Received: 4 January 2023

- Revised: 28 February 2023

Accepted: 24 March 2023

https://doi.org/10.1016/j.jtha.2023.03.036

ORIGINAL ARTICLE

Long-term outcome of chronic thromboembolic pulmonary
hypertension using direct oral anticoagulants and warfarin: aJapanese prospective cohort study
Kazuya Hosokawa1 | Kohtaro Abe1 | Kouta Funakoshi2 | Yuichi Tamura3 |Naoki Nakashima4 | Koji Todaka2 | Yu Taniguchi5 | Takumi Inami6 |Shiro Adachi7 | Ichizo Tsujino8 | Jun Yamashita9 | Shun Minatsuki10 |Nobutaka Ikeda11 | Hiroto Shimokawahara12 | Takashi Kawakami13 | Takeshi Ogo14 |Masaru Hatano10 | Hitoshi Ogino15 | Yoshihiro Fukumoto16 | Nobuhiro Tanabe17 |Hiromi Matsubara12 | Keiichi Fukuda18 | Koichiro Tatsumi19 | Hiroyuki Tsutsui1
1

Faculty of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

2

Center for Clinical and Translational Research, Kyushu University Hospital, Fukuoka, Japan

3

Pulmonary Hypertension Center, International University of Health and Welfare Mita Hospital, Tokyo, Japan

4

Medical Information Center, Kyushu University Hospital, Fukuoka, Japan

5

Division of Cardiovascular Medicine, Kobe University Hospital, Kobe, Japan

6

Department of Cardiovascular Medicine, Kyorin University School of Medicine, Tokyo, Japan

7

Department of Cardiology, Nagoya University Hospital, Nagoya, Japan

8

Division of Respiratory and Cardiovascular Innovative Research, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan

9

Department of Cardiology, Tokyo Medical University, Tokyo, Japan10

Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

11

Division of Cardiovascular Medicine, Toho University, Ohashi Medical Center, Tokyo, Japan

12

Department of Cardiology, National Hospital Organization Okayama Medical Center, Okayama, Japan

13

Department of Cardiology, Toranomon Hospital, Tokyo, Japan

14

Division of Pulmonary Circulation, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan

15

Department of Cardiovascular Surgery, Tokyo Medical University, Tokyo, Japan

16

Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan

17

Pulmonary Hypertension Center, Chibaken Saiseikai Narashino Hospital, Narashino, Japan18

Department of Cardiology, Keio University School of Medicine, Tokyo, Japan

19

Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan

Correspondence
Kazuya Hosokawa, Department of
Cardiovascular Medicine, Kyushu
University Hospital, 3-1-1 Maidashi,
Higashi-Ku, Fukuoka, 812-8582, Japan.
Email: hosokawa.kazuya.712@m.kyushu-u.
ac.jp

Abstract
Background: Chronic thromboembolic pulmonary hypertension (CTEPH) requires
lifelong anticoagulation. Long-term outcomes of CTEPH under current anticoagulants
are unclear.

Manuscript handled by: Jean Connors
Final decision: Jean Connors, 24 March 2023
Kazuya Hosokawa and Kohtaro Abe contributed equally to this work.

© 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.
J Thromb Haemost. 2023;▪:1–12

jthjournal.org

-

1

2

-

Funding information
Japan Agency for Medical Research andDevelopment; Grant Numbers:
JP20ek0109371, JP19lk0201102,
JP22lk0201125, JP19lk1601003.

HOSOKAWA ET AL.

Objectives: The CTEPH AC registry is a prospective, nationwide cohort study
comparing the safety and effectiveness of direct oral anticoagulants (DOACs) andwarfarin for CTEPH.
Patients/Methods: Patients with CTEPH, both tre atment-naïve and on treatment,
were eligible for the registry. Inclusion criteria were patients aged ≥20 years and those
who were diagnosed with CTEPH according to standard guidelines. Exclusion criteria
were not speciﬁed. The primary efﬁcacy outcome was a composite morbidity, andmortality outcome comprised all-cause death, rescue reperfusion therapy, initiation ofparenteral pulmonary vasodilators, and worsened 6-minute walk distance and WHO
functional class. The safety outcome was clinically relevant bleeding, including major
bleeding.
Results: Nine hundred twenty-seven patients on oral anticoagulants at baseline wereanalyzed: 481 (52%) used DOACs and 446 (48%) used warfarin. The 1-, 2-, and 3-year
rates of composite morbidity and mortality outcome were comparable between the
DOAC and warfarin groups (2.6%, 3.1%, and 4.2% vs 3.0%, 4.8%, and 5.9%, respectively;
P = .52). The 1-, 2-, and 3-year rates of clinically relevant bleeding were signiﬁcantly
lower in DOACs than in the warfarin group (0.8%, 2.4%, and 2.4% vs 2.5%, 4.8%, and
6.4%, respectively; P = 0.036). Multivariable Cox proportional-hazards regression
models revealed lower risk of clinically relevant bleeding in the DOAC group than thewarfarin group (hazard ratio: 0.35; 95% CI: 0.13-0.91; P = .032).
Conclusion: This registry demonstrated that under current standard of care, morbidity
and mortality events were effectively prevented regardless of anticoagulants, while
the clinically relevant bleeding rate was lower when using DOACs compared withwarfarin.
KEYWORDS

anticoagulants, hypertension, pulmonary, observational study, registries, venous
thromboembolism

1 | INTRODUCTION
Essentials
Chronic thromboembolic pulmonary hypertension (CTEPH) is acomplication of preceding pulmonary thromboembolism and develops
in approximately 3% to 4% of patients with acute pulmonary thromboembolism [1,2]. The annual incidence of CTEPH per 100 000 people
is reported to be 5.1 in the US, 3.3 to 5.0 in Europe, and 1.9 in Japan[3], and the number of patients with CTEPH has been increasing
worldwide. Although speciﬁc treatments such as pulmonary endarterectomy, balloon pulmonary angioplasty, and pulmonary vasodilators have improved the hemodynamics and long-term survival of thesepatients [4–8], lifelong anticoagulation remains essential. Vitamin K
antagonists (VKAs) are the ﬁrst-line anticoagulants used in patientswith CTEPH because of the abundant data and historical experience• The efﬁcacy and safety of direct oral anticoagulants(DOACs) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) remain unclear.
• This is the ﬁrst report from the Japanese prospective
nationwide CTEPH registry, aiming to assess the safety
and effectiveness of DOACs in patients with CTEPH.
• Half of the patients with CTEPH in Japan use DOACs.
• DOACs are as effective as warfarin in preventing
morbidity and mortality events, with a lower risk ofclinically relevant bleeding (hazard ratio: 0.35; 95% CI:
0.13, 0.91; P = .032) under current clinical practice.

supporting the prevention of recurrent pulmonary embolism andworsening of CTEPH [9,10]. Four direct oral anticoagulants (DOACs)
comprising dabigatran, rivaroxaban, apixaban, and edoxaban are

The safety and efﬁcacy of the 4 DOACs in nonvalvular atrial ﬁbrilla-currently available for the treatment of venous thromboembolism.

tion and venous thromboembolism have been established in large

- 3

HOSOKAWA ET AL.

clinical trials [11–21]. Notably, these trials provide evidence thattreatment-naïve patients and patients on treatment. No speciﬁc

DOACs have a lower risk of major bleeding than VKAs. Thus, major

exclusion criteria were deﬁned. The registry was elaborated to collect

guidelines have currently recommended DOACs as the treatment ofa wide range of cases and information on real-world clinical practice ofchoice for venous thromboembolism, rather than VKAs [22,23].

