“Author's reply” validity of current treatment guideline for patients with limb-threatening ischemia with antiphospholipid syndrome

Thank you for giving us a forum for the discussion on the question for our manuscript entitled “Challenging Endovascular Treatment for the Patient with Chronic Limb-Threatening Ischemia due to Antiphospholipid Syndrome”. Our study reported a case of antiphospholipid syndrome (APS) with severe limb-threatening ischemia (LTI). The reported patient avoided amputation for ≥9 years after endovascular treatment (EVT) because of the continuous administration of warfarin, which is a vitamin K antagonist. Furthermore, the patient had stent thrombosis after a change of anticoagulant to edoxaban, which is a direct oral anticoagulant (DOAC). Regarding the first concern of the commentator about why we continued the combination of low-dose aspirin (LDA) and high-intensity warfarin of international normalized ratio (INR) 2.5–3.5 despite repeated epistaxis, there was limited trial-based evidence on the treatment of APS with arterial thrombosis. Furthermore, there was no EVT report of stent use in patients with APS before a decade when the patients received the first EVT. The task force at the 13th International Congress on Antiphospholipid Antibodies advised at the time that high-intensity warfarin (INR >3.0) or LDA combined with moderate-intensity warfarin (INR 2.0–3.0) was recommended for the treatment of APS with arterial thrombosis. However, it was a non-graded recommendation [ [1] Ruiz I.G. Cuadrado M.J. Ruiz-Arruza I. Brey R. Crowther M. Derksen R. et al. Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: report of a task force at the 13th international congress on antiphospholipid antibodies. Lupus. 2011; 20: 206-218 Crossref PubMed Scopus (387) Google Scholar ]. Therefore, the treatment strategy was decided based on the patient's condition. Our first treatment task was to regress the popliteal artery thrombus, which was presumed to be the main cause of TLI, as soon as possible. Hence, we initially planned to maintain high-intensity warfarin (INR 2.5–3.5) until an adequate thrombus reduction was obtained. In addition, we decided to continue dual antiplatelet therapy with LDA and clopidogrel, which had been recommended for a short period after EVT to prevent stent thrombosis, for a slightly extended period because of long stenting [ [2] Tepe G. Bantleon R. Brechtel K. Schmehl J. Zeller T. Claussen C.D. et al. Management of peripheral arterial interventions with mono or dual antiplatelet therapy–the MIRROR study: a randomised and double-blinded clinical trial. Eur Radiol. 2012; 22: 1998-2006 Crossref PubMed Scopus (130) Google Scholar ]. Although we were concerned about bleeding events while using two antiplatelet agents and warfarin during 1 year after EVT, we judged that it was possible to use the three drugs in a short duration with careful follow-up because of the young age (41 years) and no history of hypertension, visceral dysfunction, or bleeding events. The HAS-BLED score was 2 points including slight epistaxis. Moreover, the predicted incidence of serious bleeding was estimated to be 1%, which was not considered high-risk [ [3] Okumura K. Inoue H. Atarashi H. Yamashita T. Tomita H. Origasa H. J-RHYTHM registry investigators. Validation of CHA₂DS₂-VASc and HAS-BLED scores in Japanese patients with nonvalvular atrial fibrillation: an analysis of the J-RHYTHM Registry. Circ J. 2014; 78: 1593-1599 Crossref PubMed Scopus (84) Google Scholar ]. Even after reducing the antiplatelet agent to one, the treatment was performed for a while without changing the target INR because of the stable symptom of the legs. Although we did not mention in the manuscript, we did not persist with INR 2.5–3.5. The dose of warfarin had been controlled to approximately 2.5–2.9 after a minor increase in nose bleeding. A decrease in INR had no effect on leg symptoms. Currently, after 10 years of the first EVT, the patient continues to be treated with LDA and warfarin controlled at INR 2.4–2.8. Furthermore, he has followed an extremely stable course without any bleeding events, lower limb ischemia, and re-decrease in ankle-brachial index. As the commentators point out, it can be said that there is no consensus guideline for the treatment of APS with arterial thrombosis, especially with LTI, because of the absence of high-quality relevant data. Unfortunately, the treatment options that the commentator mentioned, i.e. antiplatelet therapy alone, standard-intensity warfarin (INR range 2–3) with or without LDA, or higher-intensity warfarin (INR >3.0), were not established based on studies on APS with LTI [ [1] Ruiz I.G. Cuadrado M.J. Ruiz-Arruza I. Brey R. Crowther M. Derksen R. et al. Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: report of a task force at the 13th international congress on antiphospholipid antibodies. Lupus. 2011; 20: 206-218 Crossref PubMed Scopus (387) Google Scholar ]. Because there is currently no consensus treatment guideline, it is necessary to adjust the medication according to the patient's medical condition while referring to the current task force recommendations. In addition, it is very important to evaluate the bleeding risk, considering the patient's background characteristics, including hypertension, renal or liver dysfunction, history of stroke or bleeding, elderly age, use of drugs such as antiplatelet agents, and alcohol polydipsia. As a result, it can be said that the long-term administration of warfarin in INR 2.0–3.0 and LDA recommended by the current APS treatment guidelines were very successful in this case.