
==== Front
J Korean Med Sci
J Korean Med Sci
JKMS
Journal of Korean Medical Science
1011-8934
1598-6357
The Korean Academy of Medical Sciences

10.3346/jkms.2024.39.e252
Original Article
Immunology, Allergy & Rheumatology
Direct Oral Anticoagulants in Antiphospholipid Syndrome-Associated Venous Thromboembolism: Real World Evidence
https://orcid.org/0000-0001-9304-7219
Hwang Hun-Gyu 1
https://orcid.org/0000-0001-5743-6751
Lee Ju Hyun 2
https://orcid.org/0000-0002-8529-0232
Kim Sang-A 2
https://orcid.org/0000-0003-4221-6689
Kim Yang-Ki 3
https://orcid.org/0000-0003-2453-6689
Kim Myung-Shin 1
https://orcid.org/0000-0002-7829-397X
Hong Junshik 4
https://orcid.org/0000-0002-1252-5336
Yhim Ho-Young 5
https://orcid.org/0000-0002-0938-3007
Bang Soo-Mee 2
1 Respiratory Division, Department of Internal Medicine, Soonchunhyang University Gumi Hospital, Soonchunhyang University School of Medicine, Gumi, Korea.
2 Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
3 Respiratory Division, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Soonchunhyang University School of Medicine, Seoul, Korea.
4 Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
5 Department of Internal Medicine, Jeonbuk National University Medical School, Jeonju, Korea.
Address for Correspondence: Soo-Mee Bang, MD, PhD. Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82 Gumi-ro 173-beon-gil, Bundang-gu, Seongnam 13620, Republic of Korea. smbang7@snu.ac.kr
23 9 2024
31 7 2024
39 36 e25220 4 2024
15 7 2024
© 2024 The Korean Academy of Medical Sciences.
2024
The Korean Academy of Medical Sciences
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background

The efficacy and safety of direct oral anticoagulants (DOACs) versus warfarin in patients with antiphospholipid syndrome-associated venous thromboembolism (APS-VTE) remain uncertain. We aimed to evaluate efficacy and safety of DOACs in patients with APS-VTE.

Methods

Using the Korean Health Insurance Review and Assessment Service database, we retrospectively identified all APS-VTE cases. We examined the VTE recurrence, arterial thrombosis, death and bleeding in patients who received DOACs compared with warfarin for therapeutic anticoagulation.

Results

Of all the VTE cases (n = 84,916) detected between 2014 and 2018, patients with APS-VTE (n = 410) accounted for 0.48%. Most patients with APS-VTE (73%) were aged < 60 years. The recurrent VTE occurred in 8 of 209 patients (3.8%) who received DOACs and in 7 of 201 (3.5%) who received warfarin (relative risk [RR], 1.099; 95% confidence interval [CI], 0.41–2.98; P = 1.000). The arterial thrombosis (ATE) occurred in 8 of 209 patients (3.8%) who received DOAC and in 20 of 201 (10%) who received warfarin (RR, 0.385; 95% CI, 0.17–0.85; P = 0.024). The composite outcomes of VTE recurrence, ATE, or mortality were significantly lower in patients (9.1%) on DOAC than in those (16.3%) on warfarin (RR, 0.537; 95% CI, 0.32–0.91; P = 0.028). The bleeding outcome occurred in 7 of 209 (3.4%) patients in the DOACs group and 7 of 201 (3.5%) patients in the warfarin group (RR, 0.96; 95% CI, 0.34–2.69; P = 0.840).

Conclusion

In patients with APS-VTE, DOACs group showed comparable rates of recurrent VTE, bleeding, and deaths, but a significantly lower incidence of ATE and composite outcomes compared with the warfarin group in Korea.