CTEPH, and to be a national database of CTEPH in Japan. Thus, theDespite a lack of deﬁnite evidence supported by clinical trials, DOACs

number of cases registered during the study period determined theare increasingly being used for anticoagulation in patients withsample size.

established CTEPH. Two CTEPH registries—the Turkish national
database (sample size: n = 493) and the UK multicentre registry(sample size: n = 1000) reported use of DOACs in 21% and 36% of

2.3 | Baseline characteristics and outcomespatients with CTEPH, respectively [24,25]. It is imperative to clarify
whether DOACs are as safe and effective in patients with CTEPH as in

After obtaining written informed consent, the investigators docu-

patients with venous thromboembolism.

mented baseline characteristics. As baseline data, the most recent

The CTEPH AntiCoagulants registry (CTEPH AC registry) is adata available up to 12 months prior to registration were collected.

nationwide registry started on August 20, 2018, in Japan. The current

Follow-up data were electronically recorded by the investigators inreport presents the ﬁrst results, as prespeciﬁed in the protocol, of thisNovember of each year during the observation period. When theprospective nationwide cohort study aimed to compare the long-term

prespeciﬁed efﬁcacy (primary and secondary) and safety outcomessafety and efﬁcacy between DOACs and warfarin for the treatment of

occurred, the investigators input additional follow-up data to the

CTEPH under current clinical practice.

registry. No independent clinical endpoint adjudication committee wasorganized. The investigators at each site reported clinical outcomesaccording to the prespeciﬁed deﬁnitions.

2 | METHODS

The primary efﬁcacy outcome was the ﬁrst occurrence ofmorbidity and mortality events, a composite endpoint composed of

2.1 | Study design and setting

the following:This prospective, observational, cohort study was conducted from

1. All-cause death,August 2018 to December 2021, in compliance with the principles of

2. Lung transplantation,

the World Medical Association Declaration of Helsinki regarding in-

3. CTEPH worsening–related rescue pulmonary endarterectomy,

vestigations involving human subjects. The institutional review board

rescue balloon pulmonary angioplasty, or start of parenteral pul-of each participating institution approved this study. The study was
registered at UMIN Clinical Trials Registry, which is an open accessdatabase (UMIN000033784). Thirty-three Japanese institutions

monary vasodilator, and/or
4. Reduction (≥15%) in 6-minute walk distance accompanied byworsening of WHO functional class.

nationwide participated in the study. The investigators obtained
written informed consent from all registered subjects before participation according to the Patient Consent Form. Study oversight

The secondary efﬁcacy outcome was the ﬁrst occurrence ofsymptomatic venous thromboembolism.

including source data veriﬁcation was conducted by an independent

The safety outcome was the ﬁrst occurrence of clinically relevant

clinical research organization (Soiken Corp) during the study. A full list

bleeding, a composite endpoint composed of major bleeding and/orof the institutions, personnel including the investigators, and theclinically relevant nonmajor bleeding. Major bleeding and clinically

numbers and distribution of registered patients are provided in therelevant nonmajor bleeding were determined according to the Inter-

Supplementary material.

national Society on Thrombosis and Haemostasis (ISTH) deﬁnitions in
nonsurgical patients [27,28].

2.2 | Study population
2.4 | Statistical analysis
The inclusion and exclusion criteria are provided in Supplementary
Table S1. The inclusion criteria were patients aged ≥20 years who

The full analysis set (FAS) was deﬁned as patients taking oral anti-

were diagnosed with CTEPH. The diagnosis of CTEPH was based oncoagulants. Demographics and CTEPH-related characteristics are

imaging studies (ventilation-perfusion scan and CT pulmonary angio-

presented as mean and standard deviation or percentage unlessgram) and hemodynamic criteria (mean pulmonary arterial pressure ≥otherwise noted. Morbidity and mortality events, symptomatic venous

25 mm Hg and pulmonary artery wedge pressure ≤ 15 mm Hg at rest)

thromboembolism, and clinically relevant bleeding were aggregated to[26]. Patients who had been treated with pulmonary endarterectomy,

identify the time from registration to the ﬁrst occurrence of theseballoon pulmonary angioplasty, and/or pulmonary vasodilators were

events. The FAS was used for analyses of the primary, secondary, and/eligible, even though their mean pulmonary arterial pressure wasor safety outcomes. These patients, irrespective of the length oflower than 25 mm Hg at registration. Thus, this registry included both

follow-up, were grouped according to the type of anticoagulants used

4-

HOSOKAWA ET AL.

T A B L E Demographic and baseline clinical data of patients with chronic thromboembolic pulmonary hypertension on oral anticoagulation
therapy at baseline, classiﬁed into the DOAC and warfarin groups.
DOACs (n = 481)

Warfarin (n = 446)

P value

Age, years

67 ± 1367 ± 13.74

Male, no. (%)

132 (27.4)

138 (30.9).25

Time from diagnosis to registration,
median days (IQR)

352 (30-1123)

1113 (219-2449)<.001

WHO functional class, I/II/III/IV (no. [%])

80 (16.6)/238 (49.5)/156(32.4)/7 (1.5)

77 (17.3)/253 (56.7)/110(24.7)/6 (1.4).06

6-min walk distance, m

386 ± 122395 ± 127

.32

Mean PAP, mm Hg

31.4 ± 11.7

28.8 ± 11.2<.001

487 ± 339

426 ± 331.006

2.7 ± 0.7

2.7 ± 0.7

.93

Demographics

Disease severities

PVR, dyn⋅s⋅cm−5

Cardiac index, L/min/m

2

Mixed venous oxygen saturation, no. (%)

66.7 ± 7.5

67.8 ± 7.7.05

BNP, pg/mL

88 ± 154

115 ± 273

.08

Active cancer/history of cancer, no. (%)

26 (5.4)

28 (6.3).58

Thyroid disease or hormone replacement
therapy, no. (%)

21 (4.4)

20 (4.5)

1.00

Intravenous device, no. (%)

18 (4.0)

19 (4.0)

1.00

COPD/ILD, no. (%)

20 (4.2)

17 (3.8).87

History of acute VTE, no. (%)

191 (39.7)

146 (32.7).03

Hemiplegia/paraplegia, no. (%)

5 (1.0)2 (0.5).45

Use of antipsychotic, no. (%)

56 (11.6)

34 (7.6).04Inﬂammatory bowel disease, no. (%)

