Antiphospholipid Syndrome (APS) is a multisystem autoimmune disorder characterized by recurrent venous and arterial thrombotic events, as well as microthrombotic and non-thrombotic manifestations and/or pregnancy morbidity, associated with the persistent presence of antiphospholipid antibodies (aPL).⁽¹⁾ Antiphospholipid Syndrome is classified as primary when it occurs in the absence of other autoimmune disorders, and secondary when it is associated with other autoimmune diseases, particularly systemic lupus erythematosus (SLE).⁽²⁾ The management of thrombotic APS primarily focuses on thrombosis prevention, mainly achieved through anticoagulation therapy, either alone or in combination with antiplatelet agents.⁽³⁾ For patients with persistent aPL positivity and unprovoked thrombotic events, long-term anticoagulation with vitamin K antagonists (VKAs), such as warfarin, is the standard recommendation.⁽⁴⁾ This approach requires regular monitoring of the international normalized ratio (INR), target range of 2-3 or 2.5-3.5, to ensure both efficacy and safety.^(5,6) However, maintaining effective anticoagulation with VKA is challenging in clinical practice.⁽⁷⁾ Achieving a stable INR over time can be difficult due to several factors, including dietary influences, drug interactions, changes in gut microbiota, and individual variability in warfarin metabolism through the CYP2C9 and VKORC1 enzyme pathways.^(8-11)

The time in therapeutic range (TTR) is widely used in clinical trials to assess the quality of warfarin anticoagulation, particularly in patients with atrial fibrillation (AF).^(12-14) The Rosendaal method⁽¹⁵⁾ is a commonly used approach for calculating TTR, estimating the percentage of time patient's INR remains within the target range. The time in therapeutic range values range from 0% to 100%, with TTR <60% being associated with higher rates of mortality, major bleeding, myocardial infarction, and stroke.^(16,17) Two large cohorts studies highlight the importance of achieving a high TTR in patients with AF and other conditions. Liu et al. in the U.S. found that only 35% of 127,385 AF patients with AF achieved a TTR> 65%, with lower TTR being associated with increased risks of stroke, bleeding, and mortality.⁽¹⁸⁾ McAlister et al. in Canada reported similar findings, with 41% of 57,669 patients with AF achieving a TTR >65%, and lower TTR being associated with comorbidities such as heart failure, cirrhosis, and dementia.⁽¹⁹⁾ In Brazil, Silva et al. conducted a retrospective, single-center cohort study (2014 - 2016), involving 1,220 patients with non-valvular AF. Only 31% of patients achieved a TTR >65%. The study found that suboptimal TTR (<65%) was associated with an higher incidence of major bleeding events (5.3% versus 1.6%; p<0.01) and 40% higher healthcare costs in the public system (R$35,384 versus R$25,352; p<0.01) compared with patients who achieved better anticoagulation control.⁽²⁰⁾ Although numerous studies have assessed anticoagulation control in patients with AF, data on TTR in the patients with primary APS are limited, and the clinical consequences of poor INR control in this population remains unclear. These findings highlight the need for tailored management strategies to improve patient outcomes. This study aims to evaluate the quality of anticoagulation in patients with primary APS, using TTR as a key metric. Additionally, it sought to identify factors associated with poor anticoagulation control, with the goal of informing strategies to optimizing the clinical management of this high-risk population.

To evaluate the quality of anticoagulation in patients with primary Antiphospholipid Syndrome followed at the Rheumatology Department of a tertiary hospital and to assess factors associated with lower anticoagulation quality, including disease-related factors (severity profile, demographic characteristics, and presence of non-criteria manifestations) and patient-related factors (comorbidities and lifestyle habits).

A total of 133 patients were screened, and 93 were included. Of these, 50 (53.7%) had an incalculable TTR due to inadequate follow-up, while 43 (46.4%) had adequate follow-up and calculable TTR Among patients with adequate follow-up, 32 (74.4%) had TTR ≥60% and 11 (25.6%) had a TTR <60%. The median TTR among those with a calculable TTR was 93% (87.1%-99.6%). Overall, of the 93 included patients, only 32 (34.4%) achieved adequate anticoagulation (Figure 2).

Although the quality of anticoagulation has been widely studied in cardiology trials, data in primary APS remain scarce. A prospective study by Pengo et al. comparing anticoagulation control between 30 patients with APS and 30 with AF, showed a significantly lower median TTR in the APS group (53.5% versus 68%, p=0.001), APS was identified as an independent predictor of poorer anticoagulation control, requiring higher doses of VKAs than those indicated for patients with AF.⁽²⁷⁾