Graphical Abstract

Antiphospholipid Antibody
Antiphospholipid Syndrome
Arterial Thrombosis
Direct Oral Anticoagulants
Venous Thromboembolism
Vitamin K Antagonist
Korean Society on Thrombosis and Hemostasis KSTH 2017-001 Soonchunhyang University https://doi.org/10.13039/501100002560 SURF-20160740
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pmcINTRODUCTION

Antiphospholipid syndrome (APS) is an acquired autoimmune disorder marked by the the occurrence of thromboembolic events or pregnancy complications in conjunction with the presence of antiphospholipid antibodies (aPL).12 The aPLs are found in 1–5% of the general population.34 According to Petri, the annual incidence of APS is approximately five cases per 100,000 individuals, with a prevalence of about 40–50 cases per 100,000 persons.35 A recent epidemiologic study in Korea showed that the new case of APS was 0.75 per 100,000 person-year and prevalence in 2016 was 6.19 per 100,000 people.6

The treatment of thrombosis in APS involves long-term administration of vitamin K antagonists (VKAs).1 International Society on Thrombosis and Haemostasis Scientific and Standardization Subcommittee in 2020 recommended VKA over direct oral anticoagulants (DOACs) for patients with APS.7 In the recent second update of the CHEST guidelines in 2021, the panelists agreed that DOACs should not be used in patients with APS, especially if they are triple positive for aPL.8 DOACs are commonly prescribed for preventing arterial thromboembolism (ATE) and for treating and preventing recurrence of venous thromboembolism (VTE). However, whether physicians can prescribe DOACs rather than VKAs, particularly warfarin, for the treatment of APS-VTE remains unclear. This is the first nationwide population-based epidemiological study to examine the efficacy and safety of DOACs versus warfarin in patients with APS-VTE between 2014 and 2018 in South Korea.

METHODS

Data acquisition

The Korean National Health Insurance (NHI) program, administered by the Ministry of Health and Welfare, is a mandatory system that provides approximately 97% of the Korean population.9 This government-operated organization develops precise systems for evaluating and assessing claims for the NHI. The Health Insurance and Review Assessment (HIRA) reviews the claims data for the remaining 3% of the population covered by the National Medical Aid Program. According to the NHI data, the registered population was 52,272,755 in 2016.910 The NHI covers nearly the entire population of Korea, allowing it to facilitate nationwide epidemiologic studies.

Previous studies have extensively detailed the HIRA database.111213 Access to the HIRA database was granted by the HIRA Data Access Committee, adhering to the HIRA’s Rules for Data Exploration and Utilization. All information was anonymized during processing. We utilized diagnostic codes from the Korean Classification of Disease, seventh edition (KCD-7), which is a modified version based on the International Classification of Diseases 10th edition (ICD-10).

Definition of antiphospholipid syndrome-associated venous thromboembolism

The index date was defined as the occurrence of VTE when both diagnostic (from the main to the fifth minor diagnostic code) and medication codes were identified concurrently in a patient. APS-VTE is defined as both the APS code (D686) and special calculation code (V193) detected twice with a 12-week interval within 180 days after the index VTE event in patients with VTE. We also analyzed data without differentiation between outpatients and inpatients. In this study, diagnostic codes for the term “VTE” encompass the following: 1) I80.2 or I80.3 (deep vein thrombosis [DVT] of lower extremity) and 2) I26 (pulmonary embolism [PE]), I26.0 (PE with mention of acute cor pulmonale), or I26.9 (PE without mention of acute cor pulmonale) (Supplementary Table 1). If a patient present with both DVT in the lower extremities and PE, they were classified as having PE. Throughoutthis study, the term “DVT” refers to “DVT of the lower extremity without PE,” “PE” encompasses “PE with or without DVT,” and “VTE” denotes the “combination of PE or DVT.”

Medication codes for unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), DOACs (rivaroxaban, dabigatran, apixaban, and edoxaban), and warfarin were utilized, alongside concurrent diagnostic codes, to identify cases of VTE (Supplementary Table 2). Treatment of VTE was categorized into four groups: 1) DOAC, DOAC with/without preceding parenteral anticoagulants (PAC); 2) PAC, UFH, and/or LMWH; 3) warfarin, warfarin with/without preceding PAC; and 4) mixed anticoagulants, indicating a change from one regimen to the other at least once during the six-month period.