1 (0.2)3 (0.7).36

Comorbid ovarian/uterine disease, no. (%)

54 (11.2)

55 (12.3).61

28 (5.8)

48 (10.8).008

2 (0.5)8 (2.2).04

Comorbidities/past medical histories

Hypercoagulable disorder, no. (%)

a

Chronic kidney disease (eGFR ≤ 30 mL/min), no. (%)
Use of antiplatelet agent, NSAIDs, no. (%)

5 (1.0)11 (2.5).13

History of major bleeding, no. (%)

8 (1.7)7 (1.6)

1.00

Pulmonary endarterectomy, no. (%)

36 (7.5)

74 (17.0)<.001

Balloon pulmonary angioplasty, no. (%)

252 (52.4)

269 (60.3).02

No reperfusion treatment, no. (%)

207 (43.0)

139 (31.2)<.001

History of CTEPH-speciﬁc treatment

Anticoagulants
Dabigatran, no. (%)

6 (1.3)

Rivaroxaban, no. (%)

164 (34.1)

Apixaban, no. (%)

154 (32.0)

Edoxaban, no. (%)
Prothrombin time-INR 2.0-3.0, no. (%)

157 (32.6)b

187 (42.8)(Continues)

- 5

HOSOKAWA ET AL.

TABLE(Continued)
DOACs (n = 481)

Warfarin (n = 446)

P value

Any pulmonary vasodilators, no. (%)

261 (54.3)

248 (55.6).69

PDE5 inhibitors/sGC stimulators, no. (%)

244 (50.7)

222 (49.8).79

Prostacyclin analog, PGI2 receptor agonist, no. (%)

36 (7.5)

50 (11.2).05

Endothelin receptor antagonist, no. (%)

39 (8.1)

45 (10.1).30

Pulmonary vasodilators

BNP, brain natriuretic peptide; COPD/ILD, chronic obstructive pulmonary disease/interstitial lung disease; DOAC, direct oral anticoagulant; eGFR,
estimated glomerular ﬁltration rate; INR, international normalized ratio; IQR, interquartile range; NSAIDs, nonsteroidal anti-inﬂammatory drug; PAP,
pulmonary artery pressure; PDE5, phosphodiesterase 5; PGI2, prostaglandin I2; PVR, pulmonary vascular resistance; sGC, soluble guanylate cyclase; VTE,
venous thromboembolism; WHO, World Health Organization.
a
Details of hypercoagulable disorders are shown in Supplementary Table S5.
b
The distribution of prothrombin time-INR is shown in Supplementary Figure S1.

at the time of registration: DOAC and warfarin (VKA currently used inestimates for the primary and safety outcomes, as for the FAS. A P

Japan) groups. Kaplan-Meier estimates were used to estimate thevalue of < .05 is considered signiﬁcant. Missing data imputation was

cumulative event rate. Separate univariable and multivariable Cox

not performed. Analyses were performed with JMP software, version

proportional-hazards regression models that included all available

16 (SAS Institute Inc).

data of the FAS were used to estimate the overall risks of morbidity
and mortality events, symptomatic venous thromboembolism, andclinically relevant bleeding for selected covariates. As a sensitivity

3 | RESULTS

analysis, for a given anticoagulant, we used propensity-score models
that were adjusted for the following variables: age; sex; time from

3.1 | Demographic and patient characteristics

diagnosis to registration; WHO functional class; 6-minute walk distance; pulmonary vascular resistance; brain natriuretic peptide; his-

The baseline characteristics of the cohort are summarized in Table. A

toryvenoustotal of 956 patients were registered. After excluding 29 patients (nothromboembolism, chronic kidney disease, and major bleeding; pre-informed consent form: n = 5; no oral anticoagulation: n = 24), the FAS

vious reperfusion treatment; and use of pulmonary vasodilators.

consisted of 927 patients who took DOACs or warfarin (Figure 1).

Propensity-score matching was implemented using the 1:1 nearest-

Approximately one-half of patients with CTEPH on anticoagulants atneighbor strategy. Our goal was to rule out a clinically meaningfulbaseline were using DOACs: DOACs were used by 481 patients (52%),ofcancer,hypercoagulable

disorder,acutedifference in risk, which we deﬁned a priori as an absolute stan-

and warfarin by 446 patients (48%). The age and sex ratio weredardized difference of at least 0.25 points. After generating thecomparable between the 2 groups. The median observation period

matched cohorts for each anticoagulant, we computed Kaplan-Meierwas 825 (IQR; 499-886) days in the DOAC group and 838 (IQR;

FIGURE 1

Patient disposition. CTEPH, chronic thromboembolic pulmonary hypertension; DOACs, direct oral anticoagulants.

6-

HOSOKAWA ET AL.

F I G U R E 2 Kaplan-Meier analyses for the primary, secondary, and safety outcomes. Red indicates the DOAC group, and blue indicates thewarfarin group. The table in each graph shows the numbers at risk. (A) Primary efﬁcacy outcome: morbidity and mortality events deﬁned as a

- 7

HOSOKAWA ET AL.

F I G U R E 3 Independent risks of morbidity and mortality events and clinically relevant bleeding by multivariable Cox proportional-hazards
regression models. Model 1: adjusted for age, sex, and pulmonary vascular resistance. Model 2: adjusted for age, sex, pulmonary vascular
resistance, and time from diagnosis to registration. Model 3: adjusted for pulmonary vascular resistance, time from diagnosis to registration,
history of acute venous thromboembolism, history of reperfusion treatment, and use of pulmonary vasodilators. Morbidity and mortality
events are a composite endpoint comprising all-cause death; lung transplantation; CTEPH worsening–related rescue pulmonary
endarterectomy, rescue balloon pulmonary angioplasty, or start of parenteral pulmonary vasodilators; and/or worsening of CTEPH deﬁned as≥15% reduction in 6-minute walk distance accompanied by worsening of the WHO functional class. Symbols and bars indicate hazard ratios
and 95% conﬁdence intervals, respectively. BNP, brain natriuretic peptide; CTEPH, chronic thromboembolic pulmonary hypertension; DOACs,
direct oral anticoagulants; eGFR, estimated glomerular ﬁltration rate; PAP, pulmonary artery pressure; WHO, World Health Organization.

