Atrial fibrillation (AF) is associated with an increased risk of stroke, systemic thromboembolic events, and mortality (1). Long-term anticoagulation therapy, particularly with direct oral anticoagulants (DOACs), significantly reduces the risk of stroke and mortality (2). In terms of venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE), the duration of anticoagulation therapy to prevent recurrences takes into consideration the risk of recurrent VTE and the risk of bleeding (3).

AF and VTE have many pathophysiological and clinical risk factors in common. In terms of pathophysiology, the pathogenesis of arterial thromboembolism in AF has been associated with a prothrombotic state by fulfilling Virchow's triad for thrombogenesis, i.e., with abnormal blood flow (stasis) in the atria, vessel wall abnormalities and abnormal blood constituents (coagulation factors) as well as inflammation (4). Likewise, the pathogenesis of arterial thromboembolism in VTE has been associated with a prothrombotic state, i.e., with abnormal blood flow (stasis) in the vessels, vessel wall abnormalities and abnormal blood constituents (coagulation factors) as well as inflammation (5, 6). Several studies showed that VTE increases risk of atherothrombotic cardiovascular events, including myocardial infarction (MI) (7). In terms of contributing factors, AF and VTE also share similar comorbidities (3, 6), such as age, hypertension, smoking, diabetes, and obesity (8–10), peripheral artery disease (11) and malignancy (12). Moreover, one community registry study reported that AF and VTE independently contributed to each other (13). However, the duration of prescribing anticoagulation is quite different between AF and VTE in current practice. Long-term anticoagulation should be prescribed for AF patients (2, 14) whereas more limited-duration of anticoagulation is sometimes prescribed for VTE patients unless there are high risk features for recurrence (3, 15).

We hypothesized that AF and VTE, despite sharing many pathophysiological and clinical risk factors, have different duration of prescribing anticoagulation and should have differential contribution to arterial thromboembolic events and mortality in the same population. Accordingly, we tested this hypothesis in a nationwide cohort study of VTE and AF patients from the Taiwan National Health Insurance Database.

The data of this national retrospective cohort study was retrieved from the Taiwan National Health Insurance Research Database (NHIRD) released by the Taiwan National Health Research Institutes. The National Health Insurance system is a mandatory universal health insurance program that offers comprehensive medical care coverage to nearly all Taiwan residents since the inception of the program in March 1995. In the NHIRD, the patients' original identification numbers are encrypted and the encrypting procedure is consistent, so that linking claims belonging to the same enrollee is feasible and can be followed longitudinally. The available health care information included complete outpatient visits, hospitalization, and diseases, which were registered using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes (16). In addition, medication prescriptions are also recorded. Patients with newly diagnosis of AF and VTE were included in this study. The study was approved by the Institutional Review Board of Chang Gung Memorial Hospital (201900915B1).

This retrospective 10-year nationwide cohort study enrolled two national cohorts shows that the arterial thromboembolic events, ischemic stroke and MI, were higher in matched patients with AF cohort than those with VTE cohort. Second, the VTE cohort had higher incidence of ECATE than AF cohort, particularly lower extremity thromboembolism. Third, the AF cohort had higher incidence of CV death, but lower incidence of all-cause mortality compared to the VTE cohort (Figure 4; Supplementary Table 8). In subgroup analyses comparing the DVT-only, PE-only and AF cohorts, the AF patients had highest incidence of ischemic stroke among the three cohorts and had similar incidence of MI compared to patients with PE-only. Patients with DVT-only had highest incidence of ECATE among the three cohorts, particularly lower extremity thromboembolic event. In terms of mortality, patients with PE-only had highest incidence of CV death and all-cause mortality (Supplementary Table 8).

A national 20-year observational study demonstrated that patients with VTE had a 1.26-1.31-fold increased risk of subsequent arterial thromboembolic events, including MI and stroke (23). Schulman et al. also showed that VTE was associated with a 1.28-fold increased risk of MI or stroke over a 10-year follow-up period (24). Epidemiological studies and meta-analysis have also recognized that AF is independently associated with a five-fold increased risk of stroke (1), 1.47-fold increased risk of MI (25), and a two-fold increased risk of mortality (26).

Although VTE and AF contribute to similar arterial thromboembolic events, we are unaware of any study that has compared the different presentations of arterial thromboembolic events between VTE and AF patients, from the same population cohort. Based on our study, AF contributed to more arterial thromboembolic events while VTE contributed to greater all-cause mortality. In terms of the causes of mortality, more AF patients (66.6%) died from cardiovascular death than VTE patients (56.4%) while more VTE patients (13.7%) died from cancer than AF patients (8.6%) (Supplementary Table 4). Our results were generally consistent with other studies in terms of causes of death in VTE and AF patients (27).

As mentioned above there are many parallels between the epidemiology of risk factors and associated pathogenesis of thrombosis in AF and VTE (4, 6, 8, 10, 28). Nonetheless, our study showed some differential distributions of baseline characteristics between VTE and AF cohorts. Of note, the prevalence of peripheral artery disease and cancer was higher in VTE cohort than AF cohort. In contrast, the prevalence of ischemic heart disease and heart failure was higher in AF cohort than VTE cohort. Importantly, even after propensity matching, AF cohort had higher risks of arterial thromboembolic event, ischemic stroke and MI compared to the VTE cohort. VTE cohort had higher all-cause mortality while AF cohort had higher CV mortality. Therefore, VTE and AF patients have different risks in presentations related to arterial thromboembolic events.