Definition of clinical outcomes

Recurrent VTE was defined as the detection of a VTE code after at least 30 days of completing anticoagulant therapy for VTE, accompanied by a diagnostic imaging study performed between 4 weeks prior to and 2 weeks after re-registration of the VTE code. For APS-VTE patients with no history of stroke or myocardial infraction (MI) in the previous 12 months, ATE was defined as the occurrence of stroke or MI 31 days after the index VTE date.

The primary efficacy outcome was VTE recurrence. Secondary efficacy outcomes were newly developed ATE, death, and composite outcomes that incorporated VTE recurrence, development of new ATE, or mortality. Secondary safety outcomes were any bleeding, any or major gastrointestinal (GI) bleeding, or major central nervous system (CNS) bleeding (Supplementary Table 3).

Case identification

To identify inpatient and outpatient cases with both diagnostic and medication anticoagulant codes, we searched the HIRA database from July 1, 2013 to June 30, 2019. The date of VTE diagnosis was defined as initial day when both diagnostic and medication codes were concurrently assigned (Fig. 1).

Fig. 1 Overall flow of analysis.

VTE = venous thromboembolism, UFH = unfractionated heparin, LMWH = low-molecular weight heparin, AF = atrial fibrillation, DOAC = direct oral anticoagulant.

The number of index VTE cases was 95,205 (54,085 female, 56.8%), as previously described.14 We excluded 10,289 patients with bleeding at the time of initial diagnosis. Comorbidities were identified within 1 year prior to the diagnosis of VTE (Table 1). Of the 462 APS-VTE cases, 209 patients treated with DOACs were compared to 201 patients who received warfarin for the management of APS-VTE (Table 2).

Table 1 Characteristics of patients with APS-VTE versus non-APS-VTE

Variables	Total VTE	APS-VTE	Non-APS-VTE	
Values, No. (%)	84,916	462 (0.5)	84,454 (99.5)	
Age at diagnosis, median (IQR, yr)	70 (0.2–108)	44 (13–92)	70 (0.2–108)	
Female	48,486	254 (55.0)	48,232 (57.1)	
Age, yr				
	0–29	1,847	89 (19.3)	1,758 (2.1)	
	30–59	21,026	246 (53.3)	20,780 (24.6)	
	60–79	45,969	104 (22.5)	45,865 (54.3)	
	≥ 80	16,074	23 (5.0)	16,051 (19.0)	
Site				
	PE and/or DVT	44,982	292 (63.2)	44,690 (52.9)	
	DVT only	39,934	170 (36.8)	39,764 (47.1)	
Comorbiditya				
	Diabetes	28,178	80 (17.3)	28,098 (33.3)	
	Hypertension	50,700	158 (34.2)	50,542 (59.9)	
	ACS	16,304	52 (11.3)	16,252 (19.2)	
	Stroke	10,199	36 (7.8)	10,163 (12.0)	
Concomitant medication				
	Aspirin	16,005	116 (25.1)	15,889 (18.8)	
	Clopidogrel	4,693	12 (2.6)	4,681 (5.5)	
	Dual antiplatelets	4,641	17 (3.7)	4,624 (5.5)	
Anticoagulants				
	DOAC	31,687	209 (45.2)	31,478 (65.3)	
	Parenteral anticoagulants	9,663	38 (8.2)	9,625 (20.0)	
	Warfarin	6,818	201 (43.5)	6,617 (13.7)	
	Mixed anticoagulants	526	14 (3.0)	512 (1.1)	
Values are presented as number (%).

APS-VTE = antiphospholipid syndrome-related venous thromboembolism, PE = pulmonary embolism, DVT = deep vein thrombosis, ACS = acute coronary syndrome, DOAC = direct oral anticoagulant.

aComorbidities detected within 1 year before VTE diagnosis.