755-893) days in the warfarin group (P = .003). The time from diag-487 ± 339 dyn⋅s⋅cm−5 vs 426 ± 331 dyn⋅s⋅cm−5, respectively, P =nosis to registration (i.e., duration of disease) was signiﬁcantly longer.006).

in the warfarin group [352 (IQR; 30-1123) days vs 1113 (IQR; 2192449) days, P < .001]. The proportion of patients with a history ofacute venous thromboembolism was signiﬁcantly higher in the DOAC
group (39.7% vs 32.7%; P = .03) than in the warfarin group. The

3.2 | Primary outcome: morbidity and mortality
eventsproportion of patients with no history of reperfusion treatment (pulmonary endarterectomy or balloon pulmonary angioplasty) at baseline

The cumulative rates of morbidity and mortality events were com-

was signiﬁcantly higher in the DOAC group (43.0% vs 31.2%; P <parable between the DOAC group and the warfarin group [1-, 2-, and.001). The proportion of patients who used pulmonary vasodilators

3-year event rates (95% CI): 2.6% (1.4%-4.8%), 3⋅1% (1.7%-5.5%), andwas comparable between the DOAC group and the warfarin group

4.2% (2.1%-8.3%) in the DOACs group vs 3.0% (1.7%-5.3%), 4.8%

(54.3% vs 55.6%, P = .69). The mean pulmonary artery pressure and(2.8%-8.0%), and 5.9% (3.4%-10.1%) in the warfarin group, respec-

pulmonary vascular resistance were signiﬁcantly higher in the DOAC

tively; P = .52] (Figure 2A). The cumulative rates of all-cause death,group (mean pulmonary artery pressure: 31.4 ± 11.7 mm Hg vs 28.8 ±rescue reperfusion therapy and/or parenteral vasodilator use, and11.2 mm Hg, respectively, P < .001; pulmonary vascular resistance,

worsening of CTEPH were also comparable between the DOAC andcomposite endpoint of all-cause death; lung transplantation; CTEPH worsening–related rescue pulmonary endarterectomy, rescue balloon
pulmonary angioplasty, or start of parenteral pulmonary vasodilators; and/or worsening of CTEPH. Worsening of CTEPH is deﬁned as ≥15%
reduction in 6-minute walk distance accompanied by worsening of WHO functional class. No lung transplantation was reported. (B) Secondary
efﬁcacy outcome: symptomatic venous thromboembolism. (C) Safety outcome: clinically relevant bleeding comprising major bleeding and/or
clinically relevant nonmajor bleeding. The deﬁnitions of major bleeding and clinically relevant nonmajor bleeding are in accord with the ISTH
deﬁnitions [27,28]. BPA, balloon pulmonary angioplasty; CTEPH, chronic thromboembolic pulmonary hypertension; DOACs, direct oral
anticoagulants; PEA, pulmonary endarterectomy.

8-

HOSOKAWA ET AL.

warfarin groups (all P > .05). There was no case of lung trans-

acute venous thromboembolism, history of reperfusion treatment, andplantation. Parenteral vasodilator was started on day 1 after regis-

use of pulmonary vasodilators; Figure 3). The choice of warfarin or

tration in only 1 patient in the warfarin group.

DOACs was a signiﬁcant risk factor of clinically signiﬁcant bleeding,but not of morbidity and mortality events in patients with CTEPH.

3.3 | Secondary outcomes: symptomatic venous
thromboembolism

3.6 | Sensitivity analysis: Kaplan-Mayer analysis ofpropensity-score–matched patients

Four patients developed symptomatic venous thromboembolism. The
cumulative rate of symptomatic venous thromboembolism was similar

Propensity-score matching for 14 covariates measured in this study

between the DOAC and warfarin groups (P = .98; Figure 2B). Two

generated a matched DOAC cohort (n = 203) and warfarin cohort (n =patients who developed symptomatic venous thromboembolism in the203) with unbiased baseline characteristics (Supplementary Table S4).

warfarin group had risks of active cancer/history of cancer. One of the

Kaplan-Mayer analysis of the matched cohorts demonstrated a lower

2 patients that took DOACs developed venous thromboembolism 12

risk of clinically relevant bleeding in the DOAC group than in thedays after a clinically relevant nonmajor bleeding event.

warfarin group (P = .037), while the risk of morbidity and mortality
events was comparable between the DOAC and warfarin groups(Supplementary Figure S2).

3.4 | Safety outcomes: major bleeding and/or
clinically relevant nonmajor bleeding
4 | DISCUSSION
The cumulative rate of clinically relevant bleeding was signiﬁcantly
lower in the DOAC group than in the warfarin group [1-, 2-, and 3-

This ﬁrst large-scale prospective cohort study from the CTEPH AC

year event rates (95% CI): 0.8% (0.3%-2.5%), 2.4% (0.9%-5.9%), andregistry reveals that one-half of the patients with CTEPH on oral

2.4% (0.9%-5.9%) in the DOACs group vs 2.5% (1.3%-4.5%), 4.8%

anticoagulation therapy use DOACs in real-world clinical practice in(2.8%-8.3%), and 6.4% (3.4%-11.9%) in warfarin group, respectively;

Japan. In this registry, DOACs were comparable in efﬁcacy to warfarin

P = .036] (Figure 2C). The rate of major bleeding was also signiﬁcantly

for the prevention of morbidity and mortality events as well as

lower in the DOACs group than in the warfarin group (P = .007),

symptomatic venous thromboembolism. On the other hand, DOACs

whereas the rate of clinically relevant nonmajor bleeding was not

were superior in safety to warfarin in terms of clinically relevant

signiﬁcantly different (P = .28).

bleeding.

3.5 | Independent risks for morbidity and mortality
events and clinically relevant bleeding

4.1 | Choice of anticoagulants in real-world clinicalpractice

To identify the independent risk factors for morbidity and mortality

According to Japanese national statistics [29], currently, the number

events as well as for clinically relevant bleeding in all patients withof patients with CTEPH is approximately 4000, with an annual in-

CTEPH regardless of the type of oral anticoagulant used, we analyzed

crease of approximately 300. The CTEPH AC registry registered more

the demographics and baseline patient characteristics by Cox

than 900 patients, estimated to be around 25% of all Japanese pa-

proportional-hazards regression models. Univariable analyses identi-

tients with CTEPH. The rate of DOAC use was signiﬁcantly higher in

ﬁed active cancer/history of cancer, higher brain natriuretic peptide

patients with a history of venous thromboembolism (Table), probably

level, higher mean pulmonary arterial pressure, higher pulmonary

because DOACs are recommended as ﬁrst-line anticoagulants for

vascular resistance, and lower estimated glomerular ﬁltration rate as

initial treatment and medium- to long-term prevention of venous

signiﬁcant risk factors of morbidity and mortality events. Hyperco-thromboembolism [22,23]. In this study, DOACs were more frequently

agulable disorder was identiﬁed as a potential risk factor of morbidity

used than warfarin in patients with higher mean pulmonary arterial

and mortality events (Supplementary Table S2). A history of majorpressure, higher pulmonary vascular resistance, and no history of

bleeding, use of warfarin, and higher pulmonary vascular resistancereperfusion therapy. This trend reﬂects that DOACs are more likely towere identiﬁed as signiﬁcant risk factors of clinically relevant bleeding

be selected for newly diagnosed patients and is supported for a(Supplementary Table S3). Three models adjusting for different sets ofshorter time from diagnosis to registration in the DOAC group than incovariates identiﬁed these factors as independent risks: model 1

the warfarin group. On the other hand, the brain natriuretic peptide(adjusted for age, sex, and pulmonary vascular resistance); model 2

level was signiﬁcantly higher in the warfarin group. The brain natri-(adjusted for age, sex, pulmonary vascular resistance, and time fromuretic peptide level increases during renal failure. Some patients withdiagnosis to registration); and model 3 (adjusted for pulmonary

impaired renal function who used warfarin had brain natriuretic

vascular resistance, time from diagnosis to registration, history of

peptide levels exceeding 4000 pg/mL in the present study. DOACs are

- 9

HOSOKAWA ET AL.