Long-term anticoagulation therapy to prevent arterial thromboembolism is a well-established strategy in AF population (2) and a net clinical benefit more than 5 years with DOACs is still evident (14). On the other hand, long-term anticoagulation was not recommended in VTE population due to uncertain net clinical benefit in the era of vitamin K antagonists (VKA, e.g., warfarin) (15). However, some studies have shown that extended treatment with DOAC for 6-15 months resulted in less recurrent VTE events than no treatment, and had less bleeding events compared to VKA (29–32). Of note, extended low-dose aspirin in VTE patients for up to 4 years results in a significant reduction in the rate of major vascular events, with improved net clinical benefit in the ASPIRE study (33). Moreover, our study showed that anticoagulant use had a significant impact on the association between AF/VTE and individual arterial thromboembolic events and all-cause and cardiovascular mortality (Table 3). Lifelong anticoagulation is indicated in AF patients with high CHA₂DS₂-VASc score (≥2). The differential manifestations of thromboembolism sequelae and mortality between AF and VTE cohorts merit further investigation of an extended period or lifelong anticoagulation in VTE patients and validation in other ethnic population.

Our study has several limitations. First, we could not clearly identify the prevalence of provoked and unprovoked VTE in our VTE cohort. Several observational studies have reported that unprovoked VTE does not contribute to the same risk as provoked VTE in terms of clinical outcomes, including arterial thromboembolic events. However, a 20-year national observational cohort study reported no significant differences in arterial CV events between provoked and unprovoked VTE (23). In addition, the distinction between provoked/unprovoked PE is no longer supported by the 2019 ESC guidelines for the diagnosis and management of acute pulmonary embolism (34). Furthermore, clinical presentations/manifestations and laboratory data were not available in NHIRD and such information might affect the outcomes of VTE, especially those with PE (34). In order to reduce the bias, we excluded those died during hospitalization and within 3 months after discharge. Second, differentiating subtypes of AF (paroxysmal, sustained) cannot be performed because this information was not available in our national database. Although the incidence of ischemic stroke is considered to be generally lower in paroxysmal AF patients than in patients with sustained AF (35), it should not affect the outcomes between AF and VTE in such a large volume study. Third, the duration of anticoagulation therapy was different between AF vs. VTE cohorts (2, 34). We also did not compare the outcomes between AF and VTE cohorts in individual different scenarios with different durations of anticoagulation therapy. Furthermore, although there were different frequencies of anticoagulants and antiplatelets between AF and VTE cohorts before propensity matching (Table 1), our conclusion was based on the results derived from the study population after propensity matching (Tables 1, 2). Therefore, the unbalanced prescription of anticoagulants and antiplatelets between AF and VTE cohorts before propensity matching should not influence our main results derived from the study population after propensity matching. Fourth, VTE cohort had a higher incidence of lower extremity thromboembolic events than AF cohort. We could not completely exclude the possibility of more image studies performed in the VTE cohort to reveal a higher incidence rate of lower extremity thromboembolic events. Finally, propensity score matching was used to reduce the potential confounding variables in this study. However, there were potential unknown variables in the study population for matching and comparison.

Patients with AF had higher risks of arterial thromboembolic events (ischemic stroke and MI) compared to patients with VTE, despite having risk factors in common. The VTE cohort had higher risks of all-cause mortality and ECATE, particularly lower extremity events, compared to AF patients. The differential manifestations of thromboembolism sequelae and mortality between AF and VTE patients merit further investigation of an extended period or lifelong anticoagulation in VTE patients.

The data underlying this study is from the Taiwan's National Health Insurance Research Database (NHIRD), which has been transferred to the Health and Welfare Data Science Center (HWDC). Interested researchers can obtain the data through formal application to the HWDC, Department of Statistics, Ministry of Health and Welfare, Taiwan (http://dep.mohw.gov.tw/DOS/np-2497-113.html). Requests to access these datasets should be directed to (http://dep.mohw.gov.tw/DOS/np-2497-113.html).

The study was approved by the Institutional Review Board of Chang Gung Memorial Hospital: IRB number: 201900915B1. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

Y-SL, M-SL, GL, and M-CC: study concept and design. VW, Y-LC, and J-JC: acquisition of data. Y-SL, M-SL, and P-HC: analysis and interpretation of data. Y-SL, GL, and M-CC: manuscript draft. GL and M-CC: critical revision of the manuscript for important intellectual content. All authors reviewed the manuscript and completed final approval.

GL is a Consultant for Bayer/Janssen, BMS/Pfizer, Medtronic, Boehringer Ingelheim, Novartis, Verseon, and Daiichi-Sankyo. Speaker for Bayer, BMS/Pfizer, Medtronic, Boehringer Ingelheim, and Daiichi-Sankyo. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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