Table 2 Characteristics of patients with APS-VTE treated with DOACs versus warfarin

Variables	Total	DOACs	Warfarin	
Values, No. (%)	410	209 (51)	201 (49)	
Age at diagnosis, median (IQR, yr)	44 (13–92)	44 (13–92)	44 (13–88)	
Female	210 (51.2)	107 (51.2)	103 (51.2)	
Subgroup, age at VTE, yr				
	0–29	80 (19.5)	31 (14.8)	49 (24.4)	
	30–59	216 (52.7)	120 (57.4)	96 (47.8)	
	60–79	93 (22.7)	45 (21.5)	48 (23.9)	
	≥ 80	21 (5.1)	13 (6.2)	8 (4)	
Subgroup, site at VTE				
	PE and/or DVT	273 (66.6)	139 (66.5)	134 (66.7)	
	DVT	137 (33.4)	70 (33.5)	67 (33.3)	
DOACs				
	Rivaroxaban	161 (39.3)	161 (77.0)	-	
	Apixaban	23 (5.6)	23 (11.00)	-	
	Edoxaban	13 (3.2)	13 (6.2)	-	
	Dabigatran	12 (2.9)	12 (5.7)	-	
Values are presented as number (%).

APS-VTE = antiphospholipid-syndrome-related venous thromboembolism, non-APS-VTE = non-antiphospholipid-syndrome-related venous thromboembolism, DOAC = direct oral anticoagulant, DVT = deep vein thrombosis, IQR = interquartile range, PE = pulmonary embolism.

Statistical analysis

For baseline characteristics, continuous variables are reported as medians and ranges, while categorical variables are presented as numbers and frequencies (percentages). The t-test was employed to compare continuous variables, and the chi-square test was used to compare categorical variables. The Mann–Whitney U test was utilized to determine the median difference of two independent samples (Table 2). The rate of incidence and CI for recurrent VTE, ATE, death, and composite outcomes were estimated using the chi-square test, but Fisher’s exact test was used if more than 20% of the cells had expected cell counts of less than 5. Statistical significance was defined as P < 0.05. All statistical analyses were conducted using SAS Enterprise, version 6.1 (SAS Institute, Cary, NC, USA).

Ethics statement

All methods were conducted following appropriate guidelines and regulations. The data were de-identified, and the database is publicly unavailable. The requirement for informed consent was waived with approval from the HIRA committee. This study protocol was reviewed and approved by the Institutional Review Board of Seoul National University Bundang Hospital (X-2008/628-901).

RESULTS

Of the 84,916 VTE cases, only 0.5% were APS-VTEs (n = 462). Among the APS-VTE patients, 72.6% were aged < 60 years, whereas only 26.7% of the non-APS-VTE patients were aged < 60 years (Table 1 and Fig. 2). In this context, comorbidities, such as diabetes, hypertension, and acute coronary syndrome, were less common in patients with APS-VTE than in those without APS-VTE (P < 0.001). Among patients with APS-VTE in comparison to those without APS-VTE, a higher incidence of PE and/or DVT was observed (63.2% vs. 52.9%; P < 0.001). Conversely, the prevalence of DVT-only was lower in the APS-VTE group (36.8% vs. 47.1%; P < 0.001) (Table 1).

Fig. 2 The proportion of subgroups by age in APS-VTE versus non-APS-VTE. The numbers in bars represent the count of patients. The Y-axis in the graph is displayed as a cumulative percentage of the total (100%).

APS = antiphospholipid syndrome, VTE = venous thromboembolism.