contraindicated for patients with severe renal function impairment.

venous thromboembolism, may have overestimated the event rate

This selection bias could have caused the difference in brain natri-compared to the current study. The low cumulative rates of symp-

uretic peptide levels between the DOAC and warfarin groups. The

tomatic venous thromboembolism (0.31%/person-year for DOACs vsproportion of comorbid hypercoagulable disorders was higher in the

0.30%/person-year for warfarin) in the current registry might bewarfarin group than in the DOAC group. Recent clinical guidelines for

associated with the different deﬁnitions of venous thromboembolism

pulmonary embolism recommend VKAs instead of DOACs for patientsand the different study population. Similarly, there was no advantage

with high-risk triple-positive antiphospholipid syndrome [23] based onof warfarin over DOACs in terms of morbidity and mortality events.

the increased events associated with the use of rivaroxaban in thisAll-cause mortality was worse in the VKA group compared with thecondition [30]. This recommendation might have led to the preference

DOACs group in the Turkish registry due to bleeding complications

for warfarin in patients with CTEPH and hypercoagulable disorders.

(HR, 1.61; 95% CI, 0.89-2.99; P = .11) [24]. The superiority of DOACs
to VKAs regarding both risks of mortality and major bleeding has been
conﬁrmed in nonvalvular atrial ﬁbrillation [33]. The current study

4.2 | Previous studies on anticoagulation therapy
for CTEPH

showed apparently slightly lower all-cause mortality in the DOAC
group than the warfarin group (P = .39; Figure 2A), although the riskadjusted models did not demonstrate the superiority of DOACs in

The safety and efﬁcacy of DOACs in nonvalvular atrial ﬁbrillation andterms of mortality (HR, 1.63; 95% CI, 0.47-5.67; P = .44). The current

venous thromboembolism have been established in large clinical trials

results suggest that DOACs could be acceptable as an alternative to[11–21]. However, DOACs failed to show superiority or noninferiority

warfarin, given the safety of DOACs as well as the comparable efﬁ-

to VKAs under some other conditions. In a randomized controlled trial

cacy and usability.

of patients with rheumatic heart disease–associated atrial ﬁbrillation,
vitamin K antagonist therapy led to a lower rate of cardiovascular
events or death than rivaroxaban therapy, with no difference in therate of bleeding between the 2 groups [31]. A randomized controlled

4.3 | Patients who switched anticoagulants during
the study period

trial in patients with high-risk antiphospholipid syndrome reported
unacceptable rates of thromboembolic events, particularly ischemic

Since the current study was an observational study, the anticoagulants

stroke, with the use of rivaroxaban compared to warfarin [30].

were switched in some patients during the study period. Thirty-three

Recently, the Turkish CTEPH database demonstrated a higher risk

patients (6.9%) who took DOACs at registration switched to warfarin,of major bleeding in patients taking warfarin compared to rivaroxaban

and 48 patients (10.8%) treated with the warfarin at registration(hazard ratio [HR]: 1.94; 95% CI: 1.05-3.62; P = .03) [24], while the UK

switched to DOACs or no anticoagulant. The warfarin group was more

CTEPH registry showed a higher recurrence rate of venous throm-

likely to switch anticoagulant than the DOAC group (DOACs vsboembolism in DOAC users (4.62%/person-year for DOACs vs 0.76%/

warfarin, P = .04). Anticoagulants are often switched when adverse

person-year for VKAs; P = .008) [25]. The international registry

events occur or when conditions unsuitable for anticoagulation

EXPERT (EXPosurE Registry RiociguaT in patients with pulmonary

develop (such as labile INR). The patients who switched anticoagulants

hypertension; sample size: n = 956) aiming to monitor the long-termin the present study were associated with a higher incidence of clin-safety of riociguat from 2014 to 2018 also demonstrated higher

ically relevant bleeding than those who did not switch (8.6% vs 1.8%,

embolic and/or thrombotic event rates in patients who took DOACs

P = .002).

than in those who took VKAs after adjusting for drug-exposure period(4.6%/person-year for DOACs vs 1.7%/person-year for VKAs; notstatistically tested) [32]. The present study demonstrated the superiority of DOACs to warfarin in terms of bleeding risk in patients with

4.4 | Independent risks of morbidity and mortality
events and clinically relevant bleeding

CTEPH (Figure 3), which is similar to the report from the Turkish
database [24]. On the other hand, in contrast to the results of the UK

Figure 3 shows multivariable Cox proportional-hazards regression

registry and EXPERT, our study found few cases of symptomatic

models after risk adjustment for various covariates. The analysis

venous thromboembolism overall and showed comparable efﬁcacy ofidentiﬁed higher brain natriuretic peptide and increased mean pul-

DOACs and warfarin for the prevention of symptomatic venous

monary arterial pressure at baseline as the independent risk factors ofthromboembolism. The UK registry registered patients with operable

morbidity and mortality events, which is reasonable because these

CTEPH and retrospectively analyzed the entire observation period

factors reﬂect a severe disease state. In addition, comorbid cancer/a

including the perioperative period. The perioperative period is asso-

history of cancer was an independent risk of morbidity and mortality

ciated with several risks for venous thromboembolism, such as

events. Several risk factors for developing thromboembolism coexist

cessation of anticoagulation and bed rest. In addition, the deﬁnition of

in patients with cancer, such as chemotherapy and immobilization,

venous thromboembolism in the UK registry included incidental

which contribute to a hypercoagulable state in these patients [34].

asymptomatic venous thromboembolism. The outcome measures in

Moreover, patients with cancer had an extremely high recurrence rate

EXPERT, which adopted all thrombotic/embolic events includingof venous thromboembolism during VKA treatment than patients

10-

HOSOKAWA ET AL.

without cancer [35]. In CTEPH, cancer-associated thrombosis mightthe 33 institutions, as well as all the supporting staff at the 33 in-cause in situ thrombosis in pulmonary arterial lesions or recurrent

stitutions across Japan.

asymptomatic venous thromboembolism. In this study, when weanalyzed the DOAC and warfarin groups separately, comorbid cancer/
a history of cancer remained an independent risk factor of morbidity
and mortality events for both anticoagulants (HR = 4.98, 95% CI =1.37-18.11, and P = .01 for DOACs; HR = 5.14, 95% CI = 1.67-15.80,
and P = .004 for warfarin). The adjusted models indicated a lower
estimated glomerular ﬁltration rate as an independent risk ofmorbidity and mortality events (Figure 3). A lower glomerular ﬁltration rate signiﬁcantly increased the risk of all-cause death (riskadjusted models: eGFR, per decrease of 30 mL/min—HR = 18.58, 95%
CI = 3.72-92.69) without increasing the risk of rescue reperfusion
therapy or worsening of CTEPH (data not shown). Impaired kidney
function may be associated with death unrelated to CTEPH.
Meanwhile, the use of warfarin and a history of major bleeding
were identiﬁed as the independent risk factors of clinically relevant
bleeding in the risk-adjusted models (Figure 3). The risk of warfarin for

