**6. Treatment: primary and secondary prevention**

Once the workup for APS is complete, and if positive, the next logical step is to address treatment. However, prior to addressing treatment, let us first consider if APS is a primary risk factor for stroke risk. Numerous studies have been performed to address this question, culminating with a meta-analysis evaluating 15 different studies in aggregate [54]. In this evaluation, 13 of the 15 studies reported a significant association between a CVE and aPL antibodies with a cumulative odds ratio of 5.48 [54]. While this study provides insight into primary event risk, a follow-up question relates to the risk of APS with recurrent stroke. A second meta-analysis was completed looking at 8 studies to answer this question, demonstrating no statistically significant risk of recurrent ischemic stroke among APS patients [74]. Understanding why one meta-analysis demonstrated a link between aPL antibodies and single ischemic events, while another did not show a link with recurrent events remains challenging to understand. One hypothesis used to explain these incongruent findings is that clinical events do not occur frequently occur despite the presence of the antibodies, suggesting that treatment and/or lifestyle modifications after a first stroke affect the chance of a second event [74, 75]. Therefore, an understanding that APS is associated with the single cerebral vascular event, and that treatment affects the chance of a second event, indicates that secondary prevention is highly warranted.

### **6.1 Primary prevention**

Knowing that therapy is indicated, we can now evaluate various treatments on the risk of thrombosis in the setting of APS. In those individuals without any other risk factors, the risk of thrombosis is less than 1% per year [76, 77]. In this group, when they do present with a thrombus, it is normally in the setting of another thrombotic risk factor, such as cancer, surgery, pregnancy, estrogen use, acute

infection, smoking, and hypertension. On the other hand, the risk of thrombosis can be as high as 5% per year in individuals with a persistent moderate high-risk profile including aPL antibodies and a systemic autoimmune disease [78]. Therefore, with the risk of thrombosis being so variable, sometimes as low as 1% or other times as high as 5%, the question of optimal prevention strategies can be challenging.

Regarding primary prevention (before a stroke or vascular event) the answer remains controversial with only scant data based on prospective trials [79]. Some of these trials have demonstrated a decrease in thrombosis with the use of aspirin. For example, a meta-analysis of 11 mostly observational studies demonstrated a 2-fold risk reduction in the first thrombotic event with a more significant effect in those with arterial thrombosis [79]. Post subgroup analysis of only prospective trials demonstrated there was no significant difference between aspirin and those not treated [79]. Therefore, with conflicting data on aspirin, one may ask could there be a benefit with the use of anticoagulation as well as aspirin for primary prevention. While the data was limited, one primary prevention study evaluated the use of aspirin alone vs. aspirin plus anticoagulation in 166 patients, demonstrating no significant difference in terms of the amount of thrombotic events between groups, with an increased risk of bleeding in the aspirin plus warfarin arm [80]. Therefore, given the increased bleeding risk, the use of aspirin and warfarin in combination is not recommended for primary prevention, with the question of aspirin use in isolation remaining. Many agencies have weighed in on this subject including the 13th International Congress on Antiphospholipid Antibodies as well as the European League Against Rheumatism making recommendations suggesting the use of aspirin in high-risk antiphospholipid profiles, those with other thrombotic risk factors, as well as those with SLE [58, 81]. Even with these recommendations, one must also consider the risk of bleeding with the use of aspirin. One meta-analysis looking at six randomized control trials showed an association of increased annual risk of major bleeding in those patients using aspirin with hypertension, age > 65, diabetes, and male sex being the most significant associated risk factors [82].

In summary, the decision to use primary prevention remains an individualized choice based on a patient-centric decision. Overall, though one should consider the use of primary prevention with aspirin in those with cardiac risk factors, high risk antiphospholipid antibody profile, presence of other thrombotic risk factors and in the presence of other autoimmune disease always ensuring a thorough risk benefit analysis is done with concern for bleeding. See **Figure 4** for breakdown of treatment option algorithm.

**Figure 4.** *Treatment options algorithm (adapted [10]).*