Among APS-VTE patients, the use of DOACs for anticoagulation was significantly lower at 44.2%, compared to 65.3% in non-APS-VTE patients (P = 0.003). However, warfarin use was higher in the APS-VTE group than in the non-APS-VTE group (46.5% and 13.7%, respectively; P < 0.001). The prescription rate of PAC was lower in patients with APS-VTE than in those with non-APS-VTE (8.2% vs. 19.9%, P = 0.039) (Table 1). Of the 410 patients with APS-VTE, comprising 210 females (51.2%), 209 were treated with DOACs, while 201 received warfarin (n = 201) for anticoagulation (Table 2). When analyzing patients with APS-VTE by age group, those aged < 30 years had a significantly higher warfarin prescription rate (24.4%) than DOACs prescription rate (14.8%) (P = 0.020). Conversely, among patients with APS-VTE who were 30 years or older, there was no statistically significant difference in the proportion of warfarin and DOACs prescriptions. Of the four available DOAC options for the treatment of APS-VTE, rivaroxaban was the most frequently prescribed, accounting for 77% of the cases (Table 2).

Recurrent VTE occurred in 8 of 209 patients (3.8%) who received DOACs and in 7 of 201 (3.5%) who received warfarin (relative risk [RR], 1.099; 95% confidence interval [CI], 0.41–2.98; P = 1.000). The ATE (stroke and/or MI) occurred in 8 of 209 patients (3.8%) who received DOAC and in 20 of 201 (10%) who received warfarin (RR, 0.385; 95% CI, 0.17–0.85; P = 0.024) (Table 3). However, the incidence of MI was significantly lower in patients who received DOACs compared to those who received warfarin (2.4% vs 8.1%; RR, 0.283; 95% CI, 0.11–0.75; P = 0.012) (Table 3). When comparing APS-VTE patients who received DOACs vs. those who received warfarin, the incidences of stroke (1.4% vs 2.4%; RR, 0.577; 95% CI, 0.14–2.38; P = 0.679) and death (2.4% vs 4.3%; RR, 0.534; 95% CI, 0.18–1.57; P = 0.373) were comparable between the two groups. Patients who received DOACs had a significantly lower incidence of the composite outcome (9.1%) than those who received warfarin (16.3) (RR, 0.537; 95% CI, 0.32–0.91; P = 0.028) (Table 3).

Table 3 Recurrent VTE, newly developed arterial thrombosis, death, and composite outcomes in subgroups of patients with APS-VTE treated with DOACs versus warfarin

Variables	Total (N = 410)	DOACs (n = 209)	Warfarin (n = 201)	RR (95% CI)	P value	
VTE recurrence	15 (3.7)	8 (3.8)	7 (3.5)	1.1 (0.41–2.98)	0.940	
	Time to VTE recurrence, median (range, days)	492 (49–1147)	607 (116–1147)	403 (49–1145)			
	VTE recurrence in subgroup						
	Sex						
		Male	4/200 (2)	3/102 (2.9)	1/98 (1.0)	2.88 (0.3–27.24)	0.642	
		Female	11/210 (5.2)	5/107 (4.7)	6/103 (5.8)	0.80 (0.25–2.55)	0.948	
	Age at VTE, yr						
		0–29	3/80 (3.8)	1/31 (3.2)	2/49 (4.1)	0.79 (0.07–8.35)	0.684	
		30–59	4/216 (1.9)	4/120 (3.3)	0/96 (0)	-	-	
		60–79	6/93 (6.5)	3/45 (6.7)	3/48 (6.3)	1.07 (0.23–5.01)	0.733	
		≥ 80	2/21 (9.5)	0/13 (0)	2/8 (0)	-	-	
	Site at VTE						
		PE and/or DVT	12/273 (4.4)	7/139 (5.0)	5/134 (3.7)	1.35 (0.44–4.15)	0.818	
		DVT	3/137 (2.2)	1/70 (1.4)	2/67 (3.0)	0.48 (0.04–5.16)	0.969	
Arterial thrombosis	28 (6.8)	8 (3.8)	20 (10)	0.38 (0.17–0.85)	0.024	
	Time to arterial thrombosis, median (range, days)	357 (37–1852)	270.5 (39–666)	396 (37–1852)			
	Site at ATE						
		Stroke	8 (2.0)	3 (1.4)	5 (2.4)	0.58 (0.14–2.38)	0.680	
		Myocardial infarction	22 (5.4)	5 (2.4)	17 (8.1)	0.28 (0.11–0.75)	0.012	
Death	14 (3.4)	5 (2.4)	9 (4.3)	0.53 (0.18–1.57)	0.373	
Composite outcomea	52 (12,7)	19 (9.1)	34 (16.3)	0.54 (0.32–0.91)	0.027	
VTE = venous thromboembolism, APS = antiphospholipid syndrome, DOAC = direct oral anticoagulant, RR = relative risk, CI = confidence interval, ATE = arterial thromboembolism.

aThe composite outcomes included recurrent VTE, ATE, or death.