AUTHOR C ONTRIBUTIONS
K.H. initially drafted the manuscript and the writing committee further
developed it. K.A., K. Funakoshi, K. Todaka, K. Tatsumi, Y. Tamura,
T.O., H.M., K.F., N.N., and H.T. contributed substantially to theconception and design of the work. K.H., Y. Taniguchi, T.I., S.A., I.T.,
J.Y., S.M., N.I., H.S., T.K., H.O., Y.F., and N.T. contributed substantiallyto the acquisition of data. K.H., K.A., K. Funakoshi, K. Todaka, and H.T.
contributed to the analysis or interpretation of data. K.H. and K.A.
were responsible for the decision to submit the manuscript and areaccountable for all aspects of the work in ensuring that questions
related to the accuracy or integrity of any part of the work areappropriately investigated and resolved. All authors contributed todata interpretation, critical review and revision of the manuscript, andread and approved the ﬁnal paper.

bleeding events remained after adjusting for the history of major
bleeding in addition to age, sex, and pulmonary vascular resistance

DEC LA RA TI O N OF C O MPET IN G I NTER E STS(HR, 2.84; 95% CI, 1.11-7.31; P = .030). In addition, the Kaplan-Mayer

K.H. received personal fees from Janssen Pharmaceuticals, Bayerestimates after propensity-score matching (sensitivity analysis) sup-Yakuhin, Nippon Shinyaku, and Pﬁzer, outside of the submitted work.

ported a lower bleeding risk in DOACs than in warfarin (P = .037;

K.A. received a grant from Konica Minolta and Daiichi Sankyo, outside

Supplementary Figure S2B).

of the submitted work. Y. Tamura received grants from Bayer Yakuhin,
Nippon Shinyaku, and Mochida Pharmaceutical and personal fees fromBayer Yakuhin, Nippon Shinyaku, Daiichi Sankyo, and Janssen Phar-

4.5 | Study limitations

maceutical, outside of the submitted work. N.N. is member of theboard of directors of the Japan Association for Medical Informatics. K.

The current study has several limitations. First, given the observa-

Todaka reports receiving a grant from Mochida Pharmaceutical andtional design of the study, in the analyses of the association between

received a personal fee from Bayer Yakuhin, outside of the submitted

the types of anticoagulation and clinical outcomes, the possibility ofwork. Y. Taniguchi received grants from Janssen Pharmaceutical andresidual confounding cannot be completely ruled out despite adjust-

Nippon Shinyak and received personal fees from Janssen Pharma-

ment for the known, measured confounders. Second, in the current

ceutical and Nippon Shinyaku, outside of the submitted work. T.I.

study, the principal investigator at each site evaluated the clinicalreceived personal fees from Janssen Pharmaceutical and Bayer

events, but central adjudication was not performed, which could have

Yakuhin, outside of the submitted work. I.T. received personal fees

impacted the accuracy of the clinical event classiﬁcation. Third, thisfrom Janssen Pharmaceutical and Nippon Shinyak and is afﬁliated withstudy was a single-country prospective observational cohort study. To

the division supported by endowments from Nippon Shinyaku, Nippon

establish the DOACs as anticoagulant therapy for CTEPH, a ran-

Boehringer Ingelheim, and Mochida Pharmaceutical, outside of the

domized controlled trial and a larger, longer-term international reg-

submitted work. J.Y. received a grant from Abbott Vascular Japan andistry are needed.

received personal fees from Kaneka Medix, Boston Scientiﬁc Japan,
Nihon Kohden, Philips Japan, Janssen Pharmaceutical, and Bayer
Yakuhin, outside of the submitted work. N.I. received personal fees

5 | CONCLUSIONS

from Janssen Pharmaceutical, Bayer Yakuhin, Nippon Shinyaku,
Daiichi Sankyo, and Bristol-Myers Squibb, outside of the submitted

The CTEPH AC registry study demonstrated that under the current

work. H.S. received a grant from Bayer Yakuhin and received personal

standard of care, morbidity and mortality events in CTEPH werefees from Actelion Pharmaceuticals Japan, Bayer Yakuhin, and Nippon

effectively prevented up to 3 years regardless of using DOACs or

Shinyaku, outside of the submitted work. T.K. reports receiving per-warfarin, while the clinically relevant bleeding rate was lower whensonal fees from Kaneka Medix, Abbott Medical Japan, and ACIST

using DOACs compared with warfarin.

Japan, outside of the submitted work. M.H. received personal feesfrom Janssen Pharmaceutical and Bayer Yakuhin, outside of theAC KNOWL EDGMENTS

submitted work. H.O. received grants from Daiichi Sankyo, Nippon

The authors thank the research administrators and health-care pro-

Boehringer Ingelheim, Pﬁzer Japan, Eisai, GlaxoSmithKline, Mochidafessionals who contributed to setting up and delivering the study at all

Pharmaceutical, Janssen Pharmaceutical, and Nippon Shinyaku, and- 11

HOSOKAWA ET AL.

