benefit or harm for VKA plus antiplatelet agent or dual antiplatelet therapy compared to a single antiplatelet drug. Future studies should be adequately powered, with proper adherence to treatment, in order to evaluate the effects of anticoagulants, antiplatelets, or both, for secondary thrombosis prevention in APS. We have identified five ongoing trials mainly using NOACs in APS, so increasing experimental efforts are likely to yield additional evidence of clinical relevance in the near future.
Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by arterial or venous thrombosis (or both) and/or pregnancy morbidity in association with the presence of antiphospholipid antibodies. The prevalence is estimated at 40 to 50 cases per 100,000 people. The most common sites of thrombosis are cerebral arteries and deep veins of the lower limbs. People with a definite APS diagnosis have an increased lifetime risk of recurrent thrombotic events.
To assess the effects of antiplatelet or anticoagulant agents, or both, for the secondary prevention of recurrent thrombosis, particularly ischemic stroke, in people with antiphospholipid syndrome.
We searched the Cochrane Stroke Group Trials Register (February 2017), CENTRAL (last search February 2017), MEDLINE (from 1948 to February 2017), Embase (from 1980 to February 2017), and several ongoing trials registers. We also checked the reference lists of included studies, systematic reviews, and practice guidelines, and we contacted experts in the field.
We included randomized controlled trials (RCTs) that evaluated any anticoagulant or antiplatelet agent, or both, in the secondary prevention of thrombosis in people diagnosed with APS according to the criteria valid when the study took place. We did not include studies specifically addressing women with obstetrical APS.
Pairs of review authors independently selected studies for inclusion, extracted data, and assessed the risk of bias for the included studies. We resolved any discrepancies through discussion or by consulting a third review author and, in addition, one review author checked all the extracted data.
We included five studies involving 419 randomized participants with APS. Only one study was at low risk of bias in all domains. One study was at low risk of bias in all domains for objective outcomes but not for quality of life (measured using the EQ-5D-5L questionnaire). We judged the other three studies to be at unclear or high risk of bias in three or more domains.
The duration of intervention ranged from 180 days to a mean of 3.9 years. One study compared rivaroxaban (a novel oral anticoagulant: NOAC) with standard warfarin treatment and reported no thrombotic or major bleeding events, but it was not powered to detect such differences (low-quality evidence). Investigators reported similar rates of clinically relevant non-major bleeding (risk ratio (RR) 1.45, 95% confidence interval (CI) 0.25 to 8.33; moderate-quality evidence) and minor bleeding (RR 1.21, 95% CI 0.51 to 2.83) for participants receiving rivaroxaban and the standard vitamin K antagonists (VKA). This study also reported some small benefit with rivaroxaban over the standard VKA treatment in terms of quality of life health state measured at 180 days with the EQ-5D-5L 100 mm visual analogue scale (mean difference (MD) 7 mm, 95% CI 2.01 to 11.99; low-quality evidence) but not measured as health utility (MD 0.04, 95% CI −0.02 to 0.10 [on a scale from 0 to 1]).
Two studies compared high dose VKA (warfarin) with moderate/standard intensity VKA and found no differences in the rates of any thrombotic events (RR 2.22, 95% CI 0.79 to 6.23) or major bleeding (RR 0.74, 95% CI 0.24 to 2.25) between the groups (low-quality evidence). Minor bleeding analyzed using the RR and any bleeding using the hazard ratio (HR) were more frequent in participants receiving high-intensity warfarin treatment compared to the standard-intensity therapy (RR 2.55, 95% CI 1.07 to 6.07; and HR 2.03, 95% CI 1.12 to 3.68; low-quality evidence).
In one study, it was not possible to estimate the RR for stroke with a combination of VKA plus antiplatelet agent compared to a single antiplatelet agent, while for major bleeding, a single event occurred in the single antiplatelet agent group. In one study, comparing combined VKA plus antiplatelet agent with dual antiplatelet therapy, the RR of the risk of stroke over three years of observation was 5.00 (95% CI 0.26 to 98.0). In a single small study, the RR for stroke during one year of observation with a dual antiplatelet therapy compared to single antiplatelet drug was 0.14 (95% CI 0.01 to 2.60).