The incidence of any or major bleeding in patients with APS-VTE was comparable to that of those with non-APS-VTE (3% vs. 5%; RR, 0.61; 95% CI, 0.36–1.02; P = 0.072). Among patients with APS-VTE, the safety outcome, which included any bleeding, any GI bleeding, major GI bleeding, or CNS bleeding, occurred in 7 of 209 patients (3.4%) who received DOAC and in 7 of 201 patients (3.5%) who received warfarin (RR, 0.96; 95% CI, 0.34–2.69; P = 0.840) (Table 4). The incidence of bleeding in patients who received DOACs was comparable to that in patients who received warfarin in each subgroup categorized according to age, sex, and site (Table 4).

Table 4 Safety outcomes in patients with APS-VTE treated with DOACs versus warfarin

Variables	Total (N = 410)	DOACs (n = 209)	Warfarin (n = 201)	RR (95% CI)	P value	
Time to bleeding, days, median (IQR)	150 (31–337)	133 (31–235)	211 (36–337)			
Bleeding	14/410 (3.4)	7/209 (3.4)	7/201 (3.5)	0.96 (0.34–2.69)	0.840	
	Any GI bleeding	13/410	7/209	6/201	1.12 (0.38–3.28)	0.940	
	Major GI bleeding	2/410	1/209	1/201			
	Any CNS bleeding	1/410	0/209	1/201	-	-	
	Major CNS bleeding	0/410	0/209	0/201	-	-	
Sex						
	Male	7/200 (3.5)	4/102 (3.9)	3/98 (3.1)	1.28 (0.29–5.58)	0.740	
	Female	7/210 (3.3)	3/107 (2.8)	4/103 (3.9)	0.72 (0.17–3.15)	0.660	
Age at VTE, yr						
	0–29	0/80 (0)	0/31 (0)	0/49 (0)	-	-	
	30–59	11/216 (5.1)	4/120 (3.3)	7/96 (7.3)	0.46 (0.14–1.52)	0.190	
	60–79	1/93 (1.1)	1/45 (2.2)	0/48 (0)	-	-	
	≥ 80	2/21 (9.5)	2/13 (15.4)	0/8 (0)	-	-	
Site at VTE						
	PE and/or DVT	6/273 (2.2)	4/139 (2.9)	2/134 (1.5)	1.93 (0.36–10.35)	0.440	
	DVT	8/137 (5.8)	3/70 (4.3)	5/67 (7.5)	0.57 (0.14–2.31)	0.430	
APS = antiphospholipid syndrome, VTE = venous thromboembolism, DOAC = direct oral anticoagulant, RR = relative risk, CI = confidence interval, IQR = interquartile range, GI = gastrointestinal, CNS = central nervous system, PE = pulmonary embolism, DVT = deep vein thrombosis.

DISCUSSION

In this nationwide epidemiologic study, we aimed to evaluate the efficacy and safety of DOACs compared with those of warfarin in the management of APS-VTE in clinical practice. In our study, patients who used DOACs had a significantly lower incidence of ATE and composite outcomes (ATE, recurrent VTE, and death) than those who used warfarin. Our research reaffirmed that, in patients with APS-VTE, DOACs showed similar efficacy and safety outcomes compared to warfarin in terms of recurrent VTE and bleeding incidence, as shown in previous studies, including the TRAPS study by Pengo et al.15