received consulting fees from Terumo, Japan Lifeline, and Century

REFER ENC ES

Medical and personal fees from Bayer Yakuhin, Daiichi Sankyo, Pﬁzer[1] Ende-Verhaar YM, Cannegieter SC, Vonk Noordegraaf A,
Delcroix M, Pruszczyk P, Mairuhu AT, Huisman MV, Klok FA. Incidence of chronic thromboembolic pulmonary hypertension after
acute pulmonary embolism: a contemporary view of the publishedliterature. Eur Respir J. 2017;49:1601792.
[2] Pengo V, Lensing AW, Prins MH, Marchiori A, Davidson BL, Tiozzo F,
Albanese P, Biasiolo A, Pegoraro C, Iliceto S, Prandoni P. Thromboembolic Pulmonary Hypertension Study Group. Incidence of chronic
thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med. 2004;350:2257–64.
[3] Gall H, Hoeper MM, Richter MJ, Cacheris W, Hinzmann B, Mayer E.
An epidemiological analysis of the burden of chronic thromboembolic pulmonary hypertension in the USA, Europe and Japan. Eur
Respir Rev. 2017;26:160121.
[4] Delcroix M, Lang I, Pepke-Zaba J, Jansa P, D’Armini AM, Snijder R,
Bresser P, Torbicki A, Mellemkjaer S, Lewczuk J, Simkova I,
Barberà JA, de Perrot M, Hoeper MM, Gaine S, Speich R, GomezSanchez MA, Kovacs G, Jaïs X, Ambroz D, et al. Long-term outcomeof patients with chronic thromboembolic pulmonary hypertension:
results from an international prospective registry. Circulation.
2016;133:859–71.
[5] Ogawa A, Satoh T, Fukuda T, Sugimura K, Fukumoto Y, Emoto N,
Yamada N, Yao A, Ando M, Ogino H, Tanabe N, Tsujino I,
Hanaoka M, Minatoya K, Ito H, Matsubara H. Balloon pulmonary
angioplasty for chronic thromboembolic pulmonary hypertension:
results of a multicenter registry. Circ Cardiovasc Qual Outcomes.
2017;10:e004029.
[6] Simonneau G, D’Armini AM, Ghofrani HA, Grimminger F,
Hoeper MM, Jansa P, Kim NH, Wang C, Wilkins MR, Fritsch A,
Davie N, Colorado P, Mayer E. Riociguat for the treatment of chronic
thromboembolic pulmonary hypertension: a long-term extension
study (CHEST-2). Eur Respir J. 2015;45:1293–302.
[7] Aoki T, Sugimura K, Tatebe S, Miura M, Yamamoto S, Yaoita N,
Suzuki H, Sato H, Kozu K, Konno R, Miyata S, Nochioka K, Satoh K,
Shimokawa H. Comprehensive evaluation of the effectiveness andsafety of balloon pulmonary angioplasty for inoperable chronic
thrombo-embolic pulmonary hypertension: long-term effects andprocedure-related complications. Eur Heart J. 2017;38:3152–9.
[8] Tanabe N, Ogo T, Hatano M, Kigawa A, Sunaya T, Sato S. Safety andeffectiveness of riociguat for chronic thromboembolic pulmonary
hypertension in real-world clinical practice: interim data from postmarketing surveillance in Japan. Pulm Circ. 2020;10:2045894020938986.
[9] Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A,
Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M,
Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W,
Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT,
Zompatori M, et al. 2015 ESC/ERS guidelines for the diagnosis andtreatment of pulmonary hypertension: the Joint Task Force for the
Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory
Society (ERS): endorsed by: Association for European Paediatric andCongenital Cardiology (AEPC), International Society for Heart andLung Transplantation (ISHLT). Eur Heart J. 2016;37:67–119.
[10] Fukuda K, Date H, Doi S, Fukumoto Y, Fukushima N, Hatano M,
Ito H, Kuwana M, Matsubara H, Momomura SI, Nishimura M,
Ogino H, Satoh T, Shimokawa H, Yamauchi-Takihara K, Tatsumi K,
Ishibashi-Ueda H, Yamada N, Yoshida S, Abe K, et al. Guidelines forthe treatment of pulmonary hypertension (JCS 2017/JPCPHS 2017).
Circ J. 2019;83:842–945.
[11] Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J,
Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S,
Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC,

Japan, and Nippon Shinyaku, outside of the submitted work. Y.F.
received grants from Actelion Pharmaceuticals Japan, Janssen Pharmaceutical, Bayer Yakuhin, Nippon Shinyaku, Daiichi Sankyo, Pﬁzer
Japa, and personal fees from Actelion Pharmaceuticals Japan, Janssen
Pharmaceutical, Bayer Yakuhin, Nippon Shinyaku, Daiichi Sankyo,
Pﬁzer Japan, and Bristol-Myers Squibb, outside of the submitted work.
N.T. received personal fees from Janssen Pharmaceutical, Bayer
Yakuhin, and Nippon Shinyaku, outside of the submitted work. H.M.
received grants from Bayer and Nippon Shinyaku; received personal
fees from Bayer Yakuhin, Nippon Shinyaku, Mochida Pharmaceutical,
Kaneka Medix, and Janssen Pharmaceutical, , outside of the submitted
work; is a member of the board of directors or advisory committees
for the International CTEPH Association and Japanese Pulmonary
Circulation and Pulmonary Hypertension Society; and is a member ofthe data safety monitoring boards for Janssen Pharmaceutical, United
Therapeutics, and Bayer. K. Fukuda received grants from Bayer
Yakuhin, Daiichi Sankyo, Nippon Boehringer Ingelheim, Pﬁzer, Eisai,
Janssen Pharmaceutical, Nippon Shinyaku, GlaxoSmithKline, andMochida Pharmaceutical, and received personal fees from Bayer
Yakuhin, Daiichi Sankyo, Nippon Boehringer Ingelheim, Pﬁzer, Eisai,
Janssen Pharmaceutical, Nippon Shinyaku, GlaxoSmithKline, andMochida Pharmaceutical, outside of the submitted work. H.T. received
grants from Mitsubishi Tanabe Pharma, IQVIA Services Japan, Medinet, Medical Innovation Kyushu, Kowa, Daiichi Sankyo, Johnson &Johnson, NEC, and Nippon Boehringer Ingelheim; received personal
fees from Novartis Pharma, Ono Pharmaceutical, Nippon Boehringer
Ingelheim, Bayer Yakuhin, Kowa, Teijin Pharma, Mitsubishi Tanabe
Pharma, Pﬁzer Japan, Daiichi Sankyo, Novartis Pharma, Janssen
Pharmaceutical, Pﬁzer Japan, Bayer Yakuhin, Otsuka Pharmaceutical,
AstraZeneca, and Nippon Rinsho, outside the submitted work; and is
the chairman of the Japan Heart Failure Society. Soiken Corp accessedand veriﬁed the data. The remaining authors K. Funakoshi, S.A., S.M.,
K. Tatsumi, and T.O. have no competing interests to disclose.

FUND I NG
This study was supported by the Japan Agency for Medical Researchand Development (JP20ek0109371, JP19lk0201102, JP22lk0201125,
JP19lk1601003) based on a contract.

DATA AV AIL AB IL I TY
Collaborations with the CTEPH AC registry study are open tobiomedical institutions, always after an accepted proposal for a scientiﬁc work. Depending on the nature of the collaboration, electronic
data or hard-copy data should be provided. All collaborations will bemade after a collaboration agreement. Terms of the collaborationagreement will be speciﬁc for each collaboration, and the extent of theshared documentation (i.e., identiﬁed participant data, data dictionary,
hard copy, or other speciﬁed data sets) will be also speciﬁcally set on
the light of each work.

12

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

[22]

[23]

-

HOSOKAWA ET AL.

