**6.2 Secondary prevention: arterial primary event**

Knowing the indications for the use of primary prophylaxis we now consider secondary prophylaxis. Data regarding the need for secondary prophylaxis specifically in previous arterial thrombi remains scant without any consensus. For example, one study demonstrated the use of warfarin with a goal INR of 1.4–2.8 was not superior to full dose aspirin 325 mg alone for stroke prevention, with concerns that this study was flawed due to transient positivity of aPL antibodies [27]. Another study evaluating 20 patients with ischemic stroke demonstrated that the use of low-dose aspirin and warfarin with a goal INR of 2–3 was superior to lowdose aspirin alone in the prevention of further arterial thrombi [11]. While two other studies demonstrated that for older patients with stroke, and a single test showing low titers of anticardiolipin antibodies, that aspirin may be as effective as warfarin [27, 83]. With this conflicting data, there remains no consensus statement on secondary prophylaxis with many agencies weighing in on this subject. For example, the 13th International Congress on Antiphospholipid Antibodies as well as the European League Against Rheumatism both recommended secondary prophylaxis with high-intensity warfarin with an INR > 3 or low dose aspirin combined with moderate-intensity warfarin with an INR from 2 to 3 [58, 81]. Both agencies decided on using a goal INR of >3 for warfarin because in previous studies evaluating different doses of warfarin in treating thrombi, relatively few patients with arterial thrombi were enrolled [84, 85]. Overall, data remains scarce and guidelines are based upon a consensus of expert opinion. In those with recurrent arterial events, some recommend increasing target INR level and or switching to low molecular weight heparin with the addition of other adjective therapies to include statins [86].

In summary, the decision on which patient to treat and which agent to use for secondary prophylaxis with arterial thrombi remains a patient-centric decision. Those with high-risk aPL profiles, presence of other systemic autoimmune diseases, and or other risk factors for thrombus would likely benefit from treatment with either aspirin and warfarin with a goal 2–3 or warfarin alone with a goal INR 3–4. Those with recurrent events would likely benefit from increasing the INR goal or if not feasible switching to low molecular weight heparin. Moving forward it would be beneficial to validate a risk stratification model to identify those with arterial thrombosis who would benefit from more aggressive treatment [67]. See **Figure 5** demonstrates a treatment options algorithm.

#### **6.3 Secondary prevention: venous primary event**

Now knowing the indications and treatment options for the use in secondary arterial prophylaxis we now move on to secondary venous prophylaxis, which in the case of stroke would be beneficial in treating paradoxical emboli. Much different from that in arterial secondary prophylaxis, there is more of a consensus regarding the treatment of secondary venous prophylaxis using warfarin with a goal INR of 2–3 showing a decrease in recurrent venous events of 80–90% [57, 87]. Some studies have evaluated the use of higher intensity anticoagulation with a goal INR of 3.1–4.5 showing no reduced risk in thrombosis, but a significant excess of minor bleeding [84, 85].

Therefore, with the above data, we can safely say in summary for secondary prevention for venous thrombi in those with a chance of paradoxical emboli treatment with warfarin with a goal INR of 2–3 is indicated. See **Figure 5** for a treatment options algorithm.

**Figure 5.** *Arterial versus venous thrombus treatment options algorithm (adapted [13]).*

### **6.4 Other treatment considerations**

#### *6.4.1 Direct oral anticoagulants*

Following the basics of both primary and secondary prevention, one may question other anticoagulation options as adjuvant therapies. Regarding the use of direct oral anticoagulants (DOACs) there remains insufficient evidence with data suggesting an increased risk of thrombosis [88]. For example, two studies demonstrated no difference in the rate of venous thromboembolism and an increased risk of arterial thrombotic with the use of rivaroxaban over warfarin [89, 90]. Looking at this data more closely, a meta-analysis of these two studies did not find an increased risk of thrombosis in patients treated with rivaroxaban over warfarin at a 6 month follow up, however for unclear reasons, almost 3/4 of the thrombi occurred post the 6 months follow up [39]. Given the lack of prospective data, the utility of DOACs in the treatment of thrombus formation remains uncertain.

#### *6.4.2 Other therapies*

Beyond DOACs, other adjuvant therapies have been studied including statins and hydroxychloroquine. With statins being a mainstay of treatment post-stroke, it would not be unreasonable to think that they may be beneficial in APS, potentially exhibiting pleiotropic effects including anti-inflammatory, antithrombotic, and as well as the expected lipid-lowering potential [13]. To date, there have been no randomized controlled trials looking at the efficacy in this group of patients. One study however did look at the levels of pro-inflammatory and prothrombotic markers post use of Fluvastatin, which were significantly decreased suggesting their benefit in APS [91]. At this time without a randomized control trial, the 15th International Congress on Antiphospholipid Antibodies has recommended the use of statins in those with high cardiovascular risks and or recurrent thrombosis

### *Antiphospholipid Syndrome and Stroke DOI: http://dx.doi.org/10.5772/intechopen.101777*

despite adequate AC [88]. Regarding the use of hydroxychloroquine, similar to statins in addition to its immunomodulatory effect, it also has antithrombotic properties making it a good candidate as adjunctive therapy [88]. Two studies have been performed demonstrating differing results regarding treatment with hydroxychloroquine plus aspirin vs. aspirin alone. The first demonstrated no difference between rates of thrombosis between both groups [92]. The other demonstrated a significantly lower thrombotic rate compared to standard of care alone, in addition to down-trending antibody titers [93]. These data suggest that both statins and hydroxychloroquine could be beneficial as adjunctive therapies in specific situations, although more data is needed for consensus.

#### *6.4.3 Stopping therapy*

Throughout this section, we have addressed the need for primary and secondary prevention, but one question left unanswered is safety as associated with therapy cessation. Unfortunately, there remains a multitude of answers to this question, hence each case should be considered independently. In those with a history of arterial thrombotic events, the risk of repeat thrombus formation off anticoagulation is too high and therefore indefinite anticoagulation is warranted [94]. In those with a history of transient positivity of antiphospholipid antibodies who eventually become negative based on two separate studies, one can consider stopping anticoagulation [95, 96]. Specifically, this would be associated with those who only have primary APS with persistently negative antibodies where if there was a thrombotic event it occurred in association with a transient risk factor including pregnancy or immobilization as examples [96]. In these cases, it is thought that the antibodies do not play a pathogenic role, but rather are a "phenomenon". Therefore, some have recommended a 3–6-month course of anticoagulation with consideration to look for residual thrombus, which has been shown to increase the rate of recurrence by 50% [94]. Notably, the data and recommendations regarding stopping anticoagulation are based upon two small case series. Therefore, with such insufficient data, unless the risk of anticoagulation outweighs the benefit it would not be recommended to stop anticoagulation in those that become persistently negative.

### *6.4.4 Final thoughts on therapy*

Throughout this section we have addressed both preventions of stroke in APS, but what if someone should fail prevention and come in with an acute stroke. The answer to this question unlike many of the other is simple. Acute management is no different than those with or without APS [97]. Lastly, as described, APS often requires treatment with anticoagulant medications such as heparin to reduce the risk of further episodes of thrombosis and improve the prognosis of pregnancy. Warfarin (brand name Coumadin) should not be used during pregnancy because it crosses the placenta and is teratogenic. Unfractionated heparin (UFH) and low molecular weight heparin do not cross the placenta and are safe for the fetus, but long-term treatment with UFH is problematic because of its inconvenient administration, the need to monitor anticoagulant activity, and because of its potential side effects, such as heparin-induced thrombocytopenia and osteoporosis [98].