In our study, the lower occurrence of ATE contrasts with findings from previous studies. For instance, the TRAPS study indicated a higher incidence of ATE in the rivaroxaban group compared with the warfarin group. Additionally the meta-analysis incorporating three other open-label randomized controlled trials with 472 patients, revealed that DOACs compared to VKAs (with a mean time-in-therapeutic-range [TTR] of 60%) were associated with increased odds of developing arterial thrombotic events (odds ratio, 5.43; 95% CI, 1.87–15.75; P < 0.001; I2 = 0%).16

We assumed that the potential factors contributing to the lower ATE outcomes observed in our study could be associated with aPL positivity rates, particularly differing from those reported in the TRAPS study.1617 In the TRAPS study, all participants (100%) exhibited triple positivity of aPL. On the contrary, in the RAPS trial, 72% of participants exhibited single or dual aPL distribution as part of their baseline characteristics.18 The RAPS study excluded patients with ATE case. In our study, we also excluded patients who experienced ATE during initial assessment. The RAPS study did not show any differences in thrombosis or bleeding between DOACs group and warfarin group.

Regarding the proportion of single, dual, or triple positivity for aPL, the first concern, it should be noted that, to the best of our knowledge, there have been no reported laboratory results showing each positivity rates of three kinds for aPL in the general population and APS-VTE patients in South Korea.

To overcome the first limitation, we can infer positivity rates from ATE outcomes in a reverse manner. In an open-label, randomized, non-inferiority trial by Ordi-Ros et al.,17 the proportions of aPL triple positivity, LA alone (single positivity), and dual positivity were 60–61%, 32–39%, and 8%, respectively. For patients in the single/dual-positivity group, the incidence of thrombosis was comparable (2.7% vs. 2.6%) between those who received rivaroxaban and those who received VKA. Hence, we can cautiously estimate that the percentage of triple positivity among patients with APS-VTE in our study was at least less than 60%.

Additionally, other cohort studies could be used to estimate the approximate percentage of aPL positivity in patients with APS-VTE in our study. In a nationwide prospective cohort study conducted by Mustonen et al.19 in Finland between 1971 and 2009, 119 asymptomatic aPL carriers were aged 3–41 years. Among these carriers, 6% had triple positivity, 24% had double positivity (either LA + aCL or anti-β2 glycoprotein I antibody [aβ2GPI]), 56% had single LA, 8% had single aCL, and 5% had single aβ2GPI.19 Also, Yelnik et al.4 examined the long-term rate and risk factors linked to the first thrombosis in 98 aPL carriers, in which the proportion of triple positivity at the time of detection was 21.3%.

By combining the results of the aforementioned clinical research and cohort studies4151719 we may assume that the percentage of individuals with triple positivity for aPL may fall between 6% and 21.3%. Given this assumption, it is reasonable to expect that DOACs may be more effective in reducing ATE in APS-VTE patients than VKA, particularly if the majority (79% or more) of patients have single or dual positivity for aPL.

We considered that the second factor accounting for the decreased incidence of ATE in the DOACs group compared to the VKA group in our study might be associated with TTR. In real-world practice in Korea, the TTR of the international normalized ratio (INR) for the warfarin treatment is lower than the TTR observed in clinical trials. According to van Walraven et al.,20 TTR was 66.4% (95% CI, 59.4–73.3) in randomized clinical trials and 56.7% (95% CI, 51.5–62.0) in community settings. Samsa and colleagues reviewed the medical records of two communities and reported a TTR of 43.7%.21 However, in our study, it was not feasible to assess TTR in the warfarin group of patients with APS-VTE because the necessary information for their calculation were unavailable in the HIRA database. The use of VKAs as anticoagulants presents various limitations, including the instability of the INR resulting from medication and dietary interactions observed in real-world practice.22 Based on these clinical disadvantages and the aforementioned studies,202122 we can estimate that the TTR in actual clinical practice in Korea would be lower than 43.7%. Hence, the low TTR expected in our study may explain the higher incidence of ATE in the warfarin group than in the DOACs group.

In this regard, we can anticipate that diminishing the ATE in patients with APS-VTE may be achievable through hi-dose anticoagulation with warfarin, meaning increased intensity of INR. However, it remains uncertain whether high-dose anticoagulation therapy is necessary for patient with prior ATE. At this time, we should wait for gaining further insights in the following research, where Cohen et al. is currently conducting the RIvaroxaban for Stroke Patients With AntiPhospholipid Syndrome (RISAPS) study (ClinicalTrials.gov Identifier: NCT03684564). RISAPS study will compare higher intensity rivaroxaban (15 mg bid) versus higher intensity warfarin (INR 3.5) for 24 months in APS patients requiring higher intensity anticoagulation after experiencing a stroke.

In age subgroup of our study, there was no disparity in ATE outcomes between warfarin group and DOAC group. APS was well known to be more common in young to middle aged women.34 As with previous APS-VTE-related studies, our study revealed that the majority of APS-VTE patients (73%) were under the age of 60 years, whereas a recent epidemiologic study on the general population in Korea reported that the majority of VTE patients (73%) were over 60 years old.14 In contrast to other studies, our study did not show a female predominance among APS-VTE patients.

This study has several strengths. First, this is a nationwide epidemiologic study conducted over four-year period. Second, our results indicate that the use of DOACs may lower the occurrence of ATE in APS-VTE patients compared to VKA. Third, our study confirmed once again that patients with APS-VTE, undergoing treatment with DOACs, exhibits a recurrence risk of VTE comparable to those treated with VKAs. This aligns with the results observed in various other studies. Fourth, in our study, we incorporated imaging codes to improve the precision of ATE and recurrent VTE diagnoses, whereas previous studies relied only on a combination of diagnostic and drug codes.1423

However, this study has several limitations. First, this study lacked laboratory information essential for determining the proportions of single, dual, and triple aPL positivity within the study population. Second, it was imperative to carry out propensity score matching as a crucial measure to guarantee comparable populations for the comparison. Unfortunately, this analysis could not be implemented. Third, if concomitant medication was detected one or more times during study period, it was counted. However, regrettably, we did not specify and analyze the time frame for medication usage which could be pertinent for data interpretation in this study. Fourth, given that this study relied on retrospective analysis of insurance claims data from Korea, there are limitations in generalizing and applying the findings to other populations.

In conclusion, among individuals with APS-VTE, the DOACs group exhibited comparable rates of recurrent VTE, bleeding, and death. However, there were significantly fewer cases of ATE and composite outcomes in DOACs group compared to the warfarin group. Selecting DOACs for patients with APS-VTE might be available option in real-world practice where the TTR falls below the 43.7% range. Most patients with APS-VTE (73%) were younger than 60 years, whereas most patients without APS-VTE (73%) were older than 60 years. A prospective study is required to assess the efficacy and safety of DOACs versus warfarin in APS-VTE patients with single or dual aPL positivity in the near future.

ACKNOWLEDGMENTS

We would like to thank Editage (www.editage.co.kr) for the English language editing.

SUPPLEMENTARY MATERIALS

Supplementary Table 1

Diagnostic codes and definition

Supplementary Table 2

Drug codes for anticoagulants

Supplementary Table 3

Codes for bleeding outcomes

Funding: This study was supported by a grant (KSTH 2017-001) from the Korean Society on Thrombosis and Hemostasis. In addition, the study was supported by the Soonchunhyang University Research Fund (grant number: SURF-20160740).

Disclosure: The authors have no potential conflicts of interest to disclose.

Declaration of Generative AI and AI-Assisted Technologies in the Writing Process: Authors did not use of generative AI and AI-assisted technologies in the writing process.

Author Contributions: Conceptualization: Bang SM, Hwang HG.

Data curation: Bang SM, Lee JH, Hwang HG.

Formal analysis: Lee JH.

Methodology: Bang SM.

Software: Lee JH.

Writing - original draft: Hwang HG.

Writing - review & editing: Hwang HG, Bang SM.
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