Joyner CD, Wallentin L, et al. Dabigatran versus warfarin in patientswith atrial ﬁbrillation. N Engl J Med. 2009;361:1139–51.
Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S,
Eriksson H, Baanstra D, Schnee J, Goldhaber SZ, RE-COVER Study
Group. Dabigatran versus warfarin in the treatment of acute venous
thromboembolism. N Engl J Med. 2009;361:2342–52.
Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD,
Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Špinar J, Ruzyllo W,
Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I,
Hanyok JJ, Mercuri M, et al. Edoxaban versus warfarin in patientswith atrial ﬁbrillation. N Engl J Med. 2013;369:2093–104.
Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W,
Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC,
Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM. ROCKET AF
Investigators. Rivaroxaban versus warfarin in nonvalvular atrial
ﬁbrillation. N Engl J Med. 2011;365:883–91.
EINSTEIN Investigators, Bauersachs R, Berkowitz SD, Brenner B,
Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F,
Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G,
Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S. Oral
rivaroxaban for symptomatic venous thromboembolism. N Engl J
Med. 2010;363:2499–510.
Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM,
Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC,
Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M,
Gersh BJ, Golitsyn S, Goto S, et al. Apixaban versus warfarin in patients with atrial ﬁbrillation. N Engl J Med. 2011;365:981–92.
EINSTEIN–PE Investigators, Büller HR, Prins MH, Lensin AW,
Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P,
Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H,
Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S,
Segers A. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287–97.
Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M,
Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI. AMPLIFY
Investigators. Oral apixaban for the treatment of acute venous
thromboembolism. N Engl J Med. 2013;369:799–808.
Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M,
Porcari A, Raskob GE, Weitz JI. AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J
Med. 2013;368:699–708.
Investigators Hokusai-VTE, Büller HR, Décousus H, Grosso MA,
Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM,
Schwocho L, Segers A, Shi M, Verhamme P, Wells P. Edoxaban
versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369:1406–15.
Weitz JI, Lensing AWA, Prins MH, Bauersachs R, BeyerWestendorf J, Bounameaux H, Brighton TA, Cohen AT, Davidson BL,
Decousus H, Freitas MCS, Holberg G, Kakkar AK, Haskell L, vanBellen B, Pap AF, Berkowitz SD, Verhamme P, Wells PS, Prandoni P,
et al. Rivaroxaban or aspirin for extended treatment of venous
thromboembolism. N Engl J Med. 2017;376:1211–22.
Stevens SM, Woller SC, Kreuziger LB, Bounameaux H, Doerschug K,
Geersing GJ, Huisman MV, Kearon C, King CS, Knighton AJ, Lake E,
Murin S, Vintch JRE, Wells PS, Moores LK. Antithrombotic therapy
for VTE disease: second update of the CHEST guideline and expert
panel report. Chest. 2021;160:e545–608.
Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing GJ,
Harjola VP, Huisman MV, Humbert M, Jennings CS, Jiménez D,
Kucher N, Lang IM, Lankeit M, Lorusso R, Mazzolai L, Meneveau N,
Ní Áinle F, Prandoni P, Pruszczyk P, Righini M, et al. 2019 ESC
guidelines for the diagnosis and management of acute pulmonary
embolism developed in collaboration with the European Respiratory
Society (ERS). Eur Heart J. 2020;41:543–603.

[24] Sena S, Bulent M, Derya K, Deniz K, Halil A, Okan E, Bedrettin Y.
Real-life data of direct anticoagulant use, bleeding risk and venous
thromboembolism recurrence in chronic thromboembolic pulmonary
hypertension patients: an observational retrospective study. Pulm
Circ. 2020;10:2045894019873545.
[25] Bunclark K, Newnham M, Chiu YD, Ruggiero A, Villar SS, Cannon JE,
Coghlan G, Corris PA, Howard L, Jenkins D, Johnson M, Kiely DG,
Ng C, Screaton N, Sheares K, Taboada D, Tsui S, Wort SJ, PepkeZaba J, Toshner M. A multicenter study of anticoagulation in operable chronic thromboembolic pulmonary hypertension. J Thromb
Haemost. 2020;18:114–22.
[26] Kim NH, Delcroix M, Jais X, Madani MM, Matsubara H, Mayer E,
Ogo T, Tapson VF, Ghofrani HA, Jenkins DP. Chronic thromboembolic pulmonary hypertension. Eur Respir J. 2019;53:1801915.
[27] Schulman S, Kearon C. Subcommittee on Control of Anticoagulationof the Scientiﬁc and Standardization Committee of the International
Society on Thrombosis and Haemostasis. Deﬁnition of major
bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3:692–4.
[28] Kaatz S, Ahmad D, Spyropoulos AC, Schulman S, Subcommittee onControl of Anticoagulation. Deﬁnition of clinically relevant non-major
bleeding in studies of anticoagulants in atrial ﬁbrillation and venous
thromboembolic disease in non-surgical patients: communicationfrom the SSC of the ISTH. J Thromb Haemost. 2015;13:2119–26.
[29] Statistics of Japan, e-Stat. Report on public health administrationand services, social security and sanitation, health and sanitation.
https://www.e-stat.go.jp/stat-search/ﬁles?page=1&layout=datalist&
toukei=00450027&tstat=000001031469&cycle=8&tclass1=0000
01161547&tclass2=000001161548&tclass3=000001161551&stat_inﬁd=000032155828&cycle_facet=tclass1&tclass4val=0;2022.
[accessed June 1, 2022].
[30] Pengo V, Denas G, Zoppellaro G, Jose SP, Hoxha A, Ruffatti A,
Andreoli L, Tincani A, Cenci C, Prisco D, Fierro T, Gresele P, Cafolla A,
De Micheli V, Ghirarduzzi A, Tosetto A, Falanga A, Martinelli I, Testa S,
Barcellona D, et al. Rivaroxaban vs warfarin in high-risk patients with
antiphospholipid syndrome. Blood. 2018;132:1365–71.
[31] Connolly SJ, Karthikeyan G, Ntsekhe M, Haileamlak A, El Sayed A, El
Ghamrawy A, Damasceno A, Avezum A, Dans AML, Gitura B, Hu D,
Kamanzi ER, Maklady F, Fana G, Gonzalez-Hermosillo JA, Musuku J,
Kazmi K, Zühlke L, Gondwe L, Ma C, et al. Rivaroxaban in rheumaticheart disease-associated atrial ﬁbrillation. N Engl J Med. 2022;387:
978–88.
[32] Humbert M, Simonneau G, Pittrow D, Delcroix M, Pepke-Zaba J,
Langleben D, Mielniczuk LM, Escribano Subias P, Snijder RJ,
Barberà JA, Klotsche J, Meier C, Hoeper MM. Oral anticoagulants(NOAC and VKA) in chronic thromboembolic pulmonary hypertension. J Heart Lung Transplant. 2022;41:716–21.
[33] Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N,
Ezekowitz MD, Camm AJ, Weitz JI, Lewis BS, Parkhomenko A,
Yamashita T, Antman EM. Comparison of the efﬁcacy and safety of
new oral anticoagulants with warfarin in patients with atrial ﬁbrillation: a meta-analysis of randomised trials. Lancet. 2014;383:955–62.
[34] Varki A. Trousseau’s syndrome: multiple deﬁnitions and multiple
mechanisms. Blood. 2007;110:1723–9.
[35] Prandoni P, Lensing AW, Piccioli A, Bernardi E, Simioni P, Girolami B,
Marchiori A, Sabbion P, Prins MH, Noventa F, Girolami A. Recurrent
venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis.
Blood. 2002;100:3484–8.

SUPPL EMENTAR Y MAT ERIALThe online version contains supplementary material available athttps://doi.org/10.1016/j.jtha.2023.03.036