Abstract: We included nine studies involving 1044 randomised participants. The studies took place in several countries and had different funding sources. No study was at low risk of bias in all domains. We classified all included studies as at unclear or high risk of bias in two or more domains. Seven included studies focused mainly on obstetric outcomes. One study included non-pregnancy-related cases, and one study included both pregnancy-related cases and other patients with positive results for aPL antibodies. The remaining studies concerned women with aPL antibodies and a history of pregnancy failure. Four studies compared anticoagulant with or without acetylsalicylic acid (ASA) versus ASA only and observed no clear difference in thrombosis risk (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.25 to 3.77; 4 studies; 493 participants; low-quality evidence). No major bleeding was reported, but minor bleeding risk (nasal bleeding, menorrhagia) was higher in the anticoagulant with ASA group as compared with ASA alone in one study (RR 22.45, 95% CI 1.34 to 374.81; 1 study; 164 participants; low-quality evidence). In one study ASA was compared with placebo, and there were no clear differences in thrombosis (RR 5.21, 95% CI 0.63 to 42.97; 1 study; 98 participants; low-quality evidence) or minor bleeding risk between the groups (RR 3.13, 95% CI 0.34 to 29.01; 1 study; 98 participants; low-quality evidence), and no major bleeding was observed. Two studies compared ASA with low molecular weight heparin (LMWH) versus placebo or intravenous immunoglobulin (IVIG), and no thrombotic events were observed in any of the groups. Moreover, there were no clear differences in the risk of bleeding requiring transfusion (RR 9.0, 95% CI 0.49 to 164.76; 1 study; 180 participants; moderate-quality evidence) or postpartum bleeding (RR 1.30, 95% CI 0.60 to 2.81; 1 study; 180 participants; moderate-quality evidence) between the groups. Two studies compared ASA with high-dose LMWH versus ASA with low-dose LMWF or unfractionated heparin (UFH); no thrombotic events or major bleeding was reported. Mortality and quality of life data were not reported for any of the comparisons. There is insufficient evidence to demonstrate benefit or harm of using anticoagulants with or without ASA versus ASA alone in people with aPL antibodies and a history of recurrent pregnancy loss and with no such history; ASA versus placebo in people with aPL antibodies; and ASA with LMWH versus placebo or IVIG, and ASA with high-dose LMWH versus ASA with low-dose LMWH or UFH, in women with aPL antibodies and a history of recurrent pregnancy loss, for the primary prevention of thrombotic events. In a mixed population of people with a history of previous pregnancy loss and without such a history treated with anticoagulant combined with ASA, the incidence of minor bleeding (nasal bleeding, menorrhagia) was increased when compared with ASA alone. Studies that are adequately powered and that focus mainly on thrombotic events are needed to draw any firm conclusions on the primary prevention of thrombotic events in people with antiphospholipid antibodies.

Plain-language summary: The evidence is current as of December 2017. We searched for studies that randomly allocated people with aPL antibodies and without any previous thrombotic event to different treatments, including anticoagulants, antiplatelet drugs, or both. We identified nine studies involving 1044 participants. The studies took place in several different countries. One study was multicentred and had a variety of funding sources. In two studies aspirin was compared with placebo (dummy treatment). Four studies compared an anticoagulant with or without aspirin with aspirin alone. The remaining studies compared combinations of antiplatelet agents, anticoagulants, other treatments, or two different doses of the same drug. The majority of the studies concerned women with aPL antibodies and a history of pregnancy failure. One study included non-pregnancy-related cases, and one study included pregnancy-related cases and other patients with positive results for aPL antibodies. We summarised the effects of the treatments using the following comparisons: aspirin only versus placebo, anticoagulant only or with aspirin versus aspirin only, aspirin with anticoagulant versus placebo or other treatment. We found no clear differences in the number of individuals with thrombotic events in the compared groups. One study revealed an increased risk of minor bleeding (such as nasal bleeding or intensified menstruation) in participants receiving aspirin and anticoagulant. All other analyses did not show any meaningful differences in the number of participants with bleeding. None of the studies reported on risk of death or quality of life. We found no clear difference between the groups in any of the comparisons for unwanted effects other than bleeding, where this information was reported; the more common of these effects included mild gastrointestinal symptoms in the aspirin group and allergic reactions in the aspirin with anticoagulant group. We assessed none of the studies as at low risk of bias because of methodological concerns or reporting of the results. We judged the overall quality of evidence to be low to moderate, it was downgraded due to unclear or high risk of bias, small number of studies and imprecise results.