In a tertiary center in Rio de Janeiro (2015-2017), a retrospective study including 68 patients with primary APS reported a mean TTR of 36.7% ±25.0%. Only 31.7%±22.7 of INR values were within the target therapeutic range (2-3). Pastori et al. found an association between TTR <60% and systemic arterial hypertension (p=0.018) and dyslipidemia (p=0.024), while multivariate analysis identified a history of recurrent venous thromboembolism as being associated with poor anticoagulation quality.⁽²⁸⁾ In our study, a substantial proportion of patients exhibited suboptimal anticoagulation control, and less than half (46.2%) had adequate follow-up. Among those with adequate follow-up, the median TTR was 93.0%, with the majority (74.4%) achieving TTR≥60%, suggesting good anticoagulation control. However, when considering the entire cohort, only 34.4% achieved adequate anticoagulation as measured by TTR. The presence of 50 patients with incalculable TTR highlights that maintaining adequate follow-up and adherence to anticoagulation therapy remains a challenge in this population. More recently, a study by Meir et al. evaluated anticoagulation control in 67 patients with APS receiving VKA therapy between 2012 and 2023. The study found that only 29.9% of patients achieved a TTR ≥70%, with the lowest rate observed in those with three or more comorbidities (9.1%), compared with patients who had fewer comorbidities (40%). Suboptimal TTR was strongly associated with an increased risk of recurrent thrombotic events, particularly arterial thrombosis. However, the sample was not limited to primary APS, as 18% of the patients included had SLE.⁽²⁹⁾ Our proportion of well anticoagulated patients was similar to that reported in Rio de Janeiro (34.4% versus 36.7% with TTR ≥60%, respectively)⁽²⁸⁾ and in Israel (31.2% versus 29.9% with TTR ≥70%, respectively).⁽²⁹⁾ Furthermore, it is important to understand why some patients had adequate follow-up but still present <60%. Several modifiable barriers to anticoagulation therapy may contribute to this, including dietary and drug interactions. In this context, we analyzed potential demographic, clinical and laboratory factors that could influence anticoagulation quality, however no variables showed statistically significant differences between patients with adequate and poor anticoagulation control. This findings contrasts with previous studies that identified three or more comorbidities⁽²⁹⁾ and hypertension and dyslipidemia⁽²⁸⁾ as factors associated with poorer anticoagulation quality. These associations may be explained by pharmacokinetic interaction between warfarin and statins, involvingcytochrome P450 isoenzymes wichcan affect the effectiveness of VKA therapy.^(30,31) We observed nearly 40% of triple positivity in our cohort, along with a high frequency of recurrent thromboembolic events and a median aGAPSS of 11 (8-13). These findings indicate a population with a severe disease profile.⁽²⁴⁾ Notably, despite a substantial proportion of patients with severe disease, no statistically significant differences in clinical or demographic characteristics were observed when comparing patients with TTR ≥60% to those with TTR <60% or incalculable TTR.

Moreover, nearly half of the patients had at least one cardiovascular risk factor. These factors may influence anticoagulation quality, as polypharmacy for the treatment of comorbidities and greater disease severity may contribute to reduce adherence, increased drug interactions, and variability anticoagulant effect of warfarin.

During the one-year follow-up, three thrombotic events (3.4 cases/100 patients-year) and two major bleedings events (2.3 cases/100 patients-year) were recorded. Sevim et al.⁽³²⁾ reported approximately two thrombotic events per 100 patients-year in the most recent analysis of the APS ACTION data. Similarly, Balbi et al. reported a thrombotic recurrence rate of 3.82 cases per 100 patients-year in a Brazilian cohort from Rio de Janeiro (APS-Rio), 5.5 years after its inception. Therefore, we observed a slightly higher rate of thrombotic recurrence than that reported in APS ACTION, but a similar rate to that reported in the APS-Rio cohort. These differences may be influenced by factors such as study population characteristics, follow-up duration, and treatment strategies. It is important to note that the APS ACTION cohort includes a more heterogeneous APS population compared with the Brazilian cohort.

Analyzing these events individually, we found that four patients were triple-positive, and two had TTR≥60%. This finding highlights the role of additional disease-related factors in thrombotic recurrence, which may occur even in patients with adequate anticoagulation control.

One noteworthy finding is that 53.7% of patients had an incalculable TTR, likely due to inadequate follow-up. This group may include patients with poor adherence, as well as those facing barriers in accessing healthcare services and difficulties in maintaining regular INR monitoring.

Our patient population has low socioeconomic status and education level, which makes the anticoagulation follow-up even worse. These factors are already known to be associated with worse outcomes. Therefore, anticoagulation control in our setting may be less favorable than previously reported, limiting the generalizability of our findings to other populations. Identifying the causes of inadequate follow-up is essential, extending the analysis beyond anticoagulation management to include aspects related to healthcare system organization, socioeconomic disparities, and patient education. Overall anticoagulation control with vitamin K antagonists remains challenging worldwide.

Our study has several limitations. First, its retrospective design relies on medical records and patient-reported information, which may introduce information and recall bias. Additionally, survivorship bias may be present, potentially affecting the generalizability of the results. Furthermore, the study was conducted at a single tertiary center, which may limit the generalizability of the findings to other clinical settings and regions. Additionally, it is a cross-sectional analysis, which limits its ability to establish causality or assess changes over time. Lastly, the follow-up period for assessing outcomes is confined to 2019, which may not capture long-term trends or fluctuations in disease severity and treatment effectiveness. On the other hand, there is limited literature on anticoagulation monitoring in APS, particularly in PAPS patients, who were exclusively evaluated in our study.

In conclusion, our study provides valuable insights into anticoagulation control in patients with primary antiphospholipid syndrome. While we did not identify specific factors associated with poor anticoagulation control in our cohort, comorbidities and polypharmacy may contribute to suboptimal management. An intriguing finding was the recurrence of thrombosis in triple-positive patients despite well-maintained time in the therapeutic range. Further research is needed to better understand how physicians can improve anticoagulation adherence and impact clinical outcomes in this population.

The implementation of an active follow-up program, including regular telemedicine consultations, may represent an effective strategy to improve anticoagulation quality in public healthcare settings, particularly considering that 30% of patients in our study reside outside São Paulo city, which may hinder adequate follow-up. Additionally, the development of educational initiatives, such as lectures or informational videos on anticoagulation, could help reinforce the importance of treatment adherence and its impact on patient outcomes. These strategies may enhance patients’ understanding of their condition and promote active engagement in treatment, ultimately leading to improved clinical outcomes.

Further studies are needed to evaluate the factors underlying the high proportion of patients with time in therapeutic range. This assessment should include barriers within the healthcare system, patient-reported adherence challenges, and the impact of polypharmacy. Future studies designed to test interventions such as educational programs or digital monitoring tools may help address these issues. Moreover, studies aiming at identifying biomarkers or genetic predictors that influence anticoagulation control would be valuable to improve outcomes in this population.