Efficacy of Dual Antiplatelet Therapy for Preventing Recurrence of Arterial Thrombosis in Patients With Antiphospholipid Syndrome

Naoki Ohnishi; Yuichiro Fujieda; Ryo Hisada; Hiroyuki Nakamura; Masaru Kato; Kenji Oku; Toshiyuki Bohgaki; Olga Amengual; Shinsuke Yasuda; Tatsuya Atsumi


Rheumatology. 2019;58(6):969-974. 

In This Article


This retrospective cohort study of patients with APS was conducted at Hokkaido University Hospital. Patients with the diagnosis of APS were extracted from the autoimmune disease database of our outpatient clinic between April 1990 and March 2016, and the diagnosis verified by the attending physicians and authors according to the Sydney-revised Sapporo criteria for definite APS.[1] The coexistence of systemic lupus erythematosus was diagnosed according to the ACR revised criteria.[9]

We enrolled APS patients with a history of an arterial thrombotic event who received prophylactic treatment for recurrent thrombosis for at least 2 years. The observation period of each patient was defined to begin at the time of the first arterial thrombotic event, regardless of previous venous thrombotic events or pregnancy complications, and end either at the time of an event (recurrence of arterial and/or venous thrombosis, severe bleeding event, or death) or at the end of medical records. APS patients without manifestations of arterial thrombosis or with followed-up periods <2 years were excluded. The selection of the prophylactic regimen was based on the individual physician's judgement in accordance with the standard medical care in Japan at the time. All treating physicians were board-certified rheumatologists by the Japan College of Rheumatology, and the therapeutic regimen was administered following the corresponding guidelines of APS[2] and stroke.[10]

Patients were divided into four groups based on their treatment regimen: warfarin monotherapy (Wf); single antiplatelet therapy (AP); warfarin and antiplatelet combination therapy (Wf + AP); or DAPT (Supplementary Figure S1, available at Rheumatology online). Specific antiplatelet drugs included aspirin, ticlopidine, clopidogrel, cilostazol, dipyridamole, beraprost sodium, sarpogrelate hydrochloride and dilazep dihydrochloride (Supplementary Table S1, available at Rheumatologyonline). Anticoagulant refers specifically to warfarin in this study as patients on treatment with direct oral anticoagulants were excluded due to off label use of these agents for arterial thrombosis without atrial fibrillation in Japan. None of the patients were on hydroxychloroquine. In Japan, hydroxychloroquine has been used off-label for SLE before its approval on July 2015.

Figure S1.

Flow chart of the study design
Patients were categorized into four groups according to the therapy used for secondary prevention of thrombosis. APS: antiphospholipid syndrome, N: number of patients.

The primary endpoints were set as event free survival period and events were defined as the recurrence of thrombosis in either arterial or venous circulation, severe bleeding events, and death. The presence of thrombosis was confirmed by imaging, and severe bleeding was defined as those events that required hospitalization and/or blood transfusion.

Risk factors for arterial thrombosis including hypertension, diabetes mellitus, dyslipidaemia, glucocorticoid use and smoking were recorded at the end of the observation period. aPL was assayed in all the patients at the first visit to the autoimmune outpatient clinic and at least the second time, separated by at least 12 weeks (definition of risk factor and aPL assay are shown in the Supplementary data, available at Rheumatology online). The aPL score, a quantitative marker that represents the aPL profile, was calculated in each patient.[11]

This study was conducted in accordance with ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines and approved by Hokkaido University Hospital ethics committee (approval number: 017–0034).

Statistical Analysis

Categorical variables were described as counts and percentages. Continuous variables were expressed as the median and quartiles. To identify differences between groups, the Mann–Whitney U test and the Kruskal–Wallis test were performed. Kaplan–Meier curves were applied to estimate the value of secondary prevention therapy and safety, using thrombotic events and mortality/severe bleeding events. Cox regression analysis was performed to identify the risk factors for recurrence according to therapy and variables related to arterial thrombosis. In all statistical analyses, P < 0.05 was taken to indicate statistical significance. All statistical analyses were performed using JMP® Pro 12.2.0 (SAS Institute Inc., Cary, NC